Novel pyrimidinyl and triazinyl sulfonamide derivatives

Abstract

The present invention relates to novel compounds having the general formula (I) wherein R4, R5, X1, X2, X3 and Y1 are as described herein; comprising the compound; and methods of using the compounds. # imgabs0 #

Description

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

[0002] The present invention provides novel compounds of formula I,

[0003]

[0004] in,

[0005] R 4 is alkyl, halo, haloalkyl or haloalkoxy;

[0006] R 5 is halogenated or halogenated alkyl;

[0007] X1 is N, X2 is CR 2 And X3 is CR 3 , where R 2 H and R 3 is alkoxy, halo or haloalkoxy, or

[0008] X1 for CR 1 , X2 is N and X3 is N, where R 1 is an alkoxy group;

[0009] Y1 is CR 6 or N;

[0010] R 6 is H or halogenated;

[0011] and pharmaceutically acceptable salts thereof.

[0012] Furthermore, the present invention includes all racemic mixtures, all corresponding enantiomers and / or optical isomers thereof. Background Art

[0013] Myelination is a process that occurs intensely during development, and although there are abundant oligodendrocyte precursor cells (OPCs) throughout the adult CNS, the transition to myelinating oligodendrocytes and the process of generating restorative myelin around denuded axons is impaired in chronic demyelinating diseases. During development, myelination proceeds in a very orderly manner, with 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 NG2 and PDGFRα expression and gaining expression of markers such as myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG). Myelination by oligodendrocytes is a very tightly regulated process and in the CNS this may be controlled by interactions with axons, which is well understood in the peripheral nervous system but not in the central nervous system (Macklin, WB (2010). Sci. Signal. 3, pp. 32–33, “The myelin brake: When Enough Is Enough”). Myelination can also be controlled by internal brakes within the oligodendrocytes themselves through the transcription factor EB (TFEB)-PUMA axis or through GPR17 antagonism (Chen, Y. et al. (2009). Nat Neurosci 12, 1398–1406, “The oligodendrocyte-specific Gprotein-coupled receptor GPR17 is a cell-intrinsic timer of myelination”) (Sun, LO et al. (2018). Cell 175, 1811-1826.e21, “Spatiotemporal Control of CNS Myelination by Oligodendrocyte Programmed Cell Death through the TFEB-PUMAAxis”).Myelin not only protects axons and promotes neuronal transmission, but oligodendrocytes have also been shown to play an important role in axonal metabolism and maintaining 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”).

[0014] GPR17 is a class A orphan G protein-coupled receptor (GPCR). GPCR is a 7-domain transmembrane protein that binds to G α , G β , G γ The intracellular association of small heterotrimeric G protein complexes composed of subunits couples extracellular ligands to intracellular signals. α The coupling negotiation between the subunits generates downstream intracellular signaling pathways. GPR17 is known to directly bind to G αi / o This results in inhibition of adenylate cyclase activity, leading to a decrease in cyclic AMP production (cAMP). GPR17 has also been shown to bind to G q / 11 Coupling. Activation of phospholipase C leads to the cleavage of phosphatidylinositol 4,5-bisphosphate, which produces inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 then binds to IP3 receptors on the endoplasmic reticulum and causes an increase in intracellular calcium levels (Hanlon, CD and Andrew, DJ (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").

[0015] The role of GPR17 in myelination was first determined 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 (myelinating cells of the peripheral nervous system). GPR17 expression was found to be expressed only 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 in the early stages of OPCs and to increase in premyelinating oligodendrocytes before being 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 GPR17 knockout animals exhibit precocious myelination throughout the CNS, and conversely, transgenic mice overexpressing GPR17 with the CNP-Cre (2',3'-cyclic nucleotide 3'-phosphodiesterase) promoter in oligodendrocytes exhibit myelination defects, consistent with the expectation of a cell-intrinsic brake on myelination (Chen, Y. et al. (2009)).Furthermore, loss of GPR17 enhances remyelination after demyelination in 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, antagonism of GPR17, which promotes differentiation of oligodendrocyte lineage cells into mature myelin-forming oligodendrocytes, will lead to increased myelination after demyelination.

[0016] Multiple sclerosis (MS) is a chronic neurodegenerative disease characterized by the loss of myelin (the protective fatty lipid layer around the axons) in the central nervous system (CNS). Preventing myelin loss or remyelination of exposed axons is thought to prevent axonal degeneration, thereby preventing the progression of the disease (Franklin, RJ (2002), Nat Rev Neurosci 3, 705–714, “Why does remyelination fail in multiple sclerosis?”). Due to the restorative effect of myelin repair on the central nervous system, such treatment will benefit all types of MS, i.e., relapsing-remitting, secondary progressive, primary progressive, and progressive relapsing MS. Due to the neuroprotective effect of retaining axons, repairing lost myelin will alleviate the neurological symptoms associated with MS.

[0017] Since myelination plays an important role in nervous system function, promoting OPC differentiation into oligodendrocytes has the potential to impact a variety of diseases where white matter defects / irregularities due to loss of myelinating oligodendrocytes or blocked differentiation of OPC into oligodendrocytes have been observed, either due to the disease itself or inflammation. This is in addition to diseases where GPR17 expression itself is altered.

[0018] Therefore, diseases for which GPR17 antagonism could be used to produce positive disease results include, but are not limited to:

[0019] Direct damage to the myelin sheath:

[0020] - Metabolic disorders leading to central myelin destruction such as central pontine myelinolysis, extrapontine myelinolysis, due to too rapid correction of hyponatremia in cases such as, but not limited to, alcoholism, liver disease, post-transplant immunosuppression

[0021] - Carbon monoxide poisoning, oligodendrocyte dysfunction reported in deep white matter layers of the brain

[0022] and aplastic disease

[0023] -Nutrient deficiencies that lead to loss of myelin or failure to properly myelinate during development

[0024] - Virus-induced demyelination

[0025] Primary demyelinating diseases

[0026] -Multiple sclerosis (relapsing-remitting, secondary progressive, primary progressive, and progressive relapsing MS)

[0027] -Acute and multiphasic disseminated encephalomyelitis

[0028] - Neuromyelitis optica spectrum disorder, including optic neuritis

[0029] - Transverse myelitis

[0030] -Leukodystrophies such as adrenoleukodystrophy, adrenoleukodystrophy, and other hereditary leukodystrophies that cause loss of myelin

[0031] CNS diseases with associated myelin loss:

[0032] -Alzheimer's disease

[0033] - Schizophrenia

[0034] -Parkinson's disease

[0035] - Huntington's disease

[0036] -Amyotrophic lateral sclerosis

[0037] - Ischemia due to stroke

[0038] Other diseases:

[0039] - Inflammation in the CNS, eg, encephalitis, primary vasculitis, inflammation in the post-meningitis CNS The compounds of formula I bind to GPR17 and modulate its activity.

