Novel pyrimidinyl sulfonamide derivatives

Abstract

The present invention relates to novel compounds having the general formula (I): TIFF2026502630000081.tif37165 In the formula, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 The present invention relates to compounds as described herein, compositions comprising the compounds, and methods of using the compounds.

Description

[Technical Field]

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

[0002] The present invention relates to novel compounds of formula I, [ka] During the ceremony, 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 4 is H, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl is optionally substituted with oxo, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, or cyano; R 5 is H, halo, alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein the aryl, heteroaryl, arylalkyl, or heteroarylalkyl is optionally substituted with halo, alkyl, haloalkyl, alkoxy, haloalkoxy, or cyano; R 6 is H or halo, Compounds, and pharmaceutically acceptable salts thereof, are provided.

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

[0004] Myelination is a robust process during development, and despite the abundant presence of oligodendrocyte progenitor cells (OPCs) throughout the adult CNS, chronic demyelinating diseases impair their transition to myelinating oligodendrocytes and the production of reparative myelin sheaths around exposed axons. During development, myelination proceeds in a highly orderly fashion, with OPCs characterized by the expression of markers such as neural / glial antigen 2 (NG2) and platelet-derived growth factor alpha (PDGFRα) differentiating into oligodendrocytes that lose expression of NG2 and PDGFRα and gain expression of markers such as myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG). Myelin production by oligodendrocytes is a very tightly regulated process, and in the CNS, this may be controlled by interactions with axons, which are well understood in the peripheral nervous system but not in the central nervous system (Macklin, WB (2010). Sci. Signal. 3, pe32-pe32, ''The myelin brake: When Enough Is Enough''). Myelination can also be controlled by the oligodendrocyte's own internal brake, via 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, LO, et al. (2018). Cell 175, 1811-1826. e21, "Spatiotemporal Control of CNS Myelination by Oligodendrocyte Programmed Cell Death through the TFEB-PUMA Axis").Not only does myelin help protect axons and facilitate neurotransmission, but oligodendrocytes have also been shown to play an important role in axonal metabolism and in maintaining peri-axonal electrolyte balance (Schirmer, L., et al. (2014). Ann Neurol 75, 810-828, "Differential loss of KIR4.1 immunoreactivity in multiple sclerosis lesions") (Simons, M., and Nave, K.-A. (2015). Cold Spring Harb Perspect Biol. 22, "Oligodendrocytes: Myelination and Axonal Support").

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

[0006] The role of GPR17 in myelination was first identified in a screen of the optic nerves of Olig1 knockout mice to identify genes regulating myelination. GPR17 expression was found to be exclusively expressed in myelinating cells in the CNS and absent in Schwann cells, the myelinating cells of the peripheral nervous system. GPR17 expression was found to be exclusively expressed in oligodendrocyte-lineage cells and was downregulated in myelinating oligodendrocytes (Chen, Y., et al. (2009)).Specifically, GPR17 expression is found to be present at low levels in early OPCs and increases in premyelinating oligodendrocytes before being downregulated in mature myelinating oligodendrocytes (Boda, E., et al. (2011), Glia 59, 1958-1973, "The GPR17 receptor in NG2 expressing cells: Focus on in vivo cell maturation and participation in acute trauma and chronic damage") (Dziedzic, A., et al. (2020). Int. J. Mol. Sci. 21, 1852, "The gpr17 receptor - a promising goal for therapy and a potential marker of the neurodegenerative process in multiple sclerosis") (Fumagalli, M. et al. (2011), J Biol Chem 286, 10593-10604, "Phenotypic changes, signaling pathways, 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, and conversely, transgenic mice overexpressing GPR17 in oligodendrocytes with the CNP-Cre (2',3'-cyclic nucleotide 3'-phosphodiesterase) promoter exhibited myelination defects, consistent with the expected cell-intrinsic brake on the myelination process (Chen, Y., et al. (2009)).Furthermore, loss of GPR17 enhances remyelination after 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, would result in increased myelination after demyelination.

[0007] Multiple sclerosis (MS) is a chronic neurodegenerative disease characterized by the loss of myelin, a protective fatty lipid layer that surrounds axons in the central nervous system (CNS). Preventing myelin loss or remyelination of exposed axons is thought to prevent axonal degeneration and therefore disease progression (Franklin, RJ (2002), Nat Rev Neurosci 3, 705-714, "Why does remyelination fail in multiple sclerosis?"). Because of the restorative effects of myelin repair on the central nervous system, such treatment would be beneficial for all types of MS: relapsing-remitting, secondary progressive, primary progressive, and progressive relapsing MS. Restoring lost myelin alleviates the neurological symptoms associated with MS due to its neuroprotective effect of sparing axons.

[0008] Due to the essential role that myelination plays in nervous system function, promoting OPC-to-oligodendrocyte differentiation may have implications in multiple diseases in which white matter defects / irregularities resulting from either a loss of myelinating oligodendrocytes or disruption of OPC-to-oligodendrocyte differentiation have been observed, either due to the disease itself or inflammation. This is in addition to diseases in which GPR17 expression is altered.

[0009] Diseases in which GPR17 antagonism can be used in this manner to result in a positive disease outcome include, but are not limited to: Direct damage to the myelin sheath: - metabolic conditions resulting in destruction of central myelin, such as, but not limited to, central pontine myelinolysis due to overly rapid correction of hyponatremia in conditions of alcoholism, liver disease, and post-transplant immunosuppression, and extrapontine myelinolysis -Oligodendrocyte dysfunction and regeneration failure have been reported in the deep white matter layers of the brain after carbon monoxide poisoning -nutritional deficiencies that result in myelin loss or failure to properly produce myelin during development -Virus-induced demyelination Primary demyelinating disorders -Multiple sclerosis (relapsing-remitting, secondary progressive, primary progressive and progressive relapsing MS) - Acute and multiphasic disseminated encephalomyelitis - Neuromyelitis optica spectrum disorder, including optic neuritis -Transverse myelitis Leukodystrophies such as adrenoleukodystrophy, adrenomyeloneuropathy and other inherited leukodystrophies resulting in myelin loss CNS disorders with associated myelin loss: -Alzheimer's disease -Schizophrenia -Parkinson's disease -Huntington's disease -Amyotrophic lateral cord -Ischemia due to stroke Other diseases: - Inflammation of the CNS, e.g., after encephalitis, primary vasculitis, or meningitis

[0010] The compounds of Formula I bind to and modulate the activity of GPR17.

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

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

[0013] The present invention relates to novel compounds of formula I, [ka] During the ceremony, 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 4 is H, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl is optionally substituted with oxo, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, or cyano; R 5 is H, halo, alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein the aryl, heteroaryl, arylalkyl, or heteroarylalkyl is optionally substituted with halo, alkyl, haloalkyl, alkoxy, haloalkoxy, or cyano; R 6 is H or halo, Compounds, and pharmaceutically acceptable salts thereof, are provided.

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

[0015] The term "alkoxy" refers to a group in which R' is C 1-6 represents a group of formula -O-R', which is an alkyl group. 1-6 Examples of -alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. A particular example is methoxy.

