Novel 7-substituted indolesulfonamide derivatives

Abstract

The present invention relates to a compound of general formula (I): TIFF2025524062000164.tif37165 (wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as described herein) and relates to novel compounds having the same, compositions containing such compounds, and methods of using such compounds.

Description

Technical Field

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

[0002] The present invention relates to formula I:

Chemical Formula

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

Background Art

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

[0005] GPR17 is a class A orphan G protein-coupled receptor (GPCR). GPCRs are 7-transmembrane proteins that couple extracellular ligands to intracellular signaling via intracellular association with small heterotrimeric G protein complexes consisting of G α , G β , G γ subunits. The downstream intracellular signaling pathway results from the coupling of the GPCR to the G α subunit. GPR17 is known to couple directly to G α i / o , which results in the inhibition of adenylate cyclase activity and a decrease in cyclic AMP production (cAMP). GPR17 targets phospholipase C via G q / 11It has also been shown to conjugate. Activation of phospholipase C results in cleavage of phosphatidylinositol 4,5-bisphosphate to produce inositol trisphosphate (IP3) and diacylglycerol (DAG). As a result, IP3 binds to IP3 receptors on the endoplasmic reticulum, causing an increase in intracellular calcium levels (Hanlon, C.D., and Andrew, D.J. (2015). J Cell Sci. 128, 3533 - 3542, ‘‘Outside-in signaling-a brief review of GPCR signaling with a focus on the Drosophila GPCR family’’)(Inoue, A., et al. (2019), Cell 177, 1933 - 1947.e25, ‘‘Illuminating G-Protein-Coupling Selectivity of GPCRs’’).

[0006] The role of GPR17 in myelination was first identified in a screen of the optic nerves of Olig1 knockout mice to identify genes that regulate myelination. GPR17 expression was found to be expressed only in myelinating cells of the CNS and not in Schwann cells, which are myelinating cells of the peripheral nervous system. The expression of GPR17 was found to be exclusively expressed in oligodendrocyte lineage cells and was downregulated in myelinating oligodendrocytes (Chen, Y. et al. (2009)). Specifically, GPR17 expression was found to be initially present at low levels in OPCs and increased in pre-myelinating oligodendrocytes before being downregulated in mature myelinating oligodendrocytes (Boda, E., et al. (2011), Glia 59, 1958 - 1973, ‘‘The GPR17 receptor in NG2 expressing cells: Focus on in vivo cell maturation and participation in acute trauma and chronic damage’’)(Dziedzic, A., et al. (2020). Int. J. Mol. Sci. 21, 1852, ‘‘The gpr17 receptor - a promising goal for therapy and a potential marker of the neurodegenerative process in multiple sclerosis’’)(Fumagalli, M. et al. (2011), J Biol Chem 286, 10593 - 10604, ‘‘Phenotypic changes, signaling pathway, and functional correlates of GPR17 - expressing neural precursor cells during oligodendrocyte differentiation’’).GPR17 knockout animals have been shown to exhibit premature myelination throughout the CNS. Conversely, transgenic mice overexpressing GPR17 in oligodendrocytes with the CNP-Cre (2’,3’-cyclic nucleotide 3’-phosphodiesterase) promoter exhibited myelination defects, consistent with what is expected to be an intracellular brake on the myelination process (Chen, Y. et al. (2009)). Furthermore, loss of GPR17 enhances remyelination after demyelination induced by lysophosphatidylcholine (Lu, C., Dong, et al. (2018), Sci. Rep. 8, 4502, ‘‘G-Protein-Coupled Receptor Gpr17 Regulates Oligodendrocyte Differentiation in Response to Lysolecithin-Induced Demyelination’’). Thus, antagonism of GPR17, which promotes the differentiation of oligodendrocyte lineage cells into mature myelinating oligodendrocytes, will result in increased myelination after demyelination.

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

[0008] Because myelin formation plays an essential role in the function of the nervous system, promoting the differentiation of OPCs into oligodendrocytes has the potential to affect multiple diseases in which white matter defects / irregularities, resulting from either the loss of myelinating oligodendrocytes or the disruption of OPC differentiation into oligodendrocytes, are observed due to the disease itself or inflammation. In addition, there are diseases in which the expression of GPR17 itself changes.

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

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

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

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

[0013] The present invention relates to a compound of formula I:

Chemical formula

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

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

[0016] The term "aryl" represents a monovalent cyclic aromatic hydrocarbon moiety consisting of a monocyclic or bicyclic aromatic ring, alone or in combination with other groups. Preferred aryl is phenyl. Aryl may or may not be substituted as described herein. A specific example of aryl is phenyl.

[0017] The terms "halogen", "halide", and "halo" are used interchangeably herein and represent fluoro, chloro, bromo, or iodo. Specific halogens are fluoro, chloro, and bromo.

[0018] The term "haloalkyl" represents a C 1-6 -alkyl group in which at least one hydrogen atom of the C 1-6 -alkyl group is replaced by the same or different halogen atoms. Specific examples are difluoroethyl and difluoromethyl.

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

[0020] The term "cyano" represents a -C≡N group.

[0021] "Cyanoalkyl" means a moiety of the formula -R'-R'' where R' is alkyl as defined herein and R'' is cyano or nitrile. An example of cyanoalkyl is cyanoethyl.

[0022] "Cyanoalkoxy" means a moiety of the formula -R'-R'' where R' is alkoxy as defined herein and R'' is cyano or nitrile. An example of cyanoalkoxy is cyanomethoxy.

[0023] The term "heteroaryl" represents a monovalent aromatic monocyclic or bicyclic ring system of 4 to 9 ring atoms containing 1, 2, 3 or 4 ring heteroatoms selected from N and O, with the remaining ring atoms being carbon. The heteroatom can also be S. Bicyclic means consisting of two rings having one or two ring atoms in common. Examples of heteroaryl are pyrimidyl, oxazolyl, pyridazinyl, imidazolyl, pyrazinyl and pyridyl. Other examples of heteroaryl are pyrazolyl, pyrimidinyl, isoxazolyl, triazolyl, oxadiazolyl, oxazolyl, pyrrolylimidazolyl and thiazolyl.

[0024] The term "C-linked heteroaryl" means a heteroaryl system of up to 9 ring atoms, the heteroaryl system being linked to the rest of the molecule via a C atom.

[0025] The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the free base or free acid and are not biologically or otherwise undesirable. Salts are formed using inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, especially hydrochloric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine. In addition, these salts can be prepared from the addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, salts of sodium, potassium, lithium, ammonium, calcium, magnesium. Salts derived from organic bases include 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. Compounds of formula I may also exist in zwitterionic form. Particularly preferred pharmaceutically acceptable salts of the compounds of formula I are salts formed using formic acid and salts formed using hydrochloric acid that give rise to hydrochloride, dihydrochloride or trihydrochloride.

[0026] The abbreviation uM means micromolar concentration and is equivalent to the symbol μM.

[0027] The abbreviation uL means microliter and is equivalent to the symbol μL.

[0028] The abbreviation ug means microgram and is equivalent to the symbol μg.

[0029] The compounds of formula I may contain several asymmetric centers and can exist in the form of optically pure enantiomers, mixtures of enantiomers, such as racemates, etc., optically pure diastereoisomers, mixtures of diastereoisomers, racemates of diastereoisomers or mixtures of racemates of diastereoisomers.

[0030] According to the Cahn-Ingold-Prelog rules, the asymmetric carbon atoms can have the configuration of "R" or "S".

[0031] Also, one embodiment of the present invention provides a compound according to formula I described herein and a pharmaceutically acceptable salt or ester thereof, in particular a compound according to formula I described herein and a pharmaceutically acceptable salt thereof, more specifically, a compound according to formula I described herein.

[0032] One embodiment of the present invention provides a compound according to formula I described herein, wherein R 1 is alkoxy.

[0033] One embodiment of the present invention provides a compound according to formula I described herein, wherein R 2 is cyclopropyl substituted with halo, alkyl, haloalkyl, haloalkoxy, cyanoalkyl, cyanoalkoxy or cyano.

[0034] One embodiment of the present invention provides a compound according to formula I described herein, wherein R 2 is cyclopropyl substituted with haloalkyl, haloalkoxy or cyano.

[0035] One embodiment of the present invention provides a compound according to formula I described herein, wherein R 2 is alkyl, haloalkoxy or haloalkyl.

[0036] One embodiment of the present invention provides a compound according to formula I described herein, wherein R 2To provide a compound of formula I as described herein, wherein R is haloalkyl or haloalkoxy.

