Novel naphthyl and isoquinoline sulfonamide derivatives

Abstract

The present invention relates to novel compounds of general formula I TIFF2025523939000154.tif42161 (wherein R 1 , R 2 , X1, X2, X3 and W are as described herein), compositions containing the compounds, and methods of using the compounds.

Description

Technical Field

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

[0002] The present invention relates to novel compounds of formula I

Chemical formula

Chemical formula

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

Background Art

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

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

[0006] The role of GPR17 in myelination was first identified in a screen of the optic nerves of Olig1 knockout mice to identify genes that regulate myelination. GPR17 expression was found to be expressed only in myelinating cells of the CNS and not in Schwann cells, which are myelinating cells of the peripheral nervous system. The expression of GPR17 was found to be exclusively expressed in oligodendrocyte lineage cells and downregulated in myelinating oligodendrocytes (Chen, Y. et al. (2009)). Specifically, the expression of GPR17 was found to be present at low levels in the early stage of OPCs and increased in pre-myelinating 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 oligodendrocyte differentiation”).GPR17 knockout animals have been shown to exhibit premature myelination throughout the CNS. Conversely, transgenic mice overexpressing GPR17 in oligodendrocytes with the CNP-Cre (2’,3’-cyclic nucleotide 3’-phosphodiesterase) promoter exhibited hypomyelination defects, consistent with GPR17 being predicted to be a cell-intrinsic brake on the myelination process (Chen, Y. et al. (2009)). Furthermore, loss of GPR17 enhances remyelination after demyelination by lysophosphatidylcholine-induced demyelination (Lu, C., Dong et al. (2018), Sci. Rep. 8, 4502, “G-Protein-Coupled Receptor Gpr17 Regulates Oligodendrocyte Differentiation in Response to Lysolecithin-Induced Demyelination”). Thus, antagonism of GPR17, which promotes the differentiation of oligodendrocyte lineage cells into mature myelinating oligodendrocytes, will result in increased myelination after demyelination.

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

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

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

[0010] The compound of formula I binds to GPR17 and modulates GPR17 activity.

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

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

[0013] Summary of the Invention The present invention relates to a novel compound of formula I

Chemical formula

Chemical formula

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

[0015] The term "alkoxy" represents a group of the formula -O-R' where R' is a C 1-6 -alkyl group. C1-6 Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. A specific example is methoxy.

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

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

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

[0019] The term "haloalkoxy" represents a C 1-6 -alkoxy group in which at least one hydrogen atom of the C 1-6 -alkoxy group is replaced by the same or different halogen atoms. Specific examples are difluoroethoxy and difluoromethoxy.

[0020] The term "haloalkyl" represents a C 1-6 -alkyl group in which at least one hydrogen atom of the C 1-6 -alkyl group is replaced by the same or different halogen atoms. A specific example is difluoroethyl.

[0021] The term "amino" represents an -NH2 group.

[0022] The term "alkylamino" represents an amino group in which one hydrogen atom of the amino group is replaced by an alkyl group. An example is methylamino.

[0023] The term "pharmaceutically acceptable salt" refers to salts of the free base or free acid that retain the biological effectiveness and properties of the free base or free acid and are not biologically or otherwise undesirable. Salts are formed using inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, especially hydrochloric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine. In addition, these salts can be prepared from the addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, salts of sodium, potassium, lithium, ammonium, calcium, magnesium. Salts derived from organic bases include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, salts of polyamine resins, but are not limited to these. The compounds of formula I may also exist in zwitterionic form. Particularly preferred pharmaceutically acceptable salts of the compounds of formula I are salts formed using formic acid and salts formed using hydrochloric acid that yield hydrochloride, dihydrochloride or trihydrochloride.

[0024] The abbreviation uM means micromole and is equivalent to the symbol μM.

[0025] The abbreviation uL means microliter and is equivalent to the symbol μL.

[0026] The abbreviation ug means microgram and is equivalent to the symbol μg.

[0027] The compounds of formula I may contain several asymmetric centers and may exist in the form of optically pure enantiomers, mixtures of enantiomers, such as racemates, etc., optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.

[0028] According to the Cahn-Ingold-Prelog rules, the asymmetric carbon atoms can be of the "R" or "S" configuration.

[0029] Also, one embodiment of the present invention provides a compound according to formula I described herein and a pharmaceutically acceptable salt or ester thereof, in particular a compound according to formula I described herein and a pharmaceutically acceptable salt thereof, more specifically, a compound according to formula I described herein.

[0030] One embodiment of the present invention is an R 1 wherein R is cyanoalkyl, haloalkoxy or cyclopropyl, and provides a compound according to formula I described herein.

[0031] One embodiment of the present invention is an R 2 wherein R is alkoxy or halo, and provides a compound according to formula I described herein.

[0032] One embodiment of the present invention is an R 3 wherein R is alkoxy, halo or haloalkoxy, and provides a compound according to formula I described herein.

[0033] One embodiment of the present invention provides a compound according to formula I described herein, wherein X1 is CR 3 X2 is CR 4 X3 is N or CR 5 or X1 is CR3, X2 is N, and X3 is CR 5 as described herein.

[0034] One embodiment of the present invention is an R 4To provide a compound of formula I described herein, wherein R is H.

[0035] One embodiment of the present invention is that R 5 To provide a compound of formula I described herein, wherein R is H.

[0036] One embodiment of the present invention provides a compound of formula I described herein, wherein Y1 is CR 6 and Y2 is CR 7 and Y3 is CR 8 and Y4 is CR 9 or Y1 is N and Y2 is CR 7 and Y3 is CR 8 and Y4 is CR 9 or Y1 is N and Y2 is CR 7 and Y3 is N and Y4 is CR 9 or Y1 is CR 6 and Y2 is CR 7 and Y3 is N and Y4 is CR 9 is provided.

[0037] One embodiment of the present invention is that R 6 To provide a compound of formula I described herein, wherein R is H.

[0038] One embodiment of the present invention is that R 7 To provide a compound of formula I described herein, wherein R is H or methylamino.

[0039] One embodiment of the present invention is that R 8 To provide a compound of formula I described herein, wherein R is dimethylamino, H or halo.

[0040] One embodiment of the present invention is that R 9 To provide a compound of formula I described herein, wherein R is cyclopropyl, H, halo or alkyl.

[0041] One embodiment of the present invention provides a compound of formula I as described herein, wherein R 10 is H.

[0042] One embodiment of the present invention provides a compound of formula I as described herein, wherein R 11 is H.

[0043] One embodiment of the present invention provides a compound of formula I as described herein, wherein R 12 is H.

[0044] One embodiment of the present invention provides a compound of formula I as described herein, wherein R 13 is H or halo.

[0045] One embodiment of the present invention provides a compound of formula I as described herein, wherein R 14 is H or halo.

[0046] One embodiment of the present invention provides a compound of formula I as described herein, wherein R 14 is halo.

[0047] One embodiment of the present invention provides a compound of formula I as described herein, wherein Y8 is -CH-, Y9 is -CH-, and Y 10 is -CH- or -O-.

[0048] One embodiment of the present invention provides a compound of formula I as described herein, wherein Y8 is -CH-, Y9 is -CH-, and Y 10 is -O-.

[0049] One embodiment of the present invention provides a compound of formula I as described herein, wherein R 15 is H or alkyl.

[0050] One embodiment of the present invention provides a compound of formula I as described herein, wherein R 15 is alkyl.

[0051] One embodiment of the present invention provides a compound according to formula I described herein, R 2 when is H, X2 is CR 4 and R 4 is not H, R 1 when is haloalkyl, R 2 is alkoxy, R 1 when is haloalkoxy and R 2 is halo, X2 is N.

[0052] One embodiment of the present invention is a compound according to formula I described herein, wherein R 1 is selected from cyanoalkyl, haloalkoxy, haloalkyl, cyclopropyl and oxetanyl, R 2 is selected from alkoxy, H or halo, X1 is N, X2 is CR 4 and X3 is N, or X1 is CR 3 X2 is CR 4 and X3 is N or CR 5 or X1 is CR 3 X2 is N, X3 is CR 5 and R 3 is selected from alkoxy, H, halo, haloalkoxy, R 4 is selected from alkoxy, H, halo, R 5 is selected from H, halo, W is selected from ring A, ring B or ring C,

Chemical formula

[0053] Embodiments of the present invention are compounds according to formula I described herein, wherein, R 1 is selected from cyanoalkyl, haloalkoxy, haloalkyl, cyclopropyl and oxetanyl, R 2 is selected from alkoxy, H or halo, X1 is N, X2 is CR 4 and X3 is N, or X1 is CR 3 and X2 is CR 4 and X3 is N or CR 5 or X1 is CR 3 and X2 is N and X3 is CR 5 and R 3 is selected from alkoxy, H, halo, haloalkoxy, R 4 is selected from alkoxy, H, halo, R 5 is selected from H, halo, W is selected from ring A, ring B or ring C,

Chemical formula

[0054] Embodiments of the present invention are compounds according to formula I described herein, wherein R 1 is selected from cyanoalkyl, haloalkoxy, or cyclopropyl, R 2 is selected from alkoxy or halo, X1 is CR 3 and X2 is CR 4 and X3 is N or CR 5 or X1 is CR 3 and X2 is N and X3 is CR 5 and R 3 is selected from alkoxy, halo or haloalkoxy, R 4 is H, R 5 is H, W is selected from ring A, ring B or ring C,

Chemical formula

[0055] Embodiments of the present invention are compounds according to formula I described herein, wherein R1 is selected from cyanoalkyl, haloalkoxy, or cyclopropyl, R 2 is selected from alkoxy or halo, X1 is CR 3 and X2 is CR 4 and X3 is N or CR 5 or X1 is CR 3 and X2 is N and X3 is CR 5 and R 3 is selected from alkoxy, halo or haloalkoxy, R 4 is H, R 5 is H, W is selected from ring A, ring B or ring C,