[0040] Therefore, the compounds of formula I are particularly useful for treating diseases associated with GPR17 antagonism.

[0041] The compounds of formula I are particularly useful for treating or preventing multiple sclerosis (MS), conditions associated with direct damage to the myelin sheath (such as carbon monoxide poisoning or virus-induced demyelination), primary demyelinating diseases (such as acute and multiphasic disseminated encephalomyelitis), and other CNS diseases associated with myelin loss (such as Alzheimer's disease, schizophrenia, Parkinson's disease and Huntington's disease). Summary of the invention

[0042] The present invention provides novel compounds of formula I,

[0043]

[0044] in,

[0045] R 4 is alkyl, halo, haloalkyl or haloalkoxy;

[0046] R 5 is halogenated or halogenated alkyl;

[0047] X1 is N, X2 is CR 2 And X3 is CR 3 , where R 2 H and R 3 is alkoxy, halo or haloalkoxy, or

[0048] X1 for CR 1 , X2 is N and X3 is N, where R 1 is an alkoxy group;

[0049] Y1 is CR 6 or N;

[0050] R 6 is H or halogenated;

[0051] and pharmaceutically acceptable salts thereof.

[0052] The term "alkyl" refers to a monovalent straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, if not otherwise specified, the alkyl group contains 1 to 6 carbon atoms (C 1-6 -alkyl) or 1 to 4 carbon atoms (C 1-4 -alkyl). 1-6 Examples of -alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and amyl. Specific alkyl groups include methyl, ethyl and propyl. When an alkyl residue with a specific carbon number is indicated, all geometric isomers with that carbon number may be encompassed. Thus, for example, "butyl" may include n-butyl, sec-butyl, isobutyl and tert-butyl, and "propyl" may include n-propyl and isopropyl.

[0053] The term "alkoxy" refers to a group of formula -O-R', wherein R' is C 1-6 -alkyl group. 1-6 Examples of -alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Specific examples are methoxy and ethoxy.

[0054] The terms "halogen", "halide" and "halo" are used interchangeably herein and refer to fluorine, chlorine, bromine or iodine. Specific halogens are fluorine, chlorine and bromine.

[0055] The term "haloalkyl" refers to a group in which C 1-6 -alkyl radicals wherein at least one hydrogen atom has been replaced by the same or different halogen atoms 1-6 -alkyl groups. Particular examples are difluoroethyl and trifluoromethyl.

[0056] The term "haloalkoxy" refers to a group in which C 1-6 -alkoxy radicals wherein at least one hydrogen atom has been replaced by the same or different halogen atoms 1-6 - alkoxy groups. Particular examples are fluoroethoxy, difluoromethoxy and difluoroethoxy.

[0057] The term "pharmaceutical salt" refers to those salts that retain the biological effect and properties of free alkali or free acid, which are not undesirable in biology or other aspects. These salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid (particularly 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 inorganic bases or organic bases to free acids. Salts derived from inorganic bases include but are not limited to sodium, potassium, lithium, ammonium, calcium, magnesium salts. Salts derived from organic bases include, but are not limited to, 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 the form of zwitterions. Particularly preferred pharmaceutically acceptable salts of the compounds of formula I are salts formed with formic acid and salts formed with hydrochloric acid to produce hydrochlorides, dihydrochlorides or trihydrochlorides.

[0058] The abbreviation uM means micromolar, and is equivalent to the symbol μM.

[0059] The abbreviation uL means microliter, and is equivalent to the symbol μL.

[0060] The abbreviation ug means microgram, and is equivalent to the symbol μg.

[0061] The compounds of formula I may contain several asymmetric centers and may exist as optically pure enantiomers, mixtures of enantiomers (eg racemates), optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates.

[0062] According to the Cahn-Ingold-Prelog convention, asymmetric carbon atoms can be in either the "R" or "S" configuration.

[0063] Another 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 particularly a compound according to formula I as described herein.

[0064] Embodiments of the present invention provide compounds according to formula I as described herein, wherein R 4 It is a halogenated alkoxy group.

[0065] Embodiments of the present invention provide compounds according to formula I as described herein, wherein R 5 It is halogenated.

[0066] One embodiment of the present invention provides a compound according to formula I as described herein, wherein R 6 For H.

[0067] One embodiment of the present invention provides a compound according to formula I as described herein, wherein X1 is N, X2 is CR 2 , X3 is CR 3 , where R 2 H and R 3 is an alkoxy group or a halogenated alkoxy group.

[0068] Embodiments of the present invention provide compounds according to formula I as described herein, wherein

[0069] R 4 is a halogenated alkoxy group;

[0070] R 5 is halogenated;

[0071] X1 is N, X2 is CR 2 And X3 is CR 3 , where R 2 H and R 3 is an alkoxy group or a haloalkoxy group;

[0072] Y1 is CR 6 or N;

[0073] R 6 is H;

[0074] and pharmaceutically acceptable salts thereof.

[0075] Particular examples of compounds of formula I as described herein are selected from

[0076] 6-Chloro-N-(4-methoxy-2-propyl-pyrimidin-5-yl)-1H-indole-3-sulfonamide;

[0077] 6-Chloro-N-(2-ethyl-4-methoxy-pyrimidin-5-yl)-1H-indole-3-sulfonamide;

[0078] 6-Chloro-N-[2-(difluoromethoxy)-4-methoxy-pyrimidin-5-yl]-1H-indole-3-sulfonamide;

[0079] 6-Chloro-N-[2-(2,2-difluoroethoxy)-4-methoxy-pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide;

[0080] 6-Chloro-N-[2-(2,2-difluoroethoxy)-4-(difluoromethoxy)pyrimidin-5-yl]-1H-indole-3-sulfonamide;

[0081] 6-Chloro-N-(2,4-dichloropyrimidin-5-yl)-1H-indole-3-sulfonamide;

[0082] 6-Chloro-N-(2-(2-fluoroethoxy)-4-methoxypyrimidin-5-yl)-1H-indole-3-sulfonamide;

[0083] 6-Chloro-N-(2-(2,2-difluoroethoxy)-4-methoxypyrimidin-5-yl)-1H-indole-3-sulfonamide;

[0084] 6-Bromo-N-[2-(2,2-difluoroethoxy)-4-methoxy-pyrimidin-5-yl]-1H-indole-3-sulfonamide;

[0085] 6-Bromo-N-[2-(2,2-difluoroethoxy)-4-methoxy-pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide;

[0086] N-[2-(2,2-difluoroethoxy)-4-methoxy-pyrimidin-5-yl]-6-(trifluoromethyl)-1H-indole-3-sulfonamide;

[0087] 6-Chloro-N-[6-(2,2-difluoroethyl)-5-methoxy-1,2,4-triazin-3-yl]-1H-indole-3-sulfonamide; and

[0088] 6-Chloro-N-(5-methoxy-6-methyl-1,2,4-triazin-3-yl)-1H-indole-3-sulfonamide;

[0089] and pharmaceutically acceptable salts thereof.

