Nurr1 agonists with replacement of the carboxylic acid or carboxamide moiety for use in the treatment of neurodegenerative diseases

Abstract

The present relates to novel nuclear receptor related 1 (Nurr1) modulators, preferably agonists, having a new carboxylic acid / carboxamide bioisosteric moiety Y and being optionally deuterated, pharmaceutical formulations comprising them, a process for their preparation and their use as medicament, alone or in combination with one or more additional agents, for treating of various diseases, wherein the modulation of Nurr1 is beneficial in such diseases (e.g. multiple sclerosis or Parkinson's disease).

Description

[0001] 175291 WO BOEHMERT & BOEHMERT

[0002] Nurrl modulators with replacement of the carboxylic acid or carboxamide moiety

[0003] SUMMARY OF THE INVENTION

[0004] The present relates to novel nuclear receptor related 1 (Nurrl) modulators, preferably agonists, having a new carboxylic acid / carboxamide bioisosteric moiety Y and being optionally deuterated, pharmaceutical formulations comprising them, a process for their preparation and their use as medicament, alone or in combination with one or more additional agents, for treating of various diseases, wherein the modulation of Nurrl is beneficial in such diseases (e.g. multiple sclerosis or Parkinson's disease).

[0005] BACKGROUND OF THE INVENTION

[0006] Vidofludimus calcium (IMU-838) is a potent dual Nurrl agonist / dihydroorotate dehydrogenase (DHODH) inhibitor being developed for the treatment of several chronic inflammatory diseases, including relapsing-remitting multiple sclerosis (rrMS): vidofludimus

[0007] Vidofludimus calcium’s ability to activate the neuroprotective transcription factor Nurrl is associated with direct neuroprotective properties and may enhance the potential benefit for patients. Nurrl activation mediates its neuroprotective function by acting in microglia, astrocytes and neurons. In microglia and astrocytes, Nurrl activation leads to a reduction of pro- inflammatory cytokines and blocks the production of direct neurotoxic agents like reactive oxygen species and nitric oxide. Enhanced Nurrl activity in neurons mediates neuronal survival and differentiation, as well as improved neurotransmission. Therefore, activation of Nurrl by vidofludimus calcium may halt neurodegeneration and disability progression in patients suffering from MS and other degenerative diseases.

[0008] The additional mechanism of action of vidofludimus calcium is the inhibition of the intracellular metabolism of activated immune T- and B-cells by blocking the enzyme DHODH. The inhibition of the DHODH enzyme leads to metabolic stress in metabolically activated lymphocytes resulting in reduction in proinflammatory cytokines and subsequently to apoptosis of activated immune cells. Blocking of the DHODH enzyme activity has a selective effect to metabolically activated immune cells, to malignant cells and to virus-infected cells. Thus, DHODH inhibition should therefore not lead to general antiproliferative effects in other cells. IMU-838 as a second- generation DHODH inhibitor is being developed to separate the desired immunomodulatory effects from an undesirable side effect profile caused by off-target effects like neutropenia, alopecia and diarrhea. An additional benefit of DHODH inhibitors such as IMU-838 is their direct antiviral effect. During long-term treatment with immunosuppressive drugs, the reactivation of latent viruses has been observed. This can lead to serious infections, such as progressive multifocal leukoencephalopathy which can have a lethal outcome. PRIOR ART

[0009] Compounds of Formula (I) mainly containing a carboxylic acid as residue Y are described in W02004 / 056746, W02004 / 056747, W02004 / 056797, WO2010 / 052027, WO2010 / 128050, WO2012 / 001148, W02012 / 001151 , WO2015 / 169944, WO2015 / 154820, WO2018 / 177151 , WO2019 / 170848, W02019 / 101888, WO2019 / 175396, WO2022 / 214691 as well as in Bioorg. Med. Chem. Lett. 2004; 14:55, Bioorg. Med. Chem. Lett. 2005; 15:4854, Bioorg. Med. Chem. Lett. 2006;16:267, J. Med. Chem. 2006;49:1239 and ChemMedChem 2024;19:e202400292, however the modulation of Nurrl is not mentioned.

[0010] In WO2023 / 118576, optionally deuterated derivatives having a carboxylic acid bioisoster as residue Y have been described, and again no modulation of Nurrl is mentioned. For the first time structures of Formula (I) in J. Med. Chem. 2023;66:6391 and PCT / EP2024 / 058947 (filed 2. April 2024) have established the link towards Nurrl modulation, especially Nurrl agonism, when Y is selected from -C(=Z1)-R2with Z1is O, S, or NR and R2is H, OR, NR-OR, NR-SO2or NR2(with R = H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted).

[0011] As outlined in the experimental section, we surprisingly found that other Y moieties are also able to function as Nurrl modulators, especially function as Nurrl agonists.

[0012] SUMMARY OF THE INVENTION

[0013] A compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease: or an enantiomer, diastereomer, tautomer, solvate, or pharmaceutically acceptable salt thereof, wherein cycle A, B, C and residues X, Y and R2are defined as in claim 1 , with the proviso, that the following structure is excluded: The compounds of the present invention have a similar or better Nurrl agonistic activity compared to known Nurrl agonists. Additional improved microsomal stability and / or improved bioavailability can be obtained when used as medicament due to the replacement of hydrogen to deuterium at certain positions.

[0014] Thus, the present invention further relates to a pharmaceutical composition comprising a compound according to Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease and at least one pharmaceutically acceptable carrier or excipient.

[0015] The present invention is further directed to compounds according to Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease mediated by Nurrl.

[0016] Nurrl is a neuroprotective transcriptional regulator and ascribed high therapeutic potential in neurodegenerative diseases. Nurrl modulation mediates neuroprotective effects of compounds according to Formula (I) in neurodegenerative diseases or conditions

[0017] A compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease according to any one of the preceding claims, wherein said patient has a reduced level of Nurrl and / or a reduced level of Nurrl activity in neuronal cell, in particular in dopaminergic neuronal cells.

[0018] Level of Nurrl and / or Nurrl activity may be determined as described below. Reduced level of Nurrl and / or a reduced level of Nurrl activity in neuronal cell means reduced in comparison to the median level of Nurrl and / or median Nurrl activity in neuronal cell, in particular in dopaminergic neuronal cells of a healthy population. Reduced level may mean reduced expression level.

[0019] Accordingly, the present invention relates to the prophylaxis and / or treatment of the disease, disorder, therapeutic indication or medical condition which is selected from the group comprising Alexander’s disease, Alper’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), ataxia telangiectasia, Batten disease (also known as Spiel meyer-Vogt-Sjogren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, corticobasal syndrome (CBS), Creutzfeldt-Jakob disease, Down syndrome (DS), frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Huntington’s disease, HIV-associated dementia (FTD), Kennedy’s disease, Krabbe’s disease, kuru, dementia with Lewy bodies (DLB), Machado-Joseph disease (Spinocerebellar ataxia type 3), multiple sclerosis (and subgroups like relapsing form of multiple sclerosis (RMS), such as relapsing-remitting multiple sclerosis (RRMS) or active secondary progressive multiple sclerosis (active SPMS). In some embodiments, the MS is a progressive form of multiple sclerosis, such as primary progressive multiple sclerosis (PPMS), non-active secondary progressive multiple sclerosis (non-active SPMS), relapse-associated worsening (RAW) and by progression independent of relapse activity (PIRA)), multiple system atrophy, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus- Merzbacher disease, Pick’s disease, primary lateral sclerosis, prion diseases, progressive supranuclear palsy (PSP), Refsum’s disease, Sandhoff's disease, Schilder’s disease, subacute combined degeneration of spinal cord secondary to pernicious anemia, schizophrenia, drug addiction, spinocerebellar ataxia (multiple types with varying characteristics), spinal muscular atrophy, Steele-Richardson-Olszewski disease, or tabes dorsalis. More specifically, the disease, disorder, therapeutic indication or medical condition is selected from amyotrophic lateral sclerosis and Parkinson's disease. The present invention relates to the prophylaxis and / or treatment of the disease, disorder, therapeutic indication or medical condition, which is selected from Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), dementia with Lewy bodies (DLB), multiple sclerosis, PIRA and Parkinson's disease.

[0020] The present invention relates to the prophylaxis and / or treatment of the disease, disorder, therapeutic indication or medical condition, which is selected from a progressive form of multiple sclerosis, such as primary progressive multiple sclerosis (PPMS), non-active secondary progressive multiple sclerosis (non-active SPMS), relapse-associated worsening (RAW) and by progression independent of relapse activity (PIRA), preferably PIRA.

[0021] The present invention relates to the prophylaxis and / or treatment of the disease, disorder, therapeutic indication or medical condition, which is selected from a relapsing form of multiple sclerosis (RMS), such as relapsing-remitting multiple sclerosis (RRMS) or active secondary progressive multiple sclerosis (active SPMS).

[0022] The present invention relates to the prophylaxis and / or treatment of the disease, disorder, therapeutic indication or medical condition, which is selected from dementia with Lewy bodies (DLB) or Parkinson's disease, preferably Parkinson's disease.

[0023] The present invention is further directed to a pharmaceutical composition comprising a compound according to Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease and one or more additional therapeutic agents selected from anti-inflammatory agents, anti-viral agents, anti- cancer-agents, immunosuppressive and / or immunomodulatory agents, steroids, non-steroidal anti-inflammatory agents, antihistamines, analgesics and suitable mixtures thereof.

[0024] DETAILED DESCRIPTION OF THE INVENTION

[0025] Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulae. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. Rather, the invention is intended to cover all alternatives, modifications and equivalents that may be included within the scope of the present invention as defined by the claims. The present invention is not limited to the methods and materials described herein but include any methods and materials similar or equivalent to those described herein that could be used in the practice of the present invention. In the event that one or more of the incorporated literature references, patents or similar materials differ from or contradict this application, including but not limited to defined terms, term usage, described techniques or the like, this application controls.

[0026] In one aspect the invention relates to a compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease: or an enantiomer, diastereomer, tautomer, solvate, or pharmaceutically acceptable salt thereof, wherein

[0027] A is selected from a 5- or 6-membered carbocyclic or heterocyclic ring optionally containing 1 to 4 heteroatoms selected from N, O and S, said A ring is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of H, halogen, -CN, -NO2, SF5, =0 (oxo), =S, -OH, Ci-4-alkyl, -O-Ci-4-alkyl, fluoro-

[0028] Ci-4-alkyl, -O-fluoro-Ci-4-alkyl, 3- to 6-membered cycloalkyl, -0-(3- to 6-membered cycloalkyl), 3- to 8-membered heterocycloalkyl, -0-(3- to 8-membered heterocycloalkyl), CO2R11, NR11R12, CONR11R12, phenyl, 5- or 6-membered heteroaryl, wherein alkyl, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of D, halogen, -CN, OH, =0, =S, Ci-4-alkyl, Ci-4-alkyl, -O-Ci-4-alkyl and -O-fluoro-Ci-4-alkyl, ring A or its substituents having one or more hydrogen atoms optionally replaced by deuterium;

[0029] B is selected from the group consisting of phenyl and 5- or 6-membered heteroaryl, wherein phenyl and heteroaryl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, -CN, =0, =S, Ci-4-alkyl, C1-4- alkyl, -O-Ci-4-alkyl, -O-fluoro-Ci-4-alkyl; and wherein optionally two adjacent substituents in the phenyl and heteroaryl moiety form a 5- to 8-membered partially unsaturated cycle optionally containing 1 to 3 heteroatoms independently selected from O, S or N, wherein this additional cycle is optionally substituted with 1 to 4 substituents independently selected from halogen, -CN, =0, =S, -OH, Ci-4-alkyl, halo-Ci-4-alkyl; and wherein the residue -NR2on ring B is in a 1 ,4-orientation with respect to ring C, ring B or its substituents having one or more hydrogen atoms optionally replaced by deuterium;

[0030] C is selected from the group consisting of phenyl, thiophenyl, thiazolyl and pyridyl, wherein phenyl, thiophenyl, thiazolyl and pyridyl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, -CN, =0, =S, C1- 4-alkyl, Ci-4-alkyl, -O-Ci-4-alkyl, -O-fluoro-Ci-4-alkyl; and wherein optionally two adjacent substituents in the phenyl and pyridyl moiety form a 5- to 8-membered partially unsaturated cycle optionally containing 1 to 3 heteroatoms independently selected from O, S or N, wherein this additional cycle is optionally substituted with 1 to 4 substituents independently selected from halogen, -CN, =0, =S, -OH, Ci-4-alkyl, halo-Ci-4-alkyl; ring C or its substituents having one or more hydrogen atoms optionally replaced by deuterium;

[0031] X is selected from H, D, halogen, -CN, -NO2, Ci-6-alkyl, -O-Ci-6-alkyl, O-halo-Ci-6-alkyl, -O-C0-6- alkylene-phenyl, -0-Co-6-alkylene-(5- or 6-membered heteroaryl), Co-6-alkylene-OR21, Co-6- alkylene-(3- to 6-membered cycloalkyl), Co-6-alkylene-phenyl, Co-6-alkylene-(5- or 6-membered heteroaryl), Co-6-alkylene-(3- to 8-membered heterocycloalkyl), Co-6-alkylene-S(=0)n(=NR23)mR21, Co-6-alkylene-NR21S(=0)x(=NR23)yR21, C0-6-alkylene-S(=O)x(=NR23)yNR21R22, C0.6-alkylene- NR21S(=O)x(=NR23)yNR21R22, C0-6-alkylene-CO2R21, C0-6-alkylene-O-COR21, C0.6-alkylene- CONR21R22, Co-6-alkylene-NR21-COR21, C0-6-alkylene-NR21-CONR21R22, C0.6-alkylene-O- CONR21R22, Co-6-alkylene-NR21-C02R21, Co-6-alkylene-NR21R22, wherein heterocycloalkyl comprises 1 , 2, 3 or 4 heteroatoms independently selected from N, O, or S, wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, -CN, oxo, -OH, Ci-4-alkyl, halo-Ci-4-alkyl, -O-Ci-4-alkyl and -O-halo-Ci-4- alkyl, and wherein optionally two adjacent substituents in the cycloalkyl, heterocycloalkyl, phenyl and heteroaryl moiety form a 5- to 8-membered saturated, partially unsaturated or unsaturated cycle optionally containing 1 to 3 heteroatoms independently selected from O, S or N, wherein this additional cycle is optionally substituted with 1 to 4 substituents independently selected from halogen, -CN, =0, =S, -OH, Ci-4-alkyl, halo-Ci-4-alkyl;

[0032] X or its substituents having one or more hydrogen atoms optionally replaced by deuterium;

[0033] Y is selected from -B(OR11)(R12), -CONR11-CN, -CONR11-NR11R12, -NR11R12, -NR11COR12, -NR11C(=O)OR12, -NR11S(=O)n(=NR13)mR10, -NR11S(=O)x(=NR13)yNR11R12, OR11, -SO2H, -SO3H, -S(=O)n(=NR13)mR10, -S(=O)x(=NR13)yNR11R12, 3- or 8-membered carbocyclic or heterocyclic ring optionally containing 1 to 4 heteroatoms selected from N, O and S, said 3- to 8-membered carbocyclic or heterocyclic ring is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of H, halogen, -CN, - N02, SF5, =0, =S, -OH, Ci-4-alkyl, -O-Ci-4-alkyl, fluoro-Ci-4-alkyl, -O-fluoro-Ci-4-alkyl, 3- to 6-membered cycloalkyl, -0-(3- to 6-membered cycloalkyl), 3- to 8-membered heterocycloalkyl, -0-(3- to 8-membered heterocycloalkyl), CO2R11, NR11R12, CONR11R12, phenyl, 5- or 6-membered heteroaryl, wherein alkyl, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of D, halogen, -CN, OH, =0, =S, Ci-4-alkyl, Ci-4-alkyl, -O-Ci-4-alkyl, -O-fluoro-Ci-4-alkyl, -NH2, - NHCi-4-alkyl and -N(Ci-4-alkyl)2.

[0034] Y or its substituents having one or more hydrogen atoms optionally replaced by deuterium;

[0035] R2is selected from H and Ci-6-alkyl, having one or more hydrogen atoms optionally replaced by deuterium;

[0036] R10is selected from Ci-6-alkyl, 3- to 6-membered cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein alkyl, cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, -CN, Ci-4-alkyl, halo-Ci-4-alkyl, 3- to 6- membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 8-membered heterocycloalkyl, halo-(3- to 8-membered heterocycloalkyl), -OH, =0, =S, -O-Ci-4-alkyl and -O-halo-Ci-4-alkyl, wherein heterocycloalkyl comprises 1 , 2, 3 or 4 heteroatoms independently selected from N, O, or S,

[0037] R10having one or more hydrogen atoms optionally replaced by deuterium;

[0038] R11, R12, R21, R22are independently selected from H, Ci-6-alkyl, 3- to 6-membered cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein alkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, -CN, Ci-4-alkyl, halo-Ci-4-alkyl, 3- to 6- membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 8-membered heterocycloalkyl, halo-(3- to 8-membered heterocycloalkyl), -OH, =0, =S, -O-Ci-4-alkyl and -O-halo-Ci-4-alkyl, wherein heterocycloalkyl comprises 1 , 2, 3 or 4 heteroatoms independently selected from N, O, or S, R11and / or R12and / or R21and / or R22having one or more hydrogen atoms optionally replaced by deuterium; or R11and R12, R21and R22, respectively, when taken together with the atom(s) to which they are attached complete a 3- to 6-membered cycle containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N; and wherein this cycle is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, -CN, Ci-4-alkyl, halo-Ci-4-alkyl, 3- to 6-membered cycloalkyl, halo- (3- to 6-membered cycloalkyl), 3- to 8-membered heterocycloalkyl, halo-(3- to 8-membered heterocycloalkyl), -OH, =0, =S, -O-Ci-4-alkyl and -O-halo-Ci-4-alkyl,

[0039] R11and / or R12and / or R21and / or R22having one or more hydrogen atoms optionally replaced by deuterium;

[0040] R13, R23are independently selected from H, -CN, -NO2, Ci-6-alkyl, -CO-O-Ci-6-alkyl, 3- to 6- membered cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein alkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, -CN, Ci-4-alkyl, halo-Ci-4-alkyl, 3- to 6- membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 8-membered heterocycloalkyl, halo-(3- to 8-membered heterocycloalkyl), -OH, =0, =S, -O-Ci-4-alkyl and -O-halo-Ci-4-alkyl, wherein heterocycloalkyl comprises 1 , 2, 3 or 4 heteroatoms independently selected from N, O, or S,

[0041] R13and / or R23having one or more hydrogen atoms optionally replaced by deuterium; n, m are independently selected from 0 to 2; with the proviso that the sum of integer n and m for the residue linked to the same sulfur atom is independently selected from 0, 1 or 2; x, y are independently selected from 0 to 2; with the proviso that the sum of integer x and y for the residue linked to the same sulfur atom is independently selected from 1 or 2; and with the proviso, that the following structure is excluded:

[0042] In one embodiment, the compound is represented by Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease wherein or an enantiomer, diastereomer, tautomer, solvate, or pharmaceutically acceptable salt thereof, wherein

[0043] A is selected from a 5- or 6-membered carbocyclic or heterocyclic ring optionally containing 1 to 4 heteroatoms selected from N, O and S, said A ring is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of H, halogen, -CN, -NO2, SF5, =0 (oxo), =S, -OH, Ci-4-alkyl, -O-Ci-4-alkyl, fluoro-

[0044] Ci-4-alkyl, -O-fluoro-Ci-4-alkyl, 3- to 6-membered cycloalkyl, -0-(3- to 6-membered cycloalkyl), 3- to 8-membered heterocycloalkyl, -0-(3- to 8-membered heterocycloalkyl), CO2R11, NR11R12, CONR11R12, phenyl, 5- or 6-membered heteroaryl, wherein alkyl, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of D, halogen, -CN, OH, =0, =S, Ci-4-alkyl, Ci-4-alkyl, -O-Ci-4-alkyl and -O-fluoro-Ci-4-alkyl, ring A or its substituents having one or more hydrogen atoms optionally replaced by deuterium;

[0045] B is selected from the group consisting of phenyl and pyridyl, wherein phenyl and pyridyl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, -CN, =0, =S, Ci-4-alkyl, C1-4- alkyl, -O-Ci-4-alkyl, -O-fluoro-Ci-4-alkyl; and wherein optionally two adjacent substituents in the phenyl and pyridyl moiety form a 5- to 8-membered partially unsaturated cycle optionally containing 1 to 3 heteroatoms independently selected from O, S or N, wherein this additional cycle is optionally substituted with 1 to 4 substituents independently selected from halogen, -CN, =0, =S, -OH, Ci-4-alkyl, halo-Ci-4-alkyl; and wherein the residue -NR2on ring B is in a 1 ,4-orientation with respect to ring C, ring B or its substituents having one or more hydrogen atoms optionally replaced by deuterium;

[0046] C is selected from the group consisting of phenyl, thiophenyl, thiazolyl and pyridyl, wherein phenyl, thiophenyl, thiazolyl and pyridyl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, -CN, =0, =S, C1- 4-alkyl, Ci-4-alkyl, -O-Ci-4-alkyl, -O-fluoro-Ci-4-alkyl; and wherein optionally two adjacent substituents in the phenyl and pyridyl moiety form a 5- to 8-membered partially unsaturated cycle optionally containing 1 to 3 heteroatoms independently selected from O, S or N, wherein this additional cycle is optionally substituted with 1 to 4 substituents independently selected from halogen, -CN, =0, =S, -OH, Ci-4-alkyl, halo-Ci-4-alkyl; ring C or its substituents having one or more hydrogen atoms optionally replaced by deuterium;

[0047] X is selected from H, D, halogen, -CN, -NO2, Ci-6-alkyl, -O-Ci-6-alkyl, O-halo-Ci-6-alkyl, Co-6- alkylene-OR21, Co-6-alkylene-(3- to 6-membered cycloalkyl), Co-6-alkylene-(3- to 8-membered heterocycloalkyl), Co-6-alkylene-S(=0)n(=NR23)mR21, Co-6-alkylene-NR21S(=0)x(=NR23)yR21, Co-6- alkylene-S(=O)x(=NR23)yNR21R22, C0-6-alkylene-NR21S(=O)x(=NR23)yNR21R22, C0.6-alkylene- CO2R21, Co-6-alkylene-O-COR21, C0-6-alkylene-CONR21R22, C0-6-alkylene-NR21-COR21, C0-6- alkylene-NR21-CONR21R22, C0-6-alkylene-O-CONR21R22, C0-6-alkylene-NR21-CO2R21, C0-6- alkylene-NR21R22, wherein heterocycloalkyl comprises 1 , 2, 3 or 4 heteroatoms independently selected from N, O, or S, wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, -CN, oxo, -OH, Ci-4-alkyl, halo- Ci-4-alkyl, -O-Ci-4-alkyl and -O-halo-Ci-4-alkyl,

[0048] X or its substituents having one or more hydrogen atoms optionally replaced by deuterium;

[0049] Y is selected from -B(OR11)(R12), -CONR11-CN, -CONR11-NR11R12, -NR11R12, -NR11COR12, -NR11C(=O)OR12, -NR11S(=O)n(=NR13)mR10, -NR11S(=O)x(=NR13)yNR11R12, OR11, -SO2H, -SO3H, -S(=O)n(=NR13)mR10, -S(=O)x(=NR13)yNR11R12, 3- or 8-membered carbocyclic or heterocyclic ring optionally containing 1 to 4 heteroatoms selected from N, O and S, said 3- to 8-membered carbocyclic or heterocyclic ring is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of H, halogen, -CN, - NO2, SF5, =0, =S, -OH, Ci-4-alkyl, -O-Ci-4-alkyl, fluoro-Ci-4-alkyl, -O-fluoro-Ci-4-alkyl, 3- to 6-membered cycloalkyl, -0-(3- to 6-membered cycloalkyl), 3- to 8-membered heterocycloalkyl, -0-(3- to 8-membered heterocycloalkyl), CO2R11, NR11R12, CONR11R12, phenyl, 5- or 6-membered heteroaryl, wherein alkyl, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of D, halogen, -CN, OH, =0, =S, Ci-4-alkyl, Ci-4-alkyl, -O-Ci-4-alkyl and -O-fluoro-Ci-4-alkyl,

[0050] Y or its substituents having one or more hydrogen atoms optionally replaced by deuterium;

[0051] R2is selected from H and Ci-6-alkyl, having one or more hydrogen atoms optionally replaced by deuterium;

[0052] R10is selected from Ci-6-alkyl, 3- to 6-membered cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein alkyl, cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, -CN, Ci-4-alkyl, halo-Ci-4-alkyl, 3- to 6- membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 8-membered heterocycloalkyl, halo-(3- to 8-membered heterocycloalkyl), -OH, =0, =S, -O-Ci-4-alkyl and -O-halo-Ci-4-alkyl, wherein heterocycloalkyl comprises 1 , 2, 3 or 4 heteroatoms independently selected from N, O, or S,

[0053] R10having one or more hydrogen atoms optionally replaced by deuterium;

[0054] R11, R12, R21, R22are independently selected from H, Ci-6-alkyl, 3- to 6-membered cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein alkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, -CN, Ci-4-alkyl, halo-Ci-4-alkyl, 3- to 6- membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 8-membered heterocycloalkyl, halo-(3- to 8-membered heterocycloalkyl), -OH, =0, =S, -O-Ci-4-alkyl and -O-halo-Ci-4-alkyl, wherein heterocycloalkyl comprises 1 , 2, 3 or 4 heteroatoms independently selected from N, O, or S,

[0055] R11and / or R12and / or R21and / or R22having one or more hydrogen atoms optionally replaced by deuterium; or R11and R12, R21and R22, respectively, when taken together with the atom(s) to which they are attached complete a 3- to 6-membered cycle containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N; and wherein this cycle is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, -CN, Ci-4-alkyl, halo-Ci-4-alkyl, 3- to 6-membered cycloalkyl, halo- (3- to 6-membered cycloalkyl), 3- to 8-membered heterocycloalkyl, halo-(3- to 8-membered heterocycloalkyl), -OH, =0, =S, -O-Ci-4-alkyl and -O-halo-Ci-4-alkyl, R11and / or R12and / or R21and / or R22having one or more hydrogen atoms optionally replaced by deuterium;

[0056] R13, R23are independently selected from H, -CN, -NO2, Ci-6-alkyl, -CO-O-Ci-6-alkyl, 3- to 6- membered cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein alkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, -CN, Ci-4-alkyl, halo-Ci-4-alkyl, 3- to 6- membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 8-membered heterocycloalkyl, halo-(3- to 8-membered heterocycloalkyl), -OH, =0, =S, -O-Ci-4-alkyl and -O-halo-Ci-4-alkyl, wherein heterocycloalkyl comprises 1 , 2, 3 or 4 heteroatoms independently selected from N, O, or S,

[0057] R13and / or R23having one or more hydrogen atoms optionally replaced by deuterium; n, m are independently selected from 0 to 2; with the proviso that the sum of integer n and m for the residue linked to the same sulfur atom is independently selected from 0, 1 or 2; x, y are independently selected from 0 to 2; with the proviso that the sum of integer x and y for the residue linked to the same sulfur atom is independently selected from 1 or 2; and with the proviso, that the following structure is excluded:

[0058] In one embodiment, the compound is represented by Formula (I) or a solvate or pharmaceutically acceptable salt thereof, for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease wherein

[0059] Y is selected from from -CONH-CN, -CONH-NR11R12, -NHCOR12, -NHC(=O)OR12, -NHSO2R10, - NHSO2NR11R12, -SO2H, -SO3H, -SO2R10, -SO(=NR13)R10, -SO2NR11R12, 5-membered heterocyclic ring containing 1 to 4 heteroatoms selected from N, O and S, said heterocyclic ring is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of H, halogen, -CN, =0, =S, -OH, Ci-4-alkyl, -O-C1-4- alkyl, fluoro-Ci-4-alkyl, -O-fluoro-Ci-4-alkyl, CO2R11, NR11R12or CONR11R12,

[0060] Y or its substituents having one or more hydrogen atoms optionally replaced by deuterium.

[0061] In a more particular embodiment, the compound of Formula (I) or a solvate or pharmaceutically acceptable salt thereof, for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease wherein

[0062] Y is selected from from -CONH-CN, -CONH-NH2, -CONH-NH-Ci-4-alkyl, -CONH-N(Ci-4-alkyl)2, -NHCO-Ci-4-alkyl, -NHSO2-Ci-4-alkyl, -NHSO2NH2, -NHSO2NH-Ci-4-alkyl, -NHSO2N(Ci-4-alkyl)2, -SO2H, -SO3H, -SO2-Ci-4-alkyl, -SO(=NH)-Ci-4-alkyl, -SO2NH2, -SO2NH-Ci-4-alkyl, said alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, -CN, OH, =0, =S, -O-Ci-4-alkyl, -O-fluoro-Ci-4-alkyl, -NH2, -NHCi-4-alkyl and -N(Ci-4-alkyl)2,

[0063] Y or alkyl having one or more hydrogen atoms optionally replaced by deuterium.

[0064] In a more particular embodiment, the compound of Formula (I) or a solvate or pharmaceutically acceptable salt thereof, for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease wherein said alkyl is unsubstituted or substituted with 1 or 3 substituents independently selected from halogen, -CN, OH, =0, =S, -O-Ci-4-alkyl, -O-fluoro-Ci-4-alkyl, -NH2, -NHCi-4-alkyl and -N(Ci-4-alkyl)2,

[0065] Y or alkyl having one or more hydrogen atoms optionally replaced by deuterium.

[0066] In a more particular embodiment, the compound of Formula (I) or a solvate or pharmaceutically acceptable salt thereof, for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease wherein

[0067] Y is selected from from -CONH-CN, -CONH-NH2, -CONH-NH-Ci-4-alkyl, -CONH-N(Ci-4-alkyl)2, -NHCO-Ci-4-alkyl, -NHSO2-Ci-4-alkyl, -NHSO2NH2, -NHSO2NH-Ci-4-alkyl, -NHSO2N(Ci-4-alkyl)2, -SO2H, -SO3H, -SO2-Ci-4-alkyl, -SO(=NH)-Ci-4-alkyl, -SO2NH2, -SO2NH-Ci-4-alkyl, said alkyl is unsubstituted or substituted with 1 to 3 fluoro substituents, Y or alkyl having one or more hydrogen atoms optionally replaced by deuterium.

[0068] In a more particular embodiment, the compound of Formula (I) or a solvate or pharmaceutically acceptable salt thereof, for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease wherein

[0069] Y is selected from from -CONH-CN, -CONH-NH2, -CONH-NH-Ci-4-alkyl, -CONH-N(Ci-4-alkyl)2,

[0070] -NHCO-Ci-4-alkyl, -NHSO2-Ci-4-alkyl, -NHSO2NH2, -NHSO2NH-Ci-4-alkyl, -NHSO2N(Ci.4-alkyl)2,

[0071] -SO2H, -SO3H, -SO2-Ci-4-alkyl, -SO(=NH)-Ci-4-alkyl, -SO2NH2, -SO2NH-Ci-4-alkyl, said alkyl is unsubstituted or substituted with 1 or 3 fluoro substituents, Y or alkyl having one or more hydrogen atoms optionally replaced by deuterium.

[0072] In a particular embodiment, the compound of Formula (I) or a solvate or pharmaceutically acceptable salt thereof, for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease wherein

[0073] Y or methyl having one or more hydrogen atoms optionally replaced by deuterium.

[0074] In a particular embodiment, the compound of Formula (I) or a solvate or pharmaceutically acceptable salt thereof, for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease wherein

[0075] Y or methyl having one or more hydrogen atoms optionally replaced by deuterium.

[0076] In an even more particular embodiment, the compound of Formula (I) or a solvate or pharmaceutically acceptable salt thereof, for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease wherein Y is selected from from -CONH-CN, -CONH-NH2, -CONH-NHMe, -CONH-NMe2,

[0077] Y or alkyl having one or more hydrogen atoms optionally replaced by deuterium.

[0078] In an even more particular embodiment, the compound of Formula (I) or a solvate or pharmaceutically acceptable salt thereof, for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease wherein Y is selected from from

[0079] Y or methyl having one or more hydrogen atoms optionally replaced by deuterium.

