Novel 7-substituted indole sulfonamide derivatives

Abstract

The present invention relates to a novel compound having the general formula (I) (wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are as described herein), a composition comprising the compound, and a method of using the compound. TIFF2025525012000179.tif37165

Description

Technical Field

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

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

Chemical formula

Chemical formula

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

[0004] Furthermore, the present invention includes, where applicable, all substituents of the corresponding deuterated forms of the compounds of formula (I).

Background Art

[0005] Myelination is a process that occurs reliably despite the abundant presence of oligodendrocyte progenitor cells (OPCs) throughout the developing and adult CNS. In chronic demyelinating diseases, the transition to myelinating oligodendrocytes and the production of reparative myelin sheaths around demyelinated axons are impaired. During development, myelination proceeds very orderly by OPCs characterized by the expression of markers such as neural / glial antigen 2 (NG2) and platelet-derived growth factor alpha (PDGFRα), and differentiates into oligodendrocytes that lose the expression of NG2 and PDGFRα and acquire the expression of markers such as myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG). Myelin production by oligodendrocytes is a very tightly controlled process, and in the CNS, this can be controlled by interactions with axons, which are well understood in the peripheral nervous system but not in the central nervous system (Macklin, W.B. (2010). Sci. Signal. 3, pe32-pe32, "The myelin brake: When Enough Is Enough"). Myelination can also be controlled by an internal brake within the oligodendrocytes themselves 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").

[0006] GPR17 is a class A orphan G protein - coupled receptor (GPCR). GPCRs are seven - transmembrane domain membrane - spanning proteins that couple extracellular ligands to intracellular signaling via intracellular association with small heterotrimeric G protein complexes consisting of G α 、G β 、G Υ subunits. The downstream intracellular signaling pathway is brought about by the coupling of the GPCR to the G α subunit. GPR17 is known to directly couple to G α i / o which results in the inhibition of adenylate cyclase activity and a decrease in cyclic AMP production (cAMP). GPR17 also targets phospholipase C via G q / 11has 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").

[0007] The role of GPR17 in myelination was first identified in a screen of the optic nerves of Olig1 knockout mice to identify genes that regulate myelination. GPR17 expression was found to be expressed only in myelinating cells of the CNS and not in Schwann cells, which are myelinating cells of the peripheral nervous system. The expression of GPR17 was found to be exclusively expressed in oligodendrocyte lineage cells and downregulated in myelinating oligodendrocytes (Chen, Y. et al. (2009)). Specifically, GPR17 expression was found to be present at low levels in the early stage of OPCs and increased in pre-myelinating oligodendrocytes before being downregulated in mature myelinating oligodendrocytes (Boda, E. et al. (2011), Glia 59, 1958 - 1973, "The GPR17 receptor in NG2 expressing cells: Focus on in vivo cell maturation and participation in acute trauma and chronic damage") (Dziedzic, A. et al. (2020). Int. J. Mol. Sci. 21, 1852, "The gpr17 receptor - a promising goal for therapy and a potential marker of the neurodegenerative process in multiple sclerosis") (Fumagalli, M. et al. (2011), J Biol Chem 286, 10593~10604, "Phenotypic changes, signaling pathway, and functional correlates of GPR17 - expressing neural precursor cells during oligodendrocyte differentiation").GPR17 knockout animals have been shown to exhibit premature myelination throughout the CNS. Conversely, transgenic mice overexpressing GPR17 in oligodendrocytes with the CNP-Cre (2’,3’-cyclic nucleotide 3’-phosphodiesterase) promoter exhibited hypomyelination defects, consistent with GPR17 being predicted to be a cell-intrinsic brake on the myelination process (Chen, Y. et al. (2009)). Furthermore, loss of GPR17 enhances remyelination after demyelination by lysophosphatidylcholine-induced demyelination (Lu, C., Dong et al. (2018), Sci. Rep. 8, 4502, "G-Protein-Coupled Receptor Gpr17 Regulates Oligodendrocyte Differentiation in Response to Lysolecithin-Induced Demyelination"). Thus, antagonism of GPR17, which promotes the differentiation of oligodendrocyte lineage cells into mature myelinating oligodendrocytes, will result in increased myelination after demyelination.

[0008] 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, due to the reparative effects of myelin repair on the CNS. Repair of lost myelin alleviates neurological symptoms associated with MS due to its neuroprotective effect of preserving axons.

[0009] Because myelin formation plays an essential role in the function of the nervous system, promoting the differentiation of OPCs into oligodendrocytes may affect white matter defects / irregularities resulting from either the loss of myelinating oligodendrocytes or the impairment of OPC differentiation into oligodendrocytes, which are observed in multiple diseases caused by the disease itself or inflammation. This is in addition to diseases in which the expression of GPR17 itself changes.

[0010] Diseases that may benefit from GPR17 antagonism to result in positive disease outcomes include, but are not limited to, the following: Direct damage to the myelin sheath: - Metabolic conditions that cause destruction of central nervous system myelin, such as, but not limited to, central pontine myelinolysis and extrapontine myelinolysis due to overly rapid correction of hyponatremia in conditions such as alcohol dependence, liver disease, and post-transplant immunosuppression - Carbon monoxide poisoning in which oligodendrocyte dysfunction and failure of regeneration have been reported in the deep white matter layer of the brain - Nutritional deficiencies that result in loss of myelin or failure of proper production of myelin during development - Virus-induced demyelination Primary demyelinating disorders - Multiple sclerosis (relapsing-remitting, secondary progressive, primary progressive, and progressive relapsing MS) - Acute disseminated encephalomyelitis and multiphasic disseminated encephalomyelitis - Neuromyelitis spectrum disorder including optic neuritis - Transverse myelitis - Leukodystrophies such as adrenoleukodystrophy, adrenomyeloneuropathy, and other hereditary leukodystrophies that result in myelin loss CNS disorders associated with related myelin loss: - Alzheimer's disease - Schizophrenia - Parkinson's disease - Huntington's disease - Amyotrophic lateral - Ischemia due to stroke Other diseases: - For example, encephalitis, primary angiitis, inflammation of the CNS after meningitis

[0011] The compound of formula I binds to GPR17 and modulates GPR17 activity.

[0012] Therefore, the compound of formula I is particularly useful for the treatment of diseases associated with GPR17 antagonism.

[0013] The compound of formula I is particularly useful for the treatment or prevention of multiple sclerosis (MS), symptoms associated with direct damage to the myelin sheath, such as carbon monoxide poisoning or virus-induced demyelination, primary demyelinating disorders, such as acute disseminated encephalomyelitis 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

[0014] The present invention relates to a novel compound of formula I

Chemical formula

Chemical formula

[0015] The term "alkyl" represents a monovalent straight-chain or branched saturated hydrocarbon group of 1 to 6 carbon atoms. In some embodiments, unless otherwise specified, alkyl is 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 particular alkyl group is methyl. When an alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons may be included. Thus, for example, "butyl" may include n-butyl, sec-butyl, isobutyl, and t-butyl, and "propyl" may include n-propyl and isopropyl. A particular example of alkyl is methyl.

[0016] 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, isobutoxy, and tert-butoxy. A particular example of "alkoxy" is methoxy.

[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 of haloalkyl are difluoromethyl, difluoroethyl, and difluoropropyl.

[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 of haloalkoxy are fluoroethoxy, difluoroethoxy, and difluoromethoxy. Other specific examples of haloalkoxy are trifluoroethoxy such as 1,1,2-trifluoroethoxy, and 2-fluoro-1,1-dimethyl-ethoxy.

[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. Specific examples of cyanoalkyl are cyanoethyl.

[0022] "Cyanoalkoxy" means a moiety of the formula -R'-R'' where R' is alkoxy as defined herein and R'' is cyano or nitrile. A specific 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. Bicyclic means consisting of two rings having one or two ring atoms in common. Examples of heteroaryl are pyrazolyl, imidazolyl, and triazolyl.

[0024] The term "N-linked heteroaryl" represents a heteroaryl system of up to 9 ring atoms in which the heteroaryl system is attached to the remainder of the molecule through an N-heteroatom.

[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. The 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, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts. Salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, salts of polyamine resins. The compounds of formula I can also exist in zwitterionic form. Particularly preferred pharmaceutically acceptable salts of the compounds of formula I are salts formed using formic acid and salts formed using hydrochloric acid that yield hydrochloride, dihydrochloride or trihydrochloride.

[0026] The abbreviation uM means micromole 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 sequence rules, an asymmetric carbon atom can have an "R" or "S" configuration.

[0031] Furthermore, the structures shown herein also mean that they include compounds that differ only in the presence of one or more isotope-enriched atoms. For example, one or more hydrogen atoms are replaced by deuterium ( 2 H), or one or more carbon atoms are replaced by 13 C or 14 C-enriched carbon, which is within the scope of the present invention.

[0032] One embodiment of the present invention also provides a compound according to formula I described herein and its pharmaceutically acceptable salts or esters, particularly a compound according to formula I described herein and its pharmaceutically acceptable salts, more specifically, a compound according to formula I described herein.

[0033] One embodiment of the present invention provides a compound according to formula I described herein, wherein R 1 is an alkoxy.

[0034] One embodiment of the present invention provides a compound according to formula I described herein, wherein R 2Provided are compounds of formula I as described herein, wherein R is cyclopropyl optionally substituted with halo, alkyl, haloalkyl, haloalkoxy, cyanoalkyl, cyanoalkoxy, or cyano.