[0016] The terms "halogen," "halide," and "halo" are used interchangeably herein and refer to fluoro, chloro, bromo, or iodo. Examples of "halo" include fluoro.

[0017] The term "haloalkyl" refers to C 1-6 -C in which at least one hydrogen atom of the alkyl group is replaced by the same or different halogen atom 1-6 represents an alkyl group. A particular example is difluoroethyl.

[0018] The term "haloalkoxy" refers to C 1-6-C in which at least one hydrogen atom of the alkoxy group is replaced by the same or different halogen atom 1-6 -represents an alkoxy group. Particular examples are fluoroethoxy, difluoroethoxy, and difluoromethoxy.

[0019] The term "cyano" refers to the group -C≡N.

[0020] "Cyanoalkyl" means a moiety of the formula -R'-R'', where R' is alkyl as defined herein and R'' is cyano or nitrile. A particular example is cyanoethyl.

[0021] "Cyanoalkoxy" means a moiety of the formula -R'-R'', where R' is alkoxy as defined herein and R'' is cyano or nitrile.

[0022] The term "cycloalkyl" refers to a monocyclic or polycyclic saturated or partially unsaturated non-aromatic hydrocarbon. In some embodiments, unless otherwise specified, a cycloalkyl contains 3 to 8 carbon atoms, 3 to 6 carbon atoms, or 3 to 5 carbon atoms. In some embodiments, a cycloalkyl is a saturated monocyclic or polycyclic hydrocarbon. Particular examples of cycloalkyl are cyclopropyl and cyclobutyl.

[0023] The term "heterocyclic ring" or "heterocyclic" means a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of 4 to 10 ring atoms, or 4 to 9 ring atoms, containing 1, 2, or 3 ring heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon.

[0024] The term "aryl," alone or in combination with other groups, refers to a monovalent cyclic aromatic hydrocarbon moiety consisting of a monocyclic or bicyclic aromatic ring. A preferred aryl is phenyl. Aryl can be unsubstituted or substituted as described herein.

[0025] The term "arylalkyl" refers to an alkyl group in which one of the alkyl group's hydrogen atoms has been replaced by an aryl group. An example of an arylalkyl is benzyl.

[0026] The term "heteroaryl" refers to 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 that share one or two ring atoms in common. Examples of heteroaryl are thiazolyl and pyridyl. Other examples of heteroaryl are pyrimidinyl, pyridazinyl, and pyrazinyl.

[0027] The term "heteroarylalkyl" refers to an alkyl group in which one of the alkyl group's hydrogen atoms is replaced by a heteroaryl group.

[0028] The term "oxo" refers to a divalent oxygen atom =O.

[0029] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the free base or free acid, without being biologically or otherwise undesirable. Salts are formed with 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, and N-acetylcysteine. In addition, these salts can be prepared by adding inorganic or organic bases to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, and polyamine resins. The compound of Formula I can also exist in the form of a zwitterion. Particularly preferred pharmaceutically acceptable salts of the compound of Formula I are salts formed with formic acid and with hydrochloric acid to produce the hydrochloride, dihydrochloride, or trihydrochloride salt.

[0030] The abbreviation uM means micromolar and is equivalent to the symbol μM.

[0031] The abbreviation uL means microliter and is equivalent to the symbol μL.

[0032] The abbreviation ug stands for microgram and is equivalent to the symbol μg.

[0033] The compounds of formula I may contain several asymmetric centers and may exist in the form of optically pure enantiomers, mixtures of enantiomers, such as racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereomeric racemates or mixtures of diastereomeric racemates.

[0034] According to the Cahn-Ingold-Prelog rules, the asymmetric carbon atom can be of the "R" or "S" configuration.

[0035] Also, one embodiment of the present invention provides compounds according to formula I as described herein and pharmaceutically acceptable salts or esters thereof, particularly compounds according to formula I as described herein and pharmaceutically acceptable salts thereof, more particularly compounds according to formula I as described herein.

[0036] One embodiment of the present invention is R 1 is alkoxy.

[0037] One embodiment of the present invention is R 2 But R 2 is cyclopropyl substituted with haloalkyl, haloalkoxy, cyanoalkyl, or cyano.

[0038] One embodiment of the present invention is R 2 is haloalkyl or haloalkoxy.

[0039] One embodiment of the present invention is R 3 is H or alkoxy.

[0040] One embodiment of the present invention is R 3 is alkoxy.

[0041] One embodiment of the present invention is R4 is selected from cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl is optionally substituted with halo, alkyl, haloalkyl, alkoxy, haloalkoxy, or cyano.

[0042] One embodiment of the present invention is R 4 is a 5- or 6-membered heteroaryl, arylalkyl, or heteroarylalkyl containing 1-2 heteroatoms independently selected from 6-membered aryl, S, and N, wherein the 5- or 6-membered heteroaryl, arylalkyl, or heteroarylalkyl containing 1-2 heteroatoms independently selected from 6-membered aryl, S, and N is optionally substituted with halo, alkyl, haloalkyl, alkoxy, haloalkoxy, or cyano.

[0043] One embodiment of the present invention is a compound according to formula I described herein, wherein R 4 but, iH; ii. Cyclobutyl; iii. 6-membered aryl; iv. 5-membered heteroaryl containing one S heteroatom and one N heteroatom; v. 6-membered heteroaryl containing one or two N heteroatoms; vi. 6-membered aryl substituted with halo; vii. 5-membered heteroaryl containing one S heteroatom and one N heteroatom substituted by alkyl; viii. 6-membered heteroaryl containing one N heteroatom substituted with alkyl, halo, or both alkyl and oxy; The present invention provides a compound selected from:

[0044] One embodiment of the present invention is a compound according to formula I described herein, wherein R4 but, i. 6-membered aryl; ii. 5-membered heteroaryl containing one S heteroatom and one N heteroatom; iii. 6-membered heteroaryl containing one N heteroatom; iv. 6-membered aryl substituted with halo; v. 5-membered heteroaryl containing one S heteroatom and one N heteroatom substituted by alkyl; vi. 6-membered heteroaryl containing one N heteroatom substituted with alkyl or halo; The present invention provides a compound selected from:

[0045] One embodiment of the present invention is R 4 is a 6-membered aryl, or a 5- or 6-membered heteroaryl optionally substituted with halo and containing 1-2 heteroatoms independently selected from S and N.

[0046] One embodiment of the present invention is R 5 is H, arylalkyl, or arylalkyl substituted with halo.

[0047] One embodiment of the present invention is R 5 is H.

[0048] One embodiment of the present invention is R 6 is H.

[0049] One embodiment of the present invention is a compound according to formula I described herein, wherein: R 1 is alkoxy or haloalkoxy; R 2is cyclopropyl optionally substituted with up to two substituents independently selected from halo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyanoalkyl, cyanoalkoxy, or cyano and halo; R 3 is H, alkoxy, or haloalkoxy; R 4 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl is optionally substituted with halo, alkyl, haloalkyl, alkoxy, haloalkoxy, or cyano; R 5 is H, halo, alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein the aryl, heteroaryl, arylalkyl, or heteroarylalkyl is optionally substituted with halo, alkyl, haloalkyl, alkoxy, haloalkoxy, or cyano; R 6 is H or halo, Compounds, and pharmaceutically acceptable salts thereof, are provided.

