Deuterated pyrimidin-2-yl sulfonamide derivatives

Abstract

The present invention relates to novel compounds having the general formula (I) wherein the substituents R1, R2, R3, R4 and X1 are as defined above; 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 1 is H, alkoxy or haloalkoxy;

[0006] R 2 is 1,1,2,2-tetradeutero-2-fluoro-ethoxy, 1,1-dideutero-2-fluoro-ethoxy or 1,1-dideutero-2,2-difluoro-ethyl;

[0007] R 3 is an alkoxy group or a haloalkoxy group;

[0008] X1 for CR 5 or N;

[0009] R 4 is H, halo, alkyl or haloalkyl;

[0010] R 5 is H or halogenated;

[0011] And pharmaceutical salts.

[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 can 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, pe32–pe32, “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 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 1 is H, alkoxy or haloalkoxy;

[0046] R 2 is 1,1,2,2-tetradeutero-2-fluoro-ethoxy, 1,1-dideutero-2-fluoro-ethoxy or 1,1-dideutero-2,2-difluoro-ethyl;

[0047] R 3 is an alkoxy group or a haloalkoxy group;

[0048] X1 for CR 5 or N;

[0049] R 4 is H, halo, alkyl or haloalkyl;

[0050] R 5 is H or halogenated;

[0051] And pharmaceutical salts.

[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. A specific example of an alkyl group is methyl.

[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. A specific example is methoxy.

[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 group.

[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.

[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 compound of formula I may also exist in the form of zwitterions. Particularly preferred pharmaceutically acceptable salts of the compound of formula I are salts formed with formic acid and salts formed with hydrochloric acid, producing 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] An embodiment of the present invention provides a compound according to formula I as described herein, wherein R 1 is H or alkoxy.

[0065] An embodiment of the present invention provides a compound according to formula I as described herein, wherein R 2 It is 1,1,2,2-tetradeutero-2-fluoro-ethoxy or 1,1-dideutero-2,2-difluoro-ethyl.

[0066] An embodiment of the present invention provides a compound according to formula I as described herein, wherein R 3 It is an alkoxy group.

[0067] An embodiment of the present invention provides a compound according to formula I as described herein, wherein R 4 It is halogenated or alkyl.

[0068] One embodiment of the present invention provides a compound according to formula I as described herein, wherein R 4 It is halogenated.

[0069] An embodiment of the present invention provides a compound according to formula I as described herein, wherein R 5 is H or halogenated.

[0070] One embodiment of the present invention provides a compound according to formula I as described herein, wherein

[0071] R 1 is H or alkoxy;

[0072] R 2 is 1,1,2,2-tetradeutero-2-fluoro-ethoxy, 1,1-dideutero-2-fluoro-ethoxy or 1,1-dideutero-2,2-difluoro-ethyl;

[0073] R 3 is an alkoxy group;

[0074] X1 for CR 5 or N;

[0075] R 4 is halogenated or alkyl;

[0076] R 5 is H or halogenated;

[0077] And pharmaceutical salts.

[0078] One embodiment of the present invention provides a compound according to formula I as described herein, wherein

[0079] R 1 is H or alkoxy;

[0080] R 2 is 1,1,2,2-tetradeutero-2-fluoro-ethoxy or 1,1-dideutero-2,2-difluoro-ethyl;

[0081] R 3 is an alkoxy group;

[0082] X1 for CR 5 or N;

[0083] R 4 is halogenated;

[0084] R 5 is H or halogenated;

[0085] And pharmaceutical salts.

[0086] Particular examples of compounds of formula I as described herein are selected from

[0087] 6-Chloro-7-fluoro-N-[4-methoxy-5-(1,1,2,2-tetradeutetro-2-fluoro-ethoxy)pyrimidin-2-yl]-1H-indole-3-sulfonamide;

[0088] 6-Bromo-N-[4,6-dimethoxy-5-(1,1,2,2-tetradeutetro-2-fluoro-ethoxy)pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide;

[0089] 6-Chloro-N-[4,6-dimethoxy-5-(1,1,2,2-tetradeutetro-2-fluoro-ethoxy)pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide;

[0090] N-[5-(1,1-dideutero-2,2-difluoro-ethyl)-4-methoxy-pyrimidin-2-yl]-6-fluoro-1H-indole-3-sulfonamide;

[0091] and pharmaceutically acceptable salts thereof.

[0092] Other specific examples of compounds of formula I as described herein are selected from

[0093] 6-Chloro-N-[5-(1,1-dideutero-2,2-difluoro-ethyl)-4-methoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide;

[0094] 6-Chloro-N-[5-(1,1-dideutero-2-fluoro-ethoxy)-4-methoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide;

[0095] 6-Chloro-N-[5-(1,1-dideutero-2,2-difluoro-ethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide;

[0096] 6-Bromo-N-[5-(1,1-dideutero-2,2-difluoro-ethyl)-4-methoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide;

[0097] 6-Bromo-N-[5-(1,1-dideutero-2,2-difluoro-ethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide;

[0098] 6-Bromo-N-[5-(1,1-dideutero-2,2-difluoro-ethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide;

[0099] 6-Chloro-N-[5-(1,1-dideutero-2,2-difluoro-ethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide;

[0100] N-[5-(1,1-dideutero-2,2-difluoro-ethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide;

[0101] and pharmaceutically acceptable salts thereof.