[0037] One embodiment of the present invention provides a compound of formula I as described herein, wherein R 3 is H or alkoxy.

[0038] One embodiment of the present invention provides a compound of formula I as described herein, wherein R 3 is alkoxy.

[0039] One embodiment of the present invention provides a compound of formula I as described herein, wherein R 5 is H, halo or haloalkyl.

[0040] One embodiment of the present invention provides a compound of formula I as described herein, wherein R 5 is alkyl, H or halo.

[0041] One embodiment of the present invention provides a compound of formula I as described herein, wherein R 5 is H or halo.

[0042] One embodiment of the present invention provides a compound of formula I as described herein, wherein R 6 is H.

[0043] One embodiment of the present invention provides a compound of formula I as described herein, wherein R 4 is C-bonded aryl or C-bonded heteroaryl, and the C-bonded aryl or C-bonded heteroaryl is optionally substituted by one or more substituents independently selected from alkyl and halo.

[0044] One embodiment of the present invention provides a compound of formula I as described herein, wherein R 4is a C-linked aryl or C-linked heteroaryl, and the C-linked aryl or C-linked heteroaryl is optionally substituted by alkyl, halo or haloalkyl, and provides a compound according to formula I as described herein.

[0045] One embodiment of the present invention is that R 4 is i. a C-linked 6-membered aryl optionally substituted by alkyl, halo or haloalkyl, ii. a C-linked 6-membered heteroaryl containing 1 to 3 nitrogen heteroatoms optionally substituted by alkyl, halo or haloalkyl, iii. a C-linked 5-membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, S and O, optionally substituted by alkyl, halo or haloalkyl, and iv. a C-linked 8- to 9-membered bicyclic heteroaryl system containing 2 N heteroatoms and provides a compound according to formula I as described herein.

[0046] One embodiment of the present invention is that R 4 is i. a C-linked 6-membered aryl, ii. a C-linked 6-membered heteroaryl containing 1 to 2 nitrogen heteroatoms optionally substituted by alkyl or halo, iii. a C-linked 5-membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, S and O, optionally substituted by 1 to 2 substituents independently selected from alkyl and halo, and iv. a C-linked 8-membered bicyclic heteroaryl system containing 2 N heteroatoms and provides a compound according to formula I as described herein.

[0047] One embodiment of the present invention is that R 4 is i. a C-linked 6-membered heteroaryl containing 1 to 3 nitrogen heteroatoms optionally substituted by alkyl or halo, and A C-bonded 5-membered heteroaryl containing 1 to 2 heteroatoms independently selected from N and O To provide a compound of formula I as described herein, selected from

[0048] One embodiment of the present invention is that R 4 is

Chemical formula

[0049] One embodiment of the present invention is that R 4 is

Chemical formula

[0050] One embodiment of the present invention is R 1 is alkoxy, R 2 is halo, alkyl, haloalkyl, haloalkoxy, cyanoalkyl, cyanoalkoxy or cyclopropyl substituted with cyano, R 3 is H or alkoxy, R 5 is H, halo, alkyl or haloalkyl, R 6 is H or halo, R 4is a C-linked aryl or C-linked heteroaryl, said C-linked aryl or C-linked heteroaryl being optionally substituted by one or more substituents independently selected from alkyl and halo, Provided are compounds of formula I as described herein and pharmaceutically acceptable salts thereof.

[0051] One embodiment of the present invention is R 1 is alkoxy, R 2 is halo, alkyl, haloalkyl, haloalkoxy, cyanoalkyl, cyanoalkoxy or cyclopropyl substituted with cyano, R 3 is H or alkoxy, R 5 is H, halo, alkyl or haloalkyl, R 6 is H or halo, R 4 is i. a C-linked 6-membered aryl, ii. a C-linked 6-membered heteroaryl containing one or two nitrogen heteroatoms, optionally substituted with alkyl or halo, iii. a C-linked 5-membered heteroaryl containing one to three heteroatoms independently selected from N, S and O, optionally substituted with one or two substituents independently selected from alkyl and halo, and iv. a C-linked 8-membered bicyclic heteroaryl system containing two N heteroatoms Selected from, provided are compounds of formula I as described herein and pharmaceutically acceptable salts thereof.

[0052] One embodiment of the present invention is R 1 is alkoxy or haloalkoxy, R 2is cyclopropyl optionally substituted with up to two substituents independently selected from halo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyanoalkyl, cyanoalkoxy or cyano and halo, R 3 is H, alkoxy or haloalkoxy, R 5 is H, halo, alkyl or haloalkyl, R 6 is H or halo, R 4 is C-bonded aryl or C-bonded heteroaryl, said C-bonded aryl or C-bonded heteroaryl being optionally substituted by alkyl, halo or haloalkyl, There are provided compounds of formula I as described herein and pharmaceutically acceptable salts thereof.

[0053] One embodiment of the invention is, R 1 is alkoxy, R 2 is cyclopropyl substituted with haloalkyl, haloalkoxy, or cyano, R 3 is alkoxy, R 5 is H, halo or haloalkyl, R 6 is H, R 4 is,

Chemical formula

[0054] One embodiment of the invention is, R 1 is alkoxy, R 2 is a haloalkyl or haloalkoxy, R 3 is an alkoxy, R 5 is H or halo, R 6 is H, R 4 is

Chemical formula

[0055] Specific examples of the compounds of formula I described herein are 6-chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-oxazol-2-yl-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyridazin-3-yl-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(1-methylimidazol-2-yl)-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyridazin-3-yl-1H-indole-3-sulfonamide; N-[5-(2,2-Difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(1-methylimidazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(1-methylimidazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-Difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-fluoro-7-(1-methylimidazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-Difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-fluoro-7-(1-methylimidazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-Difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyridazin-3-yl-1H-indole-3-sulfonamide; N-[5-(2,2-Difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyridazin-3-yl-1H-indole-3-sulfonamide; N-[5-(2,2-Difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(4-methylpyridazin-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-oxazol-4-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazin-2-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazin-2-yl-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(2-pyridyl)-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(2-pyridyl)-1H-indole-3-sulfonamide; 6-chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazin-2-yl-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazin-2-yl-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2-cyanocyclopropyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazin-2-yl-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-fluoro-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-fluoro-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-Fluoro-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; N-[5-(Difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-fluoro-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; N-[5-(2,2-Difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazin-2-yl-1H-indole-3-sulfonamide; N-[5-(2,2-Difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-fluoro-7-pyrazin-2-yl-1H-indole-3-sulfonamide; 6-Fluoro-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazin-2-yl-1H-indole-3-sulfonamide; N-[5-(2,2-Difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-fluoro-7-pyrazin-2-yl-1H-indole-3-sulfonamide; N-[5-(Difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-fluoro-7-pyrazin-2-yl-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazin-2-yl-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazin-2-yl-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazin-2-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(5-fluoropyrazin-2-yl)-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyridazin-3-yl-1H-indole-3-sulfonamide; 6-(Difluoromethyl)-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; N-[5-(2,2-Difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-fluoro-7-(1H-imidazol-2-yl)-1H-indole-3-sulfonamide A compound selected from the above, and a pharmaceutically acceptable salt thereof.