[0090] Preferred examples of compounds of formula I as described herein are selected from

[0091] 6-Chloro-N-[2-(difluoromethoxy)-4-methoxy-pyrimidin-5-yl]-1H-indole-3-sulfonamide;

[0092] 6-Chloro-N-[2-(2,2-difluoroethoxy)-4-(difluoromethoxy)pyrimidin-5-yl]-1H-indole-3-sulfonamide;

[0093] 6-Chloro-N-(2-(2,2-difluoroethoxy)-4-methoxypyrimidin-5-yl)-1H-indole-3-sulfonamide;

[0094] 6-Bromo-N-[2-(2,2-difluoroethoxy)-4-methoxy-pyrimidin-5-yl]-1H-indole-3-sulfonamide;

[0095] 6-Bromo-N-[2-(2,2-difluoroethoxy)-4-methoxy-pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide:

[0096] and pharmaceutically acceptable salts thereof.

[0097] Processes for the manufacture of compounds of formula I as described herein are an object of the present invention.

[0098] 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 following method, which 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,

[0099]

[0100] Where R 4 , R 5 , X1, X2, X3 and Y1 are as described above.

[0101] General synthetic scheme

[0102] Compounds of formula I can be prepared according to the above process variants and the following Scheme 1. The starting materials are either commercially available or can be prepared according to known methods.

[0103] Solution 1

[0104]

[0105] Compounds of general formula I can be prepared by reacting sulfonyl chloride II with amine III in the presence of a base such as N-ethyldiisopropylamine, pyridine, potassium phosphate or sodium hydride. The starting materials are commercially available or can be prepared according to known methods.

[0106] Solution 2

[0107]

[0108] For example, amine IIIa can be synthesized by reacting compound IV with alcohol V and a base such as cesium carbonate or potassium carbonate to give compound VI. Those intermediates can be converted to compound IIIa by using a suitable reducing agent such as hydrogen in combination with a catalyst (palladium on carbon) or a metal such as iron in the presence of an acid.

[0109] Solution 3

[0110]

[0111] In addition, amine IIIb can be synthesized by reacting compound VII with an alkylating agent VIII and a base such as sodium hydride to give compound IX. Those intermediates can be converted to compound IIIb by using a suitable reducing agent such as hydrogen in combination with a catalyst (palladium on carbon) or a metal such as iron in the presence of an acid.

[0112] Solution 4

[0113]

[0114] Amine IIIc can be prepared by reacting compound X or compound XIV with alkenyl borane derivative XI or acetylene XII and a suitable catalyst such as a palladium complex or a copper catalyst to give compound XIII or XV, respectively. Those intermediates can be converted to compound IIIc by using a suitable reducing agent (such as hydrogen) in combination with a catalyst (such as palladium on carbon).

[0115] Another embodiment of the present invention provides a pharmaceutical composition or medicine containing the compounds of this invention and a therapeutic inert carrier, diluent or excipient, and a method for preparing such compositions and medicines using the compounds of this invention. In one example, the compound of formula I can be formulated as a galenical administration form by mixing with a physiologically acceptable carrier (i.e., a carrier that is nontoxic to the recipient at the dosage and concentration used) at ambient temperature at an appropriate pH and desired purity. The pH of the formulation depends primarily on the specific use and concentration of the compound, but is preferably 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.

[0116] The compositions are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered in this context 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 timing of administration, and other factors known to practitioners.

[0117] 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, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and (if necessary for local treatment) intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.

[0118] The compounds of the present invention can be administered in any convenient administration form, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain conventional components of pharmaceutical preparations, for example, diluents, carriers, pH adjusters, sweeteners, fillers and other active agents.

[0119] The usual formulations are prepared by mixing the compounds of the invention and carriers or excipients. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, for example, Ansel, Howard C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams and Wilkins, 2004; Gennaro, Alfonso R. et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams and Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulation may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavoring agents, flavoring agents, diluents and other known additives to provide an aesthetically pleasing display of the drug (e.g., a compound of the invention or a pharmaceutical composition thereof) or to aid in the preparation of a pharmaceutical product (e.g., a drug).

[0120] The compounds of formula I and their pharmaceutically acceptable salts can be processed with pharmaceutically inert inorganic or organic adjuvants to produce tablets, coated tablets, dragees, hard gelatin capsules, injections or topical preparations. For example, lactose, corn starch or its derivatives, talcum powder, stearic acid or its salts, etc. can be used as such adjuvants for tablets, dragees and hard gelatin capsules.

[0121] Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid substances and liquid polyols and the like.

[0122] Suitable adjuvants for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like.

[0123] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.

[0124] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols and the like.

[0125] Suitable adjuvants for topical ophthalmic preparations are, for example, cyclodextrins, mannitol or numerous other carriers and excipients known in the art.

[0126] In addition, the pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying the osmotic pressure, buffer masking agents or antioxidants. They may also contain other therapeutically valuable substances.

[0127] Dosage can vary over a wide range, and will certainly be suitable for various requirements in each particular case. Generally speaking, in the case of oral administration, a daily dose of about 0.1 mg to 20 mg per kg body weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g., about 300 mg per person) should be suitable, and it is preferably divided into 1 to 3 separate doses (which may be composed of, for example, the same amount). In the case of topical administration, the formulation may include 0.001% to 15% of the drug by weight, and the desired dose may be 0.1 mg to 25 mg, a single application every day or every week, or multiple applications every day (2 to 4 times), or multiple applications every week. However, it is apparent that, when shown as applicable, the upper or lower limits given herein may be exceeded.

[0128] The present invention also particularly relates to:

[0129] A compound of formula I for use as a therapeutically active substance;

[0130] A compound of formula I for use in treating a disease regulated by GPR17;

[0131] Likewise, an object of the present invention is a pharmaceutical composition comprising a compound according to formula I as described herein and a therapeutically inert carrier.

[0132] The use of compounds of formula I for the treatment or prevention of conditions caused by direct damage to the myelin sheath (including but not limited to central and extrapontine myelinolysis, carbon monoxide poisoning, nutritional deficiencies and virally induced demyelination), demyelinating diseases (including but not limited to multiple sclerosis, acute and multiphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorders and leukodystrophy), CNS diseases associated with myelin loss (including but not limited to Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and ischemia caused by stroke), and inflammation in the CNS, such as encephalitis, primary vasculitis, meningitis and inflammation in the CNS following obesity.