[0050] One embodiment of the present invention is a compound according to formula I described herein, wherein: R 1 is an alkoxy; R 2 is haloalkyl or haloalkoxy; R 3 is an alkoxy; R 4 is a 6-membered aryl or a 5- or 6-membered heteroaryl optionally substituted with halo and containing 1-2 heteroatoms independently selected from S and N; R 5 is H, R 6 But H, Compounds, and pharmaceutically acceptable salts thereof, are provided.

[0051] One embodiment of the present invention is a compound according to formula I described herein, wherein: R 1 is an alkoxy; R 2 is cyclopropyl substituted with haloalkyl, haloalkoxy, cyanoalkyl, or cyano; R 3 is H or alkoxy, R 4 but, iH; ii. Cyclobutyl; iii. 6-membered aryl; iv. 5-membered heteroaryl containing one S heteroatom and one N heteroatom; v. 6-membered heteroaryl containing one or two N heteroatoms; vi. 6-membered aryl substituted with halo; vii. 5-membered heteroaryl containing one S heteroatom and one N heteroatom substituted by alkyl; viii. 6-membered heteroaryl containing one N heteroatom substituted with alkyl, halo, or both alkyl and oxy; and R 5 is H, arylalkyl, or arylalkyl substituted with halo; R 6 But H, Compounds, and pharmaceutically acceptable salts thereof, are provided.

[0052] One embodiment of the present invention is a compound according to formula I described herein, wherein: R 1 is an alkoxy; R 2 is cyclopropyl substituted with haloalkyl, haloalkoxy, cyanoalkyl, or cyano; R 3 is an alkoxy; R 4 but, i. 6-membered aryl; ii. 5-membered heteroaryl containing one S heteroatom and one N heteroatom; iii. 6-membered heteroaryl containing one N heteroatom; iv. 6-membered aryl substituted with halo; v. 5-membered heteroaryl containing one S heteroatom and one N heteroatom substituted by alkyl; vi. 6-membered heteroaryl containing one N heteroatom substituted with alkyl or halo; and R 5 is H, R 6 But H, Compounds, and pharmaceutically acceptable salts thereof, are provided.

[0053] Specific examples of compounds of formula I described herein include the following: N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-phenyl-1H-pyrrole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-phenyl-1H-pyrrole-3-sulfonamide; N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-phenyl-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-thiazol-2-yl-1H-pyrrole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(3-fluoro-2-pyridyl)-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-(3-fluoro-2-pyridyl)-1H-pyrrole-3-sulfonamide; N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(3-fluoro-2-pyridyl)-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(3-fluoro-2-pyridyl)-1H-pyrrole-3-sulfonamide; and and pharmaceutically acceptable salts thereof.

[0054] Other specific examples of compounds of formula I described herein include the following: N-[5-(2,2-difluoroethoxy)-4-methoxy-pyrimidin-2-yl]-5-thiazol-2-yl-1H-pyrrole-3-sulfonamide; N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-thiazol-2-yl-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-isothiazol-3-yl-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-phenyl-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-thiazol-2-yl-1H-pyrrole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-thiazol-2-yl-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-thiazol-4-yl-1H-pyrrole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-thiazol-4-yl-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-(2-pyridyl)-1H-pyrrole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(2-pyridyl)-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(2-pyridyl)-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-(4-methylthiazol-2-yl)-1H-pyrrole-3-sulfonamide; 4-benzyl-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrole-3-sulfonamide; 4-benzyl-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrole-3-sulfonamide; N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-(3-fluoro-2-pyridyl)-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-5-(3-fluoro-2-pyridyl)-1H-pyrrole-3-sulfonamide; N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-thiazol-4-yl-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-thiazol-4-yl-1H-pyrrole-3-sulfonamide; N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(2-pyridyl)-1H-pyrrole-3-sulfonamide; 4-benzyl-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrole-3-sulfonamide; 4-[dideuterio-(3-fluorophenyl)methyl]-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrole-3-sulfonamide; 4-benzyl-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrole-3-sulfonamide; N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(4-methylthiazol-2-yl)-1H-pyrrole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(4-methylthiazol-2-yl)-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(4-methylthiazol-2-yl)-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-5-thiazol-2-yl-1H-pyrrole-3-sulfonamide; N-[5-(2-cyanocyclopropyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-thiazol-2-yl-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-thiazol-5-yl-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-(2-fluorophenyl)-1H-pyrrole-3-sulfonamide; N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(2-fluorophenyl)-1H-pyrrole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(2-fluorophenyl)-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(2-fluorophenyl)-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(2-keto-1-methyl-3-pyridyl)-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(2-methylthiazol-5-yl)-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-pyrimidin-2-yl-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(5-methylthiazol-2-yl)-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-pyridazin-3-yl-1H-pyrrole-3-sulfonamide; 5-(3-chloro-2-pyridyl)-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-pyrimidin-4-yl-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-pyrazin-2-yl-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(3-methyl-2-pyridyl)-1H-pyrrole-3-sulfonamide; 5-Cyclobutyl-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrole-3-sulfonamide; 5-cyclobutyl-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrole-3-sulfonamide; and and pharmaceutically acceptable salts thereof.

[0055] Preferred examples of compounds of formula I described herein include the following: N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-phenyl-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-thiazol-2-yl-1H-pyrrole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(3-fluoro-2-pyridyl)-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-(3-fluoro-2-pyridyl)-1H-pyrrole-3-sulfonamide; N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(3-fluoro-2-pyridyl)-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(3-fluoro-2-pyridyl)-1H-pyrrole-3-sulfonamide; N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-thiazol-2-yl-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-isothiazol-3-yl-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-phenyl-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-thiazol-2-yl-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-(2-pyridyl)-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(2-pyridyl)-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-(4-methylthiazol-2-yl)-1H-pyrrole-3-sulfonamide; N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-(3-fluoro-2-pyridyl)-1H-pyrrole-3-sulfonamide; N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(2-pyridyl)-1H-pyrrole-3-sulfonamide; N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(4-methylthiazol-2-yl)-1H-pyrrole-3-sulfonamide; N-[5-(2-cyanocyclopropyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-thiazol-2-yl-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-thiazol-5-yl-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-(2-fluorophenyl)-1H-pyrrole-3-sulfonamide; N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(2-fluorophenyl)-1H-pyrrole-3-sulfonamide; 5-(3-chloro-2-pyridyl)-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(3-methyl-2-pyridyl)-1H-pyrrole-3-sulfonamide; and and pharmaceutically acceptable salts thereof.

[0056] The processes for the preparation of compounds of formula I described herein are an object of the present invention.

[0057] The present compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example by the process described below, which comprises reacting a compound of formula III with a compound of formula II in the presence of a base selected from N-ethyldiisopropylamine, pyridine, potassium phosphate or sodium hydride to provide a compound of formula I: [ka] In the formula, R 1 , R 2 , R 3 , R 3 , R 4 , R 5 and R 6 is as described above.