[0056] Further specific examples of the compound of formula I described herein are 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(1,5-dimethylimidazol-4-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(1-methylimidazol-4-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(3-methylpyrazin-2-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(3-methylpyrazin-2-yl)-1H-indole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-7-pyridazin-3-yl-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-7-pyrazin-2-yl-1H-indole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-7-pyrazin-2-yl-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-fluoro-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(1-methylpyrazol-3-yl)-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(2-methylpyrimidin-4-yl)-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(6-methylpyridazin-3-yl)-1H-indole-3-sulfonamide; 6-chloro-7-(3-chloropyrazin-2-yl)-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-7-(3-chloropyrazin-2-yl)-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-7-(3-chloropyrazin-2-yl)-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(1-methylpyrazol-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-(1-methylpyrazol-3-yl)-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-(1-methylpyrazol-4-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-phenyl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidin-2-yl]-7-phenyl-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-(3-methylpyrazin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidin-2-yl]-7-(3-methylpyrazin-2-yl)-1H-indole-3-sulfonamide; N-(5-Bromo-4,6-dimethoxypyrimidin-2-yl)-6-chloro-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidin-2-yl]-7-(4-pyrimidyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-(4-pyrimidyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(cyanomethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(3-methylpyrazin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(5-methylpyrazin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(5-methylpyrazin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(5-methylpyrazin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4,6-dimethoxy-5-methyl-pyrimidin-2-yl)-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(6-methylpyrazin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(6-methylpyrazin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(6-methylpyrazin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(5-pyrimidyl)-1H-indole-3-sulfonamide; 6-Chloro-7-(5-chloropyrazin-2-yl)-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-7-(5-chloropyrazin-2-yl)-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(6-methyl-2-pyridyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(6-methyl-2-pyridyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(6-methyl-2-pyridyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyridazin-4-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(6-methylpyrimidin-4-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(3-fluoropyrazin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(3-fluoropyrazin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-(3-fluoropyrazin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-(3-methyl-2-pyridyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-(1-methyl-1,2,4-triazol-4-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidin-2-yl]-7-(3-methyl-2-pyridyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-(3-methyl-2-pyridyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-(1-methyl-1,2,4-triazol-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-(5-fluoropyrimidin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-(2-methyl-1,2,4-triazol-4-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-(2-methyl-1,2,4-triazol-4-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidin-2-yl]-7-(2-methyl-1,2,4-triazol-4-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-(2-methyl-1,2,3-triazol-4-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-(1,3,4-oxadiazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-(1-methyl-1H-pyrazol-4-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-(1-methyl-1H-pyrazol-4-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-(1-methyl-1H-pyrazol-4-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidin-2-yl]-7-(1-methyl-1H-pyrazol-4-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-thiazol-4-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-oxazol-5-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-oxazol-5-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-isoxazol-4-yl-1H-indole-3-sulfonamide; 6-chloro-N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-isoxazol-4-yl-1H-indole-3-sulfonamide; 6-chloro-N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-thiazol-4-yl-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidin-2-yl]-7-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-3-yl)-1H-indole-3-sulfonamide a compound selected from the above, and a pharmaceutically acceptable salt thereof.

[0057] Preferred examples of the compound of formula I described herein are 6-chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidin-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-pyridazin-3-yl-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidin-2-yl]-7-(1-methylimidazol-2-yl)-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidin-2-yl]-7-pyridazin-3-yl-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-(1-methylimidazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(1-methylimidazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-Difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-fluoro-7-(1-methylimidazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-oxazol-4-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazin-2-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazin-2-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(2-pyridyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(2-pyridyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazin-2-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazin-2-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazin-2-yl-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazin-2-yl-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazin-2-yl-1H-indole-3-sulfonamide A compound selected from the above, and a pharmaceutically acceptable salt thereof.

[0058] Further preferred examples of the compound of formula I described herein are 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(1,5-dimethylimidazol-4-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(1-methylimidazol-4-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(3-methylpyrazin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-(1-methylpyrazol-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-(2-methylpyrimidin-4-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-(6-methylpyridazin-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-7-(3-chloropyrazin-2-yl)-N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-7-(3-chloropyrazin-2-yl)-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-(1-methylpyrazol-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-(1-methylpyrazol-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-(3-methylpyrazin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidin-2-yl]-7-(3-methylpyrazin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidin-2-yl]-7-(4-pyrimidyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(4-pyrimidyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(3-methylpyrazin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(5-methylpyrazin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4,6-dimethoxy-5-methyl-pyrimidin-2-yl)-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(6-methylpyrazin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(6-methylpyrazin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(6-methylpyrazin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(5-pyrimidyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(6-methyl-2-pyridyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(6-methyl-2-pyridyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-(6-methylpyridin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-pyridazin-4-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-(6-methylpyrimidin-4-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidin-2-yl]-7-(3-fluoropyrazin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-(3-fluoropyrazin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-(3-fluoropyrazin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-(3-methylpyridin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-(1-methyl-1H-1,2,3-triazol-4-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidin-2-yl]-7-(3-methylpyridin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidin-2-yl]-7-(2-methyl-1H-1,2,3-triazol-4-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(2-methyl-1,2,3-triazol-4-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(2-methyl-1,2,3-triazol-4-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(1,3,4-oxadiazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-thiazol-4-yl-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-3-yl)-1H-indole-3-sulfonamide A compound selected from the above, and a pharmaceutically acceptable salt thereof.

[0059] A method for the production of the compounds of formula I described herein is an object of the present invention.

[0060] The compounds of formula I of the present invention and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by the methods described below. This method involves reacting a compound of formula III with a compound of formula II in the presence of a base selected from N-ethyldiisopropylamine, pyridine, potassium phosphate or sodium hydride to provide a compound of formula I [Chemical formula] (wherein R 1 , R 2 , R 3 , R 3 , R 4 , R5 and R 6 is as described above) comprises

[0061] General synthetic scheme The compounds of formula I can be prepared according to the variations of the above methods and according to Scheme 1 below. The starting materials are either commercially available or can be prepared according to known methods. Scheme 1

Chemical formula

[0062] Scheme 2

Chemical formula

[0063] Scheme 3

Chem.

[0064] Scheme 4

Chem.

[0065] Scheme 5

Chem.

[0066] Scheme 6

Chemical formula

[0067] Scheme 7

Chemical formula

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

[0069] The composition is formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered in this regard include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient / animal, the cause of the disorder, the site of drug delivery, the method of administration, the dosing schedule, and other factors known to the medical practitioner.

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

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

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

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

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

[0075] Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc.

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

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

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

[0079] Furthermore, pharmaceutical preparations can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for changing osmotic pressure, buffers, masking agents, or antioxidants. Pharmaceutical preparations can further contain other therapeutically valuable substances.

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

[0081] The present invention also relates, in particular, to the following: A compound of formula I for use as a therapeutic active substance; A compound of formula I for use in the treatment of a disease regulated by GPR17; Similarly, an object of the present invention is a pharmaceutical composition comprising a compound according to formula I described herein and a therapeutically inactive carrier.

[0082] Direct damage to the myelin sheath (including, but not limited to, central pontine myelinolysis and extrapontine myelinolysis, carbon monoxide poisoning, nutritional disorders, and virus-induced demyelination), demyelinating disorders (including, but not limited to, multiple sclerosis, acute and multiphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorder, and leukodystrophy), CNS disorders associated with myelin loss (including, but not limited to, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and ischemia due to stroke), and use of a compound of formula I for the treatment or prevention of symptoms resulting from inflammation in the CNS, such as encephalitis, primary vasculitis, meningitis, and after obesity.

[0083] One embodiment of the present 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.

[0084] A specific embodiment of the present invention is the use of a compound of formula I for the treatment or prevention of multiple sclerosis.

[0085] Use of a compound of formula I for the preparation of a medicament for the treatment or prevention of direct damage to the myelin sheath (including, but not limited to, central pontine myelinolysis and extrapontine myelinolysis, carbon monoxide poisoning, nutritional disorders, and virus-induced demyelination), demyelinating disorders (including, but not limited to, multiple sclerosis, acute and polymorphic disseminated encephalomyelitis, neuromyelitis optica spectrum disorder, and leukodystrophy), CNS disorders associated with myelin loss (including, but not limited to, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and ischemia due to stroke), and symptoms resulting from inflammation in the CNS, such as, for example, encephalitis, primary vasculitis, meningitis, and post-obesity.

[0086] One 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, Alzheimer's disease, Parkinson's disease, or Huntington's disease.

[0087] 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.

[0088] Use of a compound according to formula I for the treatment or prevention of direct damage to the myelin sheath (including, but not limited to, central pontine myelinolysis and extrapontine myelinolysis, carbon monoxide poisoning, nutritional disorders, and virus-induced demyelination), demyelinating disorders (including, but not limited to, multiple sclerosis, acute and polymorphic disseminated encephalomyelitis, neuromyelitis optica spectrum disorder, and leukodystrophy), CNS disorders associated with myelin loss (including, but not limited to, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and ischemia due to stroke), and symptoms resulting from inflammation in the CNS, such as, for example, encephalitis, primary vasculitis, meningitis, and post-obesity.

[0089] One embodiment of the invention is a compound of formula I for use in the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease, or Huntington's disease.

[0090] Certain embodiments of the present invention are compounds of formula I for use in the treatment or prevention of multiple sclerosis.

[0091] Direct damage to the myelin sheath (including, but not limited to, central pontine myelinolysis and extrapontine myelinolysis, carbon monoxide poisoning, nutritional disorders, and virus-induced demyelination), demyelinating disorders (including, but not limited to, multiple sclerosis, acute and polyphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorder, and leukodystrophy), CNS disorders associated with myelin loss (including, but not limited to, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and ischemia due to stroke), and methods for the treatment or prevention of symptoms resulting from inflammation in the CNS, such as encephalitis, primary vasculitis, meningitis, and post-obesity, comprising administering an effective amount of a compound of formula I to a patient in need thereof.