Chemical Structure

[0056] Specific examples of compounds of formula I described herein are N-(4-(cyanomethyl)-2,5-difluorophenyl)naphthalene-1-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]naphthalene-1-sulfonamide; 2-Chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]quinoline-5-sulfonamide; 2-Chloro-N-(6-cyclopropyl-5-fluoro-2-methoxy-3-pyridyl)quinoline-5-sulfonamide; 2-Chloro-N-[6-(cyanomethyl)-5-fluoro-2-methoxy-3-pyridyl]quinoline-5-sulfonamide; 2-Chloro-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]quinoline-5-sulfonamide; 2-Chloro-N-[5-fluoro-2-methoxy-6-(oxetan-3-yl)-3-pyridyl]quinoline-5-sulfonamide; 2-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]quinoline-5-sulfonamide; 2-Chloro-N-[5-(2,2-difluoroethoxy)-3-fluoro-6-methoxy-2-pyridyl]quinoline-5-sulfonamide; 2-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]quinoline-5-sulfonamide; N-[2,6-bis(difluoromethoxy)-5-fluoro-3-pyridyl]-2-chloro-quinoline-5-sulfonamide; 7-Chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]isoquinoline-4-sulfonamide; 7-Chloro-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]isoquinoline-4-sulfonamide; 7-Chloro-N-[5-(2,2-difluoroethoxy)-3-fluoro-6-methoxy-2-pyridyl]isoquinoline-4-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]isoquinoline-4-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-2-methyl-chroman-5-sulfonamide; 5-Chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]naphthalene-1-sulfonamide; 5-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]naphthalene-1-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]naphthalene-1-sulfonamide; 8-Chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-1-hydroxy-isoquinoline-4-sulfonamide; 7-Chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-1-keto-2H-isoquinoline-4-sulfonamide; 7-Chloro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1-keto-2H-isoquinoline-4-sulfonamide; 7-Chloro-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1-keto-2H-isoquinoline-4-sulfonamide; 7-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1-keto-2H-isoquinoline-4-sulfonamide; 7-Chloro-N-[5-(2,2-difluoroethoxy)-3-fluoro-6-methoxy-2-pyridyl]-1-oxo-2H-isoquinoline-4-sulfonamide; 7-Chloro-N-[4-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-phenyl]-1-keto-2H-isoquinoline-4-sulfonamide; N-[2,6-bis(difluoromethoxy)-5-fluoro-3-pyridyl]-7-chloro-1-keto-2H-isoquinoline-4-sulfonamide; 2-Chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-8-oxo-7H-1,7-naphthyridine-5-sulfonamide; 2-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-8-oxo-7H-1,7-naphthyridine-5-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-2-oxo-1H-quinoline-4-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-2-(dimethylamino)quinoline-5-sulfonamide; N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-2-(dimethylamino)quinoline-5-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-2-methyl-quinoline-5-sulfonamide; 6-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]naphthalene-1-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-2-(difluoromethyl)quinoline-5-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1-oxo-2-methyl-isoquinoline-4-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-2-oxo-1-methyl-quinoline-4-sulfonamide; 7,8-Dichloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-1-oxo-2H-isoquinoline-4-sulfonamide; 7,8-Dichloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1-oxo-2H-isoquinoline-4-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-5-(dimethylamino)naphthalene-1-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1-(dimethylamino)isoquinoline-4-sulfonamide; 7-Chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-1-(dimethylamino)isoquinoline-4-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1-(methylamino)isoquinoline-4-sulfonamide; 7-Chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-1-(methylamino)isoquinoline-4-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-2-(methylamino)quinoline-4-sulfonamide; 7-Chloro-8-cyano-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]isoquinoline-4-sulfonamide; 7-Chloro-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]quinoline-4-sulfonamide; 7-Chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-1-methoxy-isoquinoline-4-sulfonamide; 2-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1,7-naphthyridine-5-sulfonamide; 2-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]quinoline-5-sulfonamide; N-(4-(Cyanomethyl)-2,5-difluorophenyl)-1-oxo-1,2-dihydroisoquinoline-4-sulfonamide; 7-Chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]quinoline-4-sulfonamide; 2-Bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]quinoline-5-sulfonamide; 2-Cyclopropyl-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]quinoline-5-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-2-methoxy-quinoline-5-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1-(dimethylamino)isoquinoline-5-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]tetralin-5-sulfonamide, and is selected from pharmaceutically acceptable salts thereof.

[0057] Preferred examples of the compounds of formula I described herein are 2-Chloro-N-(6-cyclopropyl-5-fluoro-2-methoxy-3-pyridyl)quinoline-5-sulfonamide; 2-Chloro-N-[6-(cyanomethyl)-5-fluoro-2-methoxy-3-pyridyl]quinoline-5-sulfonamide; 2-Chloro-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]quinoline-5-sulfonamide; 2-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]quinoline-5-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]isoquinoline-4-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-2-methyl-chroman-5-sulfonamide; 5-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]naphthalene-1-sulfonamide; 7-Chloro-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1-oxo-2H-isoquinoline-4-sulfonamide; 7-Chloro-N-[5-(2,2-difluoroethoxy)-3-fluoro-6-methoxy-2-pyridyl]-1-oxo-2H-isoquinoline-4-sulfonamide; 7-Chloro-N-[4-(2,2-difluoroethoxy)-5-fluoro-2-methoxyphenyl]-1-oxo-2H-isoquinoline-4-sulfonamide; N-[2,6-Bis(difluoromethoxy)-5-fluoro-3-pyridyl]-7-chloro-1-oxo-2H-isoquinoline-4-sulfonamide; 2-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-8-oxo-7H-1,7-naphthyridine-5-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-2-oxo-1H-quinoline-4-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-2-methylquinoline-5-sulfonamide; 6-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]naphthalene-1-sulfonamide; 7,8-Dichloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1-oxo-2H-isoquinoline-4-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-5-(dimethylamino)naphthalene-1-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1-(methylamino)isoquinoline-4-sulfonamide; 2-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1,7-naphthyridine-5-sulfonamide; 2-Bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]quinoline-5-sulfonamide; 2-Cyclopropyl-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]quinoline-5-sulfonamide and is selected from pharmaceutically acceptable salts thereof.

[0058] A method for the production of the compounds of formula I described herein is an object of the present invention. The present compounds of formula I and pharmaceutically acceptable salts thereof can be prepared by methods known in the art, for example, by the processes described below, which processes involve reacting a compound of formula III with a compound of formula II in the presence of a base selected from N-ethyldiisopropylamine, pyridine, potassium phosphate or sodium hydride to provide a compound of formula I,

Chemical formula

[0059] General synthetic scheme The compounds of formula I can be prepared according to variations of the above methods and according to Scheme 1 below. The starting materials are commercially available or can be prepared according to known methods.

Chemical formula

[0060] The compound 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. Sulfonyl chloride II can be prepared from intermediate IV by chlorosulfonylation in the presence of a chlorosulfonylating agent such as chlorosulfonic acid or sulfonylation in the presence of a sulfonylating agent such as sulfur trioxide N,N - dimethylformamide complex, followed by chlorination of the intermediate sulfonic acid using a chlorinating agent such as thionyl chloride or oxalyl chloride (Step B). Further, sulfonyl chloride II can be prepared by oxidative chlorination of intermediate V with N - chlorosuccinimide in a mixture of organic solvents such as acetic acid and water (Step C). Intermediate V can be obtained by a backward - Hartwig - type cross - coupling using a palladium catalyst system such as Pd(OAc)2 or Pd2(dba)3 / xantphos or Xphos and a base such as DIPEA or Cs2CO3 at high temperature in a solvent such as dioxane or toluene in the reaction of an iodo - compound or bromo - compound VI with benzyl mercaptan (Step D). The starting materials are either commercially available or can be prepared according to known methods.

[0061]

Chemical formula

[0062]

Chemical formula

[0063]

Chem.

[0064]

Chem.

[0065]

Chem.

[0066]

Chem.

[0067]

Chemical formula

[0068] Another embodiment of the present invention provides a pharmaceutical composition or medicament containing a compound of the present invention and a therapeutically inert carrier, diluent or excipient, and a method of using a compound of the present invention for preparing such a composition and medicament. In one example, a compound of formula I can be formulated into a galenic dosage form by mixing it at ambient temperature, at an appropriate pH, and at the desired degree of purity, with a physiologically acceptable carrier, i.e., a carrier that is non-toxic to the recipient at the dosage and concentration used. The pH of the formulation mainly depends on the particular use and the concentration of the compound, but is preferably in the range of about 3 to about 8. In one example, a compound of formula I is formulated in an acetate buffer at pH 5. In another embodiment, a compound of formula I is sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0069] The composition is formulated, dosed, and administered in a manner consistent with good medical practice. Elements to be considered in this context include the specific disorder being treated, the specific mammal being treated, the clinical state of the individual patient, the cause of the disorder, the site of administration of the agent, the method of administration, the dosing schedule, and other elements known to medical practitioners.

[0070] The compounds of the present invention can be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intralung, intradermal, intrathecal and epidural, and intranasal, and, when local treatment is desired, intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.

[0071] The compounds of the present invention can be administered in any convenient dosage form, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions can contain conventional ingredients in pharmaceutical preparations, for example, diluents, carriers, pH adjusters, sweeteners, bulking agents and additional active agents.

[0072] Typical formulations are prepared by mixing the compounds of the present invention with carriers or additives. Suitable carriers and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel, Howard C. et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004, Gennaro, Alfonso R. et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000, and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulations may also contain one or more buffering agents, stabilizers, surfactants, wetting agents, lubricants, emulsifying agents, suspending agents, preservatives, antioxidants, opaquing agents, flow promoters, processing aids, colorants, sweeteners, fragrances, flavoring agents, diluents and other known additives to provide accurate presentation of the drug (i.e., the compound of the present invention or its pharmaceutical composition) or to assist in the manufacture of a pharmaceutical composition (i.e., a medicament).

[0073] The compounds of formula I and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, sugar-coated tablets, hard gelatin capsules, injection solutions or topical formulations. Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used, for example, as such adjuvants for tablets, sugar-coated tablets and hard gelatin capsules.

[0074] Adjuvants suitable for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances, and liquid polyols, etc.

