Novel isothiazol-3-yl and isoxazol-3-yl sulfonamide compounds

Abstract

The present invention relates to a novel compound having the general formula (I): TIFF2025523166000078.tif36165 (wherein R 1 , R 2 , R 3 , X and Y are as described herein) and to compositions containing the compound and methods of using the compound.

Description

Technical Field

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

[0002] The present invention relates to formula I:

Chemical formula

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

Background Art

[0004] Background of the Invention 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 nerve / glia antigen 2 (NG2) and platelet-derived growth factor alpha (PDGFRα), and differentiates 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 is also controlled by an internal brake within the oligodendrocytes themselves, the transcription factor EB (TFEB)-PUMA axis, or 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 intracellular association with a small heterotrimeric G protein complex consisting of G α , G β , G Υ 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 targets phospholipase C via 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, it was found that GPR17 expression is present at low levels in the early stages of OPCs, increases in pre-myelinating oligodendrocytes, and then decreases 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 the prediction that it serves as 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”). Therefore, antagonizing GPR17, which promotes the differentiation of oligodendrocyte lineage cells into mature myelinating oligodendrocytes, will result in increased myelination after demyelination.

[0007] Multiple sclerosis (MS) is a chronic neurodegenerative disease characterized by the loss of myelin, a protective lipid layer that surrounds axons in the central nervous system (CNS). Preventing remyelination of axons that have lost or shed their myelin 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, due to the reparative effects of myelin repair on the CNS. Repair of lost myelin alleviates the neurological symptoms associated with MS due to its neuroprotective effect of preserving axons.

[0008] Because myelin formation plays an essential role in the function of the nervous system, promoting the differentiation of OPCs into oligodendrocytes can affect white matter deficits / 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 in which GPR17 antagonism can be used to achieve a positive disease outcome include, but are not limited to, the following: Direct damage to the myelin sheath: - Metabolic conditions that cause destruction of central nervous system myelin, such as central pontine myelinolysis, extrapontine myelinolysis due to overly rapid correction of hyponatremia in conditions such as alcohol dependence, liver disease, post-transplant immunosuppression, etc. - Carbon monoxide poisoning in which oligodendrocyte dysfunction and failure to regenerate have been reported in the deep white matter layers of the brain - Nutritional deficiencies that result in myelin loss or failure to properly generate developing myelin - 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 angiitis, inflammation of the CNS after meningitis

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

[0011] Accordingly, 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] SUMMARY OF THE INVENTION The present invention relates to a compound of formula I:

Chemical formula

[0014] The term "alkyl" represents a monovalent straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, unless otherwise stated, alkyl is 1 to 6 carbon atoms (C 1~6 -alkyl) or 1 to 4 carbon atoms (C1~4 -alkyl). C 1-6 Examples of -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 can be included. Thus, for example, "butyl" can include n-butyl, sec-butyl, iso-butyl, and t-butyl, and "propyl" can include n-propyl and isopropyl.

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

[0016] The term "cyano" represents a -C≡N group.

[0017] "Cyanoalkyl" means a moiety of the formula -R'-R" where R' is an alkyl as defined herein and R" is cyano or nitrile. A specific example is cyanoethyl.

[0018] The terms "halogen", "halide", and "halo" are used interchangeably herein and represent fluoro, chloro, bromo, or iodo. Specific halogens are chloro and bromo.

[0019] The term "pharmaceutically acceptable salt" refers to salts of the free base or free acid 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 from the addition of 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 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, salts of polyamine resins, but are not limited thereto. 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 yield 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 may exist in the form of optically pure enantiomers, mixtures of enantiomers such as racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.

[0024] According to the Cahn-Ingold-Prelog rules, the asymmetric carbon atoms can be of the "R" or "S" configuration.

[0025] Also, one embodiment of the present invention provides a compound according to formula I as described herein and a pharmaceutically acceptable salt or ester thereof, in particular a compound according to formula I as described herein and a pharmaceutically acceptable salt thereof, more specifically, a compound according to formula I as described herein.

[0026] One embodiment of the present invention is an R 1 which is alkyl, alkoxy, cyanoalkyl or cyclopropyl, and provides a compound according to formula I as described herein.

[0027] One embodiment of the present invention is an R 2 which is H, alkyl, alkoxy, cyano, cyclopropyl or halo, and provides a compound according to formula I as described herein.