[0102] Processes for the manufacture of compounds of formula I as described herein are an object of the present invention.

[0103] The compound of formula I and its pharmaceutically acceptable salt can be prepared by methods known in the art, for example, by the following method, which comprises

[0104] a) making a compound of formula II

[0105]

[0106] With the compound of formula III

[0107]

[0108] Reaction in the presence of a base selected from N,N-diisopropylethylamine, pyridine, potassium phosphate or sodium hydride to provide a compound of formula I,

[0109]

[0110] The substituent R 1 , R 2 , R 3 , R 4 and X1 are defined as above,

[0111] General synthetic scheme

[0112] 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.

[0113] Solution 1

[0114]

[0115] Compounds of general formula I can be prepared by reacting sulfonyl chloride II with 2-amino-pyrimidine III in the presence of a base such as N,N-diisopropylethylamine, pyridine, potassium phosphate or sodium hydride. II can be prepared from intermediate IV in the presence of a chlorosulfonylating agent such as chlorosulfonic acid, or in the presence of a sulfonylating agent such as sulfur trioxide N,N-dimethylformamide complex, followed by chlorination of the intermediate sulfonic acid with a chlorinating agent such as thionyl chloride.

[0116] 2-Amino-pyrimidines of formula III may be prepared according to known methods or may be prepared according to the process variations described in Schemes 2-3 below. The starting materials are commercially available or may be prepared according to known methods.

[0117] Solution 2

[0118]

[0119] 2-amino-pyrimidine of formula IIIa (wherein R 2 1,1,2,2-tetradeuterated-2-fluoro-ethoxy group) can be prepared by deprotecting intermediate IX in the presence of an acid (such as trifluoroacetic acid), wherein P1 is a protecting group (such as p-methoxy-benzyl, 3-4-dimethoxybenzyl or Boc group). IX can be obtained by reacting a nucleophilic fluorine-containing reagent such as TBAF with tosylate VIII. In turn, VIII can be prepared by alkylating alcohol VII in the presence of a base such as cesium carbonate or potassium carbonate and an alkylating agent such as [1,1,2,2-tetradeuterated-2-(p-tolylsulfonyloxy)ethyl] 4-methylbenzenesulfonate. Alcohol VII can be prepared by reacting dihalogenated starting material V with protected amine to provide monohalogenated intermediate VI, which is hydroxylated under Pd catalytic reaction conditions or first converted into boric esters and then oxidized in the presence of an oxidant (such as hydrogen peroxide).

[0120] Solution 3

[0121]

[0122] 2-Amino-pyrimidine of formula IIIb (wherein R 2 is a 1,1-dideuterated-2,2-difluoro-ethyl group) can be prepared by deprotecting the intermediate XI in the presence of an acid such as trifluoroacetic acid, wherein P1 is a protecting group such as p-methoxy-benzyl, 3-4-dimethoxybenzyl or a Boc group. XI can be obtained by reducing ketone X in the presence of a deuterated reducing agent such as lithium aluminum deuteride. X can be prepared after lithium / halogen exchange of VI and reaction with ethyl difluoroacetate.

[0123] Solution 4

[0124]

[0125] 2-Amino-pyrimidine of formula IIIc (wherein R 2 is 1,1-dideutero-2-fluoro-ethoxy or 1,1-dideutero-2,2-difluoro-ethoxy group) can be prepared by deprotecting intermediate XV in the presence of an acid (such as trifluoroacetic acid), wherein P1 is a protecting group (such as p-methoxy-benzyl, 3-4-dimethoxybenzyl or Boc group). XV can be obtained by reacting hydroxypyrimidine compound VII with tosylate XIV in the presence of a base such as cesium carbonate or potassium carbonate. In turn, XIV can be prepared by reducing a suitable fluorine-containing carboxylic acid or carboxylate XII with lithium aluminum deuteride to give alcohol XIII, which is then reacted with p-toluenesulfonyl chloride XIV in the presence of a base.

[0126] 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.

[0127] 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.

[0128] 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.

[0129] 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.

[0130] 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 present invention or a pharmaceutical composition thereof) or to facilitate the preparation of a pharmaceutical product (e.g., a drug).

[0131] 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.

[0132] Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid substances and liquid polyols and the like.

[0133] Suitable adjuvants for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like.

[0134] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.

[0135] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols and the like.

[0136] Suitable adjuvants for topical ophthalmic preparations are, for example, cyclodextrins, mannitol or numerous other carriers and excipients known in the art.

[0137] 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.

[0138] 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.

