Vidofludimus and related structures acting as NURR1 agonists

Abstract

The present invention relates to a method for treating or improving neurodegenerative diseases such as Parkinson's disease or multiple sclerosis using compounds of formulas (I) to (V), or compound of formula (VI), or pharmaceutically acceptable salts or solvates thereof, for example, vidofludimus acting as a Nurr1 agonist.

Description

[Technical Field]

[0001] This specification describes methods for treating or improving neurodegenerative diseases, such as Parkinson's disease (PD) or multiple sclerosis (MS), using compounds of formulas (I) to (V), or formula (VI), or their pharmaceutically acceptable salts or solvates, particularly vidofludimus, which, in addition to their known mechanisms of action as dihydroorotate dehydrogenase (DHODH) inhibitors, surprisingly also act as nuclear receptor-associated 1 (Nurr1) agonists. This dual mode of action offers the remarkable benefit that a) inhibition of DHODH is beneficial against inflammation, and b) activation of Nurr1 is known to protect neurons from damage and death. Compounds previously reported as DHODH inhibitors, as well as novel compounds, have been shown to directly bind to Nurr1, activate Nurr1 expression, and mediate activity in cells via Nurr1. Therefore, the compound can be used to inhibit DHODH and / or activate Nurr1, providing benefits in the treatment of neurological disorders such as inflammatory neurological diseases like PD and MS. [Background technology]

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

[0003] The rising prevalence of neurodegenerative diseases has spurred research into improved methods for diagnosing affected individuals, as well as therapies that can slow or mitigate disease progression and / or improve disease symptoms. In some diseases, biomarkers associated with neurodegeneration provide valuable information about the molecular mechanisms by which their absence or dysfunction may contribute to the 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 (NR4A2) of the nerve growth factor-inducible b subfamily of orphan nuclear receptors. Nurr1 is a neuroprotective transcription factor primarily found in the central nervous system and highly expressed in neurons. Nurr1 possesses neuroprotective and anti-neuroinflammatory activity and has emerged as an attractive target for treating neurodegenerative pathologies, including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). The expression level of miR-132 is one of the key factors for maintaining dopaminergic function and is negatively correlated with its downstream molecule Nurr1, which is downregulated in PD.

[0005] Neurofilament light chains (NFLs) can be measured in cerebrospinal fluid (CSF) and are useful in diagnosing and predicting 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 may be well-suited for detecting neurodegeneration unrelated to relapse in MS, in contrast to the exacerbation of disability associated with relapse (Meier et al. JAMA Neurol. 2023;80:287).

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

[0008] These studies demonstrate that exemplary biomarkers play a role in the onset and / or progression of multiple sclerosis (MS). MS is a neurodegenerative disease characterized by an autoimmune attack on the myelin sheaths of neurons in the brain and spinal cord. Symptoms of MS include physical impairments such as fatigue, loss or alteration of sensation and coordination, visual impairment, muscle weakness and / or seizures, as well as mental disorders such as cognitive impairment, unstable mood, depression, and anxiety. There is no known cure for MS, and the symptoms of the disease are particularly difficult to treat due to the complex effects of inflammation and neurodegeneration across multiple disease pathways. Furthermore, MS presents in different forms, such as a relapsing form in which disease symptoms occur in isolated attacks (relapsing MS, or RMS) and a progressive form in which disease symptoms accumulate over time (progressive MS, or PMS). Patients exhibit great heterogeneity in the onset, duration, progression, and response to treatment. Therefore, while current disease-modifying therapies (DMTs) for MS can delay the onset of disability in some patients, most DMTs address only relapse-related disability exacerbations and are most effective in patients with relapse-related exacerbations (RAWs) in the earliest stages of MS. To date, most DMTs are approved for the treatment of relapses associated with RMS or PMS, but they cannot adequately treat other forms of MS. There is an unmet need for appropriate treatments for various forms of MS, as well as for treatment of both early and late stages of MS.

[0009] Recent preclinical and clinical trials using vidoflugimus suggest 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 vidoflugimus calcium significantly reduced 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), where RRMS patients treated with vidoflugimus calcium for 12 or 24 weeks had significantly fewer distinctive active brain lesions and a lower rate of confirmed disability that worsened over time compared to patients treated with placebo (US Patent No. 11877994B2). The positive effects in patients with relapsing-remitting multiple sclerosis may be due to the anti-inflammatory properties of vidoflugimus, for example, mediated by DHODH inhibition.

[0010] Other studies have shown that vidofludimus is effective and well-tolerated in human patients. The COMPONENT trial (NCT01010581) established safety data for vidofludimus in patients with rheumatoid arthritis (Muehler et al., Drugs RD 2019;19:351). Safety, tolerability, and pharmacokinetics have also been determined in healthy subjects (Muehler et al., Eur.J.Drug Metab.Pharmacokinet.2020;45:557). Furthermore, the antiviral effects of vidflugimus have been demonstrated 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, vidoflugimus has been studied as a farnesoid X receptor (FXR) modulator (Zhu et al., Front.Pharmacol.2020;11:590 and Hering et al., ACS Chem.Biol.2022;17:3159), a New Delhi metallo-beta-lactamase 1 (NDM-1) inhibitor, an antibiotic protective agent (Chinese Patent Application No. CN113842380), and a potential treatment for inflammatory diseases, including Alzheimer's disease (Patent Application No. WO 2018 / 177151).

[0011] In summary, these studies suggest that vidfludimus is a promising candidate for the treatment of many disorders, including MS. However, the field still needs to apply knowledge of immunological diseases, neurodegenerative diseases, and biomarkers to new methods for diagnosing and / or treating neurodegenerative diseases. [Brief explanation of the drawing]

[0012] [Figure 1]The binding of Example 1 (vidofludimus) and Example 3 to the transcription factor Nurr1 (NR4A2) in the isothermal titration calorimetry (ITC) assay of Example 1 is shown. The data represent Kd at 0.7 μM and 0.3 μM, respectively.

[0013] [Figure 2] The graphs on the left (Gal4 assay) and the right (full-length assay) of Example 101-B, using compound Example 1, show representative activation of the transcription factor Nurr1 (NR4A2). The data represent EC50 (Gal4-Nurr1) at 0.40 ± 0.20 μM.

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

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

[0016] [Figure 5] This shows the reduction in apoptosis in neuron-like cell lines treated with Example 3.

[0017] [Figure 6] This shows the change from baseline in serum neurofilaments based on the number of relapses during the main treatment period. A complete analysis set of Cohort 1 and Cohort 2 patients with no relapses up to week 24.

[0018] [Figure 7] This shows the powder X-ray diffraction pattern of polymorph A of IMU-838.

[0019] [Figure 8] The plots of disability progression versus time for RRMS, active SPMS, inactive SPMS, and PPMS are shown.

[0020] [Figure 9] This shows serum neurofilament data from the CALLIPER (Phase 2 PMS) biomarker interim analysis for IMU-838, with the change up to week 24 compared to placebo shown as a percentage of baseline.

[0021] [Figure 10] This report compares CALLIPER intermediate neurofilament data in PPMS and SPMS with previous studies. The reduction in NFLs is superior to other treatments available for PMS. [Overview of the Initiative]

[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 for treating and / or neuroprotecting a neurogenic condition in a subject having a neurogenic disease, wherein the compound is of formula (V), [ka] (In the formula, Ring A is, [ka] And, E is [ka] And, Y is [ka] This relates to compounds or their pharmaceutically acceptable salts or solvates.

[0023] In some embodiments, subjects exhibit abnormal levels of biomarkers associated with neurodegenerative states prior to administration.

[0024] In some embodiments, the compound is [ka] That is the case.

[0025] In some embodiments, the compound is [ka] That is the case.

[0026] In some embodiments, the compound is [ka] That is the case.

[0027] In some embodiments, the biomarker is Nurr1.

[0028] In some embodiments, the abnormal level of a biomarker associated with neurodegenerative states is downregulated Nurr1.

[0029] In some embodiments, the neurodegenerative state is multiple sclerosis.

[0030] In some embodiments, the neurodegenerative state is multiple sclerosis, and the impairment is acquired by progression unrelated to relapsing activity (PIRA).

[0031]

[0032] In some embodiments, the neurodegenerative state is brain atrophy induced by multiple sclerosis.

[0033] In some embodiments, the neurodegenerative state is an exacerbation of non-inflammatory multiple sclerosis.

[0034] In some embodiments, neuroprotection involves delaying or preventing neuronal loss induced by multiple sclerosis.

[0035] In some embodiments, neuroprotection involves delaying or preventing the loss of dopaminergic neurons induced by multiple sclerosis.

[0036] In some embodiments, the neurodegenerative state is Parkinson's disease.

[0037] In some embodiments, the method is A step of determining the level or activity of Nurr1 in a target ex vivo biological sample using an assay selected from (a) a real-time PCR assay of Nurr1 gene expression against a relevant housekeeping gene / internal control (e.g., GAPDH), (b) an immunoassay (e.g., ELISA) using an antibody suitable for the Nurr1 protein, or (c) a Western blot of the Nurr1 protein, from a biological sample selected from peripheral blood, peripheral blood lymphocytes, serum, plasma, CSF, or peripheral blood mononuclear cells; The method includes the step of administering an effective amount of the compound of formula (V) or a pharmaceutically acceptable salt or solvate thereof to a patient if the test sample from the patient has a level of Nurr1 that is less than or equal to 90% of the level in a healthy subject of the same age, sex, and / or BMI.

[0038] In some embodiments, the method is a) A step of obtaining the level of a protein in a subject, wherein the protein is downstream of Nurr1 in the biological pathway in the subject, b) The step of determining whether to administer a Nurr1 agonist to the subject based on the level of protein in the subject.

[0039] 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.

[0040] 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 for treating and / or neuroprotecting a neurodevelopmental condition in a subject with a neurodevelopmental disorder, wherein the compound is [ka] This relates to compounds or pharmaceutically acceptable salts or solvates thereof that are in the state PIRA.

[0041] In some embodiments, the compound is [ka] Therefore, the state is PIRA.

[0042] In some embodiments, the neurodegenerative state is multiple sclerosis, and the disability is acquired by progression unrelated to relapsing activity (PIRA).

[0043] In some embodiments, the therapeutically effective dose is approximately 5 mg to approximately 100 mg.

[0044] In some embodiments, administration is by oral dose in solid dosage form.

[0045] In some embodiments, administration is carried out over a first period and a second period, a) the first period being 5 to 10 consecutive days of once-daily dosing of the amount of the compound for the first period, the amount of the compound for the first period being about 15 mg to about 25 mg, and b) the second period following the first period, c) the second period being once-daily dosing of the amount of the compound for the second period, the amount of the compound for the second period being about 30 mg to about 50 mg.

[0046] In some embodiments, the method aims to prevent or delay disease progression and secondary damage by stopping or at least delaying neuronal loss.

[0047] Further aspects of this disclosure are methods for treating multiple sclerosis (MS) in patients diagnosed with relapse-free progression (PIRA), the method comprising the step of administering a compound of formula (V) to a subject, the compound being [ka] This concerns the method.

[0048] Another aspect of the present disclosure is a method for treating multiple sclerosis (MS) in a subject, the method comprising the step of administering a compound of formula (V) to the subject, the compound is [ka] And also This concerns methods for treating MS characterized by relapse-free progression (PIRA).

[0049] Another aspect of the present disclosure is a method for treating relapse-free progression (PIRA) in a subject with multiple sclerosis (MS), the method comprising the step of administering a compound of formula (V) to the subject, the compound is [ka] This concerns the method.

[0050] Another aspect of the present disclosure is a method for treating multiple sclerosis (MS) in a subject, the method comprising the step of administering a compound of formula (V) to the subject, The compound, [ka] And also This method concerns patients with MS characterized by progression unrelated to relapse (PIRA).

[0051] In some embodiments, patients have no evidence of recurrence for 24 months.

[0052] In some embodiments, the MS is a progressive MS (PMS).

[0053] In some embodiments, PMS is characterized by having little to no active lesions.

[0054] In some embodiments, the MS is primary progressive MS (PPMS).

[0055] In some embodiments, the MS is inactive secondary progressive MS (n-aSPMS).

[0056] In some embodiments, n-aSPMS is characterized by the absence of lesions for 12 months.

[0057] In some embodiments, MS is active secondary progressive MS (a-SPMS).

[0058] In some embodiments, this method reduces serum NFL levels in subjects compared to controls.

[0059] In some embodiments, this method reduces serum GFAP levels in subjects compared to controls.

[0060] In some embodiments, this method reduces the rate of percent brain volume change (PBVC) in subjects compared to controls.

[0061] In some embodiments, this method reduces the rate of change in the brain parenchymal fraction (BPF) in the subject compared to the control.

[0062] In some embodiments, this method increases the time to which a deterioration of disability is observed in a subject compared to a control, for example, based on the Integrated Disability Scale (EDSS).

[0063] In some embodiments, the method prevents and / or delays disease progression and secondary damage by stopping or at least delaying neuronal loss.

[0064] In some embodiments, the compound is administered in a therapeutically effective dose of about 5 mg to about 100 mg.

[0065] In some embodiments, the compound is administered orally in solid dosage form.

[0066] In some embodiments, the compound is administered over a first period and a second period, a) the first period being 5 to 10 consecutive days of once-daily dosing of the amount of the compound for the first period, the amount of the compound for the first period being about 15 mg to about 25 mg, and b) the second period following the first period, c) the second period being once-daily dosing of the amount of the compound for the second period, the amount of the compound for the second period being about 30 mg to about 50 mg. [Modes for carrying out the invention]

[0067] overview This specification describes methods for treating or improving a disease in subjects who have, are suspected of having, or are at risk of developing the disease, the methods comprising the step of 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, in particular vidofludimus. Compounds (I), (II), (III), (IV), (V), (VI), and their salts and solvates are described in detail herein.

[0068] In some embodiments, the disease is a neurological disease, such as a neurodegenerative disease.

[0069] In some embodiments, the present disclosure provides a method of treating a condition in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) [Chemical formula]

[0070] (wherein A is an unsubstituted or substituted ring, Z

[0071] , 14 , , 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, halo, -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 are 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), or a pharmaceutically acceptable salt thereof, and the condition is a neurogenic condition.

[0071] In one embodiment, the present disclosure provides a method for neuroprotection in a subject having a neurodevelopmental disorder, the method comprising the step of administering to the subject a therapeutically effective dose of a compound of formula (I) outlined above. In one embodiment, the subject exhibits abnormal levels of biomarkers associated with a neurodegenerative state prior to administration.

[0072] In one embodiment, a method for providing neuroprotection in a subject having a neurodevelopmental disorder comprises the step of administering to the subject a therapeutically effective dose of the compound of formula (I) outlined above. In one embodiment, the subject exhibits abnormal levels of biomarkers associated with a neurodegenerative state, particularly abnormal levels of Nurr1 in the subject, prior to administration.

[0073] In one embodiment, vidofludimus or the structures of formulas (I) to (V), or together with the compound of formula (VI), modulates Nurr1, and therefore, PIRA and drug intoxication in patients with Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), schizophrenia, and MS can be treated using the structures of formulas (I) to (V) or the compound of formula (VI).

[0074] The structures of Vidofludimus or formulas (I) to (V) within the scope of the present invention, or together with the compound of formula (VI), are characterized by their direct binding to Nurr1 and their action as Nurr1 agonists in cells having a different structure-activity relationship compared to DHODH (see Example 102).

[0075] Neurodevelopmental diseases or conditions that can be treated according to the present invention may be selected from the group including multiple sclerosis (MS) and Parkinson's disease.

[0076] In some embodiments, the condition is Parkinson's disease (PD).

[0077] In some embodiments, the present disclosure provides a method for treating Parkinson's disease in a subject, wherein the method involves administering a therapeutically effective amount of a compound of formula (I) to the subject. [ka]

[0078] (wherein A is an unsubstituted or substituted ring, Z 1 and Z 2 These are, independently, O, S, or NR. 9 E is either a linker or not, G is either a linker or not, Y is a ring, and R 2 H, OR 11 , NR 11 Ure 11 , NR 11 SO2R 11 , or NR 11 R 12 And R 3 H, halo, -OR 13 , -SR 13 , -NR 13 R 14 , alkyl, alkenyl, alkynyl, alkoxy, aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which independently is substituted or unsubstituted, and each R 8 , R 9 , R 11 , R 12 , R 13 , and R 14 The step of administering a pharmaceutically acceptable salt thereof (where 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), or a pharmaceutically acceptable salt thereof.

[0079] In one embodiment, the subject exhibits abnormal levels of Parkinson's disease-related biomarkers before administration.

[0080] In some embodiments, the condition is drug intoxication.

[0081] In some embodiments, the present disclosure provides a method for treating drug poisoning in a subject, wherein the method involves administering a therapeutically effective amount of a compound of formula (I) to the subject.

[0082] [ka]

[0083] (wherein A is an unsubstituted or substituted ring, Z 1 and Z 2 These are, independently, O, S, or NR. 9 E is either a linker or not, G is either a linker or not, Y is a ring, and R 2 H, OR 11 , NR 11 Ure 11 , NR 11 SO2R 11 , or NR 11 R 12 And R 3 H, halo, -OR 13 , -SR 13 , -NR 13 R 14 , alkyl, alkenyl, alkynyl, alkoxy, aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which independently is substituted or unsubstituted, and each R 8 , R 9 , R 11 , R 12 , R 13 , and R 14 The procedure comprises the step of administering a pharmaceutically acceptable salt thereof (wherein is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, where n is 0, 1, 2, 3, 4, or 5, where q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and where r is 0 or 1), or a pharmaceutically acceptable salt thereof. In one embodiment, the subject exhibits levels of biomarkers related to drug toxicity prior to administration.

[0084] In some embodiments, the disease is multiple sclerosis (MS).

[0085] In some embodiments, the present disclosure provides a method for treating multiple sclerosis in a subject, wherein the method involves administering a therapeutically effective amount of a compound of formula (I) to the subject. [ka]

[0086] (wherein A is an unsubstituted or substituted ring, Z 1 and Z 2 These are, independently, O, S, or NR. 9 E is either a linker or not, G is either a linker or not, Y is a ring, and R 2 H, OR 11 , NR 11 Ure 11 , NR 11 SO2R 11 , or NR 11 R 12 And R 3 H, halo, -OR 13 , -SR 13 , -NR 13 R 14 , alkyl, alkenyl, alkynyl, alkoxy, aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which independently is substituted or unsubstituted, and each R 8 , R 9 , R 11 , R 12 , R 13 , and R 14 The step of administering a pharmaceutically acceptable salt thereof (where 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), or a pharmaceutically acceptable salt thereof.

[0087] In one embodiment, the subject exhibits abnormal levels of biomarkers associated with multiple sclerosis prior to administration.

[0088] In some embodiments, the present disclosure provides a method comprising: a) obtaining the level of Nurr1 in a subject; and b) determining whether or not to administer a Nurr1 agonist to the subject based on the level of Nurr1 in the subject.

[0089] In some embodiments, the present disclosure provides a method comprising the steps of: a) obtaining the level of Nurr1 in a subject being treated for a neurodegenerative condition; and b) determining whether to continue treatment for the neurodegenerative condition based on the level of Nurr1 in the subject, wherein the treatment is Nurr1 receptor activation.

[0090] In some embodiments, the Disclosure provides a method comprising: a) obtaining a protein level in a subject, wherein the protein is downstream of Nurr1 in a biological pathway in the subject; and b) determining whether or not to administer a Nurr1 agonist to the subject based on the protein level in the subject.

[0091] In some embodiments, the present disclosure provides a method comprising: a) obtaining a protein level in a subject being treated for a neurodegenerative condition, wherein the protein is downstream of Nurr1 in a biological pathway in the subject and the treatment is Nurr1 receptor activation; and b) determining whether to continue treatment for the neurodegenerative condition based on the protein level in the subject.

[0092] In some embodiments, the present disclosure provides a method comprising: a) obtaining the activity level of a gene in a subject, wherein the gene is downstream of Nurr1 in a biological pathway in the subject; and b) determining whether to administer a Nurr1 agonist for a neurodegenerative condition to the subject based on the activity level of the gene in the subject.

[0093] In some embodiments, the present disclosure provides a method comprising: a) obtaining the activity level of a gene in a subject being treated for a neurodegenerative condition, wherein the gene is downstream of Nurr1 in a biological pathway in the subject and the treatment is Nurr1 receptor activation; and b) determining whether to continue the treatment for the neurodegenerative condition based on the activity level of the gene in the subject.

[0094] In some embodiments, the Disclosure provides a method comprising: a) determining that a subject exhibits downregulated Nurr1; b) determining that a subject exhibits upregulated miR-132; and c) identifying a subject as being at risk of a certain condition based on the determination that the subject exhibits downregulated Nurr1 and the determination that the subject exhibits upregulated miR-132.

[0095] In some embodiments, the present disclosure provides a method for treating and / or neuroprotecting a neurodevelopmental condition, the method comprising: a) determining the level or activity of Nurr1 in a target ex vivo biological sample using an assay selected from a biological sample selected from peripheral blood, peripheral blood lymphocytes, serum, plasma, CSF, and peripheral blood mononuclear cells, (a) a real-time PCR assay of Nurr1 gene expression against a relevant housekeeping gene / internal control (e.g., GAPDH), (b) an immunoassay (e.g., ELISA) using an antibody suitable for the Nurr1 protein, and (c) a Western blot of the Nurr1 protein; and b) administering a therapeutically effective dose of the compound herein to a patient if the level or activity of Nurr1 is less than or equal to about 90% of the level in a healthy subject of the same age, sex, and / or BMI.

[0096] I. Neurodegenerative Diseases and Biomarkers One aspect of the present disclosure relates to a method for treating or improving a disease in a subject, such as a neurodegenerative disease, wherein the method comprises administering to the subject a compound of formula (I) to (V), or together with a compound of formula (VI). In some embodiments, the compound is vidofludimus. In some embodiments, vidofludimus may act as a Nurr1 agonist.

[0097] In some embodiments, neurological disorders include Alexander disease, Alpas disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ataxia with 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-Streussler-Scheinker syndrome, Huntington's disease, HIV-related dementia (FTD), and Nedy's disease, Krabbe's disease, Kuru's disease, Lewy body dementia (DLB), Machado-Joseph disease (spinocerebellar degeneration type 3), multiple sclerosis, multiple system atrophy, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbach disease, Pick's disease, primary lateral sclerosis, prion disease, progressive supranuclear palsy (PSP), Refsum's disease, Sandhoff's disease, Schilder's disease, subacute combined degeneration of the spinal cord secondary to pernicious anemia, schizophrenia, spinocerebellar degeneration (multiple types with various characteristics), spinal muscular atrophy, Steele-Richardson-Olshevsky disease, or spinal fistula.

[0098] 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.

[0099] In some embodiments, the disease is multiple sclerosis (MS). In some embodiments, MS is relapsing-type multiple sclerosis (RMS), such as relapsing-remitting multiple sclerosis (RRMS) or active secondary progressive multiple sclerosis (active SPMS). In some embodiments, MS is progressive multiple sclerosis, such as primary progressive multiple sclerosis (PPMS) or inactive secondary progressive multiple sclerosis (inactive SPMS).

[0100] Neurodegenerative diseases can be characterized by changes in biomarker measurements in subjects who have, are suspected of having, or are at risk of developing a neurodegenerative disease, compared to a reference measurement. In some embodiments, the reference measurement is a biomarker measurement obtained from a healthy control subject. In some embodiments, the biomarker measurement is an increase or decrease in biomarker expression and / or activity, and / or a rate of change in biomarker expression and / or activity. For example, a low level of Nurr1 in the central nervous system of a subject compared to a reference may indicate a neurodegenerative disease in the subject.

[0101] In some embodiments, biomarkers associated with neurodegenerative diseases include, but are not limited to, Nurr1, GFAP, miR132, neurofilamentous 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, changes in one or more measurements of these biomarkers indicate neurodegenerative disease.

[0102] Nurr1, or NR4A2, is a protein encoded by the NR4A2 gene in humans. Nurr1 is a nuclear receptor and plays a crucial role in maintaining the brain's dopaminergic system. The term "Nurr1" can refer to the nucleotide or protein sequence of human NR4A2 (e.g., Entrez 4929, Uniprot P43354, RefSeq NM_006186.3, or RefSeq NP_006177.1).

[0103] For example, Nurr1 patients often exhibit lower Nurr1 expression or have lower levels of Nurr1 protein than healthy controls. Expression can be determined by measuring the RNA level of Nurr1 or the protein level of Nurr1 in blood-derived cells. Nurr1 activity can also be determined by measuring the amount of target genes regulated or the levels of related proteins in brain cells, blood-derived cells, CSF-derived cells, plasma, serum, or CSF (see, e.g., Front.Immunol.2021;12:676644 or Sci.Rep.2020;10:10755). Nurr1 activity can also be determined by measuring the corresponding cellular phenotype. For example, the regulation of apoptosis / survival in neurons can be measured (this can be determined, for example, by measuring NFL in the patient's serum or plasma or CSF). Activation of Nurr1 induces survival factors in dopaminergic neurons. Loss of this survival signal increases the number of dying neurons. NFL is known from the literature to be a marker of axonal damage in dying neurons. Therefore, activation of Nurr1 by compounds of formulas (I) to (V), or using compound of formula (VI), may reduce the level of NFL in serum, plasma, or CSF.

[0104] Glial fibrillary acidic protein (GFAP) is a type III intermediate filament (IF) protein and a marker of brain injury. GFAP is expressed in cells of the central nervous system, including astrocytes. Levels of GFAP in a patient's serum correlate with the astrocyte-mediated aspects of neurodegeneration. Activated astrocytes increase GFAP production. GFAP can be degraded into GFAP-BDP. Both products can be detected in CSF, serum, or plasma by astrocyte damage (see, e.g., Trends Neurosci. 2015;38:364). In some embodiments, when Nurr1 activity is activated by compounds of formulas (I) to (V) or using a compound of formula (VI), astrogliosis is reduced, thereby mitigating astrocyte damage, which results in a decrease in GFAP / BDP levels.

[0105] The relative expression of the Nurr1 protein or target gene in healthy controls and patients is summarized in Int.J.Mol.Sci.2019;20:4858. Relative expression of Nurr1 in patients or healthy controls can be obtained from peripheral blood by isolation of peripheral blood lymphocytes, extraction of total RNA, and then a real-time PCR assay of Nurr1 gene expression relative to internal control GAPDH (see, for example, J.Neurol.Sci.2008;273:29).

[0106] The term "NR4A3" refers to nuclear receptor 4A3 (nuclear receptor subfamily 4, group A, member 3; NR4A3), also known as neuronal orphan receptor 1 (NOR1), which is a protein encoded by the NR4A3 gene in humans. NR4A3 is a member of the nuclear receptor family of intracellular transcription factors.

[0107] miR-132 is a short, non-coding RNA molecule. This microRNA modulates the expression levels of other genes through several mechanisms, generally reducing protein levels by cleaving mRNA or repressing their translation. The expression of miR-132 in serum, plasma, or CSF can be used to determine the brain expression level of Nurr1 and, in some embodiments, is a marker that can be used to distinguish patients who may benefit more from treatment with compounds of formulas (I) to (V) or compound of formula (VI).

[0108] Neurofilament light chains (NFLs) are generally markers of axonal damage and neuronal destruction, particularly in MS. Low levels of NFL correlate with neuronal protection / survival. In PD, where Nurr1 expression levels are lower compared to healthy volunteers and low levels of Nurr1 are significantly associated with dopaminergic neuron loss, NFLs are a potential biomarker of motor impairment. The major motor symptoms of PD are caused by the death of dopaminergic neurons in the substantia nigra pars compacta. Activation of Nurr1 results in survival signals within neurons, and therefore, lower levels of NFL may be a result of Nurr1 activation (induced, e.g., by compounds of formulas (I)-(V) or using compounds of formula (VI)), which may be beneficial for patients with neurodegenerative diseases.

