Card9 inhibitors and use thereof

Abstract

The present invention relates to a compound of formula (I) or (II). The invention further relates to a use of said compound as a medicament. The invention further relates to a use of said compound in the treatment of a disease, wherein the disease is selected from multiple sclerosis and neurodegenerative diseases.

Description

[0001] CARD9 inhibitors and use thereof

[0002] Background

[0003] Caspase recruitment domain family member 9 (CARD9) is a signal transduction mediator of C-type Lectin Receptors (CLRs), which are mainly involved in fungal recognition, of NOD-Like Receptors (NLRs), which are involved in the recognition of intracellular bacteria, and of RIG-I which is involved in viral recognition. In addition to pathogenic stimuli, these receptors can also be activated by danger- associated patterns, endogenous danger molecules that are released by damaged or dying cells such as SAP-130(1). Thus, CARD9 integrates and fine-tunes signals derived from several pattern recognition receptor types toward initiating, maintaining, and controlling an efficient immune response. This broad functional role within the immune system makes CARD9 a candidate molecule to play a role in chronic inflammatory conditions. Moreover, the prominent role of CLRs in damage recognition is crucial for maintaining an equilibrium between inflammatory response and tissue destruction. Many studies highlight the prominent role of CLRs, functionally upstream of CARD9, during cell death induced by sterile inflammation. Yet, at this point, the role of CARD9 in inflammatory conditions remains ambiguous.

[0004] Dysregulation of the CLR signalling was shown to predispose and even lead to the development of inflammatory and autoimmune diseases(2 3). Accordingly, CARD9 deficiencies and polymorphisms were reported to have a role in chronic inflammatory and autoimmune diseases such as Inflammatory Bowel Disease (IBD) in humans and in Experimental Autoimmune Uveitis (EAU) in mice. In the context of IBD, despite the comprehensive understanding of the signalling mechanisms and identification of both riskpromoting and protective CARD9 variants, the translation of these into efficient pharmacological interventions has faced challenges. Pharmacological inhibition of CARD9 in IBD models had no effect on the outcome of the disease progression^11), in contrast to the cell-specific genetic deletion of CARD9, which showed a protective effect in specific colitis animal models(5). In EAU, deficiency of CARD9 can completely block disease development, whereas its activation by an agonist and through the receptor Mincle leads to disease progression. Mincle’s involvement in autoimmunity is of special relevance as this receptor is known to bind to an endogenous ligand, SAP-130, thus having a direct role in recognition of danger-associated self-antigens <6>.

[0005] In atherosclerosis, an inflammatory disease of medium and large arteries, macrophage activation constitutes a key aspect of plaque development. Activation of the macrophages is associated with upregulation of pattern recognition receptors. Hence, the role of CARD9 has been assessed in models of atherosclerosis with ambiguous outcomes(78). One study showed increased lesion size in the absence of CARD9, another found no effect on lesion size upon CARD9 deletion from hematopoietic cells, and yet again, another study detected signs of exacerbated disease in the absence of CARD9.

[0006] With strong expression in microglia and other phagocytes and its prominent role in activating these cells, CARD9 was postulated to play a prominent role in Alzheimer's disease, constituting a checkpoint of phagocytic activity towards A and tau. Surprisingly, the absence of CARD9 in a standard model of Alzheimer's disease increased Ap load and neuronal loss, while pharmacological activation of CARD9 boosts Ap clearance(9). Also in the context of cardiovascular diseases (CVDs) such as cardiac ischemia / reperfusion (l / R) injury, which contribute to cardiac death and ischemic cardiomyopathy, the critical interactions between CARD9 and a complex network of extracellular and intracellular signalling molecules have been studied. One study showed that the absence of CARD9 results in smaller infarct size with decreased cell infiltration in animal models of l / R injury. Another study showed that CARD9 deficiency decreases animal survival and aggravates cardiac dysfunction with impaired protective mechanisms such as activation of autophagy or inhibition of apoptosis, while in cardiomyocytes, overexpression of CARD9 leads to the autophagic influx and decreased apoptosis, as shown by another study (10>. These results show the gap in knowledge for the prediction of the role of CARD9 in CVDs

[0007] Hence, the outcome of Card9CARD9 inhibition for inflammatory conditions and CNS diseases is difficult to predict with current knowledge, even more so when drugs are used that affect only particular aspects of CARD9’s molecular function.

[0008] Beyond the aforementioned diseases, CARD9's reach extends to various other diseases (ankylosing spondylitis, IgA nephropathy, and rheumatoid), adding layers to its multifaceted involvement in health and pathology. Early indications suggest potential links to conditions such as rheumatoid arthritis and certain cancer types. As research delves into the molecular intricacies of these diseases, the influence of CARD9 continues to surprise and challenge conventional paradigms as a versatile and unexpected player. These studies suggest that CARD9-mediated signalling pathway may contribute to autoimmunity against the CNS.

[0009] Based on the above-mentioned state of the art, the objective of the present invention is to provide means and methods to provide CARD9 inhibitors and their use in the treatment of multiple sclerosis and neurodegenerative diseases. This objective is attained by the subject-matter of the independent claims of the present specification, with further advantageous embodiments described in the dependent claims, examples, figures and general description of this specification.

[0010] Summary of the Invention

[0011] A first aspect of the invention relates to a compound of formula (I) or (II) wherein,

[0012] R1is selected from the group consisting of -NR4C(=O)R4, -NR4C(=O)R5, -NR4C(=O)OR4, - NR4C(=O)OR5, -C(=O)NR4R5, -C(=O)NR42, -C(=O)R4, -C(=O)R5, -OR4, -OR5, -Ci-C6-alkyl-OH, -C(=O)-CF3, a substituted or unsubstituted aryl, and a substituted or unsubstituted heteroaryl,

[0013] R2is selected from the group consisting of -C(=O)OH, -C(=O)OR5, -C(=O)-NHCN, -C(=O)- NHOH, -SO2-NH2, -SO2-OH, -SO2-NHR6, -SO2-R62, -C(=O)R6, -C(=O)NR6and tetrazolyl, R3is selected from , -F, -Cl, -Br, -I, -CN, -CH2F, -CHF2, -CF3and -OH,

[0014] R7is selected from the group consisting of -N-(Ci-Ce alkyl)2, -NH-(Ci-Ce alkyl), and the group consisting of a heterocycloalkyl comprising at least one heteroatom, wherein one of the at least one heteroatoms is a nitrogen,

[0015] R8is selected from the group consisting of -C(=O)NH2, -C(=O)NHR9, -C(=O)NR92, -C(=O)OH, -C(=O)OR9, -SO2-NHR9, -SO2-R92, -SO2-NH2, -SO2-OH, wherein

[0016] R4is independently selected from the group consisting of H and C-i-6-alkyl,

[0017] R5is selected from a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl;

[0018] R6is selected from a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl;

[0019] R9is independently selected from the group consisting of C 1-6-alky I , and wherein n is 0, 1 , or 2, p is 0 or 1 ; m is 0 or 1 ,

[0020] Xi and X2are each selected from N or CH,

[0021] Y and Z are independently selected from C, N, O and S, wherein the compound does not include any of the following formulaes

[0022]

[0023] A second aspect of the invention relates to use of a compound according to the first aspect of the invention as a medicament. A third aspect of the invention relates to use of a compound according to the first aspect of the invention and a compound of formula (III) and (IV) in the treatment of a disease, wherein the disease is selected from multiple sclerosis and neurodegenerative diseases, in particular wherein the disease is multiple sclerosis.

[0024] A fifth aspect of the invention relates to a compound of formula (I) or (II) for use in the treatment of multiple sclerosis and neurodegenerative diseases wherein,

[0025] R1is selected from the group consisting of -NR4C(=O)R4, -NR4C(=O)R5, -NR4C(=O)OR4, - NR4C(=O)OR5, -C(=O)NR4R5, -C(=O)NR42, -C(=O)R4, -C(=O)R5, -OR4, -OR5, -Ci-C6-alkyl-OH, -C(=O)-CF3, a substituted or unsubstituted aryl, and a substituted or unsubstituted heteroaryl,

[0026] R2is selected from the group consisting of -C(=O)OH, -C(=O)OR6, -C(=O)-NHCN, -C(=O)- NHOH, -SO2-NH2, -SO2-OH, -SO2-NHR6, -SO2-R62, -C(=O)R6, -C(=O)NR6and tetrazolyl,

[0027] R3is selected from , -F, -Cl, -Br, -I, -ON, -CH2F, -CHF2, -CF3and -OH,

[0028] R7is selected from the group consisting of -N-(Ci-Ce alkyl)2, -NH-(Ci-Ce alkyl), and the group consisting of a heterocycloalkyl comprising at least one heteroatom, wherein one of the at least one heteroatoms is a nitrogen,

[0029] R8is selected from the group consisting of -C(=O)NH2, -C(=O)NHR9, -C(=O)NR92, -C(=O)OH, - C(=O)OR9, -SO2-NHR9, -SO2-R92, -SO2-NH2, -SO2-OH, wherein

[0030] R4is independently selected from the group consisting of H and C-i-6-alkyl,

[0031] R5is selected from a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl;

[0032] R6is selected from a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, particularly R6is selected from a substituted or unsubstituted -Ci-Ce-alkyl, more particularly R6is selected from an unsubstituted -Ci-Ce-alkyl;

[0033] R9is selected from the group consisting of C 1-6-alky I and wherein m is 0 or 1 , n is 0, 1 , or 2, p is 0 or 1 ; m is 0 or 1 ,

[0034] Xi and X2 are each selected from N or CH,

[0035] Y and Z are independently selected from C, N, O and S.

[0036] Terms and definitions

[0037] General

[0038] For purposes of interpreting this specification, the following definitions will apply and, whenever appropriate, terms used in the singular will also include the plural and vice versa. In the event that any definition set forth below conflicts with any document incorporated herein by reference, the definition set forth shall control.

[0039] The terms “comprising”, “having”, “containing”, and “including”, and other similar forms, and grammatical equivalents thereof, as used herein, are intended to be equivalent in meaning and to be open-ended in that an item or items following any one of these words is not meant to be an exhaustive listing of such item or items, or meant to be limited to only the listed item or items. For example, an article “comprising” components A, B, and C can consist of (i.e. , contain only) components A, B, and C, or can contain not only components A, B, and C but also one or more other components. As such, it is intended and understood that “comprises” and similar forms thereof, and grammatical equivalents thereof, include disclosure of embodiments of “consisting essentially of’ or “consisting of.”

[0040] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit, unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0041] Reference to “about” a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X.”

[0042] As used herein, including in the appended claims, the singular forms “a”, “or” and “the” include plural referents unless the context clearly dictates otherwise.