[0028] One embodiment of the present invention is an R 2 which is alkoxy or halo, and provides a compound according to formula I as described herein.

[0029] One embodiment of the present invention is an R 3 which is halo or alkyl, and provides a compound according to formula I as described herein.

[0030] One embodiment of the present invention is an R 3 which is halo, and provides a compound according to formula I as described herein.

[0031] One embodiment of the present invention provides a compound of formula I as described herein, wherein X is -S-.

[0032] One embodiment of the present invention is R 1 is alkyl, alkoxy, cyanoalkyl or cyclopropyl; R 2 is H, alkyl, alkoxy, cyano, cyclopropyl or halo; R 3 is halo; X is -O- or -S-; Y is CH or N; The present invention provides a compound of formula I as described herein, and a pharmaceutically acceptable salt thereof.

[0033] One embodiment of the present invention is R 1 is alkyl, alkoxy, cyanoalkyl or cyclopropyl; R 2 is alkoxy or halo; R 3 is halo; X is -S-; Y is CH or N; The present invention provides a compound of formula I as described herein, and a pharmaceutically acceptable salt thereof.

[0034] Specific examples of the compounds of formula I described herein are 6-Chloro-N-(4-chloro-5-propyl-isothiazol-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4-chloro-5-cyclopropyl-isothiazol-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4-chloro-5-cyclopropyl-isothiazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Bromo-N-(4-chloro-5-cyclopropyl-isothiazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Chloro-N-(4-chloro-5-methyl-isothiazol-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4,5-dimethylisothiazol-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(5-ethyl-4-methyl-isoxazol-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4-chloro-5-ethyl-isothiazol-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4-ethyl-5-methyl-isothiazol-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4-chloro-5-methoxy-isothiazol-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4-chloro-5-ethoxy-isothiazol-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[4-chloro-5-(2-cyanoethyl)isothiazol-3-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-(5-methylisothiazol-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4-cyclopropyl-5-methyl-isothiazol-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4-cyano-5-methyl-isothiazol-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4-methoxy-5-methyl-isothiazol-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4-methoxy-5-propyl-isothiazol-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4-methyl-5-propyl-isoxazol-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4,5-dimethylisoxazol-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4-chloro-5-methyl-isoxazol-3-yl)-1H-indole-3-sulfonamide; N-(4-Bromo-5-methyl-isoxazol-3-yl)-6-chloro-1H-indole-3-sulfonamide; and is selected from pharmaceutically acceptable salts thereof.

[0035] Preferred examples of the compounds of formula I described herein are 6-Chloro-N-(4-chloro-5-propyl-isothiazol-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4-chloro-5-cyclopropyl-isothiazol-3-yl)-1H-indole-3-sulfonamide; 6-Bromo-N-(4-chloro-5-cyclopropyl-isothiazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Chloro-N-(4-chloro-5-methyl-isothiazol-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4-chloro-5-ethyl-isothiazol-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4-chloro-5-ethoxy-isothiazol-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[4-chloro-5-(2-cyanoethyl)isothiazol-3-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-(4-methoxy-5-propyl-isothiazol-3-yl)-1H-indole-3-sulfonamide; and is selected from pharmaceutically acceptable salts thereof.

[0036] The method for the production of the compounds of formula I described in this specification is an object of the present invention.

[0037] 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 methods described below. This method involves reacting a compound of formula III with a compound of formula II in the presence of a base selected from N-ethyldiisopropylamine or pyridine, with or without the addition of the catalyst 4-dimethylaminopyridine, or in the presence of an inorganic base such as potassium phosphate, to provide a compound of formula I.

Chemical formula

[0038] General synthetic scheme The compounds of formula I can be prepared according to variations of the above methods and according to Scheme 1 below. The starting materials can be commercially available or can be prepared according to known methods.

[0039]

Chemical formula

[0040]

Chemical formula

[0041] 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, and a method of using a compound of the present invention for preparing such a composition and medicament. 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 in the range of about 3 to about 8. In one example, a compound of formula I is formulated in an acetate buffer at pH 5. In another embodiment, a 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.

[0042] The compositions are compounded, dispensed, 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 delivery of the agent, the method of administration, the dosing schedule, and other factors known to the physician.

[0043] 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, when local treatment is desired, intralesional administration. Parenteral injection includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0044] 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 include conventional ingredients in pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, bulking agents and further active agents.