[0080] In a particular embodiment, the compound of Formula (I) or a solvate or pharmaceutically acceptable salt thereof, for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease wherein

[0081] said A is unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of H, F, Cl, Br, -CN, -OH, =0, Ci-4-alkyl, -O-Ci-4-alkyl, fluoro-Ci-4-alkyl, -O-fluoro- Ci-4-alkyl, CO2R11, NR11R12and CONR11R12, ring A or its substituents having one or more hydrogen atoms optionally replaced by deuterium;

[0082] R2is H;

[0083] R11and R12are independently selected from H, Ci-6-alkyl, 3- to 6-membered cycloalkyl or 3- to 8- membered heterocycloalkyl, wherein alkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, -CN, Ci-4-alkyl, halo-Ci-4-alkyl, 3- to 6- membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 8-membered heterocycloalkyl, halo-(3- to 8-membered heterocycloalkyl), -OH, =0, =S, -O-Ci-4-alkyl and -O-halo-Ci-4-alkyl, wherein heterocycloalkyl comprises 1 , 2, 3 or 4 heteroatoms independently selected from N, O, or S, or R11and R12, when taken together with the atom(s) to which they are attached complete a 3- to 6-membered cycle containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N; and wherein this cycle is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, -CN, Ci-4-alkyl, halo-Ci-4-alkyl, 3- to 6-membered cycloalkyl, halo- (3- to 6-membered cycloalkyl), 3- to 8-membered heterocycloalkyl, halo-(3- to 8-membered heterocycloalkyl), -OH, =0, =S, -O-Ci-4-alkyl and -O-halo-Ci-4-alkyl,

[0084] R11and / or R12having one or more hydrogen atoms optionally replaced by deuterium.

[0085] In a more particular embodiment, the compound of Formula (I) or a solvate or pharmaceutically acceptable salt thereof, for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease wherein ring A having one or more hydrogen atoms optionally replaced by deuterium; and R2is H.

[0086] In an even more particular embodiment, the compound of Formula (I) or a solvate or pharmaceutically acceptable salt thereof, for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease wherein ring A having one or more hydrogen atoms optionally replaced by deuterium; and R2is H.

[0087] In a most particular embodiment, the compound of Formula (I) or a solvate or pharmaceutically acceptable salt thereof, for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease wherein

[0088] In a particular embodiment, the compound of Formula (I) or a solvate or pharmaceutically acceptable salt thereof, for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease wherein

[0089] B is selected from the group consisting of phenyl and 5- or 6-membered heteroaryl, wherein phenyl and heteroaryl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, -CN, =0, =S, Ci-4-alkyl, C1-4- alkyl, -O-Ci-4-alkyl, -O-fluoro-Ci-4-alkyl; and wherein optionally two adjacent substituents in the phenyl and heteroaryl moiety form a 5- to 8-membered partially unsaturated cycle optionally containing 1 to 3 heteroatoms independently selected from O, S or N, wherein this additional cycle is optionally substituted with 1 to 4 substituents independently selected from halogen, -CN, =0, =S, -OH, Ci-4-alkyl, halo-Ci-4-alkyl; and wherein the residue -NR2on ring B is in a 1 ,4-orientation with respect to ring C, ring B or its substituents having one or more hydrogen atoms optionally replaced by deuterium; In a particular embodiment, the compound of Formula (I) or a solvate or pharmaceutically acceptable salt thereof, for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease wherein

[0090] B is phenyl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of F, Cl, -CN, Ci-4-alkyl, Ci-4-alkyl, -O-Ci-4-alkyl, -O-fluoro-Ci-4-alkyl; ring B or its substituents having one or more hydrogen atoms optionally replaced by deuterium; and wherein the residue -NR2on ring B is in a 1 ,4-orientation with respect to ring C.

[0091] In a more particular embodiment, the compound of Formula (I) or a solvate or pharmaceutically acceptable salt thereof, for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease wherein and wherein the residue -NR2on ring B is in a 1 ,4-orientation with respect to ring C.

[0092] In a more particular embodiment, the compound of Formula (I) or a solvate or pharmaceutically acceptable salt thereof, for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease wherein -NR2B is phenyl, which is optionally substituted with 1 to 4 fluoro substituents, and wherein the residue -NR2on ring B is in a 1 ,4-orientation with respect to ring C.

[0093] In a more particular embodiment, the compound of Formula (I) or a solvate or pharmaceutically acceptable salt thereof, for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease wherein -NR2B is phenyl, which is substituted with 1 to 4 fluoro substituents, and wherein the residue -NR2on ring B is in a 1 ,4-orientation with respect to ring C.

[0094] In a more particular embodiment, the compound of Formula (I) or a solvate or pharmaceutically acceptable salt thereof, for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease wherein

[0095] -NR2B is selected from and wherein the residue -NR2on ring B is in a 1 ,4-orientation with respect to ring C.

[0096] In an even more particular embodiment, the compound of Formula (I) or a solvate or pharmaceutically acceptable salt thereof, for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease wherein -NR2B is selected from and wherein the residue -NR2on ring B is in a 1 ,4-orientation with respect to ring C.

[0097] In a particular embodiment, the compound of Formula (I) or a solvate or pharmaceutically acceptable salt thereof, for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease wherein

[0098] C is phenyl, which is optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, -CN, Ci-4-alkyl, Ci-4-alkyl, -O-Ci-4-alkyl, -O-fluoro-Ci-4-alkyl; and wherein optionally two adjacent substituents in the phenyl and pyridyl moiety form a 5- to 8-membered partially unsaturated cycle optionally containing 1 to 3 heteroatoms independently selected from O, S or N, wherein this additional cycle is optionally substituted with 1 to 4 substituents independently selected from halogen, -CN, =0, =S, -OH, Ci-4-alkyl, halo-Ci-4-alkyl; ring C or its substituents having one or more hydrogen atoms optionally replaced by deuterium.

[0099] In a more particular embodiment, the compound is represented by Formula (I) or a solvate or pharmaceutically acceptable salt thereof, for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease wherein

[0100] C is phenyl, pyridyl or thiazolyl, wherein phenyl, pyridyl or thiazolyl is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of D, F, Cl, -CN, C1-4- alkyl, fluoro-Ci-4-alkyl, O-Ci-4-alkyl and O-fluoro-Ci-4-alkyl, wherein alkyl having one or more hydrogen atoms optionally replaced by deuterium;

[0101] X is selected from D, F, Cl, -CN, Ci-4-alkyl, fluoro-Ci-4-alkyl, O-Ci-4-alkyl and O-fluoro-Ci-4-alkyl, wherein alkyl having one or more hydrogen atoms optionally replaced by deuterium.

[0102] In an even more particular embodiment, the compound is represented by Formula (I) or a solvate or pharmaceutically acceptable salt thereof, for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease wherein

[0103] C is phenyl, wherein phenyl is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of D, F, Cl, -CN, Me, CD3, CHF2, CF3, -OMe, -OCD3, -OCHF2 and -OCF3;

[0104] X is selected from D, F, Cl, -CN, Me, CD3, CHF2, CF3, Et, CD2CD3, -OMe, -OCD3, -OCHF2, -OCF3, -OEt and -OCD2CD3. In one particular embodiment, iSselected from ring C or its alkyl substituent having one or more hydrogen atoms optionally replaced by deuterium.

[0105] C or its alkyl substituent having one or more hydrogen atoms optionally replaced by deuterium.

[0106] In one particular embodiment, selected from , wherein the ring C is optionally substituted with 1 to 4 substituents selected from D and F.

[0107] _ / Q\_ X

[0108] In one more particular embodiment,;is selected from

[0109] ?— (C )— X

[0110] In one more particular embodiment, O jSselected from

[0111] In a more particular embodiment, the compound is represented by Formula (I) or a solvate or pharmaceutically acceptable salt thereof, for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease wherein In a particular embodiment, the compound is represented by Formula (I) or a solvate or pharmaceutically acceptable salt thereof, for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease wherein wherein ring C is optionally substituted with 1 to 4 substituents independently selected from D or F.

[0112] In a more particular embodiment, the compound is represented by Formula (I) or a solvate or pharmaceutically acceptable salt thereof, for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease wherein one or more hydrogen atom(s) in any substituent is replaced by deuterium, provided, that the level of deuterium incorporation at each substituent designated as deuterium is at least 52.5%.

[0113] In a more particular embodiment, the compound is represented by Formula (I) or a solvate or pharmaceutically acceptable salt thereof, for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease wherein one or more hydrogen atom(s) in ring C or any substituent of ring C is replaced by deuterium.

[0114] In a most particular embodiment, the compound is represented by Formula (I) or a solvate or pharmaceutically acceptable salt thereof, for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease wherein one or more hydrogen atom(s) in residue X is replaced by deuterium.

[0115] In one embodiment, R10is selected from Ci-6-alkyl, 3- to 6-membered cycloalkyl or 3- to 8- membered heterocycloalkyl, wherein alkyl, cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, -CN, Ci-4-alkyl, halo-Ci-4-alkyl, 3- to 6- membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 8-membered heterocycloalkyl, halo-(3- to 8-membered heterocycloalkyl), -OH, =0, =S, -O-Ci-4-alkyl and -O-halo-Ci-4-alkyl, wherein heterocycloalkyl comprises 1 , 2, 3 or 4 heteroatoms independently selected from N, O, or S, having one or more hydrogen atoms optionally replaced by deuterium;

[0116] In one embodiment, R10is selected from Ci-3-alkyl, cyclopropyl or oxetan-3-yl, wherein alkyl, cyclopropyl or oxetan-3-yl is unsubstituted or substituted with 1 to 3 substituents independently selected from F, -CN, Me, CHF2, CF3, -OH, oxo, -OMe, -OCHF2 and -OCF3; R10having one or more hydrogen atoms optionally replaced by deuterium.

[0117] In one embodiment, R10is selected from Ci-6-alkyl, 3- to 6-membered cycloalkyl or 3- to 8- membered heterocycloalkyl, wherein alkyl, cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, -CN, Ci-4-alkyl, halo- Ci-4-alkyl, 3- to 6-membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 8-membered heterocycloalkyl, halo-(3- to 8-membered heterocycloalkyl), -OH, oxo, -O-Ci-4-alkyl and -O-halo- Ci-4-alkyl, wherein heterocycloalkyl comprises 1 , 2, 3 or 4 heteroatoms independently selected from N, O, or S; R10having one or more hydrogen atoms optionally replaced by deuterium.

[0118] In a particular embodiment, R10is Ci-6-alkyl, which is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, -CN, Ci-4-alkyl, halo-Ci-4-alkyl, -OH, oxo, -O- Ci-4-alkyl and -O-halo-Ci-4-alkyl; R10having one or more hydrogen atoms optionally replaced by deuterium.

[0119] In a more particular embodiment, R10is Ci-3-alkyl, which is unsubstituted or substituted with 1 to 3 substituents independently selected from fluoro, -CN and -OH; R10having one or more hydrogen atoms optionally replaced by deuterium.

[0120] In an even more particular embodiment, R10is CH3, CD3, CH2CH2OH or CD2CD2OH.

[0121] In one embodiment, R11and R12are independently selected from H, Ci-6-alkyl, 3- to 6-membered cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein alkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, -CN, Ci-4-alkyl, halo-Ci-4-alkyl, 3- to 6- membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 8-membered heterocycloalkyl, halo-(3- to 8-membered heterocycloalkyl), -OH, =0, =S, -O-Ci-4-alkyl and -O-halo-Ci-4-alkyl, wherein heterocycloalkyl comprises 1 , 2, 3 or 4 heteroatoms independently selected from N, O, or S,

[0122] R11and / or R12having one or more hydrogen atoms optionally replaced by deuterium; or R11and R12, when taken together with the atom(s) to which they are attached complete a 3- to 6-membered cycle containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N; and wherein this cycle is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, -CN, Ci-4-alkyl, halo-Ci-4-alkyl, 3- to 6-membered cycloalkyl, halo- (3- to 6-membered cycloalkyl), 3- to 8-membered heterocycloalkyl, halo-(3- to 8-membered heterocycloalkyl), -OH, =0, =S, -O-Ci-4-alkyl and -O-halo-Ci-4-alkyl,

[0123] R11and / or R12having one or more hydrogen atoms optionally replaced by deuterium.

[0124] In one embodiment, R11and R12are independently selected from H or Ci-3-alkyl, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from F, -CN, Me, CHF2, CF3, -OH, oxo, -OMe, -OCHF2 and -OCF3; R11and / or R12having one or more hydrogen atoms optionally replaced by deuterium.

[0125] In a particular embodiment, R11and R12are independently selected from H, CH3, CD3.

[0126] In a more particular embodiment, R11and R12are H.

[0127] In one embodiment, R13is selected from H, -CN and Ci-3-alkyl, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from F, -CN, Me, CHF2, CF3, -OH, oxo, -OMe, -OCHF2 and -OCF3; R13having one or more hydrogen atoms optionally replaced by deuterium.

[0128] In a more particular embodiment, R13is H.

[0129] In one embodiment, R21and R22are independently selected from H, Ci-6-alkyl, 3- to 6-membered cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein alkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, -CN, Ci-4-alkyl, halo-Ci-4-alkyl, 3- to 6- membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 8-membered heterocycloalkyl, halo-(3- to 8-membered heterocycloalkyl), -OH, =0, =S, -O-Ci-4-alkyl and -O-halo-Ci-4-alkyl, wherein heterocycloalkyl comprises 1 , 2, 3 or 4 heteroatoms independently selected from N, O, or S,

[0130] R21and / or R22having one or more hydrogen atoms optionally replaced by deuterium; or R21and R22, when taken together with the atom(s) to which they are attached complete a 3- to 6-membered cycle containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N; and wherein this cycle is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, -CN, Ci-4-alkyl, halo-Ci-4-alkyl, 3- to 6-membered cycloalkyl, halo- (3- to 6-membered cycloalkyl), 3- to 8-membered heterocycloalkyl, halo-(3- to 8-membered heterocycloalkyl), -OH, =0, =S, -O-Ci-4-alkyl and -O-halo-Ci-4-alkyl,

[0131] R21and / or R22having one or more hydrogen atoms optionally replaced by deuterium;

[0132] In one embodiment, R21and R22are independently selected from H, CH3, CD3.

[0133] In one embodiment, R23is selected from H, -CN and Ci-3-alkyl, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from F, -CN, Me, CHF2, CF3, -OH, oxo, -OMe, -OCHF2 and -OCF3; R23having one or more hydrogen atoms optionally replaced by deuterium.

[0134] In a more particular embodiment, R23is H.

[0135] In a particular embodiment, the compound or a solvate or pharmaceutically acceptable salt thereof for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease is selected from the Examples shown in the Experimental Part.

[0136] In a particular embodiment, the compound or a solvate or pharmaceutically acceptable salt thereof for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease is selected from

[0137]

[0138] In one embodiment the patient exhibits an aberrant level of a biomarker associated with multiple sclerosis prior to the administering.

[0139] In some embodiments, the disclosure provides a method comprising: a) determining a level of Nurrl in a patient; and b) based on the level of Nurrl in the patient, determining whether to administer to the patient a Nurrl agonist.

[0140] In some embodiments, the disclosure provides a method comprising: a) determining a level of Nurrl in a patient who is undergoing a therapy for a neurodegenerative condition; and b) based on the level of Nurrl in the patient, determining whether to continue the therapy for the neurodegenerative condition, wherein the therapy is Nurrl agonism.

[0141] In some embodiments, the disclosure provides a method comprising: a) determining a level of a protein in a patient, wherein the protein is downstream of Nurrl in a biological pathway in the patient; and b) based on the level of the protein in the patient, determining whether to administer to the patient a Nurrl agonist. In some embodiments, the disclosure provides a method comprising: a) determining a level of a protein in a patient who is undergoing a therapy for a neurodegenerative condition, wherein the protein is downstream of Nurrl in a biological pathway in the patient, wherein the therapy is Nurrl agonism; and b) based on the level of the protein in the patient, determining whether to continue the therapy for the neurodegenerative condition.

[0142] In some embodiments, the disclosure provides a method comprising: a) determining a level of activity of a gene in a patient, wherein the gene is downstream of Nurrl in a biological pathway in the patient; and b) based on the level of activity of the gene in the patient, determining whether to administer to the patient a Nurrl agonist for a neurodegenerative condition.

[0143] In some embodiments, the disclosure provides a method comprising: a) determining a level of activity of a gene in a patient who is undergoing a therapy for a neurodegenerative condition, wherein the gene is downstream of Nurrl in a biological pathway in the patient, wherein the therapy is Nurrl agonism; and b) based on the level of activity of the gene in the patient, determining whether to continue the therapy for the neurodegenerative condition.

[0144] In some embodiments, the disclosure provides a method comprising: a) determining that a patient exhibits downregulated Nurrl ; b) determining that the patient exhibits upregulated miR-132; and c) based on the determining that the patient exhibits downregulated Nurrl and the determining that the patient exhibits upregulated miR-132, identifying the patient as being at risk for a condition.

[0145] In some embodiments, the disclosure provides a method comprising: a) determining a level or activity of Nurrl in an ex vivo biological sample of a patient with an assay selected from (a) a realtime PCR assay of Nurrl gene expression against relevant housekeeping genes / internal controls (e.g. GAPDH), (b) an immunoassay (such as ELISA) with the suitable antibodies for Nurrl protein, and (c) a Western blot for Nurrl protein from the biological sample selected from peripheral blood, peripheral blood lymphocytes, serum, plasma, CSF and peripheral blood mononuclear cells; and b) if the level or activity of Nurrl is no greater than about 90% of the level in a healthy subject of same age, gender and / or BMI, administering to the patient a therapeutically-effective amount of a compound herein. Representative descriptions can be found in PLoS ONE 2010; 5:e8962, Arch. Neurol. 2011 ;68:879 or J. Neuroimmunol. 2014;272:99.

[0146] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof is for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease, wherein the neurodegenerative disease is selected from Alexander’s disease, Alper’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, corticobasal syndrome (CBS), Creutzfeldt-Jakob disease, Down syndrome (DS), frontotemporal dementia, Gerstmann- Straussler-Scheinker syndrome, Huntington’s disease, HIV-associated dementia (FTD), Kennedy’s disease, Krabbe’s disease, kuru, dementia with Lewy bodies (DLB), Machado-Joseph disease (Spinocerebellar ataxia type 3), multiple sclerosis (and subgroups like relapsing form of multiple sclerosis (RMS), such as relapsing-remitting multiple sclerosis (RRMS) or active secondary progressive multiple sclerosis (active SPMS). In some embodiments, the MS is a progressive form of multiple sclerosis, such as primary progressive multiple sclerosis (PPMS), non-active secondary progressive multiple sclerosis (non-active SPMS), relapse-associated worsening (RAW) and by progression independent of relapse activity (PIRA)), multiple system atrophy, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick’s disease, primary lateral sclerosis, prion diseases, progressive supranuclear palsy (PSP), Refsum’s disease, Sandhoffs disease, Schilder’s disease, subacute combined degeneration of spinal cord secondary to pernicious anemia, schizophrenia, drug addiction, spinocerebellar ataxia (multiple types with varying characteristics), spinal muscular atrophy, Steele-Richardson- Olszewski disease, or tabes dorsalis.

[0147] In a particular embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof is for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease, wherein the neurodegenerative condition is selected from the group consisting of an inflammatory condition, a non-inflammatory disease worsening loss of neurons, a mental condition, a neurological disorder, a central nervous system condition, Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, PIRA, amyotrophic lateral sclerosis, schizophrenia, brain atrophy, and drug addiction, and wherein the neuroprotection is slowing or preventing loss of dopaminergic neurons.

[0148] In a more particular embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof is for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease, wherein the neurodegenerative condition is Alzheimer’s disease.

[0149] In a more particular embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof is for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease, wherein the neurodegenerative condition is amyotrophic lateral sclerosis.

[0150] In a more particular embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof is for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease, wherein the neurodegenerative condition is multiple sclerosis. In some embodiments, the MS is a relapsing form of multiple sclerosis (RMS), such as relapsing-remitting multiple sclerosis (RRMS) or active secondary progressive multiple sclerosis (active SPMS). In some embodiments, the MS is a progressive form of multiple sclerosis, such as primary progressive multiple sclerosis (PPMS) or non-active secondary progressive multiple sclerosis (non-active SPMS). In some embodiments the patient in need of the above-mentioned method for treating MS is human, in some embodiment particularly female humans. In some embodiments the patient in need of the above- mentioned method for treating MS belongs to the patient group with a pediatric-onset MS (POMS), which means an onset until the age of 18. In some embodiments the patient in need of the above- mentioned method for treating MS belongs to the patient group with a late-onset MS (LOMS), which means an onset in the time period from 19-50 years. In some embodiments the patient in need of the above-mentioned method for treating MS belongs to the patient group with an adultonset MS (AOMS), which means an onset >50 years (The age of a patient at onset MS seems to be e.g. a PIRA-associated factor: In one study AOMS compared with POMS has a hazard ratio of 1.42; LOMS compared with POMS has a hazard ratio of 2.98 (JAMA Neurol. 2024;81 :50). Other PIRA-associated factors seem to be the length of time of the disease (the higher the disease terms the higher the PIRA risk) and the length of time of the treatment with a DMT (the shorter the term of treatment with DMT the higher the PIRA risk)). In some embodiments the patient in need of the above-mentioned method for treating MS belongs to the patient group with clinically isolated syndrome (CIS). In some embodiments the patient in need of the above- mentioned method for treating MS belongs to the patient group characterized as transitioning MS patient. In some embodiments the patient in need of a method for preventing and or treating MS belongs to the patient group before or around onset MS or while not yet diagnosed MS if there are one or more indications e.g. by biomarkers and or genetic dispositions and or symptoms like MS prodrom which increase the risk score. Generally, onset MS means that there has been taken place a first demyelinating event. As there are many cases, e.g. patients with the the so-called benign MS, that remain undetected over many years it could be of advantage to include them into a treatment according to the invention even during the term before the detection of the MS disease, if they have a correspondent increased risk score, which can be determined by suitable biomarkers and genetic disposition.

[0151] In a more particular embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof is for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease, wherein the neurodegenerative condition is Parkinson’s disease.

[0152] In a more particular embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof is for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease, wherein the neuroprotection is slowing or preventing loss of dopaminergic neurons.

[0153] In some embodiments, the disease caused by lower levels of Nurrl is a cancer.

[0154] Neurodegenerative diseases may be characterized by a change in a measurement of a biomarker in a patient that has, is suspected of having, or is at risk for developing a neurodegenerative disease, as compared to a reference measurement. In some embodiments, the reference measurement is a measurement of the biomarker obtained from a healthy control patient. In some embodiments, the measurement of the biomarker is an increase or a decrease in expression and / or activity of the biomarker, and / or the rate of change of the expression and / or activity of the biomarker. For example, low levels of Nurrl in the central nervous system of a patient when compared to a reference may indicate neurodegenerative disease in the patient.

[0155] In some embodiments, biomarkers associated with neurodegenerative diseases include but are not limited to Nurrl , GFAP, miR132, neurofilament light chain (NFL), BDNF, GDNF, C-RET, YKL- 40 (CHI3L1), DAT, pituitary homeobox 3 (Pitx3), tyrosine hydroxylase (TH), vesicular monoamine transporter 2 (VMAT2), superoxide dismutase (SOD), and aromatic amino acid decarboxylase (AADC). In some embodiments, a change in a measurement of one or more of these biomarkers indicates neurodegenerative disease.

[0156] Nurrl or NR4A2 is the protein that in humans is encoded by the NR4A2 gene. Nurrl is a nuclear receptor and plays a key role in the maintenance of the dopaminergic system of the brain. The term “Nurrl” may refer to the nucleotide sequence or protein sequence of human NR4A2 (e.g., Entrez 4929, Uniprot P43354, RefSeq NM_006186.3, or RefSeq NP_006177.1).

[0157] Nurrl patients, for example, often exhibit lower Nurrl expression or have lower levels of Nurrl protein than healthy controls have. Expression can be determined by measuring Nurrl RNA levels or Nurrl protein level in blood derived cells. The activity of Nurrl can also be determined by measuring the amount of target genes or the related protein levels which are regulated 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). The activity of Nurrl can also be determined by measuring a corresponding cellular phenotype. For example, one can measure the regulation of apoptosis / survival in neurons (this can for example be determined by measurement of NFL in serum or plasma or CSF of patients). Nurrl activation induces survival factors for dopaminergic neurons. Loss of this survival signal leads to an increased number of dying neurons. It is known from literature, that NFL is a marker for axonal damage of dying neurons. Therefore, Nurrl activation by compound according to Formula (I) may reduce the levels of NFL in serum, plasma, or CSF.

[0158] Glial fibrillary acidic protein (GFAP) is a type III intermediate filament (IF) protein and is a marker for brain injury. GFAP is expressed in cells of the central nervous system including astrocytes. Levels of GFAP in patients' serum correlate with neurodegeneration aspects mediated by astrocytes. Astrocytes that become activated increase their production of GFAP. GFAP can be degraded into GFAP-BDP. Both products can be detected in the CSF, serum, or plasma due to astrocyte injury (see e.g. Trends Neurosci. 2015;38:364). In some embodiments, Nurrl activity reduces astrogliosis and thereby reduce astrocyte injury which results in reduced GFAP / BDP levels, when activated by a compound according to Formula (I).

[0159] The relative expression of the Nurrl protein or target gene in healthy controls and patients has been reviewed in Int. J. Mol. Sci. 2019;20:4858. The relative expression of Nurrl in patients or healthy controls can be obtained from peripheral blood via peripheral blood lymphocytes separation, total RNA extraction and then real-time PCR assay of Nurrl gene expression against internal control GAPDH (see e.g., J. Neurol. Sci. 2008;273:29).

[0160] The term “NR4A3” refers to the nuclear receptor 4A3 (nuclear receptor subfamily 4, group A, member 3; NR4A3) also known as neuron-derived orphan receptor 1 (NOR1), which is a protein that in humans is encoded by the NR4A3 gene. NR4A3 is a member of the nuclear receptor family of intracellular transcription factors. miR-132 is a short, non-coding RNA molecule. This microRNA regulates the expression levels of other genes by several mechanisms, generally reducing protein levels through the cleavage of mRNAs or the repression of their translation. miR-132 expression in serum, plasma or CSF can be used to determine Nurrl brain expression levels and is in some embodiments a marker that can be used to distinguish patients who might benefit more from treatment with a compound according to Formula (I).

[0161] Neurofilament light chain (NFL) is a marker for axonal damage and neuron destruction in general and specifically in MS. Low levels of NFL correlate with protection / survival of neurons. In PD, where Nurrl shows lower expression levels compared to healthy volunteers and low levels of Nurrl are significantly associated with dopaminergic neuron loss, NFL is a potential biomarker for motor decline. The cardinal motor symptoms of PD are caused by the death of dopaminergic neurons in the substantia nigra pars compacta. Nurrl activation leads to survival signals within neurons and therefore lower levels of NFL might be an outcome of Nurrl activation (e.g., caused by compound according to Formula (I) and beneficial for patients with neurodegenerative diseases.

[0162] Quantification of NFL in blood and CSF can be assessed by a highly sensitive electrochemiluminescence (ECL) based immunoassay (e.g. PLOS One 2013;8:e75091). For blood samples, in which NFL levels are lower compared to CSF, the single-molecule or “Simoa” assay (Quanterix Corp.) is currently the most used method, because it is very sensitive with a lower limit of quantitation of 0.1 pg / mL (eBioMedicine 2024; 101 : 104970). Quanterix received FDA breakthrough device designation for the method in 2022 to test for NFL in MS patients.

[0163] In some embodiments, NFL level in blood and CSF is measured by an electrochemiluminescence (ECL) based immunoassay. In some embodiments, NFL level in blood is measured by a singlemolecule or “Simoa” assay (Quanterix Corp.).

[0164] The same applies for the Roche Elecsys platform, which might become also one of the standards to be used.

[0165] In some embodiments, patients with a neurological disease have higher NFL levels in serum (sNFL), e.g., AD (30.8 pg / mL), GBS (79.4 pg / mL) or ALS (95.4 pg / mL) than do neurological patients without evidence of structural central nervous system (CNS) damage and healthy controls. Similar differences were seen in corresponding CSF samples (PLOS One 2013;8:e75091). The NFL levels increase during normal aging, e.g., from mean sNFL of 20.4 pg / mL at age <50 years to mean sNFL of 45.9 pg / mL at age >70 years (Nat. Commun. 2020; 11 :812), indicating an acceleration of neuronal injury at higher age, which may be driven by subclinical comorbid pathologies. This must be considered when defining the level of NFL for the healthy control or the success of treatment with a compound according to Formula (I). An overview of neurofilaments as biomarkers in neurological disorders is given in Nat. Rev. Neurol. 2018;14:577. In addition to NFL, Yuang and Nixon describe other neurofilament proteins, which can be quantified and monitored during the treatment of a neurological disease (Front. Neurosci. 2021 ;15:689938).

[0166] Brain-derived neurotrophic factor (BDNF) is a protein of which expression levels are controlled by Nurrl . Nurrl activation leads to enhanced BDNF expression. Measurement of the mature form of the BDNF protein in plasma, serum or CSF can be used as a marker for Nurrl activity and to assess the treatment effect with a compound according to Formula (I). Increased mature BDNF level correlate to higher neuron survival. Various BDNF isoform protein levels in CSF, blood and plasma samples can be determined with commercially available immunoassay kits (see e.g., Int. J. Neuropsychopharmacol. 2011 ; 14:347 or Nat. Rev. Neurosci. 2005;6:603).

[0167] Glial cell line-derived neurotrophic factor (GDNF) is also a target gene of Nurrl . Nurrl activation leads to enhanced GDNF expression. Measurement of GDNF expression in plasma, serum or CSF can be used as a marker for Nurrl activity and to assess the treatment effect with a compound according to Formula (I). Increased GDNF levels correlate to higher neuron survival.

[0168] C-RET is the RET proto-oncogene and encodes a receptor tyrosine kinase for members of the GDNF family of extracellular signaling molecules and promotes survival of the dopaminergic neuron. Nurrl activity induces C-RET expression in dopamine neurons. C-RET expression can be measured on RNA or protein level from brain biopsies taken from patients with neurodegenerative diseases. In some embodiments, lower expression C-RET in the brain of patients with neurodegenerative diseases compared to controls correlates to a greater benefit for patients treated with a compound according to Formula (I).

[0169] Glial fibrillary acidic protein (GFAP) is a type III intermediate filament (IF) protein and is a marker for brain injury. GFAP is expressed in cells of the central nervous system including astrocytes. Levels of GFAP in patients' serum correlate with neurodegeneration aspects mediated by astrocytes. Astrocytes that become activated increase their production of GFAP. GFAP can be degraded into GFAP-BDP. Both products can be detected in the CSF, serum, or plasma due to astrocyte injury (see e.g. Trends Neurosci. 2015;38:364). In some embodiments, Nurrl activity reduces astrogliosis and thereby reduce astrocyte injury which results in reduced GFAP / BDP levels, when activated by a compound according to Formula (I).

[0170] YKL-40 (CHI3L1) is a glycoprotein predominantly produced by reactive astrocytes and microglia in chronic active MS lesions (J. Neuroimmunol. 2016;292:52). YKL-40 levels are increased in the serum of RRMS patients compared to controls and is therefore proposed to be a useful marker for the inflammatory process of MS (Arq. Neuropsiquiatr. 2021 ;79:795). Within the CNS, CHI3L1 is linked to neuroinflammatory processes and reactive gliosis (Neurol. Neuroimmunol. Neuroinflamm. 2022;9:e1164), which can be reduced by Nurrl activity (see above).

[0171] Dopamine active transporter (DAT; also SLC6A3) is a membrane-spanning protein responsible for the reuptake of dopamine from the synapse back into the cytosol of the dopaminergic neurons. DAT is a target gene of Nurrl (Development 2009; 136:2363). DAT may be reduced by 50-70% in PD patients. DAT imaging with single-photon emission computed tomography (SPECT) can be used to confirm or exclude a diagnosis of dopamine deficient parkinsonism. Patients with low levels of Nurrl expression and activity have lower expression levels and activity of dopamine transporter and therefore benefit from Nurrl activation by a compound according to Formula (I).

