Novel pyrimidinyl and triazinyl sulfonamide derivatives

Abstract

The present invention relates to novel compounds having the general formula (I) TIFF2025523899000051.tif68161 (wherein R 4 , R 5 , X1, X2, X3 and Y1 are as described herein), compositions containing the compounds, and methods of using the compounds.

Description

Technical Field

[0001] The present invention relates to organic compounds useful for treatment and / or prevention in mammals, particularly compounds that modulate GPR17 activity.

[0002] The present invention relates to formula I

Chemical formula

[0003] Furthermore, the present invention includes all racemic mixtures, all corresponding enantiomers and / or optical isomers thereof.

Background Art

[0004] Myelination is a process that occurs reliably despite the abundant presence of oligodendrocyte progenitor cells (OPCs) throughout the developing and adult CNS. In chronic demyelinating diseases, the transition to myelinating oligodendrocytes and the production of reparative myelin sheaths around demyelinated axons are impaired. During development, myelination proceeds very orderly by OPCs characterized by the expression of markers such as neural / glial antigen 2 (NG2) and platelet-derived growth factor alpha (PDGFRα), differentiating into oligodendrocytes that lose the expression of NG2 and PDGFRα and acquire the expression of markers such as myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG). Myelin production by oligodendrocytes is a very tightly regulated process and in the CNS, this can be controlled by interactions with axons, which are well understood in the peripheral nervous system but not in the central nervous system (Macklin, W.B. (2010). Sci. Signal. 3, pe32-pe32, ‘‘The myelin brake: When Enough Is Enough’’). Myelination can also be controlled by an internal brake within the oligodendrocytes themselves, via the transcription factor EB (TFEB)-PUMA axis, or via GPR17 antagonism. (Chen, Y., et al. (2009). Nat Neurosci 12, 1398-1406, ‘‘The oligodendrocyte-specific G protein-coupled receptor GPR17 is a cell-intrinsic timer of myelination’’)(Sun, L.O., et al. (2018). Cell 175, 1811-1826.e21, ‘‘Spatiotemporal Control of CNS Myelination by Oligodendrocyte Programmed Cell Death through the TFEB-PUMA Axis’’).Myelin not only helps protect axons and facilitate neurotransmission, but oligodendrocytes have also been shown to play important roles in axonal metabolism and in maintaining the electrolyte balance around axons (Schirmer, L., et al. (2014). Ann Neurol 75, 810 - 828, ‘‘Differential loss of KIR4.1 immunoreactivity in multiple sclerosis lesions’’)(Simons, M., and Nave, K.-A. (2015). Cold Spring Harb Perspect Biol. 22, ‘‘Oligodendrocytes: Myelination and Axonal Support’’).

[0005] GPR17 is a class A orphan G protein-coupled receptor (GPCR). GPCRs are seven-transmembrane domain proteins that couple extracellular ligands to intracellular signaling via their intracellular association with small heterotrimeric G protein complexes consisting of G α , G β , G γ subunits. The downstream intracellular signaling pathway is brought about by the coupling of the GPCR to the G α subunit. GPR17 is known to couple directly to G α i / o , which results in the inhibition of adenylate cyclase activity and a decrease in cyclic AMP production (cAMP). GPR17 also couples to G q / 11is shown to bind to. Activation of phospholipase C results in cleavage of phosphatidylinositol 4,5-bisphosphate to produce inositol trisphosphate (IP3) and diacylglycerol (DAG). As a result, IP3 binds to IP3 receptors on the endoplasmic reticulum, causing an increase in intracellular calcium levels (Hanlon, C.D., and Andrew, D.J. (2015). J Cell Sci. 128, 3533-3542, ‘‘Outside-in signaling-a brief review of GPCR signaling with a focus on the Drosophila GPCR family’’)(Inoue, A., et al. (2019), Cell 177, 1933-1947.e25, ‘‘Illuminating G-Protein-Coupling Selectivity of GPCRs’’).

[0006] The role of GPR17 in myelination was first identified in a screen of the optic nerves of Olig1 knockout mice to identify genes that regulate myelination. GPR17 expression was found to be expressed only in myelinating cells of the CNS and not in Schwann cells, which are myelinating cells of the peripheral nervous system. The expression of GPR17 was found to be exclusively expressed in oligodendrocyte lineage cells and downregulated in myelinating oligodendrocytes (Chen, Y. et al. (2009)). Specifically, GPR17 expression was found to be present at low levels early in OPCs and increased in pre-myelinating oligodendrocytes before expression was downregulated in mature myelinating oligodendrocytes (Boda, E., et al. (2011), Glia 59, 1958 - 1973, ‘‘The GPR17 receptor in NG2 expressing cells: Focus on in vivo cell maturation and participation in acute trauma and chronic damage’’) (Dziedzic, A., et al. (2020). Int. J. Mol. Sci. 21, 1852, ‘‘The gpr17 receptor - a promising goal for therapy and a potential marker of the neurodegenerative process in multiple sclerosis’’) (Fumagalli, M. et al. (2011), J Biol Chem 286, 10593 - 10604, ‘‘Phenotypic changes, signaling pathway, and functional correlates of GPR17 - expressing neural precursor cells during oligodendrocyte differentiation’’).GPR17 knockout animals have been shown to exhibit premature myelination throughout the CNS. Conversely, transgenic mice overexpressing GPR17 in oligodendrocytes with the CNP-Cre (2’,3’-cyclic nucleotide 3’-phosphodiesterase) promoter exhibited hypomyelination defects, consistent with GPR17 being predicted to be a cell-intrinsic brake on the myelination process (Chen, Y. et al. (2009)). Furthermore, loss of GPR17 enhances remyelination after demyelination by lysophosphatidylcholine-induced demyelination (Lu, C., Dong, et al. (2018), Sci. Rep. 8, 4502, ‘‘G-Protein-Coupled Receptor Gpr17 Regulates Oligodendrocyte Differentiation in Response to Lysolecithin-Induced Demyelination’’). Thus, antagonism of GPR17, which promotes the differentiation of oligodendrocyte lineage cells into mature myelinating oligodendrocytes, would result in increased myelination after demyelination.