[0139] The present invention also particularly relates to:

[0140] A compound of formula I for use as therapeutically active substance.

[0141] A compound of formula I for use in treating a disease modulated by GPR17.

[0142] 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.

[0143] 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.

[0144] 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.

[0145] A particular embodiment of the invention is the use of a compound of formula I for the treatment or prevention of multiple sclerosis.

[0146] 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 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.

[0147] 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.

[0148] 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.

[0149] 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.

[0150] 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.

[0151] A particular embodiment of the invention are compounds according to formula I for use in the treatment or prevention of multiple sclerosis.

[0152] A method for treating or preventing a condition, the method comprising administering to a patient in need thereof an effective amount of a compound of formula I, the condition being 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.

[0153] 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.

[0154] A specific embodiment of the invention is a method for treating or preventing multiple sclerosis, comprising administering an effective amount of a compound of formula I to a patient in need thereof.

[0155] One embodiment of the present invention also provides a compound of formula I as described herein when manufactured according to any of the methods.

[0156] Determination procedure

[0157] GPR17 cAMP assay protocol:

[0158] 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 .

[0159] 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.

[0160] 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.

[0161] 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.

[0162] 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).

[0163] The hGPR17 cAMP assay results for compounds of Formula I are provided in Table 1

[0164] Table 1:

[0165]

[0166] The invention will now be illustrated by the following examples, which are not limiting.

[0167] 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.

[0168] Examples

[0169] If not stated otherwise, all examples and intermediates were prepared under nitrogen atmosphere.

[0170] Intermediate A

[0171] Intermediates A1-A4 are known and were prepared following the procedures described in the designated patent applications:

[0172]

[0173]

[0174] Intermediate B

[0175] Intermediate B1: 4-Methoxy-5-(1,1,2,2-tetradeuterated-2-fluoro-ethoxy)pyrimidin-2-amine

[0176]

[0177] Step 1: 5-Bromo-N,N-bis[(2,4-dimethoxyphenyl)methyl]-4-methoxy-pyrimidin-2-amine

[0178]

[0179] 1-(2,4-dimethoxyphenyl)-N-[(2,4-dimethoxyphenyl)methyl]methylamine (78.12g, 246.13mmol) and potassium carbonate (61.85g, 447.51mmol) were added to a solution of 5-bromo-2-chloro-4-methoxy-pyrimidine (50.0g, 223.75mmol) in DMF (400mL), and the mixture was stirred at 80°C for 16h. The reaction mixture was diluted with water (500mL) and extracted with ethyl acetate (500mL×2). The combined organic layers were washed with brine (500mL×2), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography over silica gel using a gradient of ethyl acetate / ether 0-100% to provide the title compound as a white solid (77g, 65% yield). MS (ESI): m / z=504.1[M+H] +

[0180] Step 2: 2-[Bis[(2,4-dimethoxyphenyl)methyl]amino]-4-methoxy-pyrimidin-5-ol

[0181]

[0182] To a mixture of 5-bromo-N,N-bis[(2,4-dimethoxyphenyl)methyl]-4-methoxy-pyrimidin-2-amine (10.0 g, 19.83 mmol) and sodium tert-butoxide (5716.24 mg, 59.48 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added TBUBRETTPHOS PD G3 (1000.0 mg, 1.17 mmol). The reaction mixture was degassed with nitrogen for 1 minute and heated to 120 °C and stirred at this temperature under nitrogen for 16 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate / ether 0-50% to provide the title compound as a black solid (10 g, 95% yield). MS (ESI): m / z=442.1[M+H]+

[0183] Step 3: [2-[2-[Bis[(2,4-dimethoxyphenyl)methyl]amino]-4-methoxy-pyrimidin-5-yl]oxy- 1,1,2,2-Tetradeutero-ethyl]4-methylbenzenesulfonate

[0184]

[0185] To a solution of 2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-4-methoxy-pyrimidin-5-ol (2.0 g, 4.53 mmol) and potassium carbonate (1.25 g, 9.06 mmol) in DMF (15 mL) was added [1,1,2,2-tetradeutero-2-(p-tolylsulfonyloxy)ethyl]4-methylbenzenesulfonate (2.04 g, 5.44 mmol, CAS: 164936-35-0) The reaction was vigorously stirred at 70 °C for 2 h. The reaction mixture was transferred to a separatory funnel, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 x 100 mL). The combined organic phases were dried over sodium sulfate and filtered, concentrated in vacuo to provide the title compound as a yellow oil (2.9 g, 99% yield) which was used directly in the next step without further purification.