[0043] "And / or" where used herein is to be taken as specific recitation of each of the two specified features or components with or without the other. Thus, the term "and / or" as used in a phrase such as "A and / or B" herein is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Likewise, the term "and / or" as used in a phrase such as "A, B, and / or C" is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0044] 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 (e.g., in cell culture, molecular genetics, nucleic acid chemistry, hybridization techniques and biochemistry, organic synthesis). Standard techniques are used for molecular, genetic, and biochemical methods (see generally, Sambrook et al., Molecular Cloning: A Laboratory Manual, 4th ed. (2012) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. and Ausubel et al., Short Protocols in Molecular Biology (2002) 5th Ed, John Wiley & Sons, Inc.) and chemical methods.

[0045] Any patent document cited herein shall be deemed incorporated by reference herein in its entirety.

[0046] The term inhibitor in the context of the present specification relates to any pharmaceutically acceptable agent or compound that may be used to interact with and specifically interfere with the biological activity of its designated target (CARD9). Inhibitors include small molecule drugs that fulfill the criteria summarized as Lipinski’s Rules of five (the drug fulfils at least three of the following rules: number of H- bond donors is < 5; number of H-bond acceptors is < 10; molecular mass is <500Da; octanol / water partition coefficient < 5). Specific examples of such inhibitors are mentioned herein.

[0047] As used herein, the term treating or treatment of any disease or disorder (e.g. multiple sclerosis and neurodegenerative diseases) refers in one embodiment to ameliorating the disease or disorder (e.g. slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment "treating" or "treatment" refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, "treating" or "treatment" refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. Methods for assessing treatment and / or prevention of disease are generally known in the art, unless specifically described hereinbelow.

[0048] The formulae of the present specification follow the convention of organic chemistry to not show hydrogen atoms on carbon scaffolds. Carbon is tetravalent and bonds not shown are assumed to be hydrogen unless shown otherwise.

[0049] The term alkyl in the context of the present specification relates to a saturated linear or branched hydrocarbon, wherein in certain embodiments one carbon-carbon bond may be unsaturated.

[0050] A Ci-Ce alkyl in the context of the present specification relates to a saturated linear or branched hydrocarbon having 1 , 2, 3, 4, 5 or 6 carbon atoms. Non-limiting examples for a Ci-Ce alkyl include methyl, ethyl, propyl, prop-2-enyl, n-butyl, 2-methylpropyl, tert-butyl, cyclo-butyl, cyclo-propyl, methyl- cyclo-propyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, 1 ,1 -dimethylpropyl, 1 ,2-dimethylpropyl, 1 ,2- dimethylpropyl, cyclo-pentyl, cyclo-hexyl, methyl-cyclo-pentyl.

[0051] Where used in the context of chemical formulae, the following abbreviations may be used: Me is methyl CH3, Et is ethyl -CH2CH3, Prop is propyl -(CH2)2CH3 (n-propyl, n-pr) or -CH(CH3)2 (iso-propyl, i-pr), but is butyl -C4H9, -(CH2)3CH3, -CHCH3CH2CH3, -CH2CH(CH3)2 or -C(CH3)3.

[0052] The term cycloalkyl in the context of the present specification relates to a saturated hydrocarbon ring having 3, 4, 5, 6, 7 or 8 carbon atoms, wherein in certain embodiments, one carbon-carbon bond may be unsaturated. Non-limiting examples of a cycloalkyl moiety include cyclopropyl (-C3H5), cyclobutyl (- C4H7), cyclopentenyl (-C5H9), and, cyclohexyl (-CeHg), cyclohexenyl (-CeHn) or cyclooctyl (-CsHn) moieties.

[0053] The term heterocycloalkyl in the context of the present specification relates to a saturated hydrocarbon ring having 3, 4, 5, 6, 7, 8, 9 or 10 atoms, of which one or more of these atoms is a heteroatom selected from O, N, or S wherein in certain embodiments, -if applicable- one carbon-carbon bond or one carbonheteroatom bond may be unsaturated.

[0054] The term ary / in the context of the present specification relates to a cyclic aromatic C5-C10 hydrocarbon. Examples of aryl include, without being restricted to, phenyl, benzyl and naphthyl.

[0055] The term heteroaryl in the context of the present specification relates to a cyclic aromatic C5-C10 hydrocarbon wherein at least one hydrocarbon is exchanged for a heteroatom selected from N, O and S. Examples for heteroaryl include, without being restricted to, pyrrole, thiophene, furan, imidazole, pyrazole, thiazole, oxazole, pyridine, pyrimidine, thiazin, quinoline, benzofuran and indole.

[0056] In certain embodiments, the Ci-Ce alkyl, cycloalkyl, heterocycloalkyl, aryl and / or heteroaryl is substituted or unsubstituted, wherein the term substituted in its broadest sense refers to a covalently linked atom that is not carbon or hydrogen, particularly to an atom selected from N, O, F, B, Si, P, S, Cl, Br and I, which itself may be -if applicable- linked to one or several other atoms of this group, or to hydrogen, or to an unsaturated or saturated hydrocarbon (cycloalkyl, heterocycloalkyl, aryl, or heteroaryl in their broadest sense). In a narrower sense, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and substituted heteroaryl refer to cycloalkyl, heterocycloalkyl, aryl, or heteroaryl as defined above in the broadest sense that is substituted in one or several carbon atoms by groups selected from amine NH2, alkylamine NHR, imide NH, alkylimide NR, amino(carboxyalkyl) NHCOR or NRCOR, hydroxyl OH, oxyalkyl OR, oxy(carboxyalkyl) OCOR, carbonyl O and its ketal or acetal (OR)2, nitril ON, isonitril NO, cyanate CNO, isocyanate NCO, thiocyanate CNS, isothiocyanate NCS, fluoride F, choride Cl, bromide Br, iodide I, phosphonate PO3H2, PO3R2, phosphate OPO3H2 and OPO3R2, sulfhydryl SH, suflalkyl SR, sulfoxide SOR, sulfonyl SO2R, sulfanylamide SO2NHR, sulfate SO3H and sulfate ester SO3R, with R being defined further in the description. In certain embodiments, R is itself an unsubstituted or substituted Ci to C12 alkyl in its broadest sense, and in a narrower sense, R is methyl, ethyl or propyl unless otherwise specified.

[0057] Detailed Description of the Invention

[0058] A first aspect of the invention relates to a compound of formula (I) or (II) wherein, R1is selected from the group consisting of -NR4C(=O)R4, -NR4C(=O)R5, -NR4C(=O)OR4, - NR4C(=O)OR5, -C(=O)NR4R5, -C(=O)NR42, -C(=O)R4, -C(=O)R5, -OR4, -OR5, -Ci-Ce-alkyl-OH, -C(=O)-CF3, a substituted or unsubstituted aryl, and a substituted or unsubstituted heteroaryl,

[0059] R2is selected from the group consisting of -C(=O)OH, -C(=O)OR6, -C(=O)-NHCN, -C(=O)- NHOH, -SO2-NH2, -SO2-OH, -SO2-NHR6, -SO2-R62, -C(=O)R6, -C(=O)NR6and tetrazolyl, -SO2- OH,

[0060] R3is selected from , -F, -Cl, -Br, -I, -ON, -CH2F, -CHF2, -CF3and -OH,

[0061] R7is selected from the group consisting of -N-(Ci-Ce alkyl)2, -NH-(Ci-Ce alkyl), and the group consisting of a heterocycloalkyl comprising at least one heteroatom, wherein one of the at least one heteroatoms is a nitrogen,

[0062] R8is selected from the group consisting of -C(=O)NH2, -C(=O)NHR9, -C(=O)NR92, -C(=O)OH, -C(=O)OR9, -SO2-NHR9, -SO2-R92, -SO2-NH2, -SO2-OH, wherein

[0063] R4is independently selected from the group consisting of H and C-i-6-alkyl,

[0064] R5is selected from a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl;

[0065] R6is selected from a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl,

[0066] R9is independently selected from the group consisting of C 1-6-alky I , and wherein n is 0, 1 , or 2, p is 0 or 1 ; m is 0 or 1 ,

[0067] Xi and X2 are each selected from N or CH,

[0068] Y and Z are independently selected from C, N, O and S, wherein the compound does not include any one of the following formulas

[0069]

[0070] In certain embodiments, n is 0.

[0071] In certain embodiments, R1is selected from the group consisting of -NR4C(=O)R4, -NR4C(=O)R5, - NR4C(=O)OR4, -NR4C(=O)OR5, -C(=O)NR4R5, -C(=O)NR42, -C(=O)R4, -C(=O)R5, -OR4, -OR5, -Ci-C6- alkyl-OH, -C(=O)-CF3, and a substituted or unsubstituted aryl.

[0072] In certain embodiments, R1is selected from the group consisting of -NR4C(=O)R5, -NR4C(=O)OR5, - C(=O)NR4R5and -C(=O)R5, wherein

[0073] R4is independently selected from the group consisting of H and C-i-6-alkyl,

[0074] R5is selected from a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl. In certain embodiments, R2is selected from the group consisting of -C(=O)OH, -C(=O)OR6, -C(=O)R6, -C(=O)NR6. -SO2-NHR6, -SO2-R62, wherein

[0075] R6is selected from a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl.

[0076] In certain embodiments, the compound is of formula (la) or (Ila) wherein

[0077] R1is selected from the group consisting of -NR4C(=O)R5, -NR4C(=O)OR5, -C(=O)NR4R5and - C(=O)R5;

[0078] R2is selected from the group consisting of -C(=O)OH, -C(=O)OR6, -C(=O)R6, -C(=O)NR6, -SO2- NHR6, -SO2-R62;

[0079] R7is selected from the group consisting of -N-(Ci-Ce alkyl)2, and the group consisting of a heterocycloalkyl comprising at least one heteroatom, wherein one of the at least one heteroatoms is a nitrogen,

[0080] R8is selected from the group consisting of -C(=O)NH2, -C(=O)NHR9, -C(=O)NR92, -C(=O)OH, - C(=O)OR9, wherein

[0081] R4is independently selected from the group consisting of H and C-i-6-alkyl;

[0082] R5is selected from a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl;

[0083] R6is selected from a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl;

[0084] R9is independently selected from the group consisting of C 1-6-alky I ; and wherein p is 0 or 1 ; m is 0 or 1 ,

[0085] Xi and X2are each selected from C and N;

[0086] Y and Z are independently selected from C, N, O and S.

[0087] In certain embodiments, the compound is of formula (lb) or (lib) wherein

[0088] R1is selected from the group consisting of -NR4C(=O)R5, -NR4C(=O)OR5, -C(=O)NR4R5and - C(=O)R5;

[0089] R2is selected from the group consisting of -C(=O)OH, -C(=O)OR6, -C(=O)R6, -C(=O)NR6, -SO2- NHR6, -SO2-R62;

[0090] R7is selected from the group consisting of -N-(Ci-Ce alkyl)2, and the group consisting of a heterocycloalkyl comprising at least one heteroatom, wherein one of the at least one heteroatoms is a nitrogen,

[0091] R8is selected from the group consisting of -C(=O)NH2, -C(=O)NHR9, -C(=O)NR92, -C(=O)OH, - C(=O)OR9, wherein

[0092] R4is independently selected from the group consisting of H and C-i-6-alkyl;

[0093] R5is selected from a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl;

[0094] R6is selected from a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl;

[0095] R9is independently selected from the group consisting of C 1-6-alky I and wherein p is 0 or 1 ; m is 0 or 1 ,

[0096] Y is selected from C, N, O and S.

