Novel naphthyl and isoquinoline sulfonamide derivatives

Abstract

The present invention relates to novel compounds having the general formula I wherein R1, R2, X1, X2, X3 and W are as described herein; comprising the compound; and methods of using the compounds. # imgabs0 #

Description

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

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

[0003]

[0004] in,

[0005] R 1 is selected from the group consisting of cyanoalkyl, haloalkoxy, haloalkyl, cyclopropyl and oxetanyl;

[0006] R 2 Selected from alkoxy, H or halo;

[0007] X1 is N, and X2 is CR 4 , and X3 is N, or

[0008] X1 for CR 3 , X2 is CR 4 , and X3 is N or CR 5 ,or

[0009] X1 for CR 3 , X2 is N, and X3 is CR 5 ;

[0010] R 3 Selected from alkoxy, H, halo, haloalkoxy

[0011] R 4 Selected from alkoxy, H, halo

[0012] R 5 Selected from H, halogenated

[0013] W is selected from Ring A, Ring B or Ring C

[0014]

[0015] Y1 is CR 6 , Y2 is CR 7 , Y3 is CR 8 , and Y4 is CR 9 ,or

[0016] Y1 is N, Y2 is CR 7 , Y3 is CR 8 , and Y4 is CR 9 ,or

[0017] Y1 is N, Y2 is CR 7 , Y3 is N, and Y4 is CR9 ,or

[0018] Y1 is CR 6 , Y2 is N, Y3 is CR 8 , and Y4 is CR 9 ,or

[0019] Y1 is CR 6 , Y2 is CR 7 , Y3 is N, and Y4 is CR 9 ,or

[0020] Y1 is CR 6 , Y2 is CR 7 , Y3 is CR 8 , and Y4 is N;

[0021] R 6 is H or alkylamino;

[0022] R 7 is alkoxy, dimethylamino, H, methyl, methylamino, OH;

[0023] R 8 is cyano, dimethylamino, H, halo;

[0024] R 9 is alkoxy, cyclopropyl, haloalkyl, dimethylamino, H, halo, alkyl;

[0025] R 10 is H or halogenated;

[0026] Y5 is NR 11 , Y6 is -C(=O)-, and Y7 is CR 13 or N, or

[0027] Y5 is -C(=O)-, and Y6 is NR 12 , and Y7 is CR 13 ;

[0028] R 11 is alkyl or H;

[0029] R 12 is alkyl or H;

[0030] R 13 is H, alkyl or halo;

[0031] R 14 is H, alkyl, halo or haloalkyl;

[0032] Y8 is -CH- or -N-;

[0033] Y9 is -CH- or -N-;

[0034] Y 10 is -CH2- or –O-;

[0035] R 15 is H, alkyl or haloalkyl;

[0036] and pharmaceutically acceptable salts thereof.

[0037] Furthermore, the present invention includes all racemic mixtures, all corresponding enantiomers and / or optical isomers thereof. Background Art

[0038] Myelination is a process that occurs intensely during development, and although there are abundant oligodendrocyte precursor cells (OPCs) throughout the adult CNS, the transition to myelinating oligodendrocytes and the process of generating restorative myelin around denuded axons is impaired in chronic demyelinating diseases. During development, myelination proceeds in a very orderly manner, with OPCs characterized by the expression of markers such as neural / glial antigen 2 (NG2) and platelet-derived growth factor alpha (PDGFRα), differentiating into oligodendrocytes that lose NG2 and PDGFRα expression and gaining expression of markers such as myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG). Myelination by oligodendrocytes is a very tightly regulated process and in the CNS this may be controlled by interactions with axons, which is well understood in the peripheral nervous system but not in the central nervous system (Macklin, WB (2010). Sci. Signal. 3, pp. 32–33, “The myelin brake: When Enough Is Enough”). Myelination can also be controlled by internal brakes within the oligodendrocytes themselves through the transcription factor EB (TFEB)-PUMA axis or through GPR17 antagonism (Chen, Y. et al. (2009). Nat Neurosci 12, 1398–1406, “The oligodendrocyte-specific Gprotein-coupled receptor GPR17 is a cell-intrinsic timer of myelination”) (Sun, LO et al. (2018). Cell 175, 1811-1826.e21, “Spatiotemporal Control of CNS Myelination by Oligodendrocyte Programmed Cell Death through the TFEB-PUMAAxis”).Myelin not only protects axons and promotes neuronal transmission, but oligodendrocytes have also been shown to play an important role in axonal metabolism and maintaining electrolyte balance around axons (Schirmer, L. et al. (2014). Ann Neurol 75, 810–828, “Differential loss of KIR4.1 immunoreactivity in multiple sclerosis lesions”) (Simons, M. and Nave, K.-A. (2015). Cold Spring Harb Perspect Biol. 22, “Oligodendrocytes: Myelination and Axonal Support”).

[0039] 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").

[0040] The role of GPR17 in myelination was first determined in a screen of the optic nerves of Olig1 knockout mice to identify genes that regulate myelination. GPR17 expression was found to be expressed only in myelinating cells of the CNS and not in Schwann cells (myelinating cells of the peripheral nervous system). GPR17 expression was found to be expressed only in oligodendrocyte lineage cells and downregulated in myelinating oligodendrocytes (Chen, Y. et al. (2009)). Specifically, GPR17 expression was found to be present at low levels in the early stages of OPCs and to increase in premyelinating oligodendrocytes before being downregulated in mature myelinating oligodendrocytes (Boda, E. et al. (2011), Glia 59, 1958–1973, “The GPR17 receptor in NG2 expressing cells: Focus on in vivo cell maturation and participation in acute trauma and chronic damage”) (Dziedzic, A. et al. (2020). Int. J. Mol. Sci. 21, 1852, “The gpr17 receptor—a promising goal for therapy and a potential marker of the neurodegenerative process in multiple sclerosis”) (Fumagalli, M. et al. (2011), J Biol Chem 286, 10593–10604, “Phenotypic changes, signaling pathway, and functional correlates of GPR17-expressing neural precursor cells during GPR17 knockout animals exhibit precocious myelination throughout the CNS, and conversely, transgenic mice overexpressing GPR17 with the CNP-Cre (2',3'-cyclic nucleotide 3'-phosphodiesterase) promoter in oligodendrocytes exhibit myelination defects, consistent with the expectation of a cell-intrinsic brake on myelination (Chen, Y. et al. (2009)).Furthermore, loss of GPR17 enhances remyelination after demyelination in lysophosphatidylcholine-induced demyelination (Lu, C., Dong et al. (2018), Sci. Rep. 8, 4502, “G-Protein-Coupled Receptor Gpr17 Regulates Oligodendrocyte Differentiation in Response to Lysolecithin-Induced Demyelination”). Therefore, antagonism of GPR17, which promotes differentiation of oligodendrocyte lineage cells into mature myelin-forming oligodendrocytes, will lead to increased myelination after demyelination.

[0041] Multiple sclerosis (MS) is a chronic neurodegenerative disease characterized by the loss of myelin (protective fatty lipid layer around 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.

[0042] 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.

[0043] Therefore, diseases for which GPR17 antagonism could be used to produce positive disease results include, but are not limited to:

[0044] Direct damage to the myelin sheath:

[0045] - 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

[0046] - Carbon monoxide poisoning, oligodendrocyte dysfunction and regeneration failure reported in deep white matter layers of the brain

[0047] - Nutritional deficiencies that lead to loss of myelin or failure to properly myelinate during development

[0048] - Virus-induced demyelination

[0049] Primary demyelinating diseases

[0050] -Multiple sclerosis (relapsing-remitting, secondary progressive, primary progressive, and progressive relapsing MS)

[0051] -Acute and multiphasic disseminated encephalomyelitis

[0052] - Neuromyelitis optica spectrum disorder, including optic neuritis

[0053] - Transverse myelitis

[0054] - Leukodystrophies such as adrenoleukodystrophy, adrenoleukodystrophy, and other hereditary leukodystrophies that cause loss of myelin

[0055] CNS diseases with associated myelin loss:

[0056] -Alzheimer's disease

[0057] - Schizophrenia

[0058] - Parkinson's disease

[0059] - Huntington's disease

[0060] -Amyotrophic lateral sclerosis

[0061] - Ischemia due to stroke

[0062] Other diseases:

[0063] - 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.

[0064] Therefore, the compounds of formula I are particularly useful for treating diseases associated with GPR17 antagonism.

[0065] 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

[0066] The present invention provides novel compounds of formula I,

[0067]

[0068] in,

[0069] R 1 is selected from the group consisting of cyanoalkyl, haloalkoxy, haloalkyl, cyclopropyl and oxetanyl;

[0070] R 2 Selected from alkoxy, H or halo;

[0071] X1 is N, and X2 is CR 4 , and X3 is N, or

[0072] X1 for CR 3 , X2 is CR 4 , and X3 is N or CR 5 ,or

[0073] X1 for CR 3 , X2 is N, and X3 is CR 5 ;

[0074] R 3 Selected from alkoxy, H, halo, haloalkoxy;

[0075] R 4 Selected from alkoxy, H, halo;

[0076] R 5 Selected from H, halo;

[0077] W is selected from Ring A, Ring B or Ring C;

[0078]

[0079] Y1 is CR 6 , Y2 is CR 7 , Y3 is CR 8 , and Y4 is CR 9 ,or

[0080] Y1 is N, Y2 is CR 7 , Y3 is CR 8 , and Y4 is CR 9 ,or

[0081] Y1 is N, Y2 is CR 7 , Y3 is N, and Y4 is CR 9 ,or

[0082] Y1 is CR 6 , Y2 is N, Y3 is CR 8 , and Y4 is CR 9 ,or

[0083] Y1 is CR 6 , Y2 is CR 7 , Y3 is N, and Y4 is CR 9 ,or

[0084] Y1 is CR 6 , Y2 is CR 7 , Y3 is CR 8 , and Y4 is N;

[0085] R 6 is H or alkylamino;

[0086] R 7 is alkoxy, dimethylamino, H, methyl, methylamino, OH;

[0087] R 8 is cyano, dimethylamino, H, halo;

[0088] R 9 is alkoxy, cyclopropyl, haloalkyl, dimethylamino, H, halo, alkyl;

[0089] R 10 is H or halogenated;

[0090] Y5 is NR 11 , Y6 is -C(=O)-, and Y7 is CR 13 or N, or

[0091] Y5 is -C(=O)-, and Y6 is NR 12 , and Y7 is CR 13 ;

[0092] R 11 is alkyl or H;

[0093] R 12 is alkyl or H;

[0094] R 13 is H, alkyl or halo;

[0095] R 14 is H, alkyl, halo or haloalkyl;

[0096] Y8 is -CH- or -N-;

[0097] Y9 is -CH- or -N-;

[0098] Y 10 is -CH2- or –O-;

[0099] R 15 is H, alkyl or haloalkyl;

[0100] and pharmaceutically acceptable salts thereof.

[0101] 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. Particular alkyl groups include methyl and ethyl. 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.

[0102] 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.

[0103] The term "cyano" refers to a C≡N group.

[0104] "Cyanoalkyl" means a moiety of the formula -R'-R" wherein R' is alkyl as defined herein and R" is cyano or nitrile. A specific example is cyanomethyl.

[0105] The terms "halogen", "halide" and "halo" are used interchangeably herein and refer to fluorine, chlorine, bromine or iodine. Specific halogens are chlorine and fluorine.

[0106] 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. Specific examples are difluoroethoxy and difluoromethoxy.

[0107] 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. A specific example is difluoroethyl.

[0108] The term "amino" refers to a -NH2 group.

[0109] The term "alkylamino" denotes an amino group wherein one of the hydrogen atoms of the amino group has been replaced by an alkyl group. An example is methylamino.

[0110] 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.

[0111] The abbreviation uM means micromolar, and is equivalent to the symbol μM.

[0112] The abbreviation uL means microliter, and is equivalent to the symbol μL.

[0113] The abbreviation ug means microgram, and is equivalent to the symbol μg.

[0114] 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.

[0115] According to the Cahn-Ingold-Prelog convention, asymmetric carbon atoms can be in either the "R" or "S" configuration.

[0116] 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.

[0117] Embodiments of the present invention provide compounds according to formula I as described herein, wherein R 1 is cyanoalkyl, haloalkoxy or cyclopropyl.

[0118] Embodiments of the present invention provide compounds according to formula I as described herein, wherein R 2 is alkoxy or halogenated.

[0119] Embodiments of the present invention provide compounds according to formula I as described herein, wherein R 3 It is alkoxy, halogenated or halogenated alkoxy.

[0120] Embodiments of the present invention provide compounds according to formula I as described herein, wherein X1 is CR 3 、X2 is CR 4 , and X3 is N or CR 5 , or X1 is CR3, X2 is N, and X3 is CR 5 .

[0121] Embodiments of the present invention provide compounds according to formula I as described herein, wherein R 4 For H.

[0122] Embodiments of the present invention provide compounds according to formula I as described herein, wherein R 5 For H.

[0123] Embodiments of the present invention provide compounds according to formula I as described herein, wherein

[0124] Y1 is CR 6 , Y2 is CR 7 , Y3 is CR 8 , and Y4 is CR 9 ,or

[0125] Y1 is N, Y2 is CR 7 , Y3 is CR 8 , and Y4 is CR 9 ,or

[0126] Y1 is N, Y2 is CR 7 , Y3 is N, and Y4 is CR 9 ,or

[0127] Y1 is CR 6 , Y2 is CR 7 , Y3 is N, and Y4 is CR 9 .

[0128] Embodiments of the present invention provide compounds according to formula I as described herein, wherein R 6 For H.

[0129] Embodiments of the present invention provide compounds according to formula I as described herein, wherein R 7 is H or methylamino.

[0130] Embodiments of the present invention provide compounds according to formula I as described herein, wherein R 8 is dimethylamino, H or halogenated.

[0131] Embodiments of the present invention provide compounds according to formula I as described herein, wherein R 9 is cyclopropyl, H, halo or alkyl.

[0132] Embodiments of the present invention provide compounds according to formula I as described herein, wherein R 10 For H.

[0133] Embodiments of the present invention provide compounds according to formula I as described herein, wherein R 11 For H.

[0134] Embodiments of the present invention provide compounds according to formula I as described herein, wherein R 12 For H.

[0135] Embodiments of the present invention provide compounds according to formula I as described herein, wherein R 13 is H or halogenated.

[0136] Embodiments of the present invention provide compounds according to formula I as described herein, wherein R 14 is H or halogenated.

[0137] Embodiments of the present invention provide compounds according to formula I as described herein, wherein R 14 It is halogenated.

[0138] Embodiments of the present invention provide compounds according to formula I as described herein, wherein Y8 is -CH-, Y9 is -CH-, and Y 10 It is –CH- or –O-.

[0139] Embodiments of the present invention provide compounds according to formula I as described herein, wherein Y8 is -CH-, Y9 is -CH-, and Y 10 It is –O-.

[0140] Embodiments of the present invention provide compounds according to formula I as described herein, wherein R 15 is H or alkyl.

[0141] Embodiments of the present invention provide compounds according to formula I as described herein, wherein R 15 It is an alkyl group.

[0142] Embodiments of the present invention provide compounds according to formula I as described herein, wherein

[0143] When R 2 When it is H, then X2 is CR 4 And R 4 Not for H;

[0144] When R 1When it is a halogenated alkyl group, R 2 is an alkoxy group; and

[0145] When R 1 is a halogenated alkoxy group and R 2 When it is halogenated, X2 is N.