[0186] Step 4: N,N-bis[(2,4-dimethoxyphenyl)methyl]-4-methoxy-5-(1,1,2,2-tetradeuterated-2-fluoro- (ethoxy)pyrimidin-2-amine

[0187]

[0188] To a solution of [2-[2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-4-methoxy-pyrimidin-5-yl]oxy-1,1,2,2-tetradeuterated-ethyl]4-methylbenzenesulfonate (2.9 g, 4.5 mmol) in acetonitrile (20 mL) was added TBAF (13.51 mL, 13.51 mmol) at 25 °C. The mixture was heated to 85 °C for 1 h. The reaction mixture was transferred to a separatory funnel, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over sodium sulfate and filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate / ether 0-30% to provide the title compound as a light yellow oil (1.3 g, 56% yield). MS (ESI): m / z=492.2[M+H]+

[0189] Step 5: 4-methoxy-5-(1,1,2,2-tetradeuterated-2-fluoro-ethoxy)pyrimidin-2-amine

[0190]

[0191] To a solution of N,N-bis[(2,4-dimethoxyphenyl)methyl]-4-methoxy-5-(1,1,2,2-tetradeuterated-2-fluoro-ethoxy)pyrimidine-2-amine (11.0 g, 22.38 mmol) in dichloromethane (35 mL) was added TFA (35.0 mL) at 0°C. The mixture was stirred at 25°C for 2 h, quenched with saturated aqueous sodium bicarbonate solution (600 mL) and extracted with ethyl acetate (3×200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was mixed with petroleum ether (30 mL), stirred at 25°C for 30 min and filtered to provide the title compound as a white solid (2.3 g, 53% yield). MS (ESI): m / z=192.1[M+H]+

[0192] Intermediate B2: 4,6-Dimethoxy-5-(1,1,2,2-tetradeuterated-2-fluoro-ethoxy)pyrimidin-2-amine

[0193]

[0194] Step 1: N,N-bis[(2,4-dimethoxyphenyl)methyl]-4,6-dimethoxy-pyrimidin-2-amine

[0195]

[0196] To a solution of 2-chloro-4,6-dimethoxypyrimidine (20.0 g, 114.56 mmol) and 1-(2,4-dimethoxyphenyl)-N-[(2,4-dimethoxyphenyl)methyl]methylamine (43.63 g, 137.47 mmol) in NMP (400 mL) was added cesium carbonate (74.69 g, 229.12 mmol). The mixture was stirred at 120 ° C for 16 h. The reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (500 mL×2). The combined organic layers were washed with brine (200 mL×2), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was ground in ethyl acetate. The resulting solid was filtered and dried to provide 25 g of the title compound. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography over silica gel using a gradient of ethyl acetate / ether 0-100% to provide a white solid. This solid was combined with the solid obtained above by filtration to provide the title compound as a white solid (43 g, 75% yield). MS (ESI): m / z = 456.2 [M+H] +

[0197] Step 2: 5-Bromo-N,N-bis[(2,4-dimethoxyphenyl)methyl]-4,6-dimethoxy-pyrimidin-2-amine

[0198]

[0199] To a solution of N,N-bis[(2,4-dimethoxyphenyl)methyl]-4,6-dimethoxy-pyrimidine-2-amine (32.0 g, 70.25 mmol) in MeCN (320 mL) was added N-bromosuccinimide (11.25 g, 63.23 mmol). The mixture was stirred at 20 ° C for 3 h. After the reaction was completed, the mixture was quenched with an aqueous solution of sodium sulfite (500 mL) and stirred at 20 ° C for 0.5 h. The mixture was extracted with dichloromethane (500 mL×2). The combined organic layers were washed with brine (500 mL×2), dried over sodium sulfate, filtered and concentrated in vacuo. The gum was ground in ethyl acetate and the precipitate formed was filtered to provide the title compound as a white solid (28 g, 62% yield). MS (ESI): m / z=534.2[M+H]+

[0200] Step 3: 2-[Bis[(2,4-dimethoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-ol

[0201]

[0202] To a solution of 5-bromo-N,N-bis[(2,4-dimethoxyphenyl)methyl]-4,6-dimethoxy-pyrimidin-2-amine (33.0 g, 61.75 mmol) in THF (650 mL) was added n-butyl lithium (32.11 mL, 80.28 mmol) at -70°C. The mixture was stirred at -70°C for 0.5 h. Trimethyl borate (13.81 mL, 123.5 mmol) was then added at -70°C and the mixture was stirred at -70°C for 2 h. The mixture was warmed to 0°C and acetic acid (7.84 mL, 135.85 mmol), hydrogen peroxide (13.87 mL, 135.85 mmol) were added at 0°C. The mixture was stirred at 20°C for 2 h. After the reaction was completed, the mixture was quenched with an aqueous solution of sodium sulfite (500 mL), stirred at 20°C for 0.5 h, and extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with brine (20 mL x 2), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate / ether 0-50% to provide the title compound as a yellow oil (23.8 g, 76% yield). MS (ESI): m / z = 472.3 [M+H] +

[0203] Step 4: [2-[2-[Bis[(2,4-dimethoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-yl] Oxy-1,1,2,2-tetradeutero-ethyl]4-methylbenzenesulfonate

[0204]

[0205] The title compound was prepared in analogy to Intermediate B1 Step 3 from 2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-ol as a white solid. MS (ESI): m / z=674.4 [M+H]+