[0035] One embodiment of the invention provides a compound of formula I as described herein, wherein R 2 is cyclopropyl substituted with haloalkyl, haloalkoxy, or cyano.

[0036] One embodiment of the invention provides a compound of formula I as described herein, wherein R 2 is haloalkoxy.

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

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

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

[0040] One embodiment of the invention provides a compound of formula I as described herein, wherein R 6 is H.

[0041] One embodiment of the invention provides a compound of formula I as described herein, wherein at least one but no more than two of A1, A2, A3, and A4 are N, and R y1 , R y2 , R y3 , and R y4 are independently selected from H, halo, and alkyl.

[0042] One embodiment of the present invention is at least one of A1, A2, A3, and A4, but two or less are N, and R y1 , R y2 , R y3 , and R y4 are independently selected from H and alkyl, and provides a compound according to formula I described herein.

[0043] One embodiment of the present invention is that R 4 is

Chemical formula

[0044] One embodiment of the present invention is that R 4 is

Chemical formula

[0045] One embodiment of the present invention is that R 4 is

Chemical formula

[0046] One embodiment of the present invention is that R 4 is

Chemical formula

[0047] One embodiment of the present invention is that R 4 is triazolyl, and provides a compound according to formula I described herein.

[0048] One embodiment of the present invention provides a compound of formula I as described herein, wherein R 4 is

Chem.

[0049] One embodiment of the present invention wherein R 1 is alkoxy; wherein R 2 is halo, alkyl, haloalkyl, haloalkoxy, cyanoalkyl, cyanoalkoxy, or cyclopropyl substituted with cyano; wherein R 3 is H or alkoxy; wherein R 5 is H, halo, alkyl, or haloalkyl; wherein R 6 is H or halo; wherein R<l 4 is heteroaryl linked by N or substituted heteroaryl linked by N, represented by the following

Chem.

[0050] One embodiment of the present invention wherein R 1is an 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

Chemical formula

[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; R 4 is

Chemical formula

[0052] One embodiment of the present invention is R 1 is alkoxy; R2 is haloalkoxy; R 3 is alkoxy; R 5 is halo; R 6 is H; R 4 is,

Chem.

[0053] One embodiment of the present invention is, R 1 is alkoxy or haloalkoxy; R 2 is halo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyanoalkyl, cyanoalkoxy, or cyclopropyl optionally substituted with up to 2 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 is heteroaryl linked by N or substituted heteroaryl linked by N represented by the following

Chem.

[0054] One embodiment of the present invention is, R 1 is alkoxy; R 2 is cyclopropyl optionally substituted with haloalkyl, haloalkoxy, or cyano; R 3 is H or alkoxy; R 5 is H, halo, alkyl, or haloalkyl; R 6 is H; R 4 is,

Chemical formula

[0055] One embodiment of the present invention is, R 1 is alkoxy; R 2 is cyclopropyl optionally substituted with haloalkyl, haloalkoxy, or cyano; R 3 is alkoxy; R 5 is H, halo, alkyl, or haloalkyl; R 6 is H; R 4 is,

Chemical formula

[0056] Specific examples of the compounds of formula I described herein are as follows: N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(3-methylpyrazol-1-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(3,5-dimethylpyrazol-1-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-imidazol-1-yl-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(2-methylimidazol-1-yl)-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-imidazol-1-yl-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-imidazol-1-yl-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(1,2,4-triazol-4-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,3-difluoropropyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(3,3-difluoropropyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-cyanocyclopropyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-Difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(2-Cyanocyclopropyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-Difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(2-Fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(Difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]--6-methyl-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-Difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(2-Cyanocyclopropyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2-cyanocyclopropyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-Difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-fluoro-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Fluoro-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(Difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-fluoro-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-Difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-fluoro-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(2-Cyanocyclopropyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-fluoro-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(1,2,4-triazol-1-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(4-methyltriazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(4-methyltriazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-1-yl)-1H-indole-3-sulfonamide; 6-(difluoromethyl)-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-7-(triazol-2-yl)-1H-indole-3-sulfonamide; and It is selected from pharmaceutically acceptable salts thereof.

[0057] Other 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-(4-methylpyrazol-1-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(3-methylpyrazol-1-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(4-fluoropyrazol-1-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(5-methylpyrazol-1-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(4-fluoropyrazol-1-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(4-fluoropyrazol-1-yl)-1H-indole-3-sulfonamide; N-[5-(Difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-7-pyrazol-1-yl-1H-indole-3-sulfonamide; N-[5-(2,2-Difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-(Difluoromethyl)-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; N-[5-(2,2-Difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(3-fluoropyrazol-1-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(3-fluoropyrazol-1-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(3-fluoropyrazol-1-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(3-fluoropyrazol-1-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[4,6-dimethoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoro-1,1-dimethyl-ethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(1,1-dideuterio-2,2-difluoro-ethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(cyanomethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4,6-dimethoxy-5-methyl-pyrimidin-2-yl)-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-(5-Bromo-4,6-dimethoxy-pyrimidin-2-yl)-6-chloro-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-fluoro-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[4,6-dimethoxy-5-(1,1,2,2-tetradeuterio-2-fluoro-ethoxy)pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(cyanomethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(1,1-dideuterio-2,2-difluoro-ethyl)-4-methoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-cyanocyclopropyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(1,1-dideuterio-2,2-difluoro-ethyl)-4-methoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-Difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; N-[5-(2-Fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Bromo-N-[4,6-dimethoxy-5-(1,1,2,2-tetradeuterio-2-fluoro-ethoxy)pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[4,6-dimethoxy-5-(1,1,2,2-tetradeuterio-2-fluoro-ethoxy)pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(1,1-dideuterio-2,2-difluoro-ethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; and are selected from its pharmaceutically acceptable salts.

[0058] Preferred examples of the compounds of formula I described herein are N-[5-(2,2-Difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(3,5-dimethylpyrazol-1-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(2-methylimidazol-1-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,3-difluoropropyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(3,3-difluoropropyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-cyanocyclopropyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(2-Fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(Difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]--6-methyl-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-Difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(2-Cyanocyclopropyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2-cyanocyclopropyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(4-methyltriazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(4-methyltriazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-1-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-Difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-7-(triazol-2-yl)-1H-indole-3-sulfonamide; and It is selected from pharmaceutically acceptable salts thereof.

[0059] Other preferred examples of the compounds of formula I described herein are 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(4-methylpyrazol-1-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(3-methylpyrazol-1-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(4-fluoropyrazol-1-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(5-methylpyrazol-1-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(4-fluoropyrazol-1-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(3-fluoropyrazol-1-yl)-1H-indole-3-sulfonamide; 6-chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(3-fluoropyrazol-1-yl)-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(3-fluoropyrazol-1-yl)-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(3-fluoropyrazol-1-yl)-1H-indole-3-sulfonamide; 6-chloro-N-[5-(cyanomethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-chloro-N-(4,6-dimethoxy-5-methyl-pyrimidin-2-yl)-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-(5-bromo-4,6-dimethoxy-pyrimidin-2-yl)-6-chloro-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[4,6-dimethoxy-5-(1,1,2,2-tetradeuterio-2-fluoro-ethoxy)pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(1,1-dideuterio-2,2-difluoro-ethyl)-4-methoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-cyanocyclopropyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(1,1-dideuterio-2,2-difluoro-ethyl)-4-methoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Bromo-N-[4,6-dimethoxy-5-(1,1,2,2-tetradeuterio-2-fluoro-ethoxy)pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[4,6-dimethoxy-5-(1,1,2,2-tetradeuterio-2-fluoro-ethoxy)pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(1,1-dideuterio-2,2-difluoro-ethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; and is selected from pharmaceutically acceptable salts thereof.

[0060] The most preferred examples of the compounds of formula I described herein are 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; and is selected from pharmaceutically acceptable salts thereof.

[0061] A method for producing the compounds of formula I described herein is an object of the present invention.

[0062] The present compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by the methods described below, which involve reacting a compound of formula III with a compound of formula II in the presence of a base selected from N-ethyldiisopropylamine, pyridine, potassium phosphate, or sodium hydride to obtain a compound of formula I

Chemical formula

[0063] General synthetic scheme The compound of formula I can be prepared according to the variations of the above methods and Scheme 1 below. The starting materials are either commercially available or can be prepared according to known methods. Scheme 1

Chemical formula

[0064] The compound of general formula I can be prepared by reacting sulfonyl chloride II with amine III in the presence of a base such as N - ethyldiisopropylamine, pyridine, potassium phosphate or sodium hydride. Furthermore, the compound of general formula I can be obtained by the reaction of the aforementioned amine III with sulfonyl chloride IV and a base, followed by the reaction of the resulting compound V with heterocycle VI using an appropriate palladium or copper catalyst and a base. The starting materials are either commercially available or can be prepared according to known methods or the methods described in the following schemes. Scheme 2

Chemical formula

[0065] The intermediate of formula II can be prepared by reacting compound VII with heterocycle VI using a suitable palladium or copper catalyst and a base, followed by reacting the resulting compound VIII with a chlorosulfonylating agent such as chlorosulfonic acid, or a sulfonylating agent such as sulfuric acid or sulfur trioxide N,N-dimethylformamide complex, and then chlorinating with a chlorinating agent such as thionyl chloride of the intermediate sulfonic acid. Further, the 2-fluoronitro derivative IX can be reacted with heterocycle VI and a base to form intermediate X, which can undergo a Bartoli reaction in the presence of vinylmagnesium bromide to produce compound VIII by an alternative route. Scheme 3

Chem.