[0075] Adjuvants suitable for the production of liquid and syrup preparations are, for example, water, polyols, sucrose, invert sugar, glucose, etc.

[0076] Adjuvants suitable for injection solutions are, for example, water, alcohol, polyols, glycerol, vegetable oils, etc.

[0077] Adjuvants suitable for suppositories are, for example, natural oils or hardened oils, waxes, fats, semi-solid or liquid polyols, etc.

[0078] Suitable adjuvants for ophthalmic topical preparations are, for example, cyclodextrin, mannitol, or many other carriers and additives known in the art.

[0079] Furthermore, the pharmaceutical preparation can contain preservatives, solubilizers, viscosity increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for changing the osmotic pressure, buffers, masking agents, or antioxidants. They can also contain still other therapeutically valuable substances.

[0080] The dosage can vary widely and, of course, be adapted to the individual requirements in each particular case. Generally, in the case of oral administration, a daily dosage of about 0.1 mg to 20 mg per kg of body weight, preferably about 0.5 mg to 4 mg per kg of body weight (for example, about 300 mg per person), is preferably divided into 1 to 3 individual administrations, which can, if appropriate, consist of, for example, the same amounts. In the case of topical administration, the preparation can contain 0.001 wt% to 15 wt% of the medicament, and the required dosage can be between 0.1 and 25 mg and can be administered either by a single administration per day or per week, by multiple administrations per day (2 to 4 times), or by multiple administrations per week. However, it will be obvious that it can exceed the upper or lower limits given herein if so indicated.

[0081] The present invention also particularly relates to the following: Compounds of formula I for use as therapeutic active substances; Compounds of formula (I) for use in the treatment of diseases regulated by GPR17.

[0082] Similarly, an object of the present invention is a pharmaceutical composition comprising a compound according to formula I described herein and a therapeutically inert carrier.

[0083] Direct damage to the myelin sheath (including, but not limited to, central and extracerebral myelinolysis, carbon monoxide poisoning, malnutrition, and virus-induced demyelination), demyelinating disorders (including, but not limited to, multiple sclerosis, acute and polymorphic disseminated encephalomyelitis, neuromyelitis optica spectrum disorder, and leukodystrophy), CNS disorders associated with myelin loss (including, but not limited to, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and ischemia due to stroke), and use of a compound of formula I for treating or preventing symptoms resulting from inflammation of the CNS, for example, after encephalitis, primary vasculitis, meningitis, and obesity.

[0084] One embodiment of the present invention is the use of a compound of formula I for treating or preventing multiple sclerosis, Alzheimer's disease, Parkinson's disease, or Huntington's disease.

[0085] A specific embodiment of the present invention is the use of a compound of formula I for treating or preventing multiple sclerosis.

[0086] Use of a compound of formula I for the preparation of a medicament for treating or preventing direct damage to the myelin sheath (including, but not limited to, central and extracerebral myelinolysis, carbon monoxide poisoning, malnutrition, and virus-induced demyelination), demyelinating disorders (including, but not limited to, multiple sclerosis, acute and polymorphic disseminated encephalomyelitis, neuromyelitis optica spectrum disorder, and leukodystrophy), CNS disorders associated with myelin loss (including, but not limited to, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and ischemia due to stroke), and symptoms resulting from inflammation of the CNS, for example, after encephalitis, primary vasculitis, meningitis, and obesity.

[0087] One embodiment of the invention is the use of a compound of formula I for the preparation of a medicament for treating or preventing multiple sclerosis, Alzheimer's disease, Parkinson's disease, or Huntington's disease.

[0088] A particular embodiment of the invention is the use of a compound of formula I for the preparation of a medicament for treating or preventing multiple sclerosis.

[0089] A compound according to formula I for use in the treatment or prevention of direct damage to the myelin sheath (including, but not limited to, central and extracerebral myelinolysis, carbon monoxide poisoning, malnutrition, and virus-induced demyelination), demyelinating disorders (including, but not limited to, multiple sclerosis, acute and polymorphic disseminated encephalomyelitis, neuromyelitis optica spectrum disorder, and leukodystrophy), CNS disorders associated with myelin loss (including, but not limited to, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and ischemia due to stroke), and symptoms resulting from inflammation of the CNS, for example, after encephalitis, primary vasculitis, meningitis, and obesity.

[0090] One embodiment of the invention is a compound of formula I for use in the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease, or Huntington's disease.

[0091] Certain embodiments of the invention are compounds of formula I for use in the treatment or prevention of multiple sclerosis.

[0092] A method for treating or preventing direct damage to the myelin sheath (including, but not limited to, central and extracerebral myelinolysis, carbon monoxide poisoning, malnutrition, and virus-induced demyelination), demyelinating disorders (including, but not limited to, multiple sclerosis, acute and polyphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorder, and leukodystrophy), CNS disorders associated with myelin loss (including, but not limited to, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and ischemia due to stroke), and symptoms resulting from inflammation of the CNS, for example, after encephalitis, primary vasculitis, meningitis, and obesity, the method comprising administering an effective amount of a compound of formula I to a patient in need thereof.

[0093] One embodiment of the invention is a method for treating or preventing multiple sclerosis, Alzheimer's disease, Parkinson's disease, or Huntington's disease, the method comprising administering an effective amount of a compound of formula I to a patient in need thereof.

[0094] Certain embodiments of the invention are methods for treating or preventing multiple sclerosis, the methods comprising administering an effective amount of a compound of formula I to a patient in need thereof.

[0095] Also, one embodiment of the invention provides a compound of formula I described herein when manufactured according to any one of the methods described.

[0096] Assay procedure GPR17 cAMP assay protocol: CHO-K1 cells stably expressing a vector containing untagged human GPR17 short isoform (Roche) were cultured at 37 °C / 5% CO2 in DMEM (Dulbecco's Modified Eagle Medium):F-12 (1:1) supplemented with 10% fetal bovine serum and 400 μg / ml Geneticin.

[0097] Changes in intracellular cyclic adenosine monophosphate (cAMP) levels were quantified using the Nano-TRF Detection Assay Kit (Roche Diagnostics, catalog number 05214386001). This assay enables direct cAMP quantification in a homogeneous solution. cAMP is detected based on time-resolved fluorescence energy transfer (TR-FRET) and competitive binding of ruthenium-labeled cAMP and endogenous cAMP to an anti-cAMP monoclonal antibody labeled with AlexaFluor-700. The ruthenium complex acts as a FRET donor and transfers energy to AlexaFluor-700. The FRET signal is inversely proportional to the cAMP concentration.

[0098] CHO-GPR17S cells were detached with Accutase and resuspended in assay buffer consisting of Hank's balanced salt solution (HBSS), 10 mM HEPES (4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid solution), and 0.1% bovine serum albumin (pH 7.4). Cells were seeded at a density of 10,000 cells / 20 μl assay buffer in black 384-well plates (Corning) until the addition of compounds.

[0099] The test antagonist compound was serially diluted with dimethyl sulfoxide (DMSO) and spotted onto a 384-well plate. The compound was then diluted in HBSS buffer supplemented with MDL29,951 (3-(2-carboxy-4,6-dichloroindol-3-yl)propionic acid) (GPR17 agonist) at EC80 concentration + 3-isobutyl-1-methylxanthine (IBMX) (final concentration 0.5 mM) and added to the cells at room temperature. Forskolin (final concentration 15 μM) was added 5 minutes after the test compound, and the cells were incubated at room temperature for 30 minutes. The assay was stopped by adding the cAMP detection mixture (containing a surfactant for cell lysis) for 90 minutes at room temperature.

[0100] The cAMP in the cells was measured using a Paradigm reader (Molecular Devices). Using the raw data, the FRET signal was calculated based on the P factor of the assay according to the instructions of the cAMP kit. The data was normalized against the maximum activity of the reference antagonist, and the dose-response curve was fitted to the percent activity of the test compound using a sigmoid dose-response model (Genedata Screener).

[0101] The results of the hGPR17 cAMP assay are provided for the compounds of formula I in Table 1.

Table 1

[0102] The present invention will now be described by the following examples, which have no limiting features.

[0103] When the preparation example is obtained as a mixture of enantiomers, the pure enantiomers can be obtained by the methods described herein or methods known to those skilled in the art, such as chiral chromatography or crystallization.

Example

[0104] Unless otherwise specified, all examples and intermediates were prepared under a nitrogen atmosphere.

[0105] Intermediate A Intermediate A1: 1-Naphthalenesulfonyl chloride [Chemical formula] Intermediate A1 is commercially available (CAS: 85-46-1).

[0106] Intermediate A2: 7-Chloroquinoline-4-sulfonyl fluoride [Chemical formula] In a three-necked flask, under argon, at -78 °C, a solution of 4-bromo-7-chloroquinoline (CAS 98519-65-4, 1.0 g, 4.12 mmol, 1.0 equivalent) in THF (20 ml) was added dropwise with n-butyllithium (1.6 M hexane solution (2.0 ml, 4.95 mmol)). After stirring for 15 minutes, sulfur dioxide (2.64 g, 41.24 mmol) was added dropwise as a solution in THF (10 ml). The resulting mixture was slowly warmed to room temperature and stirred for 3 hours. During this time, the precipitation of sulfinate was observed. After cooling the resulting mixture to 0 °C, N-fluorobenzenesulfonimide (1.43 mg, 4.54 mmol, 1.1 equivalents) was added all at once, and the resulting mixture was stirred for an additional 3 hours. The resulting mixture was poured into brine (20 ml) and extracted with ethyl acetate (2 × 20 ml). The combined organic phases were evaporated. The residue was subjected to silica gel column chromatography (heptane / ethyl acetate) to obtain 7-chloroquinoline-4-sulfonyl fluoride (103.9 mg, 0.42 mmol, yield 10.3%) as a yellow solid. 1H NMR (500 MHz, CDCl3) δ = 9.19 (br s, 1H), 8.43 (br d, J = 9.1 Hz, 1H), 8.31 (br s, 1H), 8.10 (br d, J = 3.0 Hz, 1H), 7.79 (br d, J = 9.1 Hz, 1H)

[0107] Intermediate A3: 2-Chloroquinoline-5-sulfonyl chloride

Chem.