[0092] One embodiment of the present invention is a method for the treatment or prevention of 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.

[0093] Certain embodiments of the present invention are methods for the treatment or prevention of multiple sclerosis, comprising administering an effective amount of a compound of formula I to a patient in need thereof.

[0094] Also, one embodiment of the present invention provides a compound of formula I described herein when manufactured according to any one of the methods described.

[0095] Assay procedure GPR17 cAMP assay protocol: CHO-K1 cells stably expressing a vector containing untagged human GPR17 short isoform (Roche) were cultured at 37 °C / 5% CO2 in DMEM (Dulbecco's Modified Eagle Medium):F-12 (1:1) supplemented with 10% fetal bovine serum and 400 μg / ml Geneticin.

[0096] Changes in intracellular cyclic adenosine monophosphate (cAMP) levels were quantified using the Nano-TRF Detection Assay kit (Roche Diagnostics, catalog number 05214386001). This assay enables direct cAMP quantification in a homogeneous solution. cAMP is detected based on time-resolved fluorescence energy transfer (TR-FRET) and competitive binding of ruthenium-labeled cAMP and endogenous cAMP to an anti-cAMP monoclonal antibody labeled with AlexaFluor-700. The ruthenium complex acts as a FRET donor and transfers energy to AlexaFluor-700. The FRET signal is inversely proportional to the cAMP concentration.

[0097] CHO-GPR17S cells were detached with Accutase and resuspended in assay buffer consisting of Hank's balanced salt solution (HBSS), 10 mM HEPES (4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid solution), and 0.1% bovine serum albumin (pH 7.4). Cells were seeded at a density of 10,000 cells / 20 μl assay buffer in black 384-well plates (Corning) until the addition of compounds.

[0098] The test antagonist compound was serially diluted with dimethyl sulfoxide (DMSO) and spotted onto a 384-well plate. The compound was then diluted in HBSS buffer supplemented with MDL29,951 (3-(2-carboxy-4,6-dichloroindol-3-yl)propionic acid) (GPR17 agonist) at EC80 concentration + 3-isobutyl-1-methylxanthine (IBMX) (0.5 mM final concentration) and added to the cells at room temperature. Forskolin (15 μM final concentration) was added 5 minutes after the test compound, and the cells were incubated at room temperature for 30 minutes. The assay was stopped by adding the cAMP detection mixture (containing surfactant for cell lysis) for 90 minutes at room temperature.

[0099] cAMP in the cells was measured using a Paradigm reader (Molecular Devices). Using the raw data, the FRET signal was calculated based on the P factor of the assay according to the instructions of the cAMP kit. The data was normalized against the maximum activity of the reference antagonist, and the dose-response curve was fitted to the percent activity of the test compound using a sigmoid dose-response model (Genedata Screener).

[0100] Table 1 provides the results of the hGPR17 cAMP assay for the compounds of formula I.

Table 1

[0101] The present invention will now be described by the following examples which have no limiting features.

[0102] When the preparation example is obtained as a mixture of enantiomers, the pure enantiomers can be obtained by the methods described herein or by methods known to those skilled in the art, such as chiral chromatography or crystallization.

Example

[0103] Unless otherwise specified, all examples and intermediates were prepared under a nitrogen atmosphere.

[0104] Intermediate A Intermediate A1: 6-Chloro-7-pyrimidin-2-yl-1H-indole-3-sulfonyl chloride

Chemical Structure

[0105] Step 1: 1-(6-Chloroindol-1-yl)-2,2-dimethyl-propan-1-one

Chemical Structure

[0106] Step 2: 6-Chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole

Chemical Structure

[0107] Step 3: 6-Chloro-7-pyrimidin-2-yl-1H-indole

Chemical Structure

[0108] Step 4: 6-Chloro-7-pyrimidin-2-yl-1H-indole-3-sulfonyl chloride

Chemical Structure

[0109] Intermediate A2: 6-Chloro-7-oxazol-2-yl-1H-indole-3-sulfonyl chloride

Chem.

[0110] Step 1: 2-(6-Chloro-1H-indol-7-yl)oxazole

Chem.

[0111] Step 2: 6-Chloro-7-pyrimidin-2-yl-1H-indole-3-sulfonyl chloride

Chem.

[0112] Intermediate A3: 6-Chloro-7-pyridazin-3-yl-1H-indole-3-sulfonyl chloride

Chemical formula

[0113] Step 1: 6-Chloro-7-pyridazin-3-yl-1H-indole

Chemical formula

[0114] Step 2: 6-Chloro-7-pyrimidin-2-yl-1H-indole-3-sulfonyl chloride

Chemical Structure

[0115] Intermediate A4: 7-(1-Methylimidazol-2-yl)-1H-indole-3-sulfonyl chloride

Chem.

[0116] Intermediate A5: 6-Chloro-7-(2-pyridyl)-1H-indole-3-sulfonyl chloride

Chem.

[0117] Intermediate A6: 6-Chloro-7-(1-methylimidazol-2-yl)-1H-indole-3-sulfonyl chloride

Chem.

[0118] Intermediate A7: 7-Pyridazin-3-yl-1H-indole-3-sulfonyl chloride [Chemical formula] Instead of 6-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole, the title compound was prepared as an off-white solid from 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (CAS 642494-37-9) in the same manner as Intermediate A3. MS(ESI) m / z: 294.1 [M+H] +

[0119] Intermediate A8: 7-(4-Methylpyridazin-3-yl)-1H-indole-3-sulfonyl chloride [Chemical formula] Instead of 3-chloro-pyridazine, 3-chloro-4-methyl-pyridazine and instead of 6-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole, 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (CAS 642494-37-9), the title compound was prepared as a light brown solid in the same manner as Intermediate A3. MS(ESI) m / z: 308.1 [M+H] +

[0120] Intermediate A9: 6-Chloro-7-oxazol-4-yl-1H-indole-3-sulfonyl chloride [Chemical formula]

[0121] Step 1: 4-(6-Chloro-1H-indol-7-yl)oxazole [Chemical formula] A mixture of 6-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (see Intermediate A1, 400 mg, 1.31 mmol), cesium carbonate (1.29 g, 3.93 mmol), XPhos Pd G2 (CAS 1310584-14-5, 103 mg, 131 μmol, 0.10 equiv), and 4-bromooxazole (245 mg, 1.57 mmol) in 1,4-dioxane (3 ml) and water (1.5 ml) was heated in a microwave at 90 °C for 30 minutes. The reaction mixture was poured into brine and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0% - 30% ethyl acetate in heptane) to give 4-(6-chloro-1H-indol-7-yl)oxazole (40 mg, 14%) as a pale yellow solid. MS (ESI) m / z: 219.0 [M+H] +

[0122] Step 2: 6-Chloro-7-oxazol-4-yl-1H-indole-3-sulfonyl chloride [Chemical Structure Diagram] A solution of 4-(6-chloro-1H-indol-7-yl)oxazole (39 mg, 178 μmol) in acetonitrile (1.5 ml) was cooled to 0 °C. Chlorosulfonic acid (54 mg, 31 μl, 464 μmol) was added. The reaction mixture was stirred at 0 °C for 30 minutes and at room temperature for 3 days. Then, phosphorus oxychloride (137 mg, 83 μl, 892 μmol) was added. The reaction mixture was heated to 70 °C, stirred for 10 hours, then poured into ice and ethyl acetate and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (55 mg, 97% yield) as a light brown solid. MS (ESI) m / z: 315.0 [M-H] -

[0123] Intermediate A10: 6-Chloro-7-pyrazin-2-yl-1H-indole-3-sulfonyl chloride

Chemical formula

[0124] Intermediate A11: 7-Pyrimidin-2-yl-1H-indole-3-sulfonyl chloride

Chemical formula

[0125] Intermediate A12: 7-Pyrazin-2-yl-1H-indole-3-sulfonyl chloride

Chemical formula

[0126] Intermediate A13: 6-Fluoro-7-pyrimidin-2-yl-1H-indole-3-sulfonyl chloride

Chem.

[0127] Intermediate A14: 6-Fluoro-7-(1-methylimidazol-2-yl)-1H-indole-3-sulfonyl chloride

Chem.

[0128] Intermediate A15: 6-Fluoro-7-pyrazin-2-yl-1H-indole-3-sulfonyl chloride

Chem.