[0066] R 2 The 2-amino-pyrimidine of formula IIIa where R is an alkoxy group can be prepared by deprotection of intermediate XIV in the presence of an acid such as trifluoroacetic acid, and P1 is a protecting group such as p-methoxy-benzyl, 3,4-dimethoxybenzyl or Boc group. XIV can be obtained by alkylation of alcohol XIII in the presence of a base such as cesium carbonate or potassium carbonate or sodium hydroxide or potassium hydroxide and an alkylating agent RX. Alcohol XIII can be prepared from the dihalogenated starting material XI by reacting XI with a protected amine to obtain intermediate XII, first converting this to a boronic acid ester, and then oxidizing in the presence of an oxidizing agent such as hydrogen peroxide. Scheme 4

Chem.

[0067] R 2The 2-amino-pyrimidines of formula IIIb where R is alkyl, alkenylalkyl, alkynyl, cyanoalkyl, cycloalkyl, heterocycloalkyl can be prepared by deprotection of intermediate XV in the presence of an acid such as trifluoroacetic acid, where P1 is a protecting group such as p-methoxy-benzyl or a Boc group. Compound XV can be obtained from intermediate XII under well-known metal-catalyzed cross-coupling reaction conditions. Scheme 5

Chemical formula

[0068] The 2-amino-pyrimidines of formula IIIc where R1 and R3 are alkoxy groups can be prepared by reaction of the halogenated starting material XVIII in the presence of a base such as alcohol and sodium hydride. Compound XVII can be prepared from malonic ester XVI by reaction with guanidine-hydrochloride in the presence of a base such as sodium methoxide to give intermediate XVII, which is then reacted with a halogenating agent such as phosphorus oxychloride to give the halogenated starting material XVIII.

[0069] Another embodiment of the invention provides a pharmaceutical composition or medicament containing a compound of the invention and a therapeutically inert carrier, diluent or excipient, and a method of using a compound of the invention for preparing such compositions and medicaments. In one example, a compound of formula I can be formulated into a galenical dosage form by mixing at ambient temperature, at a suitable 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 depends mainly on the particular use and the concentration of the compound, but is preferably somewhere in the range of about 3 to about 8. In one example, a compound of formula I is formulated in an acetate buffer at pH 5. In another embodiment, a compound of formula I is sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0070] The composition is formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered in this context include the specific disorder being treated, the specific mammal being treated, the clinical symptoms of the individual patient, the cause of the disorder, the site of drug delivery, the method of administration, the dosing schedule, and other factors known to medical professionals.

[0071] The compounds of the present invention can be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intralung, intradermal, intrathecal and epidural, and intranasal, and, when local treatment is desired, intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.

[0072] 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 conventional components in pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, fillers, and additional active agents.

[0073] 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, emulsifying agents, suspending agents, preservatives, antioxidants, opacifying agents, flow promoters, processing aids, coloring agents, sweetening agents, flavoring agents, perfuming agents, diluents and other known additives to provide an excellent appearance of the drug (i.e., the compound of the present invention or its pharmaceutical composition) or to assist in the manufacture of pharmaceuticals (i.e., medicaments).

[0074] The compounds of formula I and their pharmaceutically acceptable salts can be processed using pharmaceutically inert, inorganic or organic adjuvants for the manufacture 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 as such adjuvants for, for example, tablets, sugar-coated tablets and hard gelatin capsules.

[0075] Adjuvants suitable for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc.

[0076] Adjuvants suitable for the manufacture of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc.

[0077] Adjuvants suitable for injections are, for example, water, alcohol, polyol, glycerol, vegetable oil, etc.

[0078] Adjuvants suitable for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc.

[0079] Adjuvants suitable for topical ophthalmic preparations are, for example, cyclodextrin, mannitol or many other carriers and excipients known in the art.

[0080] Furthermore, the pharmaceutical preparation can contain preservatives, solubilizers, viscosity increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for changing the osmotic pressure, buffers, masking agents or antioxidants. These can also contain further therapeutically valuable substances.

[0081] The dosage can vary within a wide range and, of course, is adapted to the individual requirements in each particular case. Generally, in the case of oral administration, a daily dosage of about 0.1 mg to 20 mg per kg of body weight, preferably about 0.5 mg to 4 mg per kg of body weight (for example, about 300 mg per person), is preferably divided into 1 to 3 individual administrations, which can, if appropriate, consist of, for example, the same amounts. In the case of topical administration, the preparation can contain 0.001 wt% to 15 wt% of the medicament, and the required dosage, which can be between 0.1 and 25 mg, can be administered either by a single administration per day or per week, or by multiple administrations per day (2 to 4 times), or by multiple administrations per week. However, it will be obvious that this can exceed the upper or lower limits given herein if so indicated.

[0082] The present invention also particularly relates 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 diseases regulated by GPR17;

[0083] Similarly, an object of the present invention is a pharmaceutical composition comprising a compound according to formula I described herein and a therapeutically inert carrier.

[0084] Use of a compound of formula I for treating or preventing symptoms resulting from inflammation of the CNS, such as, for example, encephalitis, primary vasculitis, meningitis and post-obesity, direct damage to the myelin sheath (including, but not limited to, central pontine myelinolysis and extrapontine myelinolysis, carbon monoxide poisoning, nutritional deficiencies, and virus-induced demyelination), demyelinating disorders (including, but not limited to, multiple sclerosis, acute disseminated encephalomyelitis 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).

[0085] One embodiment of the present invention is the use of a compound of formula I for treating or preventing multiple sclerosis, Alzheimer's disease, Parkinson's disease, or Huntington's disease.

[0086] A particular embodiment of the present invention is the use of a compound of formula I for treating or preventing multiple sclerosis.

[0087] Use of a compound of formula I for preparing a medicament for treating or preventing symptoms resulting from inflammation of the CNS, such as, for example, encephalitis, primary vasculitis, meningitis and post-obesity, direct damage to the myelin sheath (including, but not limited to, central pontine myelinolysis and extrapontine myelinolysis, carbon monoxide poisoning, nutritional deficiencies, and virus-induced demyelination), demyelinating disorders (including, but not limited to, multiple sclerosis, acute disseminated encephalomyelitis 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).

[0088] One embodiment of the present invention is the use of a compound of formula I for preparing a medicament for treating or preventing multiple sclerosis, Alzheimer's disease, Parkinson's disease, or Huntington's disease.

[0089] A particular embodiment of the present invention is the use of a compound of formula I for preparing a medicament for treating or preventing multiple sclerosis.

[0090] A compound according to formula I for use in the treatment or prevention of symptoms resulting from inflammation of the CNS, such as, for example, encephalitis, primary vasculitis, meningitis and post-obesity, and direct damage to the myelin sheath (including, but not limited to, central pontine myelinolysis and extrapontine myelinolysis, carbon monoxide poisoning, nutritional deficiencies, and virus-induced demyelination), demyelinating disorders (including, but not limited to, multiple sclerosis, acute disseminated encephalomyelitis 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).

[0091] One embodiment of the present 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.

[0092] A particular embodiment of the present invention is a compound according to formula I for use in the treatment or prevention of multiple sclerosis.

[0093] Methods for treating or preventing symptoms resulting from direct damage to myelin sheaths (including, but not limited to, central pontine myelinolysis and extrapontine myelinolysis, carbon monoxide poisoning, nutritional deficiencies, and virus-induced demyelination), demyelinating disorders (including, but not limited to, multiple sclerosis, acute disseminated encephalomyelitis and multiphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorder, and leukodystrophy), CNS disorders associated with myelin loss (including, but not limited to, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and ischemia due to stroke), and, for example, encephalitis, primary vasculitis, meningitis, and post-obesity, CNS inflammation, the method comprising administering an effective amount of a compound of formula I to a patient in need thereof.

[0094] One embodiment of the invention is a method for treating or preventing multiple sclerosis, Alzheimer's disease, Parkinson's disease, or Huntington's disease, the method comprising administering an effective amount of a compound of formula I to a patient in need thereof.

[0095] A particular embodiment of the invention is a method for treating or preventing multiple sclerosis, the method comprising administering an effective amount of a compound of formula I to a patient in need thereof.

[0096] Also provided is a compound of formula I described herein when manufactured according to any one of the methods described.

[0097] 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.

[0098] 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 the competitive binding of ruthenium-labeled cAMP and endogenous cAMP to an anti-cAMP monoclonal antibody labeled with time-resolved fluorescence energy transfer (TR-FRET) and 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.

[0099] CHO-GPR17S cells were detached with Accutase and resuspended in an assay buffer consisting of Hank's balanced salt solution (HBSS), 10 mM HEPES (4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid solution), and 0.1% bovine serum albumin (pH 7.4). Cells were seeded into black 384-well plates (Corning) at a density of 10,000 cells / 20 μl assay buffer until the addition of the compound.

[0100] The test antagonist compound was serially diluted with dimethyl sulfoxide (DMSO) and spotted onto 384-well plates. The compound was then diluted in HBSS buffer supplemented with MDL29,951 (3-(2-carboxy-4,6-dichlorophenyl)-propionic acid) (GPR17 agonist) at the EC80 concentration + 3-isobutyl-1-methylxanthine (IBMX) (final concentration 0.5 mM) and added to the cells at room temperature. Forskolin (final concentration 15 μM) was added 5 minutes after the test compound, and the cells were incubated at room temperature for 30 minutes. The assay was stopped by adding the cAMP detection mixture (containing a surfactant for cell lysis) at room temperature for 90 minutes.