[0097] In certain embodiments, the compound of formula (II) wherein, R1is selected from the group consisting of -NR4C(=O)R4, -NR4C(=O)R5, -NR4C(=O)OR4, - NR4C(=O)OR5, -C(=O)NR4R5, -C(=O)NR42, -C(=O)R4, -C(=O)R5, -OR4, -OR5, -Ci-Ce-alkyl-OH, -C(=O)-CF3, a substituted or unsubstituted aryl, and a substituted or unsubstituted heteroaryl,

[0098] R2is selected from the group consisting of -C(=O)OH, -C(=O)OR6, -C(=O)-NHCN, -C(=O)- NHOH, -SO2-NH2, -SO2-OH, -SO2-NHR6, -SO2-R62, -C(=O)R6, -C(=O)NR6and tetrazolyl,

[0099] R3is selected from , -F, -Cl, -Br, -I, -ON, -CH2F, -CHF2, -CF3and -OH,

[0100] R7is selected from the group consisting of -N-(Ci-Ce alkyl)2, -NH-(Ci-Ce alkyl), and the group consisting of a heterocycloalkyl comprising at least one heteroatom, wherein one of the at least one heteroatoms is a nitrogen, wherein

[0101] R4is independently selected from the group consisting of H and C-i-6-alkyl,

[0102] R5is selected from a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl;

[0103] R6is selected from a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl; and wherein n is 0, 1 , or 2, particularly 0, p is 0 or 1 ; m is 0 or 1 ,

[0104] Xi and X2 are each selected from N or CH,

[0105] Y and Z are independently selected from C, N, O and S.

[0106] In certain embodiments, Y is C or N.

[0107] In certain embodiments, Y is N.

[0108] In certain embodiments, R6is selected from a substituted or unsubstituted -Ci-Ce-alkyl.

[0109] In certain embodiments, R6is selected from an unsubstituted -Ci-Ce-alkyl.

[0110] In certain embodiments, R6is selected from the group consisting of -Ci-Cs-alkyl.

[0111] In certain embodiments, the substituted alkyl, or the substituted aryl, or the substituted heteroaryl, or the substituted cycloalkyl, or the substituted heterocycloalkyl are independently substituted with R10q, wherein R10is independently selected from

[0112] - the group consisting of halogens,

[0113] - the group consisting of substituted or unsubstituted -Ci-Ce alkyl,

[0114] - the group consisting of -O-C1-C6 alkyls, - the group consisting of -CN, -C(=O)OH, -C(=O)H, -C(=O)NR122, -C(=O)O-Ci-C6alkyl, -Ci-Ce-alkyl-OH, -CH2F, -CHF2, -CF3, -C(=O)-CF3, and -NR122, wherein R12is independently selected from H and Ci-6-alkyl, and wherein q is independently selected from 1 , 2, 3, 4 and 5. In certain embodiments, the substituted aryl is substituted with R10q, wherein R10is selected from

[0115] - the group consisting of -O-Ci-Ce alkyls,

[0116] - the group consisting of -CN, -C(=O)OH, -C(=O)H, -C(=O)NR122, -C(=O)O-Ci-C6alkyl, - Ci-Ce-alkyl-OH, -CH2F, -CHF2, -CF3, -C(=O)-CF3, and -NR122, wherein R12is independently selected from H and Ci-Ce-alkyl and wherein q is independently selected from 1 , 2, 3, 4 and 5.

[0117] In certain embodiments, the substituted alkyl, or the substituted heteroaryl, or the substituted cycloalkyl, or the substituted heterocycloalkyl are independently substituted with R10q, wherein R10is independently selected from

[0118] - the group consisting of halogens,

[0119] - the group consisting of substituted or unsubstituted -Ci-Ce alkyl,

[0120] - the group consisting of -O-Ci-Ce alkyls,

[0121] - the group consisting of -CN, -C(=O)OH, -C(=O)H, -C(=O)NR122, -C(=O)O-Ci-C6alkyl, - Ci-C6-alkyl-OH, -CH2F, -CHF2, -CF3, -C(=O)-CF3, and -NR122, wherein R12is independently selected from H and Ci-Ce-alkyl and wherein q is independently selected from 1 , 2, 3, 4 and 5.

[0122] In certain embodiments, q is 1 .

[0123] In certain embodiments, the substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, is selected from a Cs to C10 substituted or unsubstituted aryl, or a Cs to C10 substituted or unsubstituted heteroaryl.

[0124] In certain embodiments, the substituted or unsubstituted cycloalkyl, or the substituted or unsubstituted heterocycloalkyl is selected from a C3to C10 substituted or unsubstituted cycloalkyl, or a C3to C12 substituted or unsubstituted heterocycloalkyl.

[0125] A second aspect of the invention relates to use of a compound according to the first aspect of the invention as a medicament.

[0126] A third aspect of the invention relates to the use of a compound according to the first aspect of the invention and a compound of formula (III) and (IV) in the treatment of a disease, wherein the disease is selected from multiple sclerosis and neurodegenerative conditions.

[0127] In certain embodiments, the invention relates to the use of a compound of formula (II) according to the first aspect of the invention and a compound of formula (III) and (IV) in the treatment of a disease, wherein the disease is selected from multiple sclerosis and neurodegenerative conditions. In certain embodiments, the invention relates to the use of a compound according to the first aspect of the invention and a compound of formula (IV) in the treatment of a disease, wherein the disease is selected from multiple sclerosis and neurodegenerative conditions.

[0128] In certain embodiments, the invention relates to the use of a compound of formula (II) according to the first aspect of the invention and a compound of formula (IV) in the treatment of a disease, wherein the disease is selected from multiple sclerosis and neurodegenerative conditions.

[0129] In certain embodiments, the invention relates to the use of a compound according to the first aspect of the invention in the treatment of a disease, wherein the disease is selected from multiple sclerosis and neurodegenerative conditions.

[0130] In certain embodiments, the invention relates to the use of a compound of formula (II) according to the first aspect of the invention in the treatment of a disease, wherein the disease is selected from multiple sclerosis and neurodegenerative conditions. In certain embodiments, the diseases is multiple sclerosis.

[0131] A fourth aspect of the invention relates to the use of the compound according to the first aspect of the invention and a compound of formula (III) and (IV) for the manufacture of a medicament for the treatment of multiple sclerosis and neurodegenerative diseases. In certain embodiments, the invention relates to the use of the compound according to the first aspect of the invention and a compound of formula (IV) for the manufacture of a medicament for the treatment of multiple sclerosis and neurodegenerative diseases.

[0132] In certain embodiments, the invention relates to the use of the compound of formula (II) according to the first aspect of the invention and a compound of formula (IV) for the manufacture of a medicament for the treatment of multiple sclerosis and neurodegenerative diseases.

[0133] In certain embodiments, the invention relates to the use of the compound according to the first aspect of the invention for the manufacture of a medicament for the treatment of multiple sclerosis and neurodegenerative diseases.

[0134] In certain embodiments, the invention relates to the use of the compound of formula (II) according to the first aspect of the invention for the manufacture of a medicament for the treatment of multiple sclerosis and neurodegenerative diseases.

[0135] In certain embodiments, the compound is for the manufacture of a medicament for the treatment of multiple sclerosis.

[0136] A fifth aspect of the invention relates to a compound of formula (I) or (II) for use in the treatment of multiple sclerosis and neurodegenerative diseases wherein,

[0137] R1is selected from the group consisting of -NR4C(=O)R4, -NR4C(=O)R5, -NR4C(=O)OR4, - NR4C(=O)OR5, -C(=O)NR4R5, -C(=O)NR42, -C(=O)R4, -C(=O)R5, -OR4, -OR5, -Ci-C6-alkyl-OH, -C(=O)-CF3, a substituted or unsubstituted aryl, and a substituted or unsubstituted heteroaryl,

[0138] R2is selected from the group consisting of -C(=O)OH, -C(=O)OR6, -C(=O)-NHCN, -C(=O)- NHOH, -SO2-NH2, -SO2-OH, -SO2-NHR6, -SO2-R62, -C(=O)R6, -C(=O)NR6and tetrazolyl,

[0139] R3is selected from , -F, -Cl, -Br, -I, -ON, -CH2F, -CHF2, -CF3and -OH,

[0140] R7is selected from the group consisting of -N-(Ci-Ce alkyl)2, -NH-(Ci-Ce alkyl), and the group consisting of a heterocycloalkyl comprising at least one heteroatom, wherein one of the at least one heteroatoms is a nitrogen,

[0141] R8is selected from the group consisting of -C(=O)NH2, -C(=O)NHR9, -C(=O)NR92, -C(=O)OH, - C(=O)OR9, -SO2-NHR9, -SO2-R92, -SO2-NH2, -SO2-OH, wherein

[0142] R4is independently selected from the group consisting of H and C-i-6-alkyl, R5is selected from a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl;

[0143] R6is selected from a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, particularly R6is selected from a substituted or unsubstituted -Ci-Ce-alkyl, more particularly R6is selected from an unsubstituted -Ci-Ce-alkyl;

[0144] R9is selected from the group consisting of C 1-6-alky I and wherein m is 0 or 1 , n is 0, 1 , or 2, p is 0 or 1 ; m is 0 or 1 ,

[0145] Xi and X2are each selected from N or CH,

[0146] Y and Z are independently selected from C, N, O and S.

[0147] In certain embodiments, n is 0.

[0148] In certain embodiments, R1is selected from the group consisting of -NR4C(=O)R4, -NR4C(=O)R5, - NR4C(=O)OR4, -NR4C(=O)OR5, -C(=O)NR4R5, -C(=O)NR42, -C(=O)R4, -C(=O)R5, -OR4, -OR5, -Ci-C6- alkyl-OH, -C(=O)-CF3, and a substituted or unsubstituted aryl.

[0149] In certain embodiments, R1is selected from the group consisting of -NR4C(=O)R5, -NR4C(=O)OR5, - C(=O)NR4R5and -C(=O)R5, wherein

[0150] R4is independently selected from the group consisting of H and C-i-6-alkyl,

[0151] R5is selected from a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl.

[0152] In certain embodiments, R2is selected from the group consisting of -C(=O)OH, -C(=O)OR6, -C(=O)R6, -C(=O)NR6. -SO2-NHR6, -SO2-R62, wherein

[0153] R6is selected from a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl.