[0007] Multiple sclerosis (MS) is a chronic neurodegenerative disease characterized by the loss of myelin, a protective fatty lipid layer that surrounds axons in the central nervous system (CNS). Prevention of remyelination of demyelinated or exposed axons is thought to prevent axonal degeneration and thus disease progression (Franklin, R.J. (2002), Nat Rev Neurosci 3, 705-714, ‘‘Why does remyelination fail in multiple sclerosis?’’). Such treatments would be beneficial in all types of MS, namely relapsing-remitting, secondary progressive, primary progressive, and progressive relapsing MS, because of the reparative effects of myelin repair on the CNS. Repair of lost myelin alleviates neurological symptoms associated with MS due to its neuroprotective effect of preserving axons.

[0008] Because myelination plays an essential role in the function of the nervous system, promoting the differentiation of OPCs into oligodendrocytes may affect white matter defects / irregularities resulting from either the loss of myelinating oligodendrocytes or the disruption of OPC differentiation into oligodendrocytes, which are observed in multiple diseases caused by the disease itself or inflammation. This is in addition to diseases in which the expression of GPR17 itself changes.

[0009] Diseases that may benefit from GPR17 antagonism to produce a positive disease outcome include, but are not limited to, the following. Direct damage to the myelin sheath: - Metabolic conditions that result in the destruction of central nervous system myelin, such as, but not limited to, central pontine myelinolysis and extrapontine myelinolysis due to the overly rapid correction of hyponatremia in conditions such as alcohol dependence, liver disease, and post-transplant immunosuppression - Carbon monoxide poisoning in which oligodendrocyte dysfunction and failure of regeneration have been reported in the deep white matter layer of the brain - Nutritional deficiencies that result in myelin loss or failure of proper myelin production during development - Virus-induced demyelination Primary demyelinating disorders - Multiple sclerosis (relapsing-remitting, secondary progressive, primary progressive, and progressive relapsing MS) - Acute and polyphasic disseminated encephalomyelitis - Neuromyelitis spectrum disorder including optic neuritis - Transverse myelitis - Leukodystrophies such as adrenoleukodystrophy, adrenomyeloneuropathy, and other hereditary leukodystrophies that result in myelin loss CNS disorders associated with related myelin loss: - Alzheimer's disease - Schizophrenia - Parkinson's disease - Huntington's disease - Amyotrophic lateral - Ischemia due to stroke Other diseases: - For example, encephalitis, primary vasculitis, inflammation of the CNS after meningitis

[0010] The compounds of formula I bind to GPR17 and modulate GPR17 activity.

[0011] Therefore, the compounds of formula I are particularly useful for the treatment of diseases associated with GPR17 antagonism.

[0012] The compounds of formula I are particularly useful for the treatment or prevention of multiple sclerosis (MS), symptoms associated with direct damage to the myelin sheath, such as carbon monoxide poisoning or virus-induced demyelination, primary demyelinating disorders, such as acute and polyphasic disseminated encephalomyelitis, and other CNS disorders associated with myelin loss, such as Alzheimer's disease, schizophrenia, Parkinson's disease and Huntington's disease.

Summary of the Invention

[0013] The present invention relates to a compound of formula I

Chemical formula

[0014] The term "alkyl" refers to a monovalent straight-chain or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. In some embodiments, unless otherwise specified, alkyl is C 1~6 -alkyl or C 1~4 -alkyl containing 1 to 4 carbon atoms. Examples of C 1~6 -alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and pentyl. Specific alkyl groups include methyl, ethyl, and propyl. When an alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons may be included. Thus, for example, "butyl" may include n-butyl, sec-butyl, iso-butyl, and t-butyl, and "propyl" may include n-propyl and isopropyl.

[0015] The term "alkoxy" refers to a group of the formula -O-R', where R' is a C 1~6 -alkyl group. Examples of C 1~6 -alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, and tert-butoxy. Specific examples are methoxy and ethoxy.

[0016] The terms "halogen", "halide", and "halo" are used interchangeably herein and represent fluoro, chloro, bromo, or iodo. Specific halogens are fluoro, chloro, and bromo.

[0017] The term "haloalkyl" refers to a C 1~6 -alkyl group in which at least one hydrogen atom of the C 1~6 -alkyl group is replaced by the same or different halogen atoms. Specific examples are difluoroethyl and trifluoromethyl.

[0018] The term "haloalkoxy" refers to C 1~6- A C in which at least one hydrogen atom of the alkoxy group is replaced by the same or different halogen atoms 1~6 - represents an alkoxy group. Specific examples are fluoroethoxy, difluoromethoxy and difluoroethoxy.

[0019] The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the free base or free acid and are not biologically or otherwise undesirable. The salts are formed using inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, especially hydrochloric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine. In addition, these salts can be prepared by adding an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, salts of sodium, potassium, lithium, ammonium, calcium, magnesium. Salts derived from organic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyamine resins. The compounds of formula I may also exist in zwitterionic form. Particularly preferred pharmaceutically acceptable salts of the compounds of formula I are salts formed using formic acid and salts formed using hydrochloric acid that give rise to hydrochloride, dihydrochloride or trihydrochloride.

[0020] The abbreviation uM means micromole and is equivalent to the symbol μM.

[0021] The abbreviation uL means microliter and is equivalent to the symbol μL.

[0022] The abbreviation ug means microgram and is equivalent to the symbol μg.