[0101] Cell cAMP 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).

[0102] The results of the hGPR17 cAMP assay are provided for the compounds of formula I in Table 1.

Table 1

[0103] The present invention will now be described by the following examples which have no limiting features.

[0104] When a 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.

Examples

[0105] Unless otherwise specified, all examples and intermediates were prepared under a nitrogen atmosphere.

[0106] Intermediate A Intermediate A1: 7-(2-Methylimidazol-1-yl)-1H-indole-3-sulfonyl chloride

Chemical formula

[0107] Step 1: 7-(2-Methylimidazol-1-yl)-1H-indole

Chemical formula

[0108] Step 2: 7-(2-Methylimidazol-1-yl)-1H-indole-3-sulfonyl chloride

Chemical formula

[0109] Intermediate A2: 6-chloro-7-(triazol-2-yl)-1H-indole-3-sulfonyl chloride

Chemical formula

[0110] Step 1: 2-(2-chloro-6-nitro-phenyl)triazole and 1-(2-chloro-6-nitro-phenyl)triazole

Chemical formula

[0111] Step 2: 6-chloro-7-(triazol-2-yl)-1H-indole

Chemical formula

[0112] Process 3: 6-Chloro-7-(triazol-2-yl)-1H-indole-3-sulfonyl chloride

Chem.

[0113] Intermediate A3: 6-Chloro-7-imidazol-1-yl-1H-indole-3-sulfonyl chloride

Chem.

[0114] Intermediate A4: 6-Chloro-7-(triazol-1-yl)-1H-indole-3-sulfonyl chloride

Chem.

[0115] Intermediate A5: 6-(Difluoromethyl)-7-(triazol-2-yl)-1H-indole-3-sulfonyl chloride

Chem.

[0116] Step 1: 1-(Difluoromethyl)-2-fluoro-3-nitro-benzene

Chem.

[0117] Step 2: 2-[2-(Difluoromethyl)-6-nitro-phenyl]triazole

Chem.

[0118] Step 3: 6-(Difluoromethyl)-7-(triazol-2-yl)-1H-indole

Chemical Structure

[0119] Step 4: 6-(Difluoromethyl)-7-(triazol-2-yl)-1H-indole-3-sulfonyl chloride [Chemical formula] A solution of 6-(difluoromethyl)-7-(1,2,3-triazol-2-yl)-1H-indole (180 mg, 769 μmol) in acetonitrile (12 mL) was cooled to 0 °C, and chlorosulfonic acid (269 mg, 154 μL, 2.31 mmol) was added. The ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. Phosphorus oxychloride (471 mg, 286 μL, 3.07 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into ice and water and extracted twice with ethyl acetate. The combined organic layers were washed with ice and brine, dried over sodium sulfate and concentrated in vacuo to give the title compound (202 mg, 79% yield) as a brown semi-solid. MS (ESI) m / z = 331.1 [M-H] -

[0120] Intermediate A6: 7-(1,2,3-triazol-2-yl)-1H-indole-3-sulfonyl chloride [Chemical formula] The title compound was prepared as a purple solid in the same manner as Intermediate A2 from 2-fluoro-3-nitrobenzene instead of 1-chloro-2-fluoro-3-nitrobenzene in Step 1). MS (ESI) m / z = 281.0 [M-H] -

[0121] Intermediate A7: 6-methyl-7-(1,2,3-triazol-2-yl)-1H-indole-3-sulfonyl chloride [Chemical formula] The title compound was prepared as a purple solid in the same manner as Intermediate A2 from 2-fluoro-1-methyl-3-nitrobenzene instead of 1-chloro-2-fluoro-3-nitrobenzene in Step 1). MS (ESI) m / z = 295.0 [M-H] -

[0122] Intermediate A8: 6-Bromo-7-(triazol-2-yl)-1H-indole-3-sulfonyl chloride

Chem.

[0123] Intermediate A9: 6-Fluoro-7-(triazol-2-yl)-1H-indole-3-sulfonyl chloride

Chem.

[0124] Intermediate A10: 6-Chloro-7-(1,2,4-triazol-1-yl)-1H-indole-3-sulfonyl chloride

Chem.

[0125] Step 1: 4-(2-Chloro-6-nitro-phenyl)-1,2,4-triazole and 4-(2-Chloro-6-nitro-phenyl)-1,2,4-triazole

Chem.

[0126] Step 2: 6-Chloro-7-(1,2,4-triazol-1-yl)-1H-indole

Chemical formula

[0127] Step 3: 6-Chloro-7-(1,2,4-triazol-1-yl)-1H-indole-3-sulfonyl chloride

Chemical formula

[0128] Intermediate A11: 6-Chloro-7-(1,2,4-triazol-4-yl)-1H-indole-3-sulfonyl chloride

Chemical formula

[0129] Intermediate A12: 6-Chloro-7-(4-methyltriazol-2-yl)-1H-indole-3-sulfonyl chloride [Chemical formula]

[0130] Process 1: 2-(2-Chloro-6-nitro-phenyl)-4-methyl-triazole [Chemical formula] A solution of 1-chloro-2-fluoro-3-nitro-benzene (447 mg, 0.300 ml, 2.55 mmol) and 4-methyl-1H-triazole (254 mg, 3.06 mmol) in acetonitrile (6 ml) was cooled to 0 °C. Cesium carbonate (1.66 g, 5.09 mmol) was added, the ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate, the solid was filtered off and washed with ethyl acetate. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 0% - 50% ethyl acetate in heptane) to give 2-(2-chloro-6-nitro-phenyl)-4-methyl-triazole (258 mg, 42%) as an off-white solid. MS(ESI) m / z = 239.0 [M+H] +

[0131] Process 2: 6-Chloro-7-(4-methyltriazol-2-yl)-1H-indole-3-sulfonyl chloride The title compound was prepared as an off-white solid in the same manner as Intermediate A10 from 2-(2-chloro-6-nitro-phenyl)-4-methyl-triazole instead of 1-(2-chloro-6-nitro-phenyl)-1,2,4-triazole in step 2). MS(ESI) m / z = 329.0 [M-H] -

[0132] Intermediate A13: 6-Chloro-7-pyrazol-1-yl-1H-indole-3-sulfonyl chloride [Chemical formula]

[0133] Project 1: 1-(2-Chloro-6-nitro-phenyl)pyrazole

Chem.

[0134] Project 2: 6-Chloro-7-pyrazol-1-yl-1H-indole

Chem.

[0135] Step 3: 6-Chloro-7-pyrazol-1-yl-1H-indole-3-sulfonyl chloride [Chemical formula] A solution of 6-chloro-7-pyrazol-1-yl-1H-indole (2.54 g, 11.5 mmol) in acetonitrile (60 ml) was cooled to 0 °C. Chlorosulfonic acid (1.75 g, 1.01 ml, 15.02 mmol) was added. The ice bath was removed and the reaction mixture was stirred at room temperature for 2 hours. Phosphorus oxychloride (7.09 g, 4.31 ml, 46.2 mmol) was added and the reaction mixture was stirred at 60 °C overnight. The reaction mixture was poured into ice and water and extracted with ethyl acetate. The organic layer was washed with ice and brine, dried over Na2SO4 and concentrated in vacuo to give the title compound (1.35 g, yield 28%) as a brown solid, MS (ESI) m / z: 315.9 [M+H] + .

[0136] Intermediate A14: 6-Bromo-7-pyrazol-1-yl-1H-indole-3-sulfonyl chloride [Chemical formula] The title compound was prepared as a light brown solid in the same manner as Intermediate A13 from 1-bromo-2-fluoro-3-nitro-benzene instead of 1-chloro-2-fluoro-3-nitro-benzene in Step 1). MS (ESI) m / z: 361.9 [M+H] + .

[0137] Intermediate A15: 6-Methyl-7-pyrazol-1-yl-1H-indole-3-sulfonyl chloride [Chemical formula] The labeled compound was prepared as a pale yellow solid in the same manner as Intermediate A13 from 2-fluoro-1-methyl-3-nitro-benzene instead of 1-chloro-2-fluoro-3-nitro-benzene in Step 1). MS(ESI) m / z: 296.1 [M+H] + 。

[0138] Intermediate A16: 6-chloro-5-fluoro-7-(triazol-2-yl)-1H-indole-3-sulfonyl chloride

Chem.

[0139] Intermediate A17: 6-chloro-7-(5-methylpyrazol-1-yl)-1H-indole-3-sulfonyl chloride

Chem.

[0140] Intermediate A18: 6-chloro-7-(3-methylpyrazol-1-yl)-1H-indole-3-sulfonyl chloride

Chem.

[0141] Intermediate A19: 6-chloro-7-(4-fluoropyrazol-1-yl)-1H-indole-3-sulfonyl chloride

Chemical formula

[0142] Intermediate A20: 6-chloro-7-(4-methylpyrazol-1-yl)-1H-indole-3-sulfonyl chloride

Chemical formula

[0143] Intermediate A21: 6-chloro-7-(3-fluoropyrazol-1-yl)-1H-indole-3-sulfonyl chloride

Chemical formula

[0144] Intermediate A22: 6-(difluoromethyl)-7-pyrazol-1-yl-1H-indole-3-sulfonyl chloride

Chem.