[0172] Pituitary homeobox 3 (Pitx3) is the gene that encodes a member of the RIEG / PITX homeobox family, which is in the bicoid class of homeodomain proteins and act as transcription factors. Pitx3 is involved in the maintenance of dopaminergic neurons. The term “Pitx3” may refer to the nucleotide sequence or protein sequence of human Pitx3.

[0173] Tyrosine hydroxylase (TH) is an enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA). In humans, tyrosine hydroxylase is encoded by the TH gene. In some embodiments, Nurrl activation in dopaminergic neurons leads to upregulation of tyrosine hydroxylase expression. Tyrosine hydroxylase activity converts tyrosine to L-DOPA. L-DOPA converts into dopamine, which is a neurotransmitter that provides signals for executive functions, motor control, motivation, arousal, reinforcement and reward. Lower-level functions are lactation, sexual gratification, and nausea.

[0174] 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 cellular cytosol into synaptic vesicles. VMAT2 is a direct target gene of Nurrl and is upregulated by Nurrl activation. VMAT2 expression can be determined on RNA and protein level in neurons from brain biopsies. In addition, VMAT2 activity can be determined by DTBZ PET. [11C]dihydrotetrabenazine (DTBZ) can be used as a radioligand for VMAT2 and can be visualized by PET imaging. VMAT2 is involved in packaging of dopamine. In nigrostriatal pathway and mesolimbic pathway dopamine-releasing neurons, SLC18A2 function is also necessary for the vesicular release of the neurotransmitter GABA. In some embodiments, Nurrl activation by a compound according to Formula (I) induces higher VMAT2 expression and therefore is beneficial for patients lacking proper VMAT2 activity due to mutations, and low Nurrl activation status or cocaine abuse. Increasing VMAT2 expression by two single-nucleotide polymorphisms (SNPs) in the promotor region reduces PD risk. In some embodiments, induction of higher expression and activity levels of VMAT2 is beneficial in neurodegenerative diseases. Superoxide dismutase (SOD) is an enzyme that alternately catalyzes the dismutation (or partitioning) of the superoxide (O2") radical into ordinary molecular oxygen and hydrogen peroxide. SOD is upregulated by Nurrl activation. SOD is an enzyme reducing oxidative stress in neurons and therefore reduces apoptotic signals in neurons. SOD expression can be measured on RNA or protein level from brain biopsies, CSF, or blood samples. Patients exhibit lower levels of SOD compared to control can benefit from treatment with a compound according to Formula (I) due to enhanced Nurrl activation.

[0175] Aromatic amino acid decarboxylase (AADC; also known as DOPA decarboxylase (DDC)), is a lyase enzyme. AADC is a direct target gene of Nurrl and is upregulated by Nurrl activation. AADC mediates the final step in the synthesis for the neurotransmitters dopamine and serotonin. Lower levels of AADC or dysfunction of AADC in neurons lead to accumulation of intracellular L- DOPA, which is then chemically transformed into 5-hydroxytryptophan and 3-O-methyldopa. 5- hydroxytryptophan (5-HTP) and 3-O-methyldopa (3-OMD) can be determined in blood by using UPLC-MS / MS (described e.g. J. Chromatogr. B Biomed. Appl. 2021 ;1185:122999). In some embodiments, patients with lower levels or lower functionality of AADC determined by UPLC- MS / MS compared to controls can benefit from a treatment with a compound according to Formula (I) by activation of Nurrl and subsequent upregulation of AADC.

[0176] In some embodiments, the change of a target gene (e.g., VMAT2), a target protein (e.g., Nurrl) or a peptide (e.g., NFL) is assessed after a treatment period of about 6 weeks, about 12 weeks, about 24 weeks, about 1 month, about 3 months, about 6 months, about 12 months in relation to the initial value at the start of treatment.

[0177] In some embodiments, the change of a target gene (e.g., VMAT2), a target protein (e.g., Nurrl) or a peptide (e.g., NFL) is assessed at beginning of treatment in relation to a healthy person of same age, gender and / or BMI.

[0178] In an aspect is provided a method of modulating the level or activity of Nurrl in a patient in need thereof, the method including administering to the patient in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the level or activity of Nurrl in the patient is increased by about 1.2-, about 1.3-, about 1.4-, about 1.5-, about 2-, about 3-, about 4-, about 5-, about 6-, about 7-, about 8-, about 9-, about 10-, about 15-, about 20-, about 25-, about 30-, about 35-, about 40-, about 45-, about 50-, about 60-, about 70-, about 80- , about 90-, about 100-fold, or more. In some embodiments, the level or activity of Nurrl in the patient is increased 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-fold, or more.

[0179] In an aspect is provided a method of decreasing the level of NFL in plasma in a patient in need thereof, the method including administering to the patient in need thereof a therapeutically effective amount of a compound according to Formula (I) described herein. In embodiments, the level of NFL in plasma in the patient is decreased by about 3%, 4%, 5%, 7%, 10%, 12%, 15%, 20%, 30%, 40%, 50%, or more compared to the level at beginning of treatment. In embodiments, the level of NFL in plasma in the patient is decreased by at least 3%, 4%, 5%, 7%, 10%, 12%, 15%, 20%, 30%, 40%, 50%, or more compared to the level at beginning of treatment. In an aspect is provided a method of decreasing the level of NFL in serum in a patient in need thereof, the method including administering to the patient in need thereof a therapeutically effective amount of a compound according to Formula (I) described herein. In embodiments, the level of NFL in serum in the patient is decreased by about 3%, 4%, 5%, 7%, 10%, 12%, 15%, 20%, 30%, 40%, 50%, or more compared to the level at beginning of treatment. In embodiments, the level of NFL in serum in the patient is decreased by at least 3%, 4%, 5%, 7%, 10%, 12%, 15%, 20%, 30%, 40%, 50%, or more compared to the level at beginning of treatment.

[0180] In an aspect is provided a method of decreasing the level of NFL in CSF in a patient in need thereof, the method including administering to the patient in need thereof a therapeutically effective amount of a compound according to Formula (I) described herein. In embodiments, the level of NFL in CSF in the patient is decreased by about 3%, 4%, 5%, 7%, 10%, 12%, 15%, 20%, 30%, 40%, 50%, or more compared to the level at beginning of treatment. In embodiments, the level of NFL in CSF in the patient is decreased by at least 3%, 4%, 5%, 7%, 10%, 12%, 15%, 20%, 30%, 40%, 50%, or more compared to the level at beginning of treatment.

[0181] In an aspect is provided a method of decreasing the increased level of NFL in plasma in a patient in need thereof, the method including administering to the patient in need thereof a therapeutically effective amount of a compound according to Formula (I) described herein. In embodiments, the level of NFL in plasma in the patient is decreased by about 3%, 4%, 5%, 7%, 10%, 12%, 15%, 20%, 30%, 40%, 50%, or more towards the level of a healthy person with the same age, gender and / or BMI. In embodiments, the level of NFL in plasma in the patient is decreased by at least 3%, 4%, 5%, 7%, 10%, 12%, 15%, 20%, 30%, 40%, 50%, or more towards the level of a healthy person with the same age, gender and / or BMI.

[0182] In an aspect is provided a method of decreasing the increased level of NFL in serum in a patient in need thereof, the method including administering to the patient in need thereof a therapeutically effective amount of a compound according to Formula (I) described herein. In embodiments, the level of NFL in serum in the patient is decreased by about 3%, 4%, 5%, 7%, 10%, 12%, 15%, 20%, 30%, 40%, 50%, or more towards the level of a healthy person with the same age, gender and / or BMI. In embodiments, the level of NFL in serum in the patient is decreased by at least 3%, 4%, 5%, 7%, 10%, 12%, 15%, 20%, 30%, 40%, 50%, or more towards the level of a healthy person with the same age, gender and / or BMI.

[0183] In an aspect is provided a method of decreasing the increased level of NFL in CSF. In an aspect is provided a method of decreasing the level of NFL in plasma in a patient in need thereof, the method including administering to the patient in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the level of NFL in plasma in the patient is decreased 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 beginning of treatment. In some embodiments, the level of NFL in plasma in the patient is decreased 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 beginning of treatment.

[0184] In an aspect is provided a method of decreasing the level of NFL in serum in a patient in need thereof, the method including administering to the patient in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the level of NFL in serum in the patient is decreased 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 beginning of treatment. In some embodiments, the level of NFL in serum in the patient is decreased 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 beginning of treatment.

[0185] In an aspect is provided a method of decreasing the level of NFL in CSF in a patient in need thereof, the method including administering to the patient in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the level of NFL in CSF in the patient is decreased 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 beginning of treatment. In some embodiments, the level of NFL in CSF in the patient is decreased 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 beginning of treatment.

[0186] In an aspect is provided a method of decreasing the increased level of NFL in plasma in a patient in need thereof, the method including administering to the patient in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the level of NFL in plasma in the patient is decreased 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 with the same age, biological sex and / or BMI. In some embodiments, the level of NFL in plasma in the patient is decreased 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 with the same age, gender and / or BMI.

[0187] In an aspect is provided a method of decreasing the increased level of NFL in serum in a patient in need thereof, the method including administering to the patient in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the level of NFL in serum in the patient is decreased 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 with the same age, biological sex and / or BMI. In some embodiments, the level of NFL in serum in the patient is decreased 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 with the same age, gender and / or BMI.

[0188] In an aspect is provided a method of decreasing the increased level of NFL in CSF in a patient in need thereof, the method including administering to the patient in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the level of NFL in CSF in the patient is decreased 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 with the same age, gender and / or BMI. In some embodiments, the level of NFL in CSF in the patient is decreased 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 with the same age, gender and / or BMI. In an aspect is provided a method of increasing the level or activity of Pitx3 in a patient in need thereof, the method including administering to the patient in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the level or activity of Pitx3 in the patient is increased by about 1.2-, about 1.3-, about 1.4-, about 1.5-, about 2-, about 3-, about 4-, about 5-, about 6-, about 7-, about 8-, about 9-, about 10-, about 15-, about 20-, about 25-, about 30-, about 35-, about 40-, about 45-, about 50-, about 60-, about 70-, about 80- , about 90-, about 100-fold, or more. In some embodiments, the level or activity of Pitx3 in the patient is increased 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 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-fold, or more.

[0189] In an aspect is provided a method of increasing the level or activity of VMAT2 in a patient in need thereof, the method including administering to the patient in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the level or activity of VMAT2 in the patient is increased by about 1.2-, about 1.3-, about 1.4-, about 1.5-, about 2-, about 3-, about 4-, about 5-, about 6-, about 7-, about 8-, about 9-, about 10-, about 15-, about 20-, about 25-, about 30-, about 35-, about 40-, about 45-, about 50-, about 60-, about 70-, about 80-, about 90-, about 100-fold, or more. In some embodiments, the level or activity of VMAT2 in the patient is increased 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 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-fold, or more.

[0190] In an aspect is provided a method of increasing the level or activity of AADC in a patient in need thereof, the method including administering to the patient in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the level or activity of AADC in the patient is increased by about 1.2-, about 1.3-, about 1.4-, about 1.5-, about 2-, about 3-, about 4-, about 5-, about 6-, about 7-, about 8-, about 9-, about 10-, about 15-, about 20-, about 25-, about 30-, about 35-, about 40-, about 45-, about 50-, about 60-, about 70-, about 80- , about 90-, about 100-fold, or more. In some embodiments, the level or activity of AADC in the patient is increased 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 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-fold, or more.

[0191] In an aspect is provided a method of increasing the level or activity of DAT in a patient in need thereof, the method including administering to the patient in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the level or activity of DAT in the patient is increased by about 1.2-, about 1.3-, about 1.4-, about 1.5-, about 2-, about 3-, about 4-, about 5-, about 6-, about 7-, about 8-, about 9-, about 10-, about 15-, about 20-, about 25-, about 30-, about 35-, about 40-, about 45-, about 50-, about 60-, about 70-, about 80- , about 90-, about 100-fold, or more. In some embodiments, the level or activity of DAT in the patient is increased 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 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. In an aspect is provided a method of increasing the level or activity of BDNF in a patient in need thereof, the method including administering to the patient in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the level or activity of BDNF in the patient is increased by about 1.2-, about 1.3-, about 1.4-, about 1.5-, about 2-, about 3-, about 4-, about 5-, about 6-, about 7-, about 8-, about 9-, about 10-, about 15-, about 20-, about 25-, about 30-, about 35-, about 40-, about 45-, about 50-, about 60-, about 70-, about 80- , about 90-, about 100-fold, or more. In some embodiments, the level or activity of BDNF in the patient is increased 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 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-fold, or more.

[0192] In an aspect is provided a method of increasing the level or activity of GDNF in a patient in need thereof, the method including administering to the patient in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the level or activity of GDNF in the patient is increased by about 1.2-, about 1.3-, about 1.4-, about 1.5-, about 2-, about 3-, about 4-, about 5-, about 6-, about 7-, about 8-, about 9-, about 10-, about 15-, about 20-, about 25-, about 30-, about 35-, about 40-, about 45-, about 50-, about 60-, about 70-, about 80- , about 90-, about 100-fold, or more. In some embodiments, the level or activity of GDNF in the patient is increased 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 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-fold, or more.

[0193] In an aspect is provided a method of increasing the level or activity of GDNF receptor C-RET in a patient in need thereof, the method including administering to the patient in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the level or activity of GDNF receptor C-RET in the patient is increased by about 1.2-, about 1.3-, about 1.4-, about 1.5-, about 2-, about 3-, about 4-, about 5-, about 6-, about 7-, about 8-, about 9-, about 10-, about 15-, about 20-, about 25-, about 30-, about 35-, about 40-, about 45-, about 50- , about 60-, about 70-, about 80-, about 90-, about 100-fold, or more. In some embodiments, the level or activity of GDNF receptor C-RET in the patient is increased 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 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-fold, or more.

[0194] In an aspect is provided a method of increasing the level or activity of GFAP in a patient in need thereof, the method including administering to the patient in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the level or activity of GFAP in the patient is increased by about 1.2-, about 1.3-, about 1.4-, about 1.5-, about 2-, about 3-, about 4-, about 5-, about 6-, about 7-, about 8-, about 9-, about 10-, about 15-, about 20-, about 25-, about 30-, about 35-, about 40-, about 45-, about 50-, about 60-, about 70-, about 80- , about 90-, about 100-fold, or more. In some embodiments, the level or activity of GFAP in the patient is increased 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 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-fold, or more. In an aspect is provided a method of increasing the level or activity of tyrosine hydroxylase (TH) in a patient in need thereof, the method including administering to the patient in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the level or activity of TH in the patient is increased by about 1.2-, about 1.3-, about 1.4-, about 1.5-, about

[0195] 2-, about 3-, about 4-, about 5-, about 6-, about 7-, about 8-, about 9-, about 10-, about 15-, about 20-, about 25-, about 30-, about 35-, about 40-, about 45-, about 50-, about 60-, about 70-, about 80-, about 90-, about 100-fold, or more. In some embodiments, the level or activity of TH in the patient is increased 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 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-fold, or more.

[0196] In an aspect is provided a method of increasing the level or activity of SOD in a patient in need thereof, the method including administering to the patient in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the level or activity of SOD in the patient is increased by about 1.2-, about 1.3-, about 1.4-, about 1.5-, about 2-, about

[0197] 3-, about 4-, about 5-, about 6-, about 7-, about 8-, about 9-, about 10-, about 15-, about 20-, about 25-, about 30-, about 35-, about 40-, about 45-, about 50-, about 60-, about 70-, about 80- , about 90-, about 100-fold, or more. In some embodiments, the level or activity of SOD in the patient is increased 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 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-fold, or more.

[0198] In an aspect is provided a method of reducing the level or activity of TN Fa in a patient in need thereof, the method including administering to the patient in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the level or activity of TNFa in the patient is reduced by about 1.2-, about 1.3-, about 1.4-, about 1.5-, about 2-, about 3-, about 4-, about 5-, about 6-, about 7-, about 8-, about 9-, about 10-, about 15-, about 20-, about 25-, about 30-, about 35-, about 40-, about 45-, about 50-, about 60-, about 70-, about 80- , about 90-, about 100-fold, or more. In some embodiments, the level or activity of TNFa in the patient is reduced 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 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-fold, or more.

[0199] In an aspect is provided a method of reducing the level or activity of iNOS in a patient in need thereof, the method including administering to the patient in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the level or activity of iNOS in the patient is reduced by about 1.2-, about 1.3-, about 1.4-, about 1.5-, about 2-, about 3-, about 4-, about 5-, about 6-, about 7-, about 8-, about 9-, about 10-, about 15-, about 20-, about 25-, about 30-, about 35-, about 40-, about 45-, about 50-, about 60-, about 70-, about 80- , about 90-, about 100-fold, or more. In some embodiments, the level or activity of iNOS in the patient is reduced 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 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-fold, or more. In an aspect is provided a method of reducing the level or activity of IL-1 p in a patient in need thereof, the method including administering to the patient in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the level or activity of I L-1 in the patient is reduced by about 1.2-, about 1.3-, about 1.4-, about 1.5-, about 2-, about

[0200] 3-, about 4-, about 5-, about 6-, about 7-, about 8-, about 9-, about 10-, about 15-, about 20-, about 25-, about 30-, about 35-, about 40-, about 45-, about 50-, about 60-, about 70-, about 80- , about 90-, about 100-fold, or more. In some embodiments, the level or activity of IL-1 p in the patient is reduced 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 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-fold, or more.

[0201] In some embodiments, the method includes increasing the level of dopamine in a patient in need thereof, the method including administering to the patient in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the level of dopamine in the patient is increased by about 1.2-, about 1.3-, about 1.4-, about 1.5-, about 2-, about 3-, about 4-, about 5-, about 6-, about 7-, about 8-, about 9-, about 10-, about 15-, about 20-, about 25-, about 30-, about 35-, about 40-, about 45-, about 50-, about 60-, about 70-, about 80-, about 90-, about 100-fold, or more. In some embodiments, the level or activity of dopamine in the patient is increased 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

[0202] 4-, at least 5-, at least 6-, at least 7-, at least 8-, at least 9-, at least 10-, at least 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-fold, or more.

[0203] In some embodiments, the method includes increasing development of dopaminergic neurons with a compound described herein as compared to a control (e.g., absence of the compound). In some embodiments, the level of development of dopaminergic neurons is increased by about 1.2- , about 1.3-, about 1.4-, about 1.5-, about 2-, about 3-, about 4-, about 5-, about 6-, about 7-, about 8-, about 9-, about 10-, about 15-, about 20-, about 25-, about 30-, about 35-, about 40-, about 45-, about 50-, about 60-, about 70-, about 80-, about 90-, about 100-fold, or more. In some embodiments, the level of development of dopaminergic neurons in the patient is increased 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 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-fold, or more.

[0204] In some embodiments, the method includes increasing maintenance of dopaminergic neurons with a compound described herein as compared to a control (e.g., absence of the compound). In some embodiments, the level of maintenance of dopaminergic neurons is increased by about 1.2- , about 1.3-, about 1.4-, about 1.5-, about 2-, about 3-, about 4-, about 5-, about 6-, about 7-, about 8-, about 9-, about 10-, about 15-, about 20-, about 25-, about 30-, about 35-, about 40-, about 45-, about 50-, about 60-, about 70-, about 80-, about 90-, about 100-fold, or more. In some embodiments, the level of maintenance of dopaminergic neurons in the patient is increased 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 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-fold, or more. In some embodiments, the method includes increasing survival of dopaminergic neurons with a compound described herein as compared to a control (e.g., absence of the compound). In some embodiments, the level of survival of dopaminergic neurons is increased by about 1.2-, about 1.3- , about 1 .4-, about 1 .5-, about 2-, about 3-, about 4-, about 5-, about 6-, about 7-, about 8-, about 9-, about 10-, about 15-, about 20-, about 25-, about 30-, about 35-, about 40-, about 45-, about 50-, about 60-, about 70-, about 80-, about 90-, about 100-fold, or more. In some embodiments, the level of survival of dopaminergic neurons in the patient is increased 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 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-fold, or more.

[0205] In embodiments, the method includes stabilizing a Nurrl monomer with a compound according to Formula (I) described herein. In embodiments, the method includes stabilizing a Nurrl homodimer with a compound according to Formula (I) described herein. In embodiments, the method includes stabilizing a head-to-tail Nurrl homodimer with a compound according to Formula (I) described herein. In embodiments, the method includes stabilizing a Nurrl heterodimer with a compound according to Formula (I) described herein. In embodiments, the Nurrl heterodimer is a heterodimer with RXRa.

[0206] In embodiments, the method includes contacting a Nurrl monomer with a compound according to Formula (I) described herein. In embodiments, the method includes contacting a Nurrl homodimer with a compound according to Formula (I) described herein. In embodiments, the method includes contacting a head-to-tail Nurrl homodimer with a compound according to Formula (I) described herein. In embodiments, the method includes contacting a Nurrl heterodimer with a compound according to Formula (I) described herein. In embodiments, the Nurrl heterodimer is a heterodimer with RXRa.

[0207] In embodiments, the method includes binding a Nurrl monomer with a compound according to Formula (I) described herein. In embodiments, the method includes binding a Nurrl homodimer with a compound according to Formula (I) described herein. In embodiments, the method includes binding a head-to-tail Nurrl homodimer with a compound according to Formula (I) described herein. In embodiments, the method includes binding a Nurrl heterodimer with a compound according to Formula (I) described herein. In embodiments, the Nurrl heterodimer is a heterodimer with RXRa.

[0208] In embodiments, the method includes precluding the formation of Nurrl :RXR heterodimers with a compound according to Formula (I) described herein.

[0209] In embodiments, the method includes binding a Nurrl and inducing Nurrl binding to a NBRE, a NuRE, or a DR-5 response element. In embodiments, the method includes binding a Nurrl and inducing Nurrl binding to a NBRE. In embodiments, the method includes binding a Nurrl and inducing Nurrl binding to a NuRE. In embodiments, the method includes binding a Nurrl and inducing Nurrl binding to a DR-5 response element.

[0210] In embodiments, the compound according to Formula (I) stabilizes a Nurrl monomer. In embodiments, the compound according to Formula (I) stabilizes a Nurrl homodimer. In embodiments, the compound according to Formula (I) stabilizes a head-to-tail Nurrl homodimer. In embodiments, the compound according to Formula (I) stabilizes a Nurrl heterodimer. In embodiments, the Nurrl heterodimer is a heterodimer with RXRa.

[0211] In embodiments, the compound according to Formula (I) stabilizes a Nurrl monomer relative to a control (e.g., absence of the compound). In embodiments, the compound according to Formula (I) stabilizes a Nurrl homodimer relative to a control (e.g., absence of the compound). In embodiments, the compound according to Formula (I) stabilizes a head-to-tail Nurrl homodimer relative to a control (e.g., absence of the compound). In embodiments, the compound according to Formula (I) stabilizes a Nurrl heterodimer relative to a control (e.g., absence of the compound). In embodiments, the Nurrl heterodimer is a heterodimer with RXRa.

[0212] In embodiments, the compound according to Formula (I) contacts a Nurrl monomer. In embodiments, the compound according to Formula (I) contacts a Nurrl homodimer. In embodiments, the compound according to Formula (I) contacts a head-to-tail Nurrl homodimer. In embodiments, the compound according to Formula (I) contacts a Nurrl heterodimer. In embodiments, the Nurrl heterodimer is a heterodimer with RXRa.

[0213] In embodiments, the compound according to Formula (I) binds a Nurrl monomer. In embodiments, the compound according to Formula (I) binds a Nurrl homodimer. In embodiments, the compound according to Formula (I) binds a head-to-tail Nurrl homodimer. In embodiments, the compound according to Formula (I) binds a Nurrl heterodimer. In embodiments, the Nurrl heterodimer is a heterodimer with RXRa.

[0214] In embodiments, the compound according to Formula (I) precludes the formation of Nurrl :RXR heterodimers. In embodiments, the compound according to Formula (I) inhibits the formation of Nurrl :RXR heterodimers. In embodiments, compound according to Formula (I) binding to Nurrl inhibits the resulting compound: Nurrl complex from binding to RXR.

[0215] In embodiments, the compound according to Formula (I) acts as an agonist to a Nurrl monomer. In embodiments, the compound according to Formula (I) acts as an agonist to a Nurrl homodimer. In embodiments, the compound according to Formula (I) acts as an agonist to a head-to-tail Nurrl homodimer. In embodiments, the compound according to Formula (I) acts as an agonist to a Nurrl heterodimer. In embodiments, the Nurrl heterodimer is a heterodimer with RXRa.

[0216] In embodiments, the compound according to Formula (I) binds Nurrl and induces Nurrl binding to a NBRE, a NuRE, or a DR-5 response element. In embodiments, the compound according to Formula (I) binds Nurrl and induces Nurrl binding to a NBRE. In embodiments, the compound according to Formula (I) binds Nurrl and induces Nurrl binding to a NuRE. In embodiments, the compound according to Formula (I) binds Nurrl and induces Nurrl binding to a DR-5 response element.

[0217] In embodiments, the lower levels of Nurrl results in an impaired function or activity of Nurrl . In embodiments, the lower levels of Nurrl can be restored by applying a compound according to Formula (I). In embodiments, the compounds according to Formula (I) act as Nurrl agonists.

[0218] Multiple Sclerosis A further aspect of the present disclosure relates to methods of treating or ameliorating multiple sclerosis (MS) in a patient who has MS, comprising administering to the patient a compound according to Formula (I).

[0219] Multiple sclerosis (MS) can be divided to relapsing forms of MS (RMS) and progressive forms of MS (PMS). Relapsing-remitting MS (RRMS) and active secondary progressive MS (active SPMS) are primarily driven by focal inflammatory disease and characterized by the presence of magnetic resonance imaging (MRI) lesions and relapses. It is however known from a recent meta-analysis of a large patient database that disability worsening in these two subtypes are driven by relapse- associated worsening (RAW) and by progression independent of relapse activity (PIRA). RRMS is characterized by the domination of relapses and MRI lesions over the clinical course. Active SPMS (aSPMS) is characterized by fewer relapses and lesions with continuous disability progression.

[0220] Primary progressive MS (PPMS) and non-active secondary progressive MS (non-active SPMS or n-aSPMS) are the two predominantly progressive forms of MS, which are characterized by an ongoing disability worsening without or almost without any MRI lesions or relapses being present. It is known from a recent meta-analysis of a large patient database that disability worsening in these two subtypes are almost exclusively driven by PIRA. Non-active SPMS is characterized by continuous disability progression while relapses have stopped. PPMS is characterized by disability worsening from the start.

[0221] Definitions and subcategorizations of PPMS and SPMS may vary. In one exemplary definition, all SPMS may be considered to belong to the category of PMS, so that all SPMS patients considered to be PMS patients, with no differentiation between aSPMS and n-aSPMS. In another exemplary definition, active-SPMS may be considered to belong to the category of RMS, while non-active- SPMS may be considered to belong to the category of PMS. Thus, the terms "n-aSPMS" and "SPMS" are used synonymously in the present invention.

[0222] The separation of PIRA compared to RAW can be as follows (JAMA Neurol. 2023;80:151): A PIRA event can be defined as experiencing confirmed disability worsening (CDW) in the EDSS scale at 6 months during a period free of relapses (PFRs). A PFR is the time between two consecutive relapses, starting 3 months after a relapse (or 6 months after the first demyelinating event). The first EDSS score obtained at least 6 months after the first attack or 3 months after any other attack was referred to as the baseline EDSS score and rebaseline EDSS score, respectively. It was set that no rebaseline EDSS score could be lower than the first recorded (baseline) EDSS score. Confirmed disability accumulation (CDA) was defined as an increase in the EDSS score of 1 .5, 1.0, or 0.5 if the baseline / rebaseline EDSS score was, respectively, 0, 1.0 to 5.0, or greater than 5.0. The date of PIRA was the date of the confirmation of the CDA. Any other episodes of CDA that did not qualify for PIRA (i.e. , which occurred outside the PFR) were considered to be RAW events. Those patients with at least 1 CDA but who did not present with any PIRA event were considered patients with RAW.

[0223] In the clinical study of Kopp et al. (Mult. Scler. Relat. Disord. 2021 ;56: 103319) the following inclusion criteria were applied on a MS population with a diagnosis of clinical SPMS assigned by an MS-neurologist and RRMS patients fulfilling the MSBase diagnostic definition for conversion to SPMS. This m-EXPAND criteria identify patients with recent worsening on the EDSS score likely not explained by a recent relapse: (a) An EDSS from 3.0 to 6.5 (both inclusive) (at index date + / - 6 months); and

[0224] (b) EDSS progression within the last 2 years before data extraction, defined as EDSS progression of 1 point or more in patients with an EDSS score of less than 6.0 or > 0.5 point in patients with EDSS score > 6.0, in the absence of relapses 6 months prior to progression and EDSS > 3.0 at time of progression; and

[0225] (c) Disability progression.

[0226] Currently, there is no FDA-approved treatment option for SPMS other than mitoxantrone. However, for treatment with mitoxantrone, no distinction regarding relapse activity (active SPMS vs non-active SPMS) is made. Notably, treatment of mitoxantrone is associated with significant toxicities including cardiotoxicity and secondary malignancy, which limits the length of treatment to ~3 years (lifetime dose of 140 mg / m2). In addition, patient populations in this trial were predominately with relapsing type of SPMS, and the benefit in non-active SPMS is unclear. Siponimod, natalizumab, and interferon beta-1 b are approved for active SPMS but have not shown benefit in non-active SPMS. For PPMS patients, ocrelizumab has been approved, however due to the strong attenuation of the immune response it contains a black box warning towards progressive multifocal leukoencephalopathy and immune-mediated colitis. Other treatment options currently being tested in clinical trials (e.g. fenebrutinib with risk of liver damages) also do not offer a favorable safety profile. Therefore, there is an urgent unmet need given the lack of effective therapies for PIRA in its entirety.

[0227] MS usually begins with a clinically isolated syndrome (CIS). This is the first episode of symptoms caused by inflammation and damage to the myelin covering on nerves in the brain or spinal cord. In CIS, a person has an attack suggestive of demyelination, but does not fulfill the criteria for MS. 30 to 70% of persons experiencing CIS later develop MS.

[0228] There exists an additional subgroup of MS patients, i.e. patients with MS transitioning between relapsing MS and PIRA. For this disease the term "transitioning MS" is used herein. Transitioning MS patients can be identified by one or more of the following test methods:

[0229] (a) The symbol digit modalities test (SDMT),

[0230] (b) Multiple Sclerosis Functional Composite (MSFC),

[0231] (c) EDSS,

[0232] (d) timed 25-foot walk (T25FW),

[0233] (e) 9-hole peg test (9HPT)

[0234] (f) The MSProDiscuss™ clinical tool

[0235] (g) Composite scores integrating several tests like e.g. EDSS, timed 25-foot walk (T25FW), SDMT and 9-hole peg test (9HPT), MSProDiscuss™ clinical tool.

[0236] Progression Independent of Relapse (PIRA)

[0237] Another aspect of the present disclosure relates to methods of treating progression of MS, e.g., progression independent of relapse (PIRA) in a patient, comprising administering to the patient a compound according to Formula (I).

[0238] PIRA is a contributing factor in all forms of multiple sclerosis (MS). PIRA plays a significant role in disease worsening in RRMS and is the principal way by which patients acquire disability in progressive multiple sclerosis (PMS), e.g., forms of PMS in which there are few or no relapses. PIRA can occur even early in the disease, as shown in a study in patients with successful suppression of inflammation with efficacious DMTs, providing evidence for an ongoing treatmentresistant pathology from the start.

[0239] This elevates the importance of any new drug that reduces or is slowing down PIRA (measured as confirmed disability worsening but also by assessment of brain atrophy). It can also be of importance to provide a new drug that: (a) reduces relapse activity AND (b) reduces or is slowing down PIRA (measured as confirmed disability worsening but also by assessment of brain atrophy).

[0240] Thus, the present invention aims for treating the relapse-independent accumulation of neurological deficits worsening in one embodiment.

[0241] Thus, the present invention aims for treating progression independent of relapse activity (PIRA).