[0146] Embodiments of the present invention provide compounds according to formula I as described herein, wherein

[0147] R 1 Selected from cyanoalkyl, haloalkoxy, haloalkyl, cyclopropyl and oxetane

[0148] alkyl;

[0149] R 2 Selected from alkoxy, H or halo;

[0150] X1 is N, and X2 is CR 4 , and X3 is N, or

[0151] X1 for CR 3 , X2 is CR 4 , and X3 is N or CR 5 ,or

[0152] X1 for CR 3 , X2 is N, and X3 is CR 5 ;

[0153] R 3 Selected from alkoxy, H, halo, haloalkoxy;

[0154] R 4 Selected from alkoxy, H, halo;

[0155] R 5 Selected from H, halo;

[0156] W is selected from Ring A, Ring B or Ring C

[0157]

[0158] Y1 is CR 6 , Y2 is CR 7 , Y3 is CR 8 , and Y4 is CR 9 ,or

[0159] Y1 is N, Y2 is CR 7 , Y3 is CR 8 , and Y4 is CR 9 ,or

[0160] Y1 is N, Y2 is CR 7, Y3 is N, and Y4 is CR 9 ,or

[0161] Y1 is CR 6 , Y2 is N, Y3 is CR 8 , and Y4 is CR 9 ,or

[0162] Y1 is CR 6 , Y2 is CR 7 , Y3 is N, and Y4 is CR 9 ,or

[0163] Y1 is CR 6 , Y2 is CR 7 , Y3 is CR 8 , and Y4 is N;

[0164] R 6 is H or alkylamino;

[0165] R 7 is alkoxy, dimethylamino, H, methyl, methylamino, OH;

[0166] R 8 is cyano, dimethylamino, H, halo;

[0167] R 9 is alkoxy, cyclopropyl, haloalkyl, dimethylamino, H, halo, alkyl;

[0168] R 10 is H or halogenated;

[0169] Y5 is NR 11 , Y6 is -C(=O)-, and Y7 is CR 13 or N, or

[0170] Y5 is -C(=O)-, and Y6 is NR 12 , and Y7 is CR 13 ;

[0171] R 11 is alkyl or H;

[0172] R 12 is alkyl or H;

[0173] R 13 is H or halogenated;

[0174] R 14 is H or halogenated;

[0175] Y8 is -CH-;

[0176] Y9 is -CH-;

[0177] Y 10 is -CH2- or –O-;

[0178] R 15 is H or alkyl;

[0179] and pharmaceutically acceptable salts thereof.

[0180] Embodiments of the present invention provide compounds according to formula I as described herein, wherein

[0181] R 1 Selected from cyanoalkyl, haloalkoxy, haloalkyl, cyclopropyl and oxetane

[0182] alkyl;

[0183] R 2 Selected from alkoxy, H or halo;

[0184] X1 is N, and X2 is CR 4 , and X3 is N, or

[0185] X1 for CR 3 , X2 is CR 4 , and X3 is N or CR 5 ,or

[0186] X1 for CR 3 , X2 is N, and X3 is CR 5 ;

[0187] R 3 Selected from alkoxy, H, halo, haloalkoxy;

[0188] R 4 Selected from alkoxy, H, halo;

[0189] R 5 Selected from H, halo;

[0190] W is selected from Ring A, Ring B or Ring C

[0191]

[0192] Y1 is CR 6 , Y2 is CR 7 , Y3 is CR 8 , and Y4 is CR 9 ,or

[0193] Y1 is N, Y2 is CR 7 , Y3 is CR 8 , and Y4 is CR 9 ,or

[0194] Y1 is N, Y2 is CR 7 , Y3 is N, and Y4 is CR 9 ,or

[0195] Y1 is CR 6 , Y2 is N, Y3 is CR 8 , and Y4 is CR 9 ,or

[0196] Y1 is CR 6 , Y2 is CR 7 , Y3 is N, and Y4 is CR 9 ,or

[0197] Y1 is CR 6 , Y2 is CR 7 , Y3 is CR 8 , and Y4 is N;

[0198] R 6 is H or alkylamino;

[0199] R 7 is alkoxy, dimethylamino, H, methyl, methylamino, OH;

[0200] R 8 is cyano, dimethylamino, H, halo;

[0201] R 9 is alkoxy, cyclopropyl, haloalkyl, dimethylamino, H, halo, alkyl;

[0202] R 10 is H or halogenated;

[0203] Y5 is NR 11 , Y6 is -C(=O)-, and Y7 is CR 13 or N, or

[0204] Y5 is -C(=O)-, and Y6 is NR 12 , and Y7 is CR 13 ;

[0205] R 11 is alkyl or H;

[0206] R 12 is alkyl or H;

[0207] R 13 is H or halogenated;

[0208] R 14 is H or halogenated;

[0209] Y8 is -CH-;

[0210] Y9 is -CH-;

[0211] Y 10 is -CH2- or –O-;

[0212] R 15 is H or alkyl;

[0213] in,

[0214] When R 2 When it is H, then X2 is CR 4 And R 4 Not for H;

[0215] When R 1 When it is a halogenated alkyl group, R 2 is an alkoxy group; and

[0216] When R 1 is a halogenated alkoxy group and R 2 When it is halogenated, X2 is N;

[0217] and pharmaceutically acceptable salts thereof.

[0218] Embodiments of the present invention provide compounds according to formula I as described herein, wherein

[0219] R 1 is selected from cyanoalkyl, haloalkoxy or cyclopropyl;

[0220] R 2 Selected from alkoxy or halo;

[0221] X1 for CR 3 , X2 is CR 4 , and X3 is N or CR 5 ,or

[0222] X1 for CR 3 , X2 is N, and X3 is CR 5 ;

[0223] R 3 Selected from alkoxy, halo or haloalkoxy;

[0224] R 4 is H;

[0225] R 5 is H;

[0226] W is selected from Ring A, Ring B or Ring C

[0227]

[0228] Y1 is CR 6 , Y2 is CR 7, Y3 is CR 8 , and Y4 is CR 9 ,or

[0229] Y1 is N, Y2 is CR 7 , Y3 is CR 8 , and Y4 is CR 9 ,or

[0230] Y1 is N, Y2 is CR 7 , Y3 is N, and Y4 is CR 9 ,or

[0231] Y1 is CR 6 , Y2 is CR 7 , Y3 is N, and Y4 is CR 9 ;

[0232] R 6 is H;

[0233] R 7 is H or methylamino;

[0234] R 8 is dimethylamino, H or halo;

[0235] R 9 is cyclopropyl, H, halo or alkyl;

[0236] R 10 is H;

[0237] Y5 is NR 11 , Y6 is -C(=O)-, and Y7 is CR 13 or N, or

[0238] Y5 is -C(=O)-, and Y6 is NR 12 , and Y7 is CR 13 ;

[0239] R 11 is H;

[0240] R 12 for;

[0241] R 13 is H or halogenated;

[0242] R 14 is halogenated;

[0243] Y8 is -CH-;

[0244] Y9 is -CH-;

[0245] Y 10 is –O-;

[0246] R 15 is an alkyl group;

[0247] and pharmaceutically acceptable salts thereof.

[0248] Embodiments of the present invention provide compounds according to formula I as described herein, wherein

[0249] R 1 is selected from cyanoalkyl, haloalkoxy or cyclopropyl;

[0250] R 2 Selected from alkoxy or halo;

[0251] X1 for CR 3 , X2 is CR 4 , and X3 is N or CR 5 ,or

[0252] X1 for CR 3 , X2 is N, and X3 is CR 5 ;

[0253] R 3 Selected from alkoxy, halo or haloalkoxy;

[0254] R 4 is H;

[0255] R 5 is H;

[0256] W is selected from Ring A, Ring B or Ring C

[0257]

[0258] Y1 is CR 6 , Y2 is CR 7 , Y3 is CR 8 , and Y4 is CR 9 ,or

[0259] Y1 is N, Y2 is CR 7 , Y3 is CR 8 , and Y4 is CR 9 ,or

[0260] Y1 is N, Y2 is CR 7 , Y3 is N, and Y4 is CR 9 ,or

[0261] Y1 is CR 6 , Y2 is CR 7 , Y3 is N, and Y4 is CR 9 ;

[0262] R 6is H;

[0263] R 7 is H or methylamino;

[0264] R 8 is dimethylamino, H or halo;

[0265] R 9 is cyclopropyl, H, halo or alkyl;

[0266] R 10 is H;

[0267] Y5 is NR 11 , Y6 is -C(=O)-, and Y7 is CR 13 or N, or

[0268] Y5 is -C(=O)-, and Y6 is NR 12 , and Y7 is CR 13 ;

[0269] R 11 is H;

[0270] R 12 for;

[0271] R 13 is H or halogenated;

[0272] R 14 is halogenated;

[0273] Y8 is -CH-;

[0274] Y9 is -CH-;

[0275] Y 10 is –O-;

[0276] R 15 is an alkyl group;

[0277] in,

[0278] When R 2 When it is H, then X2 is CR 4 And R 4 Not for H;

[0279] When R 1 When it is a halogenated alkyl group, R 2 is an alkoxy group; and when R 1 is a halogenated alkoxy group and R 2 When it is halogenated, X2 is N;

[0280] and pharmaceutically acceptable salts thereof.

[0281] Particular examples of compounds of formula I as described herein are selected from

[0282] N-(4-(Cyanomethyl)-2,5-difluorophenyl)naphthalene-1-sulfonamide;

[0283] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]naphthalene-1-sulfonamide;

[0284] 2-Chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]quinoline-5-sulfonamide;

[0285] 2-Chloro-N-(6-cyclopropyl-5-fluoro-2-methoxy-3-pyridinyl)quinoline-5-sulfonamide;

[0286] 2-Chloro-N-[6-(cyanomethyl)-5-fluoro-2-methoxy-3-pyridinyl]quinoline-5-sulfonamide;

[0287] 2-Chloro-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]quinoline-5-sulfonamide;

[0288] 2-Chloro-N-[5-fluoro-2-methoxy-6-(oxetan-3-yl)-3-pyridinyl]quinoline-5-sulfonamide;

[0289] 2-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]quinoline-5-sulfonamide;

[0290] 2-Chloro-N-[5-(2,2-difluoroethoxy)-3-fluoro-6-methoxy-2-pyridinyl]quinoline-5-sulfonamide;

[0291] 2-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]quinoline-5-sulfonamide;

[0292] N-[2,6-bis(difluoromethoxy)-5-fluoro-3-pyridyl]-2-chloro-quinoline-5-sulfonamide;

[0293] 7-Chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]isoquinoline-4-sulfonamide;

[0294] 7-Chloro-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]isoquinoline-4-sulfonamide; 7-Chloro-N-[5-(2,2-difluoroethoxy)-3-fluoro-6-methoxy-2-pyridinyl]isoquinoline-4-sulfonamide;

[0295] 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]isoquinoline-4-sulfonamide;

[0296] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-2-methyl-chroman-5-sulfonamide;

[0297] 5-Chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]naphthalene-1-sulfonamide;

[0298] 5-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]naphthalene-1-sulfonamide;

[0299] 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]naphthalene-1-sulfonamide;

[0300] 8-Chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-1-hydroxy-isoquinoline-4-sulfonamide;

[0301] 7-Chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-1-keto-2H-isoquinoline-4-sulfonamide;

[0302] 7-Chloro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1-one-2H-isoquinoline-4-sulfonamide;

[0303] 7-Chloro-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-1-keto-2H-isoquinoline-4-sulfonamide;

[0304] 7-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1-one-2H-isoquinoline-4-sulfonamide;

[0305] 7-Chloro-N-[5-(2,2-difluoroethoxy)-3-fluoro-6-methoxy-2-pyridinyl]-1-oxo-2H-isoquinoline-4-sulfonamide;

[0306] 7-Chloro-N-[4-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-phenyl]-1-keto-2H-isoquinoline-4-sulfonamide;

[0307] N-[2,6-bis(difluoromethoxy)-5-fluoro-3-pyridyl]-7-chloro-1-keto-2H-isoquinoline-4-sulfonamide;

[0308] 2-Chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-8-oxo-7H-1,7-naphthyridine-5-sulfonamide;

[0309] 2-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-8-keto-7H-1,7-naphthyridine-5-sulfonamide;

[0310] 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-2-keto-1H-quinoline-4-sulfonamide;

[0311] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-2-(dimethylamino)quinoline-5-sulfonamide;

[0312] N-[4-(Cyanomethyl)-2,5-difluoro-phenyl]-2-(dimethylamino)quinoline-5-sulfonamide;

[0313] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-2-methyl-quinoline-5-sulfonamide;

[0314] 6-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]naphthalene-1-sulfonamide;

[0315] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-2-(difluoromethyl)quinoline-5-sulfonamide;

[0316] 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-1-keto-2-methyl-isoquinoline-4-sulfonamide;

[0317] 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-2-keto-1-methyl-quinoline-4-sulfonamide;

[0318] 7,8-Dichloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-1-keto-2H-isoquinoline-4-sulfonamide;

[0319] 7,8-Dichloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-1-keto-2H-isoquinoline-4-sulfonamide;

[0320] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-5-(dimethylamino)naphthalene-1-sulfonamide;

[0321] 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-1-(dimethylamino)isoquinoline-4-sulfonamide;

[0322] 7-Chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-1-(dimethylamino)isoquinoline-4-sulfonamide;

[0323] 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-1-(methylamino)isoquinoline-4-sulfonamide;

[0324] 7-Chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-1-(methylamino)isoquinoline-4-sulfonamide;

[0325] 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-2-(methylamino)quinoline-4-sulfonamide;

[0326] 7-Chloro-8-cyano-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]isoquinoline-4-sulfonamide;

[0327] 7-Chloro-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]quinoline-4-sulfonamide;

[0328] 7-Chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-1-methoxy-isoquinoline-4-sulfonamide;

[0329] 2-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-1,7-naphthyridine-5-sulfonamide;

[0330] 2-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]quinoline-5-sulfonamide;

[0331] N-(4-(cyanomethyl)-2,5-difluorophenyl)-1-oxo-1,2-dihydroisoquinoline-4-sulfonamide;

[0332] 7-Chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]quinoline-4-sulfonamide;

[0333] 2-Bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]quinoline-5-sulfonamide;

[0334] 2-Cyclopropyl-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]quinoline-5-sulfonamide;

[0335] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-2-methoxy-quinoline-5-sulfonamide;

[0336] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1-(dimethylamino)isoquinoline-5-sulfonamide;

[0337] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]tetrahydronaphthalene-5-sulfonamide; and pharmaceutically acceptable salts thereof.

[0338] Preferred examples of compounds of formula I as described herein are selected from

[0339] 2-Chloro-N-(6-cyclopropyl-5-fluoro-2-methoxy-3-pyridinyl)quinoline-5-sulfonamide;

[0340] 2-Chloro-N-[6-(cyanomethyl)-5-fluoro-2-methoxy-3-pyridinyl]quinoline-5-sulfonamide;

[0341] 2-Chloro-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]quinoline-5-sulfonamide;

[0342] 2-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]quinoline-5-sulfonamide;

[0343] 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]isoquinoline-4-sulfonamide;

[0344] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-2-methyl-chroman-5-sulfonamide;

[0345] 5-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]naphthalene-1-sulfonamide;

[0346] 7-Chloro-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-1-keto-2H-isoquinoline-4-sulfonamide;

[0347] 7-Chloro-N-[5-(2,2-difluoroethoxy)-3-fluoro-6-methoxy-2-pyridinyl]-1-oxo-2H-isoquinoline-4-sulfonamide;

[0348] 7-Chloro-N-[4-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-phenyl]-1-keto-2H-isoquinoline-4-sulfonamide;

[0349] N-[2,6-bis(difluoromethoxy)-5-fluoro-3-pyridyl]-7-chloro-1-keto-2H-isoquinoline-4-sulfonamide;

[0350] 2-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-8-keto-7H-1,7-naphthyridine-5-sulfonamide;

[0351] 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-2-keto-1H-quinoline-4-sulfonamide;

[0352] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-2-methyl-quinoline-5-sulfonamide;

[0353] 6-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]naphthalene-1-sulfonamide;

[0354] 7,8-Dichloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-1-keto-2H-isoquinoline-4-sulfonamide;

[0355] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-5-(dimethylamino)naphthalene-1-sulfonamide;

[0356] 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-1-(methylamino)isoquinoline-4-sulfonamide;

[0357] 2-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-1,7-naphthyridine-5-sulfonamide;

[0358] 2-Bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]quinoline-5-sulfonamide;

[0359] 2-Cyclopropyl-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]quinoline-5-sulfonamide;

[0360] and pharmaceutically acceptable salts thereof.

[0361] Processes for the manufacture of compounds of formula I as described herein are an object of the present invention.

[0362] The present compound of formula I and its pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by the following method, which comprises reacting a compound of formula III with a compound of formula II in the presence of a base selected from N-ethyldiisopropylamine, pyridine, potassium phosphate or sodium hydride to provide a compound of formula I,

[0363]

[0364] Where R 1 , R 2 , R 3 , X1, X2, X3 and W are as described above.