[0145] Intermediate B Intermediate B1: 5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-amine

Chem.

[0146] Step 1: Diethyl 2-(2,2-difluoroethyl)propanedioate

Chem.

[0147] Step 2: 2-Amino-5-(2,2-difluoroethyl)pyrimidine-4,6-diol

Chemical Structure

[0148] Step 3: 4,6-Dichloro-5-(2,2-difluoroethyl)pyrimidin-2-amine

Chemical Structure

[0149] Step 4: 5-(2,2-Difluoroethyl)-4,6-dimethoxypyrimidin-2-amine

Chem.

[0150] Intermediate B2: 5-(2-Fluoroethoxy)-4-methoxypyrimidin-2-amine

Chem.

[0151] Step 1: [4-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]-bis(p-anisyl)amine

Chem.

[0152] Step 2: 2-[Bis(p-anisyl)amino]-4-methoxy-pyrimidin-5-ol [Chemical formula] A solution of [4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]-bis(p-anisyl)amine (130 mg, 0.265 mmol) in tetrahydrofuran (2.5 mL) was cooled to 0 °C. 35% Hydrogen peroxide (500 μL, 5.71 mmol) was added. The reaction mixture was stirred at 0 °C for 15 minutes, warmed to room temperature and stirred for 3 hours. The reaction mixture was poured into cold 0.1 N sodium sulfite solution and extracted twice with EtOAc. The organic layer was washed twice with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as a pale yellow viscous oil (103 mg, 100% yield). MS(ESI): m / z = 382.3 [M+H] +

[0153] Step 3: [5-(2-Fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-bis(p-anisyl)amine [Chemical formula] A suspension of 2-[bis(p-anisyl)amino]-4-methoxy-pyrimidin-5-ol (100 mg, 0.236 mmol), potassium carbonate (98.82 mg, 0.708 mmol) and 1-bromo-2-fluoroethane (61.14 mg, 35.75 uL, 0.472 mmol) in acetonitrile (2.5 mL) was stirred at room temperature for 15 minutes and at 80 °C for 6 hours. The reaction mixture was poured into water and extracted twice with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography using a gradient of ethyl acetate / heptane 0 - 30% to give the title compound as a colorless viscous oil (22 mg, 22% yield). MS (ESI): m / z = 428.3 [M+H] +

[0154] Step 4: [5-(2-Fluoroethoxy)-4-methoxy-pyrimidin-2-yl]amine [Chemical formula] A solution of [5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-bis(p-anisyl)amine (87 mg, 0.204 mmol) in dichloromethane (500 uL) was cooled to 0 °C. Trifluoroacetic acid (1.41 g, 944.56 uL, 12.21 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 16 hours and at 55 °C for a further 2 hours. The resulting purple solution was poured into saturated aqueous sodium bicarbonate and extracted twice with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography using a gradient of ethyl acetate / heptane 0 - 100% to give the title compound as an off-white solid (27 mg, 71% yield). MS (ESI): m / z = 188.1 [M+H]+

[0155] Intermediate B3: 5-(2,2-Difluoroethyl)-4-methoxy-pyrimidin-2-amine

Chem.

[0156] Step 1: (5-Bromo-4-methoxypyrimidin-2-yl)-bis(p-anisyl)amine

Chem.

[0157] Step 2: 5-[(E)-2-Ethoxyvinyl]-4-methoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine

Chem.

[0158] Step 3: 2-[2-[Bis[(4-methoxyphenyl)methyl]amino]-4-methoxy-pyrimidin-5-yl]acetaldehyde

Chemical Structure

[0159] Step 4: 4,5-(2,2-Difluoroethyl)-4-methoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine

Chem.

[0160] Step 5: 5-(2,2-Difluoroethyl)-4-methoxy-pyrimidin-2-amine

Chem.

[0161] Intermediate B4: 5-(2,2-Difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-amine

Chemical formula

[0162] Step 1: 5-Bromo-4,6-dimethoxy-pyrimidin-2-amine

Chemical formula

[0163] Step 2: 5-Bromo-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine [Chemical formula] 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, stirred for 1 hour, carefully quenched with saturated ammonium chloride solution, poured into water, and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography using a gradient of ethyl acetate / heptane 0 - 20% to give the title compound as a white solid (1.11 g, 100% yield). MS (ESI): m / z = 476.2 [M+H] +

[0164] Step 3: 2-[Bis[(4-methoxyphenyl)methyl]amino]-4,6-dimethoxypyrimidin-5-ol [Chemical formula] To a colorless solution of 5-bromo-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine (500 mg, 1 mmol) in tetrahydrofuran (3.5 mL) was added dropwise a 1.6 M solution of n-butyllithium in hexane (699.71 mg, 813.61 uL, 1.3 mmol) at -78 °C. The resulting yellow solution was stirred at -78 °C for 30 minutes. Trimethyl borate (156.08 mg, 167.47 uL, 1.5 mmol) was added dropwise and stirring was continued at -78 °C for 1.5 hours. The reaction mixture was warmed to 0 °C and acetic acid (120.27 mg, 114.62 uL, 2 mmol) and subsequently 35% hydrogen peroxide (145.98 mg, 131.51 uL, 1.5 mmol) were added dropwise. Stirring was continued at 0 °C for 1.5 hours. The resulting pink suspension was poured into 0.1 N sodium thiosulfate solution and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography using a gradient of ethyl acetate / heptane 0 - 30% to give the title compound as a pale yellow viscous oil (194 mg, 47% yield). MS (ESI): m / z = 412.3 [M+H] +

[0165] Step 4: 5-(2,2-Difluoroethoxy)-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine

Chemical formula

[0166] Step 5: 5 - (2,2 - Difluoroethoxy)-4,6 - dimethoxy - pyrimidin - 2 - amine

Chemical Structure

[0167] Intermediate B5: 5 - (2 - Fluoroethoxy)-4,6 - dimethoxy - pyrimidin - 2 - amine [Chemistry]

[0168] Process 1: 5-(2-Fluoroethoxy)-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine [Chemistry] A suspension of 2-[bis[(4-methoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-ol (2 g, 4.52 mmol, Intermediate B4, Process 3), potassium carbonate (1.89 g, 13.56 mmol), and 1-bromo-2-fluoroethane (1.76 g, 1.03 mL, 13.56 mmol) in N,N-dimethylformamide (45 mL) was heated to 80 °C and stirred for 2.5 hours. The reaction mixture was poured into brine and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography using a gradient of ethyl acetate / heptane 0 - 30% to give the title compound as a white solid (1.79 g, 85% yield). MS (ESI): m / z = 458.3 [M+H] +

[0169] Process 2: 5-(2-Fluoroethoxy)-4,6-dimethoxypyrimidin-2-amine [Chemistry] A stirred solution of 5-(2-fluoroethoxy)-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine (1.79 g, 3.83 mmol) in dichloromethane (4 mL) was treated with trifluoroacetic acid (26.23 g, 17.62 mL, 230.06 mmol). The reaction mixture was stirred at 50 °C for 3 h and at room temperature for 15 h, then concentrated in vacuo. The residue was poured into saturated NaHCO3 and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by silica gel flash chromatography using a gradient of ethyl acetate / heptane 0 - 60% afforded the title compound as an off-white solid (885 mg, 100% yield). MS (ESI): m / z = 218.1 [M+H] +

[0170] Intermediate B6: 5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-amine

Chemical Structure

[0171] Step 1: 5-(difluoromethoxy)-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine

Chemical Structure

[0172] Step 2: 5 - (Difluoromethoxy)-4,6 - dimethoxypyrimidin - 2 - amine

Chemical Structure

[0173] Intermediate B7: 5-(2,3-Difluoropropyl)-4,6-dimethoxy-pyrimidin-2-amine

Chem.

[0174] Step 1: 5-Allyl-4,6-dimethoxypyrimidin-2-amine

Chem.

[0175] Step 2: 5-Allyl-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine

Chem.

[0176] Step 3: 3-[2-[Bis[(4-methoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-yl]propane-1,2-diol

Chemical Structure

[0177] Step 4: 4,5-Bis[(4-methoxyphenyl)methyl]-2-(2,3-difluoropropyl)-4,6-dimethoxypyrimidin-2-amine

Chem.

[0178] Step 5: 5-(2,3-Difluoropropyl)-4,6-dimethoxypyrimidin-2-amine

Chem.

[0179] Intermediate B8: 5-(3,3-Difluoropropyl)-4,6-dimethoxypyrimidin-2-amine

Chem.

[0180] Step 1: Diethyl 2-(3,3-difluoropropyl)propanedioate

Chem.

[0181] Step 2: 2-Amino-5-(3,3-difluoropropyl)pyrimidine-4,6-diol

Chem.

[0182] Step 3: 4,6-Dichloro-5-(3,3-difluoropropyl)pyrimidin-2-amine

Chemical formula

[0183] Step 4: 5-(3,3-Difluoropropyl)-4,6-dimethoxypyrimidin-2-amine

Chem.

[0184] Intermediate B9: 2-(2-Amino-4,6-dimethoxypyrimidin-5-yl)cyclopropanecarbonitrile

Chem.

[0185] Step 1: N,N-Bis[(2,4-dimethoxyphenyl)methyl]-4,6-dimethoxypyrimidin-2-amine

Chem.