[0129] Intermediate A16: 6-Bromo-7-pyrimidin-2-yl-1H-indole-3-sulfonyl chloride

Chem.

[0130] Intermediate A17: 6-Bromo-7-pyrazin-2-yl-1H-indole-3-sulfonyl chloride

Chem.

[0131] Intermediate A18: 6-Chloro-7-(5-fluoropyrazin-2-yl)-1H-indole-3-sulfonyl chloride

Chem.

[0132] Intermediate A19: 6-Bromo-7-pyridazin-3-yl-1H-indole-3-sulfonyl chloride

Chem.

[0133] Intermediate A20: 6-(Difluoromethyl)-7-pyrimidin-2-yl-1H-indole-3-sulfonyl chloride

Chemical Structure

[0134] Step 1: 7-Bromo-6-(difluoromethyl)-1H-indole

Chemical Structure

[0135] Step 2: 6-(Difluoromethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole

Chemical Structure

[0136] Step 3: 6-(Difluoromethyl)-7-pyrimidin-2-yl-1H-indole [Chemical formula] A mixture of 6-(difluoromethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (729 mg, 2.49 mmol), 2-bromopyrimidine (475 mg, 2.98 mmol), tetrakis(triphenylphosphine)palladium(0) (288 mg, 249 μmol, 0.1 equiv), and cesium carbonate (1.62 g, 4.97 mmol) in 1,4-dioxane (10 ml) and water (2.5 ml) was heated in a microwave at 100 °C for 30 minutes. The mixture was poured into water and extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification of the residue by flash chromatography (SiliaSep Amine silica gel, 0% - 80% ethyl acetate in heptane) gave 6-(difluoromethyl)-7-pyrimidin-2-yl-1H-indole (193 mg, 32% yield) as a white semi-solid. MS(ESI) m / z: 246.1 [M+H] +

[0137] Step 4: 6-(Difluoromethyl)-7-pyrimidin-2-yl-1H-indole-3-sulfonyl chloride

Chem.

[0138] Intermediate A21: 6-Fluoro-7-(1H-imidazol-2-yl)-1H-indole-3-sulfonyl chloride

Chem.

[0139] Intermediate A22: 6-Methyl-7-pyrimidin-2-yl-1H-indole-3-sulfonyl chloride

Chem.

[0140] Intermediate A23: 6-Chloro-7-phenyl-1H-indole-3-sulfonyl chloride

Chem.

[0141] Step 1: 6-Chloro-7-phenyl-1H-indole

Chem.

[0142] Step 2: 6-Chloro-7-phenyl-1H-indole-3-sulfonyl chloride

Chemical Structure

[0143] Intermediate A24: 6-Chloro-7-(3-methylpyrazin-2-yl)-1H-indole-3-sulfonyl chloride

Chem.

[0144] Intermediate A25: 6-Chloro-7-oxazol-5-yl-1H-indole-3-sulfonyl chloride

Chem.

[0145] Step 1: 5-(6-Chloro-1H-indol-7-yl)oxazole

Chem.

[0146] Step 2: 6-chloro-7-oxazol-5-yl-1H-indole-3-sulfonyl chloride

Chemical Structure

[0147] Intermediate A26: 6-Chloro-7-pyrimidin-4-yl-1H-indole-3-sulfonyl chloride

Chemical formula

[0148] Intermediate A27: 7-(3-Methylpyrazin-2-yl)-1H-indole-3-sulfonyl chloride

Chemical formula

[0149] Intermediate A28: 6-Chloro-7-isoxazol-5-yl-1H-indole-3-sulfonyl chloride [Chemical formula] In step 1), instead of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (CAS 928664-98-6) was used to prepare the title compound as a brown solid in the same manner as Intermediate A25. MS(ESI) m / z: 314.9 [M-H] - .

[0150] Intermediate A29: 6-Methyl-7-pyridazin-3-yl-1H-indole-3-sulfonyl chloride [Chemical formula] Instead of 6-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole, 2,2-dimethyl-1-[6-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indol-1-yl]propan-1-one (CAS 2376879-97-7) was used to prepare the title compound as a light brown solid in the same manner as Intermediate A3. MS(ESI) m / z: 308.1 [M+H] + .

[0151] Intermediate A30: 6-Chloro-7-(1,5-dimethylimidazol-4-yl)-1H-indole-3-sulfonyl chloride

Chemical Structure

[0152] Intermediate A31: 6-Methyl-7-pyrazin-2-yl-1H-indole-3-sulfonyl chloride

Chemical Structure

[0153] Intermediate A32: 6-Chloro-7-(5-methylpyrazin-2-yl)-1H-indole-3-sulfonyl chloride

Chemical Structure

[0154] Intermediate A33: 6-Chloro-7-(6-methylpyrazin-2-yl)-1H-indole-3-sulfonyl chloride

Chem.

[0155] Intermediate A34: 6-Chloro-5-fluoro-7-pyrimidin-2-yl-1H-indole-3-sulfonyl chloride

Chem.

[0156] Intermediate A35: 6-Chloro-7-pyrimidin-5-yl-1H-indole-3-sulfonyl chloride

Chem.

[0157] Intermediate A36: 6-Chloro-7-(1-methylpyrazol-3-yl)-1H-indole-3-sulfonyl chloride

Chem.

[0158] Intermediate A37: 6-chloro-7-(1-methylimidazol-4-yl)-1H-indole-3-sulfonyl chloride

Chem.

[0159] Intermediate A38: 6-chloro-7-(5-chloropyrazin-2-yl)-1H-indole-3-sulfonyl chloride

Chem.

[0160] Intermediate A39: 6-chloro-7-(6-methyl-2-pyridyl)-1H-indole-3-sulfonyl chloride

Chem.

[0161] Intermediate A40: 6-Chloro-7-pyridazin-4-yl-1H-indole-3-sulfonyl chloride

Chemical formula

[0162] Intermediate A41: 6-Chloro-7-(2-methylpyrimidin-4-yl)-1H-indole-3-sulfonyl chloride

Chemical formula

[0163] Intermediate A42: 6-Chloro-7-(6-methylpyrimidin-4-yl)-1H-indole-3-sulfonyl chloride

Chemical formula

[0164] Intermediate A43: 6-Chloro-7-(3-fluoropyrazin-2-yl)-1H-indole-3-sulfonyl chloride

Chemical formula

[0165] Intermediate A44: 6-chloro-7-(6-methylpyridazin-3-yl)-1H-indole-3-sulfonyl chloride

Chem.

[0166] Intermediate A45: 6-chloro-7-(3-chloropyrazin-2-yl)-1H-indole-3-sulfonyl chloride

Chem.

[0167] Intermediate A46: 6-chloro-7-(3-methyl-2-pyridyl)-1H-indole-3-sulfonyl chloride

Chem.

[0168] Intermediate A47: 6-Chloro-7-(1-methyl-1H-1,2,4-triazol-4-yl)-1H-indole-3-sulfonyl chloride

Chem.

[0169] Intermediate A48: 6-Bromo-7-(1-methyl-1H-pyrazol-4-yl)-1H-indole-3-sulfonyl chloride

Chem.

[0170] Intermediate A49: 6-Chloro-7-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indole-3-sulfonyl chloride

Chem.

[0171] Intermediate A50: 6-Chloro-7-(5-fluoropyrimidin-2-yl)-1H-indole-3-sulfonyl chloride

Chem.

[0172] Intermediate A51: 6-chloro-7-(2-methyl-1,2,3-triazol-4-yl)-1H-indole-3-sulfonyl chloride

Chem.

[0173] Intermediate A52: 6-chloro-7-(1,3,4-oxadiazol-2-yl)-1H-indole-3-sulfonyl chloride

Chem.

[0174] Step 1: 6-chloro-1H-indole-7-carboxylic acid

Chem.

[0175] Step 2: tert-Butyl N-[(6-chloro-1H-indole-7-carbonyl)amino]carbamate

Chemical formula

[0176] Step 3: 6-Chloro-1H-indole-7-carbohydrazide [Chemical formula] A mixture of tert-butyl N-[(6-chloro-1H-indole-7-carbonyl)amino]carbamate (900 mg, 2.91 mmol) and HCl (4 M, 18.0 ml, 72.0 mmol) in dioxane was stirred at 20 °C for 1 hour. Then, the pH of the mixture was adjusted to 7 with saturated NaHCO3 solution, and the mixture was extracted with ethyl acetate (20 ml × 2). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to obtain 6-chloro-1H-indole-7-carbohydrazide (600 mg, yield 98%) as a yellow solid. MS(ESI) m / z: 208.1 [M-H] - .