[0365] General Synthesis Schemes Compounds of formula I can be prepared according to the above process variations and the following Scheme 1. The starting materials are either commercially available or can be prepared according to known methods.

[0366] Solution 1

[0367]

[0368] The compound of 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 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 or oxalyl chloride (step B). In addition, sulfonyl chloride II can be prepared by oxidative chlorination of intermediate V with N-chlorosuccinimide in a mixture of an organic solvent such as acetic acid and water (step C). Intermediate V can be obtained by a Buchwald-Hartwig type cross coupling reaction of iodo or brominated compound VI with benzyl mercaptan at elevated temperature in a solvent such as dioxane or toluene, 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 (step D). Starting materials are commercially available or can be prepared according to known methods.

[0369] Solution 2

[0370]

[0371] In addition, compounds of general formula I can be prepared by reacting compound VI with sulfur dioxide and NFSI (N-fluorobenzenesulfonimide) to give sulfonyl fluoride VII, which is then reacted with amine III in the presence of a base such as LiHMDS or LDA to obtain I as the final product of the sequence (Scheme 2).

[0372] Solution 3

[0373]

[0374] Compounds of general formula Ib can be prepared from compounds Ia by reaction with suitable reagents to replace the chlorine atom (Scheme 3). To produce compounds where R9 is MeO, a solution of sodium methoxide in methanol can be used. If compounds with R9 = Br are desired, the reaction of Ia with trimethylsilyl bromide can be used. To synthesize compounds Ib with R9 = cyclopropyl, Ia can be reacted with cyclopropylboronic acid and a palladium catalyst.

[0375] Solution 4

[0376]

[0377] Compounds of general formula Id can be prepared by reacting compound Ic with dimethylamine or a salt thereof in the presence of a base in a suitable solvent such as ethanol at elevated temperature (Scheme 4).

[0378] Solution 5

[0379]

[0380] Compounds of general formula If can be prepared by reacting compound Ie with a suitable reagent such as 4-isoxazoleboronic acid pinacol ester, a base such as potassium fluoride and a palladium catalyst such as Pd(dppf)Cl2 in DMSO at elevated temperature (Scheme 5).

[0381] Solution 6

[0382]

[0383] Aminopyrimidine IIIa can be prepared by reacting malonate derivative VIII with guanidine hydrochloride and a base such as sodium methoxide to give compound IX, which is then reacted with a halogenating agent such as phosphorus oxychloride to form compound X, followed by reaction with alcohol XI and a base such as sodium hydride to obtain IIIa (Scheme 6).

[0384] Solution 7

[0385]

[0386] Amine IIIb can be prepared by alkylation of compound XII with an alkylating agent XIII (X is a leaving group such as iodide, bromide, mesylate, triflate, phosphonate, etc.) and a base such as sodium hydride, potassium tert-butoxide, potassium carbonate or cesium carbonate in a suitable solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone or tetrahydrofuran, followed by removal of the protecting group using known methods such as acidic or hydrogenolytic cleavage. Preferably, the protecting group PG is p-methoxybenzyl, which can be removed by treatment with trifluoroacetic acid with or without a solvent such as dichloromethane at room temperature or elevated temperature.

[0387] Solution 8

[0388]

[0389] Amines IIIc can be prepared by reacting compound XV with reagent XVI using a photocatalytic reaction (Scheme 8). Preferred conditions are the use of iridium and nickel catalysts in ethylene glycol dimethyl ether and irradiation at a wavelength of 450 nM.

[0390] 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 example, 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.

[0391] 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.

[0392] 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.

[0393] 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.

[0394] 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 include 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 (i.e., a compound of the present invention or a pharmaceutical composition thereof) or to aid in the preparation of a pharmaceutical product (i.e., a medicament).

[0395] 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.

[0396] Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid substances and liquid polyols and the like.

[0397] Suitable adjuvants for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like.

[0398] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.

[0399] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols and the like.

[0400] Suitable adjuvants for topical ophthalmic preparations are, for example, cyclodextrins, mannitol or numerous other carriers and excipients known in the art.

[0401] 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.

[0402] 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.

[0403] The present invention also particularly relates to:

[0404] A compound of formula I for use as a therapeutically active substance;

[0405] A compound of formula I for use in treating a disease regulated by GPR17;

[0406] 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.

[0407] 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.

[0408] 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.

[0409] A particular embodiment of the invention is the use of a compound of formula I for the treatment or prevention of multiple sclerosis.

[0410] 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.

[0411] 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.

[0412] 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.

[0413] 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.

[0414] 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.

[0415] A particular embodiment of the invention are compounds according to formula I for use in the treatment or prevention of multiple sclerosis.

[0416] A method for treating or preventing a condition, comprising administering to a patient in need thereof an effective amount of a compound of formula I, wherein the condition is caused by direct damage to the myelin sheath (including but not limited to central and extrapontine myelinolysis, carbon monoxide poisoning, nutritional deficiencies, and virally induced demyelination), demyelinating diseases (including but not limited to multiple sclerosis, acute and multiphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorders, and leukodystrophy), CNS diseases associated with myelin loss (including but not limited to Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and ischemia caused by stroke), and inflammation in the CNS, such as encephalitis, primary vasculitis, meningitis, and inflammation in the CNS following obesity.

[0417] 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.

[0418] A specific embodiment of the invention is a method for treating or preventing multiple sclerosis, which method comprises administering an effective amount of a compound of formula I to a patient in need thereof.

[0419] One embodiment of the present invention also provides a compound of formula I as described herein when manufactured according to any of the methods.

[0420] Determination procedure

[0421] GPR17 cAMP Assay Protocol:

[0422] 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 .

[0423] 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.

[0424] 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.

[0425] 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.

[0426] 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).

[0427] The hGPR17 cAMP assay results for compounds of Formula I are provided in Table 1

[0428] Table 1:

[0429]

[0430] The invention will now be illustrated by the following examples, which are not limiting.

[0431] 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.

[0432] Examples

[0433] If not stated otherwise, all examples and intermediates were prepared under nitrogen atmosphere.

[0434] Intermediate A

[0435] Intermediate A1: 1-Naphthalenesulfonyl chloride

[0436]

[0437] Intermediate A1 is commercially available (CAS: 85-46-1)

[0438] Intermediate A2: 7-Chloroquinoline-4-sulfonyl fluoride

[0439]

[0440] In a three-necked flask, n-butyllithium (1.6M hexane solution (2.0 ml, 4.95 mmol)) was added dropwise to a solution of 4-bromo-7-chloro-quinoline (CAS 98519-65-4, 1.0 g, 4.12 mmol, 1.0 eq) in THF (20 ml) at -78 °C under argon. After stirring for 15 min, a solution of sulfur dioxide (2.64 g, 41.24 mmol) in THF (10 ml) was added dropwise. The resulting mixture was slowly warmed to room temperature and stirred for 3 h. During this period, precipitation of sulfinate was observed. After the resulting mixture was cooled to 0 °C. N-fluorobenzenesulfonimide (1.43 mg, 4.54 mmol, 1.1 eq) was added in one portion, and the resulting mixture was stirred for another 3 h. The resulting mixture was poured into brine (20 ml) and extracted with ethyl acetate (2 x 20 ml). The combined organic phases were evaporated. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give 7-chloroquinoline-4-sulfonyl fluoride (103.9 mg, 0.42 mmol, 10.3% yield) as a yellow solid. 1H NMR (500 MHz, CDCl 3 ) 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).

[0441] Intermediate A3: 2-Chloroquinoline-5-sulfonyl chloride

[0442]

[0443] 2-Chloroquinoline (4 g, 24.45 mmol) was dissolved in chlorosulfonic acid (37.41 g, 21.5 ml, 318 mmol). The reaction mixture was heated to 140 ° C and stirred for 2 days, then cooled to room temperature and carefully quenched in ice / ethyl acetate. The organic layer was separated and the aqueous layer was re-extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by silica gel flash chromatography (120 g, 0% to 10% ethyl acetate / heptane) to give 2-chloroquinoline-5-sulfonyl chloride (383 mg, 6.0%) as a white solid. MS (ESI) m / z: 262.0 [M + H] +; 1H NMR (300 MHz, DMSO-d6) δ = 9.21 (dd, J = 0.8, 8.9 Hz, 1H), 8.00 (dd, J = 1.4, 7.3 Hz, 1H), 7.92 (td, J = 1.1, 8.3 Hz, 1H), 7.78-7.72 (m, 1H), 7.64 (d, J = 8.9 Hz, 1H), and 2-chloroquinoline-6-sulfonyl chloride (406 mg, 6.2%) as a white solid. MS (ESI) m / z: 262.0 [M + H] +; 1H NMR (300MHz, DMSO-d6) δ = 8.55 (d, J = 8.5Hz, 1H), 8.28 (d, J = 1.8Hz, 1H), 7.99 (dd, J = 1.9, 8.8Hz, 1H), 7.93-7.88 (m, 1H), 7.61 (d, J = 8.7Hz, 1H).

[0444] Intermediate A4: 7-Chloroisoquinoline-4-sulfonyl chloride

[0445]

[0446] Step 1: 4-(Benzylthio)-7-chloro-isoquinoline

[0447]

[0448] A mixture of 4-bromo-7-chloro-isoquinoline (250 mg, 1.03 mmol), benzyl mercaptan (141 mg, 134 ul, 1.13 mmol), N,N-diethylisopropylamine (266 mg, 360 ul, 2.06 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 (2 ml) was heated to 80° C. and stirred for 1.5 h. The reaction mixture was filtered and washed (2 x 10 ml ethyl acetate) and the filtrate was extracted with water / ethyl acetate. The organic layer was dried (Na2SO4) and concentrated in vacuo. The crude material was purified by silica gel flash chromatography (25 g, 20% to 100% ethyl acetate / heptane) and the collected fractions were evaporated to provide 4-(benzylthio)-7-chloro-isoquinoline (282 mg, 95.71%) as a yellow oil. MS (ESI) m / z: 286.1 [M+H]+

[0449] Step 2: 7-Chloroisoquinoline-4-sulfonyl chloride

[0450]

[0451] To a solution of 4-(benzylthio)-7-chloro-isoquinoline (282 mg, 0.99 mmol) in acetic acid (3 ml) and water (0.3 ml) was added N-chlorosuccinimide (395 mg, 2.96 mmol) in portions at room temperature over 15 min. The clear solution was stirred at room temperature for 2 h, and then the solvent was evaporated. The residue was extracted twice with ethyl acetate and ice water, the organic layer was dried over MgSO4, filtered and concentrated under vacuum to give 7-chloroisoquinoline-4-sulfonyl chloride (259 mg, 100%) as a yellow solid, MS: 262.0 [M+H] + ESI pos.

[0452] Intermediate A5: 1-Oxo-2H-isoquinoline-4-sulfonyl chloride

[0453]

[0454] Chlorosulfonic acid (496 mg, 285 μl, 4.13 mmol) was added to isoquinolin-1(2H)-one (100 mg, 0.69 mmol) under nitrogen. The reaction mixture was stirred at 95 °C for 2 h. The mixture was cooled to 20 °C and ice (10 g) was carefully added. The gray-brown suspension was transferred to a plastic tube and centrifuged twice (water was decanted). The solid residue was transferred to a flask with ethyl acetate / acetonitrile and the solvent was evaporated to give 1-oxo-1,2-dihydroisoquinoline-4-sulfonyl chloride (74 mg, 0.304 mmol, 44.1% yield). MS: 244.0 [M+H] + ESI pos.

[0455] Intermediate A6: 2-Methylchroman-5-sulfonyl chloride

[0456]

[0457] Step 1: 4-(2-Bromo-6-hydroxy-phenyl)but-3-en-2-one

[0458]

[0459] To a solution of 2-bromo-6-hydroxybenzaldehyde (1.0 g, 4.97 mmol) in acetone (6 ml) was slowly added NaOH (1 M in water, 9.0 ml, 9.0 mmol) and stirred for 16 h at 25° C. The mixture was acidified by dropwise addition of aqueous HCl (1.0 N, 12 mk) at <10° C. The resulting yellow solid was separated by filtration and dried under vacuum to give the crude compound, which was purified by silica gel column (petroleum ether / ethyl acetate=5 / 1) to give 4-(2-bromo-6-hydroxy-phenyl)but-3-en-2-one (0.85 g, 3.53 mmol, 71% yield) as a white solid, 1H NMR (400 MHz, DMSO-d6) δ ppm 10.85-10.93 (m, 1H) 7.66-7.78 (m, 1H) 7.09-7.21 (m, 3H) 6.92-7.00 (m, 1H) 2.28-2.35 (m, 3H).

[0460] Step 2: 3-Bromo-2-(3-hydroxybut-1-enyl)phenol

[0461]

[0462] Sodium borohydride (121 mg, 3.2 mmol) was slowly added to a solution of 4-(2-bromo-6-hydroxy-phenyl)but-3-ene-2-one (700 mg, 2.9 mmol) in tetrahydrofuran (10 ml) at 0 ° C and the mixture was stirred at 25 ° C for 2 h. The reactant was slowly poured into HCl (1M in water, 5 ml) at 0 ° C and stirred for 10 min, and then pH>=7 was adjusted by NaHCO3 (aqueous solution). The mixture was dissolved in ethyl acetate (20 ml) and the organic layer was washed with water (20 ml) and saturated brine solution (10 ml). The combined organic layers were dried (Na2SO4), concentrated in vacuo to dryness and purified by column chromatography (silica gel, petroleum ether / ethyl acetate=3 / 1) to give 3-bromo-2-(3-hydroxybut-1-enyl)phenol (590 mg, 2.43 mmol, 83.6% yield) as a light yellow gum.

[0463] Step 3: 3-Bromo-2-(3-hydroxybutyl)phenol

[0464]

[0465] To a solution of 3-bromo-2-(3-hydroxybut-1-enyl)phenol (5.0 g, 20.57 mmol) in tetrahydrofuran (100 ml) was added p-toluenesulfonyl hydrazide (15.3 g, 82.3 mmol) and sodium acetate trihydrate (11.2 g, 82.3 mmol), and then stirred at 70 ° C for 16 h. The reactant was dissolved in ethyl acetate (60 ml), and the organic matter was washed with water (30 ml) and saturated brine solution (20 ml). The organic matter was separated and dried (Na2SO4), and then concentrated to dryness. The crude material was purified by silica gel column (petroleum ether / ethyl acetate=3 / 1) to give 3-bromo-2-(3-hydroxybutyl)phenol (3.4 g, 13.87 mmol, 67.4% yield) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.71

[0466] -9.78(m,1H)6.88-7.06(m,2H)6.74-6.84(m,1H)4.43-4.54(m,1H)3.96

[0467] -4.09(m,1H)3.57-3.70(m,1H)2.72-2.86(m,1H)2.56-2.68(m,1H)1.38

[0468] -1.62(m,2H)1.08-1.13(m,2H).

[0469] Step 4: 5-Bromo-2-methyl-chroman

[0470]

[0471] To a solution of 3-bromo-2-(3-hydroxybutyl)phenol (3.4g, 13.0mmol) in tetrahydrofuran (650ml) was added diisopropyl azodicarboxylate (DIAD, 3.87ml, 19.53mmol) and triphenylphosphine (5.12g, 19.53mmol) at 0°C and the mixture was stirred at 25°C for 2h. The reactant was concentrated to dryness and the residue was dissolved in ethyl acetate (50ml). The combined organic layer was washed with water (30ml) and saturated brine solution (10ml). The organic matter was then separated and dried (Na2SO4) before being concentrated to dryness. The crude material was then purified by silica gel column (petroleum ether / ethyl acetate=10 / 1) to obtain 5-bromo-2-methyl-chroman (1.9g, 7.81mmol, 60% yield) as a colorless oil. 1H NMR(400MHz,DMSO-d6)δppm 7.12(dd,J=7.95,0.98Hz,1H)6.98-7.06(m,1H)6.73-6.80(m,1H)4.02-4.16( m,1H)2.56-2.76(m,2H)1.96-2.09(m,1H)1.51-1.70(m,1H)1.29-1.34(m,3H).