[0109] Quantitative analysis of NFL in blood and CSF can be performed by immunoassays based on highly sensitive electrochemiluminescence (ECL) (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 widely used method due to its high sensitivity with a lower limit of quantification of 0.1 pg / mL (eBioMedicine 2024;101:104970). In 2022, Quanterix received FDA Breakthrough Device designation for its method of testing NFL in MS patients.

[0110] In some embodiments, NFL levels in blood and CSF are measured by an electrochemiluminescence (ECL)-based immunoassay. In some embodiments, NFL levels in blood are measured by a single-molecule assay or the "Simoa" assay (Quanterix Corp.).

[0111] The same applies to Roche's Elecsys platform, which could also become one of the standards used.

[0112] In some embodiments, patients with neurological disorders, such as AD (30.8 pg / mL), GBS (79.4 pg / mL), or ALS (95.4 pg / mL), have higher serum NFL levels (sNFL) than patients with neurological disorders without evidence of structural central nervous system (CNS) damage and healthy controls. Similar differences have been observed in corresponding CSF samples (PLOS One 2013;8:e75091). NFL levels increase during normal aging, for example, from a mean sNFL of 20.4 pg / mL at ages under 50 to a mean sNFL of 45.9 pg / mL at ages over 70 (Nat.Commun.2020;11:812), indicating an acceleration of neuronal damage at higher ages, which may be caused by potential comorbidities. This should be considered when defining NFL levels for healthy controls or the success of treatment with compounds of formulas (I)-(V) or (VI). An overview of neurofilaments as biomarkers in neuropathy is presented in Nat. Rev. Neurol. 2018; 14: 577. In addition to NFL, Yuang and Nixon describe other neurofilament proteins that can be quantified and monitored during the treatment of neurological disorders (Front. Neurosci. 2021; 15: 689938).

[0113] Brain-derived neurotrophic factor (BDNF) is a protein whose expression is regulated by Nurr1. Activation of Nurr1 leads to enhanced BDNF expression. Measurement of mature BDNF protein in plasma, serum, or CSF can be used as a marker of Nurr1 activity and to evaluate the efficacy of therapies using compounds of formulas (I)–(V) or (VI). Increased levels of mature BDNF correlate with higher neuronal survival. Protein levels of various BDNF isoforms in CSF, blood, and plasma samples can be determined using commercially available immunoassay kits (see, e.g., Int.J.Neuropsychopharmacol.2011;14:347 or Nat.Rev.Neurosci.2005;6:603).

[0114] Glial cell line-derived neurotrophic factor (GDNF) is also a target gene of Nurr1. Activation of Nurr1 leads to enhanced GDNF expression. Measurement of GDNF expression in plasma, serum, or CSF can be used as a marker of Nurr1 activity and to evaluate the effectiveness of treatment with compounds of formulas (I) to (V) or formula (VI). Increased GDNF levels correlate with higher neuronal survival.

[0115] C-RET is a RET proto-oncogene that encodes a receptor tyrosine kinase, a member of the GDNF family of extracellular signaling molecules, and promotes the survival of dopaminergic neurons. Nurr1 activity induces C-RET expression in dopaminergic neurons. C-RET expression can be measured at the RNA or protein level from brain biopsies taken from patients with neurodegenerative diseases. In some embodiments, lower C-RET expression in the brains of patients with neurodegenerative diseases compared to controls correlates with greater benefit in patients treated with compounds of formulas (I) to (V) or formula (VI).

[0116] Glial fibrillary acidic protein (GFAP) is a type III intermediate filament (IF) protein and a marker of brain injury. GFAP is expressed in cells of the central nervous system, including astrocytes. Levels of GFAP in a patient's serum correlate with the astrocyte-mediated neurodegeneration. Activated astrocytes increase GFAP production. GFAP can be degraded into GFAP-BDP. Both products can be detected in CSF, serum, or plasma by astrocyte damage (e.g., Trends Neurosci. 2015;38:364). In some embodiments, when Nurr1 activity is activated by compounds of formulas (I) to (V) or using a compound of formula (VI), astrogliosis is reduced, thereby mitigating astrocyte damage, which results in a decrease in GFAP / BDP levels.

[0117] YKL-40 (CHI3L1) is a glycoprotein primarily produced by reactive astrocytes and microglia in chronic active MS lesions (J. Neuroimmunol. 2016;292:52). YKL-40 levels are elevated in the serum of RRMS patients compared to controls, and it has therefore been suggested to be 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), and it can be reduced by Nurr1 activity (see above).

[0118] The dopamine-active transporter (DAT; also known as SLC6A3) is a transmembrane protein responsible for the reuptake of dopamine from the synapse into the cytosol of dopaminergic neurons. DAT is a target gene of Nurr1 (Development 2009;136:2363). DAT may be reduced by 50–70% in PD patients. DAT imaging by single-photon emission computed tomography (SPECT) can be used to confirm or rule out the diagnosis of dopamine-deficiency parkinson's syndrome. Patients with low levels of Nurr1 expression and activity have lower levels of dopamine transporter expression and activity and therefore benefit from Nurr1 activation by compounds of formulas (I)–(V) or with compound of formula (VI).

[0119] Pituitary homeobox 3 (Pitx3) is a gene that encodes a member of the RIEG / PITX homeobox family, belonging to the bicoid class of homeodomain proteins and acting as a transcription factor. Pitx3 is involved in the maintenance of dopaminergic neurons. The term "Pitx3" may refer to the nucleotide sequence or protein sequence of human Pitx3.

[0120] Tyrosine hydroxylase (TH) is an enzyme that catalyzes 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 results in upregulation of tyrosine hydroxylase expression. Tyrosine hydroxylase activity converts tyrosine to L-DOPA. L-DOPA is converted to dopamine, a neurotransmitter that provides signals for executive function, motor control, motivation, arousal, reinforcement, and reward. Low-level functions include lactation, sexual satisfaction, and nausea.

[0121] Vesicular monoamine transporter 2 (VMAT2; also 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 cell cytosol into synaptic vesicles. VMAT2 is a direct target gene of Nurr1 and is upregulated by activation of Nurr1. The expression of VMAT2 can be determined at the RNA and protein levels in neurons derived from brain biopsies. Furthermore, VMAT2 activity can be determined by DTBZ PET. 11 C]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. In dopamine-releasing neurons of the nigrostriatal and mesolimbic pathways, SLC18A2 function is also required for the vesicular release of the neurotransmitter GABA. In some embodiments, activation of Nurr1 by the compounds of formulas (I)-(V) or using the compound of formula (VI) induces higher VMAT2 expression and is thus beneficial for patients lacking appropriate VMAT2 activity due to mutations and low Nurr1 activation states or cocaine abuse. Increased expression of VMAT2 due to two single nucleotide polymorphisms (SNPs) in the promoter region reduces the risk of PD. In some embodiments, induction of higher expression and activity levels of VMAT2 is beneficial in neurodevelopmental disorders.

[0122] Superoxide dismutase (SOD) is superoxide (O2 -SOD is an enzyme that alternately catalyzes the disproportionation (or distribution) of radicals to normal molecular oxygen and hydrogen peroxide. SOD is upregulated by activation of Nurr1. SOD is an enzyme that reduces oxidative stress in neurons and therefore reduces apoptotic signaling in neurons. SOD expression can be measured at the RNA or protein level from brain biopsy, CSF, or blood samples. Patients showing lower levels of SOD compared to controls may benefit from treatment with compounds of formulas (I) to (V) or formula (VI) by enhancing Nurr1 activation.

[0123] 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 Nurr1 activation. AADC is involved in the final stage of the synthesis of the neurotransmitters dopamine and serotonin. Lower levels of AADC or AADC dysfunction in neurons lead to the 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) can be determined in blood by using ULC-MS / MS (e.g., described in J.Chromatogr.B Biomed.Appl.2021;1185:122999). In some embodiments, patients with lower levels or reduced functionality of AADC as determined by UPLC-MS / MS compared to controls may benefit from treatment with compounds of formulas (I) to (V) or formula (VI) by activation of Nurr1 and subsequent upregulation of AADC.

[0124] II. Multiple Sclerosis Further aspects of this disclosure relate to a method for treating or improving multiple sclerosis (MS) in a subject having MS, the method comprising administering to the subject a compound of formula (I) to (V), or a compound of formula (VI), such as vidofludimus.

[0125] Multiple sclerosis (MS) can be classified into relapsing-remitting MS (RMS) and progressive MS (PMS). Relapsing-remitting MS (RRMS) and active secondary progressive MS (active SPMS) are primarily caused by focal inflammatory disease and are characterized by the presence of magnetic resonance imaging (MRI) lesions and relapses. However, recent meta-analyses of large patient databases have shown that the progression of disability in these two subtypes is caused by relapse-related exacerbations (RAW) and progression unrelated to relapse activity (PIRA). RRMS is characterized by a predominance of relapses and MRI lesions throughout the clinical course. Active SPMS (aSPMS) is characterized by fewer relapses and lesions with continuous progression of disability (see Figure 8).

[0126] Primary progressive MS (PPMS) and inactive secondary progressive MS (inactive SPMS or n-aSPMS) are the two main progressive forms of MS, characterized by ongoing disability progression with little to no MRI lesions or relapses. Recent meta-analyses of large patient databases have shown that disability progression in these two subtypes is almost entirely caused by PIRA. Inactive SPMS is characterized by continuous disability progression between periods of cessation of relapses. PPMS is characterized by disability progression from the onset (see Figure 8).

[0127] The definitions and subcategories of PPMS and SPMS are subject to change. In one exemplary definition, all SPMS can be considered to belong to the category of PMS, and consequently, all SPMS patients are considered PMS patients without distinction between aSPMS and n-aSPMS. In another exemplary definition, active SPMS can be considered to belong to the category of RMS, while inactive SPMS can be considered to belong to the category of PMS. Therefore, the terms "n-aSPMS" and "SPMS" are used synonymously in this invention.

[0128] The distinction between PIRA and RAW may be as follows (JAMA Neurol. 2023;80:151). A PIRA event can be defined as experiencing a confirmed disability worsening (CDW) on the EDSS scale during a 6-month period without relapse (PFR). PFR is the time between two consecutive relapses, starting 3 months after the relapse (or 6 months after the first demyelinating event). The first EDSS scores obtained at least 6 months after the first seizure or 3 months after any other seizure were referred to as the baseline EDSS score and the re-baseline EDSS score, respectively. It was set so that there would be no re-baseline EDSS score lower than the initially recorded (baseline) EDSS score. If the baseline / re-baseline EDSS scores were 0, 1.0–5.0, or greater than 5.0, respectively, confirmed disability accumulation (CDA) was defined as an increase of 1.5, 1.0, or 0.5 in the EDSS score. The date of PIRA was the date of confirmation of CDA. All other episodes of CDA that did not qualify for PIRA (i.e., occurred outside of PFR) were considered RAW events. Patients with at least one CDA but who did not exhibit any PIRA events were considered to have RAW.

[0129] In the clinical study by Kopp et al. (Mult.Scler.Relat.Disord.2021;56:103319), the following inclusion criteria were applied to the MS population with a clinical SPMS diagnosis assigned by an MS neurologist, and to RRMS patients who met the MSBase diagnostic definition for conversion to SPMS. This m-EXPAND criterion identifies patients with a recent worsening of EDSS scores that is unlikely to be explained by a recent relapse, as follows: (a) EDSS (index day + / - 6 months) for 3.0 to 6.5 (including both ends), and (b) EDSS progression within the last two years prior to data extraction, defined as EDSS progression of 1 point or more for patients with an EDSS score less than 6.0, or 0.5 points or more for patients with an EDSS score of 6.0 or higher, and there was no relapse six months prior to progression, and the EDSS score at the time of progression was ≥3.0, and

[0130] (c) Progression of the disability.

[0131] Currently, there are no FDA-approved treatment options for SPMS other than mitoxantrone. However, mitoxantrone treatment does not distinguish between relapsed and active SPMS (active SPMS vs. inactive SPMS). In particular, mitoxantrone treatment is associated with significant toxicity, including cardiotoxicity and secondary malignancies, which limits the treatment duration to approximately 3 years (total dose 140 mg / m²). 2Furthermore, the patient population in this trial primarily had relapsing SPMS, and the benefit in inactive SPMS is unclear. Siponimod, natalizumab, and interferon beta-1b are approved for active SPMS but have not shown benefit in inactive SPMS. Ocrelizumab is approved for PPMS patients, but it strongly attenuates the immune response and therefore has black-box warnings for progressive multifocal leukoencephalopathy and immune-mediated colitis. Other treatment options currently being tested in clinical trials (e.g., fenebrutinib, which carries a risk of hepatic impairment) also do not offer a favorable safety profile for vidofludimus. Thus, there is an urgent unmet need as there is no effective treatment for PIRA as a whole.

[0132] MS typically begins with clinically isolated syndrome (CIS), which is the first episode of symptoms caused by inflammation and damage to the myelin that covers the nerves in the brain or spinal cord. In CIS, there are seizures that suggest demyelination, but the criteria for MS are not met. 30–70% of people who experience CIS later develop MS.

[0133] There is a further subgroup of MS patients, namely those who transition between relapsing MS and PIRA. The term “transitional MS” is used herein in relation to this disease. Transitional MS patients can be identified by one or more of the following testing methods. (a) Symbol-Numeric Modality Test (SDMT), (b)Multiple Sclerosis Functional Composite (MSFC), (c)EDSS, (d) 25-foot walking time test (T25FW), (e) 9-hole peg test (9HPT), (f) MSProDiscuss(trademark) clinical tools, (g) A composite score that integrates several tests, such as the EDSS, 25-foot walk time test (T25FW), SDMT and 9-hole peg test (9HPT), and the MSProDiscuss® clinical tool.

[0134] III. Progression unrelated to relapse (PIRA) Another aspect of this disclosure relates to a method for treating the progression of MS in a subject, for example, progression unrelated to relapse (PIRA), comprising administering to the subject a compound of formula (I) to (V), or together with a compound of formula (VI). In some embodiments, the compound is vidofludimus.

[0135] PIRA is a contributing factor in all forms of multiple sclerosis (MS). PIRA plays a significant role in disease progression in RRMS and is a major pathway by which patients develop impairment in progressive multiple sclerosis (PMS), such as forms of PMS with little or no relapses. PIRA can also occur early in the disease, as shown in studies of patients who successfully suppressed inflammation with effective DMT, providing evidence of treatment-resistant pathology that progresses from the outset.

[0136] This increases the importance of all new drugs that reduce or slow PIRA (measured as worsening of confirmed disability, but also by assessment of brain atrophy). It may also be important to provide novel drugs that (a) reduce relapse activity and (b) reduce or slow PIRA (measured as worsening of confirmed disability, but also by assessment of brain atrophy).

[0137] Therefore, in one embodiment, the present invention aims to treat the worsening of the accumulation of neurological defects unrelated to recurrence.

[0138] Therefore, the present invention aims to treat progression (PIRA) that is unrelated to relapse activity.

[0139] The relapse-independent accumulation of neurological defects that worsen or progress independently of relapse activity is defined in Fred Lublin's https: / / doi.org / 10.1093 / brain / awac016 (Brain 2022;145:3147), and the detection of neurological defects that worsen or progress independently of relapse activity is detected as described in Fred Lublin's https: / / doi.org / 10.1093 / brain / awac016 (Brain 2022;145:3147) and is incorporated herein by reference as one embodiment.

[0140] There are two main mechanisms by which patients with multiple sclerosis (MS) acquire disability: (i) the gradual accumulation of functional impairment due to incomplete recovery from relapses [i.e., relapse-related exacerbation (RAW)], and (ii) relapse-independent progression (PIRA). The former is considered the main cause of permanent disability in relapsing-type MMS, while the latter is thought to promote the typical insidious progression in primary and secondary progressive MMS (PPMS and SPMS). One example of detecting relapse-independent progression is the detection and measurement of the expanded disability status scale (EDSS) by Kurtzke, JF, "Rating neurologic impairment in multiple sclerosis: An expanded disability status scale (EDSS)," Neurology. 1983;33:1444-1452.

[0141] There are currently no satisfactory drug therapies available to treat the major, pent-up portion of the disorder's exacerbation that is unrelated to relapse. Surprisingly, the present invention shows that compounds of formulas (I) to (V), or together with compounds of formula (VI), particularly vidofludimus, exhibit dual action as a DHODH inhibitor and a Nurr1 agonist, and can function as a neuroprotective agent in addition to their established activity as anti-inflammatory agents.

[0142] In particular, patients with low levels of Nurr1 benefit from treatment with compounds of formulas (I) to (V), or compound of formula (VI). Therefore, the first evidence has been shown that patients with reduced Nurr1 activity benefit more from treatment with vidofludimus calcium (IMU-838) than patients with normal Nurr1 activity, and that DHODH inhibition is beneficial against inflammation, while Nurr1 activation is novel and aims to protect neurons from death. Diseases and conditions exhibiting lower Nurr1 expression or activity result in reduced survival or function of dopaminergic neurons, leading to neurodegeneration.

[0143] Patients with brain and spinal cord disorders or diseases including neurodegeneration can be beneficially treated with compounds of formulas (I) to (V) or of formula (VI). These conditions include diseases with symptoms such as motor impairment, cognitive impairment, fatigue, depression, or drug addiction.

[0144] Focusing on the disease MS, the positive effects on RRMS patients may be due to the anti-inflammatory properties of compounds of formulas (I) to (V), or together with compound of formula (VI), preferably vidofludimus, or its isotopic variants, pharmaceutically acceptable salts, or solvates.

[0145] In some embodiments, MS patients can be classified into two groups: (a) patients with relapses, i.e., patients with relapse-related exacerbations (RAW), and (b) other patients with progressive (depressive) disease exacerbations, i.e., patients with progression unrelated to relapse activity (PIRA), and these groups require fundamentally different treatments. In some embodiments, group (a) requires anti-inflammatory treatment, while group (b) requires neuroprotective treatment to mitigate disease exacerbations. For group (b), there are few treatment options, as pure DHODH inhibitors are not particularly expected to provide beneficial treatment. In one embodiment, the compounds of the present invention can act as nuclear receptor-associated 1 (Nurr1).

[0146] Thus, vidofludimus has not been tested in MS patients who have had no relapses or who have not experienced relapses for at least 12 or 24 months. Surprisingly, the inventors have found that vidofludimus, or its isotopic variants, pharmaceutically acceptable salts, or solvates, preferably with compounds of formulas (I) to (V), or with compound (VI), not only has a beneficial effect on group (a) but also on group (b), which appears to be superior to other treatment options currently being tested for this group. This may be due to neuroprotective Nurr1 receptor activation induced by compounds of formulas (I) to (V), or preferably vidofludimus using compounds of formula (VI). This new finding enables the use of compounds of formulas (I) to (V), or preferably vidofludimus, together with compound (VI), for all diseases involving abnormal levels of Nurr1.

[0147] In one embodiment, the patient treated according to the present invention is an MS patient who has had no relapses or has not had a relapse for at least 12 months. In another embodiment, the patient treated according to the present invention is an MS patient who has had no relapses or has not had a relapse for at least 24 months.

[0148] In one embodiment, the patient treated according to the present invention is a PIRA patient who has had no relapses at all, or who has not had a relapse for at least 12 or 24 months.

[0149] In one embodiment of the present invention, PIRA was defined as a confirmed disease exacerbation (CDW) event that occurred more than 90 days after the onset of a relapse reported by the last investigator (regardless of EDSS confirmation), and lasted for 3 months, 6 months, or preferably 12 months, or 24 months.

[0150] Furthermore, for an event to be classified as a PIRA event, a relapse must not occur within 30 days before or after the EDSS assessment. If a relapse occurs with incomplete recovery, the baseline (i.e., reference EDSS value) may be reset more than 90 days after the onset of the relapse in order to identify the next PIRA event. In individual patients, the baseline may be reset multiple times (i.e., after each relapse) until a PIRA event is detected or until the individual EDSS profile is completed.

[0151] A persistent PIRA is a 3-month or 6-month PIRA event in which the worsening of the EDSS persists in all of the following assessments, i.e., the patient did not recover in the available long-term data.

[0152] Clinical evidence for the disability can be obtained from the following surrogate endpoints. For example, Annual percentage change in brain volume up to 120 weeks Annual rate of change in whole brain atrophy.

[0153] Clinical evidence can also be obtained through the following biomarker responses. To slow or reduce the increase in serum NFL levels by at least 5% (or to define a hazard ratio of 0.9) Reduce CSF, serum, or plasma GFAP levels by at least 3% over a period of 48 weeks.

[0154] The progression of disability can be assessed using the Integrated Disability Scale (EDSS), the 9-Hole Peg Test (9-HPT), the 25-Foot Walk Time Test (T25FWT), or any combination thereof.

[0155] Methods for evaluating disability progression may include evaluating the onset of complex 12-week confirmed disability progression (cCDP12), and the onset of cCDP12 is a. An increase of at least 1.0 point from baseline in the EDSS score for subjects with a baseline EDSS score of 5.5 points or less, or an increase of at least 0.5 points from baseline in the EDSS score for subjects with a baseline EDSS score of 5.5 points or more. b.9- An increase of at least 20% from baseline in the time to complete HPT, and c. At least a 20% increase from baseline in T25FWT, The disease includes at least one progressive event selected from the group consisting of the following, and the progressive event is confirmed at least 12 weeks after the initial progression.

[0156] Observational and controlled clinical trials provide evidence that PIRA is likely the most frequent manifestation of disability accumulation across the entire range of traditional MS phenotypes, including CIS and early RRMS, thus providing another perspective on the conceptual distinction between the course or stage of relapsing and progressive disease. In some embodiments, the following determinants can be used to diagnose PIRA in both RRMS and progressive MS, as an additional set of determinants.

[0157] A. Baseline / Reference Score: A roving baseline may be applied, where a new reference score is set each time an individual EDSS or composite measure is lower than a previous measure and confirmed at the next visit. The reference score may also be reset if a relapse results in residual disability.

[0158] B. Event Score: Classification to PIRA may be considered if an increase in the EDSS or composite measure is not determined within 30 days prior to and 90 days after the onset reported by the principal investigator as a relapse. In addition to the EDSS (an increase of 1.5 points if baseline is 0, 1.0 point between 1 and 5.5, and 0.5 points if >5.5), composite measures may be recommended and must include upper limb function (9HPT, threshold: >20% decrease), gait speed (T25FWT, threshold: >20% decrease), and cognitive tests (SDMT, threshold: 4 points or >10% decrease).

[0159] C. Confirmation score: Confirmation visits may be made 3 months after the initial increase in disability, preferably 6 months or 12 months or later, and should not be made 30 days or 90 days before the onset of a relapse reported by the principal investigator.

[0160] D. Persistence score: The EDSS score that defines PIRA may not improve even after at least 12 months, or even 24 months, from the onset of PIRA, by the end of follow-up.

[0161] In one embodiment, the patient treated according to the present invention is a PIRA patient who has not experienced a relapse or has not experienced a relapse for at least 12 or 24 months, and the pharmacopoeia is vidofludimus in a daily dose of 30 mg to 45 mg of vidofludimus calcium.

[0162] In one embodiment, the patient treated according to the present invention is a PIRA patient who has not experienced a relapse or has not experienced a relapse for at least 12 or 24 months, and the pharmacopoeia is vidofludimus in a daily dose of 30 mg of vidofludimus calcium.

[0163] In one embodiment, the patient treated according to the present invention is a PIRA patient who has not experienced a relapse or has not experienced a relapse for at least 12 or 24 months, and the pharmacopoeia is vidofludimus in a daily dose of 45 mg of vidofludimus calcium.

[0164] It has been found that MS patients acquire a considerable degree of disability not only through relapse-related exacerbations (RAWs) but also through progression unrelated to relapse activity (PIRAs).

[0165] PIRA can be quantified by confirmed disability exacerbation (CDW) events. PIRA begins early in the disease progression, occurs in all phenotypes, and can be a major contributing factor to the accumulation of disability at different stages of disease progression.

[0166] PIRA is a major contributing factor to the accumulation of impairment during the progression of the disease. PIRA may be associated with the exacerbation of unknown “hidden symptoms” such as fatigue, sphincter dysfunction, and cognitive symptoms. Patients may have MS that transitions between relapsing and progressive disease. Regardless of disease classification, an underlying progressive course exists in all MS patients. In one embodiment, a PIRA patient may be a SPMS patient with no recent relapses, no MRI activity suggestive of active inflammation, and evidence of recent progression unrelated to relapses.

[0167] PIRA and RAW can be further subdivided into smaller groups such as "early PIRA," "late PIRA," "active PIRA," or "inactive PIRA" (JAMA Neurol. 2023;80:151).

[0168] Patients with early-stage PIRA show a significantly steeper increase in the Overall Disability Scale (EDSS) than patients with later-stage PIRA.

[0169] Furthermore, patients with early-stage PIRA were at a higher risk of reaching an EDSS score of 6.0 at a faster rate than patients with late-stage PIRA.

[0170] PIRA can be an irreversible phenomenon associated with an undesirable long-term disability outcome, especially if such PIRA events occur early in the course of the disease.

[0171] Identifying all individuals who are at risk of developing PIRA as soon as possible after the initial demyelinating event, especially early-stage PIRA, may lead to better treatment choices and subsequent better long-term outcomes.