[0154] In certain embodiments, the compound is of formula (la) or (Ila) wherein

[0155] R1is selected from the group consisting of -NR4C(=O)R5, -NR4C(=O)OR5, -C(=O)NR4R5and - C(=O)R5;

[0156] R2is selected from the group consisting of -C(=O)OH, -C(=O)OR6, -C(=O)R6, -C(=O)NR6, -SO2- NHR6, -SO2-R62;

[0157] R7is selected from the group consisting of -N-(Ci-Ce alkyl)2, and the group consisting of a heterocycloalkyl comprising at least one heteroatom, wherein one of the at least one heteroatoms is a nitrogen,

[0158] R8is selected from the group consisting of -C(=O)NH2, -C(=O)NHR9, -C(=O)NR92, -C(=O)OH, - C(=O)OR9, wherein

[0159] R4is independently selected from the group consisting of H and C-i-6-alkyl;

[0160] R5is selected from a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl;

[0161] R6is selected from a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl;

[0162] R9is independently selected from the group consisting of C 1-6-alky I ; and wherein p is 0 or 1 ; m is 0 or 1 ,

[0163] Xi and X2are each selected from C and N;

[0164] Y and Z are independently selected from C, N, O and S.

[0165] In certain embodiments, the compound is of formula (lb) or (lib) wherein R1is selected from the group consisting of -NR4C(=O)R5, -NR4C(=O)OR5, -C(=O)NR4R5and - C(=O)R5;

[0166] R2is selected from the group consisting of -C(=O)OH, -C(=O)OR6, -C(=O)R6, -C(=O)NR6, -SO2- NHR6, -SO2-R62;

[0167] R7is selected from the group consisting of -N-(Ci-Ce alkyl)2, and the group consisting of a heterocycloalkyl comprising at least one heteroatom, wherein one of the at least one heteroatoms is a nitrogen,

[0168] R8is selected from the group consisting of -C(=O)NH2, -C(=O)NHR9, -C(=O)NR92, -C(=O)OH, - C(=O)OR9, wherein

[0169] R4is independently selected from the group consisting of H and C-i-6-alkyl;

[0170] R5is selected from a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl;

[0171] R6is selected from a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl;

[0172] R9is independently selected from the group consisting of C 1-6-alky I ; and wherein p is 0 or 1 ; m is 0 or 1 ,

[0173] Y is selected from C, N, O and S.

[0174] In certain embodiments, the compound of formula (II) wherein,

[0175] R1is selected from the group consisting of -NR4C(=O)R4, -NR4C(=O)R5, -NR4C(=O)OR4, - NR4C(=O)OR5, -C(=O)NR4R5, -C(=O)NR42, -C(=O)R4, -C(=O)R5, -OR4, -OR5, -Ci-C6-alkyl-OH, -C(=O)-CF3, a substituted or unsubstituted aryl, and a substituted or unsubstituted heteroaryl,

[0176] R2is selected from the group consisting of -C(=O)OH, -C(=O)OR6, -C(=O)-NHCN, -C(=O)- NHOH, -SO2-NH2, -SO2-OH, -SO2-NHR6, -SO2-R62, -C(=O)R6, -C(=O)NR6and tetrazolyl,

[0177] R3is selected from , -F, -Cl, -Br, -I, -ON, -CH2F, -CHF2, -CF3and -OH, R7is selected from the group consisting of -N-(Ci-Ce alkyl)2, -NH-(Ci-Ce alkyl), and the group consisting of a heterocycloalkyl comprising at least one heteroatom, wherein one of the at least one heteroatoms is a nitrogen, wherein

[0178] R4is independently selected from the group consisting of H and C-i-6-alkyl,

[0179] R5is selected from a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl;

[0180] R6is selected from a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl; and wherein n is 0, 1 , or 2, particularly 0, p is 0 or 1 ; m is 0 or 1 ,

[0181] Xi and X2 are each selected from N or CH,

[0182] Y and Z are independently selected from C, N, O and S.

[0183] In certain embodiments, Y is C or N.

[0184] In certain embodiments, Y is N.

[0185] In certain embodiments, R6is selected from a substituted or unsubstituted -Ci-Ce-alkyl.

[0186] In certain embodiments, R6is selected from an unsubstituted -Ci-Ce-alkyl.

[0187] In certain embodiments, R6is selected from the group consisting of -Ci-Cs-alkyl.

[0188] In certain embodiments, R5is selected from a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl.

[0189] In certain embodiments, the substituted alkyl, or the substituted aryl, or the substituted heteroaryl, or the substituted cycloalkyl, or the substituted heterocycloalkyl are independently substituted with R10q, wherein R10is independently selected from

[0190] - the group consisting of halogens,

[0191] - the group consisting of substituted or unsubstituted -Ci-Ce alkyl,

[0192] - the group consisting of -O-Ci-Ce alkyls,

[0193] - the group consisting of -CN, -C(=O)OH, -C(=O)H, -C(=O)NR122, -C(=O)O-Ci-C6alkyl, - Ci-C6-alkyl-OH, -CH2F, -CHF2, -CF3, -C(=O)-CF3, and -NR122, wherein R12is independently selected from H and Ci-6-alkyl, and wherein q is independently selected from 1 , 2, 3, 4 and 5. In certain embodiments, the substituted aryl is substituted with R10q, wherein R10is selected from

[0194] - the group consisting of -O-Ci-Ce alkyls,

[0195] - the group consisting of -CN, -C(=O)OH, -C(=O)H, -C(=O)NR122, -C(=O)O-Ci-C6alkyl, - Ci-Ce-alkyl-OH, -CH2F, -CHF2, -CF3, -C(=O)-CF3, and -NR122, wherein R12is independently selected from H and Ci-Ce-alkyl and wherein q is independently selected from 1 , 2, 3, 4 and 5.

[0196] In certain embodiments, the substituted alkyl, or the substituted heteroaryl, or the substituted cycloalkyl, or the substituted heterocycloalkyl are independently substituted with R10q, wherein R10is independently selected from

[0197] - the group consisting of halogens,

[0198] - the group consisting of substituted or unsubstituted -Ci-Ce alkyl,

[0199] - the group consisting of -O-Ci-Ce alkyls,

[0200] - the group consisting of -CN, -C(=O)OH, -C(=O)H, -C(=O)NR122, -C(=O)O-Ci-C6alkyl, - Ci-Ce-alkyl-OH, -CH2F, -CHF2, -CF3, -C(=O)-CF3, and -NR122, wherein R12is independently selected from H and Ci-Ce-alkyl and wherein q is independently selected from 1 , 2, 3, 4 and 5.

[0201] In certain embodiments, q is 1 .

[0202] In certain embodiments, the substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, is selected from a Cs to C10 substituted or unsubstituted aryl, or a Cs to C10 substituted or unsubstituted heteroaryl.

[0203] In certain embodiments, the substituted or unsubstituted cycloalkyl, or the substituted or unsubstituted heterocycloalkyl is selected from a C3to C10 substituted or unsubstituted cycloalkyl, or a C3to C12 substituted or unsubstituted heterocycloalkyl. In certain embodiments, the compound of formula (I) or (II) is for use in the treatment of multiple sclerosis.

[0204] In certain embodiments, compound for use in the treatment of multiple sclerosis and neurodegenerative diseases, in particular multiple sclerosis according to any of the preceding claims, wherein the compound is selected from compounds (I), (II), (III), and (IV)

[0205]

[0206] In certain embodiments, the compound for use in the treatment of multiple sclerosis and neurodegenerative diseases, in particular multiple sclerosis according to any of the preceding claims, wherein the compound is

[0207] Medical treatment

[0208] Similarly, within the scope of the present invention is a method or treating multiple sclerosis and neurodegenerative diseases in a patient in need thereof, comprising administering to the patient a compound according to the above description.

[0209] Pharmaceutical Compositions, Administration / Dosaqe Forms and Salts

[0210] According to one aspect of the compound according to the invention, the compound according to the invention is provided as a pharmaceutical composition, pharmaceutical administration form, or pharmaceutical dosage form, said pharmaceutical composition, pharmaceutical administration form, or pharmaceutical dosage form comprising at least one of the compounds of the present invention or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, diluent or excipient.

[0211] The skilled person is aware that any specifically mentioned drug compound mentioned herein may be present as a pharmaceutically acceptable salt of said drug. Pharmaceutically acceptable salts comprise the ionized drug and an oppositely charged counterion. Non-limiting examples of pharmaceutically acceptable anionic salt forms include acetate, benzoate, besylate, bitatrate, bromide, carbonate, chloride, citrate, edetate, edisylate, embonate, estolate, fumarate, gluceptate, gluconate, hydrobromide, hydrochloride, iodide, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl bromide, methyl sulfate, mucate, napsylate, nitrate, pamoate, phosphate, diphosphate, salicylate, disalicylate, stearate, succinate, sulfate, tartrate, tosylate, triethiodide and valerate. Non-limiting examples of pharmaceutically acceptable cationic salt forms include aluminium, benzathine, calcium, ethylene diamine, lysine, magnesium, meglumine, potassium, procaine, sodium, tromethamine and zinc.

[0212] In certain embodiments of the invention, the compound of the present invention is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to give the patient an elegant and easily handleable product.

[0213] The invention further encompasses a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0214] Certain embodiments of the invention relate to a dosage form for enteral administration, such as nasal, buccal, rectal, transdermal or oral administration, or suppository. In addition, the pharmaceutical compositions of the present invention can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders, or suppositories), or in a liquid form (including without limitation solutions, suspensions or emulsions).

[0215] Certain embodiments of the invention relate to a dosage form for parenteral administration, such as subcutaneous, intravenous, intrahepatic or intramuscular injection forms. Optionally, a pharmaceutically acceptable carrier and / or excipient may be present.

[0216] The dosage regimen for the compounds of the present invention will vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired. In certain embodiments, the compounds of the invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.

[0217] In certain embodiments, the pharmaceutical composition or combination of the present invention can be in unit dosage of about 0.01-1000 mg of active ingredient(s) for a subject of about 50-70 kg. The therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof, is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.

[0218] The pharmaceutical compositions of the present invention can be subjected to conventional pharmaceutical operations such as sterilization and / or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc. They may be produced by standard processes, for instance by conventional mixing, granulating, dissolving or lyophilizing processes. Many such procedures and methods for preparing pharmaceutical compositions are known in the art, see for example L. Lachman et al. The Theory and Practice of Industrial Pharmacy, 4th Ed, 2013 (ISBN 8123922892).

[0219] Method of Manufacture and Method of Treatment according to the invention

[0220] The invention further encompasses, as an additional aspect, the use of a compound as identified herein, or its pharmaceutically acceptable salt, as specified in detail above, for use in a method of manufacture of a medicament for the treatment or prevention of multiple sclerosis and neurodegenerative diseases, in particular multiple sclerosis.

[0221] Similarly, the invention encompasses methods of treatment of a patient having been diagnosed with a disease associated with multiple sclerosis and neurodegenerative diseases, such as Marburg Variant of MS (Marburg MS), Acquired Demyelinating Syndromes (ADS), MOG antibody disease, Neuromyelitis Optica (NMO) or Neuromyelitis Optica Spectrum Disorder (NMOSD) , Acute Disseminated Encephalomyelitis (ADEM), Lupus (Systemic Lupus Erythematosus), Susac Syndrome, Tumefactive MS. This method entails administering to the patient an effective amount of a compound as identified herein, or its pharmaceutically acceptable salt, as specified in detail herein.