[0133] An embodiment of the invention is the use of a compound of formula I for the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease or Huntington's disease.

[0134] A particular embodiment of the invention is the use of a compound of formula I for the treatment or prevention of multiple sclerosis.

[0135] The compounds of formula I are used for the preparation of medicaments for the treatment or prevention of conditions caused by direct damage to the myelin sheath (including but not limited to central and extrapontine myelinolysis, carbon monoxide poisoning, nutritional deficiencies and viral-induced demyelination), demyelinating diseases (including but not limited to multiple sclerosis, acute and multiphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorders and leukodystrophy), CNS diseases associated with myelin loss (including but not limited to Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and ischemia caused by stroke), and inflammation in the CNS, such as encephalitis, primary vasculitis, meningitis and inflammation in the CNS following obesity.

[0136] An embodiment of the present invention is the use of a compound of formula I for the preparation of a medicament for the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease or Huntington's disease.

[0137] A particular embodiment of the invention is the use of a compound of formula I for the preparation of a medicament for the treatment or prevention of multiple sclerosis.

[0138] Compounds according to formula I are useful for treating or preventing conditions caused by direct damage to the myelin sheath (including but not limited to central and extrapontine myelinolysis, carbon monoxide poisoning, nutritional deficiencies and virally induced demyelination), demyelinating diseases (including but not limited to multiple sclerosis, acute and multiphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorders and leukodystrophy), CNS diseases associated with myelin loss (including but not limited to Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and ischemia caused by stroke), and inflammation in the CNS, such as encephalitis, primary vasculitis, meningitis and inflammation in the CNS following obesity.

[0139] An 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.

[0140] A particular embodiment of the invention are compounds according to formula I for use in the treatment or prevention of multiple sclerosis.

[0141] A method for treating or preventing a condition comprising administering to a patient in need thereof an effective amount of a compound of formula I, wherein the condition is caused by direct damage to the myelin sheath (including but not limited to central and extrapontine myelinolysis, carbon monoxide poisoning, nutritional deficiencies, and virally induced demyelination), demyelinating diseases (including but not limited to multiple sclerosis, acute and multiphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorders, and leukodystrophy), CNS diseases associated with myelin loss (including but not limited to Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and ischemia caused by stroke), and inflammation in the CNS, such as encephalitis, primary vasculitis, meningitis, and inflammation in the CNS following obesity.

[0142] An embodiment of the present invention is a method for treating or preventing multiple sclerosis, Alzheimer's disease, Parkinson's disease or Huntington's disease, comprising administering an effective amount of a compound of formula I to a patient in need thereof.

[0143] A specific embodiment of the invention is a method for treating or preventing multiple sclerosis, which method comprises administering an effective amount of a compound of formula I to a patient in need thereof.

[0144] One embodiment of the present invention also provides a compound of formula I as described herein when manufactured according to any of the methods.

[0145] Determination procedure

[0146] GPR17 cAMP Assay Protocol:

[0147] CHO-K1 cells stably expressing untagged human GPR17 (Roche) were cultured in DMEM (Dulbecco's Modified Eagle's Medium):F-12 (1:1) supplemented with 10% fetal bovine serum and 400 μg / ml Geneticin at 37° C. / 5% CO 2 .

[0148] Nano-TRF detection analysis kit (Roche Diagnostics, Cat. No. 05214386001) is used to quantify the changes in intracellular cyclic adenosine monophosphate (cAMP) levels. This assay allows cAMP to be quantified directly in a homogenous solution. cAMP is detected based on time-resolved fluorescence energy transfer (TR-FRET) and competitive binding of ruthenium cAMP and endogenous cAMP with anti-cAMP monoclonal antibodies labeled with AlexaFluor-700. Ruthenium complexes act as FRET donors and transfer energy to AlexaFluor-700. FRET signal is inversely proportional to cAMP concentration.

[0149] 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). These cells were then seeded in a black 384-well plate (Corning) at a density of 10'000 cells / 20 μl assay buffer per well until compound addition.

[0150] Test antagonist compounds were serially diluted in dimethyl sulfoxide (DMSO) and spotted in 384-well plates. Compounds were then diluted in HBSS buffer supplemented with EC80 concentrations of MDL29,951 (3-(2-carboxy-4,6-dichloroindol-3-yl) propionic acid) (GPR17 agonist) and 3-isobutyl-1-methylxanthine (IBMX) (0.5 mM final concentration) and added to cells at room temperature. Forskolin (15 μM final concentration) was added 5 minutes after the addition of the test compounds, and the cells were incubated at room temperature for 30 minutes. The assay was stopped by adding cAMP detection mix (containing detergent for cell lysis) for 90 minutes at room temperature.

[0151] Cellular cAMP was measured using a Paradigm reader (Molecular Devices). Raw data were used to calculate the FRET signal based on the measured P factor according to the instructions of the cAMP kit. Data were normalized to the maximum activity of the reference antagonist, and the dose-response curve was fitted to the activity percentage of the test compound using a sigmoidal dose-response model (Genedata Screener).

[0152] The hGPR17 cAMP assay results for compounds of Formula I are provided in Table 1

[0153] Table 1:

[0154]

[0155] Microsomal Clearance Assay Protocol:

[0156] On a TECAN (Tecan Group Ltd, Switzerland) automated liquid handling system, incubate in microsomes at 37°C in 96-well plates with 1 mM test compound (0.5 mg / mL) and cofactor NADPH. The final concentration of the test compound in the incubation was 1 microM. After a 10-minute pre-incubation step of the test compound with the microsomes, the enzymatic reaction was initiated by adding cofactors. At 1, 3, 6, 9, 15, 25, 35, and 45 minutes, aliquots of the culture were taken out and quenched with 1:3 (v / v) acetonitrile containing an internal standard. The samples were then cooled and centrifuged, and the supernatant was subsequently analyzed by LC-MS / MS.

[0157] Reference Examples RE-A and RE-B were prepared as described herein.

[0158] The microsomal clearance of the reference compounds was tested against the exemplary compounds to assess the stability of the metabolites. The results are shown in Table 2 below.

[0159] Table 2.

[0160]

[0161]

[0162] The invention will now be illustrated by the following examples, which are not limiting.

[0163] If preparations are obtained as mixtures of enantiomers, the pure enantiomers may be obtained by methods described herein or by methods known to those skilled in the art such as, for example, chiral chromatography or crystallization.

[0164] Examples

[0165] If not stated otherwise, all examples and intermediates were prepared under nitrogen atmosphere.