[0023] The compounds of formula I may contain several asymmetric centers and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as racemates, etc., optically pure diastereoisomers, mixtures of diastereoisomers, racemates of diastereoisomers or mixtures of racemates of diastereoisomers.

[0024] According to the Cahn-Ingold-Prelog rules, an asymmetric carbon atom can have an "R" or "S" configuration.

[0025] Also, certain embodiments of the present invention provide compounds according to formula I described herein and pharmaceutically acceptable salts or esters thereof, particularly compounds according to formula I described herein and pharmaceutically acceptable salts thereof, more specifically, compounds according to formula I described herein.

[0026] Certain embodiments of the present invention provide compounds according to formula I described herein wherein R 4 is haloalkyl.

[0027] Certain embodiments of the present invention provide compounds according to formula I described herein wherein R 5 is halo.

[0028] Certain embodiments of the present invention provide compounds according to formula I described herein wherein R 6 is H.

[0029] Certain embodiments of the present invention provide compounds according to formula I described herein wherein X1 is N, X2 is CR 2 wherein X3 is CR 3 wherein R 2 is H and R 3 is alkoxy or haloalkoxy.

[0030] One embodiment of the present invention is a compound according to formula I described herein, wherein: R 4 is haloalkoxy, R 5 is halo, X1 is N, X2 is CR 2 and X3 is CR 3 and R 2 is H, and R 3 is alkoxy or haloalkoxy, Y1 is CR 6 or N, R 6 is H, and provides a compound and a pharmaceutically acceptable salt thereof.

[0031] Specific examples of the compounds of formula I described herein are 6-chloro-N-(4-methoxy-2-propyl-pyrimidin-5-yl)-1H-indole-3-sulfonamide; 6-chloro-N-(2-ethyl-4-methoxy-pyrimidin-5-yl)-1H-indole-3-sulfonamide; 6-chloro-N-[2-(difluoromethoxy)-4-methoxy-pyrimidin-5-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[2-(2,2-difluoroethoxy)-4-methoxy-pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-chloro-N-[2-(2,2-difluoroethoxy)-4-(difluoromethoxy)pyrimidin-5-yl]-1H-indole-3-sulfonamide; 6-chloro-N-(2,4-dichloropyrimidin-5-yl)-1H-indole-3-sulfonamide; 6-chloro-N-(2-(2-fluoroethoxy)-4-methoxypyrimidin-5-yl)-1H-indole-3-sulfonamide; 6-chloro-N-(2-(2,2-difluoroethoxy)-4-methoxypyrimidin-5-yl)-1H-indole-3-sulfonamide; 6-Bromo-N-[2-(2,2-difluoroethoxy)-4-methoxy-pyrimidin-5-yl]-1H-indole-3-sulfonamide; 6-Bromo-N-[2-(2,2-difluoroethoxy)-4-methoxy-pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; N-[2-(2,2-Difluoroethoxy)-4-methoxy-pyrimidin-5-yl]-6-(trifluoromethyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[6-(2,2-difluoroethyl)-5-methoxy-1,2,4-triazin-3-yl]-1H-indole-3-sulfonamide; and 6-Chloro-N-(5-methoxy-6-methyl-1,2,4-triazin-3-yl)-1H-indole-3-sulfonamide, and is selected from pharmaceutically acceptable salts thereof.

[0032] Preferred examples of the compounds of formula I described herein are 6-Chloro-N-[2-(difluoromethoxy)-4-methoxy-pyrimidin-5-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[2-(2,2-difluoroethoxy)-4-(difluoromethoxy)pyrimidin-5-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-(2-(2,2-difluoroethoxy)-4-methoxypyrimidin-5-yl)-1H-indole-3-sulfonamide; 6-Bromo-N-[2-(2,2-difluoroethoxy)-4-methoxy-pyrimidin-5-yl]-1H-indole-3-sulfonamide; 6-Bromo-N-[2-(2,2-difluoroethoxy)-4-methoxy-pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide, and is selected from pharmaceutically acceptable salts thereof.

[0033] The process for the manufacture of the compounds of formula I described herein is an object of the present invention.

[0034] The compounds of formula I of the present invention and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example by the processes described below, which process comprises reacting a compound of formula III with a compound of formula II in the presence of a base selected from N-ethyldiisopropylamine, pyridine, potassium phosphate or sodium hydride to provide a compound of formula I.

Chemical formula

[0035] General synthetic scheme The compounds of formula I can be prepared according to variations of the above process and according to Scheme 1 below. The starting materials are commercially available or can be prepared according to known methods.

[0036] Scheme 1

Chemical formula

[0037] Scheme 2

Chemical formula

[0038] Scheme 3

Chem.

[0039] Scheme 4

Chem.

[0040] Another embodiment of the present invention provides a pharmaceutical composition or medicament containing a compound of the present invention and a therapeutically inert carrier, diluent or excipient, as well as a method of using the compound of the present invention for preparing such compositions and medicaments. In one example, a compound of formula I can be formulated into a galenical dosage form by mixing it with a physiologically acceptable carrier, i.e., a carrier that is non-toxic to the recipient at the dosage and concentration used, at ambient temperature, at an appropriate pH, and with the desired degree of purity. The pH of the formulation mainly depends on the particular use and the concentration of the compound, but is preferably somewhere in the range of about 3 to about 8. In one example, the compound of formula I is formulated in an acetate buffer at pH 5. In another embodiment, the compound of formula I is sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0041] The compositions are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered in this regard include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of drug delivery, the method of administration, the dosing schedule, and other factors known to the medical practitioner.

[0042] The compounds of the present invention can be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intralung, intradermal, intrathecal and epidural, and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0043] The compounds of the present invention can be administered in any convenient dosage form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions can contain conventional constituents in pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, fillers, and additional active agents.