[0045] Typical formulations are prepared by mixing the compounds of the present invention with a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art, for example, 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 can also include one or more buffering agents, stabilizers, surfactants, wetting agents, lubricants, emulsifying agents, suspending agents, preservatives, antioxidants, opacifying agents, flow promoters, processing aids, coloring agents, sweeteners, fragrances, flavoring agents, diluents and other known additives to provide an excellent appearance of the drug (i.e., the compound of the present invention or its pharmaceutical composition) or to assist in the manufacture of the pharmaceutical product (i.e., the medicine).

[0046] 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.

[0047] Adjuvants suitable for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances, and liquid polyols.

[0048] Adjuvants suitable for the manufacture of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc.

[0049] Adjuvants suitable for injection solutions are, for example, water, alcohol, polyols, glycerol, vegetable oils, etc.

[0050] Adjuvants suitable for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc.

[0051] Adjuvants suitable for topical ophthalmic preparations are, for example, cyclodextrin, mannitol or many other carriers and excipients known in the art.

[0052] Furthermore, the pharmaceutical preparation may contain preservatives, solubilizers, viscosity increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for changing the osmotic pressure, buffers, masking agents, or antioxidants. They may also contain further other therapeutically valuable substances.

[0053] The dosage can be varied widely and, of course, can be adapted to the individual requirements in each particular 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, if appropriate, can consist of, for example, the same amounts. In the case of topical administration, the formulation can contain 0.001 wt% to 15 wt% of the medicament, 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, if so indicated, it can exceed the upper or lower limits given herein.

[0054] The present invention also relates, in particular, to the following: A compound of formula I for use as a therapeutic active substance; A compound of formula (I) for use in the treatment of a disease regulated by GPR17.

[0055] 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.

[0056] 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, direct damage to the myelin sheath (including, but not limited to, central and extracerebral 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 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).

[0057] 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.

[0058] A specific embodiment of the present invention is the use of a compound of formula I for treating or preventing multiple sclerosis.

[0059] The use of a compound of formula I for preparing a medicament for treating or preventing symptoms resulting from inflammation of the CNS, such as, for example, encephalitis, primary vasculitis, meningitis, and after obesity, as well as direct damage to the myelin sheath (including, but not limited to, central and peripheral myelinolysis, carbon monoxide poisoning, nutritional deficiency, 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).

[0060] One embodiment of the present invention is the use of a compound of formula I for preparing a medicament for treating or preventing multiple sclerosis, Alzheimer's disease, Parkinson's disease, or Huntington's disease.

[0061] A specific embodiment of the present invention is the use of a compound of formula I for preparing a medicament for treating or preventing multiple sclerosis.

[0062] Direct damage to the myelin sheath (including, but not limited to, central and periaxonal myelinolysis, carbon monoxide poisoning, nutritional deficiency, 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 compounds of formula I for use in the treatment or prevention of symptoms resulting from inflammation of the CNS, such as, for example, encephalitis, primary vasculitis, meningitis, and post-obesity.

[0063] 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.

[0064] A particular embodiment of the invention is a compound of formula I for use in the treatment or prevention of multiple sclerosis.

[0065] A method for treating or preventing direct damage to the myelin sheath (including, but not limited to, central and periaxonal myelinolysis, carbon monoxide poisoning, nutritional deficiency, 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 symptoms resulting from inflammation of the CNS, 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.

[0066] One embodiment of the invention is a method for treating or preventing multiple sclerosis, Alzheimer's disease, Parkinson's disease, or Huntington's disease, the method comprising administering an effective amount of a compound of formula I to a patient in need thereof.

[0067] A particular embodiment of the present invention is a method for treating or preventing multiple sclerosis, the method comprising administering to a patient in need thereof an effective amount of a compound of formula I.

[0068] Also, an embodiment of the present invention provides a compound of formula I described herein when manufactured according to any one of the methods described.

[0069] Assay Procedure GPR17 cAMP Assay Protocol: CHO-K1 cells stably expressing a vector containing 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.

[0070] 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 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.

[0071] CHO-GPR17S cells were detached with Accutase and resuspended in an 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 in black 384-well plates (Corning) at a density of 10,000 cells / 20 μl assay buffer until the addition of the compound.

[0072] Test antagonist compounds were serially diluted with dimethyl sulfoxide (DMSO) and spotted onto 384-well plates. The compounds were 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 of 0.5 mM) and added to the cells at room temperature. Forskolin (final concentration of 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 a surfactant for cell lysis) at room temperature for 90 minutes.