[0166] Intermediate A

[0167] Intermediate A1: 6-Chloro-1H-indole-3-sulfonyl chloride

[0168]

[0169] Intermediate A1 is commercially available (CAS 1216060-79-5)

[0170] Intermediate A2: 6-Bromo-1H-indole-3-sulfonyl chloride

[0171]

[0172] Intermediate A2 is commercially available (CAS 2137914-35-1)

[0173] Intermediate A3: 6-Bromo-1H-pyrrolo[2,3-b]pyridine-3-sulfonyl chloride

[0174]

[0175] Intermediate A3 is known (CAS 2231234-27-6) and was synthesized according to WO 2018 / 122232.

[0176] Intermediate A4: 6-Chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonyl chloride

[0177]

[0178] Intermediate A4 is known (CAS 2231234-21-0) and was synthesized according to WO 2018 / 122232.

[0179] Intermediate A5: 6-(Trifluoromethyl)-1H-indole-3-sulfonyl chloride

[0180]

[0181] Intermediate A5 is known (CAS 1784173-91-6) and was synthesized according to WO 2018 / 122232.

[0182] Intermediate B

[0183] Intermediate B1: 4-Methoxy-2-propyl-pyrimidin-5-amine

[0184]

[0185] Step 1: 2-iodo-4-methoxy-5-nitro-pyrimidine

[0186]

[0187] In a 10 ml glass tube under argon, 2-chloro-4-methoxy-5-nitro-pyrimidine (CAS 282102-07-2, 380 mg, 2.0 mmol) was dissolved in ultra-dry acetonitrile (4.2 ml) and trimethylsilyl iodide (481 mg, 361 ul, 2.41 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 30 min and at 40 ° C for 1 h. After cooling to room temperature, ethyl acetate (10 ml) was added. The mixture was extracted with NaHCO3 solution (5%), sodium thiosulfate solution (1%) and saturated sodium chloride solution. The combined organic layers were dried with MgSO4, filtered and the solvent was removed under vacuum. The residue was purified by flash chromatography (silica gel, 0% to 20% n-heptane in ethyl acetate) to obtain 2-iodo-4-methoxy-5-nitro-pyrimidine (310 mg, yield 44%) as a light yellow viscous oil. MS m / z: 282.0 [M+H] + , ESI pos.

[0188] Step 2: (2-iodo-4-methoxy-pyrimidin-5-yl)amine

[0189]

[0190] A suspension of 2-iodo-4-methoxy-5-nitro-pyrimidine (205 mg, 0.730 mmol) and iron (326 mg, 5.84 mmol) in acetic acid (6 ml) was stirred at room temperature for 2 h. The reaction mixture was filtered through a diatomaceous earth pad and the filtrate was concentrated in vacuo. The residue was poured into a saturated NaHCO solution and extracted twice with ethyl acetate. The combined organic layers were dried over NaSO, filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel, 0 to 20% n-heptane in ethyl acetate) to obtain (2-iodo-4-methoxy-pyrimidine-5-yl) amine (157 mg, 73.8%) as a white solid. MS m / z: 252.0 [M+H] + , ESI pos.

[0191] Step 3: (4-methoxy-2-prop-1-ynyl-pyrimidin-5-yl)amine

[0192]

[0193] To a solution of prop-1-yne (1M dimethylformamide solution, 1.23ml, 1.23mmol) add (2-iodo-4-methoxy-pyrimidine-5-yl) amine (154ml, 0.613mmol), triethylamine (186ml, 256ul, 1.84mmol), bis(triphenylphosphine)palladium chloride (II) (30ml, 0.043mmol) and copper iodide (I) (6ml, 0.03mmol). The solution is stirred at 40 ℃ for 4h, then the reaction mixture is diluted with ethyl acetate and extracted with 5% NaHCO3 solution, water and saturated NaCl solution successively. The organic phase is dried with MgSO4, filtered and desolvated under vacuum. By chromatography (silica gel, 0 to 100% n-heptane in ethyl acetate) purification of residue, to obtain (4-methoxy-2-prop-1-ynyl-pyrimidine-5-yl) amine (57mg, 54%), it is a light yellow solid. MS m / z:164.1[M+H] + , ESI pos.

[0194] Step 4: 4-Methoxy-2-propyl-pyrimidin-5-amine

[0195]

[0196] In a 10 ml glass tube under argon, (4-methoxy-2-prop-1-ynyl-pyrimidin-5-yl)amine (55 ml, 0.337 mmol) was dissolved in ethyl acetate (3 ml) and 10% palladium on carbon (54 mg) was added. After flashing with hydrogen 3 times, a balloon filled with hydrogen was used and the mixture was stirred for 5 h, then filtered through diatomaceous earth and concentrated to give the title compound (53 mg, yield 85%) as a colorless viscous oil. MS m / z: 168.1 [M+H] + , ESI pos.

[0197] Intermediate B2: 2-Ethyl-4-methoxy-pyrimidin-5-amine

[0198]

[0199] 2-Chloro-4-methoxy-5-nitro-pyrimidine (CAS282102-07-2, 160mg, 0.844mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborinane (143mg, 159ul, 0.928mmol) and potassium phosphate (538mg, 2.53mmol) in 1,4-dioxane (6.4ml) and water (1.6ml) solution were degassed under Ar. Then 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane adduct (69mg, 0.084mmol) was added and the reaction mixture was heated at 80°C for 15min. The mixture was diluted with dichloromethane (20ml) and filtered on a diatomaceous earth pad. Water was added, the aqueous layer was extracted with dichloromethane, and the combined organic layer was concentrated. The residue was dissolved in methanol (3 ml) and palladium on carbon (10%, 65 mg) was added under a stream of argon. A balloon filled with hydrogen was used and the mixture was stirred for 2 h, then filtered through diatomaceous earth and concentrated. The residue was purified by preparative HPLC (column Gemini NX, 12 nm, 5 um, 100 x 30 mm, solvent: acetonitrile / water + 0.1% trimethylamine) to obtain the title compound (5 mg, yield 5%), which is a light brown oil. MS m / z: 154.1 [M+H] + , ESI pos.

[0200] Intermediate B3: 2-(Difluoromethoxy)-4-methoxy-pyrimidin-5-amine

[0201]

[0202] Step 1: 4-Methoxy-5-nitro-pyrimidin-2-ol

[0203]

[0204] 2-Chloro-4-methoxy-5-nitro-pyrimidine (CAS282102-07-2, 150 mg, 0.79 mmol) was dissolved in ethanol (5 ml). Then a solution of sodium acetate (136 mg, 1.66 mmol) in water (1 ml) and acetic acid (475 mg, 453 ul, 7.9 mmol) were added and the mixture was stirred at 80 ° C for 7 h. The mixture was evaporated to dryness and the crude product was used in the next step. Yellow solid, MS m / z: 172.1 [M+H] + , ESI pos.