[0044] Typical formulations are prepared by mixing the compounds of the present invention with carriers or additives. Suitable carriers and additives are well known to those skilled in the art and are described in detail, for example, in Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulations may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, flow promoters, processing aids, colorants, sweeteners, flavors, fragrances, diluents and other known additives for presenting the drug (i.e., the compound of the present invention or its pharmaceutical composition) well or for assisting in the manufacture of pharmaceutical products (i.e., pharmaceuticals).

[0045] The compounds of formula I and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, sugar-coated tablets, hard gelatin capsules, injection solutions or topical formulations. Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used, for example, as such adjuvants for tablets, sugar-coated tablets and hard gelatin capsules.

[0046] Examples of adjuvants suitable for soft gelatin capsules include vegetable oils, waxes, fats and oils, semi-solids, liquid polyols, etc.

[0047] Adjuvants suitable for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc.

[0048] Suitable adjuvants for injection solutions are, for example, water, alcohol, polyols, glycerol, vegetable oils, etc.

[0049] Adjuvants suitable for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc.

[0050] Suitable adjuvants for ophthalmic topical preparations are, for example, cyclodextrin, mannitol, or many other carriers and excipients known in the art.

[0051] Furthermore, the pharmaceutical preparation can contain preservatives, solubilizers, viscosity increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for changing the osmotic pressure, buffers, masking agents or antioxidants. It can also contain other therapeutically useful substances.

[0052] The dosage can vary within a wide range and, of course, is adapted to the individual requirements in each specific case. Generally, in the case of oral administration, a daily dosage of about 0.1 mg to 20 mg per kg of body weight, preferably about 0.5 mg to 4 mg per kg of body weight (for example, about 300 mg per person), is preferably divided into 1 to 3 individual administrations, which can, if appropriate, consist of, for example, the same amount. In the case of topical administration, the preparation can contain 0.001% to 15% by weight of the pharmaceutical, and the required dosage can be between 0.1 and 25 mg and can be administered either by a single administration per day or per week, by multiple administrations per day (2 to 4 times), or by multiple administrations per week. However, it will be clear that it can exceed the upper or lower limits given herein if so indicated.

[0053] The present invention also particularly relates to the following: Compounds of formula I for use as therapeutic active substances; Compounds of formula (I) for use in the treatment of diseases regulated by GPR17.

[0054] Similarly, an object of the present invention is a pharmaceutical composition comprising a compound according to formula I described herein and a therapeutically inert carrier.

[0055] Direct damage to the myelin sheath (including, but not limited to, central pontine myelinolysis and extrapontine myelinolysis, carbon monoxide poisoning, malnutrition, and virus-induced demyelination), demyelinating disorders (including, but not limited to, multiple sclerosis, acute and polyphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorder, and leukodystrophy), CNS disorders associated with myelin loss (including, but not limited to, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and ischemia due to stroke), and use of a compound of formula I for treating or preventing symptoms resulting from inflammation of the CNS, such as, for example, encephalitis, primary vasculitis, meningitis, and after obesity.

[0056] One embodiment of the present invention is the use of a compound of formula I for treating or preventing multiple sclerosis, Alzheimer's disease, Parkinson's disease, or Huntington's disease.

[0057] A specific embodiment of the present invention is the use of a compound of formula I for treating or preventing multiple sclerosis.

[0058] Use of a compound of formula I for the preparation of a medicament for treating or preventing symptoms resulting from direct damage to the myelin sheath (including, but not limited to, central pontine myelinolysis and extrapontine myelinolysis, carbon monoxide poisoning, nutritional deficiencies, and virus-induced demyelination), demyelinating disorders (including, but not limited to, multiple sclerosis, acute and polyphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorder, and leukodystrophy), CNS disorders associated with myelin loss (including, but not limited to, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and ischemia due to stroke), and inflammation of the CNS, for example, after encephalitis, primary vasculitis, meningitis, and obesity.

[0059] One embodiment of the invention is the use of a compound of formula I for the preparation of a medicament for treating or preventing multiple sclerosis, Alzheimer's disease, Parkinson's disease, or Huntington's disease.

[0060] A particular embodiment of the invention is the use of a compound of formula I for the preparation of a medicament for treating or preventing multiple sclerosis.

[0061] A compound according to formula I for use in the treatment or prevention of symptoms resulting from direct damage to the myelin sheath (including, but not limited to, central pontine myelinolysis and extrapontine myelinolysis, carbon monoxide poisoning, nutritional deficiencies, and virus-induced demyelination), demyelinating disorders (including, but not limited to, multiple sclerosis, acute and polyphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorder, and leukodystrophy), CNS disorders associated with myelin loss (including, but not limited to, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and ischemia due to stroke), and inflammation of the CNS, for example, after encephalitis, primary vasculitis, meningitis, and obesity.

[0062] One embodiment of the invention is a compound of formula I for use in the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease, or Huntington's disease.

[0063] Certain embodiments of the invention are compounds of formula I for use in the treatment or prevention of multiple sclerosis.

[0064] A method for treating or preventing symptoms resulting from direct damage to the myelin sheath (including, but not limited to, central pontine myelinolysis and extrapontine myelinolysis, carbon monoxide poisoning, nutritional deficiencies, and virus-induced demyelination), demyelinating disorders (including, but not limited to, multiple sclerosis, acute and polymorphic disseminated encephalomyelitis, neuromyelitis optica spectrum disorder, and leukodystrophy), CNS disorders associated with myelin loss (including, but not limited to, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and ischemia due to stroke), and CNS inflammation such as, for example, encephalitis, primary vasculitis, meningitis, and post-obesity, the method comprising administering an effective amount of a compound of formula I to a patient in need thereof.

[0065] Certain embodiments of the invention are methods for treating or preventing multiple sclerosis, Alzheimer's disease, Parkinson's disease, or Huntington's disease, the methods comprising administering an effective amount of a compound of formula I to a patient in need thereof.