[0206] Step 5: N,N-bis[(2,4-dimethoxyphenyl)methyl]-4,6-dimethoxy-5-(1,1,2,2-tetradeuterated- 2-Fluoro-ethoxy)pyrimidin-2-amine

[0207]

[0208] The title compound was prepared in analogy to Intermediate B1 Step 4 from [2-[2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-yl]oxy-1,1,2,2-tetradeuterated-ethyl]4-methylbenzenesulfonate as a white solid. MS (ESI): m / z=522.4 [M+H]+

[0209] Step 6: 4,6-dimethoxy-5-(1,1,2,2-tetradeuterated-2-fluoro-ethoxy)pyrimidin-2-amine

[0210]

[0211] The title compound was prepared as a white solid from N,N-bis[(2,4-dimethoxyphenyl)methyl]-4,6-dimethoxy-5-(1,1,2,2-tetradeuterated-2-fluoro-ethoxy)pyrimidin-2-amine in analogy to Intermediate B1 Step 5. MS (ESI): m / z=222.2 [M+H]+

[0212] Intermediate B3: 5-(1,1-Dideutero-2,2-difluoro-ethyl)-4-methoxy-pyrimidin-2-amine

[0213]

[0214] Step 1: 1-[2-[Bis[(2,4-dimethoxyphenyl)methyl]amino]-4-methoxy-pyrimidin-5-yl]-2,2- Difluoro-ethyl ketone

[0215]

[0216] At -70 ° C, 5-bromo-N, N-bis[(2,4-dimethoxyphenyl)methyl]-6-methoxy-pyridine-2-amine (2000.0 mg, 3.97 mmol, intermediate B1 step 1) was added to a solution of THF (3 mL) in batches of n-butyl lithium (1.91 mL, 4.77 mmol), and the solution was stirred at -70 ° C for 0.5 hours. Then difluoroethyl acetate (1.31 mL, 11.92 mmol) was added in batches at -70 ° C. The solution was stirred at 20 ° C for 2 hours. The reaction mixture was poured into a saturated ammonium chloride solution (250 mL) and extracted with ethyl acetate (150 ml × 3). The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate / ether 0-30% to provide the title compound as a yellow oil (0.8 g, 33% yield). MS (ESI): m / z = 504.1 [M + H] +

[0217] Step 2: 5-(1,1-dideutero-2,2-difluoro-ethyl)-N,N-bis[(2,4-dimethoxyphenyl)methyl]-4- Methoxy-pyrimidin-2-amine

[0218]

[0219] To a solution of LiAlD4 (2.0 g, 47.67 mmol) and AlCl3 (6.99 g, 52.43 mmol) in diethyl ether (200 mL) stirred for 15 min under a nitrogen atmosphere was added a solution of 1-[2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-4-methoxy-pyrimidin-5-yl]-2,2-difluoro-ethanone (24.0 g, 47.67 mmol) in diethyl ether (50 mL). The mixture was stirred at 20 °C for 2 h, quenched with D2O (100 mL), followed by 6N sulfuric acid (100 mL), and then diluted with water (150 mL). The aqueous layer was extracted with ethyl acetate (3×300 mL), and the combined organic layers were washed with water and with 10% aqueous sodium bicarbonate solution. The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate / diethyl ether 0-30% to provide the title compound as a yellow oil (15 g, 64% yield). MS (ESI): m / z=492.2 [M+H]+

[0220] Step 3: 5-(1,1-dideutero-2,2-difluoro-ethyl)-4-methoxy-pyrimidin-2-amine

[0221]

[0222] The title compound was prepared in analogy to Intermediate B1 Step 5 from 5-(1,1-dideutero-2,2-difluoro-ethyl)-N,N-bis[(2,4-dimethoxyphenyl)methyl]-4-methoxy-pyrimidin-2-amine as a white solid. MS (ESI): m / z=192.1 [M+H]+

[0223] Intermediate B4: 5-(1,1-Dideuterated-2-fluoro-ethoxy)-4-methoxy-pyrimidin-2-amine

[0224]

[0225] Step 1: (1,1-Dideutero-2-fluoro-ethyl) 4-methylbenzenesulfonate

[0226]

[0227] To a solution of ethyl fluoroacetate (500 mg, 4.71 mmol) in tetrahydrofuran (10 ml) was added lithium aluminum deuteride (198 mg, 4.71 mmol) in portions at 0-10 ° C, and the mixture was stirred at 20 ° C for 1 h. Water (170 mg, 9.43 mmol) was then added dropwise carefully, followed by dropwise addition of Na2SO4 (1 g). The mixture was filtered and washed with dichloromethane (10 ml). Triethylamine (1.96 ml, 14.14 mmol) and p-toluenesulfonyl chloride (1.35 g, 7.07 mmol) were added to the filtrate at 0-10 ° C and the mixture was stirred at 20 ° C for 16 h. The reaction mixture was diluted with dichloromethane (30 ml), washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1:0 to 5:1) to give (1,1-dideutero-2-fluoro-ethyl) 4-methylbenzenesulfonate (230 mg, 21% yield) as a colorless oil.