[0177] Step 4: 2-(6-chloro-1H-indol-7-yl)-1,3,4-oxadiazole [Chemical formula] A solution of 6-chloro-1H-indole-7-carbohydrazide (600 mg, 2.86 mmol) and ammonium chloride (152 mg, 2.86 mmol) in triethyl orthoformate (15 ml, 98.28 mmol) was stirred at 145 °C for 1 hour. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1:0 to 5:1) to obtain 2-(6-chloro-1H-indol-7-yl)-1,3,4-oxadiazole (425 mg, yield 62%) as a white solid. MS(ESI) m / z: 220.2 [M+H] + .

[0178] Step 5: 6-chloro-7-(1,3,4-oxadiazol-2-yl)-1H-indole-3-sulfonyl chloride [Chemical formula] A stirred suspension of 2-(6-chloro-1H-indol-7-yl)-1,3,4-oxadiazole (100 mg, 0.414 mmol) in acetonitrile (5 ml) was cooled to 0 °C and chlorosulfonic acid (125 mg, 72 μl, 1.08 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 30 minutes. Phosphoryl chloride (318 mg, 193 μl, 2.07 mmol) was added in one portion. The reaction mixture was heated to 60 °C for 22 hours. The reaction mixture was poured into ice / ethyl acetate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give the title compound (81 mg, 54% yield) as a pink solid. MS (ESI) m / z: 318.0 [M+H] + 。

[0179] Intermediate A53: 6-Chloro-7-(1-methylpyrazol-4-yl)-1H-indole-3-sulfonyl chloride

Chemical formula

[0180] Intermediate A54: 6-Chloro-7-thiazol-4-yl-1H-indole-3-sulfonyl chloride

Chemical formula

[0181] Intermediate B Intermediate B1: 5-(2,2-Difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-amine [Chemistry]

[0182] Step 1: 5-Bromo-4,6-dimethoxypyrimidin-2-amine [Chemistry] A solution of N-bromosuccinimide (10.33 g, 57.48 mmol) in acetonitrile (100 mL) was added dropwise to a stirred solution of (4,6-dimethoxypyrimidin-2-yl)amine (7 g, 44.22 mmol, CAS: 36315-01-2) in acetonitrile (100 mL) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes. 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 under reduced pressure. The precipitate was filtered off, washed with heptane, and the title compound was obtained as a white solid (9.26 g, 87% yield). MS(ESI) m / z = 234.1 [M+H] +

[0183] Step 2: 5-Bromo-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine [Chemistry] A solution of 5-bromo-4,6-dimethoxypyrimidin-2-amine (517 mg, 2.21 mmol) in N,N-dimethylacetamide (9 mL) was cooled to 0 °C. Sodium hydride (265.05 mg, 6.63 mmol) was added portionwise (3 × 88 mg). Stirring was continued at 0 °C for 30 minutes. 4-Methoxybenzyl chloride (706. mg, 608.62 μL, 4.42 mmol) was added dropwise. The reaction mixture was warmed to room temperature and 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 under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate / heptane 0 - 20% to afford the title compound as a white solid (1.11 g, yield 100%). MS (ESI) m / z = 476.2 [M+H] +

[0184] Step 3: 2-[[bis[(4-methoxyphenyl)methyl]amino]-4,6-dimethoxypyrimidin-5-ol

Chemical Structure

[0185] Step 4: 5-(2,2-Difluoroethoxy)-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine

Chemical Structure

[0186] Step 5: 5-(2,2-Difluoroethoxy)-4,6-dimethoxypyrimidin-2-amine

Chemical formula

[0187] Intermediate B2: 5-(2,2-Difluoroethyl)-4,6-dimethoxypyrimidin-2-amine [Chemistry]

[0188] Process 1: Diethyl 2-(2,2-difluoroethyl)propanedioate [Chemistry] Diethyl malonate (75.8 mL, 500 mmol) was combined with tetrahydrofuran (450 mL). Sodium ethoxide (prepared from ethanol (150 mL) and sodium (11.48 g, 500 mmol)) was added at room temperature, and the reaction mixture was stirred at room temperature for 15 minutes. A solution of 2,2-difluoroethyl trifluoromethanesulfonate (76 mL, 500 mmol) in tetrahydrofuran (10 mL) was added slowly. 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 under reduced pressure to give the title compound (100.5 g, 90% yield). MS (ESI) m / z = 225.0 [M+H] +

[0189] Process 2: 2-Amino-5-(2,2-difluoroethyl)pyrimidine-4,6-diol [Chemistry] To a stirred solution of diethyl 2-(2,2-difluoroethyl)propanedioate (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 h. The reaction mixture was concentrated to half its volume, and 50 mL of water was added, followed by acetic acid (42.57 g, 709 mmol). The mixture was heated to 80 °C, stirred for 10 min, and then cooled to room temperature. The solid product was separated by filtration and washed successively with water, ethanol, and methyl tert-butyl ether to afford the title compound (22.3 g, 50% yield). MS (ESI) m / z = 192.0 [M+H]+

[0190] Step 3: 4,6-Dichloro-5-(2,2-difluoroethyl)pyrimidin-2-amine

Chemical formula

[0191] Step 4: 5-(2,2-Difluoroethyl)-4,6-dimethoxypyrimidin-2-amine

Chemical formula

[0192] Intermediate B3: 5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-amine

Chem.

[0193] Step 1: 5-(difluoromethoxy)-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine

Chem.

[0194] Step 2: 5-(Difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-amine

Chem.

[0195] Intermediate B4: 5-(2-Fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-amine

Chem.

[0196] Step 1: 5-(2-Fluoroethoxy)-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine

Chem.

[0197] Step 2: 5 - (2 - Fluoroethoxy)-4,6 - dimethoxy - pyrimidin - 2 - amine

Chemical formula

[0198] Intermediate B5: 2 - (2 - Amino - 4,6 - dimethoxy - pyrimidin - 5 - yl)cyclopropanecarbonitrile

Chemical formula

[0199] Step 1: N,N-Bis[(2,4-dimethoxyphenyl)methyl]-4,6-dimethoxy-pyrimidin-2-amine

Chem.

[0200] Step 2: N,N-Bis[(2,4-dimethoxyphenyl)methyl]-5-iodo-4,6-dimethoxy-pyrimidin-2-amine

Chem.

[0201] Step 3: (E)-3-[2-[Bis[(2,4-dimethoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-yl]prop-2-enenitrile

Chemical Structure

[0202] Step 4: 2-[2-[Bis[(2,4-dimethoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-yl]cyclopropanecarbonitrile

Chemical formula

[0203] Step 5: 2-(2-Amino-4,6-dimethoxy-pyrimidin-5-yl)cyclopropanecarbonitrile [Chemical formula] To a solution of 2-[2-[[bis[(2,4-dimethoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-yl]cyclopropanecarbonitrile (3.0 g, 5.76 mmol) in dichloromethane (10 mL) was added dropwise trifluoroacetic acid (15 mL, 197 mmol) at 10 °C, and the mixture was stirred at 10 °C for 4 hours. The reaction mixture was diluted with water (100 mL), and the pH was adjusted to 7 with saturated sodium bicarbonate solution at 0 - 10 °C. The mixture was extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine (50 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with ethyl acetate (4 mL) and filtered. The filter cake was dried under reduced pressure to give the title compound (907 mg, yield 70%) as a white solid. MS (ESI) m / z = 221.1 [M+H] +

[0204] Intermediate B6: 5-Bromo-4,6-dimethoxy-pyrimidin-2-amine [Chemical formula] To a stirred solution of (4,6-dimethoxypyrimidin-2-yl)amine (7 g, 44.2 mmol, CAS: 36315-01-2) in acetonitrile (100 mL) was added dropwise a solution of N-bromosuccinimide (10.3 g, 57.5 mmol) in acetonitrile (100 mL) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes. 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 under reduced pressure. The precipitate was separated by filtration and washed with heptane to give the title compound as a white solid (9.26 g, yield 87%). MS (ESI) m / z = 234.1 [M+H] + .

[0205] Intermediate B7: 2-(2-Amino-4,6-dimethoxy-pyrimidin-5-yl)oxyacetonitrile

Chem.

[0206] Step 1: 2-[2-[Bis[(4-methoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-yl]oxyacetonitrile

Chem.