[0242] Relapse-independent accumulation of neurological deficits worsening or progression independent of relapse activity has been defined in Brain 2022; 145:3147 by Fred Lublin wherein detection of neurological deficits worsening or progression independent of relapse activity is detected as described in Brain 2022; 145:3147 and there are included herein by reference as one embodiment.

[0243] There are two main mechanisms by which patients with multiple sclerosis acquire disability: (i) step-wise accrual of impairment due to incomplete recovery from a relapse [i.e. relapse- associated worsening (RAW)]; and (ii) progression independent of relapse activity (PIRA). While the former is considered to be the main source of permanent disability in relapsing multiple sclerosis, the latter is thought to drive the insidious progression typical in primary and secondary progressive multiple sclerosis (PPMS and SPMS). One example of detection of progression independent of relapse activity is detected and measured according to Kurtzke, JF “Rating neurologic impairment in multiple sclerosis: An expanded disability status scale (EDSS)”, Neurvlogy.'\983 33:1444.

[0244] No satisfactory medication is currently available to treat the major smoldering portion of disability worsening, which is independent of relapses. Surprisingly, the present inventions show that a compound according to Formula (I), which acts as Nurrl agonist, can function as a neuroprotective drug in addition to their established activity as anti-inflammatory drug.

[0245] In particular, patients with low levels of Nurrl will benefit from a treatment with a compound according to Formula (I)..

[0246] Patients with diseases comprising brain and spinal cord disorders or neurodegeneration can be beneficially treated with a compound according to Formula (I). These conditions comprise diseases with symptoms like motor deficits, cognitive deficits, fatigue, depression, or drug addiction.

[0247] When focused on the disease MS, the positive effects for patients with RRMS can be attributed to the anti-inflammatory properties of the compounds of Formula (I) or an isotopic variant, a pharmaceutically acceptable salt or solvate thereof.

[0248] In some embodiments, MS patients can be classified in two groups: (a) the one with relapses, i.e. relapse-associated worsening (RAW) patients and (b) the others with progredient (smoldering) disease worsening, i.e. patients with progression independent of relapse activity (PIRA), which need fundamentally different treatments. In some embodiments, Group (a) needs an antiinflammatory treatment, while group (b) needs a neuroprotective treatment to attenuate the disease worsening. For group (b) nearly no treatment options exist, particularly since a pure DHODH inhibitor would not be expected to lead to beneficial treatment. In one embodiment, a compound according to the present invention may act as a nuclear receptor related 1 (Nurrl).

[0249] In one embodiment the patient treated according to the present invention is a patient with MS that has been without any relapses or that has a free-relapse period of at least 12 months. In another embodiment the patient treated according to the present invention is a patient with MS that has been without any relapses or that has a free-relapse period of at least 24 months.

[0250] In one embodiment the patient treated according to the present invention is a patient with PIRA that has been without any relapses or that has a free-relapse period of at least 12 or 24 months.

[0251] In one embodiment of the invention PIRA was defined as a 3- or 6 or preferably, 12 or 24 -month confirmed disability worsening (CDW) event with either no prior relapse or an onset more than 90 days after the start date of the last investigator-reported relapse (irrespective of the EDSS confirmation).

[0252] In addition, to qualify as a PIRA event, no relapse must occur within 30 days before or after the EDSS confirmation. If a relapse with incomplete recovery occurred, the baseline (i.e. the reference EDSS value) maybe reset >90 days after the relapse onset to identify the next PIRA event. In an individual patient, the baseline could be reset multiple times (i.e. after each relapse) until either a PIRA event was discovered, or until the individual EDSS profile ended.

[0253] Sustained PIRA may be a 3- or 6-month PIRA event in which the EDSS-worsening was sustained in all following assessments, i.e. the patient never recovered in the available longitudinal data.

[0254] Clinical evidence for disability may come from surrogate endpoints, e.g., annualized rate of percent brain volume change up to 120 weeks annualized rate of change in whole brain atrophy.

[0255] Clinical evidence may also come from biomarker response by slowing down or reducing increase of serum NFL levels by at least 5% (or defining Hazard ration of 0.9) reducing the level of GFAP in CSF, serum, or plasma by at least 3% for a period of 48 weeks.

[0256] Disability progression may evaluated using the Expanded Disability Status Scale (EDSS), the 9- Hole Peg Test (9-HPT), or the Timed 25-Foot Walk Test (T25FWT), or any combinations thereof.

[0257] Methods for evaluating disability progression may comprise evaluating the onset of composite 12-week confirmed disability progression (cCDP12), wherein onset of the cCDP12 comprises at least one progression event selected from the group consisting of: an increase from baseline in EDSS score of at least 1.0 point in a patient with a baseline EDSS score of less than or equal to 5.5 points; or an increase from baseline in EDSS score of at least 0.5 point in a patient with a baseline EDSS score of greater than 5.5 points; increase from baseline of at least 20% in time to complete the 9-HPT; and increase from baseline of at least 20% in T25FWT, and wherein the progression event is confirmed at least 12 weeks after the initial progression.

[0258] Observational and controlled clinical trials provide evidence that PIRA is likely the most frequent manifestation of disability accumulation across the full spectrum of traditional MS phenotypes, including CIS and early RRMS, thus providing another perspective of the conceptual distinction between relapsing and progressive disease courses or stages. In some embodiments, as an additional set of determinants, the following determinants may be used for diagnosing PIRA both in RRMS and progressive MS:

[0259] A. Baseline / reference score: A roving baseline may be applied, that sets a new reference score every time the EDSS or individual measure of the composite is lower than the previous measure and confirmed at the following visit. The reference score may also be reset if a relapse causes residual disability.

[0260] B. Event score: An increase of EDSS or composite measure may be considered for classification to PIRA, if it is not determined within 30 days before and 90 days after the onset of an investigator reported relapse. Besides EDSS (increase of 1.5 points if baseline is 0, 1.0 point between 1 and 5.5, 0.5 points >5.5), a composite measure may be recommended and should include upper limb function (9HPT, threshold: >20% decline), walking speed (T25FWT, threshold: >20% decline) and cognitive testing (SDMT, threshold: 4 points or >10% decline).

[0261] C. Confirmation score: The confirmation visit may take place no earlier than 3 months, preferably 6, or 12 months after the initial disability increase and should not happen 30 days before and 90 days after the onset of an investigator-reported relapse.

[0262] D. Sustained score: The EDSS score defining PIRA may not improve until the end of follow up, sensibly at least 12 or even 24 months apart from start of PIRA.

[0263] It has been discovered that patients with MS acquire disability not only by relapse-associated worsening (RAW) but to a large extend by progression independent of relapse activity (PIRA).

[0264] PIRA maybe quantified with help of confirmed disability worsening (CDW) events. PIRA may start early in the disease process, may occur in all phenotypes, and may become the principal driver of disability accumulation in the progressive phase of the disease.

[0265] PIRA is the principal driver of disability accumulation during the progressive phase of the disease. PIRA may be associated with worsening unknown “hidden symptoms” such as fatigue, sphincter, and cognitive symptoms. Patients may have MS transitioning between relapsing and progressive disease. There is an underlying progressive course in all MS patients independently of the disease classification. In one embodiment PIRA patients maybe SPMS patients without a recent relapse and no MRI activity suggestive of active inflammation, and with evidence of recent progression independent of relapses.

[0266] PIRA and RAW can be subdivided in smaller groups like "early PIRA", "late PIRA", "active PIRA" or "nonactive PIRA" (JAMA Neurol. 2023;80:151).

[0267] Patients with early PIRA show significantly steeper Expanded Disability Status Scale (EDSS) increase rates than those with late PIRA.

[0268] Furthermore, patients with early PIRA had a greater risk of reaching EDSS 6.0 at faster rates than those with late PIRA. PIRA may be a nonreversible phenomenon associated with unfavorable long-term disability outcomes, especially if such PIRA events occur early in the disease course.

[0269] Identifying all who will develop PIRA as soon as possible after the first demyelinating event, especially early PIRA, may lead to better treatment choices, and subsequently, better long-term outcomes.

[0270] In some embodiments, the treatment of PIRA is evaluated using the Expanded Disability Status Scale (EDSS), the 9-Hole Peg Test (9-HPT), or the Timed 25-Foot Walk Test (T25FWT), or any combinations thereof. In some embodiments, the treatment of PIRA is evaluated based the time to onset of confirmed disability progression (e.g., 12-week or 24-week CDP), or based on the time to onset of a composite confirmed disability progression (e.g., 12-week or 24-week cCDP). In other embodiments, the 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 level, GFAP level, BDNF level or Nurrl expression level. In other embodiments, the treatment of PIRA is evaluated based on BDNF, GDNF, C-RET, GFAP, DAT, Pitx3, TH, VMAT2, SOD1 , AADC, TNFa, iNOS, YKL-40 or IL-1 . For example, in some embodiments, treating a patient with PIRA comprises delaying the progression of PIRA, wherein the progression 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 level, GFAP level, BDNF level or Nurrl expression level; or the onset of at least one progression event, which may be described by CDP12, cCDP12, CDP24, or cCDP24. In some embodiments, treating PIRA comprises delaying progression of PIRA. In certain embodiments, treating PIRA comprises delaying the onset of at least one progression event in the patient. In some embodiments, treating PIRA comprises reducing the risk of the patient experiencing at least one progression event. In certain embodiments, treating PIRA comprises delaying progression, or delaying the onset of at least one progression event, by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or at least 35% (e.g., as evaluated using T25FWT time, or 9-HPT time, or EDSS score, or CDP12, or cCDP12, or CDP24, or cCDP24 etc.). In certain embodiments, treating PIRA comprises delaying progression, or delaying the onset of at least one progression event, by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or at least 35% as compared to another patient with PIRA (e.g., a comparative patient), wherein the other patient is not administered a compound of Formula (I). 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 patient is administered an anti-CD20 antibody (such as a CD20-directed cytolytic antibody). In still further embodiments, treating PIRA comprises reducing the risk the patient has 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 certain embodiments, the risk is reduced over a period of time, for example reducing the risk of having at least one progression event over 12 weeks, 18 weeks, 24 weeks, 36 weeks, 48 weeks, 60 weeks, 72 weeks, 84 weeks, 96 weeks, 108 weeks, or 120 weeks. In some embodiments, the risk is reduced as compared to another patient with PIRA (e.g., a comparative patient) who is not administered a compound of Formula (I), and who is optionally administered an anti-CD20 antibody. In some embodiments, the other patient is administered an anti-CD20 antibody (such as a CD20-directed cytolytic antibody). In some embodiments, the risk is reduced by at least 5%. In some embodiments, the risk is reduced by at least 10%. In some embodiments, the risk is reduced by at least 15%. In some embodiments, the risk is reduced by at least 20%. In some embodiments, the risk is reduced by at least 25% In some embodiments, the risk is reduced by at least 25%. In some embodiments, the risk is reduced by at least 30%. In some embodiments, the risk is reduced by at least 35%. In certain embodiments, treating PIRA comprises an improvement of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, or at least 30% in a metric of PIRA (e.g., in T25FWT time, or 9-HPT time, or EDSS score, etc.), as compared to the same metric evaluated in the same patient prior to beginning administration of a compound according to Formula (I). In some embodiments, the improvement is compared to the same metric evaluated in the same patient within 1 week, or within 0 to 28 days, or within 6 weeks prior to beginning administration of a compound according to Formula (I). In other embodiments, treating PIRA comprises 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 a metric of PIRA (e.g., in T25FWT time, or 9-HPT time, or EDSS score, etc.), as compared to the same metric evaluated in another patient with PIRA, wherein the other patient is not administered a compound according Formula (I). 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 patient is administered an anti- CD20 antibody (such as a CD20-directed cytolytic antibody). In some embodiments, the PIRA subgroup is selected from the subgroup consisting of: (a) active secondary progressive multiple sclerosis (aSPMS); (b) non-active secondary progressive multiple sclerosis (n-aSPMS); (c) secondary progressive multiple sclerosis (SPMS); (d) primary progressive multiple sclerosis (PPMS); (e) progressive multiple sclerosis (PMS); (f) early PIRA; (g) late PIRA; (h) active PIRA; (i) nonactive 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 patient has POMS. In some embodiments, the patient has LOMS. In some embodiments, the patient has AOMS.

[0271] Further provided is a method of treating (e.g., slowing) progression of PIRA in a patient in need thereof, by administering to the patient a therapeutically effective amount of a compound according to Formula (I). In some embodiments, the progression of PIRA is evaluated using the Expanded Disability Status Scale (EDSS), the 9-Hole Peg Test (9-HPT), or the Timed 25-Foot Walk Test (T25FWT), or any combinations thereof. In some embodiments, the progression of PIRA is evaluated based the time to onset of confirmed disability progression (e.g., 12-week or 24-week CDP), or based on the time to onset of a composite confirmed disability progression (e.g., 12-week or 24-week cCDP). In certain embodiments, the progression of PIRA is slowed at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or at least 35%. In some embodiments, the progression is slowed at least 5%. In some embodiments, the progression is slowed at least 10%. In some embodiments, the progression is slowed at least 15%. In some embodiments, the progression is slowed at least 20%. In some embodiments, the progression is slowed at least 25%. In some embodiments, the progression is slowed at least 30%. In some embodiments, the progression is slowed at least 35%. In some embodiments, progression is slowed as measured by the onset of cCDP12 (e.g., by increasing the time to onset of cCDP12) or by the risk of cCDP12 (e.g., reducing the risk of experiencing cCDP12 during a period of time). In some embodiments, the other patient is administered an anti-CD20 antibody (such as a CD20-directed cytolytic antibody). In some embodiments, the PIRA subgroup is selected from the subgroup consisting of: (a) active secondary progressive multiple sclerosis (aSPMS); (b) non-active secondary progressive multiple sclerosis (n-aSPMS); (c) secondary progressive multiple sclerosis (SPMS); (d) primary progressive multiple sclerosis (PPMS); (e) progressive multiple sclerosis (PMS); (f) early PIRA; (g) late PIRA; (h) active PIRA; (i) nonactive PIRA; (j) clinically isolated syndrome (CIS); (k) transitioning MS; or a combination thereof.

[0272] 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 patient has POMS. In some embodiments, the patient has LOMS. In some embodiments, the patient has AOMS.

[0273] In still further embodiments, provided herein is a method of decreasing disability in a patient with PIRA, comprising administering to the patient a therapeutically effective amount of a compound according to Formula (I). In still further embodiments, provided herein is a method of decreasing disability in a patient with PIRA, comprising administering to the patient a compound according to Formula (I). In some embodiments, provided is a compound for use in a method of decreasing disability in a patient with PIRA with a compound according to Formula (I). In further embodiments, provided herein is a compound for use in the manufacture of a medicament for use in a method of decreasing disability in a patient with PIRA with a compound according to Formula (I). Decreasing disability may comprise reducing the psychological impact of MS; increasing upper limb function; increasing walking ability; decreasing fatigue; improving work status; or decreasing global impression of MS severity; or any combinations thereof. Decreasing disability may further include decreasing one or more symptoms of PIRA or decreasing one or more physical impacts of PIRA on the patient. The decrease in disability (including, for example, one or more symptoms or physical impacts, or other aspects as described herein) may be evaluated as described herein, such as using the 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 level, GFAP level, BDNF level or Nurrl expression level. In some embodiments, one or more of 9-HPT, T25FWT, or EDSS is used. In some embodiments, decreasing disability comprises a patient that can complete the T25FWT anchor 9-HPT more quickly, or a decrease in the EDSS score (e.g., closer to "normal"). In certain embodiments, a decrease in disability comprises an improvement in one or more metrics of PIRA, such as one evaluated using the 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 level, GFAP level, BDNF level or Nurrl expression level. In certain embodiments, 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 metric of PIRA (e.g., in T25FWT time, or 9-HPT time, or EDSS score), as compared to the same metric evaluated in the same patient prior to beginning administration of a compound according to Formula (I). In some embodiments, two, three, four, five or more metrics are improved, wherein each improvement level is independent (e.g., one metric improves by at least 10%, another metric 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 metric evaluated in the same patient within 1 week, or within 0 to 28 days, or within 6 weeks prior to beginning administration of a compound according to Formula (I). In some embodiments, the PIRA subgroup is selected from the subgroup consisting of: (a) active secondary progressive multiple sclerosis (aSPMS); (b) non-active secondary progressive multiple sclerosis (n-aSPMS); (c) secondary progressive multiple sclerosis (SPMS); (d) primary progressive multiple sclerosis (PPMS); (e) progressive multiple sclerosis (PMS); (f) early PIRA; (g) late PIRA; (h) active PIRA; (i) nonactive 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 patient has POMS. In some embodiments, the patient has LOMS. In some embodiments, the patient has AOMS.

[0274] In some embodiments as provided herein, the progression of PIRA may be evaluated 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 level, GFAP level, BDNF level or Nurrl expression level. Thus, for example, in some embodiments the progression of PIRA is evaluated by one or more of EDSS, T25FWT, or 9-HPT. Further, in some embodiments the progression of PIRA is evaluated by a sustained increase in one or more PIRA symptoms or signs, such as an increase that is sustained over at least 12 weeks (e.g., confirmed to still be increased at least 12 weeks after the initial increase observed), or at least 24 weeks (e.g., confirmed to still be increased at least 24 weeks after the initial increase observed). In certain embodiments, the progression of PIRA is evaluated by a cCDP or CDP, such as cCDP-12, CDP-12, cCDP24, or CDP24, or any combinations thereof. In some embodiments, progression of PIRA is evaluated by cCDP12. In certain embodiments, progression of PIRA is evaluated by EDSS. In certain embodiments, the risk of experiencing cCDP12 is decreased, or time to onset of cCDP12 is increased, in combination with reducing the risk of experiencing CDP12, or in combination with increasing the time to onset of CDP12. In certain embodiments, the risk of experiencing cCDP12 is decreased, or time to onset of cCDP12 is increased, in combination with reducing the risk of experiencing cCDP24, or in combination with increasing the time to onset of cCDP24. In still further embodiments, the risk of experiencing cCDP12 is decreased, in combination with both: reducing the risk of experiencing CDP12, and reducing the risk of experiencing cCDP24. In still further embodiments, time to onset of cCDP12 is increased in combination with both: increasing the time to onset of CDP 12, and increasing the time to onset of cCDP24. In some embodiments, the PIRA subgroup is selected from the subgroup consisting of: (a) active secondary progressive multiple sclerosis (aSPMS); (b) non-active secondary progressive multiple sclerosis (n-aSPMS); (c) secondary progressive multiple sclerosis (SPMS); (d) primary progressive multiple sclerosis (PPMS); (e) progressive multiple sclerosis (PMS); (f) early PIRA; (g) late PIRA; (h) active PIRA; (i) nonactive 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 patient has POMS. In some embodiments, the patient has LOMS. In some embodiments, the patient has AOMS.

[0275] Pharmaceutical Compositions In some embodiments is provided a pharmaceutical composition including a compound according to Formula (I) described herein and a pharmaceutically acceptable excipient.

[0276] In some embodiments, the pharmaceutical composition includes a therapeutically effective amount of the compound according to Formula (I).

[0277] In some embodiments, the pharmaceutical composition includes a therapeutically-effective amount of a second agent, wherein the second agent is an agent for treating a neurodegenerative disease. In some embodiments, the neurodegenerative disease is Parkinson’s disease. In some embodiments, the second agent is a Parkinson’s disease drug, for example, 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 includes a therapeutically effective amount of the second agent.

[0278] In some embodiments, the pharmaceutical composition includes a therapeutically-effective amount of a second agent, wherein the second agent is an agent for treating an inflammatory disease, for example, acetaminophen, duloxetine, aspirin, ibuprofen, naproxen, diclofenac, prednisone, beta-rnethasone, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, codeine, fentanyl, hydrocodone, hydromorphone, morphine, meperidine, or oxycodone. In embodiments, the pharmaceutical composition includes a therapeutically effective amount of the second agent.

[0279] In some embodiments, the pharmaceutical composition includes a therapeutically-effective amount of a second agent, wherein the second agent is an anti-cancer agent.

[0280] Additional Definitions

[0281] At various places in the present specification, substituents of compounds of the present disclosure are disclosed in groups or in ranges. It is specifically intended that the present disclosure include each and every individual sub-combination of the members of such groups and ranges. The following is a non-limiting list of term definitions.

[0282] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains.

[0283] The term "level or activity" refers to the expression level of either mRNA or protein of the respective target or the activity, which is due to the expression level either of mRNA or protein regulated by the respective target. The activity can also be measured for certain target genes and proteins by means of PET scan or SPECT. In case of dopamine or its metabolites, "activity" means an increase or decrease of the respective molecule.

[0284] The term “effective amount” or “therapeutically effective amount” refers to that amount of a compound or pharmaceutical composition described herein that is sufficient to affect the intended application including, but not limited to, disease treatment or biomarker / target gene outcome, as illustrated below. The therapeutically effective amount can vary depending upon the intended application, or the patient and disease condition being treated, e.g., the weight (e.g. as assessed by the body mass index (BMI)), age and / or gender, the severity of the disease condition, the manner of administration and the like, the response towards a biomarker or Nurrl target gene and the like, which can readily be determined by one of ordinary skill in the art. The specific dose will vary depending on, for example, the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other agents, timing of administration, duration of treatment, the tissue to which it is administered, and the physical delivery system in which it is carried.

[0285] As used herein, the term “patient” refers to any member of the animal kingdom including humans. In some embodiments, “patient” refers to humans, at any stage of development. In some embodiments, “patient” refers to a human patient.

[0286] Patients can be of a certain age, such as, for example, about 1 to about 5 years old, about 5 to about 10 years old, about 10 to about 15 years old, about 15 to about 20 years old, about 20 to about 25 years old, about 25 to about 30 years old, about 30 to about 35 years old, about 35 to about 40 years old, about 40 to about 45 years old, about 45 to about 50 years old, about 50 to about 55 years old, about 55 to about 60 years old, about 60 to about 65 years old, about 65 to about 70 years old, about 70 to about 75 years old, about 75 to about 80 years old, about 80 to about 85 years old, about 85 to about 90 years old, about 90 to about 95 years old, about 95 to about 100 years old, about 1 to 8 years old, about 1 to 10 years old, about 1 to 12 years old, about 1 to 14 years old, about 1 to 16 years old, about 1 to 18 years old, about 1 to 20 years old, about 20 to 40 years old, about 20 to 60 years old, about 20 to 80 years old, about 20 to 100 years old, about 40 to 80 years old, or about 60 to 80 years old.

[0287] In some embodiments, a patient is at least about 1 year old, at least about 5 years old, at least about 10 years old, at least about 12 years old, at least about 14 years old, at least about 16 years old, at least about 18 years old, at least about 20 years old, at least about 25 years old, at least about 30 years old, at least about 40 years old, at least about 50 years old, at least about 60 years old, at least about 70 years old, or at least about 80 years old. In some embodiments, a patient is no more than about 1 year old, no more than about 5 years old, no more than about 10 years old, no more than about 12 years old, no more than about 14 years old, no more than about 16 years old, no more than about 18 years old, no more than about 20 years old, no more than about 25 years old, no more than about 30 years old, no more than about 40 years old, no more than about 50 years old, no more than about 60 years old, no more than about 70 years old, or no more than about 80 years old.

[0288] In some embodiments the patient in need of the above-mentioned method for treating MS belongs to the patient group with a pediatric-onset MS (POMS), which means an onset until the age of 18.

[0289] In some embodiments the patient in need of the above-mentioned method for treating MS belongs to the patient group with a late-onset MS (LOMS), which means an onset in the time period from 19-50 years.

[0290] In some embodiments the patient in need of the above-mentioned method for treating MS belongs to the patient group with an adult-onset MS (AOMS), which means an onset >50 years.

[0291] Patients can have a certain body mass index (BMI), such as, for example, about 15 kg / m2to about 18 kg / m2, about 15 kg / m2to about 18.5 kg / m2, about 18.5 kg / m2to about 24.9 kg / m2, about 25 kg / m2to about 29.9 kg / m2, or about 30 kg / m2to about 40 kg / m2. In some embodiments, a patient has a BMI of at least about 15 kg / m2, at least about 18.5 kg / m2, or at least about 25 kg / m2. In some embodiments, a patient has a BMI of no more than about 25 kg / m2, no more than about 30 kg / m2, or no more than about 40 kg / m2. The terms “agonist”, “activator”, “upregulator” etc. refer to a substance capable of detectably increasing the expression or activity of a given gene or protein. The agonist can increase expression or activity by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% in comparison to a control in the absence of the agonist. In certain instances, expression or activity is 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or higher than the expression or activity in the absence of the agonist.

[0292] The term “modulator” refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule or the physical state of the target of the molecule (e.g., a target may be a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)) relative to the absence of the composition.

[0293] The term “expression” includes any step involved in the production of the polypeptide including, but not limited to, transcription, post-transcriptional modification, translation, post-translational modification, and secretion. Expression can be detected using conventional techniques for detecting protein (e.g., ELISA, Western blotting, flow cytometry, immunofluorescence, immunohistochemistry, etc.).

[0294] The term “modulate” is used in accordance with its plain ordinary meaning and refers to the act of changing or varying one or more properties. “Modulation” refers to the process of changing or varying one or more properties. For example, as applied to the effects of a modulator on a target protein, to modulate means to change by increasing or decreasing a property or function of the target molecule or the amount of the target molecule. For example, as applied to the effects of a modulator on a target gene, to modulate means to change by increasing or decreasing expression of the gene or the activity of the gene.

[0295] The term "aberrant" as used herein refers to different from normal. When used to describe enzymatic activity, aberrant refers to activity that is greater or less than a normal control or the average of normal non-diseased control samples. In one embodiment the aberrant level is at least 10%, preferably at least 20%, more preferably at least 30%, even more preferably at least 40%, yet more preferably at least 50% different from the level of a healthy subject. In particular, the upregulated level is at least 10%, preferably at least 20%, more preferably at least 30%, even more preferably at least 40%, yet more preferably at least 50% higher from the level of a healthy subject. In particular, the downregulated level is at least 10%, preferably at least 20%, more preferably at least 30%, even more preferably at least 40%, yet more preferably at least 50% lower from the level of a healthy subject. When used to describe a target gene level, aberrant refers to a gene expression that is greater or less than a normal control or the average of normal non-diseased control samples. Aberrant activity may refer to an amount of activity that results in a disease, wherein returning the aberrant activity to a normal or non- disease-associated amount (e.g., by using a method as described herein), results in reduction of the disease or one or more disease symptoms.

[0296] A "week" preferably refers to a period of or about 5, about 6 or about 7 days. It may be about 5-8 days. Most preferred week is a period of 7 days. A "month" preferably refers to a period of or about 28, about 29, about 30 or about 31 days. It may be about 26-33 days. Most preferred month is a period of 30 days.

[0297] As used herein, the term “evening” refers to the period of time between late afternoon and early nightfall, preferably from 16:00 to 23:00 local time.

[0298] As used herein, the term “morning” refers to the period of time from the early hours of dawn until approximately midday, preferably from 5:00 to 12:00 local time.

[0299] The term “about” as used herein with respect to numbers, figures, ranges and / or amounts is preferably meant to mean “circa” and / or “approximately”. The meaning of those terms is well known in the art and preferably includes a variance, deviation and / or variability of the respective number, figure, range and / or amount of plus / minus 15% and especially of plus / minus 10%.

[0300] “Treatment” as used herein preferably comprises the sequential succession of an “induction treatment” and then the “maintenance treatment”. For example, a treatment according to the invention comprises an induction treatment for about one week in which the half daily dose is administered, followed by maintenance treatment in which the full daily dose is administered (see e.g. WO 2019 / 101888).

[0301] “Daily dose” preferably refers to the total dose of a compound according to Formula (I) orally administered to the patient each day of administration. The daily dose can be reached through a single or several administrations per day, such as for example once a day, twice a day or three times a day. Preferably, it is reached or achieved by single administration per day, preferably consisting of one or more tablets or capsules, preferably tablets or capsules as described herein.

[0302] “Relapses” preferably involve neurologic problems that occur over a short period, typically days but sometimes as short as hours or even minutes. These attacks most often involve motor, sensory, visual or coordination problems early in the disease. Later, bladder, bowel, sexual and cognitive problems may be shown. Sometimes the attack onset occurs over several weeks. Typical MS relapse involves a period of worsening, with development of neurological deficits, then a plateau, in which the patient is not getting any better but also not getting any worse followed by a recovery period. Recovery usually begins within a few weeks.

[0303] The "annualized relapse rate" is the average number of relapses a group of patients in a clinical study have in one year. See e.g. Multiple Sclerosis Coalition. The Use Of Disease - Modifying Therapies In Multiple Sclerosis: Principles and Current Evidence Summary. Available at http: / / www.nationalmssociety.org / getmedia / 1e64b96c-9e55-400e-9a64- 0cdf5e2d60fe / summaryDMTpaper_-final.

[0304] The "hazard ratio" is measure of how often a particular event happens in one group compared to how often it happens in another group over time. A hazard ratio of exactly 1.0 means that the study drug provides zero risk reduction, compared to the control treatment.

[0305] The "Expanded Disability Status Scale" (EDSS) is a clinician-reported outcome measure for quantifying changes in the disability level of a patient with MS overtime. The EDSS is based on a standard neurological examination, incorporating functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel and bladder, and cerebral [or mental]) that are rated and then scored as a functional system score (FSS), and ambulation, which is scored as ambulation score. Each FSS is an ordinal clinical rating scale ranging from 0 to 5 or 6, and an ambulation score that is rated from 0 to 12. These ratings may then be used in conjunction with observations, as well as information, concerning ambulation and use of assistive devices to determine the total EDSS score. The EDSS is a disability scale that ranges in 0.5-point steps from 0 (normal) to 10.0 (death) (Kurtzke, Neurology 1983;33:1444). In some embodiments of the methods provided herein, the item sexual dysfunction and fatigue are not included in the EDSS score. Typically, a decrease in EDSS score corresponds to an improvement in the disease and conversely, an increase in EDSS score corresponds to a worsening of the disease.

[0306] The "9-Hole Peg Test" (9-HPT) is a quantitative measure of upper extremity (arm and hand) function (Arch. Phys. Med. Rehabil. 1988;69:850). The test device consists of a container with nine pegs and a block containing nine empty holes. The patient is to pick up each of the nine pegs one at a time and as quickly as possible place them in the nine holes. Once all the pegs are in the holes, the patient is to remove them again one at a time as quickly as possible and replace them into the container. The total time to complete the task is recorded. Both the dominant and non-dominant hands are tested twice (two successfully completed trials of the dominant hand, followed immediately by two successfully completed trials of the non-dominant hand). The two trials for each hand are averaged, converted to the reciprocals of the mean times for each hand, and the two reciprocals are averaged. The 9-HPT may be administered, for example, as described in the Multiple Sclerosis Functional Composite (MSFC) Administration and Scoring Manual (National Multiple Sclerosis Society, 2001). A meaningful change in upper extremity function may, for example, be indicated by a 20% worsening from baseline of the averaged 9-HPT times.

[0307] The "Timed 25-Foot Walk Test'" (T25FWT) is a quantitative measure of mobility and leg function, based on a timed 25-foot walk. The patient is directed to start at one end of a clearly marked 25- foot course and is instructed to walk 25 feet as quickly and safely as possible, and how long it takes the patient to go from start of the walk to the end of the 25 feet is timed. In some embodiments, the task is administered immediately again by having the patient walk back the same distance, and the time for both completed trials averaged to produce the score for the T25FWT. Patients may use assistive devices (e.g., cane or wheelchair) when performing the task. The T25FWT may be administered, for example, as described in the MSFC Administration and Scoring Manual. A clinically meaningful change in mobility and leg function may, for example, be indicated by a 20% worsening from baseline of the averaged T25FWT time.

[0308] The "Symbol Digit Modalities Test" (SDMT) is a test used to evaluate the presence of cognitive impairment and / or changes in cognitive functioning over time and in response to treatment. The SDMT may be particularly sensitive to slowed processing of information that is commonly seen in MS (Mult. Scler. 2017;23:721). The SDMT comprises a substitution task. Using a reference key, the patient has 90 seconds to pair specific numbers with given geometric figures. Responses may be collected orally, and the number of correct responses is considered the SDMT score. A clinically meaningful change in cognitive processing may, for example, be indicated by a decrease by 4 points on the SDMT score from baseline.