[0066] Certain embodiments of the invention are methods for treating or preventing multiple sclerosis, the methods comprising administering an effective amount of a compound of formula I to a patient in need thereof.

[0067] Also, certain embodiments of the invention provide a compound of formula I described herein when manufactured according to any one of the described processes.

[0068] Assay procedure GPR17 cAMP assay protocol: CHO-K1 cells stably expressing a vector containing the untagged human GPR17 short isoform (Roche) were cultured at 37°C / 5% CO2 in DMEM (Dulbecco's Modified Eagle Medium):F-12 (1:1) supplemented with 10% fetal bovine serum and 400 μg / ml Geneticin.

[0069] Changes in intracellular cyclic adenosine monophosphate (cAMP) levels were quantified using the Nano-TRF Detection Assay Kit (Roche Diagnostics, catalog number 05214386001). This assay enables direct cAMP quantification in a homogeneous solution. cAMP is detected based on time-resolved fluorescence energy transfer (TR-FRET) and the competitive binding of ruthenium-labeled cAMP and endogenous cAMP to an anti-cAMP monoclonal antibody labeled with AlexaFluor-700. The ruthenium complex acts as the FRET donor and transfers energy to AlexaFluor-700. The FRET signal is inversely proportional to the cAMP concentration.

[0070] CHO-GPR17S cells were detached with Accutase and resuspended in assay buffer consisting of Hank's balanced salt solution (HBSS), 10 mM HEPES (4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid solution), and 0.1% bovine serum albumin (pH 7.4). Cells were seeded at a density of 10,000 cells / 20 μl assay buffer in black 384-well plates (Corning) until the addition of compounds.

[0071] The test antagonist compound was serially diluted with dimethyl sulfoxide (DMSO) and spotted onto a 384-well plate. The compound was then diluted in HBSS buffer supplemented with MDL29,951 (3-(2-carboxy-4,6-dichlorophenyl)-propionic acid) (GPR17 agonist) at EC80 concentration + 3-isobutyl-1-methylxanthine (IBMX) (final concentration 0.5 mM) and added to the cells at room temperature. Forskolin (final concentration 15 μM) was added 5 minutes after the test compound, and the cells were incubated at room temperature for 30 minutes. The assay was stopped by adding the cAMP detection mixture (containing surfactant for cell lysis) for 90 minutes at room temperature.

[0072] The cAMP in the cells was measured using a Paradigm reader (Molecular Devices). Using the raw data, the FRET signal was calculated based on the P factor of the assay according to the instructions of the cAMP kit. The data was normalized against the maximum activity of the reference antagonist, and the dose-response curve was fitted to the percent activity of the test compound using a sigmoid dose-response model (Genedata Screener).

[0073] The results of the hGPR17 cAMP assay are provided for the compounds of formula I in Table 1.

Table 1

[0074] Microsome Clearance Assay Protocol: Incubation with microsomes (0.5 mg / mL) and 1 mM of the test compound in the cofactor NADPH is carried out in a 96-well plate at 37 °C using a TECAN (Tecan Group Ltd, Switzerland) automated liquid handling system. The final concentration of the test compound during incubation is 1 μM. After a 10-minute pre-incubation step of the test compound with microsomes, the enzyme reaction is initiated by the addition of the cofactor. At 1, 3, 6, 9, 15, 25, 35, and 45 minutes, aliquots of the incubation are removed and quenched with 1:3 (v / v) acetonitrile containing an internal standard. The samples are then cooled and centrifuged, and the supernatant is analyzed by LC-MS / MS.

[0075] Reference Examples RE-A and RE-B are prepared as described herein.

[0076] To evaluate the stability of the metabolites, reference compounds were tested as exemplified for microsomal clearance. The results are shown in Table 2 below.

Table 2

[0077] The present invention will now be described by the following examples, which have no limiting features.

[0078] When a preparation example is obtained as a mixture of enantiomers, the pure enantiomers can be obtained by the methods described herein or methods known to those skilled in the art, such as chiral chromatography or crystallization.

Example

[0079] Unless otherwise specified, all examples and intermediates were prepared under a nitrogen atmosphere.

[0080] Intermediate A Intermediate A1: 6-Chloro-1H-indole-3-sulfonyl chloride [Chemical formula] Intermediate A1 is commercially available (CAS 1216060-79-5).

[0081] Intermediate A2: 6-Bromo-1H-indole-3-sulfonyl chloride [Chemical formula] Intermediate A2 is commercially available (CAS 2137914-35-1).

[0082] Intermediate A3: 6-Bromo-1H-pyrrolo[2,3-b]pyridine-3-sulfonyl chloride [Chemical formula] Intermediate A3 is known (CAS 2231234-27-6) and was synthesized according to International Publication No. WO 2018 / 122232.

[0083] Intermediate A4: 6-Chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonyl chloride [Chemical formula] Intermediate A4 is known (CAS 2231234-21-0) and was synthesized according to International Publication No. WO 2018 / 122232.

[0084] Intermediate A5: 6-(Trifluoromethyl)-1H-indole-3-sulfonyl chloride [Chemical formula] Intermediate A5 is known (CAS 1784173-91-6) and was synthesized according to International Publication No. WO 2018 / 122232.

[0085] Intermediate B Intermediate B1: 4-Methoxy-2-propyl-pyrimidin-5-amine

Chem.

[0086] Step 1: 2-Iodo-4-methoxy-5-nitro-pyrimidine

Chem.

[0087] Step 2: (2-Iodo-4-methoxy-pyrimidin-5-yl)amine

Chem.