[0058] Alternatively, the present compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example by the process described below, which comprises reacting a protected sulfonyl chloride IV with an amine III in the presence of a base such as N-ethyldiisopropylamine or pyridine to form compound V, which is then treated with a base such as potassium hydroxide or sodium hydroxide in ethanol or methanol to give the desired compound I: [ka] In the formula, R 1 , R 2 , R 3 , R 3 , R 4 , R 5 and R 6 is as described above.

[0059] Alternatively, the present compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by the process described below, which involves reacting amine III with a protected sulfonyl chloride VI in the presence of a base such as N-ethyldiisopropylamine or pyridine to form compound VII, which is then treated with a base such as potassium hydroxide or sodium hydroxide in ethanol or methanol to give intermediate VIII, which can be brominated using N-bromosuccinimide to form intermediate IX, which is further reacted with bis(pinacolato)diboron in the presence of a base such as potassium acetate and a suitable palladium catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) to form intermediate X. Reaction of X with heteroaryl-halides XI in the presence of a base such as potassium phosphate, potassium carbonate, or cesium carbonate and a palladium source such as tetrakis(triphenylphosphine)-palladium(0), XPhos Pd G4, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) provides the desired compounds I. [ka] In the formula, R 1 , R 2 , R 3 , R 3 , R 4 , R 5 and R 6 is as described above.

[0060] General synthetic scheme Compounds of formula I can be prepared according to the process variations described above and the following Scheme 1. Starting materials are commercially available or can be prepared according to known methods.

[0061] Scheme 1 [ka]

[0062] Compounds 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. The starting materials are commercially available or can be prepared according to known methods.

[0063] Scheme 2 [ka]

[0064] Additionally, compounds of general formula I can be prepared by reacting a protected sulfonyl chloride IV with an amine III in the presence of a base such as N-ethyldiisopropylamine or pyridine to form compound V, which is then treated with a base such as potassium hydroxide or sodium hydroxide in ethanol or methanol to give the desired compound I.

[0065] Scheme 3 [ka]

[0066] Additionally, amine III can be reacted with a protected sulfonyl chloride VI in the presence of a base such as N-ethyldiisopropylamine or pyridine to form compound VII, which can then be treated with a base such as potassium hydroxide or sodium hydroxide in ethanol or methanol to give intermediate VIII. This compound can be brominated using N-bromosuccinimide to form intermediate IX, which can be further reacted with bis(pinacolato)diboron in the presence of a base such as potassium acetate and a suitable palladium catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) to form intermediate X. Reaction of X with a heteroaryl-halide XI in the presence of a base such as potassium phosphate, potassium carbonate, or cesium carbonate and a palladium source such as tetrakis(triphenylphosphine)-palladium(0), XPhos Pd G4, or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) affords the desired compound I.

[0067] Another embodiment of the present invention provides pharmaceutical compositions or medicaments containing a compound of the present invention and a therapeutically inert carrier, diluent, or excipient, as well as methods of using the compounds of the present invention to prepare such compositions and medicaments. In one example, a compound of Formula I can be formulated into a galenic dosage form by mixing it at ambient temperature, at an appropriate pH, and to the desired degree of purity with a physiologically acceptable carrier, i.e., a carrier that is nontoxic to recipients at the dosage and concentration used. The pH of the formulation will depend primarily on the particular application and the concentration of the compound, but is preferably in the range of about 3 to about 8. In one example, a compound of Formula I is formulated in an acetate buffer at pH 5. In another embodiment, the compound of Formula I is sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0068] The compositions are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to consider in this regard include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the administration schedule, and other factors known to medical practitioners.

[0069] The compounds of the present invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural, and intranasal, and, if desired for local treatment, intralesional administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0070] The compounds of the present invention may be administered in any convenient dosage form, such as, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions contain elements common in pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, fillers, and additional active agents.

[0071] Typical preparation is prepared by mixing the compound of the present invention with carrier or excipient.Suitable carrier and excipient are well known to those skilled in the art, and are described in detail in, for example, Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems.Philadelphia: Lippincott, Williams & 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 formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricating agents, emulsifying agents, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, flavors, flavorings, diluents, and other known additives to present the drug (i.e., a compound of the present invention or a pharmaceutical composition thereof) aesthetically or to aid in the manufacture of a pharmaceutical product (i.e., a medicament).

[0072] The compounds of formula I and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, sugar-coated tablets, hard gelatin capsules, injection solutions or topical preparations.Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used as such adjuvants for tablets, sugar-coated tablets and hard gelatin capsules.

[0073] Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances, and liquid polyols.

[0074] Suitable adjuvants for the production of solutions and syrups are, by way of example, water, polyols, saccharose, invert sugar, glucose etc.

[0075] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.

[0076] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols etc.

[0077] Suitable adjuvants for topical ophthalmic formulations are, for example, cyclodextrins, mannitol or many other carriers and excipients known in the art.

[0078] In addition, pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for varying osmotic pressure, buffers, masking agents, or antioxidants. They may also contain still other therapeutically valuable substances.

[0079] Dosages can vary widely and will, of course, be adapted to the individual requirements of each particular case. Generally, for oral administration, a daily dose 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 (e.g., about 300 mg per person), is preferably divided into 1 to 3 individual doses, which may, if appropriate, consist of equal amounts. For topical administration, the formulation may contain 0.001% to 15% by weight of the drug, and the required dose, which may be between 0.1 and 25 mg, may be administered either as a single dose per day or per week, as multiple doses (2 to 4 times) per day, or as multiple doses per week. However, it will be apparent that the upper or lower limits given herein may be exceeded if indicated.

[0080] The present invention also relates, inter alia, to: A compound of formula I for use as a therapeutically active substance; A compound of formula I for use in the treatment of a disease modulated by GPR17.

[0081] Likewise, an object of the present invention is a pharmaceutical composition comprising a compound according to formula I as described herein and a therapeutically inert carrier.

[0082] Use of compounds of Formula I to treat or prevent direct damage to the myelin sheath (including, but not limited to, centropontine and extrapontine myelinolysis, carbon monoxide poisoning, nutritional deficiencies, and viral-induced demyelination), demyelinating disorders (including, but not limited to, multiple sclerosis, acute and multiphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorders, and leukodystrophies), 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 conditions resulting from inflammation of the CNS, for example, after encephalitis, primary vasculitis, meningitis, and obesity.

[0083] 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.

[0084] A particular embodiment of the invention is the use of a compound of formula I for treating or preventing multiple sclerosis.

[0085] Use of a compound of Formula I for the preparation of a medicament for the treatment or prevention of direct damage to the myelin sheath (including, but not limited to, centropontine and extrapontine myelinolysis, carbon monoxide poisoning, nutritional deficiencies, and viral-induced demyelination), demyelinating disorders (including, but not limited to, multiple sclerosis, acute and multiphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorders, and leukodystrophies), 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 conditions resulting from inflammation of the CNS, for example, after encephalitis, primary vasculitis, meningitis, and obesity.

[0086] One embodiment of the present invention is the use of a compound of formula I for the preparation of a medicament for treating or preventing multiple sclerosis, Alzheimer's disease, Parkinson's disease, or Huntington's disease.

[0087] A particular embodiment of the invention is the use of a compound of formula I for the preparation of a medicament for treating or preventing multiple sclerosis.