[0472] Step 5: 5-Benzylthio-2-methyl-chroman

[0473]

[0474] To a solution of 5-bromo-2-methyl-chroman (1.10 g, 4.84 mmol) in tetrahydrofuran (30 ml) was added n-butyl lithium solution (2.91 ml, 7.27 mmol) at -78 ° C. The mixture was then stirred at -78 ° C for 0.5 h. A solution of dibenzyl disulfide (1.43 g, 5.8 mmol) in tetrahydrofuran (10 ml) was added at -78 ° C. The mixture was then stirred for another 1 h at -78 ° C. The reaction mixture was quenched by adding saturated ammonium chloride solution (10 ml) and extracted with ethyl acetate (20 ml × 3). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (silica gel, petroleum ether) to obtain 5-benzyl sulfhydryl-2-methyl-chroman (0.3 g, 1.11 mmol, 23% yield) as a colorless oil. 1H NMR(400MHz,DMSO-d6)δppm 1.31(d,J=6.24Hz,3H)1.58(dtd,J=13.45,10.79,10.79,5.56Hz,1H)1.92-2.00(m,1H)2.62-2.73(m,1H)2.74-2.8 7(m,1H)3.74(s,2H)4.06-4.16(m,1H)6.70(d,J=8.19Hz,1H)6.74-6.83(m,1H)7.00-7.08(m,2H)7.24-7.37(m,5H)

[0475] Step 6: 2-Methylchroman-5-sulfonyl chloride

[0476]

[0477] N-Chlorosuccinimide (89 mg, 0.67 mmol, 3.0 eq) was added to a solution of 5-benzylsulfhydryl-2-methyl-chroman (60 mg, 0.22 mmol, 1.0 eq) in acetic acid (1.8 ml) and water (0.2 ml) in three portions at 30 ° C and the mixture was stirred for 16 h. The reactants were dissolved in ethyl acetate (4 ml), and the combined organic layers were washed with water (2 ml) and saturated brine solution (2 ml). The combined organic layers were separated and dried (Na2SO4), then concentrated to dryness. The crude material was purified by preparative TLC (petroleum ether / ethyl acetate = 20 / 1) to give 2-methylchroman-5-sulfonyl chloride (30 mg, 0.12 mmol, 55% yield) as a colorless oil. For analysis, an aliquot of the compound was reacted with aqueous ammonia, and the LCMS sample of the reaction was measured: according to the expected results, MS m / z 226 ([M-Cl+NH2] - ).

[0478] Intermediate A7:2-Chloro-1,7-naphthyridine-5-sulfonyl chloride

[0479]

[0480] Step 1: 5-Bromo-1-oxo-1,7-naphthyridin-1-ium

[0481]

[0482] In a 25ml round-bottom flask, 5-bromo-1,7-naphthyridine (2.5g, 12.0mmol) was dissolved in dichloromethane (17.5ml) and cooled to 0-3°C. Next, meta-chloroperbenzoic acid (3.1g, 12.56mmol) was added in batches at 2°C-4°C in 20min. The reaction mixture was stirred for 5h at 2°C-22°C, and then the solvent was removed under vacuum. The residue was purified by 80g silica column with methanol (0 to 10%, in 30min) in dichloromethane to obtain a mixture of two possible N-oxides. The mixture was further purified using SFC (column chirality AY-H, 5μm, 250x 20mm, 0-40% MeOH) to obtain 5-bromo-1-oxo anion base-1,7-naphthyridine-1-ium (394mg, 14%) as a yellow solid. MS m / z: 225.0[M+H]+. ESI pos.

[0483] Step 2: 5-Benzylsulfhydryl-1-oxide-1,7-naphthyridin-1-ium

[0484]

[0485] A mixture of 5-bromo-1-oxoanionyl-1,7-naphthyridin-1-ium (392 mg, 1.71 mmol), benzyl mercaptan (254 mg, 242 ul, 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), N,N-diisopropylethylamine (441 mg, 600 ul, 3.41 mmol) in 1,4-dioxane (12 ml) was heated at 90°C for 5 h. After cooling to room temperature, the mixture was concentrated under reduced pressure and purified by flash chromatography (25 g SiO2, gradient 0 to 20% methanol / dichloromethane) to give 5-(benzylthio)-1-oxoanionyl-1,7-naphthyridin-1-ium (440 mg, 90%) as an orange solid. MS m / z 269.1 [M+H]+, ESI pos.

[0486] Step 3: 5-Benzylthiosulfonyl-2-chloro-1,7-naphthyridine

[0487]

[0488] To a stirred solution of 5-(benzylthio)-1-oxo-1,7-naphthyridin-1-ium (159 mg, 0.557 mmol) in dichloromethane (superanhydrous, 5.5 ml) was added phosphorus oxychloride (102 mg, 62 ul, 0.668 mmol) at 0°C, followed by dropwise addition of dimethylformamide (20 mg, 22 ul, 0.28 mmol) under argon. The resulting reaction mixture was warmed to 23°C and stirred at this temperature for 6 h. Saturated aqueous sodium carbonate solution was slowly added to the reaction mixture to adjust the pH to 7-8. The resulting mixture was separated and the aqueous phase was thoroughly extracted with dichloromethane. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated under reduced pressure and purified by flash chromatography (silica gel, 10% to 70% ethyl acetate / heptane) to give 5-(benzylthio)-2-chloro-1,7-naphthyridine (50 mg, 31%) as a light yellow solid, MS m / z 287.1 [M+H]+, ESI pos

[0489] Step 4: 2-Chloro-1,7-naphthyridine-5-sulfonyl chloride

[0490]

[0491] 5-(Benzylthio)-2-chloro-1,7-naphthyridine (45 mg, 0.155 mmol) was dissolved in a mixture of acetic acid (390 ul) and water (39 ul). 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 in the next step without further purification. MS m / z 263.0 [M+H] +, ESI pos.

[0492] Intermediate A8: 2-Methylquinoline-5-sulfonyl chloride

[0493]

[0494] Chlorosulfonic acid (5.34g, 3.07ml, 45.4mmol) was carefully added to quinadine (500mg, 472ul, 3.49mmol), and the reaction mixture was heated to 140°C for 2h. LCMS showed complete conversion and formation of 3 regional 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 layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by silica gel flash chromatography (80g, 0% to 100% ethyl acetate / heptane) to obtain 2-methylquinoline-8-sulfonyl chloride (255.8mg, 29.4%) as a white solid, 2-methylquinoline-6-sulfonyl chloride (25mg, 3.0%) as a light brown solid, and the title compound 2-methylquinoline-5-sulfonyl chloride (21.9mg, 2.4%) as a white solid. 1H NMR (600MHz, DMSO-d6) δppm 9.69 (d, J=9.1Hz, 1H), 8.20 (dt, J=8.5, 1.0Hz, 1H), 8.18 (dd, J=7.3, 1.1Hz, 1H), 8.14 -8.15(m,1H),8.01-8.07(m,2H),2.95(s,3H).

[0495] Intermediate A9: 6-Chloronaphthalene-1-sulfonyl chloride

[0496]

[0497] Step 1: 6-Chloro-1-iodo-naphthalene

[0498]

[0499] To a solution of p-toluenesulfonic acid monohydrate (803.16 mg, 4.22 mmol) in acetonitrile (5 ml) was added (6-chloro-1-naphthyl)amine (CAS 50885-10-4, 250 mg, 1.41 mmol). The resulting amine salt suspension was cooled to 0 ° C, and a solution of sodium nitrite (194 mg, 2.81 mmol) and potassium iodide (584 mg, 3.52 mmol) in water (0.85 ml) was gradually added. The reaction mixture was stirred at 0 ° C for 30 min, then allowed to warm to room temperature and stirred for another 2 h. The reaction mixture was diluted with saturated NaHCO3 solution and extracted twice with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated to dryness. The crude material was purified by flash chromatography on silica gel (40 g, ethyl acetate 0-30% in heptane) to obtain 6-chloro-1-iodo-naphthalene (20 mg, 5% yield) as a yellow oil. 1H NMR (300MHz, DMSO-d6) δ=8.17 (dd, J=1.0, 7.5Hz, 1H), 8.11 (d, J=2.2Hz, 1H), 8.05-7.97 (m, 2H), 7.67 (dd, J=2.2, 8.9Hz, 1H), 7.34 (dd, J=7.5, 8.3Hz, 1H).

[0500] Step 2: 1-Benzylthio-6-chloro-naphthalene

[0501]

[0502] 6-Chloro-1-iodo-naphthalene (18 mg, 0.062 mmol) was dissolved in 1,4-dioxane (super anhydrous, 0.6 ml), then benzyl mercaptan (8.52 mg, 8 ul, 0.069 mmol), tris(dibenzylideneacetone)dipalladium(0) (1.7 mg, 0.002 mmol), Xantphos (1.8 mg, 0.003 mmol) and NN-diisopropylethylamine (16 mg, 22 ul, 0.125 mmol) were added at room temperature and argon. The mixture was stirred at 90 ° C for 3 hours. The reaction mixture was diluted with saturated NaHCO3 solution and extracted twice with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated to dryness. The crude material was purified by silica gel flash chromatography (12 g, ethyl acetate in heptane 0-30%) to give 1-benzylsulfhydryl-6-chloro-naphthalene (16 mg, 86%) as a light yellow oil.

[0503] Step 3: 6-Chloronaphthalene-1-sulfonyl chloride

[0504]

[0505] 1-benzyl sulfhydryl-6-chloro-naphthalene (16mg, 0.054mmol) is dissolved in acetic acid (0.5ml) and water (0.05ml). N-chlorosuccinimide (22mg, 0.162mmol) is added and the mixture is stirred at room temperature for 1h. Dichloromethane and a few drops of water are added to the mixture. After being stirred at room temperature for 5min, each layer is separated and the aqueous layer is extracted with dichloromethane. The combined organic layer is dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a yellow oil. The crude material is directly used in the next step without further purification.

[0506] Intermediate A10: 5-Chloronaphthalene-1-sulfonyl chloride

[0507]

[0508] Intermediate A10 is commercially available (CAS: 6291-07-2)

[0509] Intermediate A11: 7-Chloronaphthalene-1-sulfonyl chloride

[0510]

[0511] Intermediate A11 is commercially available (CAS: 102153-62-8)

[0512] Intermediate A12: 8-Chloro-1-hydroxy-isoquinoline-4-sulfonyl chloride

[0513]

[0514] Step 1: 8-Chloro-2-oxo-isoquinolin-2-ium

[0515]

[0516] To a solution of 8-chloroisoquinoline (10.0 g, 61.12 mmol, 1.0 eq) in dichloromethane (250 ml) was added 3-chloroperoxybenzoic acid (25.6 g, 103.9 mmol) in portions and the reaction mixture was stirred at 25 °C for 3 h. Next, dichloromethane (300 ml) and methanol (50 ml) were added. The organic layer was washed with 2M sodium hydroxide solution (2 x 300 ml), dried (Na2SO4) and evaporated to dryness to give 8-chloro-2-oxo-isoquinolin-2-ium (10.0 g, 55.68 mmol, 77.4% yield). 1H NMR (500MHz, CDCl3) δ = 9.11 (s, 1H), 8.14 (dd, J = 1.6, 7.1Hz, 1H), 7.72-7.60 (m, 3H), 7.51-7.44 (m, 1H)

[0517] Step 2: 8-Chloroisoquinolin-1-ol

[0518]

[0519] 8-Chloro-2-oxo-isoquinolin-2-ium (10.0 g, 55.7 mmol) was stirred in acetic anhydride (250 ml) at 140 ° C for 16 h. The reaction mixture was evaporated to dryness, then 350 ml of 2M aqueous sodium hydroxide solution was added to the oily residue and the reaction mixture was stirred at 80 ° C for 3 h. The mixture was cooled and acidified to pH 4-5 (4M aqueous NaHSO4 solution) and extracted with dichloromethane (2 x 300 ml). The combined organic layers were dried (Na2SO4) and evaporated to give 8-chloroisoquinolin-1-ol (11.0 g, 61.25 mmol, 82.5% yield) as a brown solid. 1H NMR (500MHz, DMSO-d6) δ=11.22(br s,7H),7.59-7.50(m,3H),7.50-7.36(m,2H),7.20-7.11(m,1H),6.50(d,J=7.1Hz,1H)

[0520] Step 3: 8-Chloro-1-hydroxy-isoquinoline-4-sulfonyl chloride

[0521]

[0522] Chlorosulfonic acid (11.1 ml, 167 mmol) was added to 8-chloroisoquinolin-1-ol (3.0 g, 16.7 mmol, 1.0 eq) at 100°C and the reaction mixture was placed at 100°C for 16 h. The reaction mixture was poured very carefully onto ice (200 g) and quickly extracted with ethyl acetate (300 ml). The organic layer was dried and evaporated to dryness, and the residue was triturated in dichloromethane (5 x 30 ml), filtered and dried under an argon atmosphere to give 8-chloro-1-hydroxy-isoquinoline-4-sulfonyl chloride (925 mg, 3.33 mmol, 19% yield). 1H NMR (500MHz, CDCl3) δ = 10.87 (br, s, 1H), 9.03-9.07 (m, 1H), 8.97-9.02 (m, 1H), 8.63 (q, J = 7.8Hz, 1H), 8.56-8.48 (m, 1H).

[0523] Intermediate A13: 7-Chloro-1-oxo-2H-isoquinoline-4-sulfonyl chloride

[0524]

[0525] A solution of 7-chloroisoquinolin-1(2H)-one (CAS24188-74-7, 14.5 mg, 0.081 mmol) and chlorosulfonic acid (261 mg, 150 ul, 2.17 mmol) was stirred at 95 °C for 2 hr. The reaction mixture was diluted with water (5 ml) and extracted with ethyl acetate (3 x 5 ml). The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered and concentrated to dryness to give 7-7-chloro-1-oxo-2H-isoquinoline-4-sulfonyl chloride (22.5 mg, 95%) as a light yellow solid. MS 278.1 [M+H] + ,ESI pos.,1HNMR(300MHz,CDCl3)δppm 7.84-7.90(m,1H)8.15-8.20(m,1H)8.30-8.35(m,1H)8.45-8.48(m,1H)9.67-9.85(m,1H).

[0526] Intermediate A14: 2-Chloro-8-oxo-7H-1,7-naphthyridine-5-sulfonyl chloride

[0527]

[0528] Step 1: 1-oxyanion radical-7H-1,7-naphthyridin-1-ium-8-one

[0529]

[0530] To a solution of 1,7-naphthyridin-8-ol (CAS 67967-11-7, 0.5 g, 3.42 mmol) in acetic acid (15 ml) was added hydrogen peroxide (30% in water, 0.78 ml, 6.84 mmol) portionwise and the reaction mixture was stirred for 16 h at 80° C. The reaction mixture was carefully evaporated to dryness to give 600 mg of a dark brown solid which was used in the next step without further purification.

[0531] Step 2: 2-Chloro-7H-1,7-naphthyridin-8-one

[0532]

[0533] Oxalyl chloride (0.44 ml, 5.18 mmol) was added dropwise to a suspension of 1-oxoanion-7H-1,7-naphthyridine-1-ium-8-one (600 mg, 3.7 mmol) in dimethylformamide (15 ml) at 0 ° C. After the addition was completed, the mixture was warmed to room temperature and stirred for 30 min. Methanol (20 ml) was added to quench the excess oxalyl chloride, and the mixture was evaporated to dryness. The residue was purified by chromatography (silica gel, ethyl acetate / heptane 0-50%) to give 2-chloro-7H-1,7-naphthyridine-8-one (200 mg, 1.11 mmol, 28% yield). 1H NMR (500MHz, DMSO-d6) δ = 7.90 (d, J = 8.4Hz, 1H), 7.59 (d, J = 8.4Hz, 1H), 7.43-7.34 (m, 1H), 7.29-7.22 (m, 1H), 6.54 (br d, J = 6.4Hz, 1H).