[0309] The "Columbia-Suicide Severity Rating Scale" (C-SSRS) is a tool used to assess the lifetime suicidality of a patient and may be used to track suicidal events through treatment or a portion thereof. The structured interview prompts recollection of suicidal ideation, including the intensity of the ideation, behavior, and attempts with actual / potential lethality. A "baseline" C-SSRS may include, for example, C-SSRS collected prior to beginning administration of a compound of Formula (I). Such score may be compared, for example, to subsequent C-SSRS collected after beginning administration of a compound of Formula (I). Comparisons between different e valuation periods (which may, for example, occur during visits with a clinician) may be described, in some embodiments, as "since last visit" C-SSRS.

[0310] The "EQ-5D-5L" is a validated self-reported health status questionnaire that can used to calculate a health status utility score for use in health economic analyses (Qual. Life Res. 2011 ;20:1727; Qual. Life Res. 2013;22:1717). There are two components to the EQ-5D-5L: a five-item health state profile that assesses mobility, self-care, usual activities, pain / discomfort, and anxiety / depression, as well as a visual analog scale (VAS) that measures health state. The EQ- 5D-5L is designed to capture a patients current health status. Published weighting systems may allow for creation of a single composite score of the patient's health status. The "Multiple Sclerosis Impact Scale-29 Version 2" (MSIS-29, Version 2) is a 29-item subject-reported measure of the physical and psychological impacts of MS (Brain 2001 ;124:962). Patients are asked to rate how much their functioning and well-being has been impacted over the past 14 days on a 4-point scale, from "Not at all" (1) to "Extremely" (4). The physical score is the sum of items 1 to 20, which is then transformed to a 0-100 scale. The psychological score is the sum of items 21-29, transformed to a 0-100 scale. Higher scores may indicate a greater impact of 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.

[0311] The "Multiple Sclerosis Walking Scale, 12-ltem" (MSWS-12) is a 12-item self-report measure of the impact of MS on the individual's ability to walk during the past 2 weeks. Each item is scored on a 5-point Likert scale, and total scores are converted to a 0-100 scale with higher scores indicating greater impact of MS on walking ability.

[0312] 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, which involves patients with MS through each stage of its development (Qual. Life Res. 2012;21 :475). Items include assessments of dressing, cooking, eating, cleaning, and writing from which the patient uses a 5-point Likert scale to rate his or her performance ranging from "without any difficulty" (5) to "unable to do" (1). Item scores are summed, multiplied by 20 and divided by 20 minus the number of any unanswered items. Scores range from 20-100, where a higher score indicates better upper limb function. In accordance with the NINDS User Manual (2015), scores can be calculated as long as at least 50% of the items have been answered.

[0313] The "PROMIS-FatigueMS" is an 8-item scale developed as a measure of fatigue for patients with MS (Qual. Life Res. 2012;21 :1021) with a recall period of the previous 7 days. It comprises a 5- point Likert-type scale that produces a score between 1 and 5 for each scored question. The total raw score is the sum of the values of each scored question. The total raw score ranges from 8- 40. Scores can also be transformed to a PROMIS T-score where the mean is 50 and a standard deviation of 10. T-scores range from 34.7-81.3. A higher score is associated with worse fatigue.

[0314] The "Patient Global Impression of Change" (PGI-C) is a single-item assessment of a patient's impression of his or her change in MS symptoms compared with a point 6 months previous. Patients respond on a 7-point Likert scale from "very much better" (i) to "very much worse" (7). The PGI-C is used as an anchor for determining what is a clinically meaningful change in the MSIS-29.

[0315] The "Patient Global Impression of Severity" (PGI-S) is a single-item assessment of a patient's impression of the severity of his or her MS symptoms from the past 7 days. A patient respond on a 5-point Likert scale from "none" (1) to "very severe" (5). The PGI-S is used as an anchor for determining what is a clinically meaningful change in the MSIS-29.

[0316] The "Work Productivity and Activity Impairment: Multiple Sclerosis" (WPAI:MS) is a 6-item scale. A patient estimates the amount of time that their work and daily activities were affected by their MS over the previous 7 days (Pharmacoeconomics 1993;4:353). The WPAI:MS assesses absenteeism as well as "presenteeism," which accounts for the time when a patient was present for work or activities, but believed their health had a negative effect on their ability to perform at the usual level. A higher score represents a greater impairment in productivity.

[0317] "Confirmed Disability Progression" (CDP) refers to an increase in the patient's EDSS score that is sustained over a particular time period. This may be evaluated, for example, by calculating the patient's EDSS score, determining that the score is increased over a previous score (such as a baseline score, which may be a score taken before the patient began administration of a compound of Formula (I), and then confirming the score is still increased after a specified period of time has elapsed from the initial increase (e.g., by reevaluating the patient and recalculating it again). For example, a 12-week confirmed disability progression (CDP12) refers to an EDSS score that remains increased at least 12 weeks after the initial increase (e.g., as confirmed by recalculating the EDSS score at least 12 weeks after the initial increase). A 24-week confirmed disability progression (CDP24) refers to an EDSS score remains increased at least 24 weeks after the initial increase (e.g., as confirmed by recalculating the EDSS score at least 24 weeks after the initial increase). The initial increase may be compared to a baseline EDSS score (such as prior to beginning administration of a compound of Formula (I), or may be compared to a prior EDSS score that had remained stable over time, such as over 12, 24, 36, 48, or 60 weeks. In some embodiments, a CDP refers to an increase of >1.0 point from the baseline EDSS score in a patient with a baseline EDSS score of <5.5 points, or an increase of >0.5 point from the baseline EDSS score in a patient with a baseline EDSS score of >5.5 points. Time to onset of a CDP (e.g., time to onset of CDP 12 or CDP24) refers to the time period from when the prior EDSS score was established (for example, a baseline EDSS score from before beginning administration of a compound of Formula (I)) until the sustained increase of EDSS score is observed.

[0318] "Composite Confirmed Disability Progression" (cCDP) is a composite measure of disability progression using a combination of EDSS, 9 -HPT and T25FWT. It evaluates the progression of patient's disability over a particular time 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., increase of >1.0 point from the baseline EDSS score in a patient with a baseline EDSS score of <5.5 points, or an increase of >0.5 point from the baseline EDSS score in a patient with a baseline EDSS score of >5.5 points); an increase of >20% from baseline in time to complete the 9-Hole Peg Test (9-HPT); or an increase of >20% from baseline in the Timed 25-Foot Walk Test (T25FWT); wherein the occurrence of the progression event is confirmed at after a specified period of time has elapsed from the initial occurrence. For example, a composite 12-week continued disability progression (cCDP12) refers to the occurrence of at least one progression event at an initial time point, and the same progression event is confirmed at least 12 weeks later (e.g., by re-evaluating the patient using the same test). A composite 24-week confirmed disability progression (cCDP12) refers to the occurrence of at least one progression event at an initial time period, and same progression event is confirmed at least 24 weeks later. Time to onset of a cCDP (e.g., time to onset of cCDP12 or cCDP24) refers to the time period from when the prior evaluation scores were established (for example, baseline scores before beginning administration of a compound of Formula (I)) until the initial progression event is observed. Without wishing to be bound by theory, compared with endpoints based exclusively on the Expanded Disability Status Scale (EDSS), which emphasizes lower limb function, the cCDP12 requires at least one of the following: 1) an increase in EDSS score of >1.0 point from a baseline (BL) score of <5.5 points, or >0.5 point increase from a BL score of >5.5 points (Confirmed Disability Progression); 2) a 20% increase from BL in time to complete the 9-Hole Peg Test; 3) a 20% increase from BL in the Timed 25-Foot Walk Test. Thus, the cCDP 12 is a more sensitive assessment of disability, especially at early disease stages. The use of the cCDP12 as a primary outcome may provide a clearer, more complete picture of disability progression or improvement than the EDSS alone.

[0319] The "Confirmed Disease Worsening" (CDW), measures the increase in a patient’s EDSS score that is sustained over a pre-determined time period, which means a patient’s physical disability has increased as described in e.g. Drugs 2015;75:947.

[0320] In some embodiments the confirmed disease progression is measured by Kurtzke Expanded Disability Status Scale (EDSS) score in a patient having MS in need of.

[0321] In some embodiments the confirmed disease progression is at least a 1 point increase of the EDSS score.

[0322] In some embodiments, the MS patient had confirmed disease progression of at least a 0.5 point increase of the EDSS score.

[0323] In some embodiments, the hazard ratio for no confirmed disability worsening is decreased by 20- 60%.

[0324] In some embodiments, the hazard ratio for no confirmed disability worsening is decreased by 30- 50%.

[0325] In some embodiments, the hazard ratio for no confirmed disability worsening is decreased by at least 30%.

[0326] In some embodiments, the hazard ratio for no confirmed disability worsening is decreased by at least 40%.

[0327] In some embodiments, the hazard ratio for no confirmed disability worsening is decreased by at least 50%.

[0328] The term "brain atrophy" describes one of the most destructive consequences of MS. Brain atrophy can be seen in the earliest stages of MS and may lead to irreversible neurological and cognitive impairments. Progressive loss of brain tissue bulk can be detected in vivo in a sensitive and reproducible manner by MRI. See e.g. Lancet Neurol. 2006;5:158. “Efficacy” of a treatment according to the invention can be preferably measured based on changes in the course of disease in response to a use according to the invention. For example, treatment of MS efficacy can be measured by the frequency of relapses in RRMS and the presence or absence of new lesions in the CNS as detected using methods such as the MRI technique (Neurology 1996;47(Suppl 4):S217; Ann. Neurology 1997;41 :125).

[0329] Preferably, the observation of the reduction and / or suppression of MRI T1 gadolinium-enhanced lesions (thought to represent areas of active inflammation) gives a primary efficacy variable. Shows active lesions that appear bright white on an MRI scan after administration of an intravenous imaging contrast agent (gadolinium). Secondary efficacy variables preferably include MRI T1 enhanced brain lesion volume, MRI T1 enhanced lesion number, MRI T2 lesion volume (thought to represent total disease burden, i.e. demyelination, gliosis, inflammation and axon loss), MRI T 1 enhanced hypointense lesion volume (thought to represent primarily demyelination and axon loss), time-to-progression of MS, frequency and severity of exacerbations and time-to- exacerbation, Expanded Disability Status Scale score and Scripps Neurologic Rating Scale (SNRS) score (Neurology 1984;34:1368). Methods of early and accurate diagnosis of multiple sclerosis and of following the disease progression are described in Mattson, Expert Rev. Neurother. 2002;2:319.

[0330] White matter lesions on brain MRI in MS may contribute to misdiagnosis, especially when trying to assign a patient to a subgroup. A subset of MS lesions shows paramagnetic rims on susceptibility-weighted MRI sequences, reflecting iron accumulation in microglia. These paramagnetic rim lesions have been proposed as a marker of compartmentalized smoldering disease (AJR 2022;219:120). Paramagnetic rim lesion detection occurs rarely in other neurological conditions (52% of MS vs 7% of non-MS cases) and yielded high specificity (93%) in differentiating MS from non-MS (Ann Neurol. 2020;88:1034). Paramagnetic rim lesions may be an emerging marker of chronic neuroinflammation in MS and could help to assign a MS patient to a subgroup, e.g. PPMS.

[0331] As used herein, the term "effective amount" includes a dosage sufficient to produce a desired result with respect to the indicated disorder, condition, or mental state. The desired result may comprise a subjective or objective improvement in the recipient of the dosage.

[0332] As used herein, the term "administering" includes activities associated with providing a patient an amount of a compound according to Formula (I). Administering includes providing unit dosages of compositions set forth herein to a patient in need thereof. Administering includes providing effective amounts of a compound according to Formula (I), for a specified period of time, e.g. for about 6, 9, 12, 15 or more months, or about 1 , 2, 3, 4, 5 or more years.

[0333] “Disease” or “condition” refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein. In some embodiments, the disease is a disease related to (e.g., caused by) a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule). In embodiments, the disease is a neurodegenerative disease. In embodiments, the disease is an inflammatory disease. In embodiments, the disease is a cancer. In some embodiments, a level of Nurrl , a level of activity of a gene downstream of Nurrl , or a level of a protein downstream of Nurrl (e.g., NCAM, CFB, LTA, A2M, HSD11 B1 , BHLHE41 , MARCO, BDNF, GDNF, C-RET, GFAP, DAT, Pitx3, TH, VMAT2, SOD1 , AADC, TNFa, iNOS, or IL-1 p) is measured in a patient, and then compared to the analogous value obtained from a healthy control patient that has the same biological sex, a similar or identical body mass index (BMI), or a similar or identical age relative to the patient. For example, the healthy control subject can have an age that is within ±1 year, ±2 years, ±3 years, ±4 years, ±5 years, ±10 years, ±15 years, ±20 years, or ±30 years of the age of the patient. In some embodiments, the healthy control subject has a BMI that is within ±1 kg / m2, ±2 kg / m2, ±3 kg / m2, ±4 kg / m2, ±5 kg / m2, ±10 kg / m2, ±15 kg / m2, or ±20 kg / m2of the BMI of the patient. Age, BMI, and biological sex can be independently assessed in the patient or the healthy control subject when a level of a protein (e.g., Nurrl) or gene is measured.

[0334] In some embodiments, a level of Nurrl , a level of activity of a gene downstream of Nurrl , or a level of a protein downstream of Nurrl in a sample (e.g., NCAM, CFB, LTA, A2M, HSD11 B1 , BHLHE41 , MARCO, BDNF, GDNF, C-RET, GFAP, DAT, Pitx3, TH, VMAT2, SOD1 , AADC, TNFa, iNOS, or IL-1 ) is measured in a patient, and then compared to a level of Nurrl , a level of activity of a gene downstream of Nurrl , or a level of a protein downstream of Nurrl in another sample of the subject to see decline or decrease of said level.

[0335] In some embodiments, a level of Nurrl , a level of activity of a gene downstream of Nurrl , or a level of a protein downstream of Nurrl in a sample (e.g., GDNF, GFAP, or VMAT2) is measured in a patient more than once and then compared to a level of Nurrl , a level of activity of a gene downstream of Nurrl , or a level of a protein downstream of Nurrl in another sample of the patient to monitor the decline or decrease of said level over time.

[0336] The level of Nurrl , a level of activity of a gene downstream of Nurrl , or a level of a protein downstream of Nurrl can be determined and / or quantified from suitable fluids from the subject (e.g. plasma or CSF) or cells (e.g. peripheral blood mononuclear cells or CD4+T cells) as described, e.g. in PLoS ONE 2010;5:e8962, Arch. Neurol. 2011 ;68:879 or J. Neuroimmunol. 2014;272:99.

[0337] Non-limiting examples of a mental condition include anxiety, depression, bipolar disorder, dementia, schizophrenia, and other psychoses.

[0338] Non-limiting examples of a central nervous system condition or disease include neurological diseases or disorders that affect the structure or function of the brain or spinal cord, which collectively form the central nervous system (CNS), for example addiction, encephalitis, Parkinson’s and multiple sclerosis.

[0339] Non-limiting examples of a neurodegenerative disease or condition include a disease or condition in which the function of a patient’s nervous system becomes impaired, for example, Alper’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, corticobasal syndrome (CBS), Creutzfeldt-Jakob disease, Down syndrome (DS), frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Huntington’s disease, HIV-associated dementia (FTD), Kennedy’s disease, Krabbe’s disease, kuru, dementia with Lewy bodies (DLB), Machado-Joseph disease (Spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick’s disease, primary lateral sclerosis, prion diseases, progressive supranuclear palsy (PSP), Refsum’s disease, Sandhoffs disease, Schilder’s disease, subacute combined degeneration of spinal cord secondary to pernicious anemia, schizophrenia, spinocerebellar ataxia (multiple types with varying characteristics), spinal muscular atrophy, Steele-Richardson-Olszewski disease, and tabes dorsalis.

[0340] As used herein, the term “neuroprotection” refers to the relative preservation of neuronal structure and / or function, i.e. to a therapeutic strategy for slowing or preventing the otherwise irreversible loss of neurons overtime. In the case of an ongoing insult (a neurodegenerative insult) the relative preservation of neuronal integrity implies a reduction in the rate of neuronal loss over time. It is a widely explored treatment option for many CNS disorders including neurodegenerative diseases, stroke, traumatic brain injury, spinal cord injury, and acute management of neurotoxin consumption (i.e. methamphetamine overdoses). Neuroprotection aims to prevent or slow disease progression and secondary injuries by halting or at least slowing (mitigate) the loss of neurons. Despite differences in symptoms or injuries associated with CNS disorders, many of the mechanisms behind neurodegeneration are the same. Common mechanisms of neuronal injury include decreased delivery of oxygen and glucose to the brain, energy failure, increased levels in oxidative stress, mitochondrial dysfunction, excitotoxicity, inflammatory changes, iron accumulation, and protein aggregation.

[0341] As used herein, the term “inflammatory disease” or “inflammatory condition” refers to an inflammatory disease or condition can be, for example, a disease or condition characterized by aberrant inflammation (e.g., an increased level of inflammation compared to a control such as a healthy person not suffering from a disease). Non-limiting examples of inflammatory diseases include autoimmune diseases, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile onset diabetes, diabetes mellitus type 1 , Guillain-Barre syndrome, Hashimoto’s encephalitis, Hashimoto’s thyroiditis, ankylosing spondylitis, psoriasis, Sjogren’s syndrome, vasculitis, glomerulonephritis, auto-immune thyroiditis, Behcet’s disease, Crohn’s disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison’s disease, vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, scleroderma, and atopic dermatitis.

[0342] Non-limiting examples of cancer include neoplasm, malignant tumors, leukemia, lymphoma, carcinomas, sarcomas, cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head and neck, liver, kidney, lung, non-small cell lung, ovary, sarcoma, stomach, or uterus, melanoma, mesothelioma, medulloblastoma, colorectal cancer, pancreatic cancer, Hodgkin’s disease, NonHodgkin’s lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, malignant pancreatic insulinoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, and prostate cancer. Non-limiting examples of leukemia include progressive, malignant diseases of the blood-forming organs characterized by a distorted proliferation and development of leukocytes and precursors in the blood and bone marrow, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross’ leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling’s leukemia, stem cell leukemia, subleukemic leukemia, and undifferentiated cell leukemia.

[0343] Non-limiting 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 (monocytoid B-cell) lymphoma, splenic lymphoma, diffuse large cell B-lymphoma, Burkitt’s lymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, anaplastic large cell lymphoma, mycosis fungoides, and precursor T-lymphoblastic lymphoma.

[0344] Non-limiting examples of sarcoma includes tumors made of a substance like the embryonic connective tissue and are generally composed of closely packed cells embedded in a fibrillar or homogeneous substance. Sarcomas that may be treated with a compound or method provided herein include a, chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms’ tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing’s sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen’s sarcoma, Kaposi’s sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, and telangiectaltic sarcoma.

[0345] Non-limiting examples of melanomas include tumors arising from the melanocytic system of the skin and other organs. Melanomas that may be treated with a compound or method provided herein include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman’s melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma, or superficial spreading melanoma.

[0346] Non-limiting examples of carcinomas include medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypemephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher’s carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, Schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, and carcinoma villosum.

[0347] ENUMERATED EMBODIMENTS

[0348] Embodiment A1 : A compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease according to any one of the preceding non-enumerated embodiments, wherein the method comprises: a) determining a level of activity of a gene in a patient, wherein the gene is downstream of Nurrl in a biological pathway in the patient; and b) based on the level of activity of the gene in the patient, determining whether to administer to the patient a Nurrl agonist for a neurodegenerative condition.

[0349] Embodiment A2: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy of a neurodegenerative condition or disease for neuroprotection according to Embodiment A1 , wherein the level of activity of the gene in the patient indicates that the gene is upregulated.

[0350] Embodiment A3: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy of a neurodegenerative condition or disease for neuroprotection according to Embodiment A1 or A2, wherein the method further comprises, based on the level of activity of the gene in the patient, administering to the patient a therapeutically effective amount of the Nurrl agonist.

[0351] Embodiment A4: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy of a neurodegenerative condition or disease for neuroprotection according to any one of the preceding non-enumerated embodiments, wherein the method comprises: a) determining a level of activity of a gene in a patient who is undergoing a therapy for a neurodegenerative condition, wherein the gene is downstream of Nurrl in a biological pathway in the patient, wherein the therapy is Nurrl agonism; and b) based on the level of activity of the gene in the patient, determining whether to continue the therapy for the neurodegenerative condition.

[0352] Embodiment A5: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy of a neurodegenerative condition or disease for neuroprotection according to Embodiment A4, wherein the level of activity of the gene in the patient is higher than the level was prior to the therapy.

[0353] Embodiment A6: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy of a neurodegenerative condition or disease for neuroprotection according to any of Embodiments A1 to A5, wherein the obtaining the level of activity of the gene in the patient comprises obtaining a result of an assay of an ex vivo biological sample of the patient, wherein the assay determines a level of activity of the gene in the ex vivo biological sample of the patient.

[0354] Embodiment A7: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy of a neurodegenerative condition or disease for neuroprotection according to any of Embodiments A1 to A5, wherein the obtaining the level of activity of the gene in the patient comprises performing an assay of an ex vivo biological sample of the patient, wherein the assay determines a level of activity of the gene in the ex vivo biological sample of the patient.

[0355] Embodiment A8: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy of a neurodegenerative condition or disease for neuroprotection according to Embodiment A6 or A7, wherein the assay is a real-time PCR assay of Nurrl gene expression against relevant housekeeping genes / internal controls (e.g. GAPDH) from the tissue selected from peripheral blood, peripheral blood lymphocytes, serum, plasma, CSF or peripheral blood mononuclear cells.

[0356] Embodiment A9: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy of a neurodegenerative condition or disease for neuroprotection according to any of Embodiments A6 to A8, wherein the ex vivo biological sample is a blood sample.

[0357] Embodiment A10: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy of a neurodegenerative condition or disease for neuroprotection according to any of Embodiments A1 to A9, wherein the gene is selected from the group consisting of NCAM, CFB, LTA, A2M, HSD11B1, BHLHE41 , MARCO, BDNF, GDNF, C-RET, GFAP, DAT, Pitx3, TH, VMAT2, SOD1 , AADC, TNFa, iNOS and IL-1 .

[0358] Embodiment A11 : A method comprising: a) determining in a sample obtained from a patient that the patient exhibits downregulated Nurrl ; b) determining in a sample obtained from the patient that the patient exhibits upregulated miR- 132; and c) based on the determining that the patient exhibits downregulated Nurrl and the determining that the patient exhibits upregulated miR-132, identifying the patient as being at risk for a condition.

[0359] Embodiment A12: The method of Embodiment A11 , wherein the determining that the patient exhibits downregulated Nurrl comprises obtaining a result of a first assay of an ex vivo biological sample of the patient, wherein the first assay determines a level of Nurrl in the ex vivo biological sample of the patient; and the determining that the patient exhibits upregulated miR-132 comprises obtaining a result of a second assay of the ex vivo biological sample of the patient, wherein the second assay determines a level of miR-132 in the ex vivo biological sample of the patient.

[0360] Embodiment A13: The method of Embodiment A11 , wherein the determining that the patient exhibits downregulated Nurrl comprises performing a first assay of an ex vivo biological sample of the patient, wherein the first assay determines a level of Nurrl in the ex vivo biological sample of the patient; and the determining that the patient exhibits upregulated miR-132 comprises performing a second assay of the ex vivo biological sample of the patient, wherein the second assay determines a level of miR-132 in the ex vivo biological sample of the patient.

[0361] Embodiment A14: The method of Embodiment A12 or A13, wherein the first assay determines the level of Nurrl in the ex vivo biological sample of the patient by determining a concentration of Nurrl in the ex vivo biological sample of the patient.

[0362] Embodiment A15: The method of Embodiment A12 or A13, wherein the first assay determines the level of Nurrl in the ex vivo biological sample of the patient by determining a level of activity of Nurrl in the ex vivo biological sample of the patient.

[0363] Embodiment A16: The method of any of Embodiments A12 to A15, wherein the first assay is a reverse transcription real-time quantitative PCR (RT-qPCR) assay from peripheral blood lymphocytes.

[0364] Embodiment A17: The method of any of Embodiments A12 to A16, wherein the second assay determines the level of miR-132 in the ex vivo biological sample of the patient by determining a concentration of miR-132 in the ex vivo biological sample of the patient.

[0365] Embodiment A18: The method of any of Embodiments A12 to A16, wherein the second assay determines the level of miR-132 in the ex vivo biological sample of the patient by determining a level of activity of miR-132 in the ex vivo biological sample of the patient.

[0366] Embodiment A19: The method of any of Embodiments A12 to A18, wherein the second assay is a reverse transcription real-time quantitative PCR (RT-qPCR) assay from plasma.

[0367] Embodiment A20: The method of any of Embodiments A11 to A19, wherein the ex vivo biological sample is a blood sample.

[0368] Embodiment A21 : The method of any of Embodiments A11 to A20, wherein the level of Nurrl in the ex vivo biological sample of the patient is no greater than about 90% of the level in a healthy subject of same age, gender and / or BMI. Embodiment A22: The method of any of Embodiments A11 to A21 , wherein the level of miR-132 in the ex vivo biological sample of the patient is at least 110% of the level in a healthy subject of same age, gender and / or BMI.

[0369] Embodiment A23: The method of any of Embodiments A11 to A22, wherein the condition is selected from the group consisting of a neurodegenerative condition, an inflammatory condition, a mental condition, a central nervous system condition, Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, PIRA, amyotrophic lateral sclerosis, schizophrenia and drug addiction.

[0370] Embodiment A24: The method of any of Embodiments A11 to A23, further comprising, based on the determining that the patient exhibits downregulated Nurrl and the determining that the patient exhibits upregulated miR-132, identifying the patient as a candidate for therapy for a condition.

[0371] Embodiment A25: The method of any of Embodiments A11 to A23, further comprising, based on the determining that the patient exhibits downregulated Nurrl and the determining that the patient exhibits upregulated miR-132, administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof that modulates Nurrl .

[0372] Embodiment A26: The method of Embodiment A25, wherein the compound that modulates Nurrl agonizes Nurrl .

[0373] Embodiment A27: The method of any of Embodiments A25 to A26, wherein the administering is oral.

[0374] Embodiment A28: The method of any of Embodiments A25 to A27, wherein the administering is oral by a solid dosage form.

[0375] Embodiment B1 : The compound of Formula (I) or a pharmaceutically acceptable salt or a solvate thereof for use in therapy of a neurodegenerative condition or disease for neuroprotection wherein the method comprises: determining a level or activity of Nurrl in the ex vivo biological sample of the patient with an assay selected from

[0376] (a) a real-time PCR assay of Nurrl gene expression against relevant housekeeping genes / internal controls (e.g. GAPDH),

[0377] (b) an immunoassay (such as ELISA) with the suitable antibodies for Nurrl protein, or

[0378] (c) a Western blot for Nurrl protein from the biological sample selected from peripheral blood, peripheral blood lymphocytes, serum, plasma, CSF or peripheral blood mononuclear cells; and if the test sample from the patient comprises a level of Nurrl of no greater than about 90% of the level in a healthy subject of same age, gender and / or BMI, administering to the patient an effective amount of Formula (I) or a pharmaceutically acceptable salt or a solvate thereof.

[0379] Embodiment B2: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy of a neurodegenerative condition or disease for neuroprotection according to Embodiment B1 , wherein the neurodegenerative condition is Alzheimer’s disease.

[0380] Embodiment B3: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy of a neurodegenerative condition or disease for neuroprotection according to Embodiment B1 , wherein the neurodegenerative condition is amyotrophic lateral sclerosis. Embodiment B4: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy of a neurodegenerative condition or disease for neuroprotection according to Embodiment B1 , wherein the neurodegenerative condition is Parkinson’s disease.

[0381] Embodiment B5: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy of a neurodegenerative condition or disease for neuroprotection according to Embodiment B1 , wherein the neuroprotection is slowing or preventing loss of dopaminergic neurons.

[0382] Embodiment B6: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy of a neurodegenerative condition or disease for neuroprotection according to Embodiment B1 , wherein the neurodegenerative condition is multiple sclerosis.

[0383] Embodiment B7: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy of a neurodegenerative condition or disease for neuroprotection according to Embodiment B1 , wherein the neurodegenerative condition is multiple sclerosis.

[0384] Embodiment B8: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy of a neurodegenerative condition or disease for neuroprotection according to Embodiment B1 , wherein the neurodegenerative condition is multiple sclerosis.

[0385] Embodiment B9: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy of a neurodegenerative condition or disease for neuroprotection according to Embodiment B1 , wherein the neurodegenerative condition is primary progressive multiple sclerosis.

[0386] Embodiment B10: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy of a neurodegenerative condition or disease for neuroprotection according to Embodiment B1 , wherein the neurodegenerative condition is relapsing remitting multiple sclerosis.

[0387] Embodiment B11 : The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy of a neurodegenerative condition or disease for neuroprotection according to Embodiment B1 , wherein the neurodegenerative condition is multiple sclerosis, wherein the disability is acquired through relapse-associated worsening (RAW).

[0388] Embodiment B12: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy of a neurodegenerative condition or disease for neuroprotection according to Embodiment B1 , wherein the neurodegenerative condition is multiple sclerosis, wherein the disability is acquired through progression independent of relapse activity (PIRA).

[0389] Embodiment B13: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy of a neurodegenerative condition or disease for neuroprotection according to Embodiment B1 , wherein the neurodegenerative condition is brain atrophy induced by multiple sclerosis.

[0390] Embodiment B14: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy of a neurodegenerative condition or disease for neuroprotection according to Embodiment B1 , wherein the neurodegenerative condition is non-inflammatory multiple sclerosis worsening.

[0391] Embodiment B14: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy of a neurodegenerative condition or disease for neuroprotection according to Embodiment B1 , wherein the neuroprotection is slowing or preventing loss of neurons induced by multiple sclerosis.

[0392] Embodiment B15: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy of a neurodegenerative condition or disease for neuroprotection according to Embodiment B1 , wherein the neuroprotection is slowing or preventing loss of dopaminergic neurons induced by multiple sclerosis.

[0393] Embodiment B16: The compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy of a neurodegenerative condition or disease for neuroprotection according to Embodiment B1 , wherein the neurodegenerative condition is PIRA.

[0394] Embodiment C1: A compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease according to any one of the preceding non-enumerated embodiments in a patient, the therapy comprising administering to the patient a therapeutically-effective amount of a compound of Formula (I), wherein the patient exhibits an aberrant level of a biomarker associated with the neurodegenerative disease prior to the administering.

[0395] Embodiment C2: The use in therapy of Embodiment C1, wherein the biomarker is Nurrl.

[0396] Embodiment C3: The use in therapy of Embodiment C1, wherein the biomarker is miR-132.

[0397] Embodiment C4: The use in therapy of Embodiment C1, wherein the aberrant level of the biomarker associated with the neurodegenerative condition is downregulated Nurrl .

[0398] Embodiment C5: The use in therapy of Embodiment C1, wherein the aberrant level of the biomarker associated with the neurodegenerative condition is upregulated miR-132.

[0399] Embodiment C6: The use in therapy of Embodiment C1, wherein the therapeutically-effective amount is about 5 mg to about 100 mg.

[0400] Embodiment C7: The use in therapy of Embodiment C1, wherein the administering is oral.

[0401] Embodiment C8: The use in therapy of Embodiment C1, wherein the administering is oral by a solid dosage form.

[0402] Embodiment C9: The use in therapy of Embodiment C1, wherein the patient is human.

[0403] Embodiment D1: A compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease according to any one of the preceding non-enumerated embodiments comprising: a) determining a level of Nurrl in a patient; and b) based on the level of Nurrl in the patient, determining whether to administer to the patient a compound if Formula (I).

[0404] Embodiment D2: The use in therapy of Embodiment D1, wherein the obtaining the level of Nurrl in the patient comprises obtaining a result of an assay of an ex vivo biological sample of the patient, wherein the assay determines a level of Nurrl in the ex vivo biological sample of the patient.