[0172] This specification provides a method for treating PIRA in subjects requiring it by administering a therapeutically effective dose of vidofludimus, or its isotopic variants, pharmaceutically acceptable salts, or solvates, preferably vidofludimus calcium salt dihydrate as "polymorph A," to the subject. Furthermore, it provides a method for treating PIRA in subjects requiring it by administering a once-daily dose of approximately 30-45 mg of vidofludimus, or an equivalent amount of its isotopic variants, pharmaceutically acceptable salts, or solvates, preferably vidofludimus calcium salt dihydrate as "polymorph A," to subjects in the maintenance phase. Furthermore, it provides a compound for use in a method for treating PIRA in subjects requiring it, the compound being approximately 30-45 mg of vidofludimus, or an equivalent amount of its isotopic variants, pharmaceutically acceptable salts, or solvates, preferably vidofludimus calcium salt dihydrate as "polymorph A," to the subject in the maintenance phase. In further embodiments, this specification provides compounds for use in the manufacture of pharmaceuticals for the treatment of PIRA in subjects requiring it, the compounds being vidofludimus in a once-daily dose of about 30-45 mg during the maintenance phase, or equivalent amounts thereof of its isotopic variants, pharmaceutically acceptable salts or solvates, preferably vidofludimus calcium salt dihydrate as "polymorph A". In some embodiments, the treatment of PIRA is assessed using the Integrated Disability Rating Scale (EDSS), the 9-Hole Peg Test (9-HPT), or the 25-Foot Walk Time Test (T25FWT), or any combination thereof. In some embodiments, the treatment of PIRA is assessed based on the time to onset of confirmed disability progression (e.g., 12-week or 24-week CDP) or based on the time to onset of composite confirmed disability progression (e.g., 12-week or 24-week cCDP).For example, in some embodiments, treating subjects with PIRA by administering a once-daily dose of approximately 30-45 mg of vidofludimus, or an equivalent amount of an isotopic variant, a pharmaceutically acceptable salt or solvate thereof, preferably vidofludimus calcium salt dihydrate as "polymorph A," during the maintenance phase can result in: a delay in the worsening of EDSS (e.g., an increase of 0.5, 1.0, 1.5 or more points compared to baseline), a delay in the worsening of 9-HPT time (e.g., more than 20% compared to baseline), a delay in the worsening of T25FWT time (e.g., more than 20% compared to baseline), a delay in the onset of CDP12, a delay in the onset of CDP24, a delay in the onset of cCDP12, a delay in the onset of cCDP24, a delay in the onset of at least one progression event, a reduction in the risk of having at least one progression event, or a reduction in disability in subjects with PIRA. In other embodiments, treatment of PIRA is evaluated based on MSIS-29, Neuro-QoL upper extremity, 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 PIRA is evaluated 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, treatment of a subject having PIRA includes delaying the progression of PIRA, where progression is assessed based on the occurrence of at least one progression event that can be described by 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 CDP12, cCDP12, CDP24, or cCDP24. In some embodiments, treatment of PIRA includes delaying the progression of PIRA.In some embodiments, treatment of PIRA includes delaying the onset of at least one progression event in the subject. In some embodiments, treatment of PIRA includes reducing the risk for a subject to experience at least one progression event. In some embodiments, treatment of PIRA includes delaying progression by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or at least 35% (as assessed using, for example, T25FWT time, or 9-HPT time, or EDSS score, or CDP12, or cCDP12, or CDP24, or cCDP24, etc.), or delaying the onset of at least one progression event. In some embodiments, treatment of PIRA includes delaying progression or 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% compared to another subject having PIRA (e.g., a comparator) that has not been administered vidofludimus or its isotope variants, pharmaceutically acceptable salts, or solvates. 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 (such as a CD20-targeted cell-lytic antibody). In further embodiments, treatment of PIRA includes reducing the risk of the subject 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 over a period of time, for example, over 12, 18, 24, 36, 48, 60, 72, 84, 96, 108, or 120 weeks.In some embodiments, the risk is reduced compared to another subject having PIRA (e.g., a comparator) that has not been administered vidofludimus or its isotopic variants, pharmaceutically acceptable salts or solvates, but has been optionally administered an anti-CD20 antibody. In some embodiments, the other subject is administered an anti-CD20 antibody (e.g., a CD20-targeted 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 some embodiments, treatment of PIRA includes an improvement of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, or at least 30% in the PIRA criteria (e.g., T25FWT time, or 9-HPT time, or EDSS score) compared to the same criteria evaluated in the same subjects before the initiation of administration of vidofludimus, or an equivalent amount thereof isotopic variant, a pharmaceutically acceptable salt, or solvate, preferably vidofludimus calcium salt dihydrate as "Polymorph A". In some embodiments, the improvement is compared to the same criteria evaluated in the same subjects within one week, or within 0 to 28 days, or within 6 weeks prior to the initiation of administration of vidofludimus, or an equivalent amount thereof isotopic variant, a pharmaceutically acceptable salt, or solvate. In other embodiments, treatment of PIRA includes an improvement of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or at least 40% in the PIRA assessment criteria (e.g., T25FWT time, or 9-HPT time, or EDSS score) compared to the same criteria assessed in another subject with PIRA who has not been administered vidofludimus or its isotopic variants, pharmaceutically acceptable salts, or solvates. 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 subjects are administered an anti-CD20 antibody (such as a CD20-targeted cell-lytic antibody). In some embodiments, the PIRA subgroup is selected from subgroups consisting of (a) active secondary progressive multiple sclerosis (aSPMS), (b) inactive 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) inactive PIRA, (j) clinically isolated syndrome (CIS), (k) transitioning MS, or combinations 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 an AOMS.

[0173] Furthermore, this specification provides a method for treating (e.g., delaying) the progression of PIRA in subjects requiring it by administering a therapeutically effective dose of vidofludimus, or its isotopic variants, pharmaceutically acceptable salts or solvates, preferably vidofludimus calcium salt dihydrate as "polymorph A," to a subject. Furthermore, it provides administering vidofludimus, or an equivalent amount of its isotopic variants, pharmaceutically acceptable salts or solvates, preferably vidofludimus calcium salt dihydrate as "polymorph A," to a subject during the maintenance phase. Accordingly, this specification provides a method for treating (e.g., delaying) the progression of PIRA in subjects requiring it by administering vidofludimus, or an equivalent amount of its isotopic variants, pharmaceutically acceptable salts or solvates, preferably vidofludimus calcium salt dihydrate as "polymorph A," to a subject during the maintenance phase. Furthermore, the present invention provides a compound for use in a method to slow the progression of PIRA in subjects requiring it, the compound being vidofludimus or its isotopic variant, pharmaceutically acceptable salt or solvate, and the method comprising administering to a subject a once-daily dose of approximately 30-45 mg of vidofludimus or its isotopic variant, pharmaceutically acceptable salt or solvate, preferably vidofludimus calcium salt dihydrate as "polymorph A". In further embodiments, this specification provides compounds for use in the manufacture of pharmaceuticals for use in a method of treating (e.g., slowing) the progression of PIRA in subjects requiring it, wherein the compounds are vidofludimus or its isotopic variants, pharmaceutically acceptable salts or solvates, and the method comprises administering to subjects in the maintenance phase a once-daily dose of about 30-45 mg of vidofludimus or its isotopic variants, pharmaceutically acceptable salts or solvates, preferably vidofludimus calcium salt dihydrate as "polymorph A". In some embodiments, the progression of PIRA is assessed using the Integrated Disability Rating Scale (EDSS), the 9-Hole Peg Test (9-HPT), or the 25-Foot Walk Time Test (T25FWT), or any combination thereof.In some embodiments, PIRA progression is assessed based on the time to onset of confirmed disability progression (e.g., 12-week or 24-week CDP) or based on the time to onset of composite confirmed disability progression (e.g., 12-week or 24-week cCDP). In some embodiments, PIRA progression 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, progression is slowed by at least 5%. In some embodiments, progression is slowed by at least 10%. In some embodiments, progression is slowed by at least 15%. In some embodiments, progression is slowed by at least 20%. In some embodiments, progression is slowed by at least 25%. In some embodiments, progression is slowed by at least 30%. In some embodiments, progression is slowed by at least 35%. In some embodiments, progression is slowed, as measured by the onset of cCDP12 (e.g., by extending the time to the onset of cCDP12) or by the risk of cCDP12 (e.g., by reducing the risk of experiencing cCDP12 over a period of time). In some embodiments, the progression of PIRA is slowed compared to another subject with PIRA (e.g., a comparator), the other subject has not been administered vidofludimus or its isotopic variants, pharmaceutically acceptable salts, or solvates. In some embodiments, the other subject is administered an anti-CD20 antibody (e.g., a CD20-targeted cytolytic antibody) and not a DHODH inhibitor (e.g., vidofludimus or its isotopic variants, pharmaceutically acceptable salts, or solvates). In some embodiments, the total evaluation period is 12 weeks, 18 weeks, 24 weeks, 36 weeks, 48 ​​weeks, 60 weeks, 72 weeks, 84 weeks, 96 weeks, 108 weeks, 14 weeks, or 120 weeks.In some embodiments, the total evaluation period is at least 120 weeks, and for example, the progression of PIRA is slower over 120 weeks compared to another subject with PIRA that has not been administered vidofludimus or its isotopic variants, pharmaceutically acceptable salts or solvates, and has optionally been administered a CD20-targeted cytolytic antibody, when evaluated over 120 weeks. In some embodiments, the other subject is administered an anti-CD20 antibody (such as a CD20-targeted cytolytic antibody). In some embodiments, the PIRA subgroup includes (a) active secondary progressive multiple sclerosis (aSPMS), (b) inactive 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) inactive PIRA, (j) clinically isolated syndrome (CIS), (k) transitioning 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 an AOMS.

[0174] In further embodiments, this specification provides a method for reducing impairment in subjects having PIRA, the method comprising administering a therapeutically effective dose of vidofludimus, or its isotopic variant, pharmaceutically acceptable salt or solvate, preferably vidofludimus calcium salt dihydrate as "polymorph A," to the subject. In further embodiments, this specification provides a method for administering vidofludimus, or an equivalent amount of its isotopic variant, pharmaceutically acceptable salt or solvate, preferably vidofludimus calcium salt dihydrate as "polymorph A," to a subject in the maintenance phase. In further embodiments, this specification provides a method for reducing impairment in subjects having PIRA, the method comprising administering vidofludimus, or an equivalent amount of its isotopic variant, pharmaceutically acceptable salt or solvate, preferably vidofludimus calcium salt dihydrate as "polymorph A," to a subject in the maintenance phase. In some embodiments, compounds are provided for use in methods to reduce impairment in subjects having PIRA, wherein the compounds are vidofludimus or its isotopic variants, pharmaceutically acceptable salts or solvates, and the method comprises administering to subjects in a maintenance phase a once-daily dose of about 30-45 mg of vidofludimus or its isotopic variants, pharmaceutically acceptable salts or solvates, preferably vidofludimus calcium salt dihydrate as "polymorph A". In further embodiments, this specification provides compounds for use in the manufacture of pharmaceuticals for use in methods to reduce impairment in subjects having PIRA, wherein the compounds are vidofludimus or its isotopic variants, pharmaceutically acceptable salts or solvates, and the method comprises administering to subjects in a maintenance phase a once-daily dose of about 30-45 mg of vidofludimus or its isotopic variants, pharmaceutically acceptable salts or solvates, preferably vidofludimus calcium salt dihydrate as "polymorph A". Reducing disability may include reducing the psychological impact of MS, increasing upper limb function, increasing walking ability, reducing fatigue, improving behavioral status, reducing the overall impression of MS severity, or any combination thereof.Reducing disability may further include reducing one or more symptoms of PIRA or mitigating 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 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, as described herein. In some embodiments, one or more of 9-HPT, T25FWT, or EDSS are used. In some embodiments, disability reduction includes subjects who can complete T25FWT-anchor 9-HPT more quickly, or a reduction in EDSS scores (e.g., closer to "normal"). In one embodiment, the reduction in disability includes improvement in one or more assessment criteria, such as those 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 one embodiment, the improvement is at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or at least 35% in at least one PIRA assessment criterion (e.g., T25FWT time, or 9-HPT time, or EDSS score) compared to the same assessment criterion assessed in the same subject before the initiation of administration of vidofludimus or its isotopic variant, pharmaceutically acceptable salt or solvate, preferably vidofludimus calcium salt dihydrate as "Polymorph A". In some embodiments, two, three, four, five, or more evaluation criteria are improved, and the level of improvement of each criterion is independent (for example, one criterion improves by at least 10%, and another improves 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 evaluation criteria evaluated in the same subject within one week, or within 0 to 28 days, or within 6 weeks prior to the initiation of administration of vidofludimus or its isotope variants, pharmaceutically acceptable salts or solvates. In some embodiments, the PIRA subgroup includes (a) active secondary progressive multiple sclerosis (aSPMS), (b) inactive 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) inactive PIRA, (j) clinically isolated syndrome (CIS), (k) transitioning 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 an AOMS.

[0175] Further embodiments provide a method for delaying the onset of at least one progressive event in a subject having PIRA, the method comprising administering a therapeutically effective dose of vidofludimus, or its isotopic variant, pharmaceutically acceptable salt or solvate, preferably vidofludimus calcium salt dihydrate as "polymorph A," to the subject. Further embodiments provide a method for delaying the onset of at least one progressive event in a subject having PIRA, the method comprising administering to a subject in the maintenance phase a once-daily dose of approximately 30-45 mg of vidofludimus, or an equivalent amount of its isotopic variant, pharmaceutically acceptable salt or solvate, preferably vidofludimus calcium salt dihydrate as "polymorph A." Furthermore, the present invention provides a compound for use in a method for delaying the onset of at least one progressive event in a subject having PIRA, wherein the compound is vidofludimus, or an isotopic variant thereof, a pharmaceutically acceptable salt, or a solvate thereof, and the method comprises administering to a subject in the maintenance phase a once-daily dose of approximately 30-45 mg of vidofludimus, or an equivalent amount of an isotopic variant thereof, a pharmaceutically acceptable salt, or a solvate thereof, preferably vidofludimus calcium salt dihydrate as "polymorph A". Further embodiments provide a compound for use in the manufacture of a pharmacopoeia for a method of delaying the onset of at least one progression event in a subject having PIRA, wherein the compound is vidofludimus, or an isotopic variant thereof, a pharmaceutically acceptable salt, or a solvate thereof, and the method comprises administering to a subject in the maintenance phase a once-daily dose of about 30-45 mg of vidofludimus, or an equivalent amount of an isotopic variant thereof, a pharmaceutically acceptable salt, or a solvate thereof, preferably vidofludimus calcium salt dihydrate as "polymorph A". Progression events include, for example, an increase from baseline in the time required to complete 9-HPT, or an increase from baseline in the time required to complete T25FWT, or an increase from baseline in the EDSS score. In some embodiments, the increase from baseline in the time required to complete 9-HPT is at least a 20% increase (e.g., 20%, 25%, 30%, 35%, etc.).In some embodiments, the increase from baseline in the time required to complete the T25FWT is at least a 20% increase (e.g., 20%, 25%, 30%, 35%, etc.). In further embodiments, the increase from baseline in the EDSS score is at least a 1.0 increase, where the baseline is 5.5 points or less, or at least a 0.5 point increase for subjects with a baseline score greater than 5.5 points. In some embodiments, the progression event is confirmed at a specific period, such as at least 12 weeks or at least 24 weeks, after the initial progression. In some embodiments, the baseline used in determining the progression event is the same assessment criteria (e.g., T25FWT, 9-HPT, EDSS, or a combination thereof) evaluated in the same subject within one week, or between 0 and 28 days, or within 6 weeks prior to the initiation of administration of vidofludimus or its isotopic variant, pharmaceutically acceptable salt, or solvate. In some embodiments, the use of a method, a compound for use, or a compound in the manufacture of a pharmaceutical product delays the onset of at least one progressive 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 compared to another subject having PIRA (e.g., a comparator), the other subject not being administered a DHODH inhibitor (e.g., vidofludimus, or its isotopic variants, pharmaceutically acceptable salts, or solvates). In some embodiments, other subjects are administered an anti-CD20 antibody (e.g., a CD20-targeted cell-lytic antibody) but not a DHODH inhibitor (e.g., vidofludimus, or its isotopic variants, pharmaceutically acceptable salts, or solvates).In some embodiments, the total evaluation 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 some embodiments, the total evaluation period is at least 120 weeks, and for example, the time to the onset of at least one progression event 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% when evaluated over 120 weeks compared to another subject having PIRA who has not been administered a DHODH inhibitor (e.g., vidofludimus, or its isotopic variant, pharmaceutically acceptable salt or solvate) and has optionally been administered an anti-CD20 antibody (e.g., a CD20-targeted cytolytic antibody). In some embodiments, calculating the delay in the onset of at least one progression event may include, for example, calculating the additional time to the onset of the progression event in subjects administered with vidofludimus or its isotopic variants, pharmaceutically acceptable salts, or solvates compared to subjects not administered with vidofludimus or its isotopic variants, pharmaceutically acceptable salts, or solvates (and optionally administered with an anti-CD20 antibody). In some embodiments, the PIRA subgroup is selected from subgroups consisting of (a) active secondary progressive multiple sclerosis (aSPMS), (b) inactive 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) inactive PIRA, (j) clinically isolated syndrome (CIS), (k) transitioning MS, or combinations 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 an AOMS.

[0176] This specification further provides a method for reducing the risk in subjects having PIRA with at least one progressive event, the method comprising administering a therapeutically effective dose of vidofludimus, or its isotopic variant, pharmaceutically acceptable salt or solvate, preferably vidofludimus calcium salt dihydrate as "polymorph A," to the subject. Furthermore, a compound is provided for use in a method to reduce the risk of subjects having PIRA with at least one progressive event, wherein the compound is vidofludimus, or an isotopic variant thereof, a pharmaceutically acceptable salt, or a solvate, and the method comprises administering to a subject in the maintenance phase a once-daily dose of approximately 30-45 mg of vidofludimus, or an isotopic variant thereof, a pharmaceutically acceptable salt, or a solvate, preferably vidofludimus calcium salt dihydrate as "polymorph A". In a further embodiment, a compound is provided for use in the manufacture of a pharmaceutical for reducing the risk of subjects having PIRA with at least one progressive event, wherein the compound is vidofludimus, or an isotopic variant thereof, a pharmaceutically acceptable salt, or a solvate, and the subject is administered to a subject in the maintenance phase a once-daily dose of approximately 30-45 mg of vidofludimus, or an isotopic variant thereof, a pharmaceutically acceptable salt, or a solvate, preferably vidofludimus calcium salt dihydrate as "polymorph A". Progressive events include, for example, an increase from baseline in the time required to complete the 9-HPT, an increase from baseline in the time required to complete the T25FWT, or an increase from baseline in the EDSS score. In some embodiments, the increase from baseline in the time required to complete the 9-HPT is at least a 20% increase (for example, it may be 20%, 25%, 30%, etc.).In some embodiments, the increase from baseline in the time required to complete the T25FWT is at least a 20% increase (e.g., 20%, 25%, 30%, etc.). In further embodiments, the increase from baseline in the EDSS score is at least a 1.0 increase (e.g., 1.0, 1.5, 2.0, etc.), and the baseline is 5.5 points or less, or at least a 0.5 point increase for subjects with a baseline score greater than 5.5 points (e.g., 0.5, 1.0, 1.5, etc.). In some embodiments, the progression event continues for a certain period of time, such as at least 12 weeks or at least 24 weeks, after the initial progression (e.g., as CDP12, cCDP12, CDP24, or cCDP24). In some embodiments, the baseline used in determining progression events is the same evaluation criteria (e.g., T25FWT, 9-HPT, EDSS, or a combination thereof) evaluated in the same subject within one week, or within 0 to 28 days, or within 6 weeks prior to the initiation of administration of vidofludimus or its isotopic variant, pharmaceutically acceptable salt, or solvate. In certain embodiments, the method, the compound for use, or the use of the compound in the manufacture of a pharmaceutical reduces the risk of a subject with 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 risk of having at least one progression event includes reducing the risk of experiencing cCDP12 or reducing the risk of worsening according to the EDSS.In some embodiments, the risk of having at least one reduced progression event is reduced compared to another subject having PIRA, and the other subject is not administered a DHODH inhibitor (e.g., vidofludimus, or its isotopic variant, pharmaceutically acceptable salt, or solvate). In some embodiments, the other subject is administered an anti-CD20 antibody (e.g., a CD20-targeted cytolytic antibody) and is not administered a DHODH inhibitor (e.g., vidofludimus, or its isotopic variant, pharmaceutically acceptable salt, or solvate). In some embodiments, the total evaluation 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 one embodiment, the total evaluation period is at least 120 weeks, and for example, subjects with PIRA administered with vidofludimus or its isotopic variant, pharmaceutically acceptable salt or solvate have at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or at least 35% lower risk of having at least one progression event over 120 weeks compared to another subject with PIRA who has not been administered vidofludimus or its isotopic variant, pharmaceutically acceptable salt or solvate, but optionally administered a CD20-targeted cytolytic antibody. Such reduced risk of having at least one progression event can be calculated, for example, by calculating the rate of progression events (e.g., over 60 weeks or over 120 weeks) in one or more subjects with PIRA who were administered vidofludimus or its isotopic variant, pharmaceutically acceptable salt or solvate, and comparing that rate to the rate of progression events in one or more subjects with PIRA who were not administered vidofludimus or its isotopic variant, pharmaceutically acceptable salt or solvate, but who were optionally administered an anti-CD20 antibody (e.g., a CD20-targeted cell-lytic antibody).In some embodiments, the PIRA subgroup is selected from subgroups consisting of (a) active secondary progressive multiple sclerosis (aSPMS), (b) inactive 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) inactive PIRA, (j) clinically isolated syndrome (CIS), (k) transitioning MS, or combinations 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 an AOMS.

[0177] This specification provides a method for increasing motility in a subject having PIRA, wherein the subject comprises administering to the subject a therapeutically effective dose of vidofludimus, or an isotopic variant thereof, a pharmaceutically acceptable salt or solvate, preferably vidofludimus calcium salt dihydrate as "polymorph A". This specification also provides a method for increasing motility in a subject having PIRA, wherein the subject comprises administering to the subject in the maintenance phase a once-daily dose of approximately 30-45 mg of vidofludimus, or an equivalent amount of an isotopic variant thereof, a pharmaceutically acceptable salt or solvate, preferably vidofludimus calcium salt dihydrate as "polymorph A". Accordingly, this specification provides a method for increasing mobility in subjects requiring it by administering to subjects in the maintenance phase a once-daily dose of approximately 30-45 mg of vidofludimus, or an equivalent amount thereof, an isotopic variant, a pharmaceutically acceptable salt or solvate, preferably vidofludimus calcium salt dihydrate as "Polymorph A," the subject having PIRA. Increased mobility in the subject may include, for example, increased ability to walk, increased ability to run, increased ability to go up and / or down stairs, increased ability to stand up, improved balance when walking or standing, increased distance the subject can walk, reduced effort required to walk, reduced reliance on support when walking indoors and / or outdoors (e.g., walking stick, leaning on furniture, walking frame, etc.), reduced concentration required to walk, or increased uniformity / smoothness of walking, or any combination thereof. In some embodiments, one, two or more of these aspects of mobility are improved, but not more than one. For example, an increase in mobility in a subject may include an increase in the ability to walk, but one or more other elements of mobility may not be improved. Such an increase in mobility can be assessed, for example, using a subject questionnaire. In some embodiments, increased mobility, or one or more components of increased mobility, as described herein, can be assessed using MSWS-12.In some embodiments, the increase in motility is evaluated compared to the subject's motility before administration of vidofludimus or its isotopic variant, pharmaceutically acceptable salt, or solvate (e.g., assessed using MSWS-12). In some embodiments, the PIRA subgroup is selected from the subgroups consisting of (a) active secondary progressive multiple sclerosis (aSPMS), (b) inactive 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) inactive PIRA, (j) clinically isolated syndrome (CIS), (k) transitioning MS, or combinations 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.

[0178] In some embodiments provided herein, the progression of PIRA can be assessed by one or more clinical or laboratory endpoints selected from the group consisting of MSIS-29, Neuro-QoL upper extremity, 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. For example, in some embodiments, the progression of PIRA is assessed by one or more of EDSS, T25FWT, or 9-HPT. Furthermore, in some embodiments, the progression of PIRA is assessed by a sustained increase in one or more symptoms or signs of PIRA, for example, an increase that persists for at least 12 weeks (e.g., still observed at least 12 weeks after the initial observed increase) or at least 24 weeks (e.g., still observed at least 24 weeks after the initial observed increase). In some embodiments, the progression of PIRA is assessed by cCDP or CDP, for example, cCDP-12, CDP-12, cCDP24, or CDP24, or any combination thereof. In some embodiments, the progression of PIRA is assessed by cCDP12. In some embodiments, the progression of PIRA is assessed by EDSS. In some embodiments, the risk of experiencing cCDP12 is reduced, or the time to the onset of cCDP12 is extended, in conjunction with a reduction in the risk of experiencing CDP12, or in conjunction with an extension of the time to the onset of CDP12. In some embodiments, the risk of experiencing cCDP12 is reduced, or the time to the onset of cCDP12 is extended, in conjunction with a reduction in the risk of experiencing cCDP24, or in conjunction with an extension of the time to the onset of cCDP24. In further embodiments, the risk of experiencing cCDP12 is reduced, in conjunction with both a reduction in the risk of experiencing CDP12 and a reduction in the risk of experiencing cCDP24. In further embodiments, the time until the onset of cCDP12 is extended by combining the extension of the time until the onset of CDP12 and the time until the onset of cCDP24.In some embodiments, the PIRA subgroup is selected from subgroups consisting of (a) active secondary progressive multiple sclerosis (aSPMS), (b) inactive 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) inactive PIRA, (j) clinically isolated syndrome (CIS), (k) transitioning MS, or combinations 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 an AOMS.

[0179] In some embodiments described herein, the response of a subject administered with vidoflugimus, or its isotopic variants, pharmaceutically acceptable salts, or solvates, can be compared to that of another subject administered with an antibody against CD20 (e.g., an anti-CD20 antibody). As used herein, an anti-CD20 antibody may include an antibody that binds to CD20, a cell surface antigen present on pre-B lymphocytes and mature B lymphocytes. In some embodiments, the antibody is a humanized monoclonal antibody against CD20-expressing B cells. In some embodiments, binding of the anti-CD20 antibody to the cell surface of B lymphocytes can result in antibody-dependent cytolysis and complement-mediated lysis. In some embodiments, the anti-CD20 antibody is a CD20-targeted cytolytic antibody. An example of such an antibody is ocrelizumab, a recombinant humanized glycosylated monoclonal IgG1 antibody that selectively targets and depletes CD20-expressing B cells.

[0180] In the methods described herein, the compounds for use, or some embodiments of the use of the compounds, a therapeutically effective dose of vidofludimus, or its isotopic variant, pharmaceutically acceptable salt or solvate, preferably vidofludimus calcium salt dihydrate as "polymorph A," is administered to a subject having PIRA, the subject having a progressive disease from onset, and having been in a progressive stage for at least 12 months prior to the initiation of administration of vidofludimus, or its isotopic variant, pharmaceutically acceptable salt or solvate. In the methods described herein, the compounds for use, or certain embodiments of the use of the compounds, during the maintenance phase, approximately 30-45 mg of vidofludimus, or an equivalent amount thereof, an isotopic variant, a pharmaceutically acceptable salt, or a solvate, preferably vidofludimus calcium salt dihydrate as "polymorph A," is administered once daily to subjects having PIRA, the subjects having a progressive disease from onset and having been in a progressive stage for at least 12 months prior to the initiation of administration of vidofludimus, or its isotopic variant, a pharmaceutically acceptable salt, or a solvate. In some embodiments, subjects having PIRA have one or more T2-weighted lesions in one or more periventricular, cortical, paracortical, or subtentorial brain regions, two or more T2-weighted lesions in the spinal cord, or the presence of oligoclonal bands specific to the cerebrospinal fluid. In one embodiment, a subject having PIRA has at least two of the following: one or more T2-weighted lesions in one or more periventricular, cortical, or paracortical brain regions, or infratentorial brain regions; two or more T2-weighted lesions in the spinal cord; or the presence of oligoclonal bands specific to cerebrospinal fluid. In a further embodiment, a subject having PIRA has a progressive disease from onset, has been in a progressive stage for at least 12 months prior to the initiation of administration of vidofludimus or its isotope variant, pharmaceutically acceptable salt or solvate, and has at least two of the following: one or more T2-weighted lesions in one or more periventricular, cortical, or paracortical brain regions, or infratentorial brain regions; two or more T2-weighted lesions in the spinal cord; or the presence of oligoclonal bands specific to cerebrospinal fluid. T2-weighted lesions can be evaluated, for example, by MRI.The presence of oligoclonal bands specific to cerebrospinal fluid can be assessed, for example, by lumbar puncture. In further embodiments, subjects with PIRA may have an EDSS score of 3.0–6.5 prior to the initiation of administration of vidofludimus or its isotopic variant, pharmaceutically acceptable salt, or solvate. In some embodiments, subjects with PIRA are neurologically stable for at least 30 days prior to the initiation of administration of vidofludimus or its isotopic variant, pharmaceutically acceptable salt, or solvate. In some such embodiments, the method, compound for use, or use of the compound is for the treatment of PIRA, treatment of the progression of PIRA (e.g., delaying it), reduction of disability, delay of the onset of at least one progression event, reduction of the risk of having at least one progression event, increase of mobility, or extension of the time to the onset of cCDP12 in subjects having PIRA requiring it, and comprises administering to subjects in the maintenance phase a once-daily dose of approximately 30-45 mg of vidofludimus, or an equivalent amount thereof of an isotopic variant, a pharmaceutically acceptable salt or solvate, preferably vidofludimus calcium salt dihydrate as "polymorph A".