[0073] Cell cAMP 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 percentage of activity of the test compound using a sigmoid dose-response model (Genedata Screener).

[0074] The results of the hGPR17 cAMP assay are provided for the compounds of formula I in Table 1.

Table 1

[0075] The present invention will now be described by the following examples, which have no limiting features.

[0076] When the 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.

Examples

[0077] Unless otherwise specified, all examples and intermediates were prepared under an argon atmosphere.

[0078] Intermediate A Intermediate A1: 6-Chloro-1H-indole-3-sulfonyl chloride

Chemical formula

[0079] Intermediate A2: 6-Chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonyl chloride

Chemical formula

[0080] Intermediate A3: 6-Bromo-1H-pyrrolo[2,3-b]pyridine-3-sulfonyl chloride

Chemical formula

[0081] Intermediate B Intermediate B1: 4-Chloro-5-propyl-isothiazol-3-amine hydrochloride

Chemical formula

[0082] Step 1: Methyl 4-chloro-5-prop-1-en-1-yl-isothiazole-3-carboxylate

Chem.

[0083] Step 2: Methyl 4-chloro-5-propyl-isothiazole-3-carboxylate

Chem.

[0084] The reaction mixture was filtered through Celite and concentrated in vacuo to give methyl 4-chloro-5-propyl-isothiazole-3-carboxylate (33 mg, 24%) as an off-white liquid. MS m / z: 220.1 [M+H] + ,ESI pos.

[0085] Step 3: 4-Chloro-5-propyl-isothiazole-3-carboxylic acid

Chemical formula

[0086] Step 4: tert-Butyl N-(4-chloro-5-propyl-isothiazol-3-yl)carbamate

Chemical formula

[0087] Step 5: 4-Chloro-5-propyl-isothiazol-3-amine hydrochloride

Chem.

[0088] Intermediate B2: 4-Methoxy-2-propyl-pyrimidin-5-amine hydrochloride

Chem.

[0089] Step 1: Methyl 4-chloro-5-cyclopropyl-isothiazole-3-carboxylate [Chem.] A reaction mixture of methyl 4,5-dichloro-isothiazole-3-carboxylate (CAS 166668-76-4, 200 mg, 0.943 mmol), potassium cyclopropyl(trifluoro)borate (698 mg, 4.72 mmol), palladium(II) acetate (11 mg, 0.047 mmol), di(adamantan-1-yl)(butyl)phosphine (17 mg, 0.047 mmol) and cesium carbonate (922 mg, 2.83 mmol) in toluene (3.5 ml) and water (0.35 ml) was stirred at 100 °C for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate (2 × 20 ml). The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0 - 25% ethyl acetate in heptane) to give methyl 4-chloro-5-cyclopropyl-isothiazole-3-carboxylate (111 mg, 51% yield) as a pale yellow oil. MS m / z: 218.0 [M+H] + , ESI pos.

[0090] Step 2: 4-Chloro-5-cyclopropyl-isothiazole-3-carboxylic acid [Chem.] To a solution of methyl 4-chloro-5-cyclopropyl-isothiazole-3-carboxylate (111 mg, 0.484 mmol) in tetrahydrofuran (2 ml) was added 1 M aqueous sodium hydroxide solution (581 μl, 0.581 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was acidified with 1 M aqueous hydrochloric acid and extracted with ethyl acetate (3 × 10 ml). The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered and concentrated to give 4-chloro-5-cyclopropyl-isothiazole-3-carboxylic acid (97 mg, 97%) as a light brown powder. MS m / z: 204.0 [M+H] + , ESI pos.

[0091] Step 3: tert-Butyl N-(4-chloro-5-cyclopropyl-isothiazol-3-yl)carbamate

Chem.

[0092] Step 4: 4-Methoxy-2-propyl-pyrimidin-5-amine hydrochloride

Chem.

[0093] Intermediate B3: 4-Chloro-5-methyl-isothiazol-3-amine

Chem.

[0094] Step 1: Methyl 4,5-dichloro-isothiazole-3-carboxylate

Chem.

[0095] Step 2: 4-Chloro-5-methyl-isothiazole-3-carboxylic acid

Chem.