[0222] Wherever alternatives for single separable features are laid out herein as “embodiments”, it is to be understood that such alternatives may be combined freely to form discrete embodiments of the invention disclosed herein.

[0223] The invention is further illustrated by the following examples and figures, from which further embodiments and advantages can be drawn. These examples are meant to illustrate the invention but not to limit its scope.

[0224] Description of the Figures

[0225] Fig. 1 shows in vitro assays of activation of human monocytes with an agonist of the CLR pathway (beta-scleroglucan) in increasing concentrations (up to 100 pg / mL) to identify the EC50 and EC90 based on two downstream functional molecules CD80 and CCR7.

[0226] Fig. 2 shows the percentage of inhibition using increasing concentrations of CARD9 inhibitor

[0227] 2-(4'-carbamoyl-[1 ,4'-bipiperidin]-1 '-yl)-5-(4-methylbenzamido)nicotinic acid (from 0.5pM to 200 pM) on activated human monocytes (with based beta-scleroglucan) on EC50 / EC90

[0228] Fig. 3 shows the in vivo treatment of C57BL / 6 mice with EAE which were treated with three concentrations of CARD9 inhibitor 2-(4'-carbamoyl-[1 ,4'-bipiperidin]-1 '-yl)-5-(4- methylbenzamido)nicotinic acid before onset of symptoms. The mice did not develop symptoms until peak disease (day16); x-axis: days post induction; y-axis: median clinical score.

[0229] Fig. 4 shows the in vivo treatment of C57BL / 6 mice with EAE which were treated every 5 days with CARD9 inhibitor 2-(4'-carbamoyl-[1 ,4'-bipiperidin]-1 '-yl)-5-(4- methylbenzamido)nicotinic acid at onset of disease and were monitored until day 28 and did not develop severe clinical symptoms; x-axis: days post induction; y-axis: median clinical score.

[0230] Fig.5 shows the in vivo treatment of SJL mice with EAE which were treated with three concentrations of CARD9 inhibitor 2-(4'-carbamoyl-[1 ,4'-bipiperidin]-1 '-yl)-5-(4- methylbenzamido)nicotinic acid before onset of symptoms. The mice did not develop severe symptoms; x-axis: days post induction; y-axis: median clinical score.

[0231] Fig. 6 shows a dose response curve for activation of HEK-Blue cells with increasing concentration of TBD; x-axis: TBD concentration (pg / ml); y-axis: OD (640 nm).

[0232] Fig. 7 shows a dose response curve for inhibition of mincle pathway on cells activated with

[0233] TBD (100 pg / ml) and increasing concentrations of 2-(4'-carbamoyl-[1 ,4'-bipiperidin]-1 '- yl)-5-(4-methylbenzamido)nicotinic acid; x-axis: inhibitor concentration (pg / ml); y-axis: OD (640 nm).

[0234] Fig. 8 shows a dose response curve for inhibition of mincle pathway on cells activated with

[0235] TBD (100 pg / ml) and increasing concentrations of 5-(2-chlorobenzamido)-2-(4- (pyrrolidin-1 -ylmethyl)piperidin-1 -yl)nicotinic acid; x-axis: inhibitor concentration (pg / ml); y-axis: OD (640 nm).

[0236] Fig. 9. shows a dose response curve for inhibition of mincle pathway on cells activated with

[0237] TBD (100 pg / ml) and increasing concentrations of methyl 5-(2-chlorobenzamido)-2-(4- (pyrrolidin-1 -ylmethyl)piperidin-1 -yl)nicotinate; x-axis: inhibitor concentration (pg / ml); y- axis: OD (640 nm).

[0238] Fig. 10 shows a dose response curve for inhibition of mincle pathway on cells activated with TBD (100 pg / ml) and increasing concentrations of methyl 5-pentanamido-2-(4- (pyrrolidin-1 -ylmethyl)piperidin-1 -yl)nicotinate; x-axis: inhibitor concentration (pg / ml); y- axis: OD (640 nm).

[0239] Examples

[0240] Example 1 : Induction of Experimental Autoimmune Encephalomyelitis (EAE)

[0241] Preparation of Peptide Stock Solution

[0242] A stock solution of MOG35-55 peptide was prepared at a concentration of 5mg / mL. Initially, 30 mg of MOG 35-55 (GenScript Cat. No. RP10245) was dissolved in 1 mL of deionized water. Subsequently, an additional 5 mL of deionized water was added to the solution, ensuring a clear and transparent solution indicative of complete dissolution. The solution was aliquoted into 500 pL volumes and stored at -80°C until further use.

[0243] Preparation of CFA+ Adjuvant Solution

[0244] The adjuvant solution was formulated by suspending 25 mg of desiccated Mycobacteria tuberculosis H37 Ra (avirulent, disssecated) (BD™ 264011 ; DF31 14-33-8, Thermo Fisher) in 10 mL of Complete Freund’s Adjuvant (BD™ 231131 ; DF3113-60-5, Thermo Fisher), achieving a final concentration of 2.5 mg / mL. This suspension was stored at 4°C. Prior to use, the suspension was vigorously mixed to redistribute any settled particles.

[0245] Preparation of MOG35-55 / CFA Emulsion for Immunization

[0246] For the immunization procedure, the final emulsion volume is composed of an equal ratio of the two components. The MOG35-55 stock solution was diluted with Phosphate-Buffered Saline (PBS) to a final concentration of 1 mg / mL, and was pipetted into a syringe. An equal volume of the previously prepared CFA+ adjuvant solution with M. tuberculosis was pipetted into another syringe. The two solutions then were then emulsified by transferring between two syringes connected by a metal adaptor, ensuring a homogenous and white emulsion without air bubbles.

[0247] Calculation for Emulsion Volume

[0248] The final volume for immunization was calculated based on the number of animals. For instance, for 10 mice, a total volume of 2 mL of the emulsion was required (200 pL per mouse). The emulsion was composed of equal volumes of MOG35-55 in PBS and CFA+. To achieve the final concentration of 1 mg / mL MOG35-55 in the emulsion, 400 pL of the 5 mg / mL MOG35-55 stock solution was diluted with 600 pL PBS. The volume of CFA+ adjuvant solution was adjusted accordingly to maintain the volume ratio.

[0249] Experimental Autoimmune Encephalomyelitis (EAE) Induction

[0250] Animals were anesthetized using isoflurane (SOP-LTK-TRT-13-EN Isoflurane anesthesia) and weighed prior to the immunization procedure. The MOG35-55 / CFA emulsion was administered subcutaneously at two sites on either side of the midline on the lower back, with each site receiving 100pL of the emulsion. Immediately following the emulsion injection, 100 pL of Pertussis Toxin (BioLabs, #179B) was administered intraperitoneally (SOP-LTK-TRT-10-EN ip injection). The anesthetization, weighing and intraperitoneal Pertussis Toxin administration was repeated on day 2 post-immunization.

[0251] Subcutaneous Injection

[0252] Animals were housed in cages and placed under a laminar flow hood or at a changing station. For immobilization, the mouse was gently restrained on the cage grid, allowing it to grasp the grid with its paws. The mouse was then moderately pressed down with one hand while using the forefinger and thumb of the same hand to lift the skin on the back. Subcutaneous injections were performed either above the scapular region or on the flank, ensuring the needle was inserted well below the fingers and parallel to the mouse's body to avoid damage to underlying structures. The injectate was administered slowly, and upon withdrawal of the needle, the injection site was observed for leakage. Presence of a bleb indicated successful injection. The mouse was then returned to its cage.

[0253] Intraperitoneal Injection

[0254] Mice were similarly placed under a laminar flow hood. Each mouse was restrained by one hand, with additional support by restraining one hind limb to prevent movement during injection. The mouse was positioned to expose the ventral side, tilting the head downward. The injection needle was inserted at a 30-degree angle into the lower right abdomen, avoiding blood vessels and intestines, as indicated by aspiration before injection. Following a clear aspiration test, the injectate was administered. Postinjection, the mouse was observed for distress or trauma signs before being returned to its housing.

[0255] Isoflurane anaesthesia

[0256] Prior to anaesthesia, the oxygen supply was checked to ensure adequacy for the experiment's duration, calculated as the product of pressure (in bar) and the volume of the oxygen bottle (in Liters). The coal filter's weight was verified against its usage limit; a filter exceeding this limit was replaced to prevent anaesthetic agent accumulation. The evacuation pump's functionality and the level of isoflurane were also checked, with refills made as necessary. After ensuring all connections were secure and setting the vaporizer to 0%, oxygen supply and gas flow to the vaporizer were initiated at 1000 ml / min. For induction, the vaporizer was set to 5%, and the animal placed in the induction chamber for 2-3 minutes until the loss of the righting reflex was observed. Maintenance of anaesthesia was achieved by adjusting the vaporizer to 2% and the gas flow to 650 ml / min. The animal was then placed on the nose cone for the procedure, with immediate activation of the coal filter's evacuation pump.

[0257] Example 2: Treatment of EAE mice

[0258] The treatment protocol for Experimental Autoimmune Encephalomyelitis (EAE) mice involves several key steps to ensure the effective administration and monitoring of effects of test compound 2-(4'- carbamoyl-[1 ,4'-bipiperidin]-1 '-yl)-5-(4-methylbenzamido)nicotinic acid. First, a stock solution of 2-(4'- carbamoyl-[1 ,4'-bipiperidin]-1 '-yl)-5-(4-methylbenzamido)nicotinic acid is prepared at a concentration of 2mg / mL in DMSO, with a final treatment concentration of 200 pM (or 46.5 pg / kg) utilized for the experiments.

[0259] To prepare the working solution, 4.65 pL of the stock solution of test compound 2-(4'-carbamoyl-[1 ,4'- bipiperidin]-1 '-yl)-5-(4-methylbenzamido)nicotinic acid is diluted in PBS to a total volume of 1 mL. Subsequently, 100 pL of the prepared solution is administered per 25g mouse via intraperitoneal injection (ip), resulting in the desired treatment concentration.

[0260] Two treatment schedules are outlined: prophylactic and therapeutic. Prophylactic treatment involves administering the compound at day 0, 1 , and 2 following EAE induction, with continued observation and scoring until day 15 (disease peak day). Therapeutic treatment options include administering the compound at day 7, 8, and 9 after EAE induction, or initiating treatment at day 8 and continuing every 5 days, and continue observation and clinical scoring until day 28, representing the full course of EAE.

[0261] DMSO concentration in the injection should not exceed 10% per mouse to avoid any adverse effects.