[0181] Furthermore, this specification also provides pharmaceutical compositions and formulations comprising vidofludimus, or its isotopic variants, pharmaceutically acceptable salts, or solvates, for use in the therapeutic methods described herein (e.g., treatment of PIRA, delay of PIRA progression, etc.). In some embodiments, the pharmaceutical compositions and formulations further comprise one or more pharmaceutically acceptable carriers.

[0182] Vidofludimus, or its isotopic variants, pharmaceutically acceptable salts, or solvates, preferably vidofludimus calcium salt dihydrate as "polymorph A," can be administered by any preferred means, including orally, parenterally, intrapulmonaryly, intranasally, and intrafocally when topical treatment is desired. In some embodiments, oral administration is used.

[0183] Compounds of formulas (I) to (V), or compound of formula (VI), preferably pharmaceutically acceptable salts of vidofludimus or its isotopic variants, can be used in the methods herein. As used herein, the term “pharmaceutically acceptable salt” means a salt of the active compound prepared using a relatively non-toxic acid or base, depending on the specific substituents found on the compounds described herein. If the compounds of this disclosure contain relatively acidic functionalities, a base addition salt can be obtained by contacting a neutral form of such compound with a sufficient amount of the desired base in a solvent-free manner or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese, manganese, potassium, sodium, and zinc. Examples of salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, such as substituted amines, cyclic amines, and naturally occurring amines, including arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydravamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, and tromethamine.

[0184] In some embodiments provided herein, an oral dose of a compound of formulas (I) to (V), or of formula (VI), preferably vidofludimus, or an isotopic variant thereof, a pharmaceutically acceptable salt, or a solvate, is administered in one or more tablets or capsules. For example, in some embodiments, during the maintenance phase, about 30 to 45 mg of vidofludimus calcium salt dihydrate as "polymorph A" is administered once daily as one tablet.

[0185] Further embodiments provided herein offer a product or kit comprising a compound of formulas (I) to (V), or a compound of formula (VI), preferably vidofludimus, or an isotopic variant thereof, a pharmaceutically acceptable salt, or a solvate, and a container. In some embodiments, the product or kit further includes a package insert containing instructions for using the compound of formulas (I) to (V), or a compound of formula (VI), preferably vidofludimus, or an isotopic variant thereof, a pharmaceutically acceptable salt, or a solvate. Suitable containers for the kit include, for example, bottles, boxes, blister packs, or a combination thereof (e.g., blister packs in a box). In some embodiments, the container holds the formulation, and labels on or accompanying the container may indicate instructions for use. The product or kit may further include other materials desirable from a commercial and user perspective, including a package insert containing instructions for use.

[0186] This specification is considered sufficient for those skilled in the art to carry out the invention. In addition to those shown and described herein, various modifications of the invention will be apparent to those skilled in the art from the foregoing description and are included in the appended claims. All publications, patents, and patent applications referenced herein are incorporated herein by reference in their entirety for all purposes.

[0187] IV. Medical Use of Compounds One aspect of the present disclosure relates to compounds of formulas (I) to (V), or in combination with compounds of formula (VI), for use in treating diseases caused by lower levels of Nurr1 in the central nervous system of subjects requiring such treatment.

[0188] In some embodiments, diseases caused by lower levels of Nurr1 include Alexander disease, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ataxia with 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-Streussler-Scheinker syndrome, Huntington's disease, and HIV. These include related dementias (FTD), Kennedy disease, Krabbe disease, Kuru disease, Lewy body dementia (DLB), Machado-Joseph disease (spinocerebellar degeneration type 3), multiple sclerosis, multiple system atrophy, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbach disease, Pick's disease, primary lateral sclerosis, prion diseases, progressive supranuclear palsy (PSP), Refsum disease, Sandhoff disease, Schilder's disease, subacute combined degeneration of the spinal cord secondary to pernicious anemia, schizophrenia, spinocerebellar degeneration (multiple types with various characteristics), spinal muscular atrophy, Steele-Richardson-Olshevsky disease, or spinal fistula.

[0189] In some embodiments, diseases caused by lower levels of Nurr1 include Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, schizophrenia, or drug addiction.

[0190] In some embodiments, the disease is Parkinson's disease.

[0191] In some embodiments, the disease is Alzheimer's disease.

[0192] In some embodiments, the disease is multiple sclerosis, particularly relapsing-remitting 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 inactive secondary progressive multiple sclerosis (inactive SPMS).

[0193] In some embodiments, the subjects requiring the above method for treating MS are humans, and in some embodiments, in particular, human women.

[0194] In some embodiments, the subjects requiring the above methods for treating MS belong to a group of patients with childhood-onset MS (POMS), meaning the onset of symptoms before the age of 18.

[0195] In some embodiments, the subjects requiring the above methods for treating MS belong to the group of patients with late-onset MS (LOMS), meaning onset between 19 and 50 years of age.

[0196] In some embodiments, the subjects requiring the above methods for treating MS belong to the group of patients with adult-onset MS (AOMS), meaning that the onset occurred more than 50 years ago.

[0197] The patient's age at the onset of MS appears to be a PIRA-related factor, for example. One study showed that AOMS had a hazard ratio of 1.42 compared to POMS, and LOMS had a hazard ratio of 2.98 compared to POMS (JAMA Neurol. 2024;81:50).

[0198] Other factors associated with PIRA appear to be the duration of the disease (the longer the disease duration, the higher the risk of PIRA) and the duration of DMT treatment (the shorter the duration of DMT treatment, the higher the risk of PIRA).

[0199] In some embodiments, the subjects requiring the above methods for treating MS belong to a group of patients with clinically isolated syndrome (CIS).

[0200] In some embodiments, the subjects requiring the above methods for treating MS belong to a group of patients characterized as transitioning MS patients.

[0201] In some embodiments, the subjects requiring a method for preventing and / or treating MS belong to a group of patients who are not yet diagnosed with MS, either before or around the onset of MS, or who have one or more signs of symptoms such as biomarkers and / or genetic predispositions that increase the risk score and / or signs of MS symptoms. Generally, the onset of MS means that the first demyelinating event has occurred. Since many cases, for example, so-called benign MS patients, remain undetected for many years, it may be useful to include them in the treatment according to the present invention, even during the period before detection of MS disease, if they can be determined by suitable biomarkers and genetic predispositions and have a corresponding increased risk score.

[0202] In some embodiments, the disease is progressive multiple sclerosis.

[0203] In some embodiments, the disease is primary progressive multiple sclerosis.

[0204] In some embodiments, the disease is inactive secondary progressive multiple sclerosis (inactive SPMS).

[0205] In some embodiments, the disease is active secondary progressive multiple sclerosis (active SPMS).

[0206] In some embodiments, the disease is relapsing-remitting multiple sclerosis.

[0207] In some embodiments, the disease is multiple sclerosis, and the disability is acquired through relapse-related exacerbations (RAWs).

[0208] In some embodiments, the disease is multiple sclerosis, and the disability is acquired through progression unrelated to relapsing activity (PIRA).

[0209] In some embodiments, the disease is relapsing-remitting multiple sclerosis (RRMS), and the disability is acquired through relapse-related exacerbations (RAWs).

[0210] In some embodiments, the disease is relapsing-remitting multiple sclerosis (RRMS), and the disability is acquired through progression unrelated to relapsing activity (PIRA).

[0211] In some embodiments, the disease is active secondary progressive multiple sclerosis (active SPMS), and the disability is acquired through relapse-related exacerbations (RAWs).

[0212] In some embodiments, the disease is active secondary progressive multiple sclerosis (active SPMS), and the disability is acquired through progression unrelated to relapsing activity (PIRA).

[0213] In some embodiments, the disease is primary progressive multiple sclerosis (PPMS), and the disability is acquired through progression unrelated to relapsing activity (PIRA).

[0214] In some embodiments, the disease is inactive secondary progressive multiple sclerosis (inactive SPMS), and the disability is acquired through progression unrelated to relapsing activity (PIRA).

[0215] In some embodiments, the disease is a clinically isolated syndrome (CIS).

[0216] In some embodiments, the disease is a progressive MS.

[0217] In some embodiments, the state is PIRA.

[0218] In some embodiments, the disease is amyotrophic lateral sclerosis (ALS).

[0219] In some embodiments, the disorder is schizophrenia.

[0220] In some embodiments, the disease is drug addiction.

[0221] In some embodiments, the disease caused by lower levels of Nurr1 is cancer.

[0222] In some embodiments, the compound is of formula (I)

Chemical formula

[0223] In some embodiments, the compound is of formula (I) [ka] (In the formula, Ring A has 1 to 4 residues R 1 A 5-membered or 6-membered carbocyclic or heterocyclic ring optionally substituted with, Z 1 and Z 2 These are, independently, O, S, or NR. 9 And, E is alkylene, alkenylene, alkynylene, arylene, heteroarylene, or cycloalkylene. G is O, S, SO2, NR 10 , or CH2, Y is an aryl, heteroaryl, heterocyclyl, or cycloalkyl, R 1 H, halo, -OR 13 , -SR 13 , -NR 13 R 14 These are alkyl, alkenyl, alkynyl, alkoxy, aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted. R 2 H, OR 11 , NR 11 Ure 11 , NR 11 SO2R 11 , or NR 11 R 12 And, R 3 H, halo, -OR 13 , -SR 13 , -NR 13 R14 These are alkyl, alkenyl, alkynyl, alkoxy, aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted. Each R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 These are independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted. n is either 0 or 1. q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. r is either 0 or 1. (In which one or more hydrogen atoms may be substituted with deuterium), or a pharmaceutically acceptable salt or solvate thereof.

[0224] In some embodiments, the compound is of formula (II) [ka] (In the formula, X is O, S, NR 9 , SO, or SO2, Z 2 is O, S, or NR 12 And, E is alkylene, alkenylene, alkynylene, arylene, heteroarylene, or cycloalkylene. G is O, S, SO2, NR 10 , or CH2, Y is an aryl, heteroaryl, heterocyclyl, or cycloalkyl, R 1 H, halo, -OR 13 , -SR 13 , -NR 13 R 14These are alkyl, alkenyl, alkynyl, alkoxy, aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted. Each R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 These are independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted. m is 0, 1, 2, 3, or 4. n is either 0 or 1. q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), or a pharmaceutically acceptable salt or solvate thereof.

[0225] In some embodiments, the compound is of formula (III) [ka] (In the formula, E is alkylene, alkenylene, alkynylene, arylene, heteroarylene, or cycloalkylene. Y is an aryl, heteroaryl, heterocyclyl, or cycloalkyl, R 1 H, halo, -OR 13 , -SR 13 , -NR 13 R 14 These are alkyl, alkenyl, alkynyl, alkoxy, aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted. Each R 8 , R 13 , and R 14(is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted), or a pharmaceutically acceptable salt or solvate thereof.

[0226] In some embodiments, E is an alkylene or cycloalkylene, each of which is optionally substituted with cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, 1-naphthyl, 2-naphthyl, 2-naphthyl, anthracenyl, N-imidazolyl, 2-imidazolyl, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 3-pyranyl, 4-pyranyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-pyradinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl, or 5-oxazolyl. In some embodiments, E is a condensed polycyclic arylene or a condensed polycyclic heteroarylene. In some embodiments, E is 9H-thioxanthene-10,10-dioxide.

[0227] In some embodiments, ring A is a 5-membered or 6-membered carbocyclic or heterocyclic ring. In some embodiments, ring A is partially unsaturated. In some embodiments, ring A is an aromatic ring. In some embodiments, ring A is a cyclopentenyl group having a double bond positioned as shown in formula (I). In some embodiments, ring A is 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, 2,5-dihydrothiophenyl, thiophene, or 2,5-dihydro-1H-pyrrole.

[0228] In some embodiments, the compound is of formula (IV) [ka] (In the formula, Each R A and R BThese are independently H, D, halo, -OR 13 , -SR 13 , -NR 13 R 14 These are alkyl, alkenyl, alkynyl, alkoxy, aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted. Each R 8 , R 13 , and R 14 These are independently H, D, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted. x is 0, 1, 2, 3, or 4. y is 0, 1, 2, 3, 4, or 5), or a pharmaceutically acceptable salt or solvate thereof.

[0229] In some embodiments, the compound is of formula (V) [ka] (In the formula, Ring A is, [ka] And, E is [ka] And, Y is [ka] It is (or a pharmaceutically acceptable salt or solvate thereof).

[0230] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0231] In some embodiments, the compound is [ka] Or an isotopic variant thereof, or a pharmaceutically acceptable salt or solvate thereof.

[0232] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0233] In some embodiments, the compound is [ka] or its solvate.

[0234] In some embodiments, the compound is [ka] That is the case.

[0235] In some embodiments, the compound is of formula (VI) [ka] (In the formula, R 2 , NR 11 R 12 And, R 11 It is selected from H, OH, optionally substituted alkyl, and optionally substituted cycloalkyl, wherein one or more hydrogen atoms in the alkyl or cycloalkyl are optionally substituted with deuterium. R 12 is selected from H or optionally substituted alkyl groups, where one or more hydrogen atoms in the alkyl group are optionally substituted with deuterium. Ring A is, [ka] And, E is [ka] And, Y is [ka] It is (or a pharmaceutically acceptable salt or solvate thereof).

[0236] In some embodiments, the compound is of formula (VI) [ka] (In the formula, R 2 NHR 11 And, and R 11 is selected from H or alkyl, and one or more hydrogen atoms in the alkyl group are optionally substituted with deuterium. Ring A is, [ka] And, E is [ka] And, Y is [ka] It is.

[0237] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0238] In some embodiments, each alkyl, alkenyl, alkynyl, alkoxy, aryl, cycloalkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more R', each R' independently being 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, haloalkyloxy, aryl, arylalkyl, or heteroaryl, and each R'' independently being H, D, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, heteroaryl, or aminoalkyl.

[0239] IV. Treatment method In one embodiment, a method is provided for treating a disease caused by lower levels of Nurr1 in the central nervous system of a subject requiring the treatment thereof, the method comprising administering to the subject requiring the treatment a therapeutically effective amount of a compound of formula (I) to (V) described herein, or together with a compound of formula (VI).

[0240] In one embodiment, a method is provided for treating a disease caused by lower levels of Nurr1 in the central nervous system of a subject requiring the treatment thereof, the method comprising administering to the subject requiring the treatment a therapeutically effective amount of vidofludimus or its solvate or a pharmaceutically acceptable salt thereof.

[0241] In one embodiment, a method is provided for treating a disease caused by lower levels of Nurr1 in the central nervous system of a subject requiring the treatment, the method comprising administering a therapeutically effective dose of IMU-838, for example as polymorph A, to the subject requiring the treatment.

[0242] In some embodiments, diseases caused by lower levels of Nurr1 include Alexander disease, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ataxia with 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-Streussler-Scheinker syndrome, Huntington's disease, and HIV. These include related dementias (FTD), Kennedy disease, Krabbe disease, Kuru disease, Lewy body dementia (DLB), Machado-Joseph disease (spinocerebellar degeneration type 3), multiple sclerosis, multiple system atrophy, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbach disease, Pick's disease, primary lateral sclerosis, prion diseases, progressive supranuclear palsy (PSP), Refsum disease, Sandhoff disease, Schilder's disease, subacute combined degeneration of the spinal cord secondary to pernicious anemia, schizophrenia, spinocerebellar degeneration (multiple types with various characteristics), spinal muscular atrophy, Steele-Richardson-Olshevsky disease, or spinal fistula.

[0243] In some embodiments, diseases caused by lower levels of Nurr1 include Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, schizophrenia, or drug addiction.

[0244] In some embodiments, the disease is Parkinson's disease.

[0245] In some embodiments, the disease is Alzheimer's disease.

[0246] In some embodiments, the disease is multiple sclerosis, particularly relapsing-remitting 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 inactive secondary progressive multiple sclerosis (inactive SPMS).

[0247] In some embodiments, the subjects requiring the above method for treating MS are humans, and in some embodiments, in particular, human females.

[0248] In some embodiments, the subjects requiring the above methods for treating MS belong to a group of patients with childhood-onset MS (POMS), meaning the onset of symptoms before the age of 18.

[0249] In some embodiments, the subjects requiring the above methods for treating MS belong to the group of patients with late-onset MS (LOMS), meaning onset between 19 and 50 years of age.

[0250] In some embodiments, the subjects requiring the above methods for treating MS belong to the group of patients with adult-onset MS (AOMS), meaning that the onset occurred more than 50 years ago.

[0251] The patient's age at the onset of MS appears to be a PIRA-related factor, for example. One study showed that AOMS had a hazard ratio of 1.42 compared to POMS, and LOMS had a hazard ratio of 2.98 compared to POMS (JAMA Neurol. 2024;81:50).

[0252] Other factors associated with PIRA appear to be the duration of the disease (the longer the disease duration, the higher the risk of PIRA) and the duration of DMT treatment (the shorter the duration of DMT treatment, the higher the risk of PIRA).

[0253] In some embodiments, the subjects requiring the above methods for treating MS belong to a group of patients with clinically isolated syndrome (CIS).

[0254] In some embodiments, the subjects requiring the above methods for treating MS belong to a group of patients characterized as transitioning MS patients.

[0255] In some embodiments, the subjects requiring a method for preventing and / or treating MS belong to a group of patients who are not yet diagnosed with MS, either before or around the onset of MS, or who have one or more signs of symptoms such as biomarkers and / or genetic predispositions that increase the risk score and / or signs of MS symptoms. Generally, the onset of MS means that the first demyelinating event has occurred. Since many cases, e.g., so-called benign MS patients, remain undetected for many years, it may be advantageous to include them in treatment according to the present invention, even during the period before detection of MS disease, if they can be determined by suitable biomarkers and genetic predispositions and have a corresponding increased risk score.

[0256] In some embodiments, the disease is progressive multiple sclerosis.

[0257] In some embodiments, the disease is primary progressive multiple sclerosis.

[0258] In some embodiments, the disease is inactive secondary progressive multiple sclerosis (inactive SPMS).

[0259] In some embodiments, the disease is active secondary progressive multiple sclerosis (active SPMS).

[0260] In some embodiments, the disease is relapsing-remitting multiple sclerosis.

[0261] In some embodiments, the disease is multiple sclerosis, and the disability is acquired through relapse-related exacerbations (RAWs).

[0262] In some embodiments, the disease is multiple sclerosis, and the disability is acquired through progression unrelated to relapsing activity (PIRA).

[0263] In some embodiments, the disease is relapsing-remitting multiple sclerosis (RRMS), and the disability is acquired through relapse-related exacerbations (RAWs).

[0264] In some embodiments, the disease is relapsing-remitting multiple sclerosis (RRMS), and the disability is acquired through progression unrelated to relapsing activity (PIRA).

[0265] In some embodiments, the disease is active secondary progressive multiple sclerosis (active SPMS), and the disability is acquired through relapse-related exacerbations (RAWs).

[0266] In some embodiments, the disease is active secondary progressive multiple sclerosis (active SPMS), and the disability is acquired through progression unrelated to relapsing activity (PIRA).

[0267] In some embodiments, the disease is primary progressive multiple sclerosis (PPMS), and the disability is acquired through progression unrelated to relapsing activity (PIRA).

[0268] In some embodiments, the disease is inactive secondary progressive multiple sclerosis (inactive SPMS), and the disability is acquired through progression unrelated to relapsing activity (PIRA).

[0269] In some embodiments, the disease is a clinically isolated syndrome (CIS).

[0270] In some embodiments, the disease is a progressive MS.

[0271] In some embodiments, the state is PIRA.

[0272] In some embodiments, the disease is amyotrophic lateral sclerosis (ALS).

[0273] In some embodiments, the disorder is schizophrenia.

[0274] In some embodiments, the disease is drug addiction.

[0275] In some embodiments, the disease caused by lower levels of Nurr1 is cancer.

[0276] In one embodiment, a method is provided for treating a disease in a subject requiring the treatment thereof, the method comprising administering to the subject requiring the treatment a therapeutically effective amount of a compound of formula (I) to (V) described herein, or together with a compound of formula (VI).

[0277] In some embodiments, changes in the target gene (e.g., VMAT2), target protein (e.g., Nurr1), or peptide (e.g., NFL) are evaluated after approximately 6 weeks, 12 weeks, 24 weeks, 1 month, 3 months, 6 months, and 12 months of treatment, relative to initial values ​​at the start of treatment.

[0278] In some embodiments, changes in a target gene (e.g., VMAT2), target protein (e.g., Nurr1), or peptide (e.g., NFL) are evaluated at the start of treatment in healthy individuals of the same age, sex, and / or BMI.

[0279] In one embodiment, a method is provided for regulating the level or activity of Nurr1 in a subject requiring such regulation, the method comprising administering a therapeutically effective amount of the compound described herein to the subject requiring such regulation. In some embodiments, the level or activity of Nurr1 in the subject increases by about 1.2 times, about 1.3 times, about 1.4 times, about 1.5 times, about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 15 times, about 20 times, about 25 times, about 30 times, about 35 times, about 40 times, about 45 times, about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, about 100 times, or more. In some embodiments, the level or activity of Nurr1 in the subject increases by at least 1.2 times, at least 1.3 times, at least 1.4 times, at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 15 times, at least 20 times, at least 25 times, at least 30 times, at least 35 times, at least 40 times, at least 45 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, at least 100 times, or more.

[0280] In one embodiment, a method is provided for reducing plasma NFL levels in a subject requiring such reduction, the method comprising administering to the subject requiring such reduction a therapeutically effective amount of a compound of formulas (I) to (V) described herein, or together with a compound of formula (VI). In the embodiment, 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 baseline level. In the embodiment, 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 baseline level.

[0281] In one embodiment, a method is provided for reducing serum NFL levels in a subject requiring such reduction, the method comprising administering to the subject requiring such reduction a therapeutically effective amount of a compound of formulas (I) to (V) described herein, or together with a compound of formula (VI). In the embodiment, 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 level at the start of treatment. In the embodiment, 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 level at the start of treatment.

[0282] In one embodiment, a method is provided for reducing the level of NFL in CSF in a subject requiring such reduction, the method comprising administering to the subject requiring such reduction a therapeutically effective amount of a compound of formula (I) to (V) described herein, or together with a compound of formula (VI). In embodiments, the level of NFL in CSF in the subject is reduced by about 3%, 4%, 5%, 7%, 10%, 12%, 15%, 20%, 30%, 40%, 50%, or more, compared to the level at the start of treatment. In embodiments, the level of NFL in CSF in the subject is reduced by at least 3%, 4%, 5%, 7%, 10%, 12%, 15%, 20%, 30%, 40%, 50%, or more, compared to the level at the start of treatment.

[0283] In one embodiment, a method is provided for reducing elevated levels of NFL in plasma in a subject requiring such reduction, the method comprising administering to the subject requiring such reduction a therapeutically effective amount of a compound of formula (I) to (V) described herein, or together with a compound of formula (VI). In embodiments, the level of NFL in plasma in the subject is reduced by about 3%, 4%, 5%, 7%, 10%, 12%, 15%, 20%, 30%, 40%, 50%, or more, toward the level of a healthy person of the same age, sex, and / or BMI. In embodiments, the level of NFL in plasma in the subject is reduced by at least 3%, 4%, 5%, 7%, 10%, 12%, 15%, 20%, 30%, 40%, 50%, or more, toward the level of a healthy person of the same age, sex, and / or BMI.

[0284] In one embodiment, a method is provided for reducing elevated levels of serum NFL in a subject in need thereof, the method comprising administering to the subject in need a therapeutically effective amount of a compound of formula (I) to (V) described herein, or together with a compound of formula (VI). In embodiments, the serum NFL level in the subject is reduced by about 3%, 4%, 5%, 7%, 10%, 12%, 15%, 20%, 30%, 40%, 50%, or more, toward the level of a healthy person of the same age, sex, and / or BMI. In embodiments, the serum NFL level in the subject is reduced by at least 3%, 4%, 5%, 7%, 10%, 12%, 15%, 20%, 30%, 40%, 50%, or more, toward the level of a healthy person of the same age, sex, and / or BMI.

[0285] In one embodiment, a method is provided for reducing elevated levels of NFL in CSF. In one embodiment, a method is provided for reducing levels of NFL in plasma in a subject requiring such reduction, the method comprising administering a therapeutically effective amount of the compound described herein to the subject requiring such reduction. In some embodiments, the levels of NFL in plasma 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 level at the start of treatment. In some embodiments, the levels of NFL in plasma 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 level at the start of treatment.

[0286] In one embodiment, a method is provided for reducing serum NFL levels in a subject requiring such reduction, the method comprising administering a therapeutically effective amount of the compound described herein to the subject requiring such reduction. In some embodiments, 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 level at the start of treatment. In some embodiments, 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 level at the start of treatment.

[0287] In one embodiment, a method is provided for reducing the level of NFL in CSF in a subject requiring such reduction, the method comprising administering a therapeutically effective amount of the compound described herein to the subject requiring such reduction. In some embodiments, the level of NFL in CSF in the subject is 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 level at the start of treatment. In some embodiments, the level of NFL in CSF in the subject is 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 level at the start of treatment.

[0288] In one embodiment, a method is provided for reducing elevated levels of NFL in plasma in a subject requiring the same, the method comprising administering a therapeutically effective amount of the compound described herein to the subject requiring the same. In some embodiments, the level of NFL in plasma in the subject is 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, towards the level of a healthy person of the same age, biological sex, and / or BMI. In some embodiments, the level of NFL in plasma in the subject is 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, towards the level of a healthy person of the same age, sex, and / or BMI.

[0289] In one embodiment, a method is provided for reducing elevated levels of serum NFL in a subject in need thereof, the method comprising administering a therapeutically effective amount of the compound described herein to the subject in need thereof. In some embodiments, the level of serum NFL in the subject is 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, towards the level of a healthy person of the same age, biological sex, and / or BMI. In some embodiments, the level of serum NFL in the subject is 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, towards the level of a healthy person of the same age, sex, and / or BMI.

[0290] In one embodiment, a method is provided for reducing an elevated level of NFL in CSF in a subject in need thereof, the method comprising administering a therapeutically effective amount of the compound described herein to the subject in need thereof. In some embodiments, the level of NFL in CSF in the subject is 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, towards the level of a healthy person of the same age, sex, and / or BMI. In some embodiments, the level of NFL in CSF in the subject is 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, towards the level of a healthy person of the same age, sex, and / or BMI.

[0291] In one embodiment, a method is provided for increasing the level or activity of Pitx3 in a subject requiring such action, the method comprising administering a therapeutically effective amount of the compound described herein to the subject requiring such action. In some embodiments, the level or activity of Pitx3 in the subject is increased by about 1.2 times, about 1.3 times, about 1.4 times, about 1.5 times, about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 15 times, about 20 times, about 25 times, about 30 times, about 35 times, about 40 times, about 45 times, about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, about 100 times, or more. In some embodiments, the level or activity of Pitx3 in the subject increases by at least 1.2 times, at least 1.3 times, at least 1.4 times, at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 15 times, at least 20 times, at least 25 times, at least 30 times, at least 35 times, at least 40 times, at least 45 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, at least 100 times, or more.