[0088] A compound according to Formula I for use in the treatment or prevention of direct damage to the myelin sheath (including but not limited to centropontine and extrapontine myelinolysis, carbon monoxide poisoning, nutritional deficiencies, and viral-induced demyelination), demyelinating disorders (including but not limited to multiple sclerosis, acute and multiphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorders, and leukodystrophies), 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 conditions resulting from inflammation of the CNS, for example following encephalitis, primary vasculitis, meningitis, and obesity.

[0089] 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.

[0090] A particular embodiment of the invention is a compound of formula I for use in the treatment or prevention of multiple sclerosis.

[0091] A method for treating or preventing direct damage to the myelin sheath (including, but not limited to, centropontine and extrapontine myelinolysis, carbon monoxide poisoning, nutritional deficiencies, and viral-induced demyelination), demyelinating disorders (including, but not limited to, multiple sclerosis, acute and multiphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorders, and leukodystrophies), 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 conditions resulting from inflammation of the CNS, for example, after encephalitis, primary vasculitis, meningitis, and obesity, comprising administering to a patient in need thereof an effective amount of a compound of formula I.

[0092] One embodiment of the present invention is a method for treating or preventing multiple sclerosis, Alzheimer's disease, Parkinson's disease, or Huntington's disease, comprising administering to a patient in need thereof an effective amount of a compound of formula I.

[0093] A particular embodiment of the invention is a method of treating or preventing multiple sclerosis, comprising administering an effective amount of a compound of formula I to a patient in need thereof.

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

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

[0096] Changes in intracellular cyclic adenosine monophosphate (cAMP) levels were quantified using the Nano-TRF Detection Assay kit (Roche Diagnostics, catalog no. 05214386001). This assay allows for direct cAMP quantification in homogeneous solution. cAMP is detected based on time-resolved fluorescence energy transfer (TR-FRET) and competitive binding of ruthenium-conjugated cAMP and endogenous cAMP to an anti-cAMP monoclonal antibody labeled with AlexaFluor-700. The ruthenium complex acts as a FRET donor, transferring energy to AlexaFluor-700. The FRET signal is inversely proportional to the cAMP concentration.

[0097] CHO-GPR17S cells were detached with Accutase and resuspended in assay buffer consisting of Hank's balanced salt solution (HBSS), 10 mM HEPES (4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid), 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 compound addition.

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

[0099] Cellular cAMP was measured using a Paradigm reader (Molecular Devices). Raw data was used to calculate FRET signals based on the P factor of the assay according to the cAMP kit instructions. Data were normalized to the maximal activity of the reference antagonist, and dose-response curves were fitted to percent activity of test compounds using a sigmoidal dose-response model (Genedata Screener).

[0100] The results of the hGPR17 cAMP assay are provided for compounds of Formula I in Table 1. [Table 1]

[0101] Microsomal Clearance Assay Protocol: Incubations with 1 mM test compound in microsomes (0.5 mg / mL) plus cofactor NADPH are carried out in 96-well plates at 37 °C using a TECAN (Tecan Group Ltd, Switzerland) automated liquid handling system. The final concentration of test compound during incubation is 1 μM. After a 10-minute preincubation step between the test compound and microsomes, the enzymatic reaction is initiated by the addition of the cofactor. At 1, 3, 6, 9, 15, 25, 35, and 45 minutes, aliquots of the incubation are removed and quenched with 1:3 (v / v) acetonitrile containing an internal standard. The samples are then cooled and centrifuged, after which the supernatants are analyzed by LC-MS / MS.

[0102] Reference Examples RE-A, RE-B, RE-C, RE-D, RE-E and RE-F were prepared as described herein.

[0103] Reference compounds were tested against the exemplified compounds for microsomal clearance, and the results are shown in Table 2 below. [Table 2] TIFF2026502630000012.tif221170

[0104] The invention will now be illustrated by the following examples, which have no limiting character.

[0105] Where preparations are obtained as mixtures of enantiomers, pure enantiomers may be obtained by methods described herein or known to those skilled in the art, such as chiral chromatography or crystallization. [Example]

[0106] Unless otherwise specified, all examples and intermediates were prepared under a nitrogen atmosphere.

[0107] Intermediates A1 to A3 Intermediates A1-A3 are known and have been prepared according to the procedures described in WO2022254027. [Table 3]

[0108] Intermediates A4 to A13 Intermediates A4-A7 are known and have been prepared according to the procedures described in WO2022254027. [Table 4]

[0109] Intermediate A8: 5-(4-methylthiazol-2-yl)-1H-pyrrole-3-sulfonyl chloride [ka]

[0110] Step 1: tert-butyl 2-(4-methylthiazol-2-yl)pyrrole-1-carboxylate [ka] A solution of (1-tert-butoxycarbonylpyrrol-2-yl)boronic acid (CAS 135884-31-0; 1.0 g, 4.64 mmol), 2-bromo-4-methyl-thiazole (861 mg, 521 uL, 4.64 mmol), potassium carbonate (1.93 g, 13.9 mmol), and tetrakis(triphenylphosphine)palladium(0) (537 mg, 0.464 mmol, 0.10 equiv) in 1,4-dioxane (20 mL) and water (2 mL) was heated to 80 °C and stirred for 15 h. The reaction mixture was poured into brine and extracted twice with ethyl acetate. The organic layer was dried over Na SO , filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0% to 30% ethyl acetate in heptane) to give tert-butyl 2-(4-methylthiazol-2-yl)pyrrole-1-carboxylate (784 mg, 62% yield) as a colorless oil. MS (ESI) m / z: 208.6 [M+H-butene] + .

[0111] Step 2: 5-(4-methylthiazol-2-yl)-1H-pyrrole-3-sulfonyl chloride [ka] To a solution of tert-butyl 2-(4-methylthiazol-2-yl)pyrrole-1-carboxylate (732 mg, 2.69 mmol) in acetonitrile (25 mL) was added dropwise chlorosulfonic acid (814 mg, 468 μL, 6.98 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 hours. Phosphorus oxychloride (1.24 g, 751 μL, 8.06 mmol) was then added, and the reaction mixture was heated to 60° C. and stirred for 15 hours. The reaction mixture was poured into ice / ethyl acetate and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 5-(4-methylthiazol-2-yl)-1H-pyrrole-3-sulfonyl chloride (542 mg, 77% yield) as a brown viscous oil. MS (ESI) m / z: 263.0 [M+H]+ .

[0112] Intermediate A9: 5-thiazol-4-yl-1H-pyrrole-3-sulfonyl chloride [ka]

[0113] Step 1: tert-butyl 2-thiazol-4-ylpyrrole-1-carboxylate [ka] To a solution of (1-tert-butoxycarbonylpyrrol-2-yl)boronic acid (CAS 135884-31-0; 2.0 g, 9.48 mmol) and 4-bromothiazole (1.71 g, 930 μL, 10.43 mmol) in 1,4-dioxane (45 mL) and water (4 mL) was added potassium carbonate (3.93 g, 28.4 mmol). The reaction mixture was degassed with argon, and then tetrakis(triphenylphosphine)palladium(0) (1.1 g, 948 μmol, 0.10 equiv.) was added. The reaction mixture was stirred at 80° C. overnight. After cooling to room temperature, the reaction mixture was filtered through decalite and washed with ethyl acetate. The filtrate was poured into water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0% to 30% ethyl acetate in heptane) to give tert-butyl 2-thiazol-4-ylpyrrole-1-carboxylate (1.73 g, 72% yield) as a colorless liquid. MS (ESI) m / z: 251.1 [M+H] + .