[0207] Step 2: 2-(2-Amino-4,6-dimethoxy-pyrimidin-5-yl)oxyacetonitrile

Chem.

[0208] Intermediate B8: 3-(2-amino-4,6-dimethoxy-pyrimidin-5-yl)propanenitrile

Chemical formula

[0209] Step 1: 3-[2-[bis[(4-methoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-yl]propanenitrile

Chemical formula

[0210] Step 2: 3-(2-Amino-4,6-dimethoxy-pyrimidin-5-yl)propanenitrile

Chemical Structure

[0211] Intermediate B9: 5-(2-Fluoroethoxy)-4-methoxy-pyrimidin-2-amine

Chem.

[0212] Step 1: [4-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]-bis(p-anisyl)amine

Chem.

[0213] Step 2: 2-[Bis(p-anisyl)amino]-4-methoxy-pyrimidin-5-ol

Chem.

[0214] Step 3: [5-(2-Fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-bis(p-anisyl)amine

Chemical formula

[0215] Step 4: [5-(2-Fluoroethoxy)-4-methoxy-pyrimidin-2-yl]amine

Chemical formula

[0216] Intermediate B10: 4,6-Dimethoxy-5-methyl-pyrimidin-2-amine

Chemical formula

[0217] Example Example 1: 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide

Chemical formula

[0218] By coupling the sulfonyl chloride Intermediate A and the amine Intermediate B shown, the following Examples 2 - 7 were prepared in the same manner as in Example 1.

Table 2

[0219] Example 8: 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(1-methylimidazol-2-yl)-1H-indole-3-sulfonamide

Chem.

[0220] Examples 9 - 10 below were prepared in the same manner as Example 8 by coupling the sulfonyl chloride Intermediate A and the amine Intermediate B shown.

Table 3

[0221] Example 11: N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyridazin-3-yl-1H-indole-3-sulfonamide

Chemical formula

[0222] By coupling the sulfonyl chloride Intermediate A and the amine Intermediate B shown, the following Examples 12 - 13 were prepared in the same manner as Example 11.

Table 4

[0223] Example 14: 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-oxazol-4-yl-1H-indole-3-sulfonamide

Chemical formula

[0224] By coupling the shown sulfonyl chloride intermediate A and amine intermediate B, the following Examples 15 - 33 were prepared in the same manner as in Example 14.

Table 5

[0225] By coupling the shown sulfonyl chloride intermediate A and amine intermediate B, the following Examples 46 - 47 were prepared in the same manner as in Example 8.

Table 6

[0226] By coupling the shown sulfonyl chloride intermediate A and amine intermediate B, Examples 48 to 71 below were prepared in the same manner as in Example 14.

Table 7

[0227] By coupling the shown sulfonyl chloride intermediate A and amine intermediate B, Examples 72 to 117 below were prepared in the same manner as in Example 11.

Table 8

[0228] Example 118: 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-isoxazol-4-yl-1H-indole-3-sulfonamide

Chemical formula

[0229] By coupling the sulfonyl chloride Intermediate A and the amine Intermediate B shown, Examples 119 - 120 below were prepared in the same manner as Example 118.

Table 9

[0230] Example 121: N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-3-yl)-1H-indole-3-sulfonamide

Chemical Structure

[0231] Step 1: 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-3-sulfonyl chloride

Chemical Structure

[0232] Step 2: N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-3-sulfonamide

Chemical formula

[0233] Step 3: 3-Iodo-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole

Chemical Structure

[0234] Step 4: N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-3-yl)-1H-indole-3-sulfonamide

Chemical Structure

[0235] Example A The compound of formula I can be used as an active ingredient in a manner known per se for producing tablets of the following composition. Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg

[0236] Example B The compound of formula I can be used as an active ingredient in a manner known per se for producing capsules of the following composition. Per capsule Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg

Claims

1. Formula I: 【Chemistry 1】 (In the formula, R １ is an alkoxy or haloalkoxy, R ２ This is a cyclopropyl compound optionally substituted with halo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyanoalkyl, cyanoalkoxy, or up to two substituents independently selected from cyano and halo. R ３ is H, alkoxy, or haloalkoxy, R ５ is H, halo, alkyl, or haloalkyl, R ６ is H or halo, R ４ (The C-bonded aryl or C-bonded heteroaryl is optionally substituted with one or more substituents independently selected from alkyl, halo, and haloalkyl groups.) Compounds of and pharmaceutically acceptable salts of.

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

3. R ２ The compound according to claim 1, wherein the compound is a cyclopropyl substituted with halo, alkyl, haloalkyl, haloalkoxy, cyanoalkyl, cyanoalkoxy, or cyano.

4. R ２ The compound according to claim 1, wherein R is alkyl, haloalkyl or haloalkoxy.

5. R ３ The compound according to claim 1, wherein the compound is H or an alkoxy.

6. R ５ The compound according to claim 1, wherein the compound is alkyl, H, or halo.

7. R ５ The compound according to claim 1, wherein the compound is H or a halo.

8. R ６ The compound according to claim 1, wherein is H.

9. R ４ The compound according to claim 1, wherein the C-bonded aryl or C-bonded heteroaryl is optionally substituted with one or more substituents independently selected from alkyl and halo.

10. R ４ but, v. C-bonded 6-membered aryl, vi. A 6-membered heteroaryl compound containing one or two nitrogen heteroatoms, optionally substituted with an alkyl or halo. vii. A 5-membered heteroaryl galace bond containing 1 to 3 heteroatoms independently selected from N, S, and O, which is optionally substituted with 1 to 2 substituents independently selected from alkyl and halo, and viiii. C-bonded 8-membered bicyclic heteroaryl system containing two N heteroatoms A compound according to claim 1, selected from the following.

11. R １ However, it is an alkoxy, R ２ However, it is a cyclopropyl substituted with halo, alkyl, haloalkyl, haloalkoxy, cyanoalkyl, cyanoalkoxy, or cyano. R ３ However, it is H or alkoxy, R ５ However, it is H, halo, alkyl, or haloalkyl, R ６ However, it is H or halo, R ４ However, the C-bonded aryl or C-bonded heteroaryl is optionally substituted with one or more substituents independently selected from alkyl and halo. The compound and pharmaceutically acceptable salt described in claim 1.

12. R １ However, it is an alkoxy, R ２ However, it is a cyclopropyl substituted with halo, alkyl, haloalkyl, haloalkoxy, cyanoalkyl, cyanoalkoxy, or cyano. R ３ However, it is H or alkoxy, R ５ However, it is H, halo, alkyl, or haloalkyl, R ６ However, it is H or halo, R ４ but, i. C-bonded 6-membered aryl, ii. A 6-membered heteroaryl compound containing one or two nitrogen heteroatoms, optionally substituted with an alkyl or halo. iii. A 5-membered heteroaryl with a carbon bond containing 1 to 3 heteroatoms independently selected from N, S, and O, which are optionally substituted with 1 to 2 substituents independently selected from alkyl and halo, and iv. C-bonded 8-membered bicyclic heteroaryl system containing two N heteroatoms Selected from, The compound and pharmaceutically acceptable salt described in claim 1.

13. 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-oxazole-2-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-pyridazine-3-yl-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-7-(1-methylimidazole-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-7-pyridazin-3-yl-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(1-methylimidazole-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(1-methylimidazole-2-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-6-fluoro-7-(1-methylimidazole-2-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-6-fluoro-7-(1-methylimidazole-2-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-7-pyridazin-3-yl-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-pyridazine-3-yl-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(4-methylpyridazine-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-oxazole-4-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-7-pyrazine-2-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-pyrazine-2-yl-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-7-(2-pyridyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(2-pyridyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-pyrazine-2-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-pyrazine-2-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-cyanocyclopropyl)-4,6-dimethoxypyrimidine-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-7-pyrazine-2-yl-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-6-fluoro-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-6-fluoro-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-Fluoro-N-[5-(2-fluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidine-2-yl]-6-fluoro-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-pyrazine-2-yl-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-6-fluoro-7-pyrazine-2-yl-1H-indole-3-sulfonamide; 6-Fluoro-N-[5-(2-Fluorethoxy)-4,6-Dimethoxypyrimidine-2-yl]-7-Pyrazine-2-yl-1H-Indole-3-Sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-6-fluoro-7-pyrazine-2-yl-1H-indole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidine-2-yl]-6-fluoro-7-pyrazine-2-yl-1H-indole-3-sulfonamide; 6-bromo-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-bromo-N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-bromo-N-[5-(2-fluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-bromo-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-7-pyrazine-2-yl-1H-indole-3-sulfonamide; 6-bromo-N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-pyrazine-2-yl-1H-indole-3-sulfonamide; 6-bromo-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-pyrazine-2-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(5-fluoropyrazine-2-yl)-1H-indole-3-sulfonamide; 6-bromo-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-7-pyridazin-3-yl-1H-indole-3-sulfonamide; 6-(difluoromethyl)-N-[5-(2-fluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-6-fluoro-7-(1H-imidazole-2-yl)-1H-indole-3-sulfonamide A compound according to claim 1, selected from the above, and a pharmaceutically acceptable salt thereof.