[0534] Step 3: 2-Chloro-8-oxo-7H-1,7-naphthyridine-5-sulfonyl chloride

[0535]

[0536] Chlorosulfonic acid (0.74 ml, 11.1 mmol) was added to 2-chloro-7H-1,7-naphthyridine-8-one (200 mg, 1.11 mmol) at 90 ° C, and the reaction mixture was placed at 90 ° C for 16 h. Ice water (10 ml) was added to the reaction mixture, which was then extracted with ethyl acetate (50 ml). The organic layer was dried and evaporated to give 2-chloro-8-oxo-7H-1,7-naphthyridine-5-sulfonyl chloride (91.8 mg, 0.33 mmol, 28.2% yield) as a brown solid, 1H NMR (400 MHz, DMSO-d6) δ = 11.60 (br, s, 1H), 8.77 (br d, J = 8.7 Hz, 1H), 7.83 (br d, J = 8.8 Hz, 1H), 7.52 (br s, 1H)

[0537] Intermediate A15: 7-Chloro-2-oxo-1H-quinoline-4-sulfonyl chloride

[0538]

[0539] The title compound was prepared as a light yellow solid by analogy to intermediate A4, replacing 4-bromo-7-chloro-isoquinoline with 4,7-dichloro-2-(1H)-quinolinone (CAS 156820-88-1). MS (ESI) m / z: 278.0 [M+H] + .

[0540] Intermediate A16:7-Chloro-1-(methylamino)isoquinoline-4-sulfonyl chloride

[0541]

[0542] Step 1: 7-Chloro-N-methyl-isoquinolin-1-amine

[0543]

[0544] A mixture of 1,7-dichloroisoquinoline (CAS 70810-24-1, 298 mg, 1.46 mmol), N,N-diisopropylethylamine (377 mg, 510 ul, 2.92 mmol) and methylamine (2M in THF, 2.19 ml, 4.38 mmol) in tetrahydrofuran (4 ml) was stirred at 60 °C for 2 h for 72 h. 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. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 50% ethyl acetate / heptane) to give a light yellow solid (127 mg, 43% yield), MS m / z 193.1 [M+H] + , ESI pos.

[0545] Step 2: 4-Bromo-7-chloro-N-methyl-isoquinolin-1-amine

[0546]

[0547] A mixture of 7-chloro-N-methyl-isoquinolin-1-amine (125 mg, 0.649 mmol) and N-bromosuccinimide (115.49 mg, 0.649 mmol) in acetonitrile (3 ml) was stirred at room temperature for 1 h. 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. The crude material was purified by flash chromatography (silica gel, 25 g, 0% to 50% ethyl acetate / heptane) to produce an off-white solid yellow oil (134 mg, 73% yield). MS273.1[M+H] + , ESI pos.

[0548] Step 3: 4-Benzylthiosulfonyl-7-chloro-N-methyl-isoquinolin-1-amine

[0549]

[0550] A mixture of 4-bromo-7-chloro-N-methyl-isoquinolin-1-amine (133 mg, 0.490 mmol), Xantphos (14.17 mg, 0.024 mmol), Pd2(dba)3 (13.46 mg, 0.015 mmol), N,N-diisopropylethylamine (126.6 mg, 171 ul, 0.98 mmol) and benzyl mercaptan (67 mg, 63.7 ul, 0.539 mmol) in 1,4-dioxane (3 ml) was heated to 90 ° C and stirred for 4 h. The reaction mixture was poured into water and extracted twice with ethyl acetate. The organic layers were combined, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 50% ethyl acetate / heptane) to give a yellow oil (140 mg, 86% yield). MS m / z 315.1 [M+H] + ,ESI pos.

[0551] Step 4: 7-Chloro-1-(methylamino)isoquinoline-4-sulfonyl chloride

[0552]

[0553] To a solution of 4-benzylsulfhydryl-7-chloro-N-methyl-isoquinolin-1-amine (133 mg, 0.422 mmol) in acetic acid (2 ml) and water (0.2 ml) was added N-chlorosuccinimide (169 mg, 1.27 mmol) at room temperature. The clear solution was stirred at room temperature for 3 h. The reactants were extracted with ice water and twice with dichloromethane. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil (120 mg, 70% purity, 97% yield). MS 291.0 [M + H] + , ESI pos. The crude material was used directly in the next step.

[0554] Intermediate A17: 7-Chloro-2-(methylamino)quinoline-4-sulfonyl chloride

[0555]

[0556] Step 1: 4-Benzylthiosulfonyl-7-chloro-1H-quinolin-2-one

[0557]

[0558] 4,7-dichloro-1H-quinolin-2-one (CAS156820-88-1, see patent WO2004 / 2960, 458mg, 2.14mmol), Xantphos (61.9mg, 0.107mmol), Pd2(dba)3 (58.78mg, 0.064mmol), N,N-diisopropylethylamine (553mg, 748ul, 4.28mmol) and benzyl mercaptan (292mg, 278uL, 2.35mmol) were heated to 100°C in a mixer in 1,4-dioxane (4ml) and stirred for 2h to produce an off-white suspension. The reaction mixture was poured into water and extracted twice with ethyl acetate. The organic layers were combined, dried over Na2SO4 and concentrated in vacuo. The residue was wet-triturated with dichloromethane and filtered. The mother liquor was concentrated and the residue was purified by flash chromatography (silica gel, 50% to 100% ethyl acetate / heptane), and the product was combined with the filter cake to give an off-white solid (522 mg, 81%). MS m / z: 302.1 [M+H] + , ESI pos.

[0559] Step 2: 4-Benzylthio-2,7-dichloro-quinoline

[0560]

[0561] A mixture of 4-benzylthio-7-chloro-1H-quinolin-2-one (549 mg, 1.73 mmol) and phosphorus oxychloride (2.38 g, 1.45 ml, 15.55 mmol) was stirred at 100 ° C for 1 h. Excess phosphorus oxychloride was removed in vacuo. The reaction mixture was diluted with dichloromethane and poured into a saturated aqueous NaHCO3 solution containing ice. The mixture was stirred at room temperature for 20 min and extracted twice with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and the residual solvent was removed under reduced pressure. The crude material was purified by flash chromatography (silica gel, 0% to 50% ethyl acetate / heptane) to give an off-white solid (454 mg, 92% yield). MS m / z: 320.0 [M+H]+, ESI pos.

[0562] Step 3: 4-Benzylthiosulfonyl-7-chloro-N-methyl-quinolin-2-amine

[0563]

[0564] A mixture of 4-benzylsulfhydryl-2,7-dichloro-quinoline (250 mg, 0.781 mmol), N,N-diisopropylethylamine (303 mg, 409 ul, 2.34 mmol) and methylamine (2M 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 layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 50% ethyl acetate / heptane) to give a white solid (180 mg, 73% yield). MS m / z 315.1[M+H] + ,ESI pos.

[0565] Step 4: 7-Chloro-2-(methylamino)quinoline-4-sulfonyl chloride

[0566]

[0567] To a solution of 4-benzylsulfhydryl-7-chloro-N-methyl-quinolin-2-amine (177 mg, 0.562 mmol) in acetic acid (2 ml) and water (0.2 ml) was added N-chlorosuccinimide (225 mg, 1.69 mmol) at room temperature. The clear solution was stirred at room temperature for 3 h, then water was added and the mixture was extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, concentrated in vacuo and used directly in the next step. Yellow amorphous solid. MS m / z: 291.1 [M+H] + , ESI pos.

[0568] Intermediate A18; 2-(Dimethylamino)quinoline-5-sulfonyl chloride

[0569]

[0570] Step 1: 5-Bromo-N,N-dimethyl-quinolin-2-amine

[0571]

[0572] In a sealed glass tube, 5-bromo-2-chloro-quinoline (CAS 99455-13-7, 250 mg, 1.03 mmol) was dissolved in tetrahydrofuran (super anhydrous, 2 ml), and then dimethylamine (2M 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 h. Ethyl acetate and water were added at room temperature. The organic layer was washed with saturated NaCl solution, dried over MgSO4 and concentrated in vacuo to give 5-bromo-N,N-dimethyl-quinolin-2-amine (260 mg, 98%) as a light yellow solid. MS (ESI) m / z 251.1 [M+H] + .

[0573] Step 2: 5-Benzylthio-N,N-dimethyl-quinolin-2-amine

[0574]

[0575] 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 h. 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 / n-heptane) to give an orange solid (204 mg, 67%). MS (ESI) m / z: 295.2 [M+H] + .

[0576] Step 3: 2-(Dimethylamino)quinoline-5-sulfonyl chloride

[0577]

[0578] In a 20ml glass tube, 5-benzylsulfhydryl-N,N-dimethyl-quinolin-2-amine (66mg, 0.224mmol) was dissolved in acetic acid (0.9ml) and water (0.1ml). N-chlorosuccinimide (90mg, 0.673mmol) was added in batches at room temperature within 15min. The reaction mixture was stirred at room temperature for 1h. The solvent was removed in vacuo. The residue was extracted twice with ethyl acetate. The combined organic layer was washed with water, saturated NaCl solution, dried over MgSO4, filtered and the solvent was removed in vacuo to obtain 2-(dimethylamino)quinoline-5-sulfonyl chloride (65mg, 96%) as a yellow solid, which was used in the next step without further purification. MS (ESI) m / z 271.1 [M+H] +

[0579] Intermediate A19: 7-Chloro-1-methoxy-isoquinoline-4-sulfonyl chloride

[0580]

[0581] Step 1: 4-Bromo-7-chloro-1-methoxy-isoquinoline

[0582]

[0583] To a freshly prepared solution of sodium methoxide (2.93 g, 54.2 mmol, 3.0 eq) in methanol (100 ml) was added 4-bromo-1,7-dichloro-isoquinoline (CAS 953421-74-4, 5.0 g, 18.05 mmol, 1.0 eq) under argon and the resulting mixture was refluxed overnight. The mixture was concentrated under reduced pressure and the residue was partitioned between water and dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give 4-bromo-7-chloro-1-methoxy-isoquinoline (4.3 g, 15.8 mmol, 87.5% yield) as a brown powder. MS (ESI) m / z: 272.0 / 274.0 / 276.0 [M+H]+.

[0584] The following step was carried out analogously to intermediate A18 using 4-bromo-7-chloro-1-methoxy-isoquinoline instead of 5-bromo-N,N-dimethyl-quinolin-2-amine in step 2. The title compound was used in the next step without further purification.

[0585] Intermediate A20: 7-Chloro-8-cyano-isoquinoline-4-sulfonyl chloride

[0586]

[0587] Step 1: 7-Chloro-isoquinoline-8-carbonitrile

[0588]

[0589] 8-Bromo-7-chloro-isoquinoline (CAS 2092424-29-6, 300 mg, 1.24 mmol) was dissolved in N,N-dimethylacetamide (3 ml) and under argon, dicyanozinc (73 mg, 0.619 mmol) and tetrakis(triphenylphosphine)palladium(0) (71.5 mg, 0.062 mmol) were added. The mixture was stirred at 100 °C overnight. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated to dryness. The crude material was purified by flash chromatography (silica gel, 0-100% ethyl acetate / heptane) to give a light yellow solid (85 mg, 36% yield), MS m / z 189.0 [M+H] + , ESI pos.

[0590] Step 2: 4-Bromo-7-chloro-isoquinoline-8-carbonitrile

[0591]

[0592] 7-Chloroisoquinoline-8-carbonitrile (85 mg, 0.451 mmol) was dissolved in 1,2-dichloroethane (superanhydrous, 2 ml). Iodobenzene diacetate (218 mg, 0.676 mmol) and potassium bromide (268 mg, 2.25 mmol) were added and the mixture was stirred at 70 ° C for 16 h. The mixture was extracted with water and dichloromethane, and the combined organic layers were dried and concentrated in vacuo. The crude material was purified by flash column (silica gel, 0-80% ethyl acetate / heptane) to give a white solid (65 mg, 54% yield), MS m / z 269.0 [M+H] + , ESI pos.

[0593] Step 3: 4-Benzylthio-7-chloro-isoquinoline-8-carbonitrile

[0594]

[0595] A mixture of 4-bromo-7-chloro-isoquinoline-8-carbonitrile (60 mg, 0.224 mmol), Xantphos (6.5 mg, 0.011 mmol), Pd2(dba)3 (6.2 mg, 0.0067 mmol), N,N-diisopropylethylamine (58 mg, 78 ul, 0.45 mmol) and benzyl mercaptan (30.6 mg, 29 ul, 1.37 mmol) in 1,4-dioxane (2 ml) was stirred at 70 ° C for 1.5 h. The reaction mixture was poured into water and extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 100% ethyl acetate / heptane) to give a yellow solid (28 mg, 40% yield), MSm / z 311.0 [M+H] + , ESI pos.

[0596] Step 4: 7-Chloro-8-cyano-isoquinoline-4-sulfonyl chloride

[0597]

[0598] 4-Benzylthio-7-chloroisoquinoline-8-carbonitrile (47 mg, 0.151 mmol) was dissolved in acetic acid (500 ul) and water (50 ul). N-succinimide (60.6 mg, 0.454 mmol) was added and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water and extracted twice with dichloromethane. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give a yellow solid which was used directly in the next step.

[0599] Intermediate A21: 2-(Difluoromethyl)quinoline-5-sulfonyl chloride

[0600]

[0601] 2-(Difluoromethyl)quinoline (CAS1075184-01-8, 150mg, 0.837mmol) was slowly added to chlorosulfonic acid (1.27g, 723uL, 10.88mmol) at 0°C. The mixture was stirred at room temperature for 1hr and then stirred at 140°C for 20h. The reaction mixture was slowly added to an ice / ethyl acetate mixture under stirring, then extracted with ethyl acetate (3x), dried over Na2SO4, filtered and concentrated in vacuo. The crude light orange oil was purified by flash chromatography (silica gel, 0 to 100% ethyl acetate / n-heptane) to obtain 2-(difluoromethyl)quinoline-5-sulfonyl chloride (9.3mg, 3.2%) as a white solid. 1H NMR(600MHz,DMSO-d6)ppm 9.39(d,J=8.9Hz,1H),8.70(d,J=8.6Hz,1H),8.31(d,J=1.5Hz,1H),8.01- 8.09(m,2H),7.85(d,J=8.9Hz,1H),7.76-7.83(m,1H),6.99-7.22(m,1H).

[0602] Intermediate A22: 5-(Dimethylamino)naphthalene-1-sulfonyl chloride

[0603]

[0604] Intermediate A22 is commercially available (CAS: 605-65-2)

[0605] Intermediate A23: 7-Chloro-2-methyl-1-oxo-isoquinoline-4-sulfonyl chloride

[0606]

[0607] Step 1: 7-Chloro-2-methyl-isoquinolin-1-one

[0608]

[0609] 7-Chloroisoquinolin-1-ol (CAS 24188-74-7, 100 mg, 0.557 mmol, 1 eq) was dissolved in N,N-dimethylformamide (superanhydrous, 1 ml). Cesium carbonate (272 mg, 0.835 mmol) and iodomethane (395 mg, 174 ul, 2.78 mmol) were added and the mixture was stirred at 60°C. After 90 min, the mixture was cooled to room temperature, quenched with saturated Na2CO3 solution and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated to give a white solid (107 mg, 99% yield), 1H NMR (600 MHz, CDCl3) d ppm 8.40 (d, J = 2.3 Hz, 1H), 7.56 (dd, J = 8.5, 2.3 Hz, 1H), 7.45 (d, J = 8.5 Hz, 1H), 7.07 (d, J = 7.4 Hz, 1H), 6.46 (d, J = 7.2 Hz, 1H), 3.60 (s, 3H).

[0610] Step 2: 7-Chloro-2-methyl-1-oxo-isoquinoline-4-sulfonyl chloride

[0611]

[0612] 7-Chloro-2-methyl-isoquinolin-1-one (70 mg, 0.343 mmol) was dissolved in chlorosulfonic acid (522 mg, 300 ul, 4.48 mmol) and the reaction mixture was heated at 100 °C for 1 h. The mixture was poured onto ice with ethyl acetate and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated to give a white solid (73 mg, 73% yield). The material was used directly in the next step.

[0613] Intermediate A24: 7-Chloro-1-methyl-2-oxo-quinoline-4-sulfonyl chloride

[0614]

[0615] The title compound was prepared as a yellow solid analogously to intermediate A4 from 4,7-dichloro-1-methyl-quinolin-2-one (CAS 98994-41-3) instead of 4-bromo-7-chloro-isoquinoline. MS (ESI) m / z: 292.0 [M+H] + .

[0616] Intermediate A25: 7,8-Dichloro-1-oxo-2H-isoquinoline-4-sulfonyl chloride

[0617]

[0618] The title compound was prepared as an off-white solid analogously to intermediate A13 by replacing 7-chloroisoquinolin-1(2H)-one with 7,8-dichloro-2H-isoquinolin-1-one (CAS 80233-87-0), MS (ESI) m / z: 313.9 [M+H] + .