[0114] Step 2: 5-Thiazol-4-yl-1H-pyrrole-3-sulfonyl chloride [ka] To a solution of tert-butyl 2-thiazol-4-ylpyrrole-1-carboxylate (1.11 g, 4.43 mmol) in acetonitrile (10 mL) was added 4 M HCl in dioxane (13.3 g, 11.1 mL, 44.3 mmol), and the mixture was stirred at 60 °C for 2 hours. After cooling to room temperature, the reaction mixture was poured into ice-cold NaHCO solution and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was dissolved in acetonitrile (15 mL), and the solution was cooled to 0 °C. Chlorosulfonic acid (517 mg, 297 μL, 4.43 mmol) was added. The ice bath was removed, and the reaction mixture was stirred at room temperature for 4 hours. Phosphorus oxychloride (2.04 g, 1.24 mL, 13.3 mmol) was then added, and the reaction mixture was stirred at 60 °C overnight. The reaction mixture was poured into cold water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 50% ethyl acetate in heptane) to afford 5-thiazol-4-yl-1H-pyrrole-3-sulfonyl chloride (418 mg, 38% yield, second eluting regioisomer) as a white solid. MS (ESI) m / z: 246.9 [M−H] - .

[0115] Intermediate A10: 5-thiazol-5-yl-1H-pyrrole-3-sulfonyl chloride [ka] The title compound was prepared as a light grey powder similarly to intermediate A8 from 5-bromothiazole instead of 2-bromo-4-methyl-thiazole in step 1). MS (ESI) m / z: 249.0 [M+H] + .

[0116] Intermediate A11: 5-Isothiazol-3-yl-1H-pyrrole-3-sulfonyl chloride [ka] The title compound was prepared as a grey solid similar to intermediate A8 from 3-bromoisothiazole instead of 2-bromo-4-methyl-thiazole in step 1). MS (ESI) m / z: 246.9 [M−H] - .

[0117] Intermediate A12: 5-(1-methyl-2-oxo-3-pyridyl)-1H-pyrrole-3-sulfonyl chloride [ka] The title compound was prepared as a dark green solid similarly to intermediate A8 from 3-bromo-1-methyl-2-pyridone instead of 2-bromo-4-methyl-thiazole in step 1). MS (ESI) m / z: 273.0 [M+H] + .

[0118] Intermediate A13: 4-[dideuterio-(3-fluorophenyl)methyl]-1H-pyrrole-3-sulfonyl chloride [ka]

[0119] Step 1: 3-[dideuterio-(3-fluorophenyl)methyl]-1H-pyrrole [ka] A mixture of 2-[dideuterio-(3-fluorophenyl)methyl]-1-(p-tolylsulfonyl)pyrrole (CAS 2877694-47-6, see WO 2022254027; 6.9 g, 20.82 mmol) and sodium hydroxide (4N in water, 26.0 mL, 104.1 mmol) in methanol (45 mL) was stirred at 80 °C for 12 h. The reaction mixture was diluted with 100 mL of water and extracted with ethyl acetate (80 mL × 3). The combined organic layers were washed with 30 mL of saturated sodium chloride solution, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (silica gel, 0–20% ethyl acetate in petroleum ether) to give 3-[dideuterio-(3-fluorophenyl)methyl]-1H-pyrrole (3.64 g, 20.6 mmol, 95% yield) as a pale yellow oil. MS(ESI)m / z:178.1[M+H] + .

[0120] Step 2: 4-[dideuterio-(3-fluorophenyl)methyl]-1H-pyrrole-3-sulfonyl chloride [ka] A stirred solution of 3-[dideuterio-(3-fluorophenyl)methyl]-1H-pyrrole (200 mg, 1.08 mmol) in acetonitrile (6 mL) was cooled to 0° C. Chlorosulfonic acid (133 mg, 76 uL, 1.14 mmol) was added dropwise and the reaction mixture was stirred at 0° C. for 90 minutes. Phosphorus oxychloride (664 mg, 404 uL, 4.33 mmol) was then added. The reaction mixture was warmed to 70° C. and stirred for 16 hours. The reaction mixture was allowed to cool to room temperature, poured into ice / ethyl acetate, and extracted three times with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (364 mg, 51% yield) as a dark brown oil. MS (ESI) m / z: 274.0 [M−H] - .

[0121] Intermediates B1~B4 Intermediates B1-B4 are known and have been prepared according to the procedures described in WO2022180136. [Table 5]

[0122] Intermediates B5~B8 Intermediates B5-B7 are known and have been prepared according to the procedures described in WO2022180136. [Table 6]

[0123] Intermediate B8: 2-(2-amino-4,6-dimethoxy-pyrimidin-5-yl)cyclopropanecarbonitrile [ka]

[0124] Step 1: N,N-bis[(2,4-dimethoxyphenyl)methyl]-4,6-dimethoxy-pyrimidin-2-amine [ka] To a solution of 2-chloro-4,6-dimethoxypyrimidine (5.0 g, 28.6 mmol) and 1-(2,4-dimethoxyphenyl)-N-[(2,4-dimethoxyphenyl)methyl]methanamine (10.9 g, 34.37 mmol) in N-methylpyrrolidone (100 ml) was added cesium carbonate (18.7 g, 57.3 mmol), and the reaction mixture was stirred at 120° C. for 16 hours. The mixture was diluted with water (500 ml) and extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with brine (100 mL×2), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1:0 to 5:1) to give N-bis[(2,4-dimethoxyphenyl)methyl]-4,6-dimethoxy-pyrimidin-2-amine (12.0 g, 89% yield) as a white solid. MS (ESI) m / z: 456.3 [M+H] +

[0125] Step 2: N,N-bis[(2,4-dimethoxyphenyl)methyl]-5-iodo-4,6-dimethoxy-pyrimidin-2-amine [ka] To a solution of N,N-bis[(2,4-dimethoxyphenyl)methyl]-4,6-dimethoxy-pyrimidin-2-amine (12.0 g, 26.3 mmol) in acetonitrile (150 mL) was added N-iodosuccinimide (7.11 g, 31.6 mmol) in portions at 20 °C, and the mixture was stirred at 20 °C for 2 hours. The reaction mixture was quenched by pouring it into saturated sodium bicarbonate solution (300 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (100 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1:0 to 3:1) to give N,N-bis[(2,4-dimethoxyphenyl)methyl]-5-iodo-4,6-dimethoxy-pyrimidin-2-amine (12.0 g, 78% yield) as a yellow solid. MS(ESI)m / z:582.2[M+H] +