[0262] In summary, the treatment protocol provides a structured approach for administering test compounds such as 2-(4'-carbamoyl-[1 ,4'-bipiperidin]-1 '-yl)-5-(4-methylbenzamido)nicotinic acid to EAE-induced mice, aiming to assess its prophylactic and therapeutic effects on disease progression. Example 3: In vitro assays for identifying EC50 and EC90 values of agonist beta-scleroglucan

[0263] Initially, human monocytes are isolated from Buffy coat samples using the EasySep™ HLA Chimerism Buffy Coat CD14 Positive Selection Kit, following manufacturer's instructions. Once isolated, the monocytes are suspended in tissue culture medium (RPMI supplemented with 10% fetal bovine serum (FBS) and Penicillin-Streptomycin (Pen-Strep, 100 U / ml - 100 pg / ml), Stimulating agents (beta- Scleroglucan 1 mg / ml), Fluorescence-conjugated human antibodies for flow cytometry staining (CD14 - BV785, CD16 - BV605, CD80 - PeCy7, CD86 - Pacific Blue, CCR7 - BV650, Live / Dead marker - Zombie Aqua / Amcyan)) at a concentration of 1x106cells / ml. To set up the stimulation flat-bottom plate, 10Oul of the stimulating agent beta-scleroglucan, prepared at a concentration of 1 mg / ml, is added to the 12thcolumn wells, and a subsequent two-fold serial dilution is performed until the 2nd column wells. Unstimulated controls with only medium are also included. The plates are then incubated for 24 hours at 37°C in a a humidified atmosphere with 5% CO2 incubator.

[0264] After the incubation period, the contents of the wells are transferred to u-bottomed plates for flow cytometry staining. Fluorescence-conjugated human antibodies specific for CD14, CD16, CD80, CD86, CCR7, and a Live / Dead marker are used for staining in MACS buffer. The stained cells are analysed using flow cytometer LSR II Fortessa 4L, to assess cellular responses to the stimuli.

[0265] Data analysis involves quantifying the fluorescence intensity of stained cells using the FlowJo software. Mean fluorescence intensity (MFI) or the percentage of positive cells is calculated to evaluate cellular activation. This protocol ensures the reproducibility and reliability of in vitro assays for identifying the EC50 and EC90 of beta-scleroglucan in human monocytes.

[0266] Figures 3, 4 and 5 illustrate the clinical course of EAE development in C57BL / 6 and SJL mice treated with 2-(4'-carbamoyl-[1 ,4'-bipiperidin]-1 '-yl)-5-(4-methylbenzamido)nicotinic acid compared to vehicle / Saline control groups. The investigation was performed to assess the efficacy of 2-(4'- carbamoyl-[1 ,4'-bipiperidin]-1 '-yl)-5-(4-methylbenzamido)nicotinic acid in preventing or ameliorating EAE symptoms. In Group A (Fig. 3), C57BL / 6 mice received ip a single concentration of 2-(4'-carbamoyl- [1 ,4'-bipiperidin]-1 '-yl)-5-(4-methylbenzamido)nicotinic acid for three consecutive days at the beginning of EAE induction, namely day 0, 1 and 2 (24 hours apart). Remarkably, mice treated with 2-(4'- carbamoyl-[1 ,4'-bipiperidin]-1 '-yl)-5-(4-methylbenzamido)nicotinic acid did not exhibit clinical symptoms until peak disease of EAE (day 16). In Group B (Fig. 4), mice were treated ip every 5 days with one concentration of 2-(4'-carbamoyl-[1 ,4'-bipiperidin]-1 '-yl)-5-(4-methylbenzamido)nicotinic acid starting at the onset of disease (day 8). Notably, these mice showed a significant delay in the onset of symptoms and did not develop severe clinical manifestations compared to the vehicle control group. In Group C (Fig. 5), SJL mice treated ip with a single concentration of 2-(4'-carbamoyl-[1 ,4'-bipiperidin]-1 '-yl)-5-(4- methylbenzamido)nicotinic acid at the onset of symptoms for three consecutive days (day 7, 8 and 9) demonstrated a marked reduction in disease severity. These mice did not develop severe symptoms characteristic of EAE until the end of disease course (day 28). Overall, the results indicate that 2-(4'- carbamoyl-[1 ,4'-bipiperidin]-1 '-yl)-5-(4-methylbenzamido)nicotinic acid treatment effectively attenuates the clinical symptoms of EAE in both C57BL / 6 and SJL mouse models. These findings suggest the potential therapeutic utility of 2-(4'-carbamoyl-[1 ,4'-bipiperidin]-1 '-yl)-5-(4-methylbenzamido)nicotinic acid in the treatment of the animal model of Multiple Sclerosis and further assessment of concentrations, routs of administration and doses could be performed leading to a better drug development for MS.

[0267] Example 4: In vitro assays of inhibition with human monocytes isolated from Buffy Coat

[0268] Human monocytes are isolated from Buffy coat samples using the EasySep™ HLA Chimerism Buffy Coat CD14 Positive Selection Kit, following manufacturer's instructions. The isolated monocytes are then suspended in tissue culture medium (RPMI supplemented with 10% fetal bovine serum (FBS), Penicillin-Streptomycin (Pen-Strep, 100 U / ml - 100 pg / ml), Stimulating agents (beta-Scleroglucan 1 mg / ml), Fluorescence-conjugated human antibodies for flow cytometry staining (CD14 - BV785, CD16 - BV605, CD80 - PeCy7, CD86 - Pacific Blue, CCR7 - BV650, Live / Dead marker - Zombie Aqua / Amcyan), supplemented with 0.1 % DMSO, at a concentration of 1x106cells / ml, so when taken 100 ul from that suspension equals with 1x105monocytes per well. All the wells are plated with 100 ul of the cell suspension, except the 12 column wells, in a flat-bottom well plate.

[0269] To prepare the monocyte suspension for experimentation, a CARD9 inhibitor, 2-(4'-carbamoyl-[1 ,4'- bipiperidin]-1 '-yl)-5-(4-methylbenzamido)nicotinic acid, is added from a 200 mM stock solution to achieve a final concentration of 200 uM, with 0.1 % DMSO. This corresponds to the top concentration and is plated with 200ul in the 12thcolumn wells. Serial dilutions of 2-(4'-carbamoyl-[1 ,4'-bipiperidin]-1 '- yl)-5-(4-methylbenzamido)nicotinic acid are performed along the plate, starting from the 12thcolumn wells until 2ndcolumn wells, to establish a dose-response curve. Meanwhile, the stimulating agent beta- scleroglucan is prepared in a separate flat-bottom well plate, at two concentrations: EC50 (1 pg / ml) and EC90 (5 pg / ml), both at 2X concentration.

[0270] After a 60-minute incubation period with the inhibitor, the monocyte suspension is combined with the beta-scleroglucan stimulant plate and incubated for 24 hours. Subsequently, the contents of the wells are transferred to u-bottomed plates for flow cytometry staining. Fluorescence-conjugated human antibodies targeting CD14, CD16, CD80, CD86, CCR7, and a Live / Dead marker are used for staining.

[0271] The stained cells are then analysed using flow cytometer LSR II Fortessa 4L to assess cellular responses to the stimuli. Data analysis involves quantifying the fluorescence intensity of stained cells and calculating the mean fluorescence intensity (MFI) or percentage of positive cells to evaluate cellular activation or inhibition. Additionally, the significance of observed differences between experimental groups is determined.

[0272] For both the flow cytometry stainings using fluorescence-conjugated human antibodies according to standard protocols in MACS buffer the following dilutions were used: Example 4: In vitro assay of Hek-Blue-mMincle

[0273] The procedure involves cell culture and maintenance of the cell line as per manufacturer’s instructions; briefly, involving thawing the Hek-Blue-mMincle cells (Invivogen), transferring them to growth medium (Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum (FBS), Penicillin-Streptomycin (Pen-Strep, 100 U / ml - 100 pg / ml), Normocin™ (100 pg / ml), and 2 mM L- glutamine), and incubating them in a tissue culture flask for several days at 37 °C in 5% CO2. Frozen stocks are prepared for long-term storage, to ensure continuation of the cell line in the lab.

[0274] Next, the reporter assay setup entails preparing the HEK-Blue™ Detection medium, as per the manufacturer's instructions, then adding 20 pl of each test compound (2-(4'-carbamoyl-[1 ,4'-bipiperidin]- 1 '-yl)-5-(4-methylbenzamido)nicotinic acid, 5-(2-chlorobenzamido)-2-(4-(pyrrolidin-1-ylmethyl)piperidin- 1 -yl)nicotinic acid, methyl 5-(2-chlorobenzamido)-2-(4-(pyrrolidin-1-ylmethyl)piperidin-1-yl)nicotinate, and methyl 5-pentanamido-2-(4-(pyrrolidin-1-ylmethyl)piperidin-1-yl)nicotinate in a two-fold serial dilution, with 0.1 % DMSO as the vehicle control to a flat-bottom 96-well plate. When test-compound- plate is ready, Hek-blue mMIncle cells are detached from the flask and resuspended at concentration of cell suspension -280,000 cells / ml in HEK-Blue™ Detection medium, and lastly added with 180 pl of cell suspension per well. The plate is then incubated at 37 °C in 5% CO2 for 16-24 hours.

[0275] Detection of the reporter protein involves observing hydrolysis of the SEAP substrate in the culture medium visually and measuring it using a spectrophotometer at a 640 nm wavelength. Data analysis includes evaluating SEAP substrate hydrolysis data to assess the response of Hek-Blue-mMincle cells to test compounds, comparing their response with positive (e.g. TDB at 100 pg / ml) and negative (Sterile endotoxin-free water) controls, calculating IC50 values and perform comparisons as appropriate.

[0276] It is crucial to perform all steps under sterile conditions and avoid the use of trypsin for cell detachment to prevent alterations in cell response.

[0277] Figures 7 to 10 illustrate the dose-response curves for activating or inhibiting the Mincle Pathway and by extension CARD9 as it is a downstream adaptor molecule of Mincle receptor. The dose-response effects of compounds targeting the Mincle pathway were investigated, specifically focusing on their inhibitory properties using Hek-Blue mMincle cells stimulated with Trehalose-6,6-dibehenate (TDB). First step was to establish the activation and subsequent release of SEAP with TDB agonist; thus, a dose-response curve was generated for the activation of Hek-Blue mMincle cells with increasing concentrations of TDB. The curve (Fig. 7) depicts the relationship between TDB concentration and the activation level of Hek-Blue mMincle cells. After having established a robust activation, evaluation of the inhibitory effect of (2-(4'-carbamoyl-[1 ,4'-bipiperidin]-1 '-yl)-5-(4-methylbenzamido)nicotinic acid, 5-(2- chlorobenzamido)-2-(4-(pyrrolidin-1-ylmethyl)piperidin-1-yl)nicotinic acid, methyl 5-(2- chlorobenzamido)-2-(4-(pyrrolidin-1-ylmethyl)piperidin-1-yl)nicotinate, and methyl 5-pentanamido-2-(4- (pyrrolidin-1 -ylmethyl)piperidin-1 -yl)nicotinate on the Mincle / Card9 pathway was employed, where Hek- Blue mMincle cells were activated with TDB (100 pg / mL) and treated with increasing concentrations of the different compounds. The resulting dose-response curves (Fig. 8 to 10) illustrate the concentration- dependent inhibition by these compounds. In all curves, it can be observed that inhibition of the pathway takes place, with some of them having a more stipe effect and others milder. This assay serves as a confirmation that not only (2-(4'-carbamoyl-[1 ,4'-bipiperidin]-1 '-yl)-5-(4-methylbenzamido)nicotinic acid but other compounds using the same backbone could be potential candidates for further clinical development. These dose-response curves provide valuable insights into the pharmacological properties of compounds targeting the Mincle / CARD9 pathway and offer a basis for further identification, characterization, and optimization of potential therapeutic agents for the treatment of autoimmune diseases and their animal models such as Multiple Sclerosis and EAE, respectively.