[0405] Embodiment D3: The use in therapy of Embodiment D1, wherein the obtaining the level of Nurrl in the patient comprises performing an assay of an ex vivo biological sample of the patient, wherein the assay determines a level of Nurrl in the ex vivo biological sample of the patient. Embodiment D4: The use in therapy of Embodiment D3, wherein the assay determines the level of Nurrl in the ex vivo biological sample of the patient by determining a concentration of Nurrl in the ex vivo biological sample of the patient.

[0406] Embodiment D5: The use in therapy of Embodiment D3, wherein the assay determines the level of Nurrl in the ex vivo biological sample of the patient by determining a level of activity of Nurrl in the ex vivo biological sample of the patient.

[0407] Embodiment D6: The use in therapy of Embodiment D3, wherein the assay is an ELISA assay, multiplex nucleic acid hybridization assay, a quantitative real time (qRT)-PCR assay, or a RNA sequencing (RNAseq) assay.

[0408] Embodiment D7: The use in therapy of Embodiment D3, wherein the ex vivo biological sample is a blood sample.

[0409] Embodiment D8: The use in therapy of Embodiment D1 , wherein the neurodegenerative condition is an inflammatory condition.

[0410] Embodiment D9: The use in therapy of Embodiment D1 , wherein the neurodegenerative condition is a mental condition.

[0411] Embodiment D10: The use in therapy of Embodiment D1 , wherein the neurodegenerative condition is a central nervous system condition.

[0412] Embodiment D11 : The use in therapy of Embodiment D1 , wherein the neurodegenerative condition is Parkinson’s disease.

[0413] Embodiment D12: The use in therapy of Embodiment D1 , wherein the neurodegenerative condition is Alzheimer’s disease.

[0414] Embodiment D13: The use in therapy of Embodiment D1 , wherein the neurodegenerative condition is multiple sclerosis, in particular relapsing form of multiple sclerosis (RMS), such as relapsing-remitting multiple sclerosis (RRMS) or active secondary progressive multiple sclerosis (active SPMS), or progressive form of multiple sclerosis, such as primary progressive multiple sclerosis (PPMS) or non-active secondary progressive multiple sclerosis (non-active SPMS).

[0415] Embodiment D13a: The use in therapy of Embodiment D1 , wherein the neurodegenerative condition is active SPMS.

[0416] Embodiment D13b: The use in therapy of Embodiment D1 , wherein the neurodegenerative condition is PPMS.

[0417] Embodiment D13c: The use in therapy of Embodiment D1 , wherein the neurodegenerative condition is non-active SPMS.

[0418] Embodiment D13d. The use in therapy of Embodiment D1 , wherein the neurodegenerative condition is PIRA.

[0419] Embodiment D13e: The use in therapy of Embodiment D1 , wherein the neurodegenerative condition is clinically isolated syndrome (CIS).

[0420] Embodiment D13f: The use in therapy of Embodiment D1 , wherein the neurodegenerative condition is transitioning MS.

[0421] Embodiment D14: The use in therapy of Embodiment D1 , wherein the neurodegenerative condition is amyotrophic lateral sclerosis. Embodiment D15: The use in therapy of Embodiment D1 , wherein the neurodegenerative condition is schizophrenia.

[0422] Embodiment D16: The use in therapy of Embodiment D1 , further comprising, based on the level of Nurrl in the patient, administering to the patient a therapeutically-effective amount of the Nurrl agonist.

[0423] Embodiment D17: The use in therapy of Embodiment D16, wherein the therapeutically-effective amount is about 5 mg to about 100 mg.

[0424] Embodiment D18: The use in therapy of Embodiment D16, wherein the administering is oral.

[0425] Embodiment D19: The use in therapy of Embodiment D16, wherein the administering is oral by a solid dosage form.

[0426] Embodiment D20: The use in therapy of Embodiment D1 wherein the patient is human.

[0427] Embodiment E1 : A compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease according to to any one of the preceding non-enumerated embodiments, said therapy comprising: a) determining a level of Nurrl in a patient who is undergoing a therapy for a neurodegenerative condition; and b) based on the level of Nurrl in the patient, determining whether to continue the therapy for the neurodegenerative condition.

[0428] Embodiment E2: The use in therapy of Embodiment E1 , wherein the obtaining the level of Nurrl in the patient comprises obtaining a result of an assay of an ex vivo biological sample of the patient, wherein the assay determines a level of Nurrl in the ex vivo biological sample of the patient.

[0429] Embodiment E3: The use in therapy of Embodiment E1 , wherein the obtaining the level of Nurrl in the patient comprises performing an assay of an ex vivo biological sample of the patient, wherein the assay determines a level of Nurrl in the ex vivo biological sample of the patient.

[0430] Embodiment E4: The use in therapy of Embodiment E3, wherein the assay determines the level of Nurrl in the ex vivo biological sample of the patient by determining a concentration of Nurrl in the ex vivo biological sample of the patient.

[0431] Embodiment E5: The use in therapy of Embodiment E3, wherein the assay determines the level of Nurrl in the ex vivo biological sample of the patient by determining a level of activity of Nurrl in the ex vivo biological sample of the patient.

[0432] Embodiment E6: The use in therapy of Embodiment E3, wherein the assay is an ELISA assay, a multiplex nucleic acid hybridization assay, a quantitative real time (qRT)-PCR assay, or a RNA sequencing (RNAseq) assay.

[0433] Embodiment E7: The use in therapy of Embodiment E3, wherein the ex vivo biological sample is a blood sample.

[0434] Embodiment E8: The use in therapy of Embodiment E1 , wherein the neurodegenerative condition is an inflammatory condition.

[0435] Embodiment E9: The use in therapy of Embodiment E1 , wherein the neurodegenerative condition is a mental condition. Embodiment E10: The use in therapy of Embodiment E1 , wherein the neurodegenerative condition is a central nervous system condition.

[0436] Embodiment E11 : The use in therapy of Embodiment E1 , wherein the neurodegenerative condition is Parkinson’s disease.

[0437] Embodiment E12: The use in therapy of Embodiment E1 , wherein the neurodegenerative condition is Alzheimer’s disease.

[0438] Embodiment E13: The use in therapy of Embodiment E1 , wherein the neurodegenerative condition is Multiple Sclerosis, in particular relapsing form of multiple sclerosis (RMS), such as relapsing-remitting multiple sclerosis (RRMS) or active secondary progressive multiple sclerosis (active SPMS), or progressive form of multiple sclerosis, such as primary progressive multiple sclerosis (PPMS) or non-active secondary progressive multiple sclerosis (non-active SPMS).

[0439] Embodiment E13a: The use in therapy of Embodiment E1 , wherein the neurodegenerative condition is active SPMS.

[0440] Embodiment E13b: The use in therapy of Embodiment E1 , wherein the neurodegenerative condition is PPMS.

[0441] Embodiment E13c: The use in therapy of Embodiment E1 , wherein the neurodegenerative condition is non-active SPMS.

[0442] Embodiment E13d: The use in therapy of Embodiment E1 , wherein the neurodegenerative condition is PIRA.

[0443] Embodiment E13e: The use in therapy of Embodiment E1 , wherein the neurodegenerative condition is clinically isolated syndrome (CIS).

[0444] Embodiment E13f: The use in therapy of Embodiment E1 , wherein the neurodegenerative condition is transitioning MS.

[0445] Embodiment E14: The use in therapy of Embodiment E1 , wherein the neurodegenerative condition is amyotrophic lateral sclerosis.

[0446] Embodiment E15: The use in therapy of Embodiment E1 , wherein the neurodegenerative condition is schizophrenia.

[0447] Embodiment E16: The use in therapy of Embodiment E1 , wherein the therapy for the neurodegenerative condition comprises administering to the patient a therapeutically-effective amount of a Nurrl agonist for the neurodegenerative condition.

[0448] Embodiment E17: The use in therapy of Embodiment E16, wherein the therapeutically-effective amount is about 5 mg to about 100 mg.

[0449] Embodiment E18: The use in therapy of Embodiment E16, wherein the administering is oral.

[0450] Embodiment E19: The use in therapy of Embodiment E16, wherein the administering is oral by a solid dosage form.

[0451] Embodiment E20: The use in therapy of Embodiment E16, wherein the patient is human.

[0452] Embodiment F1 : A compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease according to any one of the preceding non-enumerated embodiments comprising: a) determining a level of a protein in a patient, wherein the protein is downstream of Nurrl in a biological pathway in the patient; and b) based on the level of the protein in the patient, determining whether to administer to the patient a Nurrl agonist, in particular wherein the protein downstream of Nurrl in a biological pathway is selected from the group comprising glial cell line-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), glial fibrillary acidic protein (GFAP), tyrosine hydroxylase (TH) and vesicular monoamine transporter 2 (VMAT2).

[0453] Embodiment F2: The use in therapy of Embodiment F1 , wherein the obtaining the level of the protein in the patient comprises obtaining a result of an assay of an ex vivo biological sample of the patient, wherein the assay determines a level of the protein in the ex vivo biological sample of the patient.

[0454] Embodiment F3: The use in therapy of Embodiment F1 , wherein the obtaining the level of the protein in the patient comprises performing an assay of an ex vivo biological sample of the patient, wherein the assay determines a level of the protein in the ex vivo biological sample of the patient.

[0455] Embodiment F4: The use in therapy of Embodiment F3, wherein the assay determines the level of the protein in the ex vivo biological sample of the patient by determining a concentration of the protein in the ex vivo biological sample of the patient.

[0456] Embodiment F5: The use in therapy of Embodiment F3, wherein the assay determines the level of the protein in the ex vivo biological sample of the patient by determining a level of activity of the protein in the ex vivo biological sample of the patient.

[0457] Embodiment F6: The use in therapy of Embodiment F3, wherein the assay is an ELISA assay, a multiplex nucleic acid hybridization assay, a quantitative real time (qRT)-PCR assay, or a RNA sequencing (RNAseq) assay.

[0458] Embodiment F7: The use in therapy of Embodiment F1 , wherein the level of the protein in the patient indicates that the protein is upregulated.

[0459] Embodiment F8: The use in therapy of Embodiment F1 , wherein the level of the protein in the patient indicates that the protein is downregulated.

[0460] Embodiment F9: The use in therapy of Embodiment F3, wherein the ex vivo biological sample is a blood sample.

[0461] Embodiment F10: The use in therapy of Embodiment F1 , wherein the protein is Pitx3.

[0462] Embodiment F11 : The use in therapy of Embodiment F1 , wherein the protein is TH.

[0463] Embodiment F12: The use in therapy of Embodiment F1 , wherein the protein is VMAT2.

[0464] Embodiment F13: The use in therapy of Embodiment F1 , wherein the protein is dopa decarboxylase (DDC).

[0465] Embodiment F14: The use in therapy of Embodiment F1 , wherein the protein is dopamine transporter (DAT).

[0466] Embodiment F15: The use in therapy of Embodiment F1 , wherein the protein is BDNF.

[0467] Embodiment F16: The use in therapy of Embodiment F1 , wherein the protein is NGF.

[0468] Embodiment F17: The use in therapy of Embodiment F1 , wherein the protein is GDNF receptor c-Ret.

[0469] Embodiment F18: The use in therapy of Embodiment F1 , wherein the protein is GFAP. Embodiment F19: The use in therapy of Embodiment F1 , wherein the protein is SOD1.

[0470] Embodiment F20: The use in therapy of Embodiment F1 , wherein the protein is TNFa.

[0471] Embodiment F21 : The use in therapy of Embodiment F1 , wherein the protein is iNOS.

[0472] Embodiment F22: The use in therapy of Embodiment F1 , wherein the protein is I L-1 p.

[0473] Embodiment F23: The use in therapy of Embodiment F1 , wherein the neurodegenerative condition is an inflammatory condition.

[0474] Embodiment F24: The use in therapy of Embodiment F1 , wherein the neurodegenerative condition is a mental condition.

[0475] Embodiment F25: The use in therapy of Embodiment F1 , wherein the neurodegenerative condition is a central nervous system condition.

[0476] Embodiment F26: The use in therapy of Embodiment F1 , wherein the neurodegenerative condition is Parkinson’s disease.

[0477] Embodiment F27: The use in therapy of Embodiment F1 , wherein the neurodegenerative condition is Alzheimer’s disease.

[0478] Embodiment F28: The use in therapy of Embodiment F1 , wherein the neurodegenerative condition is Multiple Sclerosis, in particular relapsing form of multiple sclerosis (RMS), such as relapsing-remitting multiple sclerosis (RRMS) or active secondary progressive multiple sclerosis (active SPMS), or progressive form of multiple sclerosis, such as primary progressive multiple sclerosis (PPMS) or non-active secondary progressive multiple sclerosis (non-active SPMS).

[0479] Embodiment F28a: The use in therapy of Embodiment F1, wherein the neurodegenerative condition is active SPMS.

[0480] Embodiment F28b: The use in therapy of Embodiment F1, wherein the neurodegenerative condition is PPMS.

[0481] Embodiment F28c: The use in therapy of Embodiment F1 , wherein the neurodegenerative condition is non-active SPMS.

[0482] Embodiment F28d: The use in therapy of Embodiment F1, wherein the neurodegenerative condition is PIRA.

[0483] Embodiment F28e: The use in therapy of Embodiment F1, wherein the neurodegenerative condition is clinically isolated syndrome (CIS).

[0484] Embodiment F28f: The use in therapy of Embodiment F1, wherein the neurodegenerative condition is transitioning MS.

[0485] Embodiment F29: The use in therapy of Embodiment F1 , wherein the neurodegenerative condition is amyotrophic lateral sclerosis.

[0486] Embodiment F30: The use in therapy of Embodiment F1 , wherein the neurodegenerative condition is schizophrenia.

[0487] Embodiment F31 : The use in therapy of Embodiment F1, further comprising, based on the level of the protein in the patient, administering to the patient a therapeutically-effective amount of the Nurrl agonist. Embodiment F32: The use in therapy of Embodiment F31 , wherein the therapeutically-effective amount is about 5 mg to about 100 mg.

[0488] Embodiment F33: The use in therapy of Embodiment F31 , wherein the administering is oral.

[0489] Embodiment F34: The use in therapy of Embodiment F31 , wherein the administering is oral by a solid dosage form.

[0490] Embodiment F35: The use in therapy of Embodiment F1 , wherein the patient is human.

[0491] Embodiment G1 : A compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease according to any one of the preceding non-enumerated embodiments comprising: a) determining a level of a protein in a patient who is undergoing a therapy for a neurodegenerative condition, wherein the protein is downstream of Nurrl in a biological pathway in the patient, and b) based on the level of the protein in the patient, determining whether to continue the therapy for the neurodegenerative condition, in particular wherein the protein downstream of Nurrl in a biological pathway is selected from the group comprising glial cell line-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), glial fibrillary acidic protein (GFAP), tyrosine hydroxylase (TH) and vesicular monoamine transporter 2 (VMAT2).

[0492] Embodiment G2: The use in therapy of Embodiment G1 , wherein the obtaining the level of the protein in the patient comprises obtaining a result of an assay of an ex vivo biological sample of the patient, wherein the assay determines a level of the protein in the ex vivo biological sample of the patient.

[0493] Embodiment G3: The use in therapy of Embodiment G1 , wherein the obtaining the level of the protein in the patient comprises performing an assay of an ex vivo biological sample of the patient, wherein the assay determines a level of the protein in the ex vivo biological sample of the patient.

[0494] Embodiment G4: The use in therapy of Embodiment G3, wherein the assay determines the level of the protein in the ex vivo biological sample of the patient by determining a concentration of the protein in the ex vivo biological sample of the patient.

[0495] Embodiment G5: The use in therapy of Embodiment G3, wherein the assay determines the level of the protein in the ex vivo biological sample of the patient by determining a level of activity of the protein in the ex vivo biological sample of the patient.

[0496] Embodiment G6: The use in therapy of Embodiment G3, wherein the assay is an ELISA assay, a multiplex nucleic acid hybridization assay, a quantitative real time (qRT)-PCR assay, or a RNA sequencing (RNAseq) assay.

[0497] Embodiment G7: The use in therapy of Embodiment G1 , wherein the level of the protein in the patient is higher than the level was prior to the therapy.

[0498] Embodiment G8: The use in therapy of Embodiment G1 , wherein the level of the protein in the patient is lower than the level was prior to the therapy.

[0499] Embodiment G9: The use in therapy of Embodiment G3, wherein the ex vivo biological sample is a blood sample.

[0500] Embodiment G10: The use in therapy of Embodiment G1 , wherein the protein is Pitx3. Embodiment G11 : The use in therapy of Embodiment G1 , wherein the protein is Pitx3, and further comprising determining that the level of the protein in the patient is higher than the level was prior to the therapy.

[0501] Embodiment G12: The use in therapy of Embodiment G1 , wherein the protein is TH.

[0502] Embodiment G13: The use in therapy of Embodiment G1 , wherein the protein is TH, and further comprising determining that the level of the protein in the patient is higher than the level was prior to the therapy.

[0503] Embodiment G14: The use in therapy of Embodiment G1 , wherein the protein is VMAT2.

[0504] Embodiment G15: The use in therapy of Embodiment G1 , wherein the protein is VMAT2, and further comprising determining that the level of the protein in the patient is higher than the level was prior to the therapy.

[0505] Embodiment G16: The use in therapy of Embodiment G1 , wherein the protein is dopa decarboxylase (DDC).

[0506] Embodiment G17: The use in therapy of Embodiment G1 , wherein the protein is dopa decarboxylase (DDC), and further comprising determining that the level of the protein in the patient is higher than the level was prior to the therapy.

[0507] Embodiment G18: The use in therapy of Embodiment G1 , wherein the protein is dopamine transporter (DAT).

[0508] Embodiment G19: The use in therapy of Embodiment G1 , wherein the protein is dopamine transporter (DAT), and further comprising determining that the level of the protein in the patient is higher than the level was prior to the therapy.

[0509] Embodiment G20: The use in therapy of Embodiment G1 , wherein the protein is BDNF.

[0510] G21 : The use in therapy of Embodiment G1 , wherein the protein is BDNF, and further comprising determining that the level of the protein in the patient is higher than the level was prior to the therapy.

[0511] Embodiment G22: The use in therapy of Embodiment G1 , wherein the protein is NGF.

[0512] Embodiment G23: The use in therapy of Embodiment G1 , wherein the protein is NGF, and further comprising determining that the level of the protein in the patient is higher than the level was prior to the therapy. [

[0513] Embodiment G24: The use in therapy of Embodiment G1 , wherein the protein is GDNF receptor c-Ret.

[0514] Embodiment G25: The use in therapy of Embodiment G1 , wherein the protein is GDNF receptor c-Ret, and further comprising determining that the level of the protein in the patient is higher than the level was prior to the therapy.

[0515] Embodiment G26: The use in therapy of Embodiment G1 , wherein the protein is GFAP.

[0516] Embodiment G27: The use in therapy of Embodiment G1 , wherein the protein is GFAP, and further comprising determining that the level of the protein in the patient is higher than the level was prior to the therapy.

[0517] Embodiment G28: The use in therapy of Embodiment G1 , wherein the protein is SOD1. Embodiment G29: The use in therapy of Embodiment G1 , wherein the protein is SOD1 , and further comprising determining that the level of the protein in the patient is higher than the level was prior to the therapy.

[0518] Embodiment G30: The use in therapy of Embodiment G1 , wherein the protein is TNFa.

[0519] Embodiment G31 : The use in therapy of Embodiment G1 , wherein the protein is TNFa, and further comprising determining that the level of the protein in the patient is lower than the level was prior to the therapy.

[0520] Embodiment G32: The use in therapy of Embodiment G1 , wherein the protein is iNOS.

[0521] Embodiment G33: The use in therapy of Embodiment G1 , wherein the protein is iNOS, and further comprising determining that the level of the protein in the patient is lower than the level was prior to the therapy.

[0522] Embodiment G34: The use in therapy of Embodiment G1 , wherein the protein is I L-1 p.

[0523] Embodiment G35: The use in therapy of Embodiment G1 , wherein the protein is I L-1 p, and further comprising determining that the level of the protein in the patient is lower than the level was prior to the therapy.

[0524] Embodiment G36: The use in therapy of Embodiment G1 , wherein the neurodegenerative condition is an inflammatory condition.

[0525] Embodiment G37: The use in therapy of Embodiment G1 , wherein the neurodegenerative condition is a mental condition.

[0526] Embodiment G38: The use in therapy of Embodiment G1 , wherein the neurodegenerative condition is a central nervous system condition.

[0527] Embodiment G39: The use in therapy of Embodiment G1 , wherein the neurodegenerative condition is Parkinson’s disease.

[0528] Embodiment G40: The use in therapy of Embodiment G1 , wherein the neurodegenerative condition is Alzheimer’s disease.

[0529] Embodiment G41 : The use in therapy Embodiment G1 , wherein the neurodegenerative condition is Multiple Sclerosis, in particular relapsing form of multiple sclerosis (RMS), such as relapsing-remitting multiple sclerosis (RRMS) or active secondary progressive multiple sclerosis (active SPMS), or progressive form of multiple sclerosis, such as primary progressive multiple sclerosis (PPMS) or non-active secondary progressive multiple sclerosis (non-active SPMS

[0530] Embodiment G41a: The use in therapy of Embodiment G1 , wherein the neurodegenerative condition is active SPMS.

[0531] Embodiment G41b: The use in therapy of Embodiment G1 , wherein the neurodegenerative condition is PPMS.

[0532] Embodiment G41c: The use in therapy of Embodiment G1 , wherein the neurodegenerative condition is non-active SPMS.

[0533] Embodiment G41d: The use in therapy of Embodiment G1 , wherein the neurodegenerative condition is PIRA.

[0534] Embodiment G41e: The use in therapy of Embodiment G1 , wherein the neurodegenerative condition is clinically isolated syndrome (CIS). Embodiment G41f: The use in therapy of Embodiment G1 , wherein the neurodegenerative condition is transitioning MS.

[0535] Embodiment G42: The use in therapy of Embodiment G1 , wherein the neurodegenerative condition is amyotrophic lateral sclerosis.

[0536] Embodiment G43: The use in therapy of Embodiment G1 , wherein the neurodegenerative condition is schizophrenia.

[0537] Embodiment G44: The use in therapy of Embodiment G1 , wherein the therapy for the neurodegenerative condition comprises administering to the patient a therapeutically-effective amount of a therapeutic agent for the neurodegenerative condition.

[0538] Embodiment G45: The use in therapy of Embodiment G44, wherein the therapeutically-effective amount is about 5 mg to about 100 mg.

[0539] Embodiment G46: The use in therapy of Embodiment G44, wherein the administering is oral.

[0540] Embodiment G47: The use in therapy of Embodiment G44, wherein the administering is oral by a solid dosage form.

[0541] Embodiment G48: The use in therapy of Embodiment G1 , wherein the patient is human.

[0542] Embodiment H1 : A compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease according to any one of the preceding non-enumerated embodiments comprising: a) determining a level of activity of a gene in a patient, wherein the gene is downstream of Nurrl in a biological pathway in the patient; and b) based on the level of activity of the gene in the patient, determining whether to administer to the patient a compound of Formula (I) for a neurodegenerative condition.

[0543] Embodiment H2: The use in therapy of Embodiment H1 , wherein the obtaining the level of activity of the gene in the patient comprises obtaining a result of an assay of an ex vivo biological sample of the patient, wherein the assay determines a level of activity of the gene in the ex vivo biological sample of the patient.

[0544] Embodiment H3: The use in therapy of Embodiment H1 , wherein the obtaining the level of activity of the gene in the patient comprises performing an assay of an ex vivo biological sample of the patient, wherein the assay determines a level of activity of the gene in the ex vivo biological sample of the patient.

[0545] Embodiment H4: The use in therapy of Embodiment H3, wherein the assay is a multiplex nucleic acid hybridization assay, a quantitative real time (qRT)-PCR assay, or a RNA sequencing (RNAseq) assay.

[0546] Embodiment H5: The use in therapy of Embodiment H1 , wherein the level of activity of the gene in the patient indicates that the gene is upregulated.

[0547] Embodiment H6: The use in therapy of Embodiment H3, wherein the ex vivo biological sample is a blood sample.

[0548] Embodiment H7: The use in therapy of Embodiment H1 , wherein the gene is NCAM.

[0549] Embodiment H8: The use in therapy of Embodiment H1 , wherein the gene is CFB.

[0550] Embodiment H9: The use in therapy of Embodiment H1 , wherein the gene is LTA. Embodiment H10: The use in therapy of Embodiment H1 , wherein the gene is A2M.

[0551] Embodiment H11 : The use in therapy of Embodiment H1 , wherein the gene is HSD11 B1.

[0552] Embodiment H12: The use in therapy of Embodiment H1 , wherein the gene is BHLHE41.

[0553] Embodiment H13: The use in therapy of Embodiment H1 , wherein the gene is MARCO.

[0554] Embodiment H14: The use in therapy of Embodiment H1 , wherein the neurodegenerative condition is an inflammatory condition.

[0555] Embodiment H15: The use in therapy of Embodiment H1 , wherein the neurodegenerative condition is a mental condition.

[0556] Embodiment H16: The use in therapy of Embodiment H1 , wherein the neurodegenerative condition is a central nervous system condition.

[0557] Embodiment H17: The use in therapy of Embodiment H1 , wherein the neurodegenerative condition is Parkinson’s disease.

[0558] Embodiment H18: The use in therapy of Embodiment H1 , wherein the neurodegenerative condition is Alzheimer’s disease.

[0559] Embodiment H19: The use in therapy of Embodiment H1 , wherein the neurodegenerative condition is Multiple Sclerosis, in particular relapsing form of multiple sclerosis (RMS), such as relapsing-remitting multiple sclerosis (RRMS) or active secondary progressive multiple sclerosis (active SPMS), or progressive form of multiple sclerosis, such as primary progressive multiple sclerosis (PPMS) or non-active secondary progressive multiple sclerosis (non-active SPMS).

[0560] Embodiment H19a: The use in therapy of Embodiment H1 , wherein the neurodegenerative condition is active SPMS.

[0561] Embodiment H19b: The use in therapy of Embodiment H1 , wherein the neurodegenerative condition is PPMS.

[0562] Embodiment H19c: The use in therapy of Embodiment H1 , wherein the neurodegenerative condition is non-active SPMS.

[0563] Embodiment H19d: The use in therapy of Embodiment H1 , wherein the neurodegenerative condition is PIRA.

[0564] Embodiment H19e: The use in therapy of Embodiment H1 , wherein the neurodegenerative condition is clinically isolated syndrome (CIS). [

[0565] Embodiment H19f: The use in therapy of Embodiment H1 , wherein the neurodegenerative condition is transitioning MS.

[0566] Embodiment H20: The use in therapy of Embodiment H1 , wherein the neurodegenerative condition is amyotrophic lateral sclerosis.

[0567] Embodiment H21 : The use in therapy of Embodiment H1 , wherein the neurodegenerative condition is schizophrenia.

[0568] Embodiment H22: The use in therapy of Embodiment H1 , further comprising, based on the level of activity of the gene in the patient, administering to the patient a therapeutically-effective amount of the Nurrl agonist. Embodiment H23: The use in therapy of Embodiment H22, wherein the therapeutically-effective amount is about 5 mg to about 100 mg.

[0569] Embodiment H24: The use in therapy of Embodiment H22, wherein the administering is oral.

[0570] Embodiment H25: The use in therapy of Embodiment H22, wherein the administering is oral by a solid dosage form.

[0571] Embodiment H26: The use in therapy of Embodiment H1 , wherein the patient is human.

[0572] Embodiment 11 : A compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease according to any one of the preceding non-enumerated embodiments comprising: a) determining the level of a gene or the level of activity of a gene in a patient who is undergoing a therapy for a neurodegenerative condition, wherein the gene is downstream of Nurrl in a biological pathway in the patient; and b) based on the level of activity of the gene in the patient, determining whether to continue the therapy for the neurodegenerative condition.

[0573] Embodiment I2: The use in therapy of Embodiment 11 , wherein the obtaining the level of activity of the gene in the patient comprises obtaining a result of an assay of an ex vivo biological sample of the patient, wherein the assay determines a level of activity of the gene in the ex vivo biological sample of the patient.

[0574] Embodiment I3: The use in therapy of Embodiment 11 , wherein the obtaining the level of activity of the gene in the patient comprises performing an assay of an ex vivo biological sample of the patient, wherein the assay determines a level of activity of the gene in the ex vivo biological sample of the patient.

[0575] Embodiment I4: The use in therapy of Embodiment I3, wherein the assay is a multiplex nucleic acid hybridization assay, a quantitative real time (qRT)-PCR assay, or a RNA sequencing (RNAseq) assay.

[0576] Embodiment I5: The use in therapy of Embodiment 11 , wherein the level of activity of the gene in the patient is higher than the level was prior to the therapy.

[0577] Embodiment I6: The use in therapy of Embodiment I3, wherein the ex vivo biological sample is a blood sample.

[0578] Embodiment I7: The use in therapy of Embodiment 11 , wherein the gene is NCAM.

[0579] Embodiment I8: The use in therapy of Embodiment 11 , wherein the gene is CFB.

[0580] Embodiment I9: The use in therapy of Embodiment 11 , wherein the gene is LTA.

[0581] Embodiment 110: The use in therapy of Embodiment 11 , wherein the gene is A2M.

[0582] Embodiment 111 : The use in therapy of Embodiment 11 , wherein the gene is HSD11 B1.

[0583] Embodiment 112: The use in therapy of Embodiment 11 , wherein the gene is BHLHE41.

[0584] Embodiment 113: The use in therapy of Embodiment 11 , wherein the gene is MARCO.

[0585] Embodiment 114: The use in therapy of Embodiment 11 , wherein the neurodegenerative condition is an inflammatory condition.

[0586] Embodiment 115: The use in therapy of Embodiment 11 , wherein the neurodegenerative condition is a mental condition. Embodiment 116: The use in therapy of Embodiment 11 , wherein the neurodegenerative condition is a central nervous system condition.

[0587] Embodiment 117: The use in therapy of Embodiment 11 , wherein the neurodegenerative condition is Parkinson’s disease.

[0588] Embodiment 118: The use in therapy of Embodiment 11 , wherein the neurodegenerative condition is Alzheimer’s disease.

[0589] Embodiment 119: The use in therapy of Embodiment 11 , wherein the neurodegenerative condition is Multiple Sclerosis, in particular relapsing form of multiple sclerosis (RMS), such as relapsingremitting multiple sclerosis (RRMS) or active secondary progressive multiple sclerosis (active SPMS), or progressive form of multiple sclerosis, such as primary progressive multiple sclerosis (PPMS) or non-active secondary progressive multiple sclerosis (non-active SPMS).

[0590] Embodiment 119a: The use in therapy of Embodiment H , wherein the neurodegenerative condition is active SPMS.

[0591] Embodiment 119b: The use in therapy of Embodiment H , wherein the neurodegenerative condition is PPMS.

[0592] Embodiment 119c: The use in therapy of Embodiment H , wherein the neurodegenerative condition is non-active SPMS.

[0593] Embodiment I19d: The use in therapy of Embodiment 11 , wherein the neurodegenerative condition is PIRA.

[0594] Embodiment I19e: The use in therapy of Embodiment 11 , wherein the neurodegenerative condition is clinically isolated syndrome (CIS). [

[0595] Embodiment 119f: The use in therapy of Embodiment 11 , wherein the neurodegenerative condition is transitioning MS.

[0596] Embodiment I20: The use in therapy of Embodiment 11 , wherein the neurodegenerative condition is amyotrophic lateral sclerosis.

[0597] Embodiment 121 : The use in therapy of Embodiment 11 , wherein the neurodegenerative condition is schizophrenia.

[0598] Embodiment I22: The use in therapy of Embodiment 11 , wherein the therapy for the neurodegenerative condition comprises administering to the patient a therapeutically-effective amount of a therapeutic agent for the neurodegenerative condition.

[0599] Embodiment I23: The use in therapy of Embodiment I22, wherein the therapeutically-effective amount is about 5 mg to about 100 mg.

[0600] Embodiment I24: The use in therapy of Embodiment I22, wherein the administering is oral.