[0088] Step 3: (4-Methoxy-2-prop-1-ynyl-pyrimidin-5-yl)amine

Chemical Structure

[0089] Step 4: 4-Methoxy-2-propyl-pyrimidin-5-amine [Chem.] In a 10 mL glass tube under argon, (4-methoxy-2-prop-1-ynyl-pyrimidin-5-yl)amine (55 mg, 0.337 mmol) was dissolved in ethyl acetate (3 mL), and 10% palladium-on-charcoal (54 mg) was added. After flushing three times with hydrogen, a balloon filled with hydrogen gas was applied, and the mixture was stirred for 5 hours. Then, it was filtered through celite and concentrated to obtain the title compound (53 mg, 85% yield) as a colorless viscous oil. MS m / z: 168.1 [M+H] + , ESI pos.

[0090] Intermediate B2: 2-Ethyl-4-methoxy-pyrimidin-5-amine [Chem.] A solution of 2-chloro-4-methoxy-5-nitro-pyrimidine (CAS 282102-07-2, 160 mg, 0.844 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (143 mg, 159 μl, 0.928 mmol) and tripotassium phosphate (538 mg, 2.53 mmol) in 1,4-dioxane (6.4 ml) and water (1.6 ml) was degassed under Ar. Then, 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II) dichloromethane adduct (69 mg, 0.084 mmol) was added and the reaction mixture was heated at 80 °C for 15 minutes. The mixture was diluted with dichloromethane (20 ml) and filtered through a pad of celite. Water was added and the aqueous layer was extracted with dichloromethane and the combined organic layers were concentrated. The residue was dissolved in methanol (3 ml) and palladium-on-charcoal (10%, 65 mg) was added under a stream of argon. A balloon filled with hydrogen gas was applied and the mixture was stirred for 2 hours, then filtered through celite and concentrated. The residue was purified by preparative HPLC (column Gemini NX, 12 nm, 5 μm, 100×30 mm, solvent: acetonitrile / water + 0.1% trimethylamine) to give the title compound (5 mg, yield 5%) as a pale brown oil. MS m / z: 154.1 [M+H] + ,ESI pos.

[0091] Intermediate B3: 2-(difluoromethoxy)-4-methoxy-pyrimidin-5-amine

Chem.

[0092] Step 1: 4-methoxy-5-nitro-pyrimidin-2-ol

Chem.

[0093] Step 2: 2-(Difluoromethoxy)-4-methoxy-5-nitro-pyrimidine

Chemical formula

[0094] Step 3: 2-(Difluoromethoxy)-4-methoxy-pyrimidin-5-amine

Chemical formula

[0095] Intermediate B4: 2-(2-Fluoroethoxy)-4-methoxy-pyrimidin-5-amine

Chemical formula

[0096] Step 1: 2-(2-Fluoroethoxy)-4-methoxy-5-nitropyrimidine

Chemical formula

[0097] Step 2: 2-(2-Fluoroethoxy)-4-methoxy-pyrimidin-5-amine

Chemical formula

[0098] Intermediate B5: 2-(2,2-difluoroethoxy)-4-methoxypyrimidin-5-amine

Chem.

[0099] Intermediate B6: 2-(2,2-difluoroethoxy)-4-(difluoromethoxy)pyrimidin-5-amine

Chem.

[0100] Step 1: Sodium 2-chloro-5-nitropyrimidine-4-olate

Chem.

[0101] Step 2: 2-(2,2-Difluoroethoxy)-5-nitropyrimidin-4-ol

Chemical Structure

[0102] Step 3: 5-Amino-2-(2,2-difluoroethoxy)pyrimidin-4-ol [Chemical formula] To a solution of 2-(2,2-difluoroethoxy)-5-nitro-pyrimidin-4-ol (146 mg, 0.660 mmol) in ethyl acetate (7 ml) was added 10% palladium-on-charcoal (70 mg). The mixture was stirred at room temperature for 1 h under a hydrogen atmosphere. The reaction mixture was filtered through a pad of celite and washed with ethyl acetate. The filtrate was concentrated in vacuo to give 5-amino-2-(2,2-difluoroethoxy)pyrimidin-4-ol (94 mg, 75% yield) as an off-white solid. MS m / z: 192.2 [M+H] + , ESI pos.

[0103] Step 4: 2-(2,2-Difluoroethoxy)-4-(difluoromethoxy)pyrimidin-5-amine [Chemical formula] A suspension of 5-amino-2-(2,2-difluoroethoxy)pyrimidin-4-ol (93 mg, 0.487 mmol) and potassium carbonate (204 mg, 1.46 mmol) in N-methyl-2-pyrrolidinone (2.5 ml) was heated to 80 °C. A solution of sodium chlorodifluoroacetate (155 mg, 0.973 mmol) in N-methyl-2-pyrrolidinone (0.8 ml) was added dropwise. The reaction mixture was stirred at 80 °C for 30 min. The reaction mixture was poured into water and extracted twice with EtOAc. The organic layer was washed twice with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the crude material by flash chromatography (silica gel, 0% - 100% ethyl acetate in heptane) gave the title compound (24 mg, 10% yield) as a pale yellow viscous oil. MS m / z: 242.2 [M+H] + , ESI pos.

[0104] Intermediate B7: 2,4-Dichloropyrimidin-5-amine [Chem.] The intermediate B7 is commercially available (CAS 5177-27-5).

[0105] Intermediate B8: 6-(2,2-difluoroethyl)-5-methoxy-1,2,4-triazin-3-amine [Chem.]