[0205] Step 2: 2-(Difluoromethoxy)-4-methoxy-5-nitropyrimidine

[0206]

[0207] To a solution of 4-methoxy-5-nitro-pyrimidine-2-ol (230 mg, 1.08 mmol) in acetonitrile (5 ml) was added sodium hydride (60%, 151 mg, 3.76 mmol). After stirring for 10 min, 2-(fluorosulfonyl)difluoroacetic acid (383 mg, 223 ul, 2.15 mmol) was added and the mixture was stirred at room temperature for 2.5 h. Because the reaction was not complete, more sodium hydride (60%, 151 mg, 3.76 mmol) and 2-(fluorosulfonyl)difluoroacetic acid (383 mg, 223 ul, 2.15 mmol) were added. The reaction mixture was quenched with water at 0 ° C and extracted with dichloromethane. The aqueous layer was washed twice with dichloromethane. The combined organic layers were dried with Na2SO4 and evaporated to dryness. The residue was purified by chromatography (silica gel, 0 to 30% n-heptane in ethyl acetate) to give 2-(difluoromethoxy)-4-methoxy-5-nitro-pyrimidine as a colorless oil. MS m / z: 222.1 [M+H] + ,ESIpos.

[0208] Step 3: 2-(Difluoromethoxy)-4-methoxy-pyrimidin-5-amine

[0209]

[0210] To a solution of 2-(difluoromethoxy)-4-methoxy-5-nitro-pyrimidine (20 mg, 0.09 mmol) in methanol (1 ml) was added palladium on carbon 10% (10 mg). A balloon filled with hydrogen was used and the mixture was stirred for 5 h, then filtered through a syringe filter and concentrated to give the title compound (19 mg, yield 100%), MS m / z: 192.1 [M+H] + , ESI pos.

[0211] Intermediate B4: 2-(2-Fluoroethoxy)-4-methoxy-pyrimidin-5-amine

[0212]

[0213] Step 1: 2-(2-Fluoroethoxy)-4-methoxy-5-nitropyrimidine

[0214]

[0215] Under nitrogen, 2-fluoroethanol-1-ol (101 mg, 92 ul, 1.58 mmol) and cesium carbonate (694 mg, 2.11 mmol) were added to a solution of 2-chloro-4-methoxy-5-nitropyrimidine (CAS282102-07-2, 200 mg, 1.06 mmol) in acetonitrile (15 ml) at room temperature. The mixture was stirred at room temperature for 4 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0% to 30% ethyl acetate in n-heptane) to give 2-(2-fluoroethoxy)-4-methoxy-5-nitropyrimidine (50 mg, 22% yield) as a light yellow oil. MS m / z: 218.1 [M+H] + , ESI pos.

[0216] Step 2: 2-(2-Fluoroethoxy)-4-dimethoxy-pyrimidin-5-amine

[0217]

[0218] Under argon, to a solution of 2-(2-fluoroethoxy)-4-methoxy-5-nitropyrimidine (50 mg, 0.23 mmol) in ethyl acetate (1.4 ml) was added palladium on carbon 10% (25 mg) at room temperature. The reaction mixture was stirred for 18 h under a hydrogen atmosphere using a balloon. The reaction mixture was purged with argon, filtered through a Sartorius filter and concentrated in vacuo. The solid was triturated three times with ether and then dried to give the title compound (26 mg, 57% yield) as a light brown solid. MS m / z: 188.1 [M+H] + , ESI pos.

[0219] Middleware B5: 2-(2,2-Difluoroethoxy)-4-methoxy-pyrimidin-5-amine

[0220]

[0221] The title compound was prepared analogously to intermediate B5, using 2,2-difluoroethanol-1-ol instead of 2-fluoroethanol-1-ol, as a light brown solid. MS (ESI) m / z: 206.3 [M+H] + .

[0222] Intermediate B6: 2-(2,2-Difluoroethoxy)-4-(difluoromethoxy)pyrimidin-5-amine

[0223]

[0224] Step 1: Sodium 2-chloro-5-nitropyrimidine-4-oleate

[0225]

[0226] Under nitrogen, at 5 ° C, to a light yellow solution of 2,4-dichloro-5-nitropyrimidine (CA 49845-33-2, 2.0 g, 10 mmol) in ethanol (30 ml) was added a solution of sodium acetate (1.69 g, 20.6 mmol) in a mixture of water (5 ml) and glacial acetic acid (2 ml). The reaction mixture was stirred at 5 ° C for 3 h. The resulting precipitate was filtered and rinsed with ethanol aqueous solution. The resulting solid was vacuum dried to give 2-chloro-5-nitropyrimidine-4-sodium oleate (1.91 g, yield 97%) as a white solid. The compound was used directly without further purification. MS m / z: 174.0 [MH] - ,ESI neg.

[0227] Step 2: 2-(2,2-difluoroethoxy)-5-nitropyrimidin-4-ol

[0228]

[0229] Under nitrogen, at room temperature, 2,2-difluoroethanol-1-ol (1.28g, 991ul, 15.2mmol) and cesium carbonate (6.63g, 20.3mmol) were added to a suspension of 2-chloro-5-nitropyrimidine-4-sodium oleate in acetonitrile (42ml). The mixture was stirred at room temperature for 15h. The reaction mixture was filtered. The mother liquor was quenched with water (100ml) and acidified with hydrochloric acid (5N) until pH 1. Ethyl acetate (70ml) was added and the two layers were separated. The water layer was extracted twice with ethyl acetate. The combined organic layers were dried with Na2SO4 and evaporated to obtain 110mg of product. The filter cake was suspended in water, cooled to 0°C and carefully acidified with hydrochloric acid (5N) until pH 1 to pH 2. Ethyl acetate was then added and the two layers were separated. The water layer was extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4 and evaporated with 110 mg of the product to give 2-(2,2-difluoroethoxy)-5-nitropyrimidin-4-ol (821 mg, 73% yield) as a yellow solid. MS m / z: 222.0 [M+H] + , ESI pos

[0230] Step 3: 5-amino-2-(2,2-difluoroethoxy)pyrimidin-4-ol

[0231]

[0232] 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 palladium on carbon 10% (70 mg). The mixture was stirred at room temperature for 1 h under a hydrogen atmosphere. The reaction mixture was filtered through a celite pad 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.