[0126] Step 3: (E)-3-[2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-yl]prop-2-enenitrile [ka] To a mixture of N,N-bis[(2,4-dimethoxyphenyl)methyl]-5-iodo-4,6-dimethoxy-pyrimidin-2-amine (9.0 g, 15.5 mmol) and acrylonitrile (6.0 mL, 90.5 mmol) in 1,4-dioxane (90 mL) was added cesium carbonate (10.8 g, 33.1 mmol) and bis(triphenylphosphine)palladium chloride (681 mg, 1.55 mmol) under a nitrogen atmosphere, and the reaction mixture was stirred in a sealed tube at 100° C. for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1:0 to 5:1) to give (E)-3-[2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-yl]prop-2-enenitrile (7.5 g, 96% yield) as a brown solid. MS(ESI) m / z: 507.3 [M+H] +

[0127] Step 4: 2-[2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-yl]cyclopropanecarbonitrile [ka] To a mixture of trimethylsulfoxonium iodide (6.52 g, 29.6 mmol) in dimethyl sulfoxide (50 ml) was added sodium hydride (60% in mineral oil, 1.18 g, 29.6 mmol) in portions at 30° C., and the mixture was stirred at 30° C. for 0.5 hours. The above mixture was added to a mixture of (E)-3-[2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-yl]prop-2-enenitrile (5.0 g, 9.87 mmol) in dimethyl sulfoxide (50 mL) at 30° C., and the mixture was stirred at 30° C. for 16 hours. The reaction mixture was diluted with water (300 ml) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (100 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1:0 to 3:1) to give 2-[2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-yl]cyclopropanecarbonitrile (3.0 g, 54% yield) as a yellow oil. MS(ESI) m / z: 521.3 [M+H] +

[0128] Step 5: 2-(2-amino-4,6-dimethoxy-pyrimidin-5-yl)cyclopropanecarbonitrile [ka] To a solution of 2-[2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-yl]cyclopropanecarbonitrile (3.0 g, 5.76 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (15 mL, 197 mmol) dropwise 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 x 2). The combined organic layers were washed with brine (50 mL x 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, 70% yield) as a white solid. MS (ESI) m / z: 221.1 [M+H] +

[0129] Example Example 1: N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-phenyl-1H-pyrrole-3-sulfonamide [ka] A solution of [5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]amine (30 mg, 125.01 umol, Intermediate B4) in acetonitrile (1.2 mL) was cooled to 0° C. A 2 M solution of sodium tert-butoxide in THF (93.75 uL, 187.51 umol) was added dropwise. The reaction mixture was stirred at 0° C. for 15 minutes. A solution of 5-phenyl-1H-pyrrole-3-sulfonyl chloride (36.93 mg, 137.51 umol, Intermediate A2) in acetonitrile (600 uL) was added dropwise. The reaction mixture was warmed to room temperature, stirred for 1 hour, quenched with saturated ammonium chloride solution, and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate / heptane 0-60%, followed by another flash chromatography on a C18 RediSepRf Gold column using a gradient of acetonitrile / water 10-70% to give the title compound as a white solid (7.9 mg, 14%). MS(ESI) m / z: 441.2 [M+H] +

[0130] Example 2: N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-phenyl-1H-pyrrole-3-sulfonamide [ka] The title compound was prepared from Intermediate A2 and Intermediate B1 according to the same procedure as in Example 1 (white solid, 7.3% yield). MS (ESI) m / z: 427.2 [M+H] +

[0131] Example 3: N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-phenyl-1H-pyrrole-3-sulfonamide [ka] To a mixture of [5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]amine (55 mg, 235.5 umol, Intermediate B3) and 5-phenyl-1H-pyrrole-3-sulfonyl chloride (73.99 mg, 306.15 umol, Intermediate A2) was added pyridine (1.1 mL). The reaction mixture was stirred at room temperature for 16 hours, 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 flash chromatography on silica gel using a gradient of ethyl acetate / heptane 0-60% to give the title compound as an off-white solid (26.7 mg, 27%). MS (ESI) m / z: 423.1 [M+H]+

[0132] Example 4: N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-thiazol-2-yl-1H-pyrrole-3-sulfonamide [ka] The title compound was prepared from Intermediate A1 and Intermediate B4 according to the same procedure as in Example 3 (off-white solid, 15.5% yield). MS (ESI) m / z: 448.1 [M+H]+

[0133] Example 5: N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(3-fluoro-2-pyridyl)-1H-pyrrole-3-sulfonamide [ka] To a solution of [5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]amine (50 mg, 226.08 μmol, Intermediate B1) and 5-(3-fluoro-2-pyridyl)-1H-pyrrole-3-sulfonyl chloride (71.43 mg, 271.3 μmol, Intermediate A3) in acetonitrile (5 mL) was added diisopropylethylamine (87.66 mg, 118.45 μL, 678.24 μmol). The solution was stirred at 60° C. overnight. The solvent was evaporated in vacuo, and the residue was dissolved in ethyl acetate / water and extracted 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 on silica gel using a gradient of ethyl acetate / heptane 0-50% to give the title compound (13 mg, 13%) as a white solid. MS(ESI) m / z: 446.1 [M+H]+

[0134] Example 6: N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-(3-fluoro-2-pyridyl)-1H-pyrrole-3-sulfonamide [ka] The title compound was prepared from Intermediate A3 and Intermediate B2 according to the same procedure as in Example 5 (white solid, 18.2% yield). MS (ESI) m / z: 444.1 [M+H] +

[0135] Example 7: N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(3-fluoro-2-pyridyl)-1H-pyrrole-3-sulfonamide [ka] The title compound was prepared from Intermediate A3 and Intermediate B3 according to the same procedure as in Example 5 (white solid, 31.2% yield). MS (ESI) m / z: 442.1 [M+H] +

[0136] Example 8: N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(3-fluoro-2-pyridyl)-1H-pyrrole-3-sulfonamide [ka] The title compound was prepared from Intermediate A3 and Intermediate B4 according to the same procedure as in Example 5 (white solid, 42% yield). MS (ESI) m / z: 460.1 [M+H] +

[0137] Example 9: N-[5-(2,2-difluoroethoxy)-4-methoxy-pyrimidin-2-yl]-5-thiazol-2-yl-1H-pyrrole-3-sulfonamide [ka] To 5-thiazol-2-yl-1H-pyrrole-3-sulfonyl chloride (89 mg, 0.351 mmol, Intermediate A1) and [5-(2,2-difluoroethoxy)-4-methoxy-pyrimidin-2-yl]amine (60 mg, 0.292 mmol, Intermediate B5) was added pyridine (2.68 g, 2.7 mL) at room temperature. The resulting solution was stirred at 60° C. for 20 hours. The reaction mixture was diluted with ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered, and then concentrated in vacuo. The residue was purified by chromatography (silica gel, ethyl acetate in heptane, 0-100%) to give N-[5-(2,2-difluoroethoxy)-4-methoxy-pyrimidin-2-yl]-5-thiazol-2-yl-1H-pyrrole-3-sulfonamide (34 mg, 27% yield) as a white solid. MS (ESI) m / z: 418.0 [M+H] + .