[0292] In one embodiment, a method is provided for increasing the level or activity of VMAT2 in a subject requiring such action, the method comprising administering a therapeutically effective amount of the compound described herein to the subject requiring such action. In some embodiments, the level or activity of VMAT2 in the subject is increased by about 1.2 times, about 1.3 times, about 1.4 times, about 1.5 times, about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 15 times, about 20 times, about 25 times, about 30 times, about 35 times, about 40 times, about 45 times, about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, about 100 times, or more. In some embodiments, the level or activity of VMAT2 in the subject increases by at least 1.2 times, at least 1.3 times, at least 1.4 times, at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 15 times, at least 20 times, at least 25 times, at least 30 times, at least 35 times, at least 40 times, at least 45 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, at least 100 times, or more.

[0293] In one embodiment, a method is provided for increasing the level or activity of AADC in a subject requiring it, the method comprising administering a therapeutically effective amount of the compound described herein to the subject requiring it. In some embodiments, the level or activity of AADC in the subject increases by about 1.2 times, about 1.3 times, about 1.4 times, about 1.5 times, about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 15 times, about 20 times, about 25 times, about 30 times, about 35 times, about 40 times, about 45 times, about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, about 100 times, or more. In some embodiments, the level or activity of AADC in the subject increases by at least 1.2 times, at least 1.3 times, at least 1.4 times, at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 15 times, at least 20 times, at least 25 times, at least 30 times, at least 35 times, at least 40 times, at least 45 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, at least 100 times, or more.

[0294] In one embodiment, a method is provided for increasing the level or activity of DAT in a subject requiring it, the method comprising administering a therapeutically effective amount of the compound described herein to the subject requiring it. In some embodiments, the level or activity of DAT in the subject is increased by about 1.2 times, about 1.3 times, about 1.4 times, about 1.5 times, about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 15 times, about 20 times, about 25 times, about 30 times, about 35 times, about 40 times, about 45 times, about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, about 100 times, or more. In some embodiments, the level or activity of DAT in the subject increases by at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, or more.

[0295] In one embodiment, a method is provided for increasing the level or activity of BDNF in a subject requiring it, the method comprising administering a therapeutically effective amount of the compound described herein to the subject requiring it. In some embodiments, the level or activity of BDNF in the subject increases by about 1.2 times, about 1.3 times, about 1.4 times, about 1.5 times, about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 15 times, about 20 times, about 25 times, about 30 times, about 35 times, about 40 times, about 45 times, about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, about 100 times, or more. In some embodiments, the level or activity of BDNF in the subject increases by at least 1.2 times, at least 1.3 times, at least 1.4 times, at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 15 times, at least 20 times, at least 25 times, at least 30 times, at least 35 times, at least 40 times, at least 45 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, at least 100 times, or more.

[0296] In one embodiment, a method is provided for increasing the level or activity of GDNF in a subject requiring such increase, the method comprising administering a therapeutically effective amount of the compound described herein to the subject requiring such increase. In some embodiments, the level or activity of GDNF in the subject increases by about 1.2 times, about 1.3 times, about 1.4 times, about 1.5 times, about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 15 times, about 20 times, about 25 times, about 30 times, about 35 times, about 40 times, about 45 times, about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, about 100 times, or more. In some embodiments, the level or activity of GDNF in the subject increases by at least 1.2 times, at least 1.3 times, at least 1.4 times, at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 15 times, at least 20 times, at least 25 times, at least 30 times, at least 35 times, at least 40 times, at least 45 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, at least 100 times, or more.

[0297] In one embodiment, a method is provided for increasing the level or activity of the GDNF receptor C-RET in a subject requiring such action, the method comprising administering a therapeutically effective amount of the compound described herein to the subject requiring such action. In some embodiments, the level or activity of the GDNF receptor C-RET in the subject increases by about 1.2 times, about 1.3 times, about 1.4 times, about 1.5 times, about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 15 times, about 20 times, about 25 times, about 30 times, about 35 times, about 40 times, about 45 times, about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, about 100 times, or more. In some embodiments, the level or activity of the GDNF receptor C-RET in the subject increases by at least 1.2 times, at least 1.3 times, at least 1.4 times, at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 15 times, at least 20 times, at least 25 times, at least 30 times, at least 35 times, at least 40 times, at least 45 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, at least 100 times, or more.

[0298] In one embodiment, a method is provided for increasing the level or activity of GFAP in a subject requiring it, the method comprising administering a therapeutically effective amount of the compound described herein to the subject requiring it. In some embodiments, the level or activity of GFAP in the subject is increased by about 1.2 times, about 1.3 times, about 1.4 times, about 1.5 times, about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 15 times, about 20 times, about 25 times, about 30 times, about 35 times, about 40 times, about 45 times, about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, about 100 times, or more. In some embodiments, the level or activity of GFAP in the subject increases by at least 1.2 times, at least 1.3 times, at least 1.4 times, at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 15 times, at least 20 times, at least 25 times, at least 30 times, at least 35 times, at least 40 times, at least 45 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, at least 100 times, or more.

[0299] In one embodiment, a method is provided for increasing the level or activity of tyrosine hydroxylase (TH) in a subject requiring such action, the method comprising administering a therapeutically effective amount of the compound described herein to the subject requiring such action. In some embodiments, the level or activity of TH in the subject increases by about 1.2 times, about 1.3 times, about 1.4 times, about 1.5 times, about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 15 times, about 20 times, about 25 times, about 30 times, about 35 times, about 40 times, about 45 times, about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, about 100 times, or more. In some embodiments, the level or activity of TH in the subject increases by at least 1.2 times, at least 1.3 times, at least 1.4 times, at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 15 times, at least 20 times, at least 25 times, at least 30 times, at least 35 times, at least 40 times, at least 45 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, at least 100 times, or more.

[0300] In one embodiment, a method is provided for increasing the level or activity of SOD in a subject requiring such action, the method comprising administering a therapeutically effective amount of the compound described herein to the subject requiring such action. In some embodiments, the level or activity of SOD in the subject increases by about 1.2 times, about 1.3 times, about 1.4 times, about 1.5 times, about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 15 times, about 20 times, about 25 times, about 30 times, about 35 times, about 40 times, about 45 times, about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, about 100 times, or more. In some embodiments, the level or activity of SOD in the subject increases by at least 1.2 times, at least 1.3 times, at least 1.4 times, at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 15 times, at least 20 times, at least 25 times, at least 30 times, at least 35 times, at least 40 times, at least 45 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, at least 100 times, or more.

[0301] In one embodiment, a method is provided for reducing the level or activity of TNFα in a subject in need thereof, the method comprising administering a therapeutically effective amount of the compound described herein to the subject in need thereof. In some embodiments, the level or activity of TNFα in the subject is reduced by about 1.2 times, about 1.3 times, about 1.4 times, about 1.5 times, about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 15 times, about 20 times, about 25 times, about 30 times, about 35 times, about 40 times, about 45 times, about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, about 100 times, or more. In some embodiments, the level or activity of TNFα in the subject decreases by at least 1.2 times, at least 1.3 times, at least 1.4 times, at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 15 times, at least 20 times, at least 25 times, at least 30 times, at least 35 times, at least 40 times, at least 45 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, at least 100 times, or more.

[0302] In one embodiment, a method is provided for reducing the level or activity of iNOS in a subject requiring such reduction, the method comprising administering a therapeutically effective amount of the compound described herein to the subject requiring such reduction. In some embodiments, the level or activity of iNOS in the subject is reduced by about 1.2 times, about 1.3 times, about 1.4 times, about 1.5 times, about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 15 times, about 20 times, about 25 times, about 30 times, about 35 times, about 40 times, about 45 times, about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, about 100 times, or more. In some embodiments, the level or activity of iNOS in the subject decreases by at least 1.2 times, at least 1.3 times, at least 1.4 times, at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 15 times, at least 20 times, at least 25 times, at least 30 times, at least 35 times, at least 40 times, at least 45 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, at least 100 times, or more.

[0303] In one embodiment, a method is provided for reducing the level or activity of IL-1β in a subject requiring such reduction, the method comprising administering a therapeutically effective amount of the compound described herein to the subject requiring such reduction. In some embodiments, the level or activity of IL-1β in the subject is reduced by about 1.2 times, about 1.3 times, about 1.4 times, about 1.5 times, about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 15 times, about 20 times, about 25 times, about 30 times, about 35 times, about 40 times, about 45 times, about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, about 100 times, or more. In some embodiments, the level or activity of IL-1β in the subject decreases by at least 1.2 times, at least 1.3 times, at least 1.4 times, at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 15 times, at least 20 times, at least 25 times, at least 30 times, at least 35 times, at least 40 times, at least 45 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, at least 100 times, or more.

[0304] In some embodiments, the method comprises increasing the level of dopamine in a subject requiring it, and the method comprises administering a therapeutically effective amount of the compound described herein to the subject requiring it. In some embodiments, the level of dopamine in the subject increases by about 1.2 times, about 1.3 times, about 1.4 times, about 1.5 times, about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 15 times, about 20 times, about 25 times, about 30 times, about 35 times, about 40 times, about 45 times, about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, about 100 times, or more. In some embodiments, the level or activity of dopamine in the subject increases by at least 1.2 times, at least 1.3 times, at least 1.4 times, at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 15 times, at least 20 times, at least 25 times, at least 30 times, at least 35 times, at least 40 times, at least 45 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, at least 100 times, or more.

[0305] In some embodiments, the method involves increasing the development of dopaminergic neurons using the compounds described herein compared to a control (e.g., in the absence of the compounds). In some embodiments, the level of dopaminergic neuron development increases by about 1.2 times, about 1.3 times, about 1.4 times, about 1.5 times, about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 15 times, about 20 times, about 25 times, about 30 times, about 35 times, about 40 times, about 45 times, about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, about 100 times, or more. In some embodiments, the level of dopaminergic neuron development in the subject increases by at least 1.2 times, at least 1.3 times, at least 1.4 times, at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 15 times, at least 20 times, at least 25 times, at least 30 times, at least 35 times, at least 40 times, at least 45 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, at least 100 times, or more.

[0306] In some embodiments, the method includes improving the maintenance of dopaminergic neurons using the compounds described herein compared to a control (e.g., the absence of the compounds). In some embodiments, the level of maintenance of dopaminergic neurons is improved by about 1.2 times, about 1.3 times, about 1.4 times, about 1.5 times, about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 15 times, about 20 times, about 25 times, about 30 times, about 35 times, about 40 times, about 45 times, about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, about 100 times, or more. In some embodiments, the maintenance level of dopaminergic neurons in the subject is improved by at least 1.2 times, at least 1.3 times, at least 1.4 times, at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 15 times, at least 20 times, at least 25 times, at least 30 times, at least 35 times, at least 40 times, at least 45 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, at least 100 times, or more.

[0307] In some embodiments, the method includes improving the survival of dopaminergic neurons using the compounds described herein compared to a control (e.g., the absence of the compounds). In some embodiments, the level of survival of dopaminergic neurons is improved by about 1.2 times, about 1.3 times, about 1.4 times, about 1.5 times, about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 15 times, about 20 times, about 25 times, about 30 times, about 35 times, about 40 times, about 45 times, about 50 times, about 60 times, about 70 times, about 80 times, about 90 times, about 100 times, or more. In some embodiments, the level of survival of dopaminergic neurons in the subject is improved by at least 1.2 times, at least 1.3 times, at least 1.4 times, at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 15 times, at least 20 times, at least 25 times, at least 30 times, at least 35 times, at least 40 times, at least 45 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, at least 100 times, or more.

[0308] In embodiments, the method includes stabilizing a Nurr1 monomer using compounds of formulas (I) to (V) described herein, or using a compound of formula (VI). In embodiments, the method includes stabilizing a Nurr1 homodimer using compounds of formulas (I) to (V) described herein, or using a compound of formula (VI). In embodiments, the method includes stabilizing a head-to-tail Nurr1 homodimer using compounds of formulas (I) to (V) described herein, or using a compound of formula (VI). In embodiments, the method includes stabilizing a Nurr1 heterodimer using compounds of formulas (I) to (V) described herein, or using a compound of formula (VI). In embodiments, the Nurr1 heterodimer is a heterodimer with RXRα.

[0309] In embodiments, the method includes contacting a Nurr1 monomer with a compound of formulas (I) to (V) described herein, or with a compound of formula (VI). In embodiments, the method includes contacting a Nurr1 homodimer with a compound of formulas (I) to (V) described herein, or with a compound of formula (VI). In embodiments, the method includes contacting a head-to-tail Nurr1 homodimer with a compound of formulas (I) to (V) described herein, or with a compound of formula (VI). In embodiments, the method includes contacting a Nurr1 heterodimer with a compound of formulas (I) to (V) described herein, or with a compound of formula (VI). In embodiments, the Nurr1 heterodimer is a heterodimer with RXRα.

[0310] In embodiments, the method includes bonding a Nurr1 monomer with a compound of formulas (I) to (V) described herein, or with a compound of formula (VI). In embodiments, the method includes bonding a Nurr1 homodimer with a compound of formulas (I) to (V) described herein, or with a compound of formula (VI). In embodiments, the method includes bonding a head-to-tail Nurr1 homodimer with a compound of formulas (I) to (V) described herein, or with a compound of formula (VI). In embodiments, the method includes bonding a Nurr1 heterodimer with a compound of formulas (I) to (V) described herein, or with a compound of formula (VI). In embodiments, the Nurr1 heterodimer is a heterodimer with RXRα.

[0311] In the embodiments, the method includes preventing the formation of a Nurr1:RXR heterodimer using compounds of formulas (I) to (V) described herein, or using a compound of formula (VI).

[0312] In embodiments, the method includes binding Nurr1 and inducing binding of Nurr1 to an NBRE, NuRE, or DR-5 response element. In embodiments, the method includes binding Nurr1 and inducing binding of Nurr1 to an NBRE. In embodiments, the method includes binding Nurr1 and inducing binding of Nurr1 to a NuRE. In embodiments, the method includes binding Nurr1 and inducing binding of Nurr1 to a DR-5 response element.

[0313] In the embodiments, the compounds of formulas (I) to (V), or together with the compound of formula (VI), stabilize the Nurr1 monomer. In the embodiments, the compounds of formulas (I) to (V), or together with the compound of formula (VI), stabilize the Nurr1 homodimer. In the embodiments, the compounds of formulas (I) to (V), or together with the compound of formula (VI), stabilize the head-to-tail Nurr1 homodimer. In the embodiments, the compounds of formulas (I) to (V), or together with the compound of formula (VI), stabilize the Nurr1 heterodimer. In the embodiments, the Nurr1 heterodimer is a heterodimer with RXRα.

[0314] In the embodiment, the compounds of formulas (I) to (V), or together with the compound of formula (VI), stabilize the Nurr1 monomer compared to a control (e.g., no compound present). In the embodiment, the compounds of formulas (I) to (V), or together with the compound of formula (VI), stabilize the Nurr1 homodimer compared to a control (e.g., no compound present). In the embodiment, the compounds of formulas (I) to (V), or together with the compound of formula (VI), stabilize the head-to-tail Nurr1 homodimer compared to a control (e.g., no compound present). In the embodiment, the compounds of formulas (I) to (V), or together with the compound of formula (VI), stabilize the Nurr1 heterodimer compared to a control (e.g., no compound present). In the embodiment, the Nurr1 heterodimer is a heterodimer with RXRα.

[0315] In the embodiment, the compounds of formulas (I) to (V), or together with the compound of formula (VI), are contacted with the Nurr1 monomer. In the embodiment, the compounds of formulas (I) to (V), or together with the compound of formula (VI), are contacted with the Nurr1 homodimer. In the embodiment, the compounds of formulas (I) to (V), or together with the compound of formula (VI), are contacted with the head-to-tail Nurr1 homodimer. In the embodiment, the compounds of formulas (I) to (V), or together with the compound of formula (VI), are contacted with the Nurr1 heterodimer. In the embodiment, the Nurr1 heterodimer is a heterodimer with RXRα.

[0316] In the embodiment, the compounds of formulas (I) to (V) are bonded to the Nurr1 monomer, or together with the compound of formula (VI). In the embodiment, the compounds of formulas (I) to (V) are bonded to the Nurr1 homodimer, or together with the compound of formula (VI). In the embodiment, the compounds of formulas (I) to (V) are bonded to the head-to-tail Nurr1 homodimer, or together with the compound of formula (VI). In the embodiment, the compounds of formulas (I) to (V) are bonded to the Nurr1 heterodimer, or together with the compound of formula (VI). In the embodiment, the Nurr1 heterodimer is a heterodimer with RXRα.

[0317] In the embodiment, the compounds of formulas (I) to (V), or together with the compound of formula (VI), prevent the formation of the Nurr1:RXR heterodimer. In the embodiment, the compounds of formulas (I) to (V), or together with the compound of formula (VI), inhibit the formation of the Nurr1:RXR heterodimer. In the embodiment, the compounds of formulas (I) to (V), or together with the compound of formula (VI), bind to Nurr1, and the resulting compound:Nurr1 complex inhibits binding to RXR.

[0318] In the embodiments, the compounds of formulas (I) to (V), or together with the compound of formula (VI), act as agonists for the Nurr1 monomer. In the embodiments, the compounds of formulas (I) to (V), or together with the compound of formula (VI), act as agonists for the Nurr1 homodimer. In the embodiments, the compounds of formulas (I) to (V), or together with the compound of formula (VI), act as agonists for the head-to-tail Nurr1 homodimer. In the embodiments, the compounds of formulas (I) to (V), or together with the compound of formula (VI), act as agonists for the Nurr1 heterodimer. In the embodiments, the Nurr1 heterodimer is a heterodimer with RXRα.

[0319] In the embodiment, the compounds of formulas (I) to (V), or together with the compound of formula (VI), bind to Nurr1 and induce the binding of Nurr1 to NBRE, NuRE, or the DR-5 response element. In the embodiment, the compounds of formulas (I) to (V), or together with the compound of formula (VI), bind to Nurr1 and induce the binding of Nurr1 to NBRE. In the embodiment, the compounds of formulas (I) to (V), or together with the compound of formula (VI), bind to Nurr1 and induce the binding of Nurr1 to NuRE. In the embodiment, the compounds of formulas (I) to (V), or together with the compound of formula (VI), bind to Nurr1 and induce the binding of Nurr1 to the DR-5 response element.

[0320] In embodiments, lower levels of Nurr1 impair the function or activity of Nurr1. In embodiments, lower levels of Nurr1 can be restored by applying compounds of formulas (I) to (V), or together with the compound of formula (VI). In embodiments, compounds of formulas (I) to (V), or together with the compound of formula (VI), act as Nurr1 agonists.

[0321] V. Pharmaceutical Compositions In some embodiments, pharmaceutical compositions are provided that include a compound of formula (I) to (V) described herein, or a compound of formula (VI), together with a pharmaceutically acceptable additive.

[0322] In some embodiments, the pharmaceutical composition contains a therapeutically effective amount of a compound of formula (I) to (V), or a compound of formula (VI).

[0323] In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a second agent, the second agent being 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 agent, such as levodopa, carbidopa, selegiline, amantadine, donepezil, galantamine, rivastigmine, tacrine, bromocriptine, pergolide, pramipexole, ropinirole, trihexyphenidyl, benztropine, biperiden, procyclidine, tolcapone, or entacapone. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a second agent.

[0324] In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a second agent, the second agent being an agent for treating inflammatory diseases, such as acetaminophen, duloxetine, aspirin, ibuprofen, naproxen, diclofenac, prednisone, beta-methasone, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, codeine, fentanyl, hydrocodone, hydromorphone, morphine, meperidine, or oxycodone. In embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a second agent.

[0325] In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a second agent, the second agent being an anticancer agent.

[0326] VI. Medication and Treatment Period In some embodiments, the present invention provides a method for treating a subject, for example, a human patient in need thereof, the method comprising administering to the subject, particularly the compounds of formulas (I) to (V), or together with the compound of formula (VI), and / or their pharmaceutically acceptable salts and / or solvates, particularly hydrates, or solvates of their pharmaceutically acceptable salts, particularly hydrates, to the subject in a daily dose of about 12 to 120 μmol, for example, about 12.3 μmol to about 38.2 μmol, about 76.5 μmol, or about 115 μmol, particularly orally, for example, the daily dose may be about 12.3 μmol to about 38.2 μmol, about 25.5 μmol, or about 26.5 μmol.

[0327] In some embodiments, the present invention provides a method for treating a human patient in need, the method comprising orally administering to a human patient about 12 to 120 μmol of vidofludimus and / or a pharmaceutically acceptable salt or solvate thereof, especially a hydrate, and / or a pharmaceutically acceptable salt thereof, especially a hydrate, to the human patient in a daily dose of about 12 to 120 μmol of vidofludimus and / or a pharmaceutically acceptable salt or solvate thereof, especially a hydrate, or a pharmaceutically acceptable salt thereof, especially a hydrate, preferably about 12.3 μmol to about 38.2 μmol, about 76.5 μmol, or about 115 μmol, more preferably about 12.3 μmol to about 38.2 μmol, and most preferably about 26.5 μmol.

[0328] In some embodiments, the present invention provides a method for treating a human patient in need, the method comprising orally administering to a human patient about 115 μmol of vidofludimus, or a pharmaceutically acceptable salt or solvate thereof, particularly a hydrate, and / or a pharmaceutically acceptable salt thereof, particularly a hydrate, to the human patient in a daily dose of about 115 μmol of vidofludimus, or a pharmaceutically acceptable salt or solvate thereof, particularly a hydrate, or a pharmaceutically acceptable salt thereof, particularly a hydrate, to the human patient.

[0329] In some embodiments, the present invention provides a method for treating a human patient in need, the method comprising orally administering to a human patient about 76.5 μmol of vidofludimus, or a pharmaceutically acceptable salt or solvate thereof, particularly a hydrate, and / or a pharmaceutically acceptable salt thereof, particularly a hydrate, to the human patient in a daily dose of about 76.5 μmol of vidofludimus, or a pharmaceutically acceptable salt or solvate thereof, particularly a hydrate, or a pharmaceutically acceptable salt thereof, particularly a hydrate, to the human patient.

[0330] In some embodiments, the present invention provides a method for treating a human patient in need, the method comprising orally administering to a human patient about 12 to 38 μmol of vidofludimus, or a pharmaceutically acceptable salt or solvate thereof, particularly a hydrate, and / or a pharmaceutically acceptable salt thereof, particularly a hydrate, to a human patient in a daily dose of about 12 to 38 μmol of vidofludimus, or a pharmaceutically acceptable salt or solvate thereof, particularly a hydrate, or a pharmaceutically acceptable salt thereof, particularly a hydrate, to the human patient.

[0331] In some embodiments, the present invention provides a method for treating a human patient in need, the method comprising orally administering to a human patient about 25.5 μmol of vidofludimus, or a pharmaceutically acceptable salt or solvate thereof, particularly hydrate, and / or a pharmaceutically acceptable salt thereof, particularly hydrate, to the human patient in a daily dose of about 25.5 μmol of vidofludimus, or a pharmaceutically acceptable salt or solvate thereof, particularly hydrate, or a pharmaceutically acceptable salt thereof, particularly hydrate, to the human patient.

[0332] In the table below, μmol of the active moiety of vidofludimus is converted to mg of the free acid (i.e., active moiety) of vidofludimus and the calcium salt dihydrate of vidofludimus. [Table 1]

[0333] The daily dose in the following embodiments is based on the active portion, i.e., the free acid of Vidofludimus.

[0334] In some embodiments, the present invention relates to a method for treating a subject, for example, a human patient in need thereof, wherein the method uses a polymorph A of a vidofludimus calcium salt dihydrate having the following structure: [ka]

[0335] The present invention provides a method involving oral administration to a subject in doses ranging from approximately 5 mg to approximately 45 mg, for example, doses ranging from approximately 5 mg to approximately 15 mg, approximately 30 mg, or approximately 45 mg, approximately 5 mg to approximately 15 mg, approximately 45 mg, or approximately 10 mg. In some embodiments, administration is daily.

[0336] In some embodiments, the present invention provides a method for treating a subject, for example, a human patient in need thereof, wherein the method uses a vidofludimus calcium salt dihydrate having the following structure as "polymorph A", [ka]

[0337] This includes oral administration to human patients at a daily dose of approximately 10 mg.

[0338] In some embodiments, the present invention provides a method for treating a human patient in need, wherein the method uses a vidofludimus calcium salt dihydrate having the following structure as "polymorph A", [ka]

[0339] This includes oral administration to human patients in the form of tablets or capsules at a daily dose of approximately 45 mg.

[0340] In some embodiments, the present invention provides a method for treating a human patient in need, wherein the method uses a vidofludimus calcium salt dihydrate having the following structure as "polymorph A", [ka]

[0341] This includes oral administration to human patients in the form of tablets or capsules at a daily dose of approximately 30 mg.

[0342] In some embodiments, the administration is daily.

[0343] In some embodiments, the present invention provides a method for treating a human patient in need, wherein the method uses a vidofludimus calcium salt dihydrate having the following structure as "polymorph A", [ka]

[0344] The treatment involves orally administering approximately 15 mg per day in tablet or capsule form to human patients during the first week of treatment.

[0345] In some embodiments, the present invention provides a method for treating a human patient in need, wherein the method uses a vidofludimus calcium salt dihydrate having the following structure as "polymorph A", [ka]

[0346] This includes orally administering the drug to human patients in tablet or capsule form at a daily dose of approximately 22.5 mg during the first week of treatment.

[0347] VIII.Definitions In various parts of this specification, substituents of the compounds of this disclosure are disclosed in groups or ranges. This disclosure is specifically intended to include any individual partial combination of members of such groups and ranges. The following is a non-limiting list of definitions of terms.

[0348] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art in which this invention pertains.

[0349] The term "level or activity" refers to the expression level of either the mRNA or protein of each target, or the activity resulting from the expression level of either the mRNA or protein regulated by each target. Activity can also be measured for specific target genes and proteins by PET scan or SPECT. In the case of dopamine or its metabolites, "activity" means an increase or decrease in each molecule.

[0350] The terms “effective dose” or “therapeutic effective dose” refer to the amount of the compound or pharmaceutical composition described herein that is sufficient to affect the intended application, including but not limited to the treatment of a disease or the outcome of a biomarker / target gene, as illustrated below. The therapeutic effective dose may vary depending on the intended application, or the subject being treated and the state of the disease, e.g., body weight (e.g., assessed by body mass index (BMI)), age and / or sex, the severity of the disease state, the mode of administration, the response to the biomarker or Nurr1 target gene, etc., which can be readily determined by those skilled in the art. The specific dose will vary, for example, depending on the particular compound selected, the administration regimen to be followed, whether it is administered in combination with other drugs, the timing of administration, the duration of treatment, the tissue to which it is administered, and the body's delivery system through which it is carried.

[0351] As used herein, the term “subject” 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., rodents, mice, rats, rabbits, monkeys, dogs, cats, sheep, cattle, primates, or pigs). In some embodiments, subjects may be mammals, birds, reptiles, amphibians, fish, or worms. In some embodiments, subjects may be transgenic animals, genetically modified animals, or clones.

[0352] In some embodiments, the subject may be any member of the animal kingdom. The subject may be, for example, humans, non-human primates such as chimpanzees, and other apes and monkey species, livestock such as cattle, horses, sheep, goats, and pigs, domesticated animals such as rabbits, dogs, and cats, and laboratory animals such as rats, mice, and guinea pigs. The subject may be of any age. The subject may be, for example, the elderly, adults, adolescents, pre-adolescents, children, infants, or newborns. In some embodiments, the subject is a patient.