[0601] Embodiment I25: The use in therapy of Embodiment I22, wherein the administering is oral by a solid dosage form. [

[0602] Embodiment I26: The use in therapy of Embodiment 11 , wherein the patient is human.

[0603] Embodiment J1 : A compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease according to any one of the preceding non-enumerated embodiments comprising: a) determining that a patient exhibits downregulated Nurrl ; b) determining that the patient exhibits upregulated miR-132; and c) based on the determining that the patient exhibits downregulated Nurrl and the determining that the patient exhibits upregulated miR-132, identifying the patient as being at risk for a condition.

[0604] Embodiment J2: The use in therapy of Embodiment J1 , wherein the determining that the patient exhibits downregulated Nurrl comprises obtaining a result of a first assay of an ex vivo biological sample of the patient, wherein the first assay determines a level of Nurrl in the ex vivo biological sample of the patient; and the determining that the patient exhibits upregulated miR-132 comprises obtaining a result of a second assay of the ex vivo biological sample of the patient, wherein the second assay determines a level of miR-132 in the ex vivo biological sample of the patient.

[0605] Embodiment J3: The use in therapy of Embodiment J1 , wherein the determining that the patient exhibits downregulated Nurrl comprises performing a first assay of an ex vivo biological sample of the patient, wherein the first assay determines a level of Nurrl in the ex vivo biological sample of the patient; and the determining that the patient exhibits upregulated miR-132 comprises performing a second assay of the ex vivo biological sample of the patient, wherein the second assay determines a level of miR-132 in the ex vivo biological sample of the patient.

[0606] Embodiment J4: The use in therapy of Embodiment J3, wherein the first assay determines the level of Nurrl in the ex vivo biological sample of the patient by determining a concentration of Nurrl in the ex vivo biological sample of the patient.

[0607] Embodiment J5: The use in therapy of Embodiment J3, wherein the first assay determines the level of Nurrl in the ex vivo biological sample of the patient by determining a level of activity of Nurrl in the ex vivo biological sample of the patient.

[0608] Embodiment J6: The use in therapy of Embodiment J3, wherein the first assay is an ELISA assay, a multiplex nucleic acid hybridization assay, a quantitative real time (qRT)-PCR assay, or a RNA sequencing (RNAseq) assay

[0609] Embodiment J7: The use in therapy of Embodiment J3, wherein the second assay determines the level of miR-132 in the ex vivo biological sample of the patient by determining a concentration of miR-132 in the ex vivo biological sample of the patient.

[0610] Embodiment J8: The use in therapy of Embodiment J3, wherein the second assay determines the level of miR-132 in the ex vivo biological sample of the patient by determining a level of activity of miR-132 in the ex vivo biological sample of the patient.

[0611] Embodiment J9: The use in therapy of Embodiment J3, wherein the second assay is a multiplex nucleic acid hybridization assay, a quantitative real time (qRT)-PCR assay, or a RNA sequencing (RNAseq) assay.

[0612] Embodiment J 10: The use in therapy of Embodiment J3, wherein the ex vivo biological sample is a blood sample.

[0613] Embodiment J11 : The use in therapy of Embodiment J1 , wherein the condition is a neurodegenerative condition.

[0614] Embodiment J 12: The use in therapy of Embodiment J1 , wherein the condition is an inflammatory condition. Embodiment J13: The use in therapy of Embodiment J1 , wherein the condition is a mental condition.

[0615] Embodiment J14: The use in therapy of Embodiment J1 , wherein the condition is a central nervous system condition.

[0616] Embodiment J15: The use in therapy of Embodiment J1 , wherein the condition is Parkinson’s disease.

[0617] Embodiment J16: The use in therapy of Embodiment J1 , wherein the condition is Alzheimer’s disease.

[0618] Embodiment J17: The use in therapy of Embodiment J1 , wherein the condition is Multiple Sclerosis, in particular relapsing form of multiple sclerosis (RMS), such as relapsing-remitting multiple sclerosis (RRMS) or active secondary progressive multiple sclerosis (active SPMS), or progressive form of multiple sclerosis, such as primary progressive multiple sclerosis (PPMS) or non-active secondary progressive multiple sclerosis (non-active SPMS).

[0619] Embodiment J17a: The use in therapy of Embodiment J1 , wherein the condition is active SPMS.

[0620] Embodiment J17b: The use in therapy of Embodiment J1 , wherein the condition is PPMS.

[0621] Embodiment J17c: The use in therapy of Embodiment J1 , wherein the condition is non-active SPMS.

[0622] Embodiment J17d: The use in therapy of Embodiment J1 , wherein the condition is PIRA.

[0623] Embodiment J17e: The use in therapy of Embodiment J1 , wherein the condition is clinically isolated syndrome (CIS).

[0624] Embodiment J17f: The use in therapy of Embodiment J1 , wherein the condition is transitioning MS.

[0625] Embodiment J18: The use in therapy of Embodiment J1 , wherein the condition is amyotrophic lateral sclerosis.

[0626] Embodiment J19: The use in therapy of Embodiment J 1 , wherein the condition is schizophrenia.

[0627] Embodiment J20: The use in therapy of Embodiment J 1 , wherein the condition is drug addiction.

[0628] Embodiment J21 : The use in therapy of Embodiment J1 , further comprising, based on the determining that the patient exhibits downregulated Nurrl and the determining that the patient exhibits upregulated miR-132, identifying the patient as a candidate for therapy for a condition.

[0629] Embodiment J22: The use in therapy of Embodiment J1 , further comprising, based on the determining that the patient exhibits downregulated Nurrl and the determining that the patient exhibits upregulated miR-132, administering to the patient a therapeutically-effective amount of a compound that modulates Nurrl .

[0630] Embodiment J23: The use in therapy of Embodiment J22, wherein the compound that modulates Nurrl agonizes Nurrl .

[0631] Embodiment J24: The use in therapy of Embodiment J22, wherein the therapeutically-effective amount is about 5 mg to about 100 mg.

[0632] Embodiment J25: The use in therapy of Embodiment J22, wherein the administering is oral. Embodiment J26: The use in therapy of Embodiment J22, wherein the administering is oral by a solid dosage form.

[0633] Embodiment J27: The use in therapy of Embodiment J 1 , wherein the patient is human.

[0634] Embodiment K1 : A compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease according to any one of the preceding non-enumerated embodiments wherein the use comprises: a) determining a level or activity of Nurrl in an ex vivo biological sample of a patient with an assay selected from (a) a real-time PCR assay of Nurrl gene expression against relevant housekeeping genes / internal controls (e.g. GAPDH), (b) an immunoassay (such as ELISA) with the suitable antibodies for Nurrl protein, and (c) a Western blot for Nurrl protein from the biological sample selected from peripheral blood, peripheral blood lymphocytes, serum, plasma, CSF and peripheral blood mononuclear cells; and b) if the level or activity of Nurrl is no greater than about 90% of the level in a healthy subject of same age, gender and / or BMI, administering to the patient a therapeutically-effective amount of a compound herein.

[0635] Embodiment K2: The use in therapy of embodiment K1 , wherein the neurodegenerative condition is primary progressive multiple sclerosis.

[0636] Embodiment K3: The use in therapy of embodiment K1 , wherein the neurodegenerative condition is relapsing remitting multiple sclerosis.

[0637] Embodiment K4: The use in therapy of embodiment K1 , wherein the neurodegenerative condition is multiple sclerosis, wherein the multiple sclerosis is acquired through relapse-associated worsening (RAW).

[0638] Embodiment K5: The use in therapy of embodiment K1 , wherein the neurodegenerative condition is multiple sclerosis, wherein the multiple sclerosis is acquired through progression independent of relapse activity (PIRA).

[0639] Embodiment K6: The use in therapy of embodiment K1 , wherein the neurodegenerative condition is brain atrophy induced by multiple sclerosis.

[0640] Embodiment K7: The use in therapy of embodiment K1 , wherein the neurodegenerative condition is non-inflammatory multiple sclerosis worsening.

[0641] Embodiment K8: The use in therapy of embodiment K1 , wherein the neuroprotection is slowing or reducing a likelihood of loss of neurons induced by multiple sclerosis.

[0642] Embodiment K9: The use in therapy of embodiment K1 , wherein the neuroprotection is slowing or reducing a likelihood of loss of dopaminergic neurons induced by multiple sclerosis.

[0643] Embodiment K10: The use in therapy of embodiment K1 , wherein the neurodegenerative condition is PIRA.

[0644] Embodiment K11 : The use in therapy of embodiment K1 , wherein the neurodegenerative condition is active secondary progressive multiple sclerosis (active SPMS).

[0645] Embodiment K12: The use in therapy of embodiment K1 , wherein the neurodegenerative condition is non-active secondary progressive multiple sclerosis (non-active SPMS

[0646] Embodiment K13: The use in therapy of embodiment K1 , wherein the neurodegenerative condition is clinically isolated syndrome (CIS). Embodiment K13: The use in therapy of embodiment K1, wherein the neurodegenerative condition is transitioning MS.

[0647] Embodiment L1: A compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease according to any one of the preceding non-enumerated embodiments, wherein the method of determining the level of Nurrl comprises: a) determining the level of a gene and / or the level of activity of a gene in a patient, wherein the gene is downstream of Nurrl in a biological pathway in the patient; and b) based on the level of activity or level of the gene in the patient, determining whether to administer to the patient a compound of Formula (I) for neuroprotection.

[0648] Embodiment L2: A compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease according to embodiment L1, wherein the gene is downstream of Nurrl in a biological pathway is selected from the group comprising glial cell line-derived neurotrophic factor (GDNF), brain- derived neurotrophic factor (BDNF), glial fibrillary acidic protein (GFAP gene), tyrosine hydroxylase (T / 7 gene) and vesicular monoamine transporter 2 SLC18A2).

[0649] Embodiment L3: A compound of Formula (I) for use in therapy of embodiment L1 , wherein the biological pathway is glial cell line-derived neurotrophic factor (GDNF).

[0650] Embodiment L4: A compound of Formula (I) for use in therapy of embodiment L1 , wherein the biological pathway is glial fibrillary acidic protein (GFAP gene).

[0651] Embodiment L5: A compound of Formula (I) for use in therapy of embodiment L1 , wherein the biological pathway is tyrosine hydroxylase (T / 7 gene).

[0652] Embodiment L6: A compound of Formula (I) for use in therapy of embodiment L1 , wherein the biological pathway is vesicular monoamine transporter 2 (SLC18A2).

[0653] The invention also relates to the compound according to any of the preceding embodiments for the use as a medicament.

[0654] The invention also relates to the compound according to any of the preceding embodiments for use in the prophylaxis and / or treatment of diseases, disorders, therapeutic indications or medical conditions amenable for treatment with a Nurrl agonist.

[0655] Also provided is a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier or excipient.

[0656] Also provided is a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier or excipient ands further comprising one or more additional therapeutic agents selected from anti-inflammatory agents, anti-viral agents, immunosuppressive and / or immunomodulatory agents, steroids, non-steroidal anti-inflammatory agents, antihistamines, analgesics and suitable mixtures thereof. The term "pharmaceutically acceptable carrier" as used herein indicates that the carrier is approved or recognized for use in animals, and more particularly in humans, i.e. it is not toxic to the host or patient. In addition, a carrier of choice will not interfere with the effectiveness of the biological activity of the active ingredient. The term "carrier" refers to any auxiliary material necessary for the particular mode of administration of choice and includes e.g. solvents, diluents, excipients or other additives with which the compound of the invention is administered. Typically used diluents pharmaceutical carriers include sterile liquids, such as aqueous solutions and oils (e.g. of petroleum, animal, vegetable or synthetic origin), e.g. peanut oil, soybean oil, mineral oil, sesame oil and the like. Typically used aqueous liquids include water, saline solutions, aqueous dextrose and glycerol solutions and the like. Suitable pharmaceutical excipients include citric acid, ascorbic acid, starch, glucose, lactose, sucrose, gelatine, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Optionally the composition may comprise additives, such as wetting or emulsifying agents, pH buffering agents or binders. Examples of suitable pharmaceutical carriers are well known in the art and are described in e.g. "Remington's Pharmaceutical Sciences" by E.W. Martin (18th ed., Mack Publishing Co., Easton, PA (1990).

[0657] According to expert's knowledge the compounds of the invention as well as their salts may contain, e.g. when isolated in crystalline form, varying amounts of solvents. Included within the scope of the invention are therefore all solvates and in particular all hydrates of the compounds of Formula (I) as well as all solvates and in particular all hydrates of the salts of the compounds of Formula (I).

[0658] The present invention further relates to pharmaceutical compositions, kits and kits-of parts comprising the compounds according to the present invention.

[0659] The present invention further relates to the use of the compounds according to the present invention for the production of pharmaceutical compositions which are employed for the treatment and / or prophylaxis of the diseases, disorders, illnesses and / or conditions as mentioned herein.

[0660] The present invention further relates to the methods and medical uses described herein, encompassing the pharmaceutical compositions as described herein.

[0661] The pharmaceutical compositions as described herein comprise one or more of the compounds according to this invention and a pharmaceutically acceptable carrier or excipient.

[0662] The pharmaceutical compositions as described herein comprise one or more of the compounds according to this invention and a pharmaceutically acceptable carrier or excipient, further comprising one or more additional therapeutic agents selected from anti-inflammatory agents, anti-viral agents, anti-cancer agents, immunosuppressive and / or immunomodulatory agents, steroids, non-steroidal anti-inflammatory agents, antihistamines, analgesics and suitable mixtures thereof.

[0663] The pharmaceutical compositions as described herein comprise one or more of the compounds according to this invention and a pharmaceutically acceptable carrier or excipient, further comprising one or more additional therapeutic agents selected from anti-inflammatory agents, anti-viral agents, immunosuppressive and / or immunomodulatory agents, steroids, non-steroidal anti-inflammatory agents, antihistamines, analgesics and suitable mixtures thereof.

[0664] Additionally, the invention relates to an article of manufacture, which comprises packaging material and a pharmaceutical agent contained within said packaging material, wherein the pharmaceutical agent is therapeutically effective against the medical conditions as described herein, and wherein the packaging material comprises a label or package insert which indicates that the pharmaceutical agent is useful for preventing or treating said medical conditions, and wherein said pharmaceutical agent comprises one or more compounds of Formula (I) according to the invention. The packaging material, label and package insert otherwise parallel or resemble what is generally regarded as standard packaging material, labels and package inserts for pharmaceuticals having related utilities.

[0665] The pharmaceutical compositions according to this invention are prepared by processes which are known per se and familiar to the person skilled in the art. As pharmaceutical compositions, the compounds of the invention (= active compounds) are either employed as such, or particularly in combination with suitable pharmaceutical auxiliaries and / or excipients, e.g. in the form of tablets, coated tablets, capsules, caplets, suppositories, patches (e.g. as TTS), emulsions, suspensions, gels or solutions, the active compound content advantageously being between 0.1 and 95% and where, by the appropriate choice of the auxiliaries and / or excipients, a pharmaceutical administration form (e.g. a delayed release form or an enteric form) exactly suited to the active compound and / or to the desired onset of action can be achieved.

[0666] The person skilled in the art is familiar with auxiliaries, vehicles, excipients, diluents, carriers or adjuvants which are suitable for the desired pharmaceutical formulations, preparations or compositions on account of his / her expert knowledge. In addition to solvents, gel formers, ointment bases and other active compound excipients, for example antioxidants, dispersants, emulsifiers, preservatives, solubilizers, colorants, complexing agents or permeation promoters, can be used.

[0667] Depending upon the particular disease, to be treated or prevented, additional therapeutic active agents, which are normally administered to treat or prevent that disease, may optionally be coadministered with the compounds according to the present invention. As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease are known as appropriate for the disease being treated.

[0668] In a further aspect of the present invention, the compounds according to this invention or the salts or solvates of said compounds of Formula (I) may be combined with standard therapeutic agents which are commonly used for the treatment of the medical conditions as described herein.

[0669] The person skilled in the art is aware on the base of his / her expert knowledge of the total daily dosage(s) and administration form(s) of the additional therapeutic agent(s) coadministered. Said total daily dosage(s) can vary within a wide range. In practicing the present invention and depending on the details, characteristics or purposes of their uses mentioned above, the compounds according to the present invention may be administered in combination therapy separately, sequentially, simultaneously or chronologically staggered (e.g. as combined unit dosage forms, as separate unit dosage forms or a adjacent discrete unit dosage forms, as fixed or nonfixed combinations, as kit-of-parts or as admixtures) with one or more standard therapeutics, in particular art-known chemotherapeutic or target specific anti-cancer agents, such as those mentioned above.

[0670] Thus, a further aspect of the present invention is a combination or pharmaceutical composition comprising a first active ingredient, which is a compound according to this invention or a pharmaceutically acceptable salt or solvate thereof, a second active ingredient, which is an art- known standard therapeutic for the medical conditions as described herein, and optionally a pharmacologically acceptable carrier, diluent and / or excipient for sequential, separate, simultaneous or chronologically staggered use in therapy in any order, e.g. to treat, prevent or ameliorate in a patient the medical conditions as described herein. In this context, the present invention further relates to a combination comprising a first active ingredient, which is at least one compound according to this invention, and a second active ingredient, which is at least one art- known standard therapeutic for the medical conditions as described herein, for separate, sequential, simultaneous or chronologically staggered use in therapy, such as e.g. in therapy of those diseases mentioned herein.

[0671] The term "combination" according to this invention may be present as a fixed combination, a nonfixed combination or a kit-of-parts. A "fixed combination" is defined as a combination wherein the said first active ingredient and the said second active ingredient are present together in one unit dosage or in a single entity. One example of a "fixed combination" is a pharmaceutical composition wherein the said first active ingredient and the said second active ingredient are present in admixture for simultaneous administration, such as in a formulation. Another example of a "fixed combination" is a pharmaceutical combination wherein the said first active ingredient and the said second active ingredient are present in one unit without being in admixture.

[0672] A "kit-of-parts" is defined as a combination wherein the said first active ingredient and the said second active ingredient are present in more than one unit. One example of a "kit-of- parts" is a combination wherein the said first active ingredient and the said second active ingredient are present separately. The components of the kit-of-parts may be administered separately, sequentially, simultaneously or chronologically staggered.

[0673] The first and second active ingredient of a combination or kit-of-parts according to this invention may be provided as separate formulations (i.e. independently of one another), which are subsequently brought together for simultaneous, sequential, separate or chronologically staggered use in combination therapy; or packaged and presented together as separate components of a combination pack for simultaneous, sequential, separate or chronologically staggered use in combination therapy. The type of pharmaceutical formulation of the first and second active ingredient of a combination or kit-of-parts according to this invention can be similar, i.e. both ingredients are formulated in separate tablets or capsules, or can be different, i.e. suited for different administration forms, such as e.g. one active ingredient is formulated as tablet or capsule and the other is formulated for e.g. intravenous administration. The amounts of the first and second active ingredients of the combinations, compositions or kits according to this invention may together comprise a therapeutically effective amount for the treatment, prophylaxis or amelioration of a medical condition as described herein.

[0674] A further aspect of the present invention is a method for treating co-therapeutically the medical conditions as described herein, in a patient in need of such treatment comprising administering separately, sequentially, simultaneously, fixed or non-fixed a therapeutically effective and tolerable amount of one or more of the compounds according to the present invention and a therapeutically effective and tolerable amount of one or more art-known therapeutic agents for the medical conditions as described herein, to said patient.

[0675] References and claims to the use of a compound of the Formula (I) or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of a disease or medical condition in their general and specific forms likewise refer to the corresponding methods of treating said disease or medical condition, said method comprising administering a therapeutically effective and tolerable amount of a compound of the Formula (I) or a pharmaceutically acceptable salt or solvate thereof to a patient in need thereof, compositions comprising a compound of the Formula (I) or a pharmaceutically acceptable salt or solvate thereof for the treatment of said disease or medical condition, a compound of the Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of said disease or medical condition, and vice versa.

[0676] For the production of the pharmaceutical compositions, the compounds of the invention (= active compounds) are particularly mixed with suitable pharmaceutical auxiliaries and further processed to give suitable pharmaceutical formulations. Suitable pharmaceutical formulations are, for example, powders, emulsions, suspensions, sprays, oils, ointments, fatty ointments, creams, pastes, gels or solutions. The pharmaceutical compositions according to the invention are prepared by processes known per se.

[0677] The dosage of the active compounds is carried out in the customary order of magnitude. Topical application forms (such as ointments) thus contain the active compounds in a concentration of, for example, 0.1 to 99%. The customary dose in the case of systemic therapy (p.o.) is usually between 0.3 and 30 mg / kg per day, (i.v.) is usually between 0.3 and 30 mg kg / h. The choice of the optimal dosage regime and duration of medication, particularly the optimal dose and manner of administration of the active compounds necessary in each case can be determined by a person skilled in the art on the basis of his / her expert knowledge.

[0678] Combination or alternation therapy

[0679] The compounds or their pharmaceutically acceptable salts as described herein can be administered on top of the current standard of care for patients, or in combination or alternation with any other compound or therapy that the healthcare provider deems beneficial for the patient. The combination and / or alternation therapy can be therapeutic, adjunctive or palliative.

[0680] Based upon standard laboratory techniques known to evaluate compounds useful for treating a neurodegenerative condition and / or a method of neuroprotection in a patient having a neurodegenerative disease, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known active ingredients or medicaments that are used to treat these conditions, the effective dosage of a compound of Formula (I) or a pharmaceutically acceptable salt, a solvate, a solvate of a salt, a hydrate or a polymorph thereof can readily be determined for treatment of each desired indication. The amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.

[0681] It will be recognized that some variation of natural isotopic abundance occurs in a synthesized compound depending upon the origin of chemical materials used in the synthesis. Thus, a preparation of a compound according to Formula (I) without any depicted deuterium will inherently contain small amounts of deuterated isotopologues. The concentration of naturally abundant stable hydrogen and carbon isotopes, notwithstanding this variation, is small and immaterial as compared to the degree of stable isotopic substitution of compounds of this invention. See, for instance, Comp. Biochem. Physiol. 1998;119A:725.

[0682] The term “isotopic enrichment factor” at a particular position normally occupied by hydrogen refers to the ratio between the abundance of deuterium at the position and the natural abundance of deuterium at that position. By way of example, an isotopic enrichment factor of 3500 means that the amount of deuterium at the particular position is 3500-fold the natural abundance of deuterium, or that 52.5% of the compounds have deuterium at the particular position (i.e., 52.5% deuterium incorporation at the given position). The abundance of deuterium in the oceans of Earth is approximately one atom in 6500 hydrogen atoms (about 154 parts per million (ppm)). Deuterium thus accounts for approximately 0.015 percent (on a weight basis, 0.030 percent) of all naturally occurring hydrogen atoms in the oceans on Earth; the abundance changes slightly from one kind of natural water to another.

[0683] When a particular position in a compound of the invention (e.g., a compound represented by Formula (I) or a pharmaceutically acceptable salt and / or solvate thereof) is designated by name or structure as containing hydrogen or deuterium, it is to be understood that the position can contain hydrogen at its natural abundance or can be enriched in deuterium with an isotopic enrichment factor of, for example, at least 835 (12.5% deuterium incorporation), of at least 1670 (25% deuterium incorporation, of at least 3500 (52.5% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), 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).

[0684] When a particular position in a compound of the invention (e.g., a compound represented by Formula (I) or a pharmaceutically acceptable salt and / or solvate thereof) is designated specifically by name or structure as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition.

[0685] When a particular position in a compound of the invention (e.g., a compound represented by Formula (I) or a pharmaceutically acceptable salt and / or solvate thereof) is designated specifically by name or structure as “D” or “deuterium”, the position is understood to have deuterium at an abundance that is at least 3340 times of the natural abundance of deuterium, which is 0.015% (i.e., at least 50.1% incorporation of deuterium), at least 3500 times of the natural abundance of deuterium (52.5% deuterium incorporation), at least 4500 times of the natural abundance of deuterium (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 times of the natural abundance of deuterium (82.5% deuterium incorporation), at least 6000 times of the natural abundance of deuterium (90% deuterium incorporation), at least 6333.3 times of the natural abundance of deuterium (95% deuterium incorporation), at least 6466.7 times of the natural abundance of deuterium (97% deuterium incorporation), at least 6600 times of the natural abundance of deuterium (99% deuterium incorporation), or at least 6633.3 times of the natural abundance of deuterium (99.5% deuterium incorporation).

[0686] The percentage of deuterium incorporation can be obtained by quantitative analysis using a number of conventional methods, such as mass spectroscopy (peak area) or by quantifying the remaining residual1H-NMR signals of the specific deuteration site compared to signals from internal standards or other, non-deuterated1H signals in the compound.

[0687] When a chemical name or structure is silent as to whether a particular position in a compound normally occupied by hydrogen is isotopically enriched, it is intended that the particular position is occupied by hydrogen at its natural abundance. By way of example, the term “phenyl” or without any further designation as to isotopic enrichment indicates that all hydrogen atoms are present at natural abundance.

[0688] When ring A is a 5-membered heteroaryl ring, the double bond is within a delocated TT-system and can exist in mesomeric forms. An example is shown with the following 1 ,2,5-thiadiazole mesomeric forms:

[0689] In case the valency of each atom is not fully shown for every atom, this atom is substituted as defined for ring A, e.g.

[0690] Furthermore, the compounds of the present invention are partly subject to tautomerism. For example, if a heteroaromatic group containing a nitrogen atom in the ring is substituted with a hydroxy group on the carbon atom adjacent to the nitrogen atom, the following tautomerism can appear:

[0691] A cycloalkyl or heterocycloalkyl group can be connected straight or spirocyclic, e.g. when cyclohexane is substituted with the heterocycloalkyl group oxetane, the following structures are possible:

[0692] The term "1 ,4-orientation" (as mentioned for ring B) denotes the specific relative position of the two substituents on the same ring and means that on a ring the substituents have at least one possibility, where 4 atoms are between the two substituents in the ring attached to the ring system:

[0693] The term “compound,” when referring to any compound of this disclosure, including a compound represented by Formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, refers to a collection of molecules having an identical chemical structure, except that there may be isotopic variation among the constituent hydrogen atoms of the molecules. The relative amount of isotopic variation in a compound of this invention will depend upon a number of factors including the isotopic purity of deuterated reagents used to make the compound and the efficiency of incorporation of deuterium in the various synthesis steps used to prepare the compound.

[0694] “D” and “d” both refer to deuterium. “H” refers to hydrogen.

[0695] “Substituted with deuterium” refers to the replacement of one or more hydrogen atoms with a corresponding number of deuterium atoms. Any formula or structure given herein, is also intended to represent optionally deuterated compounds comprising in addition further isotopically labelled atoms. Examples of additional isotopes that can be incorporated (i.e. "isotopic variants") into compounds of the disclosure include further isotopes of hydrogen (i.e. tritium or3H), as well as isotopes of carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to11C,13C,14C,15N,18F,31P,32P,35S,36CI and125l. The disclosure further comprises various isotopically labelled compounds into which radioactive isotopes such as3H,13C and14C are incorporated. Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or radioactive treatment of patients.

[0696] Halogen is selected from fluorine, chlorine, bromine and iodine, more preferably fluorine or chlorine and most preferably fluorine.

[0697] In the context of the present invention "Ci-4-alkyl" means a preferably saturated hydrocarbon chain having 1 to 4 carbon atoms which may be straight chained or branched. Examples thereof include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl and tert-butyl. Preferred is Ci-3-alkyl, such as methyl, ethyl, propyl and isopropyl, most preferred is methyl. The term "alkyl" by itself or as a part of another substituent, e.g. halo-Ci-4-alkyl, unless otherwise noted, is also meant to include those derivatives of alkyl defined in more detail below as "unsaturated alkyl". An unsaturated alkyl group is one having one or more double bonds or triple bonds. Preferred unsaturated alkyl substituents are vinyl, 2-propenyl or prop-2-yn-1-yl.

[0698] In the context of the present invention the term "Ci-4-alkyl having one or more hydrogen atoms in alkyl optionally replaced by deuterium" encompasses, but is not limited to the following residues: -CD3, -CH2D, -CHD2, CD3CH2(CH2)n-, CD3CH2(CHD)n-, CD3CH2(CD2)n-, CH2DCH2(CH2)n-, CH2DCH2(CHD)n-, CH2DCH2(CD2)n-, CHD2CH2(CH2)n-, CHD2CH2(CHD)n-, CHD2CH2(CD2)n-, CD3CHD(CH2)n-, CD3CHD(CHD)n-, CD3CHD(CD2)n-, CH2DCHD(CH2)n-, CH2DCHD(CHD)n-, CH2DCHD(CD2)n-, CHD2CHD(CH2)n-, CHD2CHD(CHD)n-, CHD2CHD(CD2)n-, CH3CHD(CH2)n-, CH3CHD(CHD)n-, CH3CHD(CD2)n-, CD3CD2(CH2)n-, CD3CD2(CHD)n-, CD3CD2(CD2)n-, CH2DCD2(CH2)n-, CH2DCD2(CHD)n-, CH2DCD2(CD2)n-, CHD2CD2(CH2)n-, CHD2CD2(CHD)n-, CHD2CD2(CD2)n-, CH3CD2(CH2)n-, CH3CD2(CHD)n-, CH3CD2(CD2)n-, wherein n is an integer from 0 to 2, and CH3CH2(CHD)m-, CH3CH2(CD2)m-, wherein m is an integer from 1 to 2, as well as -CD(CD3)2, -CH(CD3)2and -C(CD3)3. Preferred Ci-2-alkyl containing deuterium are -CD3and -CD3CD2, most preferred is -CD3.

[0699] A “Co-6-alkylene” means that the respective group is divalent and connects the attached residue with the remaining part of the molecule. Moreover, in the context of the present invention, “Coalkylene” is meant to represent a bond, whereas Ci-alkylene means a methylene linker, C2- alkylene means a ethylene linker or a methyl-substituted methylene linker and so on. In the context of the present invention, a Co-6-alkylene preferably represents a bond, a methylene, a ethylene group or a propylene group. The term "alkylene", unless otherwise noted, is also meant to include a unsaturated divalent chain, if appropriate (i.e. possible for “C2-6-alkylene”). A representative example for an unsaturated C4-alkylene is -CH2-CH=CH-CH2-.

[0700] The term "fluoro-Ci-4-alkyl" or “O-fluoro-Ci-4-alkyl”, respectively, means that one or more hydrogen atoms in the alkyl chain are replaced by one or more fluoro atoms. Preferred are CHF2, CF3, CH2CF3and CF2CF3. A more preferred example thereof is the formation of a -CF3group. Similar applies to "halo-Ci-4-alkyl" or “O-halo-Ci-4-alkyl”, which means that one or more hydrogen atoms in the alkyl chain are replaced by one or more halogen atoms, independently selected from fluoro, chloro, bromo and iodo.

[0701] In the context of the present invention the term "fluoro-Ci-4-alkyl having one or more hydrogen atoms in alkyl optionally replaced by deuterium" means, that if the fluoro-Ci-4-alkyl contains one or more hydrogen atom(s), one or more hydrogen(s) can be replaced by fluorine(s), yielding the same as described above for the term "Ci-4-alkyl having one or more hydrogen atoms in alkyl optionally replaced by deuterium". It is understood that fluoro-Ci-4-alkyl can also be completely fluorinated. Preferred are fluoro-Ci-2-alkyl containing deuterium such as CDF2, CD2CF3 and CD2CF2D. Most preferred is CDF2.

[0702] A "3- to 6-membered cycloalkyl" group means a saturated or partially unsaturated mono-, bi-, spiro- or multicyclic ring system comprising 3 to 6 carbon atoms, wherein each of the atoms forming the ring system (i.e. skeletal atoms) is a carbon atom. Examples encompass, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1 .1.1 Jpentyl, bicyclo[2.1.0]pentyl and spiro[2.3]hexanyl. More preferred is cyclopropyl or cyclobutyl.