[0108] Intermediate A4: 7-Chloroisoquinoline-4-sulfonyl chloride

Chem.

Chem.

[0109] Step 2: 7-chloroisoquinoline-4-sulfonyl chloride

Chemical formula

[0110] Intermediate A5: 1-oxo-2H-isoquinoline-4-sulfonyl chloride

Chemical formula

[0111] Intermediate A6: 2-Methylchroman-5-sulfonyl chloride

Chem.

Chem.

[0112] Step 2: 3-Bromo-2-(3-hydroxybut-1-enyl)phenol

Chem.

[0113] Step 3: 3-Bromo-2-(3-hydroxybutyl)phenol

Chem.

[0114] Step 4: 5-Bromo-2-methyl-chroman

Chemical Structure

[0115] Step 5: 5-Benzylsulfanyl-2-methyl-chroman

Chemical formula

[0116] Step 6: 2-Methylchroman-5-sulfonyl chloride

Chemical Structure

[0117] Intermediate A7: 2-chloro-1,7-naphthyridine-5-sulfonyl chloride [Chemical formula] Step 1: 5-bromo-1-oxide-1,7-naphthyridin-1-ium [Chemical formula] In a 25 ml round-bottom flask, 5-bromo-1,7-naphthyridine (2.5 g, 12.0 mmol) was dissolved in dichloromethane (17.5 ml) and cooled to 0 - 3 °C. Next, m-chloroperbenzoic acid (3.1 g, 12.56 mmol) was added portionwise at 2 - 4 °C over 20 minutes. The reaction mixture was stirred at 2 - 22 °C for 5 hours and then the solvent was removed under vacuum. The residue was purified by silica column (80 g) using methanol in dichloromethane (0 to 10% in 30 minutes) to give a mixture of both possible N-oxides. This mixture was further purified by SFC (column Chiral AY-H, 5 μm, 250x20 mm, 0 - 40% MeOH) to afford 5-bromo-1-oxide-1,7-naphthyridin-1-ium (394 mg, 14%) as a yellow solid. MS m / z: 225.0 [M+H]+. ESI pos.

[0118] Step 2: 5-Benzylsulfanyl-1-oxide-1,7-naphthyridin-1-ium [Chemical formula] A mixture of 5-bromo-1-oxide-1,7-naphthyridin-1-ium (392 mg, 1.71 mmol), benzyl mercaptan (254 mg, 242 μl, 2.05 mmol), tris(dibenzylideneacetone)dipalladium(0) (46.9 mg, 0.051 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (49 mg, 0.085 mmol), and N,N-diisopropylethylamine (441 mg, 600 μl, 3.41 mmol) in 1,4-dioxane (12 ml) was heated at 90 °C for 5 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure and purified by flash chromatography (25 g of SiO2, gradient of 0 to 20% methanol in dichloromethane) to give 5-(benzylthio)-1-oxide-1,7-naphthyridin-1-ium (440 mg, 90%) as an orange solid. MS m / z 269.1 [M+H]+, ESI pos.

[0119] Step 3: 5-Benzylsulfanyl-2-chloro-1,7-naphthyridine [Chemical formula] To a stirred solution of 5-(benzylthio)-1-oxide-1,7-naphthyridin-1-ium (159 mg, 0.557 mmol) in dichloromethane (additionally dried, 5.5 ml) at 0 °C, phosphorus oxychloride (102 mg, 62 μl, 0.668 mmol) was added, followed by dropwise addition of dimethylformamide (20 mg, 22 μl, 0.28 mmol) under argon. The resulting reaction mixture was warmed to 23 °C and stirred at this temperature for 6 hours. Aqueous saturated sodium carbonate solution was gradually added to the reaction mixture to adjust the pH to 7 - 8. The resulting mixture was separated and the aqueous phase was completely extracted with dichloromethane. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by flash chromatography column (silica gel, 10 to 70% ethyl acetate in heptane) to obtain 5-(benzylthio)-2-chloro-1,7-naphthyridine (50 mg, 31%) as a pale yellow solid. MS m / z 287.1 [M+H]+, ESI pos

[0120] Step 4: 2-Chloro-1,7-naphthyridine-5-sulfonyl chloride [Chemical formula] 5-(Benzylthio)-2-chloro-1,7-naphthyridine (45 mg, 0.155 mmol) was dissolved in a mixture of acetic acid (390 μl) and water (39 μl). N-Chlorosuccinimide (62 mg, 0.466 mmol) was added and the mixture was stirred at 23 °C for 1.5 h. Dichloromethane was added and the mixture was stirred at room temperature for 5 min. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give 2-chloro-1,7-naphthyridine-5-sulfonyl chloride (47 mg, 34.5%) as a yellow oil, which was used directly as a crude material in the next step without further purification. MS m / z 263.0 [M+H]+, ESI pos.

[0121] Intermediate A8: 2-Methylquinoline-5-sulfonyl chloride [Chemical formula] Chlorosulfonic acid (5.34 g, 3.07 ml, 45.4 mmol) was carefully added to quinacrine (500 mg, 472 μl, 3.49 mmol) and the reaction mixture was heated to 140 °C for 2 h. LCMS indicated complete conversion and the formation of three positional isomers. The reaction mixture was cooled to room temperature and carefully quenched with ice / ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification of the crude material by flash chromatography on silica gel (80 g, 0% - 100% ethyl acetate in heptane) gave 2-methylquinoline-8-sulfonyl chloride (255.8 mg, 29.4%) as a white solid, 2-methylquinoline-6-sulfonyl chloride (25 mg, 3.0%) as a light brown solid and the title compound 2-methylquinoline-5-sulfonyl chloride (21.9 mg, 2.4%) as a white solid. 1H NMR (600 MHz, DMSO-d6) δ ppm 9.69 (d, J = 9.1 Hz, 1H), 8.20 (dt, J = 8.5, 1.0 Hz, 1H), 8.18 (dd, J = 7.3, 1.1 Hz, 1H), 8.14 - 8.15 (m, 1H), 8.01 - 8.07 (m, 2H), 2.95 (s, 3H).

[0122] Intermediate A9: 6-Chloronaphthalene-1-sulfonyl chloride

Chem.

Chem.

[0123] Step 2: 1-Benzylsulfanyl-6-chloronaphthalene

Chem.

[0124] Step 3: 6-Chloronaphthalene-1-sulfonyl chloride

Chemical formula

[0125] Intermediate A10: 5-Chloronaphthalene-1-sulfonyl chloride

Chemical formula

[0126] Intermediate A11: 7-chloronaphthalene-1-sulfonyl chloride

Chem.

[0127] Intermediate A12: 8-chloro-1-hydroxy-isoquinoline-4-sulfonyl chloride

Chem.

Chem.

[0128] Step 2: 8-chloroisoquinolin-1-ol

Chem.

[0129] Step 3: 8-Chloro-1-hydroxy-isoquinoline-4-sulfonyl chloride

Chemical formula

[0130] Intermediate A13: 7-Chloro-1-oxo-2H-isoquinoline-4-sulfonyl chloride

Chemical formula

[0131] Intermediate A14: 2-Chloro-8-oxo-7H-1,7-naphthyridine-5-sulfonyl chloride

Chemical Structure

Chemical Structure

[0132] Step 2: 2-Chloro-7H-1,7-naphthyridin-8-one

Chemical Structure

[0133] Step 3: 2-Chloro-8-oxo-7H-1,7-naphthyridine-5-sulfonyl chloride

Chemical formula

[0134] Intermediate A15: 7-Chloro-2-oxo-1H-quinoline-4-sulfonyl chloride

Chemical formula

[0135] Intermediate A16: 7-chloro-1-(methylamino)isoquinoline-4-sulfonyl chloride

Chemical formula

[0136] Step 1: 7-chloro-N-methyl-isoquinolin-1-amine

Chemical formula

[0137] Step 2: 4-bromo-7-chloro-N-methyl-isoquinolin-1-amine

Chemical formula

[0138] Step 3: 4-Benzylsulfanyl-7-chloro-N-methyl-isoquinolin-1-amine

Chemical formula

[0139] Step 4: 7-Chloro-1-(methylamino)isoquinoline-4-sulfonyl chloride

Chemical formula

[0140] Intermediate A17: 7-Chloro-2-(methylamino)quinoline-4-sulfonyl chloride

Chemical formula

[0141] Step 1: 4-Benzylsulfanyl-7-chloro-1H-quinolin-2-one

Chemical formula

[0142] Step 2: 4 - Benzylsulfanyl - 2,7 - dichloro - quinoline

Chemical formula

[0143] Step 3: 4-Benzylsulfanyl-7-chloro-N-methyl-quinolin-2-amine [Chemical formula] A mixture of 4-benzylsulfanyl-2,7-dichloroquinoline (250 mg, 0.781 mmol), N,N-diisopropylethylamine (303 mg, 409 μl, 2.34 mmol) and methylamine (2 M in THF, 3 ml, 6 mmol) in tetrahydrofuran (1 ml) was stirred at 60 °C for 3 days. The reaction mixture was poured into water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification of the crude material by flash chromatography (silica gel, 0% to 50% ethyl acetate in heptane) gave a white solid (180 mg, 73% yield). MS m / z 315.1 [M+H] + , ESI pos.

[0144] Step 4: 7-Chloro-2-(methylamino)quinoline-4-sulfonyl chloride [Chemical formula] N-Chlorosuccinimide (225 mg, 1.69 mmol) was added to a solution of acetic acid (2 ml) and water (0.2 ml) containing 4-benzylsulfanyl-7-chloro-N-methyl-quinolin-2-amine (177 mg, 0.562 mmol) at room temperature. The clear solution was stirred at room temperature for 3 hours, then water was added and the mixture was extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo and used directly in the next step. Yellow amorphous solid. MS m / z: 291.1 [M+H] + , ESI pos.