[0106] Step 1: 6-chloro-5-methoxy-N,N-bis[(4-methoxyphenyl)methyl]-1,2,4-triazin-3-amine [Chem.] In a 100 ml three-necked flask, 3,5,6-trichloro-1,2,4-triazine (CAS 873-41-6, 1.6 g, 8.68 mmol) was dissolved in tetrahydrofuran (25 ml), and the solution was cooled to 0 °C. Sodium methoxide (25% in MeOH, 1.87 g, 2.0 mL, 8.68 mmol) was added. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hour. Then, it was cooled to 0 °C, and N,N-diisopropylethylamine (1.68 g, 2.27 mL, 13.01 mmol) and bis(p-methoxyphenyl)amine (2.23 g, 8.68 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour and then at 50 °C overnight. The reaction mixture was poured into water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the crude material by flash chromatography (silica gel, 30% ethyl acetate in heptane) gave 6-chloro-5-methoxy-N,N-bis[(4-methoxyphenyl)methyl]-1,2,4-triazin-3-amine (1.25 g, yield 36%) as a pale yellow liquid. MS m / z: 401.3 [M+H] + , ESI pos.

[0107] Step 2: 6-(2-Ethoxyvinyl)-5-methoxy-N,N-bis[(4-methoxyphenyl)methyl]-1,2,4-triazin-3-amine

Chem.

[0108] Step 3: 6-(2,2-Difluoroethyl)-5-methoxy-N,N-bis[(4-methoxyphenyl)methyl]-1,2,4-triazin-3-amine

Chem.

[0109] Step 4: 6-(2,2-Difluoroethyl)-5-methoxy-1,2,4-triazin-3-amine

Chemical Structure

[0110] Intermediate B9: 5-Methoxy-6-methyl-1,2,4-triazin-3-amine

Chemical formula

[0111] Example Example 1: 6-Chloro-N-(4-methoxy-2-propyl-pyrimidin-5-yl)-1H-indole-3-sulfonamide [Chemistry] A mixture of 6-chloro-1H-indole-3-sulfonyl chloride (Intermediate A1, 67 mg, 0.269 mmol) and 4-methoxy-2-propyl-pyrimidin-5-amine (Intermediate B1, 50 mg, 0.269 mmol) in dichloromethane (ultra-dehydrated, 1.3 ml) was cooled to 2 - 5 °C. N,N-Diisopropylethylamine (45 mg, 61 μl, 0.350 mmol) was added. After 20 minutes, the cooling bath was removed and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column Gemini NX, 12 nm, 5 μm, 100×30 mm, solvent: acetonitrile / water + 0.1% HCOOH) to give the title compound (46 mg, 45%) as a white solid. MS m / z: 381.2 [M+H] + ,ESI pos.

[0112] The following Examples 2 - 6 were prepared in the same manner as Example 1 by coupling the indicated sulfonyl chloride Intermediate A and amine Intermediate B.

Table 3

[0113] Example 7: 6-Chloro-N-(2-(2-fluoroethoxy)-4-methoxypyrimidin-5-yl)-1H-indole-3-sulfonamide [Chemistry] A solution of 2-(2-fluoroethoxy)-4-methoxy-pyrimidin-5-amine (Intermediate B4, 25 mg, 0.134 mmol) in pyridine (dry, 0.85 ml) at 0 °C under argon was treated portionwise with 6-chloro-1H-indole-3-sulfonyl chloride (Intermediate A1, 200 mg, 0.40 mmol), followed by 4-dimethylaminopyridine (1.7 mg, 0.013 mmol). The mixture was stirred at 100 °C for 2.5 h, then cooled to room temperature and evaporated. The residue was partitioned between citric acid (1 M solution in water) and ethyl acetate. Both layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated. The residue was purified by preparative HPLC (column Gemini NX, 12 nm, 5 um, 100×30 mm, solvent: acetonitrile / water + 0.1% HCOOH) to give the title compound (11 mg, 20% yield) as an off-white solid. MS m / z: 399.1 [M-H] - ,ESI neg.

[0114] Examples 8 - 12 below were prepared in the same manner as Example 7 by coupling the indicated sulfonyl chloride Intermediate A and amine Intermediate B.

Table 4

[0115] Example 13: 6-Chloro-N-(5-methoxy-6-methyl-1,2,4-triazin-3-yl)-1H-indole-3-sulfonamide

Chem.

[0116] Reference Example RE-A: 6-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxypyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

Chem.

[0117] Reference Example RE-B: 6-Chloro-N-[5-(2,2-difluoroethyl)-3-fluoro-6-methoxypyridin-2-yl]-1H-indole-3-sulfonamide

Chem.

[0118] Example A The compound of formula I can be used as an active ingredient in a manner known per se for producing tablets of the following composition. Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg

[0119] Example B The compound of formula I can be used as an active ingredient in a manner known per se for producing capsules of the following composition. Per capsule Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg

Claims

1. Formula I 【Chemical Formula 1】 wherein R ４ is alkyl, halo, haloalkyl or haloalkoxy, R ５ is a halo or haloalkyl, X １ is N, and X ２ is CR ２ and X ３ is CR ３ and R ２ is H, and R ３ is alkoxy, halo or haloalkoxy, or X １ is CR １ and X ２ is N, and X ３ is N, and R １ is alkoxy Y １ is CR ６ or N, and R ６ is H or halo) and pharmaceutically acceptable salts thereof.

2. R ４ The compound according to claim 1, wherein R is haloalkoxy.

3. R ５ The compound according to claim 1 or 2, wherein R is halo.

4. R ６ The compound according to any one of claims 1 to 3, wherein R is H.

5. X １ is N, and X ２ is CR ２ and X ３ is CR ３ and R ２ is H, and R ３ is alkoxy or haloalkoxy, the compound according to any one of claims 1 to 4.

6. R ４ is a haloalkoxy, R ５ is a halo, and X １ is N, and X ２ is CR ２ and X ３ is CR ３ and R ２ is H, and R ３ is alkoxy or haloalkoxy, Y １ is CR ６ or N, and R ６ is H, The compound according to claim 1 and pharmaceutically acceptable salts thereof.