[0703] A "3- to 8-membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from N, O and S" group means a saturated or partially unsaturated 3 to 8 membered carbon mono-, bi-, spiro- or multicyclic ring wherein 1 , 2, 3 or 4 carbon atoms are replaced by 1 , 2, 3 or 4 heteroatoms, respectively, wherein the heteroatoms are independently selected from N, O or S. The sulfur heteroatom in the ring can also be oxidized to S=O or SO2. The carbon atom in the ring can also be oxidized to C=O. Examples thereof include epoxidyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, 1 ,4-dioxanyl, morpholinyl, 1 ,4- dihydropyridinyl and 2-oxaspiro[3.3]heptyl. The heterocycloalkyl group can be connected with the remaining part of the molecule via a carbon, nitrogen (e.g. in morpholine or piperidine) or sulfur atom. An example for a S-linked heterocycloalkyl is the cyclic sulfonimidamide

[0704] "5- or 6-membered heteroaryl" means a monocyclic aromatic ring system containing up to 4 heteroatoms independently selected from N, O and S. Examples of monocyclic heteroaromatic rings include pyrrolyl, imidazolyl, pyridyl, pyrimidinyl, furanyl, thiophenyl, tetrazolyl and oxazolyl. The nitrogen or sulphur atom of the heteroaryl system may also be optionally oxidized to the corresponding / V-oxide, S-oxide or S,S-dioxide.

[0705] The compounds of the invention may, depending on their structure, exist in tautomeric or stereoisomeric forms (enantiomers, diastereomers). The invention therefore also encompasses the tautomers, enantiomers or diastereomers and respective mixtures thereof. The stereoisomerically uniform constituents can be isolated in a known manner from such mixtures of enantiomers and / or diastereomers.

[0706] The term “diastereomer” means stereoisomers that are not mirror images of one another and are non-superimposable on one another. The term “enantiomer” means each individual optically active form of a compound of the invention, having an optical purity or enantiomeric excess (as determined by methods standard in the art) of at least 80% (i.e. at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90% and more preferably at least 98%. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Thus, the compounds of the present disclosure which contain acidic groups can be present on these groups and can be used according to the disclosure, for example, as alkali metal salts, alkaline earth metal salts or ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids. The respective salts can be obtained by customary methods which are known to the person skilled in the art like, for example, by contacting these with an organic or inorganic base in a solvent or dispersant, or by cation exchange with other salts. The present disclosure also includes all salts of the compounds of the present disclosure which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

[0707] Further the compounds of the present disclosure may be present in the form of solvates, such as those which include as solvate water, or pharmaceutically acceptable solvates, such as alcohols, in particular ethanol. A stoichiometric or non-stoichiometric amount of solvent is bound by non- covalent intermolecular forces. When the solvent is water, the "solvate" is a "hydrate." It is understood, that a "pharmaceutically acceptable salts" can in addition optionally contain a "solvate".

[0708] The term "polymorph" as used herein refers to a crystalline form of a compound or a salt, hydrate, or solvate thereof, in a particular crystal packing arrangement. All polymorphs have the same elemental composition. The term "crystalline" as used herein, refers to a solid state form which consists of orderly arrangement of structural units. Different crystalline forms of the same compound, or a salt, hydrate, or solvate thereof, arise from different packing of the molecules in the solid state, which results in different crystal symmetries and / or unit cell parameter. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility.

[0709] The term "effective amount" is meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of a disorder, disease, or condition being treated. The term "effective amount" also refers to the amount of a compound that is sufficient to elicit the biological or medical response of a cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.

[0710] With the above context, the following consecutively numbered embodiments provide further specific aspects of the invention:

[0711] X1 . A compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease: or an enantiomer, diastereomer, tautomer, solvate, or pharmaceutically acceptable salt thereof, wherein A is selected from a 5- or 6-membered carbocyclic or heterocyclic ring optionally containing 1 to 4 heteroatoms selected from N, O and S, said A ring is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of H, halogen, -CN, -NO2, SF5, =0 (oxo), =S, -OH, Ci-4-alkyl, -O-Ci-4-alkyl, fluoro-

[0712] Ci-4-alkyl, -O-fluoro-Ci-4-alkyl, 3- to 6-membered cycloalkyl, -0-(3- to 6-membered cycloalkyl), 3- to 8-membered heterocycloalkyl, -0-(3- to 8-membered heterocycloalkyl), CO2R11, NR11R12, CONR11R12, phenyl, 5- or 6-membered heteroaryl, wherein alkyl, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of D, halogen, -CN, OH, =0, =S, Ci-4-alkyl, Ci-4-alkyl, -O-Ci-4-alkyl and -O-fluoro-Ci-4-alkyl, ring A or its substituents having one or more hydrogen atoms optionally replaced by deuterium;

[0713] B is selected from the group consisting of phenyl and pyridyl, wherein phenyl and pyridyl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, -CN, =0, =S, Ci-4-alkyl, C1-4- alkyl, -O-Ci-4-alkyl, -O-fluoro-Ci-4-alkyl; and wherein optionally two adjacent substituents in the phenyl and pyridyl moiety form a 5- to 8-membered partially unsaturated cycle optionally containing 1 to 3 heteroatoms independently selected from O, S or N, wherein this additional cycle is optionally substituted with 1 to 4 substituents independently selected from halogen, -CN, =0, =S, -OH, Ci-4-alkyl, halo-Ci-4-alkyl; and wherein the residue -NR2on ring B is in a 1 ,4-orientation with respect to ring C, ring B or its substituents having one or more hydrogen atoms optionally replaced by deuterium;

[0714] C is selected from the group consisting of phenyl, thiophenyl, thiazolyl and pyridyl, wherein phenyl, thiophenyl, thiazolyl and pyridyl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, -CN, =0, =S, C1- 4-alkyl, Ci-4-alkyl, -O-Ci-4-alkyl, -O-fluoro-Ci-4-alkyl; and wherein optionally two adjacent substituents in the phenyl and pyridyl moiety form a 5- to 8-membered partially unsaturated cycle optionally containing 1 to 3 heteroatoms independently selected from O, S or N, wherein this additional cycle is optionally substituted with 1 to 4 substituents independently selected from halogen, -CN, =0, =S, -OH, Ci-4-alkyl, halo-Ci-4-alkyl; ring C or its substituents having one or more hydrogen atoms optionally replaced by deuterium;

[0715] X is selected from H, D, halogen, -CN, -NO2, Ci-6-alkyl, -O-Ci-6-alkyl, O-halo-Ci-6-alkyl, Co-6- alkylene-OR21, Co-6-alkylene-(3- to 6-membered cycloalkyl), Co-6-alkylene-(3- to 8-membered heterocycloalkyl), Co-6-alkylene-S(=0)n(=NR23)mR21, Co-6-alkylene-NR21S(=0)x(=NR23)yR21, Co-6- alkylene-S(=O)x(=NR23)yNR21R22, C0-6-alkylene-NR21S(=O)x(=NR23)yNR21R22, C0.6-alkylene- CO2R21, Co-6-alkylene-O-COR21, C0-6-alkylene-CONR21R22, C0-6-alkylene-NR21-COR21, C0-6- alkylene-NR21-CONR21R22, C0-6-alkylene-O-CONR21R22, C0-6-alkylene-NR21-CO2R21, C0-6- alkylene-NR21R22, wherein heterocycloalkyl comprises 1 , 2, 3 or 4 heteroatoms independently selected from N, O, or S, wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, -CN, oxo, -OH, Ci-4-alkyl, halo- Ci-4-alkyl, -O-Ci-4-alkyl and -O-halo-Ci-4-alkyl,

[0716] X or its substituents having one or more hydrogen atoms optionally replaced by deuterium;

[0717] Y is selected from -B(OR11)(R12), -CONR11-CN, -CONR11-NR11R12, -NR11R12, -NR11COR12, -NR11C(=O)OR12, -NR11S(=O)n(=NR13)mR10, -NR11S(=O)x(=NR13)yNR11R12, OR11, -SO2H, -SO3H, -S(=O)n(=NR13)mR10, -S(=O)x(=NR13)yNR11R12, 3- or 8-membered carbocyclic or heterocyclic ring optionally containing 1 to 4 heteroatoms selected from N, O and S, said 3- to 8-membered carbocyclic or heterocyclic ring is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of H, halogen, -CN, - NO2, SF5, =0, =S, -OH, Ci-4-alkyl, -O-Ci-4-alkyl, fluoro-Ci-4-alkyl, -O-fluoro-Ci-4-alkyl, 3- to 6-membered cycloalkyl, -0-(3- to 6-membered cycloalkyl), 3- to 8-membered heterocycloalkyl, -0-(3- to 8-membered heterocycloalkyl), CO2R11, NR11R12, CONR11R12, phenyl, 5- or 6-membered heteroaryl, wherein alkyl, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of D, halogen, -CN, OH, =0, =S, Ci-4-alkyl, Ci-4-alkyl, -O-Ci-4-alkyl and -O-fluoro-Ci-4-alkyl,

[0718] Y or its substituents having one or more hydrogen atoms optionally replaced by deuterium;

[0719] R2is selected from H and Ci-6-alkyl, having one or more hydrogen atoms optionally replaced by deuterium;

[0720] R10is selected from Ci-6-alkyl, 3- to 6-membered cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein alkyl, cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, -CN, Ci-4-alkyl, halo-Ci-4-alkyl, 3- to 6- membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 8-membered heterocycloalkyl, halo-(3- to 8-membered heterocycloalkyl), -OH, =0, =S, -O-Ci-4-alkyl and -O-halo-Ci-4-alkyl, wherein heterocycloalkyl comprises 1 , 2, 3 or 4 heteroatoms independently selected from N, O, or S,

[0721] R10having one or more hydrogen atoms optionally replaced by deuterium;

[0722] R11, R12, R21, R22are independently selected from H, Ci-6-alkyl, 3- to 6-membered cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein alkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, -CN, Ci-4-alkyl, halo-Ci-4-alkyl, 3- to 6- membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 8-membered heterocycloalkyl, halo-(3- to 8-membered heterocycloalkyl), -OH, =0, =S, -O-Ci-4-alkyl and -O-halo-Ci-4-alkyl, wherein heterocycloalkyl comprises 1 , 2, 3 or 4 heteroatoms independently selected from N, O, or S,

[0723] R11and / or R12and / or R21and / or R22having one or more hydrogen atoms optionally replaced by deuterium; or R11and R12, R21and R22, respectively, when taken together with the atom(s) to which they are attached complete a 3- to 6-membered cycle containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N; and wherein this cycle is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, -CN, Ci-4-alkyl, halo-Ci-4-alkyl, 3- to 6-membered cycloalkyl, halo- (3- to 6-membered cycloalkyl), 3- to 8-membered heterocycloalkyl, halo-(3- to 8-membered heterocycloalkyl), -OH, =0, =S, -O-Ci-4-alkyl and -O-halo-Ci-4-alkyl,

[0724] R11and / or R12and / or R21and / or R22having one or more hydrogen atoms optionally replaced by deuterium;

[0725] R13, R23are independently selected from H, -CN, -NO2, Ci-6-alkyl, -CO-O-Ci-6-alkyl, 3- to 6- membered cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein alkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, -CN, Ci-4-alkyl, halo-Ci-4-alkyl, 3- to 6- membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 8-membered heterocycloalkyl, halo-(3- to 8-membered heterocycloalkyl), -OH, =0, =S, -O-Ci-4-alkyl and -O-halo-Ci-4-alkyl, wherein heterocycloalkyl comprises 1 , 2, 3 or 4 heteroatoms independently selected from N, O, or S,

[0726] R13and / or R23having one or more hydrogen atoms optionally replaced by deuterium; n, m are independently selected from 0 to 2; with the proviso that the sum of integer n and m for the residue linked to the same sulfur atom is independently selected from 0, 1 or 2; x, y are independently selected from 0 to 2; with the proviso that the sum of integer x and y for the residue linked to the same sulfur atom is independently selected from 1 or 2; and with the proviso, that the following structure is excluded:

[0727] X2. A compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease according to Embodiment X1 , or a solvate or pharmaceutically acceptable salt thereof, wherein

[0728] Y is selected from from -CONH-CN, -CONH-NR11R12, -NHCOR12, -NHC(=O)OR12, -NHSO2R10, - NHSO2NR11R12, -SO2H, -SO3H, -SO2R10, -SO(=NR13)R10, -SO2NR11R12, 5-membered heterocyclic ring containing 1 to 4 heteroatoms selected from N, O and S, said heterocyclic ring is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of H, halogen, -CN, =0, =S, -OH, Ci-4-alkyl, -O-C1-4- alkyl, fluoro-Ci-4-alkyl, -O-fluoro-Ci-4-alkyl, CO2R11, NR11R12or CONR11R12,

[0729] Y or its substituents having one or more hydrogen atoms optionally replaced by deuterium.

[0730] X3. A compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease according to Embodiment X1 or X2, or a solvate or pharmaceutically acceptable salt thereof, wherein said A is unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of H, F, Cl, Br, -CN, -OH, =0, Ci-4-alkyl, -O-Ci-4-alkyl, fluoro-Ci-4-alkyl, -O-fluoro- Ci-4-alkyl, CO2R11, NR11R12and CONR11R12, ring A or its substituents having one or more hydrogen atoms optionally replaced by deuterium;

[0731] R2is H;

[0732] R11and R12are independently selected from H, Ci-6-alkyl, 3- to 6-membered cycloalkyl or 3- to 8- membered heterocycloalkyl, wherein alkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, -CN, Ci-4-alkyl, halo-Ci-4-alkyl, 3- to 6- membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 8-membered heterocycloalkyl, halo-(3- to 8-membered heterocycloalkyl), -OH, =0, =S, -O-Ci-4-alkyl and -O-halo-Ci-4-alkyl, wherein heterocycloalkyl comprises 1 , 2, 3 or 4 heteroatoms independently selected from N, O, or S, or R11and R12, when taken together with the atom(s) to which they are attached complete a 3- to 6-membered cycle containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N; and wherein this cycle is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, -CN, Ci-4-alkyl, halo-Ci-4-alkyl, 3- to 6-membered cycloalkyl, halo- (3- to 6-membered cycloalkyl), 3- to 8-membere...

Claims

CLAIMS:1 . A compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease:or an enantiomer, diastereomer, tautomer, solvate, or pharmaceutically acceptable salt thereof, whereinA is selected from a 5- or 6-membered carbocyclic or heterocyclic ring optionally containing 1 to 4 heteroatoms selected from N, O and S, said A ring is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of H, halogen, -CN, -NO2, SF5, =0 (oxo), =S, -OH, Ci-4-alkyl, -O-Ci-4-alkyl, fluoro-Ci-4-alkyl, -O-fluoro-Ci-4-alkyl, 3- to 6-membered cycloalkyl, -0-(3- to 6-membered cycloalkyl), 3- to 8-membered heterocycloalkyl, -O-(3- to 8-membered heterocycloalkyl), CO2R11, NR11R12, CONR11R12, phenyl, 5- or 6-membered heteroaryl, wherein alkyl, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of D, halogen, -CN, OH, =0, =S, Ci-4-alkyl, Ci-4-alkyl, -O-Ci-4-alkyl and -O-fluoro-Ci-4-alkyl, ring A or its substituents having one or more hydrogen atoms optionally replaced by deuterium;B is selected from the group consisting of phenyl and pyridyl, wherein phenyl and pyridyl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, -CN, =0, =S, Ci-4-alkyl, C1-4- alkyl, -O-Ci-4-alkyl, -O-fluoro-Ci-4-alkyl; and wherein optionally two adjacent substituents in the phenyl and pyridyl moiety form a 5- to 8-membered partially unsaturated cycle optionally containing 1 to 3 heteroatoms independently selected from O, S or N, wherein this additional cycle is optionally substituted with 1 to 4 substituents independently selected from halogen, -CN, =0, =S, -OH, Ci-4-alkyl, halo-Ci-4-alkyl; and wherein the residue -NR2on ring B is in a 1 ,4-orientation with respect to ring C, ring B or its substituents having one or more hydrogen atoms optionally replaced by deuterium;C is selected from the group consisting of phenyl, thiophenyl, thiazolyl and pyridyl, wherein phenyl, thiophenyl, thiazolyl and pyridyl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, -CN, =0, =S, C1- 4-alkyl, Ci-4-alkyl, -O-Ci-4-alkyl, -O-fluoro-Ci-4-alkyl;and wherein optionally two adjacent substituents in the phenyl and pyridyl moiety form a 5- to 8-membered partially unsaturated cycle optionally containing 1 to 3 heteroatoms independently selected from O, S or N, wherein this additional cycle is optionally substituted with 1 to 4 substituents independently selected from halogen, -CN, =0, =S, -OH, Ci-4-alkyl, halo-Ci-4-alkyl; ring C or its substituents having one or more hydrogen atoms optionally replaced by deuterium;X is selected from H, D, halogen, -CN, -NO2, Ci-6-alkyl, -O-Ci-6-alkyl, O-halo-Ci-6-alkyl, Co-6- alkylene-OR21, Co-6-alkylene-(3- to 6-membered cycloalkyl), Co-6-alkylene-(3- to 8-membered heterocycloalkyl), Co-6-alkylene-S(=0)n(=NR23)mR21, Co-6-alkylene-NR21S(=0)x(=NR23)yR21, Co-6- alkylene-S(=O)x(=NR23)yNR21R22, C0-6-alkylene-NR21S(=O)x(=NR23)yNR21R22, C0.6-alkylene- CO2R21, Co-6-alkylene-O-COR21, C0-6-alkylene-CONR21R22, C0-6-alkylene-NR21-COR21, C0-6- alkylene-NR21-CONR21R22, C0-6-alkylene-O-CONR21R22, C0-6-alkylene-NR21-CO2R21, C0-6- alkylene-NR21R22, wherein heterocycloalkyl comprises 1 , 2, 3 or 4 heteroatoms independently selected from N, O, or S, wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, -CN, oxo, -OH, Ci-4-alkyl, halo- Ci-4-alkyl, -O-Ci-4-alkyl and -O-halo-Ci-4-alkyl,X or its substituents having one or more hydrogen atoms optionally replaced by deuterium;Y is selected from -B(OR11)(R12), -CONR11-CN, -CONR11-NR11R12, -NR11R12, -NR11COR12, -NR11C(=O)OR12, -NR11S(=O)n(=NR13)mR10, -NR11S(=O)x(=NR13)yNR11R12, OR11, -SO2H, -SO3H, -S(=O)n(=NR13)mR10, -S(=O)x(=NR13)yNR11R12, 3- or 8-membered carbocyclic or heterocyclic ring optionally containing 1 to 4 heteroatoms selected from N, O and S, said 3- to 8-membered carbocyclic or heterocyclic ring is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of H, halogen, -CN, - NO2, SF5, =0, =S, -OH, Ci-4-alkyl, -O-Ci-4-alkyl, fluoro-Ci-4-alkyl, -O-fluoro-Ci-4-alkyl, 3- to 6-membered cycloalkyl, -0-(3- to 6-membered cycloalkyl), 3- to 8-membered heterocycloalkyl, -0-(3- to 8-membered heterocycloalkyl), CO2R11, NR11R12, CONR11R12, phenyl, 5- or 6-membered heteroaryl, wherein alkyl, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of D, halogen, -CN, OH, =0, =S, Ci-4-alkyl, Ci-4-alkyl, -O-Ci-4-alkyl and -O-fluoro-Ci-4-alkyl,Y or its substituents having one or more hydrogen atoms optionally replaced by deuterium;R2is selected from H and Ci-6-alkyl, having one or more hydrogen atoms optionally replaced by deuterium;R10is selected from Ci-6-alkyl, 3- to 6-membered cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein alkyl, cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, -CN, Ci-4-alkyl, halo-Ci-4-alkyl, 3- to 6- membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 8-membered heterocycloalkyl, halo-(3- to 8-membered heterocycloalkyl), -OH, =0, =S, -O-Ci-4-alkyl and-O-halo-Ci-4-alkyl, wherein heterocycloalkyl comprises 1 , 2, 3 or 4 heteroatoms independently selected from N, O, or S,R10having one or more hydrogen atoms optionally replaced by deuterium;R11, R12, R21, R22are independently selected from H, Ci-6-alkyl, 3- to 6-membered cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein alkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, -CN, Ci-4-alkyl, halo-Ci-4-alkyl, 3- to 6- membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 8-membered heterocycloalkyl, halo-(3- to 8-membered heterocycloalkyl), -OH, =0, =S, -O-Ci-4-alkyl and -O-halo-Ci-4-alkyl, wherein heterocycloalkyl comprises 1 , 2, 3 or 4 heteroatoms independently selected from N, O, or S,R11and / or R12and / or R21and / or R22having one or more hydrogen atoms optionally replaced by deuterium; or R11and R12, R21and R22, respectively, when taken together with the atom(s) to which they are attached complete a 3- to 6-membered cycle containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N; and wherein this cycle is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, -CN, Ci-4-alkyl, halo-Ci-4-alkyl, 3- to 6-membered cycloalkyl, halo- (3- to 6-membered cycloalkyl), 3- to 8-membered heterocycloalkyl, halo-(3- to 8-membered heterocycloalkyl), -OH, =0, =S, -O-Ci-4-alkyl and -O-halo-Ci-4-alkyl,R11and / or R12and / or R21and / or R22having one or more hydrogen atoms optionally replaced by deuterium;R13, R23are independently selected from H, -CN, -NO2, Ci-6-alkyl, -CO-O-Ci-6-alkyl, 3- to 6- membered cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein alkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, -CN, Ci-4-alkyl, halo-Ci-4-alkyl, 3- to 6- membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 8-membered heterocycloalkyl, halo-(3- to 8-membered heterocycloalkyl), -OH, =0, =S, -O-Ci-4-alkyl and -O-halo-Ci-4-alkyl, wherein heterocycloalkyl comprises 1 , 2, 3 or 4 heteroatoms independently selected from N, O, or S,R13and / or R23having one or more hydrogen atoms optionally replaced by deuterium; n, m are independently selected from 0 to 2; with the proviso that the sum of integer n and m for the residue linked to the same sulfur atom is independently selected from 0, 1 or 2; x, y are independently selected from 0 to 2; with the proviso that the sum of integer x and y for the residue linked to the same sulfur atom is independently selected from 1 or 2;and with the proviso, that the following structure is excluded:

2. A compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease according to claim 1 , or a solvate or pharmaceutically acceptable salt thereof, whereinY is selected from from -CONH-CN, -CONH-NR11R12, -NHCOR12, -NHC(=O)OR12, -NHSO2R10, - NHSO2NR11R12, -SO2H, -SO3H, -SO2R10, -SO(=NR13)R10, -SO2NR11R12, 5-membered heterocyclic ring containing 1 to 4 heteroatoms selected from N, O and S, said heterocyclic ring is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of H, halogen, -CN, =0, =S, -OH, Ci-4-alkyl, -O-C1-4- alkyl, fluoro-Ci-4-alkyl, -O-fluoro-Ci-4-alkyl, CO2R11, NR11R12or CONR11R12,Y or its substituents having one or more hydrogen atoms optionally replaced by deuterium.

3. A compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease according to claim 1 or 2, or a solvate or pharmaceutically acceptable salt thereof, whereinsaid A is unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of H, F, Cl, Br, -CN, -OH, =0, Ci-4-alkyl, -O-Ci-4-alkyl, fluoro-Ci-4-alkyl, -O-fluoro- Ci-4-alkyl, CO2R11, NR11R12and CONR11R12, ring A or its substituents having one or more hydrogen atoms optionally replaced by deuterium;R2is H;R11and R12are independently selected from H, Ci-6-alkyl, 3- to 6-membered cycloalkyl or 3- to 8- membered heterocycloalkyl, wherein alkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, -CN, Ci-4-alkyl, halo-Ci-4-alkyl, 3- to 6-membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 8-membered heterocycloalkyl, halo-(3- to 8-membered heterocycloalkyl), -OH, =0, =S, -O-Ci-4-alkyl and -O-halo-Ci-4-alkyl, wherein heterocycloalkyl comprises 1 , 2, 3 or 4 heteroatoms independently selected from N, O, or S, or R11and R12, when taken together with the atom(s) to which they are attached complete a 3- to 6-membered cycle containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N; and wherein this cycle is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, -CN, Ci-4-alkyl, halo-Ci-4-alkyl, 3- to 6-membered cycloalkyl, halo- (3- to 6-membered cycloalkyl), 3- to 8-membered heterocycloalkyl, halo-(3- to 8-membered heterocycloalkyl), -OH, =0, =S, -O-Ci-4-alkyl and -O-halo-Ci-4-alkyl,R11and / or R12having one or more hydrogen atoms optionally replaced by deuterium.

4. A compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease according to any one of the preceding claims, or a solvate or pharmaceutically acceptable salt thereof, whereinB is phenyl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of F, Cl, -CN, Ci-4-alkyl, Ci-4-alkyl, -O-Ci-4-alkyl, -O-fluoro-Ci-4-alkyl; ring B or its substituents having one or more hydrogen atoms optionally replaced by deuterium; and wherein the residue -NR2on ring B is in a 1 ,4-orientation with respect to ring C.

5. A compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease according to any one of the preceding claims, or a solvate or pharmaceutically acceptable salt thereof, whereinC is phenyl, which is optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, -CN, Ci-4-alkyl, Ci-4-alkyl, -O-Ci-4-alkyl, -O-fluoro-Ci-4-alkyl; and wherein optionally two adjacent substituents in the phenyl and pyridyl moiety form a 5- to 8-membered partially unsaturated cycle optionally containing 1 to 3 heteroatoms independently selected from O, S or N, wherein this additional cycle is optionally substituted with 1 to 4 substituents independently selected from halogen, -CN, =0, =S, -OH, Ci-4-alkyl, halo-Ci-4-alkyl; ring C or its substituents having one or more hydrogen atoms optionally replaced by deuterium.

6. A compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease according to any one of the preceding claims, wherein the neurodegenerative disease is selected from Alexander’s disease, Alper’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, corticobasal syndrome (CBS), Creutzfeldt-Jakob disease, Down syndrome (DS), frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Huntington’s disease, HIV-associated dementia (FTD), Kennedy’s disease, Krabbe’s disease, kuru, dementia with Lewy bodies (DLB), Machado-Joseph disease (Spinocerebellar ataxia type 3), multiple sclerosis (and subgroups like relapsing form of multiple sclerosis (RMS), such as relapsing-remitting multiplesclerosis (RRMS) or active secondary progressive multiple sclerosis (active SPMS). In some embodiments, the MS is a progressive form of multiple sclerosis, such as primary progressive multiple sclerosis (PPMS), non-active secondary progressive multiple sclerosis (non-active SPMS), relapse-associated worsening (RAW) and by progression independent of relapse activity (PIRA)), multiple system atrophy, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus- Merzbacher disease, Pick’s disease, primary lateral sclerosis, prion diseases, progressive supranuclear palsy (PSP), Refsum’s disease, Sandhoff's disease, Schilder’s disease, subacute combined degeneration of spinal cord secondary to pernicious anemia, schizophrenia, drug addiction, spinocerebellar ataxia (multiple types with varying characteristics), spinal muscular atrophy, Steele-Richardson-Olszewski disease, or tabes dorsalis.

7. A compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease according to any one of the preceding claims, wherein the neurodegenerative disease is selected from Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), dementia with Lewy bodies (DLB), multiple sclerosis, PIRA and Parkinson's disease.

8. A compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease according to any one of the preceding claims, wherein the neurodegenerative disease is dementia with Lewy bodies (DLB) or Parkinson's disease.

9. A compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease according to any one of the preceding claims, wherein said patient has a reduced level of Nurrl and / or a reduced level of Nurrl activity in neuronal cell, in particular in dopaminergic neuronal cells.

10. A compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease according to claim9, wherein the method of determining the level of Nurrl comprises: a) determining the level of a gene and / or the level of activity of a gene in a patient, wherein the gene is downstream of Nurrl in a biological pathway in the patient; and b) based on the level of activity or level of the gene in the patient, determining whether to administer to the patient a compound of Formula (I) for neuroprotection.11 A compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease according to claim10, wherein the gene is downstream of Nurrl in a biological pathway is selected from the group comprising glial cell line-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), glial fibrillary acidic protein (GFAP gene), tyrosine hydroxylase (7 / 7 gene) and vesicular monoamine transporter 2 (SLC18A2).

12. A compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease according to any one of the preceding claims in a patient, the therapy comprising administering to the patient a therapeutically-effective amount of a compound of Formula (I), wherein the patient exhibits an aberrant level of a biomarker associated with the neurodegenerative disease prior to the administering.

13. A compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease according to any one of the preceding claims comprising: a) determining a level of Nurrl in a patient; and b) based on the level of Nurrl in the patient, determining whether to administer to the patient a compound if Formula (I).

14. A compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease according to any one of the preceding claims, said therapy comprising: a) determining a level of Nurrl in a patient who is undergoing a therapy for a neurodegenerative condition; and b) based on the level of Nurrl in the patient, determining whether to continue the therapy for the neurodegenerative condition.

15. A compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease according to any one of the preceding claims comprising: a) determining a level of a protein in a patient, wherein the protein is downstream of Nurrl in a biological pathway in the patient; and b) based on the level of the protein in the patient, determining whether to administer to the patient a Nurrl agonist, in particular wherein the protein downstream of Nurrl in a biological pathway is selected from the group comprising glial cell line-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), glial fibrillary acidic protein (GFAP), tyrosine hydroxylase (TH) and vesicular monoamine transporter 2 (VMAT2).

16. A compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease according to any one of the preceding claims comprising: a) determining a level of a protein in a patient who is undergoing a therapy for a neurodegenerative condition, wherein the protein is downstream of Nurrl in a biological pathway in the patient, and b) based on the level of the protein in the patient, determining whether to continue the therapy for the neurodegenerative condition, in particular wherein the protein downstream of Nurrl in a biological pathway is selected from the group comprising glial cell line-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), glial fibrillary acidic protein (GFAP), tyrosine hydroxylase (TH) and vesicular monoamine transporter 2 (VMAT2).

17. A compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease according to any one of the preceding claims comprising: a) determining a level of activity of a gene in a patient,wherein the gene is downstream of Nurrl in a biological pathway in the patient; and b) based on the level of activity of the gene in the patient, determining whether to administer to the patient a compound of Formula (I) for a neurodegenerative condition.

18. A compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease according to any one of the preceding claims comprising: a) determining the level of a gene or the level of activity of a gene in a patient who is undergoing a therapy for a neurodegenerative condition, wherein the gene is downstream of Nurrl in a biological pathway in the patient; and b) based on the level of activity of the gene in the patient, determining whether to continue the therapy for the neurodegenerative condition.

19. A compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease according to any one of the preceding claims comprising: a) determining that a patient exhibits downregulated Nurrl ; b) determining that the patient exhibits upregulated miR-132; and c) based on the determining that the patient exhibits downregulated Nurrl and the determining that the patient exhibits upregulated miR-132, identifying the patient as being at risk for a condition.

20. A compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease according to any one of the preceding claims, wherein the level of Nurrl or the level of activity of Nuri or the level of a gene or the level of activity of a gene that is downstream of Nurrl in a biological pathway or the level of a protein that is downstream of Nurrl in a biological pathway is determined in an ex vivo biological sample of said patient selected from the group comprising peripheral blood, peripheral blood lymphocytes, serum, plasma, CSF and peripheral blood mononuclear cells and whole blood.21 . A compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease according to any one of the preceding claims wherein the method comprises: a) determining a level or activity of Nurrl in an ex vivo biological sample of a patient with an assay selected from (a) a real-time PCR assay of Nurrl gene expression against relevant housekeeping genes / internal controls (e.g. GAPDH), (b) an immunoassay (such as ELISA) with the suitable antibodies for Nurrl protein, and (c) a Western blot for Nurrl protein from the biological sample selected from peripheral blood, peripheral blood lymphocytes, serum, plasma, CSF and peripheral blood mononuclear cells; and b) if the level or activity of Nurrl is no greater than about 90% of the level in a healthy subject of same age, gender and / or BMI, administering to the patient a therapeutically-effective amount of a compound herein.

22. A compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease according to any one of the preceding claims for the use as a medicament.

23. A compound of Formula (I) for use in therapy of a neurodegenerative condition or disease for neuroprotection in a patient having a neurodegenerative condition or disease according to any one of the preceding claims for use in the prophylaxis and / or treatment of diseases, disorders, therapeutic indications or medical conditions amenable for treatment with a Nurrl agonist.

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