[0619] Intermediate A26: 7-Chloro-1-(dimethylamino)isoquinoline-4-sulfonyl chloride

[0620]

[0621] The title compound was prepared as an orange oil in analogy to intermediate A16 using dimethylamine instead of methylamine in step 1, 1H NMR (300 MHz, CDCl 3 ) δ = 8.72 (s, 1H), 8.51 (d, J = 9.1 Hz, 1H), 8.07 (d, J = 1.6 Hz, 1H), 7.77 (dd, J = 2.1, 9.2 Hz, 1H), 3.41 (s, 6H).

[0622] Intermediate A27: 8-Methylquinoline-5-sulfonyl chloride

[0623]

[0624] Intermediate A27 is commercially available (CAS 120164-05-8)

[0625] Intermediate A28: Tetralinnaphthalene-5-sulfonyl chloride

[0626]

[0627] Intermediate A28 is commercially available (CAS 62686-69-5)

[0628] Intermediate B

[0629] Intermediate B1: 2-(4-Amino-2,5-difluoro-phenyl)acetonitrile

[0630]

[0631] Intermediate B1 is known (CAS: 2092112-51-9) and was synthesized according to WO2018 / 122232, page 229.

[0632] Intermediate B2: 6-(2,2-Difluoroethoxy)-5-fluoro-2-methoxy-pyridin-3-amine

[0633]

[0634] Intermediate B2 is known (CAS: 2407471-07-0) and was synthesized according to WO2019 / 243303, page 83.

[0635] Intermediate B3: 6-Cyclopropyl-5-fluoro-2-methoxy-pyridin-3-amine

[0636]

[0637] Intermediate B3 is known (CAS: 2407471-10-5) and was synthesized according to WO2019 / 243303, page 86.

[0638] Intermediate B4: 2-(5-Amino-3-fluoro-6-methoxy-2-pyridinyl)acetonitrile

[0639]

[0640] Step 1: (6-bromo-5-fluoro-2-methoxy-3-pyridinyl)amine

[0641]

[0642] A solution of (5-fluoro-2-methoxy-3-pyridinyl)amine (3.9 g, 26.07 mmol) and N-bromosuccinimide (5.16 g, 28.67 mmol) in acetonitrile (400 ml) was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed once with saturated NaHCO3 solution, once with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 30% ethyl acetate / heptane) to give (6-bromo-5-fluoro-2-methoxy-3-pyridinyl)amine (5.26 g, 86.7%) as a dark brown solid. MS (ESI) m / z: 221.0 [M+H] + .

[0643] Step 2: (6-Bromo-5-fluoro-2-methoxy-3-pyridinyl)-bis(p-anisyl)amine

[0644]

[0645] To a stirred solution of (6-bromo-5-fluoro-2-methoxy-3-pyridyl)amine (2.5 g, 10.75 mmol) in N,N-dimethylacetamide (25 ml) was added sodium hydride (1.29 g, 32.24 mmol) (5 x 258 mg) portionwise at 0 ° C. After stirring at 0 ° C for 30 min, 4-methoxybenzyl chloride (3.43 g, 3.0 ml, 21.49 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 30 min. The reaction mixture was carefully quenched with saturated NH4Cl solution, poured into water and extracted twice with ethyl acetate. The combined organic layer was washed twice with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 10% ethyl acetate / heptane) to afford (6-bromo-5-fluoro-2-methoxy-3-pyridinyl)-bis(p-anisyl)amine (4.93 g, 99.5%) as a red viscous oil.

[0646] Step 3: [5-[Bis(p-anisyl)amino]-3-fluoro-6-methoxy-2-pyridinyl]methanol

[0647]

[0648] 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-butyl lithium (1.75 g, 2.03 mL, 3.25 mmol) was added dropwise. The resulting dark blue solution was stirred at -78 °C for 30 min. N,N-dimethylformamide (396 mg, 419 ul, 5.42 mmol) was added and stirring was continued at -78 °C for 30 min. The reaction mixture was allowed to warm to room temperature. Methanol (4 ml) was added followed by sodium borohydride (82 mg, 2.17 mmol). Stirring was continued at room temperature for 15 min. 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. The crude material was purified by flash chromatography (silica gel, 0% to 50% ethyl acetate / heptane) to give [5-[bis(p-anisyl)amino]-3-fluoro-6-methoxy-2-pyridinyl]methanol (297 mg, 32.5%) as a light yellow viscous oil. MS (ESI) m / z: 413.3 [M+H] + .

[0649] Step 4: [6-(Chloromethyl)-5-fluoro-2-methoxy-3-pyridinyl]-bis(p-anisyl)amine

[0650]

[0651] To a stirred solution of [5-[bis(p-anisyl)amino]-3-fluoro-6-methoxy-2-pyridinyl]methanol (144 mg, 0.342 mmol) in dichloromethane (1.5 ml) was added sulfuryl chloride (81.4 mg, 50 ul, 0.684 mmol) dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo to give [6-(chloromethyl)-5-fluoro-2-methoxy-3-pyridinyl]-bis(p-anisyl)amine (150 mg, 100%) as a light brown foam, which was used directly in the next step without further purification.

[0652] Step 5: 2-[5-[Bis(p-anisyl)amino]-3-fluoro-6-methoxy-2-pyridinyl]acetonitrile

[0653]

[0654] To a stirred solution of [6-(chloromethyl)-5-fluoro-2-methoxy-3-pyridinyl]-bis(p-anisyl)amine (152 mg, 0.353 mmol) in dichloromethane (700 ul) was added tetrabutylammonium bromide (11.5 mg, 0.035 mmol) followed by a solution of sodium cyanide (21 mg, 0.423 mmol) in water (130 ul). After the reaction mixture was stirred at room temperature for 15 h, more sodium cyanide (21 mg, 0.423 mmol) was added and stirring was continued at room temperature for 15 h. The reaction mixture was diluted with dichloromethane and washed twice with water. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 30% ethyl acetate / heptane) to give 2-[5-[bis(p-anisyl)amino]-3-fluoro-6-methoxy-2-pyridinyl]acetonitrile (87 mg, 58.5%) as a colorless viscous oil. MS (ESI) m / z: 422.3 [M+H] +

[0655] Step 6: 2-(5-amino-3-fluoro-6-methoxy-2-pyridinyl)acetonitrile

[0656]

[0657] A solution of 2-[5-[bis(p-anisyl)amino]-3-fluoro-6-methoxy-2-pyridinyl]acetonitrile (85 mg, 0.20 mmol) in dichloromethane (400 ul) was cooled to 0 ° C. Trifluoroacetic acid (1.38 g, 927 ul, 12.1 mmol) was added and the reaction mixture was stirred at 0 ° C for 20 min and at room temperature for 4 h. The resulting purple solution was poured into a saturated NaHCO3 solution and extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 40% ethyl acetate / heptane) to give 2-(5-amino-3-fluoro-6-methoxy-2-pyridinyl)acetonitrile (31 mg, 85%) as a light yellow solid. MS (ESI) m / z: 182.1 [M+H] +

[0658] Intermediate B5: 6-(Difluoromethoxy)-5-fluoro-2-methoxy-pyridin-3-amine

[0659]

[0660] Intermediate B5 is known (CAS: 2407470-90-8) and was synthesized according to WO2019 / 243303, page 69.

[0661] Intermediate B6:5-Fluoro-2-methoxy-6-(oxetan-3-yl)pyridin-3-amine

[0662]

[0663] Step 1: (6-bromo-5-fluoro-2-methoxy-3-pyridinyl)amine

[0664]

[0665] A solution of (5-fluoro-2-methoxy-3-pyridinyl)amine (3.9 g, 26.07 mmol) and N-bromosuccinimide (5.16 g, 28.67 mmol) in acetonitrile (400 ml) was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed once with saturated NaHCO3 solution, once with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 30% ethyl acetate / heptane) to give (6-bromo-5-fluoro-2-methoxy-3-pyridinyl)amine (5.26 g, 86.7%) as a dark brown solid. MS (ESI) m / z: 221.0 [M+H] + .

[0666] Step 2: 5-Fluoro-2-methoxy-6-(oxetan-3-yl)pyridin-3-amine

[0667]

[0668] [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridyl-N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl-N]phenyl-C]iridium(III)hexafluorophosphate (Ir[dF(CF3)ppy]2(dtbpy))PF6, CAS870987-63-6, 7.6 mg, 0.007 mmol, 0.010 eq, 6.9 M in dichloromethane) was added to a vial and the solvent was evaporated. Sodium carbonate (142 mg, 1.36 mmol, 2 eq), (6-bromo-5-fluoro-2-methoxy-3-pyridinyl)amine (150 mg, 0.679 mmol, 1 eq), 3-bromooxetane (186 mg, 113 ul, 1.36 mmol, 2 eq) and tris(trimethylsilyl)silane (226 mg, 281 ul, 0.909 mmol, 1.34 eq) were added. Ethylene glycol dimethyl ether (superanhydrous, 11 ml) was added and the reaction mixture was degassed by bubbling argon through the mixture for 2 min. Finally, nickel (ii) chloride ethylene glycol dimethyl ether complex (NiCl2*glyme / dtbbpy, CAS29046-78-4, 746ug, 0.003mmol, 0.005eq) and 4,4'-bis(tert-butyl)-2,2'-bipyridine (911ug, 0.003mmol, 0.005eq) were added and the reaction was degassed for another 5min. The vial was placed in a photoreactor and irradiated with 450nm for 14h (stirring at 900rpm, LED power was 100%). The reaction mixture was filtered and concentrated in vacuo. The residue was dissolved in dichloromethane and purified by column chromatography (silica gel, 0 to 40% ethyl acetate / heptane) to obtain 5-fluoro-2-methoxy-6-(oxetane-3-yl)pyridine-3-amine (47mg, 35%) as an off-white solid. MS (ESI) m / z: 199.1 [M+H] + .

[0669] Intermediate B7: 5-(2,2-Difluoroethyl)-4,6-dimethoxy-pyrimidin-2-amine

[0670]

[0671] Step 1: Diethyl 2-(2,2-difluoroethyl)malonate

[0672]

[0673] Diethyl malonate (75.8ml, 500mmol) was combined with tetrahydrofuran (450ml). Sodium ethoxide (prepared from ethanol (150mL) and sodium (11.48g, 500mmol)) was added at room temperature and the reaction mixture was stirred at room temperature for 15min. A solution of 2,2-difluoroethyl trifluoromethanesulfonate (76ml, 500mmol) in tetrahydrofuran (10ml) was slowly added. The reaction mixture was stirred at 20°C for 18 hours, then cooled to 0°C, quenched with saturated ammonium chloride solution and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide the title compound (100.5g, 90% yield). MS (ESI) m / z=225.0[M+H] +

[0674] Step 2: 2-Amino-5-(2,2-difluoroethyl)pyrimidine-4,6-diol

[0675]

[0676] To a stirred solution of diethyl 2-(2,2-difluoroethyl)malonate (46.8 g, 209 mmol) in ethanol (5 mL) was 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 by half, 50 ml of water was added, followed by acetic acid (42.57 g, 709 mmol). The mixture was heated to 80 ° C and stirred for 10 min, then cooled to room temperature. The solid product was filtered off and washed with water, ethanol and methyl tert-butyl ether in sequence to provide the title compound (22.3 g, 50% yield). MS (ESI) m / z=192.0[M+H]+

[0677] Step 3: 4,6-dichloro-5-(2,2-difluoroethyl)pyrimidin-2-amine

[0678]

[0679] 2-Amino-5-(2,2-difluoroethyl)pyrimidine-4,6-diol (13.2 g, 69.1 mmol) was suspended in phosphorus oxychloride (80.5 ml, 863 mmol). The reaction mixture was heated to 100 ° C and stirred for 18 hours and concentrated in vacuo. The residue was diluted with ethyl acetate and carefully poured into ice / saturated sodium bicarbonate solution. The resulting biphasic mixture was stirred at room temperature for 5 min 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 to provide the title compound (7.35 g, 47% yield). MS (ESI) m / z=227.8 [M+H] +

[0680] Step 4: 5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-amine

[0681]

[0682] In a sealed tube, a mixture of 4,6-dichloro-5-(2,2-difluoroethyl)pyrimidin-2-amine (7.6 g, 33.33 mmol) and sodium methoxide (prepared from sodium (7.66 g, 333.29 mmol) in methanol (50 ml)) was heated to 75 ° C and stirred for 18 hours. The reaction mixture was quenched with water and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to provide the title compound as a light yellow solid (6.6 g, 86% yield). MS (ESI) m / z=220.0 [M+H] +

[0683] Intermediate B8: 5-(Difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-amine

[0684]

[0685] Step 1: 5-Bromo-4,6-dimethoxy-pyrimidin-2-amine

[0686]

[0687] To a stirred solution of (4,6-dimethoxypyrimidin-2-yl)amine (7g, 44.22mmol, CAS: 36315-01-2) in acetonitrile (100ml) was added dropwise a solution of N-bromosuccinimide (10.33g, 57.48mmol) in acetonitrile (100ml) at room temperature. The reaction mixture was stirred at room temperature for 30min. The resulting white suspension was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered, diluted with heptane and concentrated in vacuo. The precipitate was filtered out and washed with heptane to provide the title compound as a white solid (9.26g, 87% yield). MS (ESI) m / z=234.1[M+H] +

[0688] Step 2: 5-Bromo-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine

[0689]

[0690] A solution of 5-bromo-4,6-dimethoxy-pyrimidine-2-amine (517mg, 2.21mmol) in N,N-dimethylacetamide (9ml) was cooled to 0°C. Sodium hydride (265mg, 6.63mmol) (3x 88mg) was added in batches. Stirring was continued at 0°C for 30min. 4-methoxybenzyl chloride (706mg, 609ul, 4.42mmol) was added dropwise. The reaction mixture was warmed to room temperature, stirred for 1 hour, carefully quenched with saturated ammonium chloride solution, 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 0-20% to provide the title compound (1.11g, 100% yield) as a white solid. MS (ESI) m / z=476.2[M+H] +

[0691] Step 3: 2-[Bis[(4-methoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-ol

[0692]

[0693] To a colorless solution of 5-bromo-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine (500 mg, 1 mmol) in tetrahydrofuran (3.5 ml) was added dropwise 1.6 M n-butyllithium in hexane (700 mg, 814 ul, 1.3 mmol) at -78°C. The resulting yellow solution was stirred at -78°C for 30 min. Trimethyl borate (156 mg, 167 ul, 1.5 mmol) was added dropwise and stirring was continued at -78°C for 1.5 hours. The reaction mixture was warmed to 0°C and acetic acid (120 mg, 115 ul, 2 mmol) was added dropwise, followed by hydrogen peroxide 35% (146 mg, 132 ul, 1.5 mmol). Stirring was continued at 0°C for 1.5 hours. The resulting pink suspension was poured into 0.1 N sodium thiosulfate solution and extracted twice with ethyl acetate. The organic layer was washed with brine, 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 0-30% to provide the title compound (194 mg, 47% yield) as a light yellow viscous oil. MS (ESI) m / z=412.3 [M+H] +

[0694] Step 4: 5-(Difluoromethoxy)-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine

[0695]

[0696] To a solution of 2-[bis[(4-methoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-ol (130 mg, 0.316 mmol) in acetonitrile (5 ml) was added dropwise 5 M potassium hydroxide solution (1.26 ml, 6.32 mmol) at 0°C, followed by the addition of bromodifluoromethyl diethylphosphonate (169 mg, 112 ul, 0.632 mmol) in acetonitrile (1 ml) at 0°C. The reaction mixture was stirred at 0°C for 10 min. The resulting light yellow biphasic 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 0-30% to provide the title compound (57 mg, 39% yield) as a white solid. MS (ESI) m / z=462.3[M+H] +

[0697] Step 5: 5-(Difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-amine

[0698]

[0699] To a stirred solution of 5-(difluoromethoxy)-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine (56 mg, 0.121 mmol) in dichloromethane (100 ul) was added trifluoroacetic acid (839 mg, 563 ul, 7.28 mmol). The reaction mixture was stirred at room temperature for 40 hours, at 50 ° C for 6 hours and concentrated in vacuo. The residue was poured into saturated NaHCO3 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 (24 mg, 89% yield) as a white solid. MS (ESI) m / z=222.1[M+H] +

[0700] Intermediate B9: 5-(2,2-Difluoroethoxy)-3-fluoro-6-methoxy-pyridin-2-amine

[0701]

[0702] Intermediate B9 is known (CAS 2404661-29-4) and was synthesized according to WO2019243398, page 55.