[0186] Step 2: N,N-bis[(2,4-dimethoxyphenyl)methyl]-5-iodo-4,6-dimethoxypyrimidin-2-amine

Chemical Structure

[0187] Step 3: (E)-3-[2-[Bis[(2,4-dimethoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-yl]prop-2-enenitrile

Chemical Structure

[0188] The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1:0 to 5:1) to obtain (E)-3-[2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-yl]prop-2-enenitrile (7.5 g, yield 96%) as a brown solid. MS(ESI): m / z = 507.3 [M+H] +

[0189] Step 4: 2-[2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-yl]cyclopropanecarbonitrile

Chemical formula

[0190] Step 5: 2-(2-amino-4,6-dimethoxy-pyrimidin-5-yl)cyclopropanecarbonitrile [Chem.] To a solution of 2-[2-[[bis[(2,4-dimethoxyphenyl)methyl]amino]-4,6-dimethoxypyrimidin-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] +

[0191] Intermediate B10: 4,6-Dimethoxy-5-methylpyrimidin-2-amine [Chem.] Intermediate B10 is known (CAS 341009-90-3).

[0192] Intermediate B11: 5-Bromo-4,6-dimethoxypyrimidin-2-amine [Chem.] A solution of (4,6-dimethoxypyrimidin-2-yl)amine (7 g, 44.2 mmol, CAS: 36315-01-2) in acetonitrile (100 ml) was stirred, and a solution of N-bromosuccinimide (10.3 g, 57.5 mmol) in acetonitrile (100 ml) was added dropwise thereto 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 in vacuo. The precipitate was filtered off 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] +

[0193] Intermediate B12: 3-(2-amino-4,6-dimethoxy-pyrimidin-5-yl)propanenitrile

Chemical formula

[0194] Step 1: 3-[2-[Bis[(4-methoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-yl]propanenitrile

Chemical formula

[0195] Step 2: 3-(2-Amino-4,6-dimethoxy-pyrimidin-5-yl)propanenitrile [Chemical formula] A mixture of 3-[2-[bis[(4-methoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-yl]propanenitrile (2300 mg, 5.13 mmol) in trifluoroacetic acid (23 ml) was stirred at 25 °C for 48 h, quenched with ice / saturated NaHCO3 solution and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by flash chromatography (silica gel, ethyl acetate / petroleum ether 0 - 100%) gave the title compound as a yellow solid (1000 mg, 89% yield). MS (ESI): m / z = 209.0 [M+H] +

[0196] Intermediate B13: 2-(2-Amino-4,6-dimethoxy-pyrimidin-5-yl)oxyacetonitrile

Chemical formula

[0197] Step 1: 2-[2-[Bis[(4-methoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-yl]oxyacetonitrile

Chemical formula

[0198] Step 2: 2-(2-Amino-4,6-dimethoxy-pyrimidin-5-yl)oxyacetonitrile

Chemical formula

[0199] Intermediate B14: 4,6-Dimethoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-amine

Chem.

[0200] Intermediate B15: 5-(2-Fluoro-1,1-dimethyl-ethoxy)-4,6-dimethoxy-pyrimidin-2-amine

Chem.

[0201] Step 1: Ethyl 2-[2-[bis[(4-methoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-yl]oxy-2-methyl-propanoate

Chem.

[0202] Step 2: 2 - [2 - [bis[(4 - methoxyphenyl)methyl]amino]-4,6 - dimethoxypyrimidin - 5 - yl]oxy - 2 - methyl - propan - 1 - ol [Chemical formula] A solution of ethyl 2-[2-[bis[(4-methoxyphenyl)methyl]amino]-4,6-dimethoxypyrimidin-5-yl]oxy-2-methylpropanoate (748 mg, 1.38 mmol) in tetrahydrofuran (12 ml) was cooled to 0 °C. Then, 1M lithium tetrahydroaluminate in THF (1.88 g, 2.07 ml, 2.07 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 4.5 hours. The reaction mixture was quenched with an NH4Cl solution, poured into brine, and extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give 2-[2-[bis[(4-methoxyphenyl)methyl]amino]-4,6-dimethoxypyrimidin-5-yl]oxy-2-methylpropan-1-ol (728 mg, 100%) as a colorless oil. MS(ESI) m / z: 483.3 [M+H] + .

[0203] Step 3: 5-(2-Fluoro-1,1-dimethylethoxy)-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine

Chemical formula

[0204] Step 4: 5-(2-Fluoro-1,1-dimethylethoxy)-4,6-dimethoxypyrimidin-2-amine [Chemical formula] A stirred solution of 5-(2-fluoro-1,1-dimethyl-ethoxy)-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine (135 mg, 228 μmol) in dichloromethane (2 ml) was slowly added trifluoroacetic acid (3.12 g, 2.0 ml, 27.36 mmol) at 0 °C. The ice bath was removed and the reaction mixture was stirred at room temperature for 40 h. The reaction mixture was carefully poured into saturated NaHCO3 solution and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0% - 40% ethyl acetate in heptane in 15 min), followed by reverse phase flash column chromatography (C18 15 g, 0% - 100% acetonitrile in water) to give 5-(2-fluoro-1,1-dimethyl-ethoxy)-4,6-dimethoxy-pyrimidin-2-amine (27 mg, 48%) as a white powder. MS(ESI) m / z: 246.2 [M+H] + 。

[0205] Intermediate B16: 4,6-Dimethoxy-5-(1,1,2,2-tetradeuterio-2-fluoro-ethoxy)pyrimidin-2-amine

Chemical formula

[0206] Step 1: N,N-Bis[(2,4-dimethoxyphenyl)methyl]-4,6-dimethoxy-pyrimidin-2-amine

Chemical formula

[0207] Step 2: 5-Bromo-N,N-bis[(2,4-dimethoxyphenyl)methyl]-4,6-dimethoxypyrimidin-2-amine

Chemical Structure

[0208] Step 3: 2-[Bis[(2,4-dimethoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-ol [Chemical formula] A solution of 5-bromo-N,N-bis[(2,4-dimethoxyphenyl)methyl]-4,6-dimethoxy-pyrimidin-2-amine (33.0 g, 61.75 mmol) in THF (650 ml) was added with n-BuLi (2.5 N in hexane, 32.1 ml, 80.28 mmol) at -70 °C. The mixture was stirred at -70 °C for 0.5 h. Then, trimethyl borate (13.8 ml, 123.5 mmol) was added at -70 °C and the mixture was stirred at -70 °C for 2 h. The mixture was warmed to 0 °C and acetic acid (7.84 ml, 135.8 mmol) and hydrogen peroxide (13.87 ml, 135.8 mmol) were added at 0 °C. The mixture was stirred at 20 °C for 2 h. After completion of the reaction, the mixture was quenched with an aqueous solution of sodium sulfite (500 ml), stirred at 20 °C for 0.5 h, and extracted with ethyl acetate (20 ml × 2). The combined organic layers were washed with brine (20 ml × 2), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography using a gradient of ethyl acetate / ether 0 - 50% to give the title compound as a yellow oil (23.8 g, yield 76%). MS(ESI): m / z = 472.3 [M + H]+

[0209] Step 4: [2-[2-[Bis[(2,4-dimethoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-yl]oxy-1,1,2,2-tetradeuterio-ethyl]-4-methylbenzenesulfonate

Chemical formula

[0210] Step 5: N,N - bis[(2,4 - dimethoxyphenyl)methyl]-4,6 - dimethoxy - 5-(1,1,2,2 - tetradeuterio - 2 - fluoro - ethoxy)pyrimidin - 2 - amine

Chem.

[0211] Step 6: 4,6-Dimethoxy-5-(1,1,2,2-tetradeuterio-2-fluoro-ethoxy)pyrimidin-2-amine [Chemical formula] A solution of N,N-bis[(2,4-dimethoxyphenyl)methyl]-4,6-dimethoxy-5-(1,1,2,2-tetradeuterio-2-fluoro-ethoxy)pyrimidin-2-amine (10.0 g, 19.17 mmol) in dichloromethane (50 ml) was added with trifluoroacetic acid (50 ml, 673 mmol) at 0 - 10 °C, and the mixture was stirred at 25 °C for 2 hours. The pH of the reaction mixture was adjusted to 7 with saturated NaHCO3 solution, and the mixture was extracted with ethyl acetate (200 ml × 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give 4,6-dimethoxy-5-(1,1,2,2-tetradeuterio-2-fluoro-ethoxy)pyrimidin-2-amine (4.14 g, yield 94%) as a white solid. MS(ESI): m / z = 222.2 [M+H] + .