7. 6-chloro-N-(4-methoxy-2-propyl-pyrimidin-5-yl)-1H-indole-3-sulfonamide; 6-chloro-N-(2-ethyl-4-methoxy-pyrimidin-5-yl)-1H-indole-3-sulfonamide; 6-chloro-N-[2-(difluoromethoxy)-4-methoxy-pyrimidin-5-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[2-(2,2-difluoroethoxy)-4-methoxy-pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-chloro-N-[2-(2,2-difluoroethoxy)-4-(difluoromethoxy)pyrimidin-5-yl]-1H-indole-3-sulfonamide; 6-chloro-N-(2,4-dichloropyrimidin-5-yl)-1H-indole-3-sulfonamide; 6-chloro-N-(2-(2-fluoroethoxy)-4-methoxypyrimidin-5-yl)-1H-indole-3-sulfonamide; 6-chloro-N-(2-(2,2-difluoroethoxy)-4-methoxypyrimidin-5-yl)-1H-indole-3-sulfonamide; 6-bromo-N-[2-(2,2-difluoroethoxy)-4-methoxy-pyrimidin-5-yl]-1H-indole-3-sulfonamide; 6-bromo-N-[2-(2,2-difluoroethoxy)-4-methoxy-pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; N-[2-(2,2-difluoroethoxy)-4-methoxy-pyrimidin-5-yl]-6-(trifluoromethyl)-1H-indole-3-sulfonamide; 6-chloro-N-[6-(2,2-difluoroethyl)-5-methoxy-1,2,4-triazin-3-yl]-1H-indole-3-sulfonamide; 6-chloro-N-(5-methoxy-6-methyl-1,2,4-triazin-3-yl)-1H-indole-3-sulfonamide The compound according to any one of claims 1 to 6 and pharmaceutically acceptable salts thereof selected from

8. 6-Chloro-N-[2-(difluoromethoxy)-4-methoxypyrimidin-5-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[2-(2,2-difluoroethoxy)-4-(difluoromethoxy)pyrimidin-5-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-(2-(2,2-difluoroethoxy)-4-methoxypyrimidin-5-yl)-1H-indole-3-sulfonamide; 6-Bromo-N-[2-(2,2-difluoroethoxy)-4-methoxypyrimidin-5-yl]-1H-indole-3-sulfonamide; 6-Bromo-N-[2-(2,2-difluoroethoxy)-4-methoxypyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide A compound according to any one of claims 1 to 7, selected from the group consisting of, and a pharmaceutically acceptable salt thereof.

9. A method for preparing a compound according to any one of claims 1 to 8, comprising reacting a compound of formula III with a compound of formula II in the presence of a base selected from N-ethyldiisopropylamine, pyridine, potassium phosphate or sodium hydride to provide a compound of formula I 【Chemical 2】 (wherein, R ４ , R ５ , X １ , X ２ , X ３ and Y １ are as described above) A method comprising.

10. A compound according to any one of claims 1 to 8 for use as a therapeutic active substance.

11. A compound according to any one of claims 1 to 8 for use in the treatment of a disease regulated by GPR17.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 and a therapeutically inert carrier.

13. Direct damage to the myelin sheath (including, but not limited to, central pontine myelinolysis and extrapontine myelinolysis, carbon monoxide poisoning, nutritional deficiencies, and viral-induced demyelination), demyelinating disorders (including, but not limited to, multiple sclerosis, acute and polyphase disseminated encephalomyelitis, neuromyelitis optica spectrum disorder, and leukodystrophy), CNS disorders associated with myelin loss (including, but not limited to, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and ischemia due to stroke), and, for example, encephalitis, primary vasculitis, meningitis and post-obesity, use of a compound according to any one of claims 1 to 8 for treating or preventing symptoms resulting from inflammation of the CNS.

14. Use of a compound according to any one of claims 1 to 8 for the treatment or prevention of multiple sclerosis.

15. Use of a compound according to any one of claims 1 to 8 for the preparation of a medicament for treating or preventing symptoms resulting from direct damage to the myelin sheath (including, but not limited to, central and peripheral myelinolysis, carbon monoxide poisoning, nutritional deficiencies, and virus-induced demyelination), demyelinating disorders (including, but not limited to, multiple sclerosis, acute and polyphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorder, and leukodystrophy), CNS disorders associated with myelin loss (including, but not limited to, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and ischemia due to stroke), and inflammation of the CNS, such as after encephalitis, primary vasculitis, meningitis, and obesity.

16. A compound according to any one of claims 1 to 8 for use in the treatment or prevention of symptoms resulting from direct damage to the myelin sheath (including, but not limited to, central and peripheral myelinolysis, carbon monoxide poisoning, nutritional deficiencies, and virus-induced demyelination), demyelinating disorders (including, but not limited to, multiple sclerosis, acute and polyphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorder, and leukodystrophy), CNS disorders associated with myelin loss (including, but not limited to, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and ischemia due to stroke), and inflammation of the CNS, such as after encephalitis, primary vasculitis, meningitis, and obesity.

17. A compound according to any one of claims 1 to 8 for use in the treatment or prevention of multiple sclerosis.

18. Direct damage to myelin sheaths (including, but not limited to, central pontine myelinolysis and extrapontine myelinolysis, carbon monoxide poisoning, nutritional deficiencies, and virus-induced demyelination), demyelinating disorders (including, but not limited to, multiple sclerosis, acute and polyphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorder, and leukodystrophy), CNS disorders associated with myelin loss (including, but not limited to, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and ischemia due to stroke), and a method for treating or preventing symptoms resulting from inflammation of the CNS, such as encephalitis, primary vasculitis, meningitis, and after obesity, comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 8.

19. A method for treating or preventing multiple sclerosis, comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 8.

20. A compound according to any one of claims 1 to 8 when manufactured according to the method of claim 9.

21. The invention as described above.

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