[0278] Cited prior art documents:

[0279] 1 . Qin, Xing, et al. "Caspase recruitment domain-containing protein 9 (CARD9) knockout reduces regional ischemia / reperfusion injury through an attenuated inflammatory response." PLoS One 13.6 (2018): e0199711.

[0280] 2. Liu, Xuanyou, et al. "CARD9 signaling, inflammation, and diseases." Frontiers in Immunology 13 (2022): 880879.

[0281] 3. Drummond, Rebecca A., et al. "CARD9+ microglia promote antifungal immunity via IL-1 p-and CXCL1 -mediated neutrophil recruitment." Nature immunology 20.5 (2019): 559-570.

[0282] 4. Leshchiner, Elizaveta S., et al. "Small-molecule inhibitors directly target CARD9 and mimic its protective variant in inflammatory bowel disease." Proceedings of the National Academy of Sciences 114.43 (2017): 11392-11397.

[0283] 5. Danne, Camille, et al. "CARD9 in neutrophils protects from colitis and controls mitochondrial metabolism and cell survival." Gut 72.6 (2023): 1081-1092.

[0284] 6. N’diaye, Marie, et al. "C-type lectin receptors Mcl and Mincle control development of multiple sclerosis-like neuroinflammation." The Journal of Clinical Investigation 130.2 (2020): 838-852.

[0285] 7. Thiem, K. et al. Deletion of haematopoietic Dectin-2 or CARD9 does not protect from atherosclerosis development under hypergly- caemic conditions. Diab. Vase. Dis. Res.

[0286] 8. Zhang, Yujiao, et al. "Genetic inhibition of CARD9 accelerates the development of atherosclerosis in mice through CD36 dependent-defective autophagy." Nature Communications 14.1 (2023): 4622.

[0287] 9. Ennerfelt, Hannah, et al. "CARD9 attenuates Ap pathology and modifies microglial responses in an Alzheimer’s disease mouse model." Proceedings of the National Academy of Sciences 120.24 (2023): e2303760120.

[0288] 10. Liu, Xuanyou, et al. "CARD9-mediated signaling and cardiovascular diseases." Basic to Translational Science 7.4 (2022): 406-409.

[0289] 11. WO 2019 / 067530 A1 ; Broad Institute Inc., Massachusetts General Hospital, Harvard College US, 2019.

[0290] 12. WO 2020 / 163715 A1 ; Cedars Sinai Medical Center US, 2020.

[0291] All scientific publications and patent documents cited in the present specification are incorporated by reference herein.

Claims

Claims1 . A compound of formula (I) or (II) for use in the treatment of multiple sclerosis and neurodegenerative diseases, in particular multiple sclerosiswherein,R1is selected from the group consisting of -NR4C(=O)R4, -NR4C(=O)R5, -NR4C(=O)OR4, - NR4C(=O)OR5, -C(=O)NR4R5, -C(=O)NR42, -C(=O)R4, -C(=O)R5, -OR4, -OR5, -Ci-C6-alkyl-OH, -C(=O)-CF3, a substituted or unsubstituted aryl, and a substituted or unsubstituted heteroaryl,R2is selected from the group consisting of -C(=O)OH, -C(=O)OR6, -C(=O)-NHCN, -C(=O)- NHOH, -SO2-NH2, -SO2-OH, -SO2-NHR6, -SO2-R62, -C(=O)R6, -C(=O)NR6and tetrazolyl,R3is selected from , -F, -Cl, -Br, -I, -ON, -CH2F, -CHF2, -CF3and -OH,R7is selected from the group consisting of -N-(Ci-Ce alkyl)2, -NH-(Ci-Ce alkyl), and the group consisting of a heterocycloalkyl comprising at least one heteroatom, wherein one of the at least one heteroatoms is a nitrogen,R8is selected from the group consisting of -C(=O)NH2, -C(=O)NHR9, -C(=O)NR92, -C(=O)OH, - C(=O)OR9, -SO2-NHR9, -SO2-R92, -SO2-NH2, -SO2-OH, whereinR4is independently selected from the group consisting of H and C-i-6-alkyl,R5is selected from a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl;R6is selected from a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, particularly R6is selected from a substituted or unsubstituted -Ci-Ce-alkyl, more particularly R6is selected from an unsubstituted -Ci-Ce-alkyl;R9is selected from the group consisting of C 1-6-alky I and wherein n is 0, 1 , or 2, particularly 0, p is 0 or 1 ; m is 0 or 1 ,Xi and X2 are each selected from N or CH,Y and Z are independently selected from C, N, O and S.

2. The compound for use in the treatment of multiple sclerosis and neurodegenerative diseases, in particular multiple sclerosis according to claim 1 , wherein R1is selected from the group consisting of -NR4C(=O)R5, -NR4C(=O)OR5, -C(=O)NR4R5and -C(=O)R5, wherein R4and R5are defined as above.

3. The compound for use in the treatment of multiple sclerosis and neurodegenerative diseases, in particular multiple sclerosis according to any of the preceding claims, wherein R2is selected from the group consisting of -C(=O)OH, -C(=O)OR6-C(=O)R6, -C(=O)NR6, -SO2-NHR6, -SO2- R62, wherein R6is defined as above.

4. The compound for use in the treatment of multiple sclerosis and neurodegenerative diseases, in particular multiple sclerosis according to any of the preceding claims wherein the compound is of formula (la) or (Ila)whereinR1is selected from the group consisting of -NR4C(=O)R5, -NR4C(=O)OR5, -C(=O)NR4R5and - C(=O)R5;R2is selected from the group consisting of -C(=O)OH, -C(=O)OR6, -C(=O)R6, -C(=O)NR6, -SO2- NHR6, -SO2-R62;R7is selected from the group consisting of -N-(Ci-Ce alkyl)2, and the group consisting of a heterocycloalkyl comprising at least one heteroatom, wherein one of the at least one heteroatoms is a nitrogen,R8is selected from the group consisting of -C(=O)NH2, -C(=O)NHR9, -C(=O)NR92, -C(=O)OH, - C(=O)OR9, whereinR4is independently selected from the group consisting of H and -Ci-Ce-alkyl;R5is selected from a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl;R6is selected from a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, particularly R6is selected from a substituted or unsubstituted -Ci-Ce-alkyl, more particularly R6is selected from an unsubstituted -C1-C6- alkyl;R9is independently selected from the group consisting of -Ci-Ce-alkyl and wherein p is 0 or 1 ; m is 0 or 1 ,Xi and X2 are each selected from C and N;Y and Z are independently selected from C, N, O and S.

5. The compound for use in the treatment of multiple sclerosis and neurodegenerative diseases, in particular multiple sclerosis according to any of the preceding claims wherein the compound is of formula (lb) or (lib)whereinR1is selected from the group consisting of -NR4C(=O)R5, -NR4C(=O)OR5, -C(=O)NR4R5and - C(=O)R5;R2is selected from the group consisting of -C(=O)OH, -C(=O)OR6, -C(=O)R6, -C(=O)NR6, -SO2- NHR6, -SO2-R62;R7is selected from the group consisting of -N-(Ci-Ce alkyl)2, and the group consisting of a heterocycloalkyl comprising at least one heteroatom, wherein one of the at least one heteroatoms is a nitrogen,R8is selected from the group consisting of -C(=O)NH2, -C(=O)NHR9, -C(=O)NR92, -C(=O)OH, - C(=O)OR9, whereinR4is independently selected from the group consisting of H and -Ci-Ce-alkyl;R5is selected from a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl;R6is selected from a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, particularly R6is selected from a substituted or unsubstituted -Ci-Ce-alkyl, more particularly R6is selected from an unsubstituted -C1-C6- alkyl;R9is independently selected from the group consisting of -Ci-Ce-alkyl and whereinp is 0 or 1 ; m is 0 or 1 ,Y is selected from C, N, O and S.

6. The compound for use in the treatment of multiple sclerosis and neurodegenerative diseases, in particular multiple sclerosis, according to claims 1 to 3, is a compound of formula (II)wherein,R1is selected from the group consisting of -NR4C(=O)R4, -NR4C(=O)R5, -NR4C(=O)OR4, - NR4C(=O)OR5, -C(=O)NR4R5, -C(=O)NR42, -C(=O)R4, -C(=O)R5, -OR4, -OR5, -Ci-C6-alkyl-OH, -C(=O)-CF3, a substituted or unsubstituted aryl, and a substituted or unsubstituted heteroaryl,R2is selected from the group consisting of -C(=O)OH, -C(=O)OR6, -C(=O)-NHCN, -C(=O)- NHOH, -SO2-NH2, -SO2-OH, -SO2-NHR6, -SO2-R62, -C(=O)R6, -C(=O)NR6and tetrazolyl,R3is selected from , -F, -Cl, -Br, -I, -ON, -CH2F, -CHF2, -CF3and -OH,R7is selected from the group consisting of -N-(Ci-Ce alkyl)2, -NH-(Ci-Ce alkyl), and the group consisting of a heterocycloalkyl comprising at least one heteroatom, wherein one of the at least one heteroatoms is a nitrogen, whereinR4is independently selected from the group consisting of H and C-i-6-alkyl,R5is selected from a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl;R6is selected from a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, particularly R6is selected from a substituted or unsubstituted -Ci-Ce-alkyl, more particularly R6is selected from an unsubstituted -Ci-Ce-alkyl; and wherein n is 0, 1 , or 2, particularly 0, p is 0 or 1 ; m is 0 or 1 ,Xi and X2 are each selected from N or CH,Y and Z are independently selected from C, N, O and S.

7. The compound for use in the treatment of multiple sclerosis and neurodegenerative diseases, in particular multiple sclerosis according to any of the preceding claims, wherein Y is C or N.

8. The compound for use in the treatment of multiple sclerosis and neurodegenerative diseases, in particular multiple sclerosis according to any of the preceding claims, wherein Y is N.

9. The compound for use in the treatment of multiple sclerosis and neurodegenerative diseases according to any of the preceding claims, wherein the substituted aryl, the substituted alkyl, or the substituted heteroaryl, or the substituted cycloalkyl, or the substituted heterocycloalkyl are independently substituted with R10q, wherein R10is independently selected from- the group consisting of halogens,- the group consisting of substituted or unsubstituted -Ci-Ce alkyl,- the group consisting of -O-Ci-Ce alkyls,- the group consisting of -CN, -C(=O)OH, -C(=O)H, -C(=O)NR122, -C(=O)O-Ci-C6alkyl, - Ci-Ce-alkyl-OH, -CH2F, -CHF2, -CF3, -C(=O)-CF3, and -NR122, wherein R12is independently selected from H and Ci-Ce-alkyl and wherein q is independently selected from 1 , 2, 3, 4 and 5.