[0703] Intermediate B10: 5-(2-Fluoroethoxy)-4-methoxy-pyrimidin-2-amine

[0704]

[0705] Step 1: (5-Bromo-4-methoxy-pyrimidin-2-yl)-bis(p-anisyl)amine

[0706]

[0707] A suspension of 5-bromo-2-chloro-4-methoxy-pyrimidine (1.02 g, 4.48 mmol, CAS: 57054-929), bis(p-anisyl)amine (1.29 g, 4.92 mmol) and N-ethyldiisopropylamine (858 ul, 4.92 mmol) in acetonitrile (20 ml) was heated at 70 ° C for 2 days. The resulting solution was poured into a saturated aqueous sodium bicarbonate solution 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 a gradient of ethyl acetate / heptane 0-20% to provide the title compound (998 mg, 50% yield) as a colorless viscous oil. MS (ESI): m / z=446.2[M+H] +

[0708] Step 2: [4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-yl] bis(p-anisyl)amine

[0709]

[0710] 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 min. 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 hours. 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 a gradient of ethyl acetate / heptane 0-30% to provide the title compound (157 mg, 29% yield) as a colorless viscous oil. MS (ESI): m / z = 492.4 [M + H] +

[0711] Step 3: 2-[Bis(p-anisyl)amino]-4-methoxy-pyrimidin-5-ol

[0712]

[0713] A solution of [4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]-bis(p-anisyl)amine (130 mg, 0.265 mmol) in tetrahydrofuran (2.5 mL) was cooled to 0 °C. Hydrogen peroxide 35% (500 ul, 5.71 mmol) was added. The reaction mixture was stirred at 0 °C for 15 min, warmed to room temperature and stirred for 3 hours. The reaction mixture was poured into a cold 0.1 N sodium sulfite solution and extracted twice with ethyl acetate. The organic layer was washed twice with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide the title compound (103 mg, 100% yield) as a light yellow viscous oil. MS (ESI): m / z=382.3[M+H]+

[0714] Step 4: [5-(2-Fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-bis(p-anisyl)amine

[0715]

[0716] 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 uL, 0.472 mmol) in acetonitrile (2.5 ml) was stirred at room temperature for 15 min 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 a gradient of ethyl acetate / heptane 0-30% to provide the title compound (22 mg, 22% yield) as a colorless viscous oil. MS (ESI): m / z=428.3[M+H]+

[0717] Step 5: [5-(2-Fluoroethoxy)-4-methoxy-pyrimidin-2-yl]amine

[0718]

[0719] A solution of [5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-bis(p-anisyl)amine (87 mg, 0.204 mmol) in dichloromethane (500 ul) was cooled to 0 ° C. Trifluoroacetic acid (1.41 g, 945 ul, 12.2 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 16 hours and stirred for another two hours at 55 ° C. The resulting purple solution was poured into saturated aqueous sodium bicarbonate solution 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 (27 mg, 71% yield) as an off-white solid. MS (ESI): m / z=188.1[M+H]+

[0720] Intermediate B11: 2,6-Bis(difluoromethoxy)-5-fluoro-pyridin-3-amine

[0721]

[0722] Step 1: 6-(Difluoromethoxy)-5-fluoro-3-nitro-pyridin-2-ol

[0723]

[0724] Boron tribromide (3.34 ml, 35.7 mmol) was added to a solution of 2-(difluoromethoxy)-3-fluoro-6-methoxy-5-nitro-pyridine (CAS2407470-89-5, see WO2020254289, 1.7 g, 7.14 mmol) in dichloromethane (24 ml) at 0 ° C, and the reaction mixture was stirred at 20 ° C for 1 h. The reaction mixture was poured into water (150 ml) and extracted with ethyl acetate (50 ml × 3). The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether to petroleum ether / ethyl acetate = 2: 1) to obtain 6-(difluoromethoxy)-5-fluoro-3-nitro-pyridine-2-ol (1.48 g, 93% yield) as a yellow oil. 1H NMR (400MHz, CDCl3) δppm 7.31-7.69 (m, 1H) 8.33 (d, J = 7.70Hz, 1H) 11.35 (br s, 1H)

[0725] Step 2: 2,6-Bis(difluoromethoxy)-3-fluoro-5-nitro-pyridine

[0726]

[0727] To a solution of 6-(difluoromethoxy)-5-fluoro-3-nitro-pyridine-2-ol (1.48 g, 6.6 mmol) in acetonitrile (20 ml) was added a solution of potassium hydroxide (3.71 g, 66.0 mmol) in water (5 ml) and diethyl (bromodifluoromethyl)phosphonate (10.580 g, 39.63 mmol) at 40 ° C, and the reaction mixture was stirred at 40 ° C for 16 h. The reaction mixture was extracted with dichloromethane (60 ml × 3). The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether to petroleum ether / ethyl acetate = 5: 1) to give 2,6-bis(difluoromethoxy)-3-fluoro-5-nitro-pyridine (2.38 g, 46% yield) as a light yellow oil. 1H NMR (400MHz, DMSO-d6) δppm7.64-8.12 (m, 2H) 8.98 (d, J = 8.93Hz, 1H).

[0728] Step 3: 2,6-Bis(difluoromethoxy)-5-fluoro-pyridin-3-amine

[0729]

[0730] To a mixture of 2,6-bis(difluoromethoxy)-3-fluoro-5-nitro-pyridine (380 mg, 1.39 mmol) in ethanol (12 ml) and water (3 ml) was added iron (389 mg, 6.93 mmol) and ammonium chloride (367 mg, 6.93 mmol) at 25 ° C, and the reaction mixture was stirred for 1 h at 25 ° C. The reaction mixture was diluted with water (3 ml) and extracted with ethyl acetate (3 x 10 ml). The combined organic layer was washed with saturated NaCl solution (5 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue, which was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 2: 1) to obtain 2,6-bis(difluoromethoxy)-5-fluoro-pyridine-3-amine (41 mg, 12% yield) as a yellow oil. MS (ESI): m / z = 244.8 [M+H] + .

[0731] Examples

[0732] Example 1: N-(4-(cyanomethyl)-2,5-difluorophenyl)naphthalene-1-sulfonamide

[0733]

[0734] 2-(4-amino-2,5-difluoro-phenyl)acetonitrile (25 mg, 0.149 mmol, intermediate B1) was added to naphthalene-1-sulfonyl chloride (50 mg, 0.223 mmol, intermediate A1), followed by ultra-anhydrous pyridine (1 ml). The reaction mixture was stirred at room temperature for 2 hours, and then the solvent was evaporated. The crude material was purified by preparative HPLC (column: YMC-Triart C18, 12 nm, 5 μm, 100x30 mm, gradient acetonitrile / water + 0.1% HCOOH) to give the title compound (37 mg, 69%) as a white powder, MS (ESI): m / z=357.2 [MH] - .

[0735] The following Examples 2-39 were prepared by coupling the indicated sulfonyl chloride intermediate A and amine intermediate B in analogy to Example 1.

[0736]

[0737]

[0738]

[0739]

[0740]

[0741]

[0742] Example 40: N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-5-(dimethylamino)naphthalene-1-sulfonamide

[0743]

[0744] A mixture of 6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-pyridin-3-amine (27 mg, 0.122 mmol, intermediate B2), 5-(dimethylamino)naphthalene-1-sulfonyl chloride (36 mg, 0.134 mmol, intermediate A22) and pyridine (48 mg, 49 uL, 0.608 mmol) in dichloromethane (4 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted twice with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 50% ethyl acetate / heptane) to give the title compound (30 mg, 54%) as a light yellow solid, MS (ESI): m / z=456.3[M+H] + .

[0745] The following Examples 41-46 were prepared in analogy to Example 40 by coupling the indicated sulfonyl chloride intermediate A and amine intermediate B.

[0746]

[0747] Example 48: 7-Chloro-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]quinoline-4-sulfonamide

[0748]

[0749] 6-(difluoromethoxy)-5-fluoro-2-methoxy-pyridine-3-amine (25.6mg, 0.123mmol, intermediate B5) is dissolved in tetrahydrofuran (0.5ml). Hexamethyldisilazide lithium solution (1M in THF, 244ul, 0.244mmol) is added dropwise at 0°C and under argon atmosphere. The reaction mixture is stirred for 15min. Then, a solution of 7-chloroquinoline-4-sulfonyl fluoride (30mg, 0.122mmol, intermediate A2) in tetrahydrofuran (0.3ml) is added dropwise. The mixture is stirred at room temperature for 3h. Saline is added to the reaction mixture and extracted with ethyl acetate (3x). The combined organic layer is dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: YMC-Triart C18, 12 nm, 5 μm, 100 x 30 mm, gradient acetonitrile / water + 0.1% HCOOH) to give the title compound as a red solid (18 mg, 32%), MS (ESI): m / z = 434.1 [M+H] + .

[0750] Example 49: 7-Chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-1-methoxy-isoquinoline-4-sulfonamide

[0751]

[0752] 7-Chloro-1-methoxy-isoquinoline-4-sulfonyl chloride (64 mg, 0.22 mmol, intermediate A19) was dissolved in pyridine (1 ml) and acetonitrile (1 ml). 2-(4-amino-2,5-difluoro-phenyl)acetonitrile (75 mg, 0.44 mmol, intermediate B1) was then added at room temperature and the mixture was stirred for 2 h, and then the solvent was evaporated. The crude material was purified by preparative HPLC (column: SunFire C18 100x19mm 5um, gradient 40-90% 0.5-6.5 min water-acetonitrile) to give the title compound (10 mg, 11% yield) as a light yellow solid, MS (ESI): m / z=424.0 [M+H] + .

[0753] Example 50: 2-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-1,7-naphthyridine-5-sulfonamide

[0754]

[0755] 2-Chloro-1,7-naphthyridine-5-sulfonyl chloride (47 mg, 0.179 mmol, intermediate A7), 6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-pyridine-3-amine (40 mg, 0.179 mmol, intermediate B2), dichloromethane (0.7 ml) and N, N-diethylisopropylamine (23 mg, 31 ul, 0.179 mmol) were loaded into a 3 ml glass tube, and the mixture was stirred at room temperature for 3 h. The mixture was distributed between dichloromethane and water. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by preparative HPLC (column: Gemini NX, 12 nm, 5 μm, 100 x 30 mm, gradient acetonitrile / water + 0.1% HCOOH) to obtain the title compound (1.5 mg, 1.7%) as an orange solid, MS m / z 449.1 [M+H] + , ESI pos.

[0756] Example 51: 2-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]quinoline-5-sulfonamide

[0757]

[0758] A solution of 5-(difluoromethoxy)-4,6-dimethoxy-pyrimidine-2-amine (7 mg, 0.025 mmol, Intermediate B8) in N,N-dimethylformamide (100 ul) was cooled to 0 °C. Sodium hydride (60%, 1.2 mg, 0.030 mmol) was added and the reaction mixture was stirred at 0 °C for 10 min. 2-Chloroquinoline-5-sulfonyl chloride (8.0 mg, 0.030 mmol, Intermediate A3) was added. The reaction mixture was allowed to warm to room temperature and stirred for 10 min. The resulting suspension was carefully quenched with water, poured into brine and extracted twice with ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 40% ethyl acetate / heptane) to give the title compound (5 mg, 43% yield) as a white solid. MS (ESI) m / z: 447.1 [M+H] +

[0759] Example 52: N-(4-(Cyanomethyl)-2,5-difluorophenyl)-1-oxo-1,2-dihydroisoquinoline-4-sulfonamide

[0760]

[0761] 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 min, 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 provide the title compound (17 mg, 29% yield) as a white solid. MS (ESI) m / z: 376.0 [M+H] +

[0762] Example 53: 7-Chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]quinoline-4-sulfonamide

[0763]

[0764] Step 1: N-(4-Bromo-2,5-difluoro-phenyl)-7-chloro-quinoline-4-sulfonamide

[0765]

[0766] A solution of bis(trimethylsilyl)lithium amide in tetrahydrofuran (1.71ml, 1.71mmol) was added dropwise to a solution of 4-bromo-2,5-difluoroaniline (169mg, 0.81mmol) in tetrahydrofuran (10ml) at 0°C and under an argon atmosphere. After 30min, a solution of 7-chloroquinoline-4-sulfonyl fluoride (200mg, 0.81mmol, intermediate A2) in tetrahydrofuran (5ml) was added dropwise, and the resulting mixture was stirred at room temperature for 12h. The resulting mixture was poured into brine and extracted with ethyl acetate (2x30ml). The combined organic layers were evaporated to obtain crude N-(4-bromo-2,5-difluoro-phenyl)-7-chloro-quinoline-4-sulfonamide (200mg, 0.48mmol, 59% yield), which was used in the next step without purification.

[0767] Step 2: 7-Chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]quinoline-4-sulfonamide

[0768]

[0769] N-(4-bromo-2,5-difluoro-phenyl)-7-chloro-quinoline-4-sulfonamide (200 mg, 0.46 mmol) was dissolved in dimethyl sulfoxide (6 ml) and water (1 ml), and potassium fluoride (80.4 mg, 1.38 mmol) and 4-isoxazole boronic acid pinacol ester (180 mg, 0.92 mmol) were added. The resulting mixture was evacuated and backfilled with argon three times. 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (18.8 mg, 0.02 mmol) was added, and the resulting mixture was heated to 120°C for 48 h, then cooled to room temperature and filtered. The filtrate was subjected to HPLC (column: SunFire C18 100x19mm 5um, 4% water-acetonitrile + 0.1% NH4OH) to give the title compound as a brown gum (5 mg, 3% yield), MS (ESI) m / z: 394.0 [M+H] +

[0770] Example 54: 2-Bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]quinoline-5-sulfonamide

[0771]

[0772] To a solution of 2-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]quinoline-5-sulfonamide (50 mg, 0.112 mmol, Example 10) in propionitrile (1.2 ml) was added trimethylsilyl bromide (34 mg, 30 ul, 0.22 mmol) and the mixture was stirred overnight. It was then poured into a mixture of 2N sodium hydroxide and ice and extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The yellow residue was purified by flash chromatography (silica gel, 0 to 100% ethyl acetate / n-heptane) to give the title compound as a red solid. (19.6 mg, 32%), MS (ESI) m / z: 494.1 / 492.0 [M+H] +

[0773] Example 55: 2-Cyclopropyl-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]quinoline-5-sulfonamide

[0774]

[0775] In a reaction tube, 2-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]quinoline-5-sulfonamide (50 mg, 0.112 mmol, Example 10), cyclopropylboronic acid (19 mg, 0.22 mmol), toluene (0.44 ml) and water (0.022 mL) were added and the mixture was purged with argon in an ultrasonic bath for 5 min. Then, tricyclohexylphosphine (6.3 mg, 0.022 mmol), palladium (II) acetate (2.5 mg, 0.011 mmol) and tripotassium phosphate (83 mg, 0.39 mmol) were added. The reaction mixture was stirred at 110 ° C for 19 h and then concentrated in vacuo. Dichloromethane was added to the residue and the insoluble portion was filtered out. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 0% to 30% ethyl acetate / n-heptane) to give the title compound as an off-white solid (2.5 mg, 5%), MS m / z = 454.3 (M+H) +

[0776] Example 56: N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-2-methoxy-quinoline-5-sulfonamide

[0777]

[0778] To a solution of 2-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]quinoline-5-sulfonamide (5 mg, 0.011 mmol, Example 10) in methanol (0.06 ml) was added sodium methoxide (1.9 mg, 0.035 mmol) under nitrogen and room temperature. The reaction mixture was stirred at 100 ° C for 19 h. The mixture was cooled to room temperature and methanol was evaporated. The residue was extracted twice with ethyl acetate and washed with water. The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude material was purified by flash chromatography (silica gel, ethyl acetate / heptane 0% to 30%) to give the title compound (5 mg, 98%) as an off-white solid, MS: m / z=444.1 (M+H) +

[0779] Example 57: N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-1-(dimethylamino)isoquinoline-5-sulfonamide

[0780]

[0781] Step 1: 1-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]isoquinoline-5-sulfonyl amine

[0782]

[0783] To a solution of 1-chloroisoquinoline-5-sulfonyl chloride (CAS141519-77-9, 50 mg, 0.19 mmol) in dichloromethane (1 ml) was added pyridine (0.05 ml, 0.57 mmol) and 6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-pyridin-3-amine (42 mg, 0.19 mmol, intermediate B2). The mixture was stirred at 25 °C for 12 h. The mixture was concentrated under reduced pressure to give a crude material, which was purified by column chromatography (petroleum ether-ethyl acetate 1:0 to 0:1) to give 1-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]isoquinoline-5-sulfonamide (89 mg, 99% yield) as a yellow solid, MS m / z=448.0 [M+H] + (ESI+).