[0096] Step 3: 4-Chloro-5-methyl-isothiazol-3-amine

Chemical formula

[0097] To obtain a second batch of the title compound, tert-butyl N-(4-chloro-5-methyl-isothiazol-3-yl)carbamate (20 mg, 0.081 mmol) was dissolved in 1,2-dichloroethane (0.17 ml) and trifluoroacetic acid (46 mg, 31 μl, 0.404 mmol). After stirring for 8 hours, the reaction mixture was quenched with saturated sodium bicarbonate solution at room temperature and extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to obtain the title compound (9 mg, yield 73%) as an off-white solid. MS m / z: 149.1 [M+H], ESI pos. + ,ESI pos.

[0098] Intermediate B4: 4,5-Dimethylisothiazol-3-amine

Chemical Structure

[0099] Project 1: tert-Butyl N-(5-Methylisothiazol-3-yl)carbamate [Chemical Formula] To a solution of 5-Methylisothiazole-3-carboxylic acid (300 mg, 2.1 mmol) and triethylamine (233 mg, 322 μl, 2.31 mmol) in tetrahydrofuran (9 ml) was added ethyl chloroformate (250 mg, 220 μl, 2.31 mmol) dropwise at -10 °C. The mixture was stirred at -10 °C for 30 minutes. Then, an aqueous solution (3 ml) of sodium azide (682 mg, 10.5 mmol) was added slowly, the mixture was warmed to room temperature and stirred for 1 hour. The mixture was diluted with ice / water (20 ml) and extracted with dichloromethane (3 × 20 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in toluene (9 ml), tert-butanol (4.5 ml) was added, and the mixture was heated at 80 °C for 3.5 hours. The mixture was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0 - 30% ethyl acetate in heptane) to give tert-Butyl N-(5-Methylisothiazol-3-yl)carbamate (233 mg, 52% yield) as a white solid. MS m / z: 159.0 [M-isobutene + H] + ,ESI pos.

[0100] Project 2: tert-Butyl N-(4-Bromo-5-methyl-isothiazol-3-yl)carbamate [Chemical Formula] A solution of tert-butyl N-(5-methylisothiazol-3-yl)carbamate (203 mg, 0.947 mmol) in acetic acid (2.6 ml) was added with sodium acetate (256 mg, 3.13 mmol) at 22 °C, and subsequently, bromine (332 mg, 108 μl, 2.08 mmol) was added. The tube was sealed and the mixture was stirred at 50 °C for 1.5 hours. After cooling, the mixture was poured into cold 10% aqueous sodium carbonate solution (60 ml). The aqueous layer was extracted with ethyl acetate (2 × 50 ml), then the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo.

[0101] The residue was purified by flash column chromatography (silica gel, 0 - 30% ethyl acetate in heptane) to give tert-butyl N-(4-bromo-5-methyl-isothiazol-3-yl)carbamate (128 mg, 46% yield) as a pale yellow oil. MS m / z: 237.0, 239.0 [M+H] + ,ESI pos.

[0102] Step 3: tert-butyl N-(4,5-dimethylisothiazol-3-yl)carbamate

Chemical formula

[0103] Step 4: 4,5-Dimethylisothiazol-3-amine

Chemical Structure

[0104] Intermediate B5: 5-Ethyl-4-methyl-isoxazol-3-amine

Chemical formula

[0105] Step 1: tert-Butyl N-(5-ethyl-4-methyl-isoxazol-3-yl)carbamate

Chemical formula

[0106] Step 2: 5-Ethyl-4-methyl-isoxazol-3-amine

Chemical formula

[0107] Intermediate B6: 4-Chloro-5-ethyl-isothiazol-3-amine

Chemical formula

[0108] Intermediate B7: 4-Ethyl-5-methyl-isothiazol-3-amine [ka]

[0109] Step 1: 5-Methyl-4-vinyl-isothiazol-3-amine [ka] tert-Butyl N-(4-bromo-5-methyl-isothiazol-3-yl)carbamate (Intermediate B4, Step 2, 300 mg, 0.972 mmol, see reference), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (195 mg, 1.26 mmol), 1,4-dioxane (4 ml), 2M aqueous sodium carbonate solution (1.46 ml, 2.92 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (80 mg, 0.097 mmol) were added under argon. The reaction mixture was stirred at 90 °C overnight. After cooling to room temperature, 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. The residue was dissolved in dichloromethane (2 ml), trifluoroacetic acid (1.11 g, 749 μl, 9.72 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was poured into saturated sodium bicarbonate solution and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0 - 50% ethyl acetate in heptane) to give 5-methyl-4-vinyl-isothiazol-3-amine (76 mg, 53% yield) as an off-white solid. MS(ESI) m / z: 141.1 [M+H] + .