[0228] Step 2: 5-(1,1-dideutero-2-fluoro-ethoxy)-N,N-bis[(2,4-dimethoxyphenyl)methyl]-4-methyl Oxy-pyrimidin-2-amine

[0229]

[0230] To a mixture of 2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-4-methoxy-pyrimidin-5-ol (2.5 g, 5.66 mmol, see Intermediate B1) and cesium carbonate (3.69 g, 11.3 mmol) in dimethylformamide (50 ml) was added (1,1-dideutero-2-fluoro-ethyl) 4-methylbenzenesulfonate (1.7 g, 7.72 mmol) and the mixture was stirred at 60 ° C for 2 h. The mixture was then diluted with water (200 ml) and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=1:0 to 5:1) to give 5-(1,1-dideutero-2-fluoro-ethoxy)-N,N-bis[(2,4-dimethoxyphenyl)methyl]-4-methoxy-pyrimidin-2-amine (1.5 g, 53% yield) as a brown oil, MS (ESI) m / z=490.3 [M+H] + .

[0231] Step 3: 5-(1,1-dideutero-2-fluoro-ethoxy)-4-methoxy-pyrimidin-2-amine

[0232]

[0233] To a solution of 5-(1,1-dideuterium-2-fluoro-ethoxy)-N,N-bis[(2,4-dimethoxyphenyl)methyl]-4-methoxy-pyrimidine-2-amine (1.40 g, 2.86 mmol) in dichloromethane (10 ml) was added trifluoroacetic acid (10 ml, 135 mmol) at 0-10°C, and the mixture was stirred at 20°C for 2 h. The pH of the mixture was then adjusted to pH 7 with saturated aqueous NaHCO3 and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was triturated with ethyl acetate (2 ml) and filtered. The filter cake was collected to give 5-(1,1-dideuterium-2-fluoro-ethoxy)-4-methoxy-pyrimidine-2-amine (467 mg, 85% yield) as a white solid, MS (ESI) m / z=190.2 [M+H] + .

[0234] Intermediate B5: 5-(1,1-Dideutero-2,2-difluoro-ethyl)-4,6-dimethoxy-pyrimidin-2-amine

[0235]

[0236] Analogously to Intermediate B3, the title compound was prepared in step 1) by replacing 5-bromo-N,N-bis[(2,4-dimethoxyphenyl)methyl]-4,6-dimethoxy-pyrimidin-2-amine (see Intermediate B2) with 5-bromo-N,N-bis[(2,4-dimethoxyphenyl)methyl]-6-methoxy-pyridin-2-amine as a white solid. MS (ESI) m / z: 222.1 [M+H] + .

[0237] Intermediate B6: 5-(1,1-Dideutero-2,2-difluoro-ethoxy)-4,6-dimethoxy-pyrimidin-2-amine

[0238]

[0239] Step 1: 1,1-Dideutero-2,2-difluoro-ethanol

[0240]

[0241] To a suspension of lithium aluminum deuteride (437 mg, 10.4 mmol) in tetrahydrofuran (20 ml) was slowly added difluoroacetic acid (1.0 g, 10.4 mmol) at 0 ° C under nitrogen, and the mixture was then stirred for 2 h at 60 ° C under a nitrogen atmosphere. After cooling to 20 ° C, wet Na2SO4 was added to the above mixture until bubbling stopped. Then dichloromethane (30 ml) and dry Na2SO4 were added and the mixture was stirred for 5 min, then filtered and evaporated carefully. A colorless liquid (875 mg, 99% yield) was obtained, which was directly used in the next step.

[0242] Step 2: (1,1-dideutero-2,2-difluoro-ethyl) 4-methylbenzenesulfonate

[0243]

[0244] To a solution of p-toluenesulfonyl chloride (2.38 g, 12.5 mmol) in dichloromethane (10 ml) was added triethylamine (2.16 ml, 15.6 mmol), N,N-dimethylpyridin-4-amine (64 mg, 0.52 mmol, 0.05 eq) and 1,1-dideuterated-2,2-difluoro-ethanol (875 mg, 10.4 mmol) and the mixture was stirred at 20 ° C for 12 h. The reaction mixture was quenched at 20 ° C by adding saturated NaHCO solution (80 ml), and then extracted with ethyl acetate (50 ml×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, ethyl acetate / petroleum ether) to give (1,1-dideutero-2,2-difluoro-ethyl) 4-methylbenzenesulfonate (1.44 g, 58% yield) as a colorless oil, MS (ESI) m / z: 238.8 [M+H] + .