[0353] The target age groups are, for example, approximately 1-5 years old, approximately 5-10 years old, approximately 10-15 years old, approximately 15-20 years old, approximately 20-25 years old, approximately 25-30 years old, approximately 30-35 years old, approximately 35-40 years old, approximately 40-45 years old, approximately 45-50 years old, approximately 50-55 years old, approximately 55-60 years old, approximately 60-65 years old, approximately 65-70 years old, approximately 70-75 years old, approximately 75-80 years old, and approximately It may also be a specific age such as 80-85 years old, 85-90 years old, 90-95 years old, 95-100 years old, 1-8 years old, 1-10 years old, 1-12 years old, 1-14 years old, 1-16 years old, 1-18 years old, 1-20 years old, 20-40 years old, 20-60 years old, 20-80 years old, 20-100 years old, 40-80 years old, or 60-80 years old.

[0354] In some embodiments, the subjects are 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 subjects are about 1 year old or younger, about 5 years old or younger, about 10 years old or younger, about 12 years old or younger, about 14 years old or younger, about 16 years old or younger, about 18 years old or younger, about 20 years old or younger, about 25 years old or younger, about 30 years old or younger, about 40 years old or younger, about 50 years old or younger, about 60 years old or younger, about 70 years old or younger, or about 80 years old or younger.

[0355] In some embodiments, the subjects requiring the above methods for treating MS belong to a group of patients with childhood-onset MS (POMS), meaning the onset of symptoms before the age of 18.

[0356] In some embodiments, the subjects requiring the above methods for treating MS belong to the group of patients with late-onset MS (LOMS), meaning onset between 19 and 50 years of age.

[0357] In some embodiments, the subjects requiring the above methods for treating MS belong to the group of patients with adult-onset MS (AOMS), meaning that the onset occurred more than 50 years ago.

[0358] For example, the target is approximately 15 kg / m 2 ~about 18kg / m 2 , about 15kg / m 2 ~Approx. 18.5kg / m 2 , about 18.5kg / m 2 ~Approx. 24.9kg / m 2 , about 25kg / m 2 ~Approx. 29.9kg / m 2 , or approximately 30 kg / m 2 ~about 40kg / m 2 They may have specific body mass index (BMI) values ​​such as those mentioned above. In some embodiments, the subject may have at least about 15 kg / m². 2 at least approximately 18.5 kg / m 2, or at least about 25 kg / m 2 It has a BMI of approximately 25 kg / m². In some embodiments, the subject is approximately 25 kg / m². 2 Below, approximately 30kg / m 2 The following, or approximately 40 kg / m 2 The following BMI is present.

[0359] Terms such as "agonist," "activator," and "upregulator" refer to substances that can detectably increase the expression or activity of a given gene or protein. An 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 some cases, the expression or activity may be 1.2 times, 1.3 times, 1.4 times, 1.5 times, 2 times, 3 times, 4 times, 5 times, 10 times, or more than the expression or activity in the absence of the agonist.

[0360] The term "modulator" refers to a composition that increases or decreases the level of a target molecule, the function of a target molecule, or the physical state of a molecular target (for example, the target may be a cellular component (e.g., a 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)) compared to the absence of the composition.

[0361] The term "expression" includes, but is not limited to, any steps involved in the production of a polypeptide, including transcription, post-transcriptional modification, translation, post-translational modification, and secretion. Expression can be detected using conventional techniques for detecting proteins (e.g., ELISA, Western blotting, flow cytometry, immunofluorescence, immunohistochemistry, etc.).

[0362] The term "modulate" is used according to its obvious and ordinary meaning, referring to the act of altering or diversifying one or more properties. "Modification" is the process of altering or diversifying one or more properties. For example, when applied to the effect of a modulator on a target protein, modulation means altering the properties or function of the target molecule or the amount of the target molecule by increasing or decreasing it. For example, when applied to the effect of a modulator on a target gene, modulation means altering the gene expression or the gene activity by increasing or decreasing it.

[0363] As used herein, the term “abnormal” means different from normal. When used to describe enzyme activity, abnormal means activity that is greater or less than the average of a normal control or normal non-disease control sample. In one embodiment, an abnormal level is at least 10%, preferably at least 20%, more preferably at least 30%, even more preferably at least 40%, and still more preferably at least 50% different from the level of a healthy subject. In particular, an upregulated level is at least 10%, preferably at least 20%, more preferably at least 30%, even more preferably at least 40%, and still more preferably at least 50% higher than the level of a healthy subject. In particular, a downregulated level is at least 10%, preferably at least 20%, more preferably at least 30%, even more preferably at least 40%, and still more preferably at least 50% lower than the level of a healthy subject. When used to describe the level of a target gene, abnormal means gene expression that is greater or less than the average of a normal control or normal non-disease control sample. Abnormal activity may refer to the amount of activity that causes disease, and restoring abnormal activity to a normal or non-disease-related amount (for example, by using the methods described herein) results in the reduction of the disease or the symptoms of one or more diseases.

[0364] A "week" preferably refers to a period of 5, approximately 6, or approximately 7 days. It may also be approximately 5 to 8 days. The most preferred week is a period of 7 days.

[0365] A "month" preferably refers to a period of approximately 28, 29, 30, or 31 days. It may also be approximately 26 to 33 days. The most preferred month is one of 30 days.

[0366] As used herein, the term “evening” refers to the time between late afternoon and night, preferably from 16:00 to 23:00 local time.

[0367] As used herein, the term “morning” refers to the time from early dawn to approximately noon, preferably from 5:00 to 12:00 local time.

[0368] As used herein with respect to numbers, figures, ranges and / or quantities, the term “about” is preferably intended to mean “approximately” and / or “roughly.” The meanings of these terms are known in the art, and preferably include plus / minus 15%, particularly plus / minus 10%, in the variance, deviation and / or variation of each number, figure, range and / or quantity.

[0369] As used herein, “treatment” preferably includes a sequential sequence of “induction treatment” followed by “maintenance treatment.” For example, treatment according to the present invention includes an induction treatment of about one week in which half of the daily dose is administered, followed by a maintenance treatment in which the full daily dose is administered (see, for example, WO2019 / 101888).

[0370] "Daily dose" preferably refers to the total dose of compounds of formulas (I) to (V), or compound of formula (VI), preferably vidofludimus, or a pharmaceutically acceptable salt or solvate thereof, administered orally to the patient on each day of administration. The daily dose can be achieved by one or more doses per day, for example, once, twice, or three times per day. Preferably, it is achieved by one dose per day, preferably consisting of one or more tablets or capsules, preferably tablets or capsules as described herein.

[0371] A “relapse” involves neurological problems that are preferably short-lived, typically lasting only a few days, but sometimes as short as a few hours or even minutes. These episodes are almost always accompanied by motor, sensory, visual, or coordination problems in the early stages of the disease. Later, bladder, bowel, sexual, and cognitive problems may appear. Sometimes, episodes of an episode can last for several weeks. A typical MS relapse involves a period of exacerbation with progressive neurological deficits, followed by a plateau period in which the patient neither improves nor worsens, and then a recovery period. Recovery usually begins within a few weeks.

[0372] The "annual relapse rate" is the average number of relapses experienced by a patient group in a clinical trial over a year. See, for example, the Multiple Sclerosis Coalition. The Use Of Disease-Modifying Therapies In Multiple Sclerosis: Principles and Current Evidence Summary is available at http: / / www.nationalmssociety.org / getmedia / 1e64b96c-9e55-400e-9a64-0cdf5e2d60fe / summaryDMTpaper_-final.

[0373] A "hazard ratio" is a measure that compares how frequently a particular event occurs in one group over a given period of time to how frequently it occurs in another group. A hazard ratio of exactly 1.0 means that the study drug provides zero risk reduction compared to the control treatment.

[0374] The Integrated Disability Rating Scale (EDSS) is a clinician-reported assessment scale for quantifying changes in disability levels over time in individuals with MS. The EDSS is based on a standard neurological examination that incorporates functional systems (visual, brainstem, pyramidal, cerebellar, sensory, intestinal and bladder, and brain [or mental]) which are assessed and then scored as functional system scores (FSS), as well as gait, which is scored as a gait score. Each FSS is a clinical assessment scale ranging from 0 to 5 or 6, and a gait score ranging from 0 to 12. These assessments are used in conjunction with observations and information regarding gait and the use of assistive devices to determine the total EDSS score. The EDSS is a disability scale ranging from 0 (normal) to 10.0 (death) in 0.5-point steps (Kurtzke, Neurology 1983;33:1444). In some embodiments of the methods provided herein, items of sexual dysfunction and fatigue are not included in the EDSS score. Typically, a decrease in the EDSS score corresponds to an improvement in the disease, while an increase in the EDSS score corresponds to a worsening of the disease.

[0375] The 9-Hole Peg Test (9-HPT) is a quantitative measure of upper limb (arm and hand) function (Arch.Phys.Med.Rehabil.1988;69:850). The test apparatus consists of a container with nine pegs and a block with nine empty holes. The subject picks up each of the nine pegs one at a time and places them into the nine holes as quickly as possible. Once all the pegs are in the holes, the subject removes the pegs one at a time again as quickly as possible and returns them to the container. The total time taken to complete the task is recorded. Both the dominant and non-dominant hands are tested twice (the dominant hand is successfully completed twice, and immediately afterward, the non-dominant hand is successfully completed twice). The two trials for each hand are averaged, converted to the reciprocal of the average time for each hand, and the two reciprocals are averaged. 9-HPT can be performed as described, for example, in the Multiple Sclerosis Functional Composite (MSFC) Administration and Scoring Manual (National Multiple Sclerosis Society, 2001). A meaningful change in upper limb function may be indicated, for example, by a 20% deterioration in mean 9-HPT time from baseline.

[0376] The 25-foot walk time test (T25FWT) is a quantitative measure of motor and leg function based on the time it takes to walk 25 feet. Participants are instructed to start from one end of a clearly marked 25-foot course and to walk 25 feet as quickly and safely as possible, with the time taken from the start of the walk to the end of the 25 feet being measured. In some embodiments, the task is immediately repeated by having the subject walk the same distance backward, and the time taken for both completed trials is averaged to produce a T25FWT score. Participants may use assistive devices (e.g., canes or wheelchairs) when performing the task. The T25FWT can be administered as described, for example, in the MSFC Administration and Scoring Manual. A clinically significant change in motor and leg function may be indicated, for example, by a 20% deterioration from baseline in the mean T25FWT time.

[0377] The Symbol-Number Modality Test (SDMT) is a test used to assess the presence of cognitive impairment and / or changes in cognitive function over time and response to treatment. The SDMT may be particularly sensitive to the slowed information processing commonly seen in MS (Mult.Scler.2017;23:721). The SDMT includes a substitution task. Using a reference key, subjects pair specific numbers with given geometric figures within 90 seconds. Answers may be collected orally, and the number of correct answers is considered the SDMT score. A clinically meaningful change in cognitive processing may be indicated, for example, by a 4-point decrease in the SDMT score from baseline.

[0378] The Columbia Suicide Severity Rating Scale (C-SSRS) is a tool used to assess a subject's lifetime suicidal tendencies and can be used to track suicidal events throughout treatment or part thereof. Structured interviews elicit recollections of suicidal ideation, including the intensity of ideation, behavior, and attempts with actual / potential lethality. "Baseline" C-SSRS may include C-SSRS collected before the initiation of administration of, for example, compounds of formulas (I)–(V), or compound (VI), or its isotopic variants, pharmaceutically acceptable salts, or solvates, particularly vidofludimus. Such scores can be compared with subsequent C-SSRS collected after the initiation of administration of, for example, compounds of formulas (I)–(V), or compound (VI), or its isotopic variants, pharmaceutically acceptable salts, or solvates, particularly vidofludimus. Comparisons between different assessment periods (e.g., occurring during clinician visits) may, in some embodiments, be described as "since last visit" C-SSRS.

[0379] The EQ-5D-5L is a validated self-report health status questionnaire that can be used to calculate health status utility values ​​for use in health economic analysis (Qual.Life Res. 2011;20:1727, Qual.Life Res. 2013;22:1717). The EQ-5D-5L has two components: a five-item health status profile that assesses mobility, self-care, routine activities, pain / discomfort, and anxiety / depression, as well as a visual scale (VAS) to measure health status. The EQ-5D-5L is designed to capture the current health status of subjects. A published weighting system can be used to create a single composite score for a subject's health status. The Multiple Sclerosis Impact Scale-29 Version 2 (MSIS-29, Version 2) is a 29-item subject-reported scale of the physical and psychological impacts of MS (Brain 2001;124:962). Participants are asked to rate the extent to which their function and health have been affected over the past 14 days on a 4-point scale from “not affected at all” (1) to “extremely affected” (4). 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, which is also converted to a 0-100 scale. A higher score may indicate a greater impact from MS. A clinically meaningful impact is indicated by a change of at least 7.5 points on the physical scale in version 1 of the MSIS-29. In version 2 of the MSIS-29, this level of change may also indicate a meaningful impact.

[0380] The Multiple Sclerosis Walking Scale, 12 items (MSWS-12) is a 12-item self-report scale that measures the impact of MS on an individual's walking ability over the past two weeks. Each item is scored on a 5-point Likert scale, and the total score is converted to a scale from 0 to 100, with higher scores indicating a greater impact of MS on walking ability.

[0381] The "Quality of Life in Neurological Disorders, Upper Extremity" (fine motor skills and activities of daily living; Neuro-QoL, Upper Extremity) is a 20-item questionnaire used to assess upper limb function, including subjects with MS at each stage of its progression (Qual.Life Res. 2012;21:475). The items include assessments of grooming, cooking, eating, cleaning, and writing, from which subjects rate their function using a 5-point Likert scale from "no difficulty" (5) to "unable to do" (1). The item scores are totaled, multiplied by 20, and divided by 20 minus the total number of unanswered items. The score ranges from 20 to 100, with higher scores indicating better upper limb function. According to the NINDS User Manual (2015), the score can be calculated as long as at least 50% of the items are answered.

[0382] The PROMIS-FatigueMS is an eight-item scale of recall over the past seven days, developed as a measure of fatigue in subjects with MS (Qual.Life Res. 2012;21:1021). It has a 5-point Likert scale that generates a score from 1 to 5 for each scoreable question. The raw score sum is the sum of the values ​​for each scored question. The raw score sum ranges from 8 to 40. The score can also be converted to a PROMIS T-score, with a mean of 50 and a standard deviation of 10. The T-score ranges from 34.7 to 81.3. Higher scores are associated with worse fatigue.

[0383] The "Patient Global Impression Change" (PGI-C) is a single-item assessment of the subject's perception of the change in their MS symptoms compared to six months prior. Subjects respond on a 7-point Likert scale from "very good" (i) to "very bad" (7). The PGI-C is used as an anchor to determine what constitutes a clinically significant change in MSIS-29.

[0384] The Patient Severity Indication-Scale (PGI-S) is a single-item assessment of a subject's perception of the severity of their MS symptoms over the past seven days. Subjects respond on a 5-point Likert scale from "none" (1) to "very severe" (5). The PGI-S is used as an anchor to determine what constitutes a clinically significant change in MSIS-29.

[0385] The "Work Productivity and Activity Impairment: Multiple Sclerosis" (WPAI:MS) is a six-item scale. Subjects estimate the amount of time their work and daily activities were affected by their MS over the past seven days (Pharmacoeconomics 1993;4:353). WPAI:MS assesses absenteeism and "attendance," which describes the amount of time a subject was present for work or activity but whose health was considered to be negatively impacting their ability to perform at a normal level. A higher score indicates a greater decline in productivity.

[0386] "Confirmed disability progression" (CDP) refers to an increase in an individual's EDSS score that persists over a specific period. This can be assessed, for example, by calculating the individual's EDSS score, determining that the score has increased compared to a previous score (e.g., the baseline score, which may be the score obtained before the initiation of administration of compounds (I)-(V), or compound (VI), or their isotopic variants, pharmaceutically acceptable salts or solvates, particularly vidofludimus), and then confirming that the score has continued to increase after a specific period has elapsed since the initial increase (e.g., by re-evaluating the individual and recalculating it again). For example, 12-week confirmed disability progression (CDP12) refers to an EDSS score that remains increased for 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) means that the EDSS score remains elevated for 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 may be compared to the baseline EDSS score (e.g., with the compounds of formulas (I)–(V), or with the compound of formula (VI), or its isotopic variants, pharmaceutically acceptable salts or solvates, particularly before the initiation of vidofludimus administration), or to a previous EDSS score that remained stable over a period such as 12, 24, 36, 48, or 60 weeks. In some embodiments, CDP refers to an increase of ≥1.0 point from the baseline EDSS score in subjects whose baseline EDSS score is ≤5.5 points, or an increase of ≥0.5 points from the baseline EDSS score in subjects whose baseline EDSS score is >5.5 points.The time to CDP onset (e.g., time to CDP12 or CDP24) refers to the period from the establishment of a previous EDSS score (e.g., a baseline EDSS score derived before the initiation of administration of vidofludimus, or its isotope variant, pharmaceutically acceptable salt, or solvate) until a sustained increase in the EDSS score is observed.

[0387] The "composite confirmed disability progression" (cCDP) is a composite measure of disability progression using a combination of the EDSS, 9-HPT, and T25FWT. It assesses the progression of a subject's disability over a specific period, as determined by the first occurrence of a progression event. A progression event may include any one of the following: a CDP (e.g., an increase of ≥1.0 point from the baseline EDSS score in subjects with a baseline EDSS score ≤5.5 points, or an increase of ≥0.5 points from the baseline EDSS score in subjects with a baseline EDSS score ≥5.5 points), a ≥20% increase from baseline in the time to complete the 9-Hole Peg Test (9-HPT), or a ≥20% increase from baseline in the T25FWT. The occurrence of a progression event is confirmed after a specified period has elapsed since the first occurrence. For example, a composite 12-week-lasting disability progression (cCDP12) refers to the occurrence of at least one progression event at an initial point in time, and confirmation of the same progression event at least 12 weeks later (e.g., by reassessing the subject using the same tests). A composite 24-week confirmed disability progression (cCDP12) refers to the occurrence of at least one progression event in the initial period and the confirmation of the same progression event at least 24 weeks later. Time to cCDP (e.g., time to cCDP12 or cCDP24) refers to the period from when a previous assessment score was established (e.g., baseline score before initiation of administration of vidofludimus, or its isotope variant, pharmaceutically acceptable salt, or solvate) to when the first progression event is observed.While not bound by theory, compared to endpoints based solely on the Comprehensive Disability Rating Scale (EDSS), which emphasizes lower limb function, the cCDP12 requires at least one of the following: 1) an increase of ≥1.0 point in the EDSS score 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) a 20% increase from the BL in the time to complete the 9-hole peg test; or 3) a 20% increase from the BL in the 25-foot walk time test. Therefore, the cCDP12 is a more sensitive assessment of disability, especially in the early stages of the disease. The use of the cCDP12 as a primary outcome can provide a clearer and more complete picture of disability progression or improvement than the EDSS alone.

[0388] "Confirmed disease exacerbation" (CDW) measures the increase in a patient's EDSS score that persists over a given period, which means an increase in the patient's disability, as described, for example, in Drugs 2015;75:947.

[0389] In some embodiments, confirmed disease progression is measured by the Kurtzke Global Disability Rating Scale (EDSS) score in subjects with MS requiring further study.

[0390] In some embodiments, confirmed disease progression is defined as an increase of at least one point in the EDSS score.

[0391] In some embodiments, disease progression was observed in MS patients with an increase of at least 0.5 points in the EDSS score.

[0392] In some embodiments, the hazard ratio is reduced by 20–60% when there is no deterioration of the identified fault.

[0393] In some embodiments, the hazard ratio is reduced by 30–50% when there is no deterioration of the identified fault.

[0394] In some embodiments, the hazard ratio is reduced by at least 30% when there is no deterioration of the identified fault.

[0395] In some embodiments, the hazard ratio is reduced by at least 40% when there is no deterioration of the identified fault.

[0396] In some embodiments, the hazard ratio is reduced by at least 50% when there is no deterioration of the identified fault.

[0397] The term "brain atrophy" describes one of the most devastating outcomes of MS. Brain atrophy can be seen in 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 by MRI in a highly sensitive and reproducible manner. See, for example, Lancet Neurol. 2006;5:158.

[0398] The "effectiveness" of the treatment according to the present invention can preferably be measured based on changes in the course of the disease in response to use according to the present invention. For example, the effectiveness of the treatment of MS can be measured by the frequency of relapses of RRMS and the presence or absence of new lesions in the central nervous system (CNS) detected using methods such as MRI (Neurology 1996;47(Suppl 4):S217 Ann.Neurology 1997;41:125).

[0399] Preferably, observation of a reduction and / or suppression of MRI T1 gadolinium-enhanced lesions (thought to represent areas of active inflammation) provides a primary efficacy variable. These are active lesions that appear as bright white on MRI scans after intravenous administration of the imaging contrast agent (gadolinium). Secondary efficacy variables preferably include MRI T1-weighted brain lesion volume, MRI T1-weighted lesion volume, MRI T2 lesion volume (thought to represent total disease burden, i.e., demyelination, gliosis, inflammation, and axonal loss), MRI T1-weighted low-intensity lesion volume (thought to represent mainly demyelination and axonal loss), time to MS progression, frequency and severity of exacerbations, time to exacerbation, scores on the Comprehensive Disability Assessment Scale, and Scripps Neurologic Rating Scale (SNRS) scores (Neurology 1984;34:1368). Early and accurate diagnostic methods for multiple sclerosis and tracking of disease progression are described in Mattson, Expert Rev. Neuroother. 2002;2:319.

[0400] White matter lesions on brain MRI in MS can contribute to misdiagnosis, particularly when attempting to assign patients to subgroups. Some MS lesions reflect iron accumulation in microglia and exhibit a paramagnetic rim on susceptibility-weighted MRI sequences. These paramagnetic rim lesions have been proposed as markers for compartmentalized smoldering disease (AJR 2022;219:120). Detection of paramagnetic rim lesions is rare in other neurological conditions (52% of MS cases vs. 7% of non-MS cases) and gave high specificity (93%) in distinguishing MS from non-MS (Ann Neurol. 2020;88:1034). Paramagnetic rim lesions may be a novel marker of chronic neuroinflammation in MS and could be useful in assigning MS patients to subgroups, such as PPMS.

[0401] As used herein, the term “effective dose” includes a dosage sufficient to produce the desired outcome with respect to the indicated disorder, condition, or mental state. The desired outcome may include subjective or objective improvement in the recipient of the administration.

[0402] As used herein, the term “administer” includes activities relating to providing a patient with a certain amount of a compound of formulas (I) to (V), or a compound of formula (VI), preferably vidofludimus, or a pharmaceutically acceptable salt or solvate thereof. Administering includes providing a unit dose of the compositions described herein to a patient in need. Administering includes providing an effective amount of a compound, e.g., vidofludimus and / or a pharmaceutically acceptable salt and / or solvate thereof, particularly the hydrate and / or solvate of a pharmaceutically acceptable salt thereof, particularly the hydrate, for a specific period, e.g., about 6, 9, 12, 15 months or longer, or about 1, 2, 3, 4, 5 years or longer.

[0403] "Disease" or "condition" means a condition or health state of a patient or subject that can be treated with the compounds or methods provided herein. In some embodiments, the disease is a disease related to (e.g., caused by) cellular components (e.g., proteins, ions, lipids, nucleic acids, nucleotides, amino acids, proteins, particles, organelles, cell compartments, microorganisms, vesicles, small molecules, protein complexes, protein aggregates, or macromolecules). In embodiments, the disease is a neurodegenerative disease. In embodiments, the disease is an inflammatory disease. In embodiments, the disease is cancer.

[0404] In some embodiments, levels of Nurr1, levels of activity of genes downstream of Nurr1, or levels of proteins downstream of Nurr1 (e.g., NCAM, CFB, LTA, A2M, HSD11B1, BHLHE41, MARCO, BDNF, GDNF, C-RET, GFAP, DAT, Pitx3, TH, VMAT2, SOD1, AADC, TNFα, iNOS, or IL-1β) are measured in a subject and then compared to similar values ​​obtained from healthy control subjects having the same biological sex, similar or identical body mass index (BMI), or similar or identical age. For example, healthy control subjects may have an age within ±1, ±2, ±3, ±4, ±5, ±10, ±15, ±20, or ±30 years of the subject's age. In some embodiments, healthy control subjects may have a BMI of ±1 kg / m² of the subject's BMI. 2 ±2 kg / m 2 ±3 kg / m 2 , ±4kg / m 2 , ±5kg / m 2 ±10 kg / m 2 ±15 kg / m 2 , or ±20 kg / m 2 The subject has a BMI within [value]. Age, BMI, and biological sex can be independently assessed in the subject or healthy control subject when measuring protein (e.g., Nurr1) or gene levels.

[0405] In some embodiments, the level of Nurr1, the level of activity of a gene downstream of Nurr1, or the level of a protein downstream of Nurr1 (e.g., NCAM, CFB, LTA, A2M, HSD11B1, BHLHE41, MARCO, BDNF, GDNF, C-RET, GFAP, DAT, Pitx3, TH, VMAT2, SOD1, AADC, TNFα, iNOS, or IL-1β) in a sample is measured in the subject, and then compared to the levels of Nurr1, the level of activity of a gene downstream of Nurr1, or the level of a protein downstream of Nurr1 in another sample of the subject to examine whether the levels have decreased or declined.

[0406] In some embodiments, the level of Nurr1, the level of activity of a gene downstream of Nurr1, or the level of a protein downstream of Nurr1 (e.g., GDNF, GFAP, or VMAT2) in a sample is measured two or more times in the subject, and then the level is compared with the level of Nurr1, the level of activity of a gene downstream of Nurr1, or the level of a protein downstream of Nurr1 in another sample of the subject to monitor the decrease or decline in the levels over time.

[0407] Non-specific examples of mental states include anxiety, depression, bipolar disorder, dementia, schizophrenia, and other psychoses.

[0408] Non-limiting examples of conditions or diseases of the central nervous system include neurological disorders or disorders that affect the structure or function of the brain or spinal cord, which collectively form the central nervous system (CNS), such as poisoning, encephalitis, Parkinson's disease, and multiple sclerosis.

[0409] Non-limiting examples of neurodegenerative diseases or conditions include diseases or conditions that impair the function of the nervous system in question, such as Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ataxia with telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjögren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, corticobasal syndrome (CBS), Creutzfeldt-Jakob disease, Down syndrome (DS), frontotemporal dementia, Gerstmann-Streussler-Scheinker syndrome, Huntington's disease, and HIV-related dementia. These include follicular dyslexia (FTD), Kennedy disease, Krabbe disease, Kuru disease, Lewy body dementia (DLB), Machado-Joseph disease (spinocerebellar degeneration type 3), multiple sclerosis, multiple system atrophy, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbach disease, Pick's disease, primary lateral sclerosis, prion diseases, progressive supranuclear palsy (PSP), Refsum disease, Sandhoff disease, Schilder's disease, subacute combined degeneration of the spinal cord secondary to pernicious anemia, schizophrenia, spinocerebellar ataxia (multiple types with various characteristics), spinal muscular atrophy, Steele-Richardson-Olshevsky disease, or spinal fistula.

[0410] Multiple sclerosis (MS) can be classified into relapsing-remitting MS (RMS) and progressive MS (PMS). Relapsing-remitting MS (RRMS) and active secondary progressive MS (active SPMS) are primarily caused by focal inflammatory disease and are characterized by the presence of magnetic resonance imaging (MRI) lesions and relapses. However, recent meta-analyses of large patient databases have shown that the progression of disability in these two subtypes is caused by relapse-related exacerbations (RAW) and progression unrelated to relapse activity (PIRA). RRMS is characterized by a predominance of relapses and MRI lesions throughout the clinical course. Active SPMS (aSPMS) is characterized by fewer relapses and lesions with continuous progression of disability (see Figure 8).