[0110] Step 2: 4-Ethyl-5-methyl-isothiazol-3-amine

Chemical Structure

[0111] Intermediate B8: 4-chloro-5-methoxy-isothiazol-3-amine

Chemical formula

[0112] Step 1: 4-chloro-5-methoxy-isothiazole-3-carboxylic acid

Chemical formula

[0113] Step 2: 4-Chloro-5-methoxy-isothiazol-3-amine

Chem.

[0114] Intermediate B9: 4-Chloro-5-ethoxy-isothiazol-3-amine

Chem.

[0115] Intermediate B10: 3-(3-Amino-4-chloro-isothiazol-5-yl)propanenitrile trifluoroacetate

Chem.

[0116] Step 1: Methyl 4-chloro-5-(2-cyanoethyl)isothiazole-3-carboxylate

Chem.

[0117] Step 2: 4-Chloro-5-(2-cyanoethyl)isothiazole-3-carboxylic acid

Chem.

[0118] Step 3: tert-Butyl N-[4-chloro-5-(2-cyanoethyl)isothiazol-3-yl]carbamate

Chem.

[0119] Step 4: 3-(3-Amino-4-chloro-isothiazol-5-yl)propanenitrile trifluoroacetate

Chemical Structure

[0120] Intermediate B11: 5-Methylisothiazol-3-amine

Chemical Structure

[0121] Intermediate B12: 4-Cyclopropyl-5-methyl-isothiazol-3-amine [Chemical formula] To a solution of tert-butyl N-(4-bromo-5-methyl-isothiazol-3-yl)carbamate (Intermediate B4 Step 2, 200 mg, 0.682 mmol, see) in toluene (4 ml) at room temperature was added cyclopropylboronic acid (147 mg, 1.71 mmol), followed by potassium phosphate in water (579 mg, 2.73 mmol) (0.8 ml). The mixture was degassed by purging with argon for 10 minutes. Then, palladium(II) acetate (7.5 mg, 0.034 mmol) was added, followed by tricyclohexylphosphine (19 mg, 0.068 mmol), and the mixture was purged with argon again. The tube was sealed and heated to 100 °C for 3 hours, then the mixture was cooled to 22 °C, treated with aqueous sodium carbonate (30 ml), and extracted with ethyl acetate (2 × 30 ml). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0 - 100% ethyl acetate in heptane) to give tert-butyl N-(4-cyclopropyl-5-methyl-isothiazol-3-yl)carbamate (45 mg, 26%) and 4-cyclopropyl-5-methyl-isothiazol-3-amine (51 mg, 48%).

[0122] To obtain the second batch of the title compound, tert-butyl N-(4-cyclopropyl-5-methyl-isothiazol-3-yl)carbamate (36 mg, 0.142 mmol) was dissolved in dichloromethane (1.3 ml), trifluoroacetic acid (162 mg, 108 μl, 1.42 mmol) was added at room temperature, and the mixture was stirred overnight. The mixture was concentrated in vacuo, the residue was treated with saturated aqueous sodium bicarbonate (10 ml), and extracted with ethyl acetate (2 × 10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 10 - 70% ethyl acetate in heptane) to give the title compound (18 mg, 80% yield) as an off-white solid. MS(ESI) m / z: 155.0 [M+H] + ,ESI pos.

[0123] Intermediate B13: 3-Amino-5-methyl-isothiazole-4-carbonitrile

Chem.

[0124] Intermediate B14: 4-Methoxy-5-methyl-isothiazol-3-amine

Chem.

[0125] Step 1: 4-Iodo-5-methyl-isothiazole-3-carboxylic acid

Chem.

[0126] Step 2: 4-Methoxy-5-methyl-isothiazole-3-carboxylic acid

Chemical formula

[0127] Step 3: 4-Methoxy-5-methyl-isothiazole-3-amine

Chemical formula

[0128] Intermediate B15: 4-Methoxy-5-propyl-isothiazol-3-amine

Chemical Structure

[0129] Step 1: Ethyl 5-bromo-4-methoxy-isothiazole-3-carboxylate

Chemical Structure

[0130] Step 2: Ethyl 4-methoxy-5-prop-1-enyl-isothiazole-3-carboxylate

Chemical formula

[0131] Step 3: Ethyl 4-methoxy-5-propyl-isothiazole-3-carboxylate

Chem.