10. The compound for use in the treatment of multiple sclerosis and neurodegenerative diseases, in particular multiple sclerosis, according to any of the preceding claims, wherein the substituted aryl is substituted with R10q, wherein R10is selected from- the group consisting of -O-Ci-Ce alkyls,- the group consisting of -CN, -C(=O)OH, -C(=O)H, -C(=O)NR122, -C(=O)O-Ci-C6alkyl, - Ci-Ce-alkyl-OH, -CH2F, -CHF2, -CF3, -C(=O)-CF3, and -NR122, wherein R12is independently selected from H and Ci-Ce-alkyl and wherein q is independently selected from 1 , 2, 3, 4 and 5, particularly wherein q is 1 .

11. The compound for use in the treatment of multiple sclerosis and neurodegenerative diseases, in particular multiple sclerosis, according to any of the preceding claims, wherein the substituted alkyl, or the substituted heteroaryl, or the substituted cycloalkyl, or the substituted heterocycloalkyl are independently substituted with R10q, wherein R10is independently selected from- the group consisting of halogens,- the group consisting of substituted or unsubstituted -Ci-Ce alkyl,- the group consisting of -O-Ci-Ce alkyls,- the group consisting of -CN, -C(=O)OH, -C(=O)H, -C(=O)NR122, -C(=O)O-Ci-C6alkyl, - Ci-C6-alkyl-OH, -CH2F, -CHF2, -CF3, -C(=O)-CF3, and -NR122, wherein R12is independently selected from H and Ci-Ce-alkyl and wherein q is independently selected from 1 , 2, 3, 4 and 5, particularly wherein q is 1 .

12. The compound for use in the treatment of multiple sclerosis and neurodegenerative diseases, in particular multiple sclerosis, according to any of the preceding claims, wherein the substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, is selected from aCs to C10 substituted or unsubstituted aryl, or a C5 to C10 substituted or unsubstituted heteroaryl.

13. The compound for use in the treatment of multiple sclerosis and neurodegenerative diseases, in particular multiple sclerosis according to any of the preceding claims, wherein the substituted or unsubstituted cycloalkyl, or the substituted or unsubstituted heterocycloalkyl is selected from a C3 to C10 substituted or unsubstituted cycloalkyl, or a C3 to C12 substituted or unsubstituted heterocycloalkyl.

14. The compound for use in the treatment of multiple sclerosis and neurodegenerative diseases, in particular multiple sclerosis according to any of the preceding claims, wherein the compound is selected from compounds (I), (II), (III), and (IV)15. The compound for use in the treatment of multiple sclerosis and neurodegenerative diseases, in particular multiple sclerosis according to any of the preceding claims, wherein the compound is16. A compound of formula (I) or (II), particularly of formula (II)wherein,R1is selected from the group consisting of -NR4C(=O)R4, -NR4C(=O)R5, -NR4C(=O)OR4, - NR4C(=O)OR5, -C(=O)NR4R5, -C(=O)NR42, -C(=O)R4, -C(=O)R5, -OR4, -OR5, -Ci-Ce-alkyl-OH, -C(=O)-CF3, a substituted or unsubstituted aryl, and a substituted or unsubstituted heteroaryl,R2is selected from the group consisting of -C(=O)OH, -C(=O)OR6, -C(=O)-NHCN, -C(=O)- NHOH, -SO2-NH2, -SO2-OH, -SO2-NHR6, -SO2-R62, -C(=O)R6, -C(=O)NR6and tetrazolyl,R3is selected from , -F, -Cl, -Br, -I, -ON, -CH2F, -CHF2, -CF3and -OH,R7is selected from the group consisting of -N-(Ci-Ce alkyl)2, -NH-(Ci-Ce alkyl), and the group consisting of a heterocycloalkyl comprising at least one heteroatom, wherein one of the at least one heteroatoms is a nitrogen,R8is selected from the group consisting of -C(=O)NH2, -C(=O)NHR9, -C(=O)NR92, -C(=O)OH, - C(=O)OR9, -SO2-NHR9, -SO2-R92, -SO2-NH2, -SO2-OH, whereinR4is independently selected from the group consisting of H and C-i-6-alkyl,R5is selected from a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl;R6is selected from a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, particularly R6is selected from a substituted or unsubstituted -Ci-Ce-alkyl, more particularly R6is selected from an unsubstituted -Ci-Ce-alkyl;R9is selected from the group consisting of C 1-6-alky I and wherein n is 0, 1 , or 2, particularly 0, p is 0 or 1 ; m is 0 or 1 ,Xi and X2 are each selected from N or CH,Y and Z are independently selected from C, N, O and S, wherein the compound does not include any of the following formulaes17. The compound according to claim 16, wherein R1is selected from the group consisting of - NR4C(=O)R5, -NR4C(=O)OR5, -C(=O)NR4R5and -C(=O)R5, wherein R4and R5are defined as above.

18. The compound according to any one of claims 16 and 17, wherein R2is selected from the group consisting of -C(=O)OH, -C(=O)OR6-C(=O)R6, -C(=O)NR6, -SO2-NHR6, -SO2-R62, wherein R6is defined as above.

19. The compound according to any one of claims 16 to 18, wherein the compound is of formula (la) or (Ila)whereinR1is selected from the group consisting of -NR4C(=O)R5, -NR4C(=O)OR5, -C(=O)NR4R5and - C(=O)R5;R2is selected from the group consisting of -C(=O)OH, -C(=O)OR6, -C(=O)R6, -C(=O)NR6, -SO2- NHR6, -SO2-R62;R7is selected from the group consisting of -N-(Ci-Ce alkyl)2, and the group consisting of a heterocycloalkyl comprising at least one heteroatom, wherein one of the at least one heteroatoms is a nitrogen,R8is selected from the group consisting of -C(=O)NH2, -C(=O)NHR9, -C(=O)NR92, -C(=O)OH, - C(=O)OR9, whereinR4is independently selected from the group consisting of H and -Ci-Ce-alkyl;R5is selected from a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl;R6is selected from a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, particularly R6is selected from a substituted or unsubstituted -Ci-Ce-alkyl, more particularly R6is selected from an unsubstituted -Ci-Ce- alkyl;R9is independently selected from the group consisting of -Ci-Ce-alkyl and wherein p is 0 or 1 ; m is 0 or 1 ,Xi and X2are each selected from C and N;Y and Z are independently selected from C, N, O and S.

20. The compound according to any one of claims 16 to 19, wherein the compound is of formula(lb) or (lib)whereinR1is selected from the group consisting of -NR4C(=O)R5, -NR4C(=O)OR5, -C(=O)NR4R5and - C(=O)R5;R2is selected from the group consisting of -C(=O)OH, -C(=O)OR6, -C(=O)R6, -C(=O)NR6, -SO2- NHR6, -SO2-R62;R7is selected from the group consisting of -N-(Ci-Ce alkyl)2, and the group consisting of a heterocycloalkyl comprising at least one heteroatom, wherein one of the at least one heteroatoms is a nitrogen,R8is selected from the group consisting of -C(=O)NH2, -C(=O)NHR9, -C(=O)NR92, -C(=O)OH, - C(=O)OR9, whereinR4is independently selected from the group consisting of H and -Ci-Ce-alkyl;R5is selected from a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl;R6is selected from a substituted or unsubstituted -Ci-Ce-alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, particularly R6is selected from a substituted or unsubstituted -Ci-Ce-alkyl, more particularly R6is selected from an unsubstituted -Ci-Ce- alkyl;R9is independently selected from the group consisting of -Ci-Ce-alkyl and wherein p is 0 or 1 ; m is 0 or 1 ,Y is selected from C, N, O and S.21 . The compound according to any one of claims 16 to 20, wherein Y is C or N, particularly wherein Y is N.

22. The compound according to any one of claims 16 to 21 , wherein the substituted aryl, the substituted alkyl, or the substituted heteroaryl, or the substituted cycloalkyl, or the substituted heterocycloalkyl are independently substituted with R10q, wherein R10is independently selected from- the group consisting of halogens,- the group consisting of substituted or unsubstituted -Ci-Ce alkyl,- the group consisting of -O-Ci-Ce alkyls,- the group consisting of -CN, -C(=O)OH, -C(=O)H, -C(=O)NR122, -C(=O)O-Ci-C6alkyl, - Ci-Ce-alkyl-OH, -CH2F, -CHF2, -CF3, -C(=O)-CF3, and -NR122, wherein R12is independently selected from H and Ci-Ce-alkyl and wherein q is independently selected from 1 , 2, 3, 4 and 5.

23. The compound according to any one of claims 16 to 22, wherein the substituted aryl is substituted with R10q, wherein R10is selected from- the group consisting of -O-Ci-Ce alkyls,- the group consisting of -CN, -C(=O)OH, -C(=O)H, -C(=O)NR122, -C(=O)O-Ci-C6alkyl, - Ci-Ce-alkyl-OH, -CH2F, -CHF2, -CF3, -C(=O)-CF3, and -NR122, wherein R12is independently selected from H and Ci-Ce-alkyl and wherein q is independently selected from 1 , 2, 3, 4 and 5, particularly wherein q is 1 .

24. The compound according to any any one of claims 16 to 23, wherein the substituted alkyl, or the substituted heteroaryl, or the substituted cycloalkyl, or the substituted heterocycloalkyl are independently substituted with R10q, wherein R10is independently selected from- the group consisting of halogens,- the group consisting of substituted or unsubstituted -Ci-Ce alkyl,- the group consisting of -O-Ci-Ce alkyls,- the group consisting of -CN, -C(=O)OH, -C(=O)H, -C(=O)NR122, -C(=O)O-Ci-C6alkyl, - Ci-Ce-alkyl-OH, -CH2F, -CHF2, -CF3, -C(=O)-CF3, and -NR122, wherein R12is independently selected from H and Ci-Ce-alkyl and wherein q is independently selected from 1 , 2, 3, 4 and 5, particularly wherein q is 1 .

25. The compound according to any one of claims 16 to 24, wherein the substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, is selected from a Cs to C10 substituted or unsubstituted aryl, or a Cs to C10 substituted or unsubstituted heteroaryl.

26. The compound according to any one of claims 16 to 25, wherein the substituted or unsubstituted cycloalkyl, or the substituted or unsubstituted heterocycloalkyl is selected from a C3to C10 substituted or unsubstituted cycloalkyl, or a C3to C12 substituted or unsubstituted heterocycloalkyl.

27. A compound according to claims 16 to 26, for use as a medicament.

28. A compound according to claims 16 to 26 and a compound of formula (III) and (IV)for use in the treatment of a disease, wherein the disease is selected from multiple sclerosis and neurodegenerative diseases, in particular wherein the disease is multiple sclerosis.

29. A compound according to claims 16 to 26 for use in the treatment of a disease, wherein the disease is selected from multiple sclerosis and neurodegenerative diseases, in particular wherein the disease is multiple sclerosis.

Images