[0411] Primary progressive MS (PPMS) and inactive secondary progressive MS (inactive SPMS or n-aSPMS) are the two main progressive forms of MS, characterized by ongoing disability progression with little to no MRI lesions or relapses. Recent meta-analyses of large patient databases have shown that disability progression in these two subtypes is almost exclusively caused by PIRA. Inactive SPMS is characterized by continuous disability progression while relapses are halted. PPMS is characterized by disability progression from the onset (see Figure 8).

[0412] The definitions and subcategories of PPMS and SPMS may change. In one exemplary definition, all SPMS can be considered to belong to the category of PMS, and consequently, all SPMS patients can be considered PMS patients without distinction between aSPMS and n-aSPMS. In another exemplary definition, active SPMS can be considered to belong to the category of RMS, while inactive SPMS can be considered to belong to the category of PMS. Therefore, the terms "n-aSPMS" and "SPMS" are used synonymously in this invention.

[0413] The separation of PIRA compared to RAW may be as follows (JAMA Neurol. 2023;80:151). A PIRA event can be defined as experiencing a confirmed disability worsening (CDW) on the EDSS scale during a 6-month period without relapse (PFR). PFR is the time between two consecutive relapses, starting 3 months after the relapse (or 6 months after the first demyelinating event). The first EDSS scores obtained at least 6 months after the first seizure or 3 months after any other seizure were referred to as the baseline EDSS score and the re-baseline EDSS score, respectively. It was set so that there would be no re-baseline EDSS score lower than the initially recorded (baseline) EDSS score. If the baseline / re-baseline EDSS scores were 0, 1.0–5.0, or greater than 5.0, respectively, confirmed disability accumulation (CDA) was defined as an increase of 1.5, 1.0, or 0.5 in the EDSS score. The date of PIRA was the date of confirmation of CDA. All other episodes of CDA that did not qualify for PIRA (i.e., occurred outside of PFR) were considered RAW events. Patients with at least one CDA but who did not exhibit any PIRA events were considered to have RAW.

[0414] In the clinical study by Kopp et al. (Mult.Scler.Relat.Disord.2021;56:103319), the following inclusion criteria were applied to the MS population with a clinical SPMS diagnosis assigned by an MS neurologist, and to RRMS patients who met the MSBase diagnostic definition for conversion to SPMS. This m-EXPAND criterion identifies patients with a recent worsening of EDSS scores that is unlikely to be explained by a recent relapse, as follows:

[0415] (a) EDSS (index day + / - 6 months) for 3.0 to 6.5 (including both ends), and

[0416] (b) EDSS progression within the last two years prior to data extraction, defined as EDSS progression of 1 point or more for patients with an EDSS score less than 6.0, or 0.5 points or more for patients with an EDSS score of 6.0 or higher, and there was no relapse six months prior to progression, and the EDSS score was ≥3.0 at the time of progression.

[0417] (c) Progression of the disability.

[0418] Currently, there are no FDA-approved treatment options for SPMS other than mitoxantrone. However, mitoxantrone treatment does not distinguish between relapsed and active SPMS (active SPMS vs. inactive SPMS). In particular, mitoxantrone treatment is associated with significant toxicity, including cardiotoxicity and secondary malignancies, which limits the treatment duration to approximately 3 years (total dose 140 mg / m²). 2 Furthermore, the patient population in this trial primarily had relapsing SPMS, and the benefit in inactive SPMS is unclear. Siponimod, natalizumab, and interferon beta-1b are approved for active SPMS but have not shown benefit in inactive SPMS. Ocrelizumab is approved for PPMS patients, but it strongly attenuates the immune response and therefore has black-box warnings for progressive multifocal leukoencephalopathy and immune-mediated colitis. Other treatment options currently being tested in clinical trials (e.g., fenebrutinib, which carries a risk of hepatic impairment) also do not offer a favorable safety profile for vidofludimus. Thus, there is an urgent unmet need as there is no effective treatment for PIRA as a whole.

[0419] MS typically begins with clinically isolated syndrome (CIS), which is the first episode of symptoms caused by inflammation and damage to the myelin that covers the nerves in the brain or spinal cord. In CIS, there are seizures that suggest demyelination, but the criteria for MS are not met. 30–70% of people who experience CIS later develop MS.

[0420] There is a further subgroup of MS patients, namely those who transition between relapsing MS and PIRA. The term “transitional MS” is used herein in relation to this disease. Transitional MS patients can be identified by one or more of the following testing methods.

[0421] (a) Symbol-Numeric Modality Test (SDMT),

[0422] (b)Multiple Sclerosis Functional Composite (MSFC),

[0423] (c)EDSS,

[0424] (d) 25-foot walking time test (T25FW),

[0425] (e) 9-hole peg test (9HPT),

[0426] (f) MSProDiscuss(trademark) clinical tools,

[0427] (g) A composite score that integrates several tests, such as the EDSS, 25-foot walk time test (T25FW), SDMT and 9-hole peg test (9HPT), and the MSProDiscuss® clinical tool.

[0428] As used herein, the term “neuroprotection” refers to therapeutic strategies for the relative preservation of neuronal structure and / or function, i.e., slowing or preventing otherwise irreversible neuronal loss over time. In the case of ongoing injury (neurodegenerative injury), relative preservation of neuronal integrity means a slowing of the rate of neuronal loss over time. It is a widely explored therapeutic option for many CNS disorders, including neurodegenerative diseases, stroke, traumatic brain injury, spinal cord injury, and acute management of neurotoxic ingestion (i.e., methamphetamine overdose). Neuroprotection aims to prevent or slow disease progression and secondary injury by stopping or at least slowing (mitigating) neuronal loss. Despite differences in the symptoms or injuries associated with CNS disorders, many of the mechanisms behind neurodegeneration are the same. Common mechanisms of nerve damage include reduced oxygen and glucose delivery to the brain, energy deficiency, increased levels of oxidative stress, mitochondrial dysfunction, excitotoxicity, inflammatory changes, iron accumulation, and protein aggregation.

[0429] As used herein, the terms “inflammatory disease” or “inflammatory condition” refer to an inflammatory disease or condition that may be characterized by abnormal inflammation, for example, an increased level of inflammation compared to a control, such as a healthy person who is not suffering from the disease. Non-exclusive examples of inflammatory diseases include autoimmune diseases, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile diabetes mellitus, type 1 diabetes mellitus, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjögren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behçet'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, graft rejection, interstitial cystitis, atherosclerosis, scleroderma, and atopic dermatitis.

[0430] Non-specific examples of cancer include neoplasms, malignant tumors, leukemia, lymphoma, carcinoma, sarcoma, thyroid, endocrine, brain, breast, neck, colon, head and neck, liver, kidney, lung, non-small cell lung, ovarian, sarcoma, stomach, or uterine cancer, melanoma, mesothelioma, medulloblastoma, colorectal cancer, pancreatic cancer, Hodgkin's disease, non-Hodgkin lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, and primary thrombocytosis. These include primary macroglobulinemia, primary brain tumors, malignant pancreatic insulinoma, malignant carcinoid, bladder cancer, pre-malignant skin lesions, testicular cancer, lymphoma, thyroid cancer, esophageal cancer, urogenital tract cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, neoplasms of the endocrine or exocrine pancreas, medullary thyroid carcinoma, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid carcinoma, hepatocellular carcinoma, and prostate cancer.

[0431] Non-limiting examples of leukemia include progressive malignant diseases of the hematopoietic organs characterized by the distorted proliferation and development of white blood cells and precursors in the blood and bone marrow, such as acute non-lymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, non-leukemic leukemia, leukocythemic leukemia, basophilic leukemia, blastic leukemia, bovine leukemia, chronic myeloid leukemia, and leukemia. Cutis, fetal leukemia, eosinophilic leukemia, Gross leukemia, hairy cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myeloid leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Rieder Examples include cell leukemia, Schilling leukemia, stem cell leukemia, subleukemia, and anaplastic cell leukemia.

[0432] Non-exclusive examples of lymphoma include cancers affecting hematopoietic and lymphoid tissues, non-Hodgkin 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 (monocytic B-cell) lymphoma, splenic lymphoma, diffuse large B-cell lymphoma, Burkitt lymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma, progenitor B-lymphoblastic lymphoma, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, anaplastic large cell lymphoma, mycosis fungoides, and progenitor T-lymphoblastic lymphoma.

[0433] Non-specific examples of sarcomas include tumors that are formed from materials such as embryonic connective tissue, and are generally composed of densely packed cells embedded in fibril or homogeneous material. Sarcomas that can be treated with the compounds or methods provided herein include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernesi's sarcoma, liposarcoma, liposarcoma, alveolar soft tissue sarcoma, epiamelosarcoma, staphyloid sarcoma, green sarcoma, choriocarcinoma, embryonal sarcoma, Wilms tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fasciosarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, Kaposi's sarcoma, B-cell immunoblastic sarcoma, lymphoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, lymphosarcoma, malignant mesenchymal sarcoma, paraosteal sarcoma, reticulosarcoma, Rouss sarcoma, cystic sarcoma, synovial sarcoma, and telangiectatic sarcoma.

[0434] Non-limiting examples of melanoma include tumors arising from melanocyte systems of the skin and other organs. Melanomas that can be treated with the compounds or methods provided herein include, for example, acral lentiginous melanoma, achromatic melanoma, benign juvenile melanoma, Cloudmann melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentiginous malignant melanoma, malignant melanoma, nodular melanoma, subungual melanoma, or superficial spreading melanoma.

[0435] Non-specific examples of carcinomas include medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma of the pancreas, acinar carcinoma, adenoid cystic carcinoma, adenomatous carcinoma, adrenocortical carcinoma, alveolar carcinoma, alveolar epithelial carcinoma, basal cell carcinoma, carcinoma basocellulare, basosquamous cell carcinoma, bronchoalveolar carcinoma, bronchiolalveolar carcinoma, bronchogenic carcinoma, cerebral carcinoma, cholangiocarcinoma, choriocarcinoma, colloid carcinoma, comedone carcinoma, uterine carcinoma, cribriform carcinoma, armory carcinoma, skin carcinoma, columnar carcinoma, columnar cell carcinoma, duct carcinoma, and carcinoma. Durum, embryonal carcinoma, encephaloid carcinoma, squamous cell carcinoma, carcinoma epitheliale adenoides, carcinoma ex ulcere, fibrous carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, adenocarcinoma, granulosa cell carcinoma, follicular carcinoma, hematoid carcinoma, hepatocellular carcinoma, Haasle's cell carcinoma, hyaline carcinoma, adrenal carcinoma, infantile embryonal carcinoma, carcinoma in situ, carcinoma in epidermis, intraepithelial carcinoma, Krompecher's carcinoma, Krutschky's cell carcinoma, large cell carcinoma, lenticular carcinoma carcinoma, lenticular carcinoma, lipoma, lymphoepithelial carcinoma, medullary carcinoma, medullary carcinoma, black carcinoma, carcinomamolle, mucinous carcinoma, mucinous secretory carcinoma, mucocell carcinoma, mucoepidermal carcinoma, mucosum carcinoma, mucosal carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid osteoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, squamous cell carcinoma, pultaceous carcinoma, renal cell carcinoma, reserve cell carcinoma, sarcomatoid carcinoma, Schneiderian carcinoma, sclerotic carcinoma, scrotal carcinoma, signet ring cell carcinoma, simple carcinoma, small cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, cavernous carcinoma, squamous carcinoma, squamous cell carcinoma, string Examples include carcinoma, telangiectaticum (carcinoma telangiectodes), transitional cell carcinoma, tuberosum (carcinoma tuberosum), tuberous carcinoma, verrucous carcinoma, and choriocarcinoma.

[0436] In some embodiments, the Disclosure provides a composition comprising a group of molecules, each molecule in the group independently being a compound of formula (I), (II), (III), (IV), (V), or formula (VI), and each molecule in the group independently containing a deuterium atom in a certain proportion. The level of deuterium uptake may be any value, such as the natural abundance or a level greater or less than the natural abundance. The level of protium in the sample may be any value, such as the natural abundance or a level greater or less than the natural abundance. The level of tritium may be any value, such as the natural abundance or a level greater or less than the natural abundance.

[0437] It is recognized that some variation in the abundance of natural isotopes occurs in the synthesized compounds depending on the origin of the chemicals used in the synthesis. Therefore, the compounds of formulas (I) to (V), or preparations with the compound of formula (VI), essentially contain small amounts of deuterated isotopic molecular species. The concentrations of naturally abundant and stable hydrogen and carbon isotopes are small and insignificant compared to the degree of stable isotopic substitution in the compounds of the present invention, despite this variation. See, for example, Comp. Biochem. Physiol. 1998; 119A:725.

[0438] If a chemical name or structure is not provided regarding whether a particular position in a compound normally occupied by hydrogen is isotopically enriched, it is assumed that the particular position is occupied by hydrogen in its natural abundance. For example, the term "phenyl" or [ka]

[0439] This indicates that, unless otherwise specified regarding isotopic enrichment, all hydrogen atoms are present in their naturally occurring abundances.

[0440] In some embodiments, 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 is given by the isotopic enrichment factor ε p / s It can be expressed by ε p / s =(R p / R s (-1) × 1000, and in the formula, R p R is the abundance of deuterium at that position within a molecular population. s is the natural abundance of deuterium at that position. The proportion of molecules in a population that contains a deuterium atom at a particular atomic position may instead be expressed as the mole percent (i.e., deuterium incorporation %) of the population that is substituted with deuterium at that atomic position.

[0441] Non-limiting examples of isotope 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).

[0442] Non-limiting examples of the amount of deuterium present in a sample of the compound of the present invention include the natural abundance, and at least 3340 times the natural abundance of deuterium (at least 50.1% deuterium uptake), at least 3500 times the natural abundance of deuterium (52.5% deuterium uptake), at least 4500 times the natural abundance of deuterium (67.5% deuterium uptake), at least 5000 (75% deuterium), and at least 5500 times the natural abundance of deuterium (82.5%). Examples include deuterium uptake of 0%, at least 6000 times the natural abundance of deuterium (90% deuterium uptake), at least 6333.3 times the natural abundance of deuterium (95% deuterium uptake), at least 6466.7 times the natural abundance of deuterium (97% deuterium uptake), at least 6600 times the natural abundance of deuterium (99% deuterium uptake), or at least 6633.3 times the natural abundance of deuterium (99.5% deuterium uptake), or any other abundance.

[0443] When a particular position in the compounds of the present invention (for example, compounds represented by formulas (I) to (V), or together with the compound of formula (VI), or their pharmaceutically acceptable salts and / or solvates) is specifically designated as "H" or "hydrogen" by name or structure, that position is understood to have hydrogen in its naturally occurring isotopic composition.

[0444] The percentage of deuterium uptake can be determined by quantitative analysis, for example, using mass spectrometry (peak area), or by the signal from an internal standard or other deuterated components in the compound. 1 Remaining residue of specific deuterated sites compared to H signaling 1 This can be obtained by quantifying the H-NMR signal.

[0445] The term “compound” refers to any compound of this disclosure, including the compounds represented by formulas (I) to (V), or together with the compound of formula (VI), or their pharmaceutically acceptable salts and / or solvates, a collection of molecules having the same chemical structure except that there may be isotopic variation among the constituent hydrogen atoms of the molecule. The relative amount of isotopic variation in the compounds of the present invention varies depending on many factors, including the isotopic purity of the deuterating reagent used to prepare the compound, and the efficiency of deuterium incorporation in the various synthetic steps used to prepare the compound.

[0446] Both "D" and "d" refer to deuterium. "H" means hydrogen.

[0447] "To be substituted with deuterium" means to replace one or more hydrogen atoms with a corresponding number of deuterium atoms.

[0448] Within the scope of the present invention, "isotope variant" refers to a deuterated variant of a compound of formula (I) to (V), or a compound of formula (VI), preferably with vidofludimus, or a pharmaceutically acceptable salt or solvate thereof.

[0449] All formulas or structures given herein are also intended to represent deuterated compounds further containing isotopically labeled atoms. Examples of further isotopes that can be incorporated into the compounds of this disclosure include further isotopes of hydrogen (i.e., tritium or 3 H), as well as isotopes of carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, but not limited to, 11 C, 13 C, 14 C, 15N, 18 F, 31 P, 32 P, 35 S, 36 Cl, and 125 I is one example. This disclosure is 3 H, 13 C, and 14 The present invention further includes various isotope-labeled compounds incorporating radioactive isotopes such as 13C. Such isotope-labeled compounds may be useful in detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including metabolic studies, reaction rate studies, tissue distribution assays of drugs or substrates, or radiotherapy for patients.

[0450] The halogen may be, for example, fluorine, chlorine, bromine, and iodine, and in some embodiments it may be fluorine or chlorine, and in some embodiments it may be fluorine.

[0451] Unless otherwise specified, alkyl groups are preferably linear or branched chains of 1 to 10 carbon atoms (C 1~10 It is an alkyl group, preferably a linear or branched chain of 1 to 8 carbon atoms (C 1~8 -alkyl) and more preferably a linear or branched chain of 1 to 6 carbon atoms (C 1~6 -alkyl) and especially a linear or branched chain of 1 to 4 carbon atoms (C 1~4(-alkyl) is a linear alkyl group. Non-limiting examples of linear alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. Branched alkyl groups include any linear alkyl group substituted with any number of alkyl groups. Non-limiting examples of branched alkyl groups include isopropyl, isobutyl, sec-butyl, and t-butyl. Preferably, the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, or hexyl groups. More preferably, the alkyl group is selected from the group consisting of methyl, ethyl, isopropyl, or t-butyl groups. Unless otherwise stated, the term "alkyl" also means alkyl derivatives, which are defined in more detail below as "unsaturated alkyl groups". Unsaturated alkyl groups have one or more double bonds (i.e., "alkenyl") or triple bonds (i.e., "alkynyl"), and are preferably vinyl, 2-propenyl, clotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologues and isomers.

[0452] The alkyl group in the compounds of formulas (I) to (IV) may optionally be substituted with one or more substituents R', and in some embodiments with fluorine.

[0453] Non-limiting examples of alkyl and alkylene groups include linear, branched, and cyclic alkyl and alkylene groups. Examples of alkyl or alkylene groups include 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 , C24 , 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 The group may be substituted or unsubstituted. Non-limiting examples of alkyl groups include C 1~4 - It may be alkyl.

[0454] The terms "alkylene," "alkenylene," "alkylylene," "arylene," "heteroarylene," or "cycloalkylene" all refer to groups that are divalent and link the attached residue to the rest of the molecule. Furthermore, in the context of this invention, "C1-alkylene" refers to a methylene linker, and "C2-alkylene" refers to an ethylene linker or a methyl-substituted methylene linker, etc. In the context of this invention, alkylene preferably represents a methylene, ethylene, or propylene group. Similarly, the term "arylene" refers to a divalent aryl group that may be substituted as defined for aryl.

[0455] 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 groups. Examples of cyclic alkyl (i.e., "cycloalkyl") groups include saturated or partially unsaturated monocyclic, dicyclic, fused, crosslinked, and spirodicyclic and higher-order fused, crosslinked, and spirocyclic systems, preferably containing 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, and even more preferably 3 to 6 carbon atoms, where each atom forming the ring system (i.e., skeletal atom) is a carbon atom. The cyclic alkyl group may 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-dihydroxycyclobuta-1-yl, cyclobuta-2-en-1-yl, cyclopentyl, cyclopenta-2-en-1-yl, cyclopenta-2,4-dien-1-yl, cyclohexyl, cyclohexa-2-en-1-yl, cycloheptyl, cyclooctanyl, 2,5-dimethylcyclopenta-1-yl, 3,5-dichlorocyclohexa-1-yl, 4 Examples include hydroxycyclohexa-1-yl, 3,3,5-trimethylcyclohexa-1-yl, octahydropentalenyl, octahydro-1H-indenyl, 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl, decahydroazlenyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, 1,3-dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl. The cycloalkyl group may optionally be substituted with one or more substituents R', where R' is defined below.

[0456] 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, haloalkyloxy, aryl, arylalkyl, or heteroaryl.

[0457] R'' is independently H, D, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, heteroaryl, or aminoalkyl.

[0458] Non-limiting examples of alkyl deuterates include monodeuterates, dideuterates, trideuterates, and perdeuterates.

[0459] Non-limiting examples of alkenyl and alkenylene groups include linear, branched, and cyclic alkenyl groups. The olefin or multiple olefinic portions of the alkenyl group may be, for example, E, Z, cis, trans, terminal, or exomethylene. The alkenyl or alkenylene group may be, for example, 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 , C33 , 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 The groups may be substituted or unsubstituted. Non-limiting examples of alkenyl and alkenylene groups include ethenyl, propa-1-en-1-yl, isopropenyl, buta-1-en-4-yl, 2-chloroethenyl, 4-hydroxybuten-1-yl, 7-hydroxy-7-methylocta-4-en-2-yl, and 7-hydroxy-7-methylocta-3,5-dien-2-yl.

[0460] Non-limiting examples of alkynyl or alkynylene groups include linear, branched, and cyclic alkynyl groups. The triple bond of the alkynyl or alkynylene group may be internal or terminal. Examples of alkynyl or alkynylene groups include 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 The group may be substituted or unsubstituted. Non-limiting examples of alkynyl or alkynylene groups include ethinyl, propa-2-in-1-yl, propa-1-in-1-yl, and 2-methyl-hexa-4-in-1-yl, 5-hydroxy-5-methylhexa-3-in-1-yl, 6-hydroxy-6-methylhepta-3-in-2-yl, and 5-hydroxy-5-ethylhepta-3-in-1-yl.

[0461] A halo-alkyl group can be any alkyl group substituted with any number of halogen atoms, such as fluorine, chlorine, bromine, and iodine atoms. A non-limiting example of a halo-alkyl group is C 1~4 -It can be a haloalkyl group. The halo-alkenyl group can be any alkenyl group substituted with any number of halogen atoms. The halo-alkynyl group can be any alkynyl group substituted with any number of halogen atoms. In one embodiment, the haloalkyl is CF3.

[0462] An alkoxy group can be, for example, an oxygen atom substituted with any alkyl, alkenyl, or alkynyl group. A non-limiting example of an alkoxy is C 1~4 - May be an alkoxy. Ethers or ether groups include alkoxy groups. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, and isobutoxy. Non-limiting examples of alkyl deuterated groups include monodeuterated, dideuterated, trideuterated, and perdeuterated alkyl.

[0463] The alkylthio group represents an S-alkyl group, and the alkyl group is as defined above.

[0464] A hydroxyalkyl group is an HO-alkyl group, and alkyl groups are defined as above.

[0465] A haloalkyloxy group means an alkoxy group substituted with 1 to 5, preferably 3, halogen atoms, and the alkoxy group is as defined above, with OCF3 being preferred.

[0466] The hydroxyalkylamino group represents either an (HO-alkyl)2-N group or an HO-alkyl-NH group, where the alkyl group is as defined above.

[0467] The alkylamino group represents an -NH-alkyl or -N-dialkyl group, where alkyl groups are defined above.

[0468] The aminoalkyl group refers to an H2N-alkyl-, monoalkylaminoalkyl, or dialkylaminoalkyl group, where the alkyl group is as defined above.

[0469] The aryl group may be heterocyclic or non-heterocyclic. The aryl group may be monocyclic or polycyclic. The aryl group may be substituted with any number of substituents described herein, such as hydrocarbyl groups, alkyl groups, alkoxy groups, and halogen atoms. The aryl group may optionally be 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, toluyl, naphthyl, pyrrolyl, pyridyl, imidazolyl, thiophenyl, and furyl. 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, 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,Examples include 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.

[0470] The arylalkyl group refers to an alkyl group substituted with 1 to 3, preferably 1, aryl group, where the alkyl group and aryl group are as defined above.

[0471] A heterocyclyl group can be any ring containing a ring atom other than carbon, such as N, O, S, P, Si, B, or any other heteroatom. The heterocyclyl group may be substituted with any number of substituents, such as alkyl groups and halogen atoms. The heterocycle 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, the heterocyclyl group contains one, two, three, or four heteroatoms, each independently selected from N, O, or S. The sulfur atom in the heterocycle may be oxidized to S=O or SO2. The carbon atoms in the heterocycle may be oxidized to C=O.

[0472] Non-limiting examples of heterocyclyl groups include heterocyclyl units having a ring containing one or more heteroatoms, such as diaziridinyl, aziridinyl, azetinidyl, oxetanyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolinyl, oxathiazolidinoyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, dihydropyranyl, tetrahydropyranyl, piperidine-2-onyl, 2,3,4,5 Examples include -tetrahydro-1H-azepinyl, 2,3-dihydro-1H-indole, and 1,2,3,4-tetrahydroquinoline; and ii) heterocyclyl units having two or more rings, one of which is a heterocyclyl ring, non-limiting examples of which include hexahydro-1H-pyrrolidinyl, 3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl, 3a,4,5,6,7,7a-hexahydro-1H-indolyl, 1,2,3,4-tetrahydroquinolinyl, and decahydro-1H-cycloocta[b]pyrrolyl. The heterocyclyl group may be optionally substituted with one or more substituents R', as defined below. The heterocyclyl group can be bonded to the rest of the molecule via carbon, nitrogen (e.g., in morpholine or piperidine), or sulfur atoms. Examples of S-bonded heterocycloalkyls include cyclic sulfonimidoamides. [ka] That is the case.

[0473] Examples of heteroaryl groups include aromatic groups containing at least one heteroatom. In one embodiment, each heteroaryl group contains 1, 2, 3, or 4 heteroatoms, and the heteroatoms are independently selected from N, O, or S. Non-limiting examples of heteroaryls include i) heteroaryl rings containing one ring, non-limiting examples of which include 1,2,3,4-tetrazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, triazinyl, thiazolyl, 1H-imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, furanyl, thiophenyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3-methylpyrimidinyl, and 4-dimethylaminopyrimidinyl, and ii) Heteroaryl rings containing two or more fused rings, one of which is a heteroaryl ring, include non-limiting examples such as 7H-prinyl, 9H-prinyl, 6-amino-9H-prinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-indolyl, quinoxalinyl, quinazolinyl, quinolinyl, 8-hydroxyquinolinyl, and isoquinolinyl.

[0474] Non-limiting examples of groups having one or more hydrogen atoms optionally substituted with deuterium include the following residues when an alkyl group contains 1 to 4 carbon atoms: -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 - is an example, where n is an integer from 0 to 2, and also CH3CH2(CHD) m -, CH3CH2(CD2) m - are examples, where m is an integer from 1 to 2, and -CD(CD3)2, -CH(CD3)2, and -C(CD3)3 are also examples.