[0145] Intermediate A18: 2-(Dimethylamino)quinoline-5-sulfonyl chloride [Chemical formula] Project 1: 5-Bromo-N,N-dimethyl-quinolin-2-amine [Chemical formula] In a sealed glass tube, 5-bromo-2-chloro-quinoline (CAS 99455-13-7, 250 mg, 1.03 mmol) was dissolved in tetrahydrofuran (additionally dried, 2 ml), and then dimethylamine (2 M in THF, 1.84 g, 2.06 ml, 4.12 mmol) and diisopropylethylamine (266 mg, 360 uL, 2.06 mmol) were added. The reaction mixture was stirred at 60 °C for 24 hours. At room temperature, ethyl acetate and water were added. The organic layer was washed with saturated NaCl solution, dried over MgSO4, and concentrated in vacuo to obtain 5-bromo-N,N-dimethyl-quinolin-2-amine (260 mg, 98%) as a pale yellow solid. MS (ESI) m / z 251.1 [M+H] + .

[0146] Project 2: 5-Benzylsulfanyl-N,N-dimethyl-quinolin-2-amine [Chemical formula] A mixture of 5-bromo-N,N-dimethyl-quinolin-2-amine (260 mg, 1.04 mmol), benzyl mercaptan (142 mg, 135 ul, 1.14 mmol), N,N-diisopropylethylamine (268 mg, 362 ul, 2.07 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (30 mg, 0.052 mmol) and tris(dibenzylideneacetone)dipalladium(0) (28 mg, 0.031 mmol) in 1,4-dioxane (3 ml) was heated to 95 °C and stirred for 16 hours. The reaction mixture was filtered and washed twice with ethyl acetate. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 80% ethyl acetate in n-heptane) to give an orange solid (204 mg, 67%). MS (ESI) m / z: 295.2 [M+H] + .

[0147] Step 3: 2-(Dimethylamino)quinoline-5-sulfonyl chloride

Chem.

[0148] Intermediate A19: 7-Chloro-1-methoxy-isoquinoline-4-sulfonyl chloride

Chem.

Chem.

[0149] In Step 2, using 4-bromo-7-chloro-1-methoxy-isoquinoline instead of 5-bromo-N,N-dimethyl-quinolin-2-amine, the following steps were carried out in the same manner as Intermediate A18. The title compound was used in the next step without further purification.

[0150] Intermediate A20: 7-chloro-8-cyano-isoquinoline-4-sulfonyl chloride

Chemical Structure

Chemical Structure

[0151] Step 2: 4-Bromo-7-chloro-isoquinoline-8-carbonitrile

Chemical formula

[0152] Step 3: 4-Benzylsulfanyl-7-chloro-isoquinoline-8-carbonitrile

Chemical formula

[0153] Step 4: 7-chloro-8-cyano-isoquinoline-4-sulfonyl chloride

Chem.

[0154] Intermediate A21: 2-(difluoromethyl)quinoline-5-sulfonyl chloride

Chem.

[0155] Intermediate A22: 5-(Dimethylamino)naphthalene-1-sulfonyl chloride

Chemical Structure

[0156] Intermediate A23: 7-Chloro-2-methyl-1-oxo-isoquinoline-4-sulfonyl chloride

Chemical Structure

Chemical Structure

[0157] Step 2: 7-Chloro-2-methyl-1-oxo-isoquinoline-4-sulfonyl chloride

Chemical formula

[0158] Intermediate A24: 7-Chloro-1-methyl-2-oxo-quinoline-4-sulfonyl chloride

Chemical formula

[0159] Intermediate A25: 7,8-Dichloro-1-oxo-2H-isoquinoline-4-sulfonyl chloride

Chem.

[0160] Intermediate A26: 7-Chloro-1-(dimethylamino)isoquinoline-4-sulfonyl chloride

Chem.

[0161] Intermediate A27: 8-Methylquinoline-5-sulfonyl chloride

Chem.

[0162] Intermediate A28: Tetralin-5-sulfonyl chloride

Chem.

[0163] Intermediate B Intermediate B1: 2-(4-Amino-2,5-difluorophenyl)acetonitrile

Chem.

[0164] Intermediate B2: 6-(2,2-Difluoroethoxy)-5-fluoro-2-methoxypyridin-3-amine

Chem.

[0165] Intermediate B3: 6-Cyclopropyl-5-fluoro-2-methoxypyridin-3-amine

Chem.

[0166] Intermediate B4: 2-(5-Amino-3-fluoro-6-methoxy-2-pyridyl)acetonitrile

Chem.

Chem.

[0167] Step 2: (6-Bromo-5-fluoro-2-methoxy-3-pyridyl)-bis(p-anisyl)amine

Chemical Structure

[0168] Step 3: [5-[Bis(p-anisyl)amino]-3-fluoro-6-methoxy-2-pyridyl]methanol [Chem.] A solution of (6-bromo-5-fluoro-2-methoxy-3-pyridyl)-bis(p-anisyl)amine (1 g, 2.17 mmol) in toluene (20 ml) was cooled to -78 °C. 1.6 M n-butyllithium (1.75 g, 2.03 mL, 3.25 mmol) was added dropwise. The resulting dark blue solution was stirred at -78 °C for 30 minutes. N,N-Dimethylformamide (396 mg, 419 μl, 5.42 mmol) was added and stirring was continued at -78 °C for 30 minutes. The reaction mixture was warmed to room temperature. After adding methanol (4 ml), sodium borohydride (82 mg, 2.17 mmol) was added. Stirring was continued at room temperature for 15 minutes. The reaction mixture was quenched with saturated NH4Cl solution and extracted twice with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the crude material by flash chromatography (silica gel, 0% to 50% ethyl acetate in heptane) gave [5-[bis(p-anisyl)amino]-3-fluoro-6-methoxy-2-pyridyl]methanol (297 mg, 32.5%) as a pale yellow viscous oil. MS(ESI) m / z: 413.3 [M+H] + .

[0169] Step 4: [6-(Chloromethyl)-5-fluoro-2-methoxy-3-pyridyl]-bis(p-anisyl)amine [Chem.] Thionyl chloride (81.4 mg, 50 μl, 0.684 mmol) was added dropwise at room temperature to a stirred solution of [5-[bis(p-anisyl)amino]-3-fluoro-6-methoxy-2-pyridyl]methanol (144 mg, 0.342 mmol) in dichloromethane (1.5 ml). The reaction mixture was stirred at room temperature for 1 hour. Concentration of the reaction mixture in vacuo gave [6-(chloromethyl)-5-fluoro-2-methoxy-3-pyridyl]-bis(p-anisyl)amine (150 mg, 100%) as a light brown foam, which was used directly in the next step without further purification.

[0170] Step 5: 2-[5-[Bis(p-anisyl)amino]-3-fluoro-6-methoxy-2-pyridyl]acetonitrile

Chem.

[0171] Step 6: 2-(5-Amino-3-fluoro-6-methoxy-2-pyridyl)acetonitrile

Chem.

[0172] Intermediate B5: 6-(Difluoromethoxy)-5-fluoro-2-methoxypyridin-3-amine

Chemical formula

[0173] Intermediate B6: 5-Fluoro-2-methoxy-6-(oxetan-3-yl)pyridin-3-amine

Chemical formula

Chemical formula

[0174] Step 2: 5-Fluoro-2-methoxy-6-(oxetan-3-yl)pyridin-3-amine

Chemical Structure

[0175] Intermediate B7: 5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-amine

Chemical Structure

[0176] Step 2: 2-Amino-5-(2,2-difluoroethyl)pyrimidine-4,6-diol [Chemical formula] To a stirred solution of diethyl 2-(2,2-difluoroethyl)propanedioate (46.8 g, 209 mmol) in ethanol (5 mL) were added guanidine hydrochloride (19.9 g, 208 mmol), followed by sodium ethoxide (prepared from ethanol and sodium (14.38 g, 625 mmol)). The resulting orange suspension was heated to 80 °C and stirred for 4 hours. The reaction mixture was concentrated to half its volume, 50 mL of water was added, followed by acetic acid (42.57 g, 709 mmol). The mixture was heated to 80 °C, stirred for 10 minutes, then cooled to room temperature. The solid product was filtered off and washed successively with water, ethanol, and methyl tert-butyl ether to give the title compound (22.3 g, 50% yield). MS (ESI) m / z = 192.0 [M+H]+

[0177] Step 3: 4,6-Dichloro-5-(2,2-difluoroethyl)pyrimidin-2-amine

Chem.

[0178] Step 4: 5-(2,2-Difluoroethyl)-4,6-dimethoxypyrimidin-2-amine

Chem.

[0179] Intermediate B8: 5-(Difluoromethoxy)-4,6-dimethoxypyrimidin-2-amine

Chem.

Chem.

[0180] Step 2: 5-Bromo-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine

Chem.

[0181] Step 3: 2 - [Bis[(4 - methoxyphenyl)methyl]amino]-4,6 - dimethoxypyrimidin - 5 - ol

Chem.

[0182] Step 4: 5 - (Difluoromethoxy)-4,6 - dimethoxy - N,N - bis[(4 - methoxyphenyl)methyl]pyrimidin - 2 - amine

Chem.

[0183] Step 5: 5-(Difluoromethoxy)-4,6 - dimethoxypyrimidin - 2 - amine

Chemical Structure

[0184] Intermediate B9: 5-(2,2 - Difluoroethoxy)-3 - fluoro - 6 - methoxypyridin - 2 - amine [Chemical] Intermediate B9 is known (CAS 2404661-29-4) and was synthesized according to page 55 of WO 2019 / 243398.