[0233] Step 4: 2-(2,2-difluoroethoxy)-4-(difluoromethoxy)pyrimidin-5-amine

[0234]

[0235] A suspension of 5-amino-2-(2,2-difluoroethoxy)pyrimidine-4-ol (93 mg, 0.487 mmol) and potassium carbonate (204 mg, 1.46 mmol) in N-methyl-2-pyrrolidone (2.5 ml) was heated to 80 ° C. A solution of sodium chlorodifluoroacetate (155 mg, 0.973 mmol) in N-methyl-2-pyrrolidone (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. The crude product was purified by flash chromatography (silica gel, 0% to 100% ethyl acetate in heptane) to obtain the title compound (24 mg, yield 10%), which was a light yellow viscous oil. MS m / z: 242.2 [M+H] + ,ESIpos.

[0236] Intermediate B7: 2,4-Dichloropyrimidin-5-amine

[0237]

[0238] Intermediate B7 is commercially available (CAS 5177-27-5)

[0239] Intermediate B8: 6-(2,2-difluoroethyl)-5-methoxy-1,2,4-triazine-3-amine

[0240]

[0241] Step 1: 6-Chloro-5-methoxy-N,N-bis[(4-methoxyphenyl)methyl]-1,2,4-triazine-3-amine

[0242]

[0243] 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 h. Then cooled to 0°C, 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 h and then stirred 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. The crude product was purified by flash chromatography (silica gel, 30% ethyl acetate in heptane) to give 6-chloro-5-methoxy-N,N-bis[(4-methoxyphenyl)methyl]-1,2,4-triazine-3-amine (1.25 g, 36% yield) as a light yellow liquid. MS m / z: 401.3 [M+H] + ,ESIpos.

[0244] Step 2: 6-(2-ethoxyvinyl)-5-methoxy-N,N-bis[(4-methoxyphenyl)methyl]-1,2,4-trimethoxy Oxazine-3-amine

[0245]

[0246] Under argon, 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (593 mg, 634 ul, 3.0 mmol), sodium carbonate (2M aqueous solution, 3.7 ml, 7.48 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (206 mg, 0.25 mmol) were added to a solution of 6-chloro-5-methoxy-N,N-bis[(4-methoxyphenyl)methyl]-1,2,4-triazine-3-amine (1 g, 2.49 mmol) in 1,4-dioxane (25 ml) . The reaction mixture was stirred at 90°C for 4 h. 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 purified by flash chromatography (silica gel, 0% to 30% ethyl acetate in heptane) to give 6-(2-ethoxyvinyl)-5-methoxy-N,N-bis[(4-methoxyphenyl)methyl]-1,2,4-triazine-3-amine (432 mg, 40% yield) as a colorless liquid. MS m / z: 437.4 [M+H] + , ESI pos.

[0247] Step 3: 6-(2,2-difluoroethyl)-5-methoxy-N,N-bis[(4-methoxyphenyl)methyl]-1,2,4-trifluoromethyl Oxazine-3-amine

[0248]

[0249] In a 25 ml round bottom flask, 6-(2-ethoxyvinyl)-5-methoxy-N,N-bis[(4-methoxyphenyl)methyl]-1,2,4-triazine-3-amine (330 mg, 0.756 mmol) was dissolved in formic acid (5 ml), and the mixture was stirred at 60°C for 1.5 h. After cooling to room temperature, the reaction mixture was poured into ice water and extracted twice with dichloromethane. The combined organic layers were washed with sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in dichloromethane (16.5 ml) and cooled to 0°C, and [bis(2-methoxyethyl)amino]sulfur trifluoride (Deoxoflor, 2.7 M toluene solution, 672 mg, 560 ul, 1.51 mmol) was added. The reaction mixture was stirred at 0°C for 1.5 h, then poured into ice-cold sodium bicarbonate solution and extracted twice with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0% to 50% ethyl acetate in heptane) to give 6-(2,2-difluoroethyl)-5-methoxy-N,N-bis[(4-methoxyphenyl)methyl]-1,2,4-triazine-3-amine (133 mg, 41% yield) as a light brown oil. MS m / z: 431.4 [M+H] + , ESI pos.

[0250] Step 4: 6-(2,2-difluoroethyl)-5-methoxy-1,2,4-triazine-3-amine

[0251]

[0252] A mixture of 6-(2,2-difluoroethyl)-5-methoxy-N,N-bis[(4-methoxyphenyl)methyl]-1,2,4-triazine-3-amine (70 mg, 0.154 mmol) and trifluoroacetic acid (1.59 g, 1.07 ml, 13.9 mmol) was stirred at 70 ° C for 3 days. The reaction mixture was concentrated in vacuo, the residue was dissolved in dichloromethane, poured into a saturated sodium bicarbonate solution, and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography (silica gel, 30% to 100% ethyl acetate in heptane) to give the title compound (28 mg, yield 98%) as an off-white solid. MS m / z: 191.1 [M+H] + , ESI pos.

[0253] Intermediate B9: 5-Methoxy-6-methyl-1,2,4-triazine-3-amine

[0254]

[0255] 3-Amino-6-methyl-4,5-dihydro-1,2,4-triazine-5-one (CAS1004-04-2, 100 mg, 0.793 mmol) was added to phosphorus oxychloride (3.65 g, 2.22 ml, 23.8 mmol) at 22 ° C. The mixture was stirred at 80 ° C for 1 h and then concentrated in vacuo. The residue was dissolved in methanol (5 ml) and the solution was added to sodium methoxide (128 mg, 2.38 mmol) and stirred at 22 ° C for 1.5 h. The mixture was quenched with saturated aqueous sodium bicarbonate solution (10 ml) and extracted with ethyl acetate (2 x 10 ml). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to the title compound (55 mg, product 50%) as a light yellow solid. MS m / z: 141.1 [M+H] + , ESI pos.

[0256] Examples

[0257] Example 1: 6-Chloro-N-(4-methoxy-2-propyl-pyrimidin-5-yl)-1H-indole-3-sulfonamide

[0258]

[0259] A mixture of 6-chloro-1H-indole-3-sulfonyl chloride (intermediate A1, 67 mg, 0.269 mmol) and 4-methoxy-2-propyl-pyrimidine-5-amine (intermediate B1, 50 mg, 0.269 mmol) in dichloromethane (ultra-dry, 1.3 ml) was cooled to 2°C to 5°C. N,N-diisopropylethylamine (45 mg, 61 ul, 0.350 mmol) was added, the cooling bath was removed after 20 min and the reaction mixture was stirred at room temperature for 2 h. 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 um, 100 x 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.

[0260] The following Examples 2 to 6 were prepared similarly to Example 1 by coupling the designated sulfonyl chloride intermediate A and amine intermediate B.