[0475] Furthermore, the compounds of the present invention undergo partial tautomerism. For example, if a heteroaromatic group containing a nitrogen atom in the ring is substituted with a hydroxyl group on a carbon atom adjacent to the nitrogen atom, the following tautomerism may occur. [ka]

[0476] In some embodiments, the compounds presented herein exist as tautomers. In environments where tautomerization is possible, a chemical equilibrium of tautomers may exist. The exact ratio of tautomers varies depending on several factors, including physical conditions, temperature, solvent, and pH. Non-limiting examples of tautomer equilibrium are given below. [ka]

[0477] If ring A is a partially saturated ring, the double bonds in ring A are located at the indicated positions. [ka] When ring A is a five-membered heteroaryl ring, the double bond is located within a delocalized π system and can exist in a mesomelic form. One example is the mesomelic form of the following thiophene. [ka]

[0478] Cycloalkyl groups or heterocyclyl groups can be linked in a linear or spirocyclic manner. For example, when cyclohexane is substituted with a heterocycloalkyl oxetane, the following structures are possible. [ka]

[0479] This disclosure provides the use of pharmaceutically acceptable salts of any compound described herein. Examples of pharmaceutically acceptable salts include acid addition salts and base addition salts. The acid added to the compound to form an acid addition salt may be an organic or inorganic acid. The base added to the compound to form a base addition salt may be an organic or inorganic base. In some embodiments, the pharmaceutically acceptable salt is a metal salt. In some embodiments, the pharmaceutically acceptable salt is an ammonium salt.

[0480] Metal salts may arise from the addition of an inorganic base to the compounds of this disclosure. The inorganic base consists of a metal cation paired with a basic counterion such as a hydroxide, carbonate, bicarbonate, or phosphate. The metal may be an alkali metal, alkaline earth metal, transition metal, or main-group element metal. In some embodiments, the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc.

[0481] In some embodiments, the metal salt is a lithium salt, sodium salt, potassium salt, cesium salt, cerium salt, magnesium salt, manganese salt, iron salt, calcium salt, strontium salt, cobalt salt, titanium salt, aluminum salt, copper salt, cadmium salt, or zinc salt.

[0482] Ammonium salts may result from the addition of ammonia or an organic amine to the compounds of the present disclosure. In some embodiments, the organic amine is triethylamine, diisopropylamine, ethanolamine, diethanolamine, triethanolamine, morpholine, N-methylmorpholine, piperidine, N-methylpiperidine, N-ethylpiperidine, dibenzylamine, piperazine, pyridine, pyrazole, piperazole (pipyrr azole), imidazole, pyrazine, or piperazine.

[0483] In some embodiments, the ammonium salt is triethylamine salt, diisopropylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, morpholine salt, N-methylmorpholine salt, piperidine salt, N-methylpiperidine salt, N-ethylpiperidine salt, dibenzylamine salt, piperazine salt, pyridine salt, pyrazole salt, piperazole salt (pipyrr particle salt), imidazole salt, pyrazine salt, or piperazine salt.

[0484] Acid addition salts may result from the addition of an acid to the compounds described herein. In some embodiments, the acid is organic. In some embodiments, the acid is inorganic. In some embodiments, the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrite, 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 hydrochloride, hydrobromide, hydroiodide, nitrate, nitrite, sulfate, sulfite, phosphate, isonicotinate, lactate, salicylate, tartrate, ascorbate, gentisinate, gluconate, glucuronate, saccharinate, formate, benzoate, glutamate, pantothenate, acetate, propionate, butyrate, fumarate, succinate, methanesulfonic acid (mesylate), ethanesulfonate, benzenesulfonate, p-toluenesulfonate, citrate, oxalate, or maleate.

[0485] In some embodiments, the compounds of the present disclosure may exist in the form of solvates, for example, those containing water as the solvate (hydrates), or solvates of pharmaceutically acceptable alcohols, particularly ethanol. Stoichiometric, substoichiometric, greater than stoichiometric, or non-stoichiometric amounts of solvent are bonded by non-covalent intermolecular forces. When the solvent is water, the “solvate” is a “hydrate.” It is understood that a “pharmaceutically acceptable salt” may further optionally include a “solvate.”

[0486] As used herein, the term “polymorph” refers to a crystalline form of a compound or its salt, hydrate, or solvate in a particular crystalline packing configuration. All polymorphs have the same elemental composition. As used herein, the term “crystalline” refers to a solid form consisting of a regular arrangement of structural units. Different crystalline forms of the same compound or its salt, hydrate, or solvate arise from different molecular packing in the solid state, resulting in different crystalline symmetries and / or unit cell parameters. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shape, optical and electrical properties, stability, and solubility.

[0487] The term "effective dose" means an amount of a compound that, when administered, is sufficient to prevent or, to some extent, alleviate the onset of one or more symptoms of the disorder, disease, or condition being treated. The term "effective dose" also refers to an amount of a compound sufficient to induce a biological or medical response in a cell, tissue, system, animal, or human, as sought by researchers, veterinarians, physicians, or clinicians.

[0488] "IMU-838" (also known as "vidofludimus calcium") is a calcium salt of vidofludimus, and in some embodiments, includes pharmaceutically acceptable solvates, hydrates, crystals, and polymorphs.

[0489] An exemplary structure of IMU-838 is the dihydrate of 2-(((3-fluoro-3'-methoxy(1,1'-biphenyl)-4-yl)amino)carbonyl)-1-cyclopentene-1-carboxylate calcium salt (2:1) having the following structure: [ka]

[0490] Polymorph A of IMU-838 is a crystalline material having the structure described above. In some embodiments, polymorph 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° in the 2-theta (±0.2°) range. In some embodiments, polymorph A of IMU-838 is characterized by the X-ray diffraction pattern outlined in Figure 7.

[0491] Listed embodiments Based on the above context, further specific aspects of the present invention are provided by the following sequentially numbered embodiments.

[0492] Embodiment 1: Compound of formula (I) for use in a method for treating a neurodevelopmental condition in a patient with a neurodevelopmental disorder, and / or a method for neuroprotection. [ka] (In the formula, Ring A has 1 to 4 residues R 1 A 5-membered or 6-membered carbocyclic or heterocyclic ring optionally substituted with, Z 1 and Z 2 These are, independently, O, S, or NR. 9 And, E is alkylene, alkenylene, alkynylene, arylene, heteroarylene, or cycloalkylene. G is O, S, SO2, NR 10 , or CH2, Y is an aryl, heteroaryl, heterocyclyl, or cycloalkyl, R 1 H, halo, -OR 13 , -SR 13 , -NR 13 R 14 , alkyl, alkenyl, alkynyl, alkoxy, aryl, cycloalkyl, heteroaryl, or heterocyclyl, R 2 H, OR11 , NR 11 Ure 11 , NR 11 SO2R 11 , or NR 11 R 12 And, R 3 H, halo, -OR 13 , -SR 13 , -NR 13 R 14 , alkyl, alkenyl, alkynyl, alkoxy, aryl, cycloalkyl, heteroaryl, or heterocyclyl, Each R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 These are independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl. n is either 0 or 1. q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. r is either 0 or 1. A pharmaceutically acceptable salt or solvate thereof (in which one or more hydrogen atoms are optionally replaced by deuterium).

[0493] Embodiment 2: A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition described in Embodiment 1, wherein the subject exhibits abnormal levels of biomarkers associated with a neurodegenerative state prior to administration.

[0494] Embodiment 3: The compound is of formula (II) [ka] (In the formula, X is O, S, NR 9 , SO, or SO2, Z 2 is O, S, or NR 12 And, E is alkylene, alkenylene, alkynylene, arylene, heteroarylene, or cycloalkylene. G is O, S, SO2, NR 10 , or CH2, Y is an aryl, heteroaryl, heterocyclyl, or cycloalkyl, R 1 H, halo, -OR 13 , -SR 13 , -NR 13 R 14 , alkyl, alkenyl, alkynyl, alkoxy, aryl, cycloalkyl, heteroaryl, or heterocyclyl, Each R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 These are independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl. m is 0, 1, 2, 3, or 4. n is either 0 or 1. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition as described in Embodiment 1 or 2, wherein q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0495] Embodiment 4: The compound is of formula (III) [ka] (In the formula, E is alkylene, alkenylene, alkynylene, arylene, heteroarylene, or cycloalkylene. Y is an aryl, heteroaryl, heterocyclyl, or cycloalkyl, R 1 H, halo, -OR 13 , -SR 13 , -NR 13 R14 , alkyl, alkenyl, alkynyl, alkoxy, aryl, cycloalkyl, heteroaryl, or heterocyclyl, and Each R 8 , R 13 , and R 14 A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to any of Embodiments 1 to 3, wherein ( is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl).

[0496] Embodiment 5: The compound is of formula (IV) [ka] (In the formula, Each R A and R B These are independently H, D, halo, -OR 13 , -SR 13 , -NR 13 R 14 , alkyl, alkenyl, alkynyl, alkoxy, aryl, cycloalkyl, heteroaryl, or heterocyclyl, Each R 8 , R 13 , and R 14 These are independently H, D, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl. x is 0, 1, 2, 3, or 4, and A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition as described in any of Embodiments 1 to 4, wherein y is 0, 1, 2, 3, 4, or 5.

[0497] Embodiment 6: The compound is of formula (V) [ka] (In the formula, Ring A is, [ka] And, E is [ka] And, Y is [ka] A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition as described in any of Embodiments 1 to 5.

[0498] Embodiment 7: The compound is [ka] A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or protecting a neurodevelopmental condition described in any of Embodiments 1 to 6.

[0499] Embodiment 7a: The compound is of formula (VI) [ka] (In the formula, R 2 , NR 11 R 12 And, R 11 It is selected from H, OH, optionally substituted alkyl, and optionally substituted cycloalkyl, wherein one or more hydrogen atoms in the alkyl or cycloalkyl are optionally substituted with deuterium. R 12 is selected from H or optionally substituted alkyl groups, where one or more hydrogen atoms in the alkyl group are optionally substituted with deuterium. Ring A is, [ka] And, E is [ka] And, Y is [ka] A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or protecting a neurodevelopmental condition as described in Embodiment 1.

[0500] Embodiment 7b: The compound is of formula (VI) [ka] (In the formula, R 2 NHR 11 And, R 11 is selected from H or alkyl, and one or more hydrogen atoms in the alkyl group are optionally substituted with deuterium. Ring A is, [ka] And, E is [ka] And, Y is [ka] A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or protecting a neurodevelopmental condition as described in Embodiment 1 or 7a.

[0501] Embodiment 7c: The compound is [ka] A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition as described in any one of Embodiments 1, 7a, or 7b.

[0502] Embodiment 8: The compound is [ka] A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or protecting a neurodevelopmental condition as described in any of Embodiments 1 to 7c.

[0503] Embodiment 9: The compound [ka] A compound of formula (I) or a solvate thereof for use in a method for treating and / or protecting a neurodevelopmental condition described in any of Embodiments 1 to 8.

[0504] Embodiment 10: A compound of formula (I) or a solvate thereof for use in a method for treating and / or protecting a neurodevelopmental condition as described in Embodiment 9, wherein the compound is a solvate, and the solvate is a dihydrate.

[0505] Embodiment 11: A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to any of Embodiments 1 to 10, wherein the neurodegenerative condition is selected from the group consisting of inflammatory conditions, non-inflammatory diseases that exacerbate neuronal loss, psychiatric conditions, neurological disorders, central nervous system conditions, Parkinson's disease, Alzheimer's disease, multiple sclerosis, PIRA, amyotrophic lateral sclerosis, schizophrenia, cerebral atrophy, and drug addiction, and the neuroprotection is slowing or preventing the loss of dopaminergic neurons.

[0506] Embodiment 12: A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition described in any of Embodiments 1 to 11, wherein the therapeutically effective dose is approximately 5 mg to approximately 100 mg.

[0507] Embodiment 13: A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to any of Embodiments 1 to 12, wherein the administration is by oral dose.

[0508] Embodiment 14: A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to any one of Embodiments 1 to 13, wherein the administration is by oral administration in solid dosage form.

[0509] Embodiment 15: The administration is carried out over a first period and a second period. a) The first period includes once-daily administration of the compound in the amount specified for the first period for at least 5 consecutive days, where the amount of the compound in the first period is approximately 5 mg to approximately 50 mg. b) The second period follows the first period, and c) A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to any of Embodiments 1 to 14, wherein the second period comprises once-daily administration of the compound in an amount equal to the amount of the second period, and the amount in the second period is greater than the amount in the first period.

[0510] Embodiment 16: The subject is a human, a) The first period consists of 5 to 10 consecutive days of once-daily administration of the compound in the amount specified for the first period, with the amount of the compound in the first period being approximately 15 mg to approximately 25 mg. b) The second period follows the first period, and c) The second period involves once-daily administration of the compound in the amount specified for the second period, where the amount for the second period is approximately 40 mg to approximately 50 mg. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or protecting a neurodevelopmental condition described in any of Embodiments 1 to 15.

[0511] Embodiment 17: A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to any of Embodiments 2 to 16, wherein the biomarker is Nurr1.

[0512] Embodiment 18: A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to any of Embodiments 2 to 16, wherein the biomarker is miR-132.

[0513] Embodiment 19: A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to any of Embodiments 2 to 16, wherein the abnormal level of a biomarker associated with a neurodegenerative condition is downregulated Nurr1.

[0514] Embodiment 20: A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to any of Embodiments 2 to 16, wherein the abnormal level of a biomarker associated with a neurodegenerative condition is upregulated miR-132.

[0515] Embodiment 21: A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to any of Embodiments 1 to 20, wherein the neurodegenerative condition is Parkinson's disease.

[0516] Embodiment 22: A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to any of Embodiments 1 to 20, wherein the neurodegenerative condition is multiple sclerosis, particularly relapsing-remitting multiple sclerosis (RMS), e.g., relapsing-remitting multiple sclerosis (RRMS) or active secondary progressive multiple sclerosis (active SPMS), or progressive multiple sclerosis, e.g., primary progressive multiple sclerosis (PPMS) or inactive secondary progressive multiple sclerosis (inactive SPMS).

[0517] Embodiment 22a. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to any of Embodiments 1 to 20, wherein the neurodegenerative condition is active SPMS.

[0518] Embodiment 22b. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to any of Embodiments 1 to 20, wherein the neurodegenerative condition is PPMS.

[0519] Embodiment 22c. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to any of Embodiments 1 to 20, wherein the neurodegenerative condition is inactive SPMS.

[0520] Embodiment A12d. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to any of Embodiments 1 to 20, wherein the neurodegenerative condition is PIRA.

[0521] Embodiment 22e. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neuroerythromatous condition according to any of Embodiments 1 to 20, wherein the neurodegenerative condition is a clinically isolated syndrome (CIS).

[0522] Embodiment 22f. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental state described in any of Embodiments 1 to 20, which is a progressive neurodegenerative MS.

[0523] Embodiment 23: A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to any of Embodiments 1 to 16, wherein the neurodegenerative condition is drug poisoning.

[0524] Embodiment 24: A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition described in Embodiment 23, wherein the subject exhibits abnormal levels of a biomarker associated with drug poisoning, and the biomarker is dopamine.

[0525] Embodiment 25: A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to Embodiment 23 or 24, wherein the drug intoxication is cocaine intoxication.

[0526] Embodiment 26: A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to Embodiment 23 or 24, wherein the drug intoxication is amphetamine intoxication.

[0527] Embodiment 27: The method is a) A step to obtain the level of Nurr1 in the target, b) A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to any of Embodiments 1 to 17, comprising the step of determining whether to administer a Nurr1 agonist to a subject based on the level of Nurr1 in the subject.

[0528] Embodiment 28: A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating and / or neuroprotecting a neurodevelopmental condition as described in Embodiment 27, wherein the level of Nurr1 in the subject is about 90% or less, preferably about 80% or less, more preferably about 70% or less, even more preferably about 60% or less, and still more preferably about 50% or less, and the determination is to administer a Nurr1 agonist to the subject.

[0529] Embodiment 29: A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition as described in 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 a Nurr1 agonist to the subject.

[0530] Embodiment 30: A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition as described in Embodiment 27, further comprising identifying that the subject has a neurodegenerative condition, wherein the level of Nurr1 in the subject is about 90% or less, preferably about 80% or less, more preferably about 70% or less, even more preferably about 60% or less, and still more preferably about 50% or less.

[0531] Embodiment 31: A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or protecting a neurodegenerative condition according to Embodiment 27, further comprising identifying that the subject has a neurodegenerative condition, where the level of Nurr1 in the subject is up to 95%, preferably at least 90%, more preferably at least 80%, even more preferably at least 70%, even more preferably at least 60%, and even more preferably at least 50% of the level in a healthy subject of the same age, sex, and / or BMI.

[0532] Embodiment 32: A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to any of Embodiments 27 to 31, further comprising administering to a subject a therapeutically effective amount of a Nurr1 agonist based on the level of Nurr1 in the subject.

[0533] Embodiment 33: The method is a) A step of obtaining the level of Nurr1 in a subject receiving treatment for a neurodegenerative condition, b) A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to any of Embodiments 1 to 17, comprising the step of determining whether to initiate or continue treatment for a neurodegenerative condition based on the level of Nurr1 in a subject, wherein the treatment is a Nurr1 agonist.

[0534] Embodiment 34: A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating and / or neuroprotecting a neurodevelopmental condition as described in Embodiment 33, wherein the level of Nurr1 in the subject is about 90% or less, preferably about 80% or less, more preferably about 70% or less, even more preferably about 60% or less, and still more preferably about 50% or less, and the decision is to initiate or continue therapy.

[0535] Embodiment 35: A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition as described in 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 initiate treatment.

[0536] Embodiment 36: A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition as described in Embodiment 33, further comprising identifying that the level of Nurr1 in the subject is about 90% or less, preferably about 80% or less, more preferably about 70% or less, even more preferably about 60% or less, and still more preferably about 50% or less, and that the subject requires initiation of treatment for or further treatment for a neurodegenerative condition.

[0537] Embodiment 37: A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating and / or neuroprotecting a neurodevelopmental condition as described in Embodiment 33, further comprising identifying that 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%, even more preferably at least 60%, and even more preferably at least 50% of the level in a healthy subject of the same age, sex, and / or BMI, and that the subject requires initiation of treatment for or further treatment for a neurodegenerative condition.

[0538] Embodiment 38: A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition as described in Embodiment 33, wherein the treatment of the neurodegenerative condition comprises administering a therapeutically effective amount of a Nurr1 agonist to the target for the neurodegenerative condition.

[0539] Embodiment 39: A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to any of Embodiments 27 to 38, wherein the step of obtaining the level of Nurr1 in the subject comprises obtaining the assay result of an ex vivo biological sample of the subject, the assay determining the level of Nurr1 in the ex vivo biological sample of the subject.

[0540] Embodiment 40: A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to any of Embodiments 27 to 38, wherein the step of obtaining the level of Nurr1 in the subject comprises performing an assay on an ex vivo biological sample of the subject, the assay determining the level of Nurr1 in the ex vivo biological sample of the subject.

[0541] Embodiment 41: A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to Embodiment 39 or 40, wherein the assay determines the level of Nurr1 in the ex vivo biological sample of interest by determining the concentration of Nurr1 in the ex vivo biological sample of interest.

[0542] Embodiment 42: A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to either Embodiment 39 or 40, wherein the assay determines the level of Nurr1 in the ex vivo biological sample of interest by determining the activity level of Nurr1 in the ex vivo biological sample of interest.

[0543] Embodiment 43: A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to any of Embodiments 39 to 40, wherein the assay is a real-time PCR assay of the expression of the Nurr1 gene against a relevant housekeeping gene / internal control (e.g., GAPDH) from tissue selected from peripheral blood, peripheral blood lymphocytes, serum, plasma, CSF, or peripheral blood mononuclear cells, (a) an immunoassay (such as ELISA) using an antibody suitable for the Nurr1 protein, or (c) a Western blot against the Nurr1 protein.

[0544] Embodiment 44: A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to any of Embodiments 39 to 43, wherein the ex vivo biological sample is a blood sample.

[0545] Embodiment 45: The method is a) A step of obtaining the level of a protein in a subject, wherein the protein is downstream of Nurr1 in the biological pathway in the subject, b) A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to any of Embodiments 1 to 17, comprising the step of determining whether to administer a Nurr1 agonist to a subject based on the level of protein in the subject.

[0546] Embodiment 46: A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition as described in Embodiment 45, wherein the level of protein in a subject indicates that the protein is upregulated.

[0547] Embodiment 47: A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition as described in Embodiment 45, wherein the level of protein in the subject indicates that the protein is downregulated.

[0548] Embodiment 48: A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to any of Embodiments 45 to 47, wherein 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.

[0549] Embodiment 49: A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to any of Embodiments 45 to 48, further comprising the step of administering a therapeutically effective amount of a Nurr1 agonist to a subject based on the level of protein in the subject.

[0550] Embodiment 50: The method is a) A step of obtaining the level of a protein in a subject being treated for a neurodegenerative condition, wherein the protein is downstream of Nurr1 in a biological pathway in the subject, and the treatment is Nurr1 receptor activation, b) A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to any of Embodiments 1 to 17, comprising the step of determining whether to continue treatment for a neurodegenerative condition based on the level of protein in the subject.

[0551] Embodiment 51: A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition described in Embodiment 50, wherein the level of protein in the subject is higher than the level before treatment.

[0552] Embodiment 52: A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodeve...

Claims

1. A compound of formula (V) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition in a subject with a neurodevelopmental disorder, wherein the compound is of formula (V) 【Chemistry 1】 (In the formula, - Ring A is, 【Chemistry 2】 And, -E is, 【Transformation 3】 And, -Y is, 【Chemistry 4】 A compound or a pharmaceutically acceptable salt or solvate thereof.

2. A compound of formula (V) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to claim 1, wherein the subject exhibits abnormal levels of biomarkers associated with a neurodegenerative state before administration.

3. The aforementioned compound, 【Transformation 5】 A compound of formula (V) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition as described in claim 1 or 2.

4. The aforementioned compound, 【Transformation 6】 A compound of formula (V) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition as described in any one of claims 1 to 3.

5. The aforementioned compound, 【Transformation 7】 A compound of formula (V) for use in a method for treating and / or neuroprotecting a neurodevelopmental condition as described in any one of claims 1 to 4.

6. A compound of formula (V) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to any one of claims 2 to 5, wherein the biomarker is Nurr1.

7. A compound of formula (V) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to any one of claims 2 to 6, wherein the abnormal level of the biomarker associated with the neurodegenerative condition is downregulated Nurr1.

8. A compound of formula (V) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to any one of claims 1 to 7, wherein the neurodegenerative condition is multiple sclerosis.

9. A compound of formula (V) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurogenesis described in any one of claims 1 to 7, wherein the neurodegenerative state is multiple sclerosis and the impairment is acquired through progression unrelated to relapsing activity (PIRA).

10. A compound of formula (V) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to any one of claims 1 to 7, wherein the neurodegenerative condition is brain atrophy induced by multiple sclerosis.

11. A compound of formula (V) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurogenesis condition according to any one of claims 1 to 7, wherein the neurodegenerative condition is an exacerbation of non-inflammatory multiple sclerosis.

12. A compound of formula (V) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurogenesis condition according to any one of claims 1 to 7, wherein the neuroprotection is to delay or prevent neuronal loss induced by multiple sclerosis.

13. A compound of formula (V) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurogenesis condition according to any one of claims 1 to 7, wherein the neuroprotection is to delay or prevent the loss of dopaminergic neurons induced by multiple sclerosis.

14. A compound of formula (V) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to any one of claims 1 to 7, wherein the neurodegenerative condition is Parkinson's disease.

15. The method described above is A step of determining the level or activity of Nurr1 in the target ex vivo biological sample using an assay selected from (a) a real-time PCR assay of Nurr1 gene expression against a relevant housekeeping gene / internal control (e.g., GAPDH), (b) an immunoassay (e.g., ELISA) using an antibody suitable for the Nurr1 protein, or (c) a Western blot for the Nurr1 protein, from a biological sample selected from peripheral blood, peripheral blood lymphocytes, serum, plasma, CSF, or peripheral blood mononuclear cells; A compound of formula (V) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to any one of claims 1 to 14, comprising the step of administering an effective amount of the compound of formula (V) or a pharmaceutically acceptable salt or solvate thereof to the patient, provided that the test sample from the patient contains a level of Nurr1 of about 90% or less of the level in a healthy subject of the same age, sex and / or BMI.

16. The method described above is a) A step of obtaining the level of a protein in a subject, wherein the protein is downstream of Nurr1 in the biological pathway in the subject, b) a compound of formula (V) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to any one of claims 1 to 14, comprising the step of determining whether to administer a Nurr1 agonist to the subject based on the level of protein in the subject.

17. A compound of formula (V) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to claim 16, wherein 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.

18. The aforementioned compound, 【Transformation 8】 A compound of formula (V) or a pharmaceutically acceptable salt or solvate thereof for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to claim 4, wherein the state is PIRA.

19. The aforementioned compound, 【Chemistry 9】 A compound of formula (V) for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to claim 5, wherein the state is PIRA.

20. A compound of formula (V) for use in a method for treating and / or neuroprotecting a neurogenesis according to claim 18 or 19, wherein the neurodegenerative state is multiple sclerosis and the impairment is acquired through progression independent of relapsing activity (PIRA).

21. A compound of formula (V) for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to claims 18 to 20, wherein the therapeutically effective dose is approximately 5 mg to approximately 100 mg.

22. A compound of formula (V) for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to any one of claims 18 to 21, wherein the administration is by oral administration in solid dosage form.

23. Compound of formula (V) for use in a method for treating and / or neuroprotecting a neurodevelopmental condition according to any one of claims 18 to 22, wherein the administration comprises a first period and a second period, a) the first period being 5 to 10 consecutive days of once-daily dosing of the amount of the compound for the first period, the amount of the compound for the first period being about 15 mg to about 25 mg, b) the second period following the first period, c) the second period comprising once-daily dosing of the amount of the compound for the second period, the amount of the compound for the second period being about 30 mg to about 50 mg.

24. A compound of formula (V) for use in a method for treating and / or neuroprotecting a neurogenesis condition according to any one of claims 18 to 23, wherein the method aims to prevent or delay disease progression and secondary damage by stopping or at least delaying (mitigating) the loss of the neurons.

25. A method for treating multiple sclerosis (MS) in a patient diagnosed with relapse-free progression (PIRA), comprising administering a compound of formula (V) to the subject, wherein the compound is 【Chemistry 10】 The method.

26. A method for treating multiple sclerosis (MS) in a subject, comprising administering a compound of formula (V) to the subject, The aforementioned compound, 【Chemistry 11】 And also The aforementioned MS is characterized by progression unrelated to recurrence (PIRA).

27. A method for treating relapse-free progression (PIRA) in a subject suffering from multiple sclerosis (MS), comprising administering a compound of formula (V) to the subject, wherein the compound is 【Chemistry 12】 The method.

28. A method for treating multiple sclerosis (MS) in a subject, comprising administering a compound of formula (V) to the subject, The aforementioned compound, 【Chemistry 13】 And also A method for which the subject has MS characterized by progression unrelated to recurrence (PIRA).

29. The method according to claim 25, wherein the patient has not had evidence of recurrence for 24 months.

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

31. The method according to claim 30, characterized in that the PMS has little to no active lesions.

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

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

34. The method according to claim 33, characterized in that the n-aSPMS has been free of lesions for 12 months.

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

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

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

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

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

40. The method according to any one of claims 25 to 39, wherein the method increases, for example, the time until deterioration of the disability in the subject is observed, compared to a control, based on the Integrated Disability Scale (EDSS).

41. The method according to any one of claims 25 to 40, wherein the method prevents and / or delays disease progression and secondary damage by stopping or at least delaying (mitigating) the loss of the neurons.

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

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

44. The method according to any one of claims 25 to 43, wherein the compound is administered over a first period and a second period, a) the first period is 5 to 10 consecutive days of once-daily dosing of the amount of the compound for the first period, the amount of the compound for the first period being about 15 mg to about 25 mg, b) the second period follows the first period, and c) the second period comprises once-daily dosing of the amount of the compound for the second period, the amount of the compound for the second period being about 30 mg to about 50 mg.

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