[0185] Intermediate B10: 5-(2-Fluoroethoxy)-4-methoxy-pyrimidin-2-amine [Chemical] Step 1: (5-Bromo-4-methoxy-pyrimidin-2-yl)-bis(p-anisyl)amine [Chemical] A suspension of 5-bromo-2-chloro-4-methoxypyrimidine (1.02 g, 4.48 mmol, CAS: 57054-929), bis(p-anisyl)amine (1.29 g, 4.92 mmol) and N-ethyldiisopropylamine (858 μl, 4.92 mmol) in acetonitrile (20 ml) was heated at 70 °C for 2 days. The resulting solution was poured into saturated aqueous sodium bicarbonate and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and dried in vacuo. The residue was purified by flash chromatography on silica gel using an ethyl acetate / heptane 0-20% gradient to give the title compound as a colorless viscous oil (998 mg, 50% yield). MS (ESI): m / z = 446.2 [M+H] +

[0186] Step 2: [4-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]-bis(p-anisyl)amine [Chemical] A suspension of (5-bromo-4-methoxy-pyrimidin-2-yl)-bis(p-anisyl)amine (500 mg, 1.13 mmol), bis(pinacolato)diboron (354 mg, 1.35 mmol) and potassium acetate (335 mg, 3.38 mmol) in 1,4-dioxane (10 ml) was purged with argon for 5 minutes. Dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (91.9 mg, 0.113 mmol) was added. The reaction mixture was heated to 90 °C and stirred for 16 h. The resulting dark suspension was poured into ethyl acetate and washed once with saturated sodium chloride solution. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography using an ethyl acetate / heptane 0 - 30% gradient to give the title compound as a colorless viscous oil (157 mg, 29% yield). MS(ESI): m / z = 492.4 [M+H] +

[0187] Step 3: 2-[Bis(p-anisyl)amino]-4-methoxy-pyrimidin-5-ol

Chemical formula

[0188] Step 4: [5-(2-Fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-bis(p-anisyl)amine [Chemical formula] A suspension of 2-[bis(p-anisyl)amino]-4-methoxy-pyrimidin-5-ol (100 mg, 0.236 mmol), potassium carbonate (98.82 mg, 0.708 mmol) and 1-bromo-2-fluoroethane (61.14 mg, 35.75 μL, 0.472 mmol) in acetonitrile (2.5 ml) was stirred at room temperature for 15 minutes and at 80 °C for 6 hours. 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 an ethyl acetate / heptane 0 - 30% gradient to give the title compound as a colorless viscous oil (22 mg, 22% yield). MS(ESI): m / z = 428.3 [M+H]+

[0189] Step 5: [5-(2-Fluoroethoxy)-4-methoxy-pyrimidin-2-yl]amine [Chemical formula] A solution of [5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-bis(p-anisyl)amine (87 mg, 0.204 mmol) in dichloromethane (500 μl) was cooled to 0 °C. Trifluoroacetic acid (1.41 g, 945 μL, 12.2 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 16 hours and at 55 °C for a further 2 hours. The resulting purple solution was poured into saturated aqueous sodium bicarbonate 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 an ethyl acetate / heptane 0 - 100% gradient to give the title compound as an off-white solid (27 mg, 71% yield). MS(ESI): m / z = 188.1 [M+H]+

[0190] Intermediate B11: 2,6-bis(difluoromethoxy)-5-fluoro-pyridin-3-amine

Chem.

Chem.

[0191] Step 2: 2,6-Bis(difluoromethoxy)-3-fluoro-5-nitro-pyridine

Chem.

[0192] Step 3: 2,6-Bis(difluoromethoxy)-5-fluoro-pyridin-3-amine [Chemical formula] To a mixture of ethanol (12 ml) and water (3 ml) containing 2,6-bis(difluoromethoxy)-3-fluoro-5-nitro-pyridine (380 mg, 1.39 mmol) was added iron (389 mg, 6.93 mmol) and ammonium chloride (367 mg, 6.93 mmol) at 25 °C, and then the reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with water (3 ml) and extracted with ethyl acetate (3 × 10 ml). The combined organic layers were washed with saturated NaCl solution (5 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 2:1) to give 2,6-bis(difluoromethoxy)-5-fluoro-pyridin-3-amine (41 mg, yield 12%) as a yellow oil. MS (ESI): m / z = 244.8 [M+H] + .

[0193] Example Example 1: N-(4-(Cyanomethyl)-2,5-difluorophenyl)naphthalene-1-sulfonamide

Chemical formula

[0194] The following Examples 2 to 39 were prepared in the same manner as Example 1 by coupling the sulfonyl chloride Intermediate A and the amine Intermediate B shown.

Table 2

[0195] Example 40: N-[6-(2,2-Difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-5-(dimethylamino)naphthalene-1-sulfonamide

Chemical formula

[0196] Examples 41 to 46 below were prepared in the same manner as Example 40 by coupling the indicated sulfonyl chloride Intermediate A and amine Intermediate B.

Table 3

[0197] Example 48: 7-Chloro-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]quinoline-4-sulfonamide

Chem.

[0198] Example 49: 7-Chloro-N-[4-(cyanomethyl)-2,5-difluorophenyl]-1-methoxyisoquinoline-4-sulfonamide

Chemical formula

[0199] Example 50: 2-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1,7-naphthyridine-5-sulfonamide

Chem.

[0200] Example 51: 2-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidin-2-yl]quinoline-5-sulfonamide

Chem.

[0201] Example 52: N-(4-(Cyanomethyl)-2,5-difluorophenyl)-1-oxo-1,2-dihydroisoquinoline-4-sulfonamide [Chemical formula] To a stirred solution of 2-(4-amino-2,5-difluorophenyl)acetonitrile (25 mg, 0.149 mmol, Intermediate B1) and 4-dimethylaminopyridine (3.7 mg, 0.03 mmol) in pyridine (0.4 ml) was added 1-oxo-2H-isoquinoline-4-sulfonyl chloride (54.3 mg, 0.22 mmol, Intermediate A5). The reaction mixture was stirred at room temperature for 60 minutes, poured into dichloromethane and extracted with 10% citric acid solution. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (silica gel, n-heptane / ethyl acetate 0 to 100%) to give the title compound as a white solid (17 mg, 29% yield). MS (ESI) m / z: 376.0 [M+H] +

[0202] Example 53: 7-Chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]quinoline-4-sulfonamide [Chemical formula] Step 1: N-(4-Bromo-2,5-difluorophenyl)-7-chloro-quinoline-4-sulfonamide [Chemical formula] A solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.71 ml, 1.71 mmol) was added dropwise at 0 °C under an argon atmosphere to a solution of 4-bromo-2,5-difluoroaniline (169 mg, 0.81 mmol) in tetrahydrofuran (10 ml). After 30 minutes, a solution of 7-chloroquinoline-4-sulfonyl fluoride (200 mg, 0.81 mmol, Intermediate A2) in tetrahydrofuran (5 ml) was added dropwise, and the resulting mixture was stirred at room temperature for 12 hours. The resulting mixture was poured into brine and extracted with ethyl acetate (2 × 30 ml). Evaporation of the combined organic layers gave crude N-(4-bromo-2,5-difluorophenyl)-7-chloro-quinoline-4-sulfonamide (200 mg, 0.48 mmol, 59% yield), which was used in the next step without purification.

[0203] Step 2: 7-Chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]quinoline-4-sulfonamide [Chemical formula] N-(4-Bromo-2,5-difluorophenyl)-7-chloroquinoline-4-sulfonamide (200 mg, 0.46 mmol) was dissolved in dimethyl sulfoxide (6 ml) and water (1 ml), and then potassium fluoride (80.4 mg, 1.38 mmol) and 4-isoxazoleboronic acid pinacol ester (180 mg, 0.92 mmol) were added. The resulting mixture was degassed and filled with argon three times. 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (18.8 mg, 0.02 mmol) was added, and the resulting mixture was heated at 120 °C for 48 hours, then cooled to room temperature and filtered. When the filtrate was subjected to HPLC (column: SunFire C18 100×19 mm 5um, 4% water-acetonitrile + 0.1% NH4OH), the title compound was obtained as a brown gum (5 mg, yield 3%). MS(ESI) m / z: 394.0 [M+H] +

[0204] Example 54: 2-Bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]quinoline-5-sulfonamide

Chemical formula

[0205] Example 55: 2-Cyclopropyl-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]quinoline-5-sulfonamide

Chem.

[0206] Example 56: N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-2-methoxy-quinoline-5-sulfonamide

Chem.

[0207] Example 57: N-[6-(2,2-Difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1-(dimethylamino)isoquinoline-5-sulfonamide

Chemical formula

Chemical formula

[0208] Step 2: N-[6-(2,2-Difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1-(dimethylamino)isoquinoline-5-sulfonamide

Chemical Structure

[0209] Example 58: N-[6-(2,2-Difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]tetralin-5-sulfonamide

Chemical Structure

[0210] Example A The compound of formula I can be used as an active ingredient in a manner known per se to produce tablets of the following composition: Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg

[0211] Example B The compound of formula I can be used as an active ingredient in a manner known per se to produce capsules of the following composition: Per capsule Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg

Claims

1. A compound of formula I 【Chemical 138】 wherein R １ is selected from cyanoalkyl, haloalkoxy, haloalkyl, cyclopropyl and oxetanyl, R ２ is selected from alkoxy, H or halo, X １ is N, and X ２ is CR ４ and X ３ is N, or X １ is CR ３ and X ２ is CR ４ and X ３ is N or CR ５ or X １ is CR ３ and X ２ is N, and X ３ is CR ５ and R ３ is selected from alkoxy, H, halo, haloalkoxy, R ４ is selected from alkoxy, H, and halo, R ５ is selected from H, halo, W is selected from ring A, ring B or ring C, 【Chemical 139】 Y １ is CR ６ and Y ２ is CR ７ and Y ３ is CR ８ and Y ４ is CR ９ or Y １ is N, and Y ２ is CR ７ and Y ３ is CR ８ and Y ４ is CR ９ or Y １ is N, and Y ２ is CR ７ and Y ３ is N, and Y ４ is CR ９ or Y １ is CR ６ and Y ２ is N, and Y ３ is CR ８ and Y ４ is CR ９ or Y １ is CR ６ and Y ２ is CR ７ and Y ３ is N, and Y ４ is CR ９ or Y １ is CR ６ and Y ２ is CR ７ and Y ３ is CR ８ and Y ４ is N R ６ is H or alkylamino, R ７ is alkoxy, dimethylamino, H, methyl, methylamino, OH, and R ８ is cyano, dimethylamino, H, halo, and R ９ is alkoxy, cyclopropyl, haloalkyl dimethylamino, H, halo, alkyl, and R １０ is H or halo, Y ５ is NR １１ and Y ６ is -C(=O)-, and Y ７ is CR １３ or N, or Y ５ is -C(=O)-, and Y ６ is NR １２ and Y ７ is CR １３ and R １１ is alkyl or H, R １２ is alkyl or H, R １３ is H, alkyl or halo, R １４ is H, alkyl, halo, or haloalkyl, Y ８ is -CH- or -N-, Y ９ is -CH- or -N-, Y １０ is -CH ２ - or -O - and R １５ is H, alkyl or haloalkyl) and pharmaceutically acceptable salts thereof.