[0261]

[0262] Example 7: 6-Chloro-N-(2-(2-fluoroethoxy)-4-methoxy-pyrimidin-5-yl)-1H-indole-3-sulfonamide

[0263]

[0264] Under argon, at 0°C, to a solution of 2-(2-fluoroethoxy)-4-methoxy-pyrimidine-5-amine (intermediate B4, 25 mg, 0.134 mmol) in pyridine (anhydrous, 0.85 ml) was added 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 distributed between citric acid (1 M aqueous solution) and ethyl acetate. The two 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 x 30 mm, solvent: acetonitrile / water + 0.1% HCOOH) to give the title compound (11 mg, yield 20%) as an off-white solid. MS m / z: 399.1 [MH] - ,ESI neg.

[0265] The following Examples 8 to 12 were prepared similarly to Example 7 by coupling the designated sulfonyl chloride intermediate A and amine intermediate B.

[0266]

[0267] Example 13: 6-Chloro-N-(5-methoxy-6-methyl-1,2,4-triazin-3-yl)-1H-indole-3-sulfonamide

[0268]

[0269] The reaction tube was flashed with argon and then filled with 5-methoxy-6-methyl-1,2,4-triazine-3-amine (Intermediate B9, 40 mg, 0.285 mmol) and dry 1,2-dichloroethane (2.9 ml), followed by N-ethyldiisopropylamine (48 mg, 63 ul, 0.371 mmol). The tube was sealed and heated to 70 ° C and 6-chloro-1H-indole-3-sulfonyl chloride (Intermediate A1, 78 mg, 0.314 mmol) was added in five portions over 30 min. The mixture was stirred at 70 ° C for 1 h, then cooled to room temperature and concentrated in vacuo. The residue was purified by preparative HPLC (column YMC-Triart C18, 12 nm, 5 um, 100 x 30 mm, solvent: acetonitrile / water + 0.1% HCOOH) to give the title compound (14 mg, 14%) as a white solid. MS m / z: 354.1 [M+H] + ,ESIpos.

[0270] Reference Example RE-A: 6-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

[0271]

[0272] RE-A is Example I-46 in WO2019243303 and was synthesized according to the procedure described therein.

[0273] Reference Example RE-B: 6-Chloro-N-[5-(2,2-difluoroethyl)-3-fluoro-6-methoxy-2-pyridinyl]-1H-indole-3-sulfonamide

[0274]

[0275] To a solution of 5-(2,2-difluoroethyl)-3-fluoro-6-methoxy-pyridine-2-amine (CAS2827059-87-8, 58 mg, 0.281 mmol) in pyridine (1 ml) was added 6-chloro-1H-indole-3-sulfonyl chloride (intermediate A1, 77 mg, 0.31 mmol) and the reaction mixture was stirred at room temperature for 90 min. The reaction mixture was concentrated in vacuo and purified by flash chromatography (silica gel, 0% to 50% ethyl acetate in heptane) to give the title compound (33 mg, 28%) as a white solid. MS m / z: 420.2 [M+H] +, ESI pos.

[0276] Example A

[0277] The compounds of formula I can be used in a manner known per se as active ingredients for the production of tablets of the following composition:

[0278]

[0279] Example B

[0280] The compounds of formula I can be used in a manner known per se as active ingredient for the production of capsules of the following composition:

[0281]

Claims

1. A compound of formula I, in, R 4 is alkyl, halo, haloalkyl or haloalkoxy; R 5 is halogenated or halogenated alkyl; X1 is N, X2 is CR 2 And X3 is CR 3 , where R 2 H and R 3 is alkoxy, halo or haloalkoxy, or X1 for CR 1 , X2 is N and X3 is N, where R 1 is an alkoxy group; Y1 is CR 6 or N; R 6 is H or halogenated; and pharmaceutically acceptable salts thereof.

2. The compound according to claim 1, wherein R 4 It is a halogenated alkoxy group.

3. The compound according to any one of claims 1 or 2, wherein R 5 It is halogenated.

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

5. The compound according to any one of claims 1 to 4, wherein X1 is N, X2 is CR 2 And X3 is CR 3 , where R 2 H and R 3 is an alkoxy group or a halogenated alkoxy group.

6. The compound according to claim 1, wherein R 4 is a halogenated alkoxy group; R 5 is halogenated; X1 is N, X2 is CR 2 And X3 is CR 3 , where R 2 H and R 3 is an alkoxy group or a haloalkoxy group; Y1 is CR 6 or N; R 6 is H; and pharmaceutically acceptable salts thereof.

7. A compound according to any one of claims 1 to 6, selected from 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; and pharmaceutically acceptable salts thereof.

8. A compound according to any one of claims 1 to 7, selected from 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 pharmaceutically acceptable salts thereof.

9. A process 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, Where R 4 , R 5 , X1, X2, X3 and Y1 are as described above.

10. Compounds according to any one of claims 1 to 8 for use as therapeutically active substances.

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

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

13. Use of a compound according to any one of claims 1 to 8 for the treatment or prevention of conditions caused by direct damage to the myelin sheath (including but not limited to central and extrapontine myelinolysis, carbon monoxide poisoning, nutritional deficiencies and virally induced demyelination), demyelinating diseases (including but not limited to multiple sclerosis, acute and multiphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorders and leukodystrophy), CNS diseases associated with myelin loss (including but not limited to Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and ischemia caused by stroke) and inflammation in the CNS such as encephalitis, primary vasculitis, meningitis and inflammation in the CNS following obesity.

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

15. The use of a compound according to any one of claims 1 to 8 for the preparation of a medicament for the treatment or prevention of conditions caused by direct damage to the myelin sheath (including but not limited to central and extrapontine myelinolysis, carbon monoxide poisoning, nutritional deficiencies and virally induced demyelination), demyelinating diseases (including but not limited to multiple sclerosis, acute and multiphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorders and leukodystrophy), CNS diseases associated with myelin loss (including but not limited to ischemia caused by Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and stroke) and inflammation in the CNS such as encephalitis, primary vasculitis, meningitis and inflammation in the CNS following obesity.

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

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

18. A method for treating or preventing conditions caused by direct damage to the myelin sheath (including but not limited to central and extrapontine myelinolysis, carbon monoxide poisoning, nutritional deficiencies and virally induced demyelination), demyelinating diseases (including but not limited to multiple sclerosis, acute and multiphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorders and leukodystrophy), CNS diseases associated with myelin loss (including but not limited to Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and ischemia caused by stroke), and inflammation in the CNS such as encephalitis, primary vasculitis, meningitis and inflammation in the CNS following obesity, the method 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 an effective amount of a compound according to any one of claims 1 to 8 to a patient in need thereof.

20. The compound according to any one of claims 1 to 8, which is produced according to the method according to claim 9.

21. The invention as hereinbefore described.

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