[0132] Step 4: 4-Methoxy-5-propyl-isothiazole-3-carboxylic acid

Chem.

[0133] Step 5: tert-Butyl N-(4-methoxy-5-propyl-isothiazol-3-yl)carbamate [Chem.] A solution of 4-methoxy-5-propyl-isothiazole-3-carboxylic acid (110 mg, 0.55 mmol), diphenylphosphonic azide (150 mg, 0.12 ml, 0.55 mmol) and triethylamine (111 mg, 0.15 ml, 1.09 mmol) in tert-butanol (0.5 ml) was heated at 90 °C for 18 h. The reaction mixture was quenched with potassium carbonate solution and extracted with ethyl acetate to give tert-butyl N-(4-methoxy-5-propyl-isothiazol-3-yl)carbamate (118 mg, 53% yield), MS (ESI) m / z: 217.02 [M-tBu+H] + , ESI pos.

[0134] Step 6: 4-Methoxy-5-propyl-isothiazol-3-amine [Chem.] Trifluoroacetic acid (0.5 ml) was added to a stirred solution of tert-butyl N-(4-methoxy-5-propyl-isothiazol-3-yl)carbamate (118 mg, 0.43 mmol) in dichloromethane (0.5 ml) and the reaction mixture was stirred at 20 °C for 18 h. Water and ammonium hydroxide solution (25%) were added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (87 mg, 85% purity, 99% yield) as an oil, MS (ESI) m / z: 173.0 [M+H] + , ESI pos.

[0135] Intermediate B16: 4-Methyl-5-propyl-isoxazol-3-amine [Chem.] Intermediate B16 is commercially available (CAS 1207175-25-4).

[0136] Intermediate B17: 4,5-Dimethylisoxazol-3-amine

Chem.

[0137] Intermediate B18: 4-Chloro-5-methyl-isoxazol-3-amine

Chem.

[0138] Intermediate B19: 4-Bromo-5-methyl-isoxazol-3-amine

Chem.

[0139] Examples Example 1: 6-Chloro-N-(4-chloro-5-propyl-isothiazol-3-yl)-1H-indole-3-sulfonamide

Chem.

[0140] Examples 2 to 4 below were prepared in the same manner as Example 1 by coupling the sulfonyl chloride intermediate A and amine intermediate B shown.

Table 2

[0141] Example 5: 6-Chloro-N-(4-chloro-5-methyl-isothiazol-3-yl)-1H-indole-3-sulfonamide

Chemical formula

[0142] The following Examples 6 - 14 were prepared in the same manner as Example 5 by coupling the sulfonyl chloride Intermediate A and the amine Intermediate B shown.

Table 3

[0143] Example 15: 6-Chloro-N-(4-cyano-5-methyl-isothiazol-3-yl)-1H-indole-3-sulfonamide

Chemical Structure

[0144] The following Examples 16 - 17 were prepared in the same manner as Example 15 by coupling the indicated sulfonyl chloride Intermediate A and amine Intermediate B.

Table 4

[0145] Example 18: 6-Chloro-N-(4-methyl-5-propyl-isoxazol-3-yl)-1H-indole-3-sulfonamide

Chem.

[0146] Example 19: 6-Chloro-N-(4,5-dimethylisoxazol-3-yl)-1H-indole-3-sulfonamide

Chem.

[0147] Example 20: 6-Chloro-N-(4-chloro-5-methyl-isoxazol-3-yl)-1H-indole-3-sulfonamide

Chem.

[0148] Example 21: N-(4-Bromo-5-methyl-isoxazol-3-yl)-6-chloro-1H-indole-3-sulfonamide

Chem.

[0149] Example A The compound of formula I can be used as an active ingredient in a manner known per se to produce tablets of the following composition: Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropyl methylcellulose 20 mg 425 mg

[0150] Example B The compound of formula I can be used as an active ingredient in a manner known per se to produce 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: 【Chemistry 1】 (In the formula, R １ These are alkyl, alkoxy, cyano, cyanoalkyl, cyclopropyl, or halo; R ２ is H, alkyl, alkoxy, cyano, cyclopropyl or halo; R ３ is halo, alkyl, or haloalkyl; X is either -O- or -S-; Y is either CH or N. Compounds thereof, or pharmaceutically acceptable salts thereof.