[0212] Intermediate B17: 5-(1,1-Dideuterio-2,2-difluoro-ethyl)-4-methoxy-pyrimidin-2-amine [Chemical formula]

[0213] Step 1: 1-[2-[Bis[(2,4-dimethoxyphenyl)methyl]amino]-4-methoxy-pyrimidin-5-yl]-2,2-difluoro-ethanone [Chemical formula] A solution of 5-bromo-N,N-bis[(2,4-dimethoxyphenyl)methyl]-4-methoxy-pyrimidin-2-amine (2.00 g, 3.97 mmol, CAS 2827058-10-4) in tetrahydrofuran (3 ml) was added dropwise with n-BuLi solution (2.5 M in hexane, 1.91 ml, 4.77 mmol) at -70 °C, and the solution was stirred at -70 °C for 0.5 h. Then ethyl difluoroacetate (1.31 ml, 11.92 mmol) was added dropwise at -70 °C. The solution was stirred at 20 °C for 2 h. The reaction mixture was poured into saturated ammonium chloride solution (250 mL) and extracted with ethyl acetate (150 ml × 3). The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography using a gradient of ethyl acetate / ether 0 - 30% to give the title compound as a yellow oil (0.8 g, yield 33%). MS(ESI): m / z = 504.1[M+H]+

[0214] Step 2: 5-(1,1-Dideuterio-2,2-difluoro-ethyl)-N,N-bis[(2,4-dimethoxyphenyl)methyl]-4-methoxy-pyrimidin-2-amine [Chemical formula] A solution of lithium aluminum deuteride (2.0 g, 47.67 mmol) and aluminum trichloride (6.99 g, 52.43 mmol) in diethyl ether (200 mL) was stirred for 15 minutes under a nitrogen atmosphere. To this solution was added a solution of 1-[2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-4-methoxy-pyrimidin-5-yl]-2,2-difluoro-ethanone (24.0 g, 47.67 mmol) in diethyl ether (50 mL). The mixture was stirred at 20 °C for 2 hours, quenched with D2O (100 mL), followed by 6 N sulfuric acid (100 mL), and then diluted with water (150 mL). The aqueous layer was extracted with ethyl acetate (3 × 300 mL), and the combined organic layers were washed with water and a 10% aqueous sodium bicarbonate solution. The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography using a gradient of ethyl acetate / ether from 0 to 30%, and the title compound was obtained as a yellow oil (15 g, 64% yield). MS (ESI): m / z = 492.2 [M+H] + 。

[0215] Step 3: 5-(1,1-Dideuterio-2,2-difluoro-ethyl)-4-methoxy-pyrimidin-2-amine

Chemical formula

[0216] Intermediate B18: 5-(1,1-Dideuterio-2,2-difluoro-ethyl)-4,6-dimethoxy-pyrimidin-2-amine

Chemical formula

[0217] Intermediate B19: 5-(1,1-Dideuterio-2,2-difluoro-ethoxy)-4,6-dimethoxy-pyrimidin-2-amine

Chem.

[0218] Step 1: 1,1-Dideuterio-2,2-difluoro-ethanol

Chem.

[0219] Step 2: (1,1-Dideuterio-2,2-difluoro-ethyl)-4-methylbenzenesulfonate

Chem.

[0220] Step 3: 5-(1,1-Dideuterio-2,2-difluoro-ethoxy)-N,N-bis[(2,4-dimethoxyphenyl)methyl]-4,6-dimethoxy-pyrimidin-2-amine

Chemical formula

[0221] Step 4: 5-(1,1-Dideuterio-2,2-difluoro-ethoxy)-4,6-dimethoxy-pyrimidin-2-amine

Chemical formula

[0222] Example Example 1: N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(3-methylpyrazol-1-yl)-1H-indole-3-sulfonamide

Chem.

[0223] Step 1: 7-Bromo-1H-indole-3-sulfonyl chloride

Chem.

[0224] Step 2: 7-Bromo-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide

Chem.

[0225] Step 3: N-[5-(2,2-Difluoroethyl)-4,6-dimethoxypyrimidin-2-yl]-7-(3-methylpyrazol-1-yl)-1H-indole-3-sulfonamide

Chemical Structure

[0226] Example 2: N-[5-(2,2-Difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(3,5-dimethylpyrazol-1-yl)-1H-indole-3-sulfonamide

Chemical formula

[0227] Example 3: N-[5-(2,2-Difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-imidazol-1-yl-1H-indole-3-sulfonamide

Chemical formula

[0228] Example 4: 6-chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide [ka] The title compound was prepared as a white solid similarly to Example 1 from 7-bromo-6-chloro-1H-indole instead of 7-bromo-1H-indole in step 1) and pyrazole instead of 3-methyl-pyrazole in step 3). MS (ESI) m / z: 499.2 [M+H] + .

[0229] Example 5: N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(2-methylimidazol-1-yl)-1H-indole-3-sulfonamide [ka] A mixture of 7-(2-methylimidazol-1-yl)-1H-indole-3-sulfonyl chloride (Intermediate A1, 88 mg, 0.30 mmol), 5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-amine (Intermediate B1, 50 mg, 0.23 mmol) and tripotassium phosphate (145 mg, 0.685 mmol) in acetonitrile (5 ml) was stirred at room temperature for 4 days. The reaction mixture was poured into water and extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0% - 100% ethyl acetate in heptane, followed by 0% - 20% methanol in ethyl acetate) to give the title compound (8 mg, 7%) as an off-white solid. MS(ESI) m / z: 479.2 [M+H] + 。

[0230] Example 6: 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-imidazol-1-yl-1H-indole-3-sulfonamide

Chemical formula

[0231] Example 7: 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide [Chemical Structure] In a 25 ml two-necked flask, 5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-amine (Intermediate B1, 50 mg, 0.228 mmol) and 6-chloro-7-(triazol-2-yl)-1H-indole-3-sulfonyl chloride (Intermediate A2, 94 mg, 0.30 mmol) were dissolved in dichloromethane (8 ml). A solution of N,N-diisopropylethylamine (88 mg, 120 μl, 0.68 mmol) in dichloromethane (1.5 ml) was added. The reaction mixture was further stirred at room temperature and then poured into water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 0% - 80% ethyl acetate in heptane), followed by another flash chromatography (RediSep Rf Gold C18 column, 10% - 80% acetonitrile in water) to give the title compound (26 mg, 22%) as a white solid. MS(ESI) m / z: 500.1 [M+H] + .

[0232] Examples 8 - 11 below were prepared in the same manner as Example 7 by coupling the sulfonyl chloride Intermediate A and the amine Intermediate B shown. [Table 2]

[0233] Example 12: 6-Chloro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide [Chemical Structure] In a 10 ml two-necked flask, 5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-amine (Intermediate B2, 50 mg, 0.267 mmol) was dissolved in dichloromethane (2 ml), then N-ethyldiisopropylamine (52 mg, 70 μl, 0.4 mmol) and a solution of 6-chloro-7-(triazol-2-yl)-1H-indole-3-sulfonyl chloride (Intermediate A2, 93 mg, 0.294 mmol) in ethyl acetate (3 ml) were added. The reaction mixture was stirred at room temperature for 2 hours, then poured into water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0% - 100% ethyl acetate in heptane), followed by another flash chromatography (RediSep Rf Gold C18 column, 10% - 70% acetonitrile in water) to give the title compound (45 mg, 35% yield) as a white solid. MS(ESI) m / z: 468.2 [M+H] + 。

[0234] The following Examples 13 - 41 were prepared in the same manner as Example 12 by coupling the sulfonyl chloride Intermediate A and the amine Intermediate B shown.

Table 3

[0235] The following Examples 43 - 59 were prepared in the same manner as Example 7 by coupling the sulfonyl chloride Intermediate A and the amine Intermediate B shown.

Table 4

[0236] Examples 60 to 86 below were prepared in the same manner as Example 12 by coupling the sulfonyl chloride intermediate A and the amine intermediate B shown. [Table 5] TIFF2025525012000161.tif222169 TIFF2025525012000162.tif226169 TIFF2025525012000163.tif229169 TIFF2025525012000164.tif78169

[0237] Example A The compound of formula I can be used as an active ingredient in a manner known per se to produce tablets of the following composition: Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg

[0238] Example B The compound of formula I can be used as an active ingredient in a manner known per se to produce capsules of the following composition: Per capsule Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg

Claims

1. A compound of formula I 【Chemical 1】 wherein R １ is alkoxy or haloalkoxy; R ２ is 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 [Chemical Formula 2] is a heteroaryl linked by N or a substituted heteroaryl linked by N, represented by A １ is CR ｙ１ or N; A ２ is either CR ｙ２ or N; A ３ is CR ｙ３ or N; A ４ is CR ｙ４ or N; wherein, R ｙ１ , R ｙ２ , R ｙ３ and R ｙ４ are independently selected from H, alkyl, halo, and haloalkyl). and a pharmaceutically acceptable salt thereof.

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

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

4. R ２ The compound according to any one of claims 1 to 3, wherein R is cyclopropyl substituted with haloalkyl, haloalkoxy, or cyano.

5. R ２ The compound according to any one of claims 1 to 4, wherein R is haloalkoxy.

6. R ３ The compound according to any one of claims 1 to 5, wherein R is H or alkoxy.

7. R ３ The compound according to any one of claims 1 to 6, wherein R is alkoxy.

8. R ５ The compound according to any one of claims 1 to 7, wherein R is halo.

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

10. A １ 、 A ２ 、 A ３ and A ４ is at least one of, but not more than two of, which are N, and R ｙ１ 、 R ｙ２ 、 R ｙ３ 、 and R ｙ４ is independently selected from H or alkyl, the compound according to any one of claims 1 to 9.

11. R ４ is [Chemical Formula 3] A compound according to any one of claims 1 to 10, selected from

12. R ４ is [Chemical Formula 4] A compound according to any one of claims 1 to 11, selected from

13. R ４ is [Chemical Formula 5] A compound according to any one of claims 1 to 12, selected from

14. R ４ is [Chemical Formula 6] A compound according to any one of claims 1 to 13, selected from

15. R ４ is 【Chemical Formula 7】 A compound according to any one of claims 1 to 14, which is

16. R １ is an alkoxy group; 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 【Chemical Formula 8】 is a heteroaryl linked by N or a substituted heteroaryl linked by N, represented by A １ is CR ｙ１ or N; A ２ is CR ｙ２ or N; A ３ is CR ｙ３ or N; A ４ is CR ｙ４ or N; wherein R ｙ１ , R ｙ２ , R ｙ３ and R ｙ４ are independently selected from H, alkyl, and halo; The compound according to claim 1 and a pharmaceutically acceptable salt thereof.