[0784] Step 2: N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-1-(dimethylamino)iso Quinoline-5-sulfonamide

[0785]

[0786] 1-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]isoquinoline-5-sulfonamide (80.0 mg, 0.18 mmol) was stirred in a dimethylamine solution (30% in ethanol, 3 ml) at 60° C. for 12 h. The mixture was concentrated under reduced pressure to give a crude material, which was purified by preparative HPLC (column: Phenomenex Synergi C18 150*25mm*10um, water, 0.2% TFA, acetonitrile) to give the title compound (74.5 mg, 91% yield) as a light red solid, MS m / z=457.1, [M+H] + (ESI pos).

[0787] Example 58: N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]tetrahydronaphthalene-5-sulfonamide

[0788]

[0789] The title compound was prepared as a white solid using tetrahydronaphthalene-5-sulfonyl chloride (Intermediate A28) instead of naphthalene-1-sulfonyl chloride and 6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-pyridin-3-amine (Intermediate B2) instead of 2-(4-amino-2,5-difluoro-phenyl)acetonitrile in analogy to Example 1, MS m / z=417.2 [M+H] + (ESI pos).

[0790] Example A

[0791] 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:

[0792]

[0793] Example B

[0794] 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:

[0795]

Claims

1. A compound of formula I, in, R 1 is selected from the group consisting of cyanoalkyl, haloalkoxy, haloalkyl, cyclopropyl and oxetanyl; R 2 Selected from alkoxy, H or halo; X1 is N, and X2 is CR 4 , and X3 is N, or X1 for CR 3 , X2 is CR 4 , and X3 is N or CR 5 ,or X1 for CR 3 , X2 is N, and X3 is CR 5 ; R 3 Selected from alkoxy, H, halo, haloalkoxy; R 4 Selected from alkoxy, H, halo; R 5 Selected from H, halo; W is selected from Ring A, Ring B or Ring C Y1 is CR 6 , Y2 is CR 7 , Y3 is CR 8 , and Y4 is CR 9 ,or Y1 is N, Y2 is CR 7 , Y3 is CR 8 , and Y4 is CR 9 ,or Y1 is N, Y2 is CR 7 , Y3 is N, and Y4 is CR 9 ,or Y1 is CR 6 , Y2 is N, Y3 is CR 8 , and Y4 is CR 9 ,or Y1 is CR 6 , Y2 is CR 7 , Y3 is N, and Y4 is CR 9 ,or Y1 is CR 6 , Y2 is CR 7 , Y3 is CR 8 , and Y4 is N; R 6 is H or alkylamino; R 7 is alkoxy, dimethylamino, H, methyl, methylamino, OH; R 8 is cyano, dimethylamino, H, halo; R 9 is alkoxy, cyclopropyl, haloalkyl, dimethylamino, H, halo, alkyl; R 10 is H or halogenated; Y5 is NR 11 , Y6 is -C(=O)-, and Y7 is CR 13 or N, or Y5 is -C(=O)-, and Y6 is NR 12 , and Y7 is CR 13 ; 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; Y8 is -CH- or -N-; Y9 is -CH- or -N-; Y 10 is -CH2- or -O-; R 15 is H, alkyl or haloalkyl; and pharmaceutically acceptable salts thereof.

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

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

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

5. The compound according to any one of claims 1 to 4, wherein X1 is CR 3 , X2 is CR 4 , and X3 is N or CR 5 , or X1 is CR3, X2 is N, and X3 is CR 5 .

6. A compound according to any one of claims 1 to 5, wherein R 4 and R 5 For H.

7. A compound according to any one of claims 1 to 6, wherein Y1 is CR 6 , Y2 is CR 7 , Y3 is CR 8 , and Y4 is CR 9 ,or Y1 is N, Y2 is CR 7 , Y3 is CR 8 , and Y4 is CR 9 ,or Y1 is N, Y2 is CR 7 , Y3 is N, and Y4 is CR 9 ,or Y1 is CR 6 , Y2 is CR 7 , Y3 is N, and Y4 is CR 9 .

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

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

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

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

12. A compound according to any one of claims 1 to 11, wherein R 10 , R 11 and R 12 For H.

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

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

15. A compound according to any one of claims 1 to 14, wherein R 14 It is halogenated.

16. A compound according to any one of claims 1 to 15, wherein Y8 is -CH-, Y9 is -CH-, and Y 10 It is -CH- or -O-.

17. A compound according to any one of claims 1 to 16, wherein Y8 is -CH-, Y9 is -CH-, and Y 10 For -O-.

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

19. A compound according to any one of claims 1 to 18, wherein R 15 It is an alkyl group.

20. A compound according to any one of claims 1 to 19, wherein When R 2 When it is H, then X2 is CR 4 And R 4 Not for H; When R 1 When it is a halogenated alkyl group, R 2 is an alkoxy group; and When R 1 is a halogenated alkoxy group and R 2 When it is halogenated, X2 is N.

21. The compound according to claim 1, wherein R 1 is selected from the group consisting of cyanoalkyl, haloalkoxy, haloalkyl, cyclopropyl and oxetanyl; R 2 Selected from alkoxy, H or halo; X1 is N, and X2 is CR 4 , and X3 is N, or X1 for CR 3 , X2 is CR 4 , and X3 is N or CR 5 ,or X1 for CR 3 , X2 is N, and X3 is CR 5 ; R 3 Selected from alkoxy, H, halo, haloalkoxy; R 4 Selected from alkoxy, H, halo; R 5 Selected from H, halo; W is selected from Ring A, Ring B or Ring C Y1 is CR 6 , Y2 is CR 7 , Y3 is CR 8 , and Y4 is CR 9 ,or Y1 is N, Y2 is CR 7 , Y3 is CR 8 , and Y4 is CR 9 ,or Y1 is N, Y2 is CR 7 , Y3 is N, and Y4 is CR 9 ,or Y1 is CR 6 , Y2 is N, Y3 is CR 8 , and Y4 is CR 9 ,or Y1 is CR 6 , Y2 is CR 7 , Y3 is N, and Y4 is CR 9 ,or Y1 is CR 6 , Y2 is CR 7 , Y3 is CR 8 , and Y4 is N; R 6 is H or alkylamino; R 7 is alkoxy, dimethylamino, H, methyl, methylamino, OH; R 8 is cyano, dimethylamino, H, halo; R 9 is alkoxy, cyclopropyl, haloalkyl, dimethylamino, H, halo, alkyl; R 10 is H or halogenated; Y5 is NR 11 , Y6 is -C(=O)-, and Y7 is CR 13 or N, or Y5 is -C(=O)-, and Y6 is NR 12 , and Y7 is CR 13 ; R 11 is alkyl or H; R 12 is alkyl or H; R 13 is H or halogenated; R 14 is H or halogenated; Y8 is -CH-; Y9 is -CH-; Y 10 is -CH2- or -O-; R 15 is H or alkyl; and pharmaceutically acceptable salts thereof.

22. A compound according to claim 1 or claim 21, wherein R 1 is selected from the group consisting of cyanoalkyl, haloalkoxy, haloalkyl, cyclopropyl and oxetanyl; R 2 Selected from alkoxy, H or halo; X1 is N, and X2 is CR 4 , and X3 is N, or X1 for CR 3 , X2 is CR 4 , and X3 is N or CR 5 ,or X1 for CR 3 , X2 is N, and X3 is CR 5 ; R 3 Selected from alkoxy, H, halo, haloalkoxy; R 4 Selected from alkoxy, H, halo; R 5 Selected from H, halo; W is selected from Ring A, Ring B or Ring C Y1 is CR 6 , Y2 is CR 7 , Y3 is CR 8 , and Y4 is CR 9 ,or Y1 is N, Y2 is CR 7 , Y3 is CR 8 , and Y4 is CR 9 ,or Y1 is N, Y2 is CR 7 , Y3 is N, and Y4 is CR 9 ,or Y1 is CR 6 , Y2 is N, Y3 is CR 8 , and Y4 is CR 9 ,or Y1 is CR 6 , Y2 is CR 7 , Y3 is N, and Y4 is CR 9 ,or Y1 is CR 6 , Y2 is CR 7 , Y3 is CR 8 , and Y4 is N; R 6 is H or alkylamino; R 7 is alkoxy, dimethylamino, H, methyl, methylamino, OH; R 8 is cyano, dimethylamino, H, halo; R 9 is alkoxy, cyclopropyl, haloalkyl, dimethylamino, H, halo, alkyl; R 10 is H or halogenated; Y5 is NR 11 , Y6 is -C(=O)-, and Y7 is CR 13 or N, or Y5 is -C(=O)-, and Y6 is NR 12 , and Y7 is CR 13 ; R 11 is alkyl or H; R 12 is alkyl or H; R 13 is H or halogenated; R 14 is H or halogenated; Y8 is -CH-; Y9 is -CH-; Y 10 is -CH2- or -O-; R 15 is H or alkyl; in, When R 2 When it is H, then X2 is CR 4 And R 4 Not for H; When R 1 When it is a halogenated alkyl group, R 2 is an alkoxy group; When R 1 is a halogenated alkoxy group and R 2 When it is halogenated, X2 is N; and pharmaceutically acceptable salts thereof.

23. The compound according to claim 1, wherein R 1 is selected from cyanoalkyl, haloalkoxy or cyclopropyl; R 2 Selected from alkoxy or halo; X1 for CR 3 , X2 is CR 4 , and X3 is N or CR 5 ,or X1 for CR 3 , X2 is N, and X3 is CR 5 ; R 3 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 Y1 is CR 6 , Y2 is CR 7 , Y3 is CR 8 , and Y4 is CR 9 ,or Y1 is N, Y2 is CR 7 , Y3 is CR 8 , and Y4 is CR 9 ,or Y1 is N, Y2 is CR 7 , Y3 is N, and Y4 is CR 9 ,or Y1 is CR 6 , Y2 is CR 7 , Y3 is N, and Y4 is CR 9 ; R 6 is H; R 7 is H or methylamino; R 8 is dimethylamino, H or halo; R 9 is cyclopropyl, H, halo or alkyl; R 10 is H; Y5 is NR 11 , Y6 is -C(=O)-, and Y7 is CR 13 or N, or Y5 is -C(=O)-, and Y6 is NR 12 , and Y7 is CR 13 ; R 11 is H; R 12 for; R 13 is H or halogenated; R 14 is halogenated; Y8 is -CH-; Y9 is -CH-; Y 10 for -O-; R 15 is an alkyl group; and pharmaceutically acceptable salts thereof.

24. A compound according to any one of claims 1 or 23, wherein R 1 is selected from cyanoalkyl, haloalkoxy or cyclopropyl; R 2 Selected from alkoxy or halo; X1 for CR 3 , X2 is CR 4 , and X3 is N or CR 5 ,or X1 for CR 3 , X2 is N, and X3 is CR 5 ; R 3 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 Y1 is CR 6 , Y2 is CR 7 , Y3 is CR 8 , and Y4 is CR 9 ,or Y1 is N, Y2 is CR 7 , Y3 is CR 8 , and Y4 is CR 9 ,or Y1 is N, Y2 is CR 7 , Y3 is N, and Y4 is CR 9 ,or Y1 is CR 6 , Y2 is CR 7 , Y3 is N, and Y4 is CR 9 ; R 6 is H; R 7 is H or methylamino; R 8 is dimethylamino, H or halo; R 9 is cyclopropyl, H, halo or alkyl; R 10 is H; Y5 is NR 11 , Y6 is -C(=O)-, and Y7 is CR 13 or N, or Y5 is -C(=O)-, and Y6 is NR 12 , and Y7 is CR 13 ; R 11 is H; R 12 for; R 13 is H or halogenated; R 14 is halogenated; Y8 is -CH-; Y9 is -CH-; Y 10 for -O-; R 15 is an alkyl group; in, When R 2 When it is H, then X2 is CR 4 And R 4 Not for H; When R 1 When it is a halogenated alkyl group, R 2 is an alkoxy group; When R 1 is a halogenated alkoxy group and R 2 When it is halogenated, X2 is N; and pharmaceutically acceptable salts thereof.

25. A compound according to any one of claims 1 to 24, selected from N-(4-(Cyanomethyl)-2,5-difluorophenyl)naphthalene-1-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]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-pyridinyl)quinoline-5-sulfonamide; 2-Chloro-N-[6-(cyanomethyl)-5-fluoro-2-methoxy-3-pyridinyl]quinoline-5-sulfonamide; 2-Chloro-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]quinoline-5-sulfonamide; 2-Chloro-N-[5-fluoro-2-methoxy-6-(oxetan-3-yl)-3-pyridinyl]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-pyridinyl]quinoline-5-sulfonamide; 2-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]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-pyridinyl]isoquinoline-4-sulfonamide; 7-Chloro-N-[5-(2,2-difluoroethoxy)-3-fluoro-6-methoxy-2-pyridinyl]isoquinoline-4-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]isoquinoline-4-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-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-pyridinyl]naphthalene-1-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]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-one-2H-isoquinoline-4-sulfonamide; 7-Chloro-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-1-keto-2H-isoquinoline-4-sulfonamide; 7-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1-one-2H-isoquinoline-4-sulfonamide; 7-Chloro-N-[5-(2,2-difluoroethoxy)-3-fluoro-6-methoxy-2-pyridinyl]-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-pyridinyl]-8-keto-7H-1,7-naphthyridine-5-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-2-keto-1H-quinoline-4-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-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-pyridinyl]-2-methyl-quinoline-5-sulfonamide; 6-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]naphthalene-1-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-2-(difluoromethyl)quinoline-5-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-1-keto-2-methyl-isoquinoline-4-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-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-pyridinyl]-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-pyridinyl]-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-pyridinyl]-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-pyridinyl]-2-(methylamino)quinoline-4-sulfonamide; 7-Chloro-8-cyano-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]isoquinoline-4-sulfonamide; 7-Chloro-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]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-pyridinyl]-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-pyridinyl]quinoline-5-sulfonamide; 2-Cyclopropyl-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]quinoline-5-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-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]tetrahydronaphthalene-5-sulfonamide; and pharmaceutically acceptable salts thereof.

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

27. A process for preparing a compound according to any one of claims 1 to 26, comprising reacting a compound of formula III with a compound of formula II in the presence of a base selected from N-ethyldiisopropylamine, pyridine, potassium phosphate or sodium hydride to provide a compound of formula I, Where R 1 , R 2 , R 3 , X1, X2, X3 and W are as described above.

28. Compounds according to any one of claims 1 to 26 for use as therapeutically active substances.

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

30. A pharmaceutical composition comprising a 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 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 inflammation in the CNS following encephalitis, primary vasculitis, meningitis and obesity.

32. Use of a compound according to any one of claims 1 to 26 for the treatment or prevention of multiple sclerosis.

33. according to the purposes of any one of claims 1 to 26 compound for the preparation of medicine, described medicine is used for treating or preventing the disease caused by: direct injury of myelin sheath (including but not limited to central and extrapontine myelinolysis, carbon monoxide poisoning, nutrient deficiency and virus-induced demyelination), demyelinating disease (including but not limited to multiple sclerosis, acute and multiphase disseminated encephalomyelitis, neuromyelitis optica spectrum disease and leukodystrophy), CNS disease (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 CNS such as inflammation in CNS after encephalitis, primary vasculitis, meningitis and obesity associated with myelin loss.

34. A compound according to any one of claims 1 to 26 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 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 inflammation in the CNS following encephalitis, primary vasculitis, meningitis and obesity.

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

36. 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 26.

37. A method for treating or preventing multiple sclerosis, the method comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 26.

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

39. The invention as hereinbefore described. ***

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