[0245] Step 3: 5-(1,1-dideutero-2,2-difluoro-ethoxy)-N,N-bis[(2,4-dimethoxyphenyl)methyl]- 4,6-Dimethoxy-pyrimidin-2-amine

[0246]

[0247] Analogously to intermediate B4, in step 2), 2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-ol (see intermediate B2) was used instead of 2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-4-methoxy-pyrimidin-5-ol and (1,1-dideutero-2,2-difluoro-ethyl)4-methylbenzenesulfonate was used instead of (1,1-dideutero-2-fluoro-ethyl)4-methylbenzenesulfonate to prepare the title compound as a yellow solid, MS (ESI): m / z=538.2 [M+H] + .

[0248] Step 4: 5-(1,1-dideutero-2,2-difluoro-ethoxy)-4,6-dimethoxy-pyrimidin-2-amine

[0249]

[0250] Analogously to intermediate B4, in step 3), 5-(1,1-dideutero-2,2-difluoro-ethoxy)-N,N-bis[(2,4-dimethoxyphenyl)methyl]-4,6-dimethoxy-pyrimidin-2-amine was used instead of 5-(1,1-dideutero-2-fluoro-ethoxy)-N,N-bis[(2,4-dimethoxyphenyl)methyl]-4-methoxy-pyrimidin-2-amine to prepare the title compound as an off-white solid, MS (ESI): m / z=238.0 [M+H] + .

[0251] Examples

[0252] Example 1: 6-Chloro-7-fluoro-N-[4-methoxy-5-(1,1,2,2-tetradeuterated-2-fluoro-ethoxy)pyrimidin-2-yl]-1H-indole-3-sulfonamide

[0253]

[0254] To 6- chloro-7- fluoro-1H- indole-3- sulfonyl chloride (337.79mg, 1.26mmol, intermediate A1) and [4- methoxy -5- (1,1,2,2- tetradeuterated -2- fluoro-ethoxy) pyrimidine -2- base] amine (172.08mg, 900umol, intermediate B1) in acetonitrile (3.5mL) solution, add potassium phosphate (286.56mg, 1.35mmol) at 22 ° C. The mixture is stirred at 22 ° C for 16h. The mixture is treated with saturated sodium bicarbonate aqueous solution (25mL) and extracted with ethyl acetate (3x25mL). The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. By flash chromatography, through silica gel, gradient ethyl acetate / heptane 30-100% is used to purify the residue, to provide the title compound, it is a white solid (190mg, 50% yield). MS (ESI): m / z = 423.1 [M+H] +.

[0255] Example 2: 6-Bromo-N-[4,6-dimethoxy-5-(1,1,2,2-tetradeutero-2-fluoro-ethoxy)pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

[0256]

[0257] A solution of [4,6-dimethoxy-5-(1,1,2,2-tetradeuterated-2-fluoro-ethoxy)pyrimidin-2-yl]amine (200 mg, 876.96 umol, intermediate B2) and n-ethyldiisopropylamine (173.48 mg, 229.47 uL, 1.32 mmol) in 1,2-dichloroethane (4 mL) was heated to 70 ° C. 6-bromo-1H-pyrrolo[2,3-b]pyridine-3-sulfonyl chloride (327.38 mg, 1.05 mmol, intermediate A3) was added in 10 portions over 27 min. Stirring was continued at 70 ° C for 15 min. The reaction mixture was poured into water and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate / heptane 0-100% to provide the title compound as a white solid (53 mg, 12% yield). MS (ESI): m / z = 482.1 [M+H]+.

[0258] Example 3: 6-Chloro-N-[4,6-dimethoxy-5-(1,1,2,2-tetradeutero-2-fluoro-ethoxy)pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

[0259]

[0260] To a stirred solution of [4,6-dimethoxy-5-(1,1,2,2-tetradeuterated-2-fluoro-ethoxy)pyrimidin-2-yl]amine (164 mg, 741.34 umol intermediate B2) and n-ethyldiisopropylamine (146.65 mg, 193.99 uL, 1.11 mmol) in dichloromethane (8 mL) was added dropwise a suspension of 6-chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonyl chloride (241.99 mg, 963.75 umol, intermediate A4) in ethyl acetate (8 mL) at room temperature. The reaction mixture was stirred for 1 hour, poured into water and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography over silica gel using a gradient of ethyl acetate / heptane 0-100% to provide the title compound as a white solid (53 mg, 16% yield). MS (ESI): m / z = 436.1 [M + H] +

[0261] Example 4: N-[5-(1,1-dideutero-2,2-difluoro-ethyl)-4-methoxy-pyrimidin-2-yl]-6-fluoro-1H-indole-3-sulfonamide

[0262]

[0263] The title compound was prepared as a white solid by coupling Intermediate A2 with Intermediate B3 in analogy to Example 3. MS (ESI): m / z=389.2 [M+H]+.

[0264] The following Examples 5-8 were prepared by coupling the indicated sulfonyl chloride intermediate A and amine intermediate B in analogy to Example 1.

[0265]

[0266] The following Examples 9-11 were prepared analogously to Example 2 by coupling the indicated sulfonyl chloride intermediate A and amine intermediate B.