2. R １ The compound according to claim 1, wherein R is cyanoalkyl, haloalkoxy or cyclopropyl.

3. R ２ The compound according to any one of claims 1 or 2, wherein R is alkoxy or halo.

4. R ３ The compound according to any one of claims 1 to 3, wherein R is alkoxy, halo or haloalkoxy.

5. X １ is CR ３ and X ２ is CR ４ and X ３ is N or CR ５ or X １ is CR3 and X ２ is N and X ３ is CR ５ and which is a compound according to any one of claims 1 to 4.

6. R ４ and R ５ is H, a compound according to any one of claims 1 to 5.

7. Y １ is CR ６ and Y ２ is CR ７ and Y ３ is CR ８ and Y ４ is CR ９ or Y １ is N, and Y ２ is CR ７ and Y ３ is CR ８ and Y ４ is CR ９ or Y １ is N, and Y ２ is CR ７ and Y ３ is N, and Y ４ is CR ９ or Y １ is CR ６ and Y ２ is CR ７ and Y ３ is N and Y ４ is CR ９ is a compound according to any one of claims 1 to 6.

8. R ６ The compound according to any one of claims 1 to 7, wherein R is H.

9. R ７ The compound according to any one of claims 1 to 8, wherein R is H or methylamino.

10. R ８ The compound according to any one of claims 1 to 9, wherein R is dimethylamino, H or halo.

11. R ９ The compound according to any one of claims 1 to 10, wherein R is cyclopropyl, H, halo or alkyl.

12. R １０ , R １１ and R １２ is H, a compound according to any one of claims 1 to 11.

13. R １３ The compound according to any one of claims 1 to 12, wherein R is H or halo.

14. R １４ The compound according to any one of claims 1 to 13, wherein R is H or halo.

15. R １４ The compound according to any one of claims 1 to 14, wherein R is halo.

16. Y ８ is -CH-, and Y ９ is -CH-, and Y １０ is -CH- or -O-, the compound according to any one of claims 1 to 15.

17. Y ８ is -CH-, and Y ９ is -CH-, and Y １０ is -O-, the compound according to any one of claims 1 to 16.

18. R １５ The compound according to any one of claims 1 to 17, wherein R is H or alkyl.

19. R １５ The compound according to any one of claims 1 to 18, wherein R is alkyl.

20. R ２ When R is H, X ２ is CR ４ and R ４ is not H R １ When R is haloalkyl, ２ R is alkoxy, R １ is haloalkoxy and, when R ２ is halo, X ２ is N, a compound according to any one of claims 1 to 19.

21. R １ is selected from cyanoalkyl, haloalkoxy, haloalkyl, cyclopropyl and oxetanyl, R ２ is selected from alkoxy, H or halo, X １ is N, and X ２ is CR ４ and X ３ is N, or X １ is CR ３ and X ２ is CR ４ and X ３ is N or CR ５ or X １ is CR ３ and X ２ is N, and X ３ is CR ５ and R ３ is selected from alkoxy, H, halo, haloalkoxy, R ４ is selected from alkoxy, H, and halo, R ５ is selected from H, halo, W is selected from ring A, ring B or ring C, 【Chemical 140】 Y １ is CR ６ and Y ２ is CR ７ and Y ３ is CR ８ and Y ４ is CR ９ or Y １ is N, and Y ２ is CR ７ and Y ３ is CR ８ and Y ４ is CR ９ or Y １ is N, and Y ２ is CR ７ and Y ３ is N, and Y ４ is CR ９ or Y １ is CR ６ and Y ２ is N, and Y ３ is CR ８ and Y ４ is CR ９ is, or Y １ is CR ６ and Y ２ is CR ７ and Y ３ is N and Y ４ is CR ９ or Y １ is CR ６ and Y ２ is CR ７ and Y ３ is CR ８ and Y ４ is N R ６ is H or alkylamino, R ７ is alkoxy, dimethylamino, H, methyl, methylamino, OH, and R ８ is cyano, dimethylamino, H, halo, and R ９ is alkoxy, cyclopropyl, haloalkyl dimethylamino, H, halo, alkyl, and R １０ is H or halo, Y ５ is NR １１ and Y ６ is -C(=O)-, and Y ７ is CR １３ or N, or Y ５ is -C(=O)-, and Y ６ is NR １２ and Y ７ is CR １３ and R １１ is alkyl or H, R １２ is alkyl or H, R １３ is H or halo, R １４ is H or halo, Y ８ is -CH-, Y ９ is -CH-, Y １０ is -CH ２ - or -O- and R １５ is H or alkyl, The compound according to claim 1, and pharmaceutically acceptable salts thereof.

22. R １ is selected from cyanoalkyl, haloalkoxy, haloalkyl, cyclopropyl and oxetanyl, R ２ is selected from alkoxy, H or halo, X １ is N, and X ２ is CR ４ and X ３ is N, or X １ is CR ３ and X ２ is CR ４ and X ３ is N or CR ５ or X １ is CR ３ and X ２ is N, and X ３ is CR ５ and R ３ is selected from alkoxy, H, halo, haloalkoxy, R ４ is selected from alkoxy, H, and halo, R ５ is selected from H, halo, W is selected from ring A, ring B or ring C, 【Chemical 141】 Y １ is CR ６ and Y ２ is CR ７ and Y ３ is CR ８ and Y ４ is CR ９ or Y １ is N, and Y ２ is CR ７ and Y ３ is CR ８ and Y ４ is CR ９ or Y １ is N, and Y ２ is CR ７ and Y ３ is N, and Y ４ is CR ９ or Y １ is CR ６ and Y ２ is N, and Y ３ is CR ８ and Y ４ is CR ９ or Y １ is CR ６ and Y ２ is CR ７ and Y ３ is N and Y ４ is CR ９ or Y １ is CR ６ and Y ２ is CR ７ and Y ３ is CR ８ and Y ４ is N R ６ is H or alkylamino, R ７ is alkoxy, dimethylamino, H, methyl, methylamino, OH, and R ８ is cyano, dimethylamino, H, halo, and R ９ is alkoxy, cyclopropyl, haloalkyl dimethylamino, H, halo, alkyl, and R １０ is H or halo, Y ５ is NR １１ and Y ６ is -C(=O)-, and Y ７ is CR １３ or N, or Y ５ is -C(=O)-, and Y ６ is NR １２ and Y ７ is CR １３ and R １１ is alkyl or H, R １２ is alkyl or H, R １３ is H or halo, R １４ is H or halo, Y ８ is -CH- and Y ９ is -CH-, Y １０ is -CH ２ - or -O - and R １５ is H or alkyl, R ２ When R is H, X ２ is CR ４ and R ４ is not H R １ When R is haloalkyl, ２ R is alkoxy, and R １ is haloalkoxy and when R ２ is halo, X ２ is N, The compound according to claim 1 or claim 21, and pharmaceutically acceptable salts thereof.

23. R １ is selected from cyanoalkyl, haloalkoxy, or cyclopropyl, R ２ is selected from alkoxy or halo, X １ is CR ３ and X ２ is CR ４ and X ３ is N or CR ５ or X １ is CR ３ and X ２ is N, and X ３ is CR ５ and R ３ is selected from alkoxy, halo or haloalkoxy, R ４ is H, R ５ is H, W is selected from ring A, ring B or ring C, 【Chemical 142】 Y １ is CR ６ and Y ２ is CR ７ and Y ３ is CR ８ and Y ４ is CR ９ or Y １ is N, and Y ２ is CR ７ and Y ３ is CR ８ and Y ４ is CR ９ or Y １ is N, and Y ２ is CR ７ and Y ３ is N, and Y ４ is CR ９ or Y １ is CR ６ and Y ２ is CR ７ and Y ３ is N and Y ４ is CR ９ and R ６ is H, R ７ is H or methylamino, R ８ is dimethylamino, H or halo, and R ９ is cyclopropyl, H, halo or alkyl, R １０ is H, Y ５ is NR １１ and Y ６ is -C(=O)-, and Y ７ is CR １３ or N, or Y ５ is -C(=O)-, and Y ６ is NR １２ and Y ７ is CR １３ and R １１ is H, R １２ is R １３ is H or halo, R １４ is a halo, Y ８ is -CH-, Y ９ is -CH-, Y １０ is -O- and R １５ wherein R is alkyl The compound according to claim 1, and pharmaceutically acceptable salts thereof.

24. R １ is selected from cyanoalkyl, haloalkoxy, or cyclopropyl, R ２ is selected from alkoxy or halo, X １ is CR ３ and X ２ is CR ４ and X ３ is N or CR ５ or X １ is CR ３ and X ２ is N, and X ３ is CR ５ and R ３ is selected from alkoxy, halo or haloalkoxy, R ４ is H, R ５ is H, W is selected from ring A, ring B or ring C, 【Chemical 143】 Y １ is CR ６ and Y ２ is CR ７ and Y ３ is CR ８ and Y ４ is CR ９ or Y １ is N, and Y ２ is CR ７ and Y ３ is CR ８ and Y ４ is CR ９ or Y １ is N, and Y ２ is CR ７ and Y ３ is N, and Y ４ is CR ９ or Y １ is CR ６ and Y ２ is CR ７ and Y ３ is N and Y ４ is CR ９ and R ６ is H, R ７ is H or methylamino, R ８ is dimethylamino, H or halo, and R ９ is cyclopropyl, H, halo or alkyl, R １０ is H, Y ５ is NR １１ and Y ６ is -C(=O)-, and Y ７ is CR １３ or N, or Y ５ is -C(=O)-, and Y ６ is NR １２ and Y ７ is CR １３ and R １１ is H, R １２ is R １３ is H or halo, R １４ is a halo, Y ８ is -CH-, Y ９ is -CH- and Y １０ is -O-, R １５ is alkyl, R ２ When R is H, X ２ is CR ４ and R ４ is not H R １ When R is haloalkyl, ２ R is alkoxy, R １ is haloalkoxy and when R ２ is halo, X ２ is N, The compound according to any one of claims 1 or 23, and pharmaceutically acceptable salts thereof.