14. 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(1,5-dimethylimidazole-4-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(1-methylimidazole-4-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-6-methyl-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-6-(difluoromethyl)-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidine-2-yl]-6-(difluoromethyl)-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-6-(difluoromethyl)-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-6-methyl-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-7-(3-methylpyrazine-2-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(3-methylpyrazine-2-yl)-1H-indole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidine-2-yl]-6-methyl-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; N-[5-(2-fluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-6-methyl-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-6-methyl-7-pyridazin-3-yl-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-6-methyl-7-pyrazine-2-yl-1H-indole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidine-2-yl]-6-methyl-7-pyrazine-2-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-5-fluoro-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(1-methylpyrazole-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(2-methylpyrimidine-4-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(6-methylpyridazine-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-7-(3-chloropyrazine-2-yl)-N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidine-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-7-(3-chloropyrazine-2-yl)-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-7-(3-chloropyrazine-2-yl)-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(1-methylpyrazole-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(1-methylpyrazole-3-yl)-1H-indole-3-sulfonamide; 6-bromo-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(1-methylpyrazole-4-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-phenyl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-7-phenyl-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(3-methylpyrazine-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-7-(3-methylpyrazine-2-yl)-1H-indole-3-sulfonamide; N-(5-bromo-4,6-dimethoxypyrimidine-2-yl)-6-chloro-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-7-(4-pyrimidyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(4-pyrimidyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(cyanomethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-cyanoethyl)-4,6-dimethoxypyrimidine-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4-methoxypyrimidine-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(3-methylpyrazine-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-7-(5-methylpyrazine-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(5-methylpyrazine-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(5-methylpyrazine-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4,6-dimethoxy-5-methylpyrimidine-2-yl)-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-7-(6-methylpyrazine-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(6-methylpyrazine-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(6-methylpyrazine-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(5-pyrimidyl)-1H-indole-3-sulfonamide; 6-Chloro-7-(5-chloropyrazine-2-yl)-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-7-(5-chloropyrazine-2-yl)-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(6-methyl-2-pyridyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-7-(6-methyl-2-pyridyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(6-methyl-2-pyridyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-pyridazine-4-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(6-methylpyrimidine-4-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-7-(3-fluoropyrazine-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(3-fluoropyrazine-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(3-fluoropyrazine-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(3-methyl-2-pyridyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(1-methyltriazole-4-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-7-(3-methyl-2-pyridyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(3-methyl-2-pyridyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(1-methyl-1,2,4-triazole-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(5-fluoropyrimidine-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(2-methyltriazole-4-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(2-methyltriazole-4-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-7-(2-methyltriazole-4-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(2-methyltriazole-4-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(1,3,4-oxadiazole-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(1-methylpyrazole-4-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(1-methylpyrazole-4-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(1-methylpyrazole-4-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-7-(1-methylpyrazole-4-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-thiazole-4-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-oxazole-5-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-oxazole-5-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-isoxazole-4-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-isoxazole-4-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-thiazole-4-yl-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-7-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-3-yl)-1H-indole-3-sulfonamide A compound according to claim 1, selected from the above, and a pharmaceutically acceptable salt thereof.

15. 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-pyridazine-3-yl-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-7-(1-methylimidazole-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-7-pyridazin-3-yl-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(1-methylimidazole-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(1-methylimidazole-2-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-6-fluoro-7-(1-methylimidazole-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-oxazole-4-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-7-pyrazine-2-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-pyrazine-2-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-7-(2-pyridyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(2-pyridyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-pyrazine-2-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-pyrazine-2-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-bromo-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-bromo-N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-bromo-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-7-pyrazine-2-yl-1H-indole-3-sulfonamide; 6-bromo-N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-pyrazine-2-yl-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-pyrazine-2-yl-1H-indole-3-sulfonamide A compound according to claim 1, selected from the above, and a pharmaceutically acceptable salt thereof.

16. 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(1,5-dimethylimidazole-4-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(1-methylimidazole-4-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-6-methyl-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-7-(3-methylpyrazine-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(1-methylpyrazole-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(2-methylpyrimidine-4-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(6-methylpyridazine-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-7-(3-chloropyrazine-2-yl)-N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidine-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-7-(3-chloropyrazine-2-yl)-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(1-methylpyrazole-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(1-methylpyrazole-3-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(3-methylpyrazine-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-7-(3-methylpyrazine-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-7-(4-pyrimidyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(4-pyrimidyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(3-methylpyrazine-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-7-(5-methylpyrazine-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4,6-dimethoxy-5-methylpyrimidine-2-yl)-7-(2-pyrimidyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-7-(6-methylpyrazine-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(6-methylpyrazine-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(6-methylpyrazine-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(5-pyrimidyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(6-methyl-2-pyridyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-7-(6-methyl-2-pyridyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(6-methyl-2-pyridyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-pyridazine-4-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(6-methylpyrimidine-4-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-7-(3-fluoropyrazine-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(3-fluoropyrazine-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(3-fluoropyrazine-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(3-methyl-2-pyridyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(1-methyltriazole-4-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-7-(3-methyl-2-pyridyl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(2-methyltriazole-4-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-7-(2-methyltriazole-4-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(2-methyltriazole-4-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-(1,3,4-oxadiazole-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidine-2-yl]-7-thiazole-4-yl-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidine-2-yl]-7-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-3-yl)-1H-indole-3-sulfonamide A compound according to claim 1, selected from the above, and a pharmaceutically acceptable salt thereof.

17. A method for preparing a compound according to any one of claims 1 to 16, To provide a compound of formula I, react 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. 【Chemistry 2】 (In the formula, R １ , R ２ , R ３ , R ３ , R ４ , R ５ and R ６ (As stated above) Methods that include...

18. A compound according to any one of claims 1 to 16, for use as a therapeutically active substance.

19. A compound according to any one of claims 1 to 16 for use in the treatment of diseases regulated by GPR17.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16 and a therapeutically inert carrier.

21. A compound comprising the compound described in any one of claims 1 to 16, Pharmaceutical compositions for the treatment or prevention of symptoms resulting from inflammation in the CNS, such as, for example, encephalitis, primary vasculitis, meningitis, and post-obesity, as well as direct damage to the myelin sheath (including, but not limited to, central and extrapontine myelinolysis, carbon monoxide poisoning, malnutrition, and virus-induced demyelination), demyelinating disorders (including, but not limited to, multiple sclerosis, acute and polyphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorder, and leukodystrophy), CNS disorders associated with myelin loss (including, but not limited to, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and ischemia due to stroke).

22. A pharmaceutical composition for the treatment or prevention of multiple sclerosis, comprising a compound according to any one of claims 1 to 16.

23. Use of the compounds according to any one of claims 1 to 16 for the preparation of pharmaceuticals for the treatment or prevention of symptoms resulting from inflammation in the CNS, such as, for example, encephalitis, primary vasculitis, meningitis, and post-obesity, as well as for the treatment or prevention of, direct damage to the myelin sheath (including, but not limited to, central and extrapleural myelinolysis of the pontine sheath, carbon monoxide poisoning, malnutrition, and virus-induced demyelination), demyelinating disorders (including, but not limited to, multiple sclerosis, acute and polyphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorder, and leukodystrophy), CNS disorders associated with myelin loss (including, but not limited to, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and ischemia due to stroke).

24. A compound according to any one of claims 1 to 16 for use in treating or preventing symptoms resulting from inflammation in the CNS, such as, for example, encephalitis, primary vasculitis, meningitis, and post-obesity, as well as in direct damage to the myelin sheath (including, but not limited to, central and extrapontine myelinolysis, carbon monoxide poisoning, malnutrition, and virus-induced demyelination), demyelinating disorders (including, but not limited to, multiple sclerosis, acute and polyphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorder, and leukodystrophy), CNS disorders associated with myelin loss (including, but not limited to, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and ischemia due to stroke).

25. A compound according to any one of claims 1 to 16, for use in the treatment or prevention of multiple sclerosis.

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