2. R １ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is alkyl, alkoxy, cyanoalkyl, or cyclopropyl.

3. R ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is H, alkyl, alkoxy, cyano, cyclopropyl, or halo.

4. R ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is an alkoxy or a halo.

5. R ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is halo or alkyl.

6. R ３ A compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is a halo.

7. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X is -S-.

8. R １ is alkyl, alkoxy, cyanoalkyl or cyclopropyl; R ２ However, it is H, alkyl, alkoxy, cyano, cyclopropyl or halo; R ３ But it's a halo; X is either -O- or -S-; Y is CH or N. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

9. R １ However, these are alkyl, alkoxy, cyanoalkyl, or cyclopropyl; R ２ However, it is an alkoxy or halo; R ３ But it's a halo; X is -S-; Y is CH or N. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

10. 6-Chloro-N-(4-Chloro-5-propyl-isothiazole-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4-Chloro-5-cyclopropyl-isothiazol-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4-Chloro-5-cyclopropyl-isothiazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-bromo-N-(4-chloro-5-cyclopropyl-isothiazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Chloro-N-(4-Chloro-5-methylisothiazol-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4,5-dimethylisothiazole-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(5-ethyl-4-methyl-isoxazole-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4-Chloro-5-ethyl-isothiazole-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4-ethyl-5-methylisothiazol-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4-Chloro-5-methoxyisothiazole-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4-Chloro-5-ethoxyisothiazole-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[4-Chloro-5-(2-cyanoethyl)isothiazol-3-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-(5-methylisothiazol-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4-cyclopropyl-5-methylisothiazol-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4-cyano-5-methylisothiazol-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4-methoxy-5-methylisothiazol-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4-methoxy-5-propyl-isothiazole-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4-methyl-5-propyl-isoxazole-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4,5-dimethylisoxazole-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4-Chloro-5-methyl-isoxazol-3-yl)-1H-indole-3-sulfonamide; N-(4-bromo-5-methyl-isoxazole-3-yl)-6-chloro-1H-indole-3-sulfonamide A compound according to claim 1, selected from, or a pharmaceutically acceptable salt thereof.

11. 6-Chloro-N-(4-Chloro-5-propyl-isothiazole-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4-Chloro-5-cyclopropyl-isothiazol-3-yl)-1H-indole-3-sulfonamide; 6-bromo-N-(4-chloro-5-cyclopropyl-isothiazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Chloro-N-(4-Chloro-5-methylisothiazol-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4-Chloro-5-ethyl-isothiazole-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4-Chloro-5-ethoxyisothiazole-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[4-Chloro-5-(2-cyanoethyl)isothiazol-3-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-(4-methoxy-5-propyl-isothiazole-3-yl)-1H-indole-3-sulfonamide A compound according to claim 1, selected from, or a pharmaceutically acceptable salt thereof.

12. A method for preparing a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, To provide a compound of formula I, by reacting a compound of formula III with a compound of formula II in the presence of a base selected from N-ethyldiisopropylamine or pyridine, or in the presence of an inorganic base such as potassium phosphate, with or without the addition of the catalyst 4-dimethylaminopyridine. 【Chemistry 2】 (In the formula, R １ , R ２ , R ３ (X and Y are as defined in any one of claims 1 to 9) Methods that include...

13. A compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

14. A compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of diseases modulated by GPR17.

15. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 for use in the treatment or prevention of conditions resulting from direct damage to the myelin sheath (including, but not limited to, central 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), or inflammation of the CNS (including, but not limited to, encephalitis, primary vasculitis, meningitis, and post-obesity).

16. A compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of multiple sclerosis.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof.

18. The pharmaceutical composition according to claim 17 for treating or preventing a disease regulated by GPR17.

19. The pharmaceutical composition according to claim 17 for treating or preventing conditions resulting from direct damage to the myelin sheath (including, but not limited to, central 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), or inflammation of the CNS (including, but not limited to, encephalitis, primary vasculitis, meningitis, and post-obesity).

20. A pharmaceutical composition according to claim 17 for treating or preventing multiple sclerosis.

21. Use of a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof for preparing a medicament for treating or preventing a disease regulated by GPR17.

22. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 for preparing a medicament for treating or preventing conditions resulting from direct damage to the myelin sheath (including, but not limited to, central 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), or inflammation of the CNS (including, but not limited to, encephalitis, primary vasculitis, meningitis, and post-obesity).

23. Use of a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof for preparing a medicament for treating or preventing multiple sclerosis.

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