17. R １ is an alkoxy group; 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 【Chemical Formula 9】 selected from The compound according to claim 1 and a pharmaceutically acceptable salt thereof.

18. R １ is an alkoxy group; 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; R ４ is 【Chemical Formula 10】 selected from The compound according to claim 1 and a pharmaceutically acceptable salt thereof.

19. R １ is an alkoxy group; R ２ is cyclopropyl optionally substituted with haloalkyl, haloalkoxy, or cyano; R ３ is H or alkoxy; R ５ is H, halo, alkyl, or haloalkyl; R ６ is H; R ４ is 【Chemical Formula 11】 selected from The compound according to claim 1 and a pharmaceutically acceptable salt thereof.

20. R １ is an alkoxy group; R ２ is cyclopropyl optionally substituted with haloalkyl, haloalkoxy, or cyano; R ３ is an alkoxy group; R ５ is H, halo, alkyl, or haloalkyl; R ６ is H; R ４ is 【Chemical 12】 selected from The compound according to claim 1 and a pharmaceutical salt thereof.

21. R １ is an alkoxy group; R ２ is a haloalkoxy; R ３ is an alkoxy group; R ５ is a halo; R ６ is H; R ４ is 【Chemical 13】 which is The compound according to claim 1 and a pharmaceutically acceptable salt thereof.

22. N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(3-methylpyrazol-1-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(3,5-dimethylpyrazol-1-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-imidazol-1-yl-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(2-methylimidazol-1-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-imidazol-1-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(1,2,4-triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-imidazol-1-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(1,2,4-triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(1,2,4-triazol-4-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-7-(1,2,4-triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-7-(1,2,4-triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(1,2,4-triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(1,2,4-triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(1,2,4-triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,3-difluoropropyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(1,2,4-triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(3,3-difluoropropyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(1,2,4-triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-cyanocyclopropyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(2-Fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-Difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(2-Cyanocyclopropyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-Difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(2-Fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(Difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-Difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(2-Cyanocyclopropyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2,2-Difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2-Fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(Difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2-cyanocyclopropyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-Difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-fluoro-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Fluoro-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(Difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-fluoro-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-Difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-fluoro-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(2-Cyanocyclopropyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-fluoro-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(1,2,4-triazol-1-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(4-methyltriazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(4-methyltriazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-1-yl)-1H-indole-3-sulfonamide; 6-(Difluoromethyl)-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(1,2,3-triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-Difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-7-(1,2,3-triazol-2-yl)-1H-indole-3-sulfonamide; and their pharmaceutically acceptable salts A compound according to any one of claims 1 to 21, selected from the above.

23. 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(4-methyl-1H-pyrazol-1-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(3-methyl-1H-pyrazol-1-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(4-fluoro-1H-pyrazol-1-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(5-methyl-1H-pyrazol-1-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(4-fluoro-1H-pyrazol-1-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(4-fluoro-1H-pyrazol-1-yl)-1H-indole-3-sulfonamide; N-[5-(Difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-7-(1H-pyrazol-1-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-Difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-7-(1H-pyrazol-1-yl)-1H-indole-3-sulfonamide; 6-(Difluoromethyl)-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; N-[5-(2,2-Difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(3-fluoropyrazol-1-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(3-fluoropyrazol-1-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(3-fluoropyrazol-1-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(3-fluoropyrazol-1-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[4,6-dimethoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoro-1,1-dimethyl-ethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(1,1-dideuterio-2,2-difluoro-ethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(cyanomethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4,6-dimethoxy-5-methyl-pyrimidin-2-yl)-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-(5-Bromo-4,6-dimethoxy-pyrimidin-2-yl)-6-chloro-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-fluoro-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[4,6-dimethoxy-5-(1,1,2,2-tetradeuterio-2-fluoro-ethoxy)pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(cyanomethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(1,1-dideuterio-2,2-difluoro-ethyl)-4-methoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-cyanocyclopropyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-bromo-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-bromo-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-chloro-N-[5-(1,1-dideuterio-2,2-difluoro-ethyl)-4-methoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-bromo-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-bromo-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-bromo-N-[4,6-dimethoxy-5-(1,1,2,2-tetradeuterio-2-fluoro-ethoxy)pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-chloro-N-[4,6-dimethoxy-5-(1,1,2,2-tetradeuterio-2-fluoro-ethoxy)pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(1,1-dideuterio-2,2-difluoro-ethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; and pharmaceutically acceptable salts thereof A compound according to any one of claims 1 to 21, selected from

24. N-[5-(2,2-Difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(3,5-dimethylpyrazol-1-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; N-[5-(2,2-Difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(2-methylimidazol-1-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,3-difluoropropyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(3,3-difluoropropyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-cyanocyclopropyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(2-cyanocyclopropyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-bromo-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-bromo-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-bromo-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-bromo-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-bromo-N-[5-(2-cyanocyclopropyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(4-methyltriazol-2-yl)-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(4-methyltriazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-1-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-7-(triazol-2-yl)-1H-indole-3-sulfonamide; and their pharmaceutically acceptable salts A compound according to any one of claims 1 to 22, selected from the above.

25. 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(4-methylpyrazol-1-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(3-methylpyrazol-1-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(4-fluoropyrazol-1-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(5-methylpyrazol-1-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(4-fluoropyrazol-1-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(3-fluoropyrazol-1-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(3-fluoropyrazol-1-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(3-fluoropyrazol-1-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(3-fluoropyrazol-1-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(cyanomethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4,6-dimethoxy-5-methyl-pyrimidin-2-yl)-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-(5-Bromo-4,6-dimethoxy-pyrimidin-2-yl)-6-chloro-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[4,6-dimethoxy-5-(1,1,2,2-tetradeuterio-2-fluoro-ethoxy)pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(1,1-dideuterio-2,2-difluoro-ethyl)-4-methoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-cyanocyclopropyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(1,1-dideuterio-2,2-difluoro-ethyl)-4-methoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; N-[5-(2,2-Difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Bromo-N-[4,6-dimethoxy-5-(1,1,2,2-tetradeuterio-2-fluoro-ethoxy)pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; 6-Chloro-N-[4,6-dimethoxy-5-(1,1,2,2-tetradeuterio-2-fluoro-ethoxy)pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(1,1-dideuterio-2,2-difluoro-ethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-pyrazol-1-yl-1H-indole-3-sulfonamide; and pharmaceutically acceptable salts thereof A compound according to any one of claims 1 to 21 or 23, selected from

26. 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-(triazol-2-yl)-1H-indole-3-sulfonamide; and pharmaceutically acceptable salts thereof A compound according to any one of claims 1 to 22 or 24, selected from

27. Reacting a compound of formula III with a compound of formula II in the presence of a base selected from N-ethyldiisopropylamine, pyridine, potassium phosphate, or sodium hydride to provide a compound of formula I 【Chemical Formula 14】 (wherein, R １ , R ２ , R ３ , R ３ , R ４ , R ５ and R ６ are as described above) A process for preparing a compound according to any one of claims 1 to 26, comprising

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

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

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

31. Direct damage to the myelin sheath (including, but not limited to, central pontine myelinolysis and extrapontine myelinolysis, carbon monoxide poisoning, nutritional deficiencies, and virus-induced demyelination), demyelinating disorders (including, but not limited to, multiple sclerosis, acute disseminated encephalomyelitis 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 resulting from stroke), and inflammation in the CNS (such as encephalitis, primary angiitis, meningitis, and after obesity), for treating or preventing a condition caused by

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

33. Use of a compound according to any one of claims 1 to 26 for preparing a medicament for treating or preventing a condition caused by direct damage to the myelin sheath (including, but not limited to, central pontine myelinolysis and extrapontine myelinolysis, carbon monoxide poisoning, nutritional deficiency, and virus-induced demyelination), demyelinating disorders (including, but not limited to, multiple sclerosis, acute disseminated encephalomyelitis 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 resulting from stroke), and inflammation in the CNS (such as encephalitis, primary vasculitis, meningitis, and post-obesity).

34. A compound according to any one of claims 1 to 26 for use in the treatment or prevention of a condition caused by direct damage to the myelin sheath (including, but not limited to, central pontine myelinolysis and extrapontine myelinolysis, carbon monoxide poisoning, nutritional deficiency, and virus-induced demyelination), demyelinating disorders (including, but not limited to, multiple sclerosis, acute disseminated encephalomyelitis 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 resulting from stroke), and inflammation in the CNS (such as encephalitis, primary vasculitis, meningitis, and post-obesity).

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

36. Methods for treating or preventing conditions resulting from direct damage to myelin sheaths (including, but not limited to, central pontine myelinolysis and extrapontine myelinolysis, carbon monoxide poisoning, nutritional deficiencies, and virus-induced demyelination), demyelinating disorders (including, but not limited to, multiple sclerosis, acute disseminated encephalomyelitis 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 resulting from stroke), and inflammation in the CNS (such as encephalitis, primary angiitis, meningitis, and post-obesity), the method comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 26.

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

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

39. The invention as described previously herein.

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