[0267]

[0268] Example 12: N-[5-(1,1-dideutero-2,2-difluoro-ethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

[0269]

[0270] Analogously to Example 3, the title compound was prepared by coupling Intermediate A6 with Intermediate B5 as a white solid. MS (ESI): m / z = 414.2 [MH] - .

[0271] Example A

[0272] 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:

[0273]

[0274] Example B

[0275] 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:

[0276]

Claims

1. A compound of formula I, in R 1 is H, alkoxy or haloalkoxy; R 2 is 1,1,2,2-tetradeutero-2-fluoro-ethoxy, 1,1-dideutero-2-fluoro-ethoxy or 1,1-dideutero-2,2-difluoro-ethyl; R 3 is an alkoxy group or a haloalkoxy group; X1 for CR 5 or N; R 4 is H, halo, alkyl or haloalkyl; R 5 is H or halogenated; And pharmaceutical salts.

2. The compound according to claim 1, wherein R 1 is H or alkoxy.

3. The compound according to claim 1 or claim 2, wherein R 2 It is 1,1,2,2-tetradeutero-2-fluoro-ethoxy or 1,1-dideutero-2,2-difluoro-ethyl.

4. A compound according to any one of claims 1 to 3, wherein R 3 It is an alkoxy group.

5. A compound according to any one of claims 1 to 4, wherein R 4 It is halogenated or alkyl.

6. A compound according to any one of claims 1 to 5, wherein R 4 It is halogenated.

7. A compound according to any one of claims 1 to 6, wherein R 5 It is halogenated.

8. The compound according to claim 1, wherein R 1 is H or alkoxy; R 2 is 1,1,2,2-tetradeutero-2-fluoro-ethoxy, 1,1-dideutero-2-fluoro-ethoxy or 1,1-dideutero-2,2-difluoro-ethyl; R 3 is an alkoxy group; X1 for CR 5 or N; R 4 is halogenated or alkyl; R 5 is H or halogenated; And pharmaceutical salts.

9. The compound according to claim 1, wherein R 1 is H or alkoxy; R 2 is 1,1,2,2-tetradeutero-2-fluoro-ethoxy or 1,1-dideutero-2,2-difluoro-ethyl; R 3 is an alkoxy group; X1 for CR 5 or N; R 4 is halogenated; R 5 is H or halogenated; And pharmaceutical salts.

10. A compound according to any one of claims 1 to 9, selected from 6-Chloro-7-fluoro-N-[4-methoxy-5-(1,1,2,2-tetradeutetro-2-fluoro-ethoxy)pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Bromo-N-[4,6-dimethoxy-5-(1,1,2,2-tetradeutetro-2-fluoro-ethoxy)pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Chloro-N-[4,6-dimethoxy-5-(1,1,2,2-tetradeutetro-2-fluoro-ethoxy)pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; N-[5-(1,1-dideutero-2,2-difluoro-ethyl)-4-methoxy-pyrimidin-2-yl]-6-fluoro-1H-indole-3-sulfonamide; and pharmaceutically acceptable salts thereof.

11. A compound according to any one of claims 1 to 9, selected from 6-Chloro-N-[5-(1,1-dideutero-2,2-difluoro-ethyl)-4-methoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(1,1-dideutero-2-fluoro-ethoxy)-4-methoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(1,1-dideutero-2,2-difluoro-ethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(1,1-dideutero-2,2-difluoro-ethyl)-4-methoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(1,1-dideutero-2,2-difluoro-ethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Bromo-N-[5-(1,1-dideutero-2,2-difluoro-ethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Chloro-N-[5-(1,1-dideutero-2,2-difluoro-ethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; N-[5-(1,1-dideutero-2,2-difluoro-ethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; and pharmaceutically acceptable salts thereof.

12. A method for preparing a compound according to any one of claims 1 to 11, the method comprising making a compound of formula II With the compound of formula III Reaction in the presence of a base selected from N,N-diisopropylethylamine, pyridine, potassium phosphate or sodium hydride to provide a compound of formula I, The substituent R 1 , R 2 , R 3 , R 4 and X1 are as defined above.

13. Compounds according to any one of claims 1 to 11 for use as therapeutically active substances.

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

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 and a therapeutically inert carrier.

16. Use of a compound according to any one of claims 1 to 11 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.

17. Use of a compound according to any one of claims 1 to 11 for the treatment or prevention of multiple sclerosis.

18. The use of a compound according to any one of claims 1 to 11 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.

19. A compound according to any one of claims 1 to 11 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.

20. A compound according to any one of claims 1 to 11 for use in the treatment or prevention of multiple sclerosis.

21. 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 11.

22. A method for treating or preventing multiple sclerosis, the method comprising administering an effective amount of a compound according to any one of claims 1 to 11 to a patient in need thereof.

23. The compound according to any one of claims 1 to 11, which is manufactured according to the method of claim 12.

24. The invention as hereinbefore described. ***

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