25. N-(4-(cyanomethyl)-2,5-difluorophenyl)naphthalene-1-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]naphthalene-1-sulfonamide; 2-chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]quinoline-5-sulfonamide; 2-chloro-N-(6-cyclopropyl-5-fluoro-2-methoxy-3-pyridyl)quinoline-5-sulfonamide; 2-chloro-N-[6-(cyanomethyl)-5-fluoro-2-methoxy-3-pyridyl]quinoline-5-sulfonamide; 2-chloro-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]quinoline-5-sulfonamide; 2-chloro-N-[5-fluoro-2-methoxy-6-(oxetan-3-yl)-3-pyridyl]quinoline-5-sulfonamide; 2-chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]quinoline-5-sulfonamide; 2-chloro-N-[5-(2,2-difluoroethoxy)-3-fluoro-6-methoxy-2-pyridyl]quinoline-5-sulfonamide; 2-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]quinoline-5-sulfonamide; N-[2,6-Bis(difluoromethoxy)-5-fluoro-3-pyridyl]-2-chloro-quinoline-5-sulfonamide; 7-Chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]isoquinoline-4-sulfonamide; 7-Chloro-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]isoquinoline-4-sulfonamide; 7-Chloro-N-[5-(2,2-difluoroethoxy)-3-fluoro-6-methoxy-2-pyridyl]isoquinoline-4-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]isoquinoline-4-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-2-methyl-chroman-5-sulfonamide; 5-Chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]naphthalene-1-sulfonamide; 5-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]naphthalene-1-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]naphthalene-1-sulfonamide; 8-Chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-1-hydroxy-isoquinoline-4-sulfonamide; 7-Chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-1-keto-2H-isoquinoline-4-sulfonamide; 7-Chloro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1-keto-2H-isoquinoline-4-sulfonamide; 7-Chloro-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1-keto-2H-isoquinoline-4-sulfonamide; 7-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1-keto-2H-isoquinoline-4-sulfonamide; 7-Chloro-N-[5-(2,2-difluoroethoxy)-3-fluoro-6-methoxy-2-pyridyl]-1-oxo-2H-isoquinoline-4-sulfonamide; 7-Chloro-N-[4-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-phenyl]-1-keto-2H-isoquinoline-4-sulfonamide; N-[2,6-bis(difluoromethoxy)-5-fluoro-3-pyridyl]-7-chloro-1-keto-2H-isoquinoline-4-sulfonamide; 2-Chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-8-oxo-7H-1,7-naphthyridine-5-sulfonamide; 2-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-8-keto-7H-1,7-naphthyridine-5-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-2-keto-1H-quinoline-4-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-2-(dimethylamino)quinoline-5-sulfonamide; N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-2-(dimethylamino)quinoline-5-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-2-methyl-quinoline-5-sulfonamide; 6-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]naphthalene-1-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-2-(difluoromethyl)quinoline-5-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1-keto-2-methyl-isoquinoline-4-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-2-keto-1-methyl-quinoline-4-sulfonamide; 7,8-Dichloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-1-keto-2H-isoquinoline-4-sulfonamide; 7,8-Dichloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1-keto-2H-isoquinoline-4-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-5-(dimethylamino)naphthalene-1-sulfonamide; 7-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1-(dimethylamino)isoquinoline-4-sulfonamide; 7-chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-1-(dimethylamino)isoquinoline-4-sulfonamide; 7-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1-(methylamino)isoquinoline-4-sulfonamide; 7-chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-1-(methylamino)isoquinoline-4-sulfonamide; 7-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-2-(methylamino)quinoline-4-sulfonamide; 7-chloro-8-cyano-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]isoquinoline-4-sulfonamide; 7-chloro-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]quinoline-4-sulfonamide; 7-chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-1-methoxy-isoquinoline-4-sulfonamide; 2-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1,7-naphthyridine-5-sulfonamide; 2-chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]quinoline-5-sulfonamide; N-(4-(cyanomethyl)-2,5-difluorophenyl)-1-oxo-1,2-dihydroisoquinoline-4-sulfonamide; 7-chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]quinoline-4-sulfonamide; 2-bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]quinoline-5-sulfonamide; 2-cyclopropyl-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]quinoline-5-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-2-methoxy-quinoline-5-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1-(dimethylamino)isoquinoline-5-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]tetralin-5-sulfonamide selected from The compound according to any one of claims 1 to 24, and a pharmaceutically acceptable salt thereof.

26. 2-chloro-N-(6-cyclopropyl-5-fluoro-2-methoxy-3-pyridyl)quinoline-5-sulfonamide; 2-chloro-N-[6-(cyanomethyl)-5-fluoro-2-methoxy-3-pyridyl]quinoline-5-sulfonamide; 2-chloro-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]quinoline-5-sulfonamide; 2-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]quinoline-5-sulfonamide; 7-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]isoquinoline-4-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-2-methyl-chroman-5-sulfonamide; 5-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]naphthalene-1-sulfonamide; 7-chloro-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1-oxo-2H-isoquinoline-4-sulfonamide; 7-chloro-N-[5-(2,2-difluoroethoxy)-3-fluoro-6-methoxy-2-pyridyl]-1-oxo-2H-isoquinoline-4-sulfonamide; 7-chloro-N-[4-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-phenyl]-1-oxo-2H-isoquinoline-4-sulfonamide; N-[2,6-bis(difluoromethoxy)-5-fluoro-3-pyridyl]-7-chloro-1-oxo-2H-isoquinoline-4-sulfonamide; 2-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-8-oxo-7H-1,7-naphthyridine-5-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-2-oxo-1H-quinoline-4-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-2-methyl-quinoline-5-sulfonamide; 6-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]naphthalene-1-sulfonamide; 7,8-Dichloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1-oxo-2H-isoquinoline-4-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-5-(dimethylamino)naphthalene-1-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1-(methylamino)isoquinoline-4-sulfonamide; 2-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1,7-naphthyridine-5-sulfonamide; 2-Bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]quinoline-5-sulfonamide; 2-Cyclopropyl-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]quinoline-5-sulfonamide selected from A compound according to any one of claims 1 to 25, and a pharmaceutically acceptable salt thereof.

27. Reacting a compound of formula III with a compound of formula II in the presence of a base selected from N-ethyldiisopropylamine, pyridine, potassium phosphate or sodium hydride to provide a compound of formula I 【Chemical 144】 (wherein, R １ , R ２ , R ３ , X １ , X ２ , X ３ and W are as described above) A process for preparing a compound according to any one of claims 1 to 26, comprising.

28. A compound according to any one of claims 1 to 26 for use as a therapeutic active substance.

29. A compound according to any one of claims 1 to 26 for use in the treatment of a disease regulated by GPR17.

30. A pharmaceutical composition comprising the compound according to any one of claims 1 to 26 and a therapeutically inert carrier.

31. Use of a compound according to any one of claims 1 to 26 for treating or preventing symptoms resulting from inflammation of the central nervous system (CNS), for example after encephalitis, primary vasculitis, meningitis and obesity, direct damage to the myelin sheath (including, but not limited to, central and extracerebral myelinolysis, carbon monoxide poisoning, malnutrition, and virus-induced demyelination), demyelinating disorders (including, but not limited to, multiple sclerosis, acute and polymorphic disseminated encephalomyelitis, neuromyelitis optica spectrum disorder, and leukodystrophy), CNS disorders associated with myelin loss (including, but not limited to, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and ischemia due to stroke).

32. Use of a compound according to any one of claims 1 to 26 for treating or preventing multiple sclerosis.

33. Use of a compound according to any one of claims 1 to 26 for preparing a medicament for treating or preventing symptoms resulting from inflammation of the central nervous system (CNS), for example after encephalitis, primary vasculitis, meningitis and obesity, direct damage to the myelin sheath (including, but not limited to, central and extracerebral myelinolysis, carbon monoxide poisoning, malnutrition, and virus-induced demyelination), demyelinating disorders (including, but not limited to, multiple sclerosis, acute and polymorphic disseminated encephalomyelitis, neuromyelitis optica spectrum disorder, and leukodystrophy), CNS disorders associated with myelin loss (including, but not limited to, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and ischemia due to stroke).

34. Direct damage to the myelin sheath (including, but not limited to, central and extracerebral myelinolysis, carbon monoxide poisoning, malnutrition, and virus-induced demyelination), demyelinating disorders (including, but not limited to, multiple sclerosis, acute and multiphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorder, and leukodystrophy), CNS disorders associated with myelin loss (including, but not limited to, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and ischemia due to stroke), and for treating or preventing symptoms resulting from CNS inflammation, for example, after encephalitis, primary vasculitis, meningitis, and obesity, a compound according to any one of claims 1 to 26.

35. A compound according to any one of claims 1 to 26 for use in the treatment or prevention of multiple sclerosis.

36. Direct damage to the myelin sheath (including, but not limited to, central and extracerebral myelinolysis, carbon monoxide poisoning, malnutrition, and virus-induced demyelination), demyelinating disorders (including, but not limited to, multiple sclerosis, acute and multiphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorder, and leukodystrophy), CNS disorders associated with myelin loss (including, but not limited to, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and ischemia due to stroke), and a method for treating or preventing symptoms resulting from CNS inflammation, for example, after encephalitis, primary vasculitis, meningitis, and obesity, the method comprising administering an effective amount of a compound according to any one of claims 1 to 26 to a patient in need thereof.

37. 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 26 to a patient in need thereof.

38. A compound according to any one of claims 1 to 26 when manufactured according to the method of claim 27.

39. The invention as described previously herein.

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