[0138] Example 10: N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-thiazol-2-yl-1H-pyrrole-3-sulfonamide [ka] The title compound was prepared as a white solid from 3-(2-amino-4,6-dimethoxy-pyrimidin-5-yl)propionitrile (Intermediate B7) instead of Intermediate B5, similar to Example 9. MS (ESI) m / z: 421.0 [M+H] + .

[0139] Example 11: N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-isothiazol-3-yl-1H-pyrrole-3-sulfonamide [ka] To a stirred solution of [5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]amine (28 mg, 115 μmol, Intermediate B4) and N-ethyldiisopropylamine (30 mg, 39 μL, 0.231 mmol) in 1,2-dichloroethane (0.3 mL) was added 5-isothiazol-3-yl-1H-pyrrole-3-sulfonyl chloride (43 mg, 0.139 mmol, Intermediate A11) in 1,2-dichloroethane (0.8 mL) dropwise at room temperature. The reaction was stirred at 70° C. overnight. The reaction mixture was cooled to room temperature, poured into brine, and extracted twice with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (12 g, 0% to 60% ethyl acetate in heptane) to give N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-isothiazol-3-yl-1H-pyrrole-3-sulfonamide (8 mg, 15% yield) as an off-white solid. MS (ESI) m / z: 448.1 [M+H] + .

[0140] Example 12: N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-phenyl-1H-pyrrole-3-sulfonamide [ka] The title compound was prepared as an off-white solid from 5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-amine (Intermediate B2) instead of Intermediate B4 and 5-phenyl-1H-pyrrole-3-sulfonyl chloride (Intermediate A2) instead of Intermediate A11, similar to Example 11. MS (ESI) m / z: 425.1 [M+H] + .

[0141] The following Examples 13-19 were prepared in a similar manner to Example 5 by coupling the sulfonyl chloride intermediate A and amine intermediate B as shown. [Table 7]

[0142] Example 20: N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-(4-methylthiazol-2-yl)-1H-pyrrole-3-sulfonamide [ka] To a stirred solution of [5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]amine (110 mg, 0.472 mmol, Intermediate B2) and N-ethyldiisopropylamine (187 mg, 247 uL, 1.42 mmol) in dichloromethane (2 mL) was added dropwise a solution of 5-(4-methylthiazol-2-yl)-1H-pyrrole-3-sulfonyl chloride (161 mg, 0.613 mmol, Intermediate A8) in ethyl acetate (1 mL) at room temperature, and the mixture was stirred at room temperature for 16 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 flash chromatography (silica gel, 0% to 70% ethyl acetate in heptane) to give N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-(4-methylthiazol-2-yl)-1H-pyrrole-3-sulfonamide (35 mg, 17% yield) as an off-white solid. MS(ESI) m / z: 446.3 [M+H] + .

[0143] Example 21: 4-Benzyl-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrole-3-sulfonamide [ka] To a stirred suspension of [5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]amine (100 mg, 0.365 mmol, Intermediate B2) and potassium phosphate tribasic (286 mg, 1.35 mmol) in acetonitrile (800 μL) was added dropwise a solution of 4-benzyl-1H-pyrrole-3-sulfonyl chloride (389 mg, 0.547 mmol, Intermediate A5) in acetonitrile (2.2 mL) at room temperature. The reaction mixture was stirred at 70° C. for 3 days. The reaction mixture was brought to room temperature, poured into brine, and extracted with ethyl acetate / methanol. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica, 0% to 60% ethyl acetate in heptane) followed by reverse-phase flash column chromatography (column YMC-Triart C18, 12 nm, 5 μm, 100 × 30 mm, acetonitrile / water + 0.1% HCOOH) to give 4-benzyl-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrole-3-sulfonamide (5 mg, 3% yield) as a white powder. MS (ESI) m / z: 439.1 [M+H] + .

[0144] Example 22: 4-Benzyl-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrole-3-sulfonamide [ka] The title compound was prepared as a white solid from 5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-amine (Intermediate B1) instead of Intermediate B2, similar to Example 21. MS (ESI) m / z: 441.1 [M+H] + .

[0145] Example 23: N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-(3-fluoro-2-pyridyl)-1H-pyrrole-3-sulfonamide [ka] A mixture of 3-(2-amino-4,6-dimethoxy-pyrimidin-5-yl)propionitrile (50 mg, 0.240 mmol, Intermediate B7) and 5-(3-fluoro-2-pyridyl)-1H-pyrrole-3-sulfonyl chloride (76 mg, 0.288 mmol, Intermediate A3) in acetonitrile (1 mL) and pyridine (1 mL) was stirred at 60° C. overnight. The reaction mixture was concentrated in vacuo, and the residue was dissolved in ethyl acetate / water, 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% to 80% ethyl acetate in heptane) to give N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-(3-fluoro-2-pyridyl)-1H-pyrrole-3-sulfonamide (34 mg, 32% yield) as a gray solid. MS (ESI) m / z: 433.1 [M+H] + .

[0146] The following Examples 24-28 were prepared similarly to Example 23 by coupling the sulfonyl chloride intermediate A and amine intermediate B as shown. [Table 8]

[0147] Example 29: 4-[dideuterio-(3-fluorophenyl)methyl]-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrole-3-sulfonamide [ka] To a stirred solution of [5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]amine (55 mg, 0.227 mmol, Intermediate B4) in pyridine (0.5 mL) was added 4-[dideuterio-(3-fluorophenyl)methyl]-1H-pyrrole-3-sulfonyl chloride (179 mg, 0.272 mmol, Intermediate A13) in acetonitrile (1.5 mL) dropwise at room temperature, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into brine and extracted three times with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0% to 55% ethyl acetate in heptane) to give 4-[dideuterio-(3-fluorophenyl)methyl]-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrole-3-sulfonamide (39 mg, 35% yield) as a light brown solid. MS(ESI) m / z: 475.1 [M+H] + .

[0148] Example 30: 4-Benzyl-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrole-3-sulfonamide [ka] The title compound was prepared as a white powder from 4-benzyl-1H-pyrrole-3-sulfonyl chloride (Intermediate A5) instead of Intermediate A13, similar to Example 29. MS (ESI) m / z: 455.1 [M+H] + .

[0149] The following Examples 31-33 were prepared in a manner similar to Example 9 by coupling the sulfonyl chloride intermediate A and amine intermediate B as shown. [Table 9]

[0150] The following Examples 34-41 were prepared similarly to Example 3 by coupling the sulfonyl chloride intermediate A and amine intermediate B as shown. [Table 10] TIFF2026502630000057.tif78170

[0151] Example 42: N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(2-methylthiazol-5-yl)-1H-pyrrole-3-sulfonamide [ka]

[0152] Step 1: N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1-(p-tolylsulfonyl)pyrrole-3-sulfonamide [ka] To a mixture of 5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-amine (3.2 g, 13.6 mmol, Intermediate B4) in pyridine (60 mL) was added 1-(p-tolylsulfonyl)pyrrole-3-sulfonyl chloride (8.7 g, 27.21 mmol, CAS 881406-27-5, see WO 2022254027) at 0 °C, and the mixture was stirred at 70 °C for 12 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with saturated sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with methanol (50 mL) at 20 °C for 30 minutes to give 3.8 g of the first batch of product. The mother liquor was concentrated under reduced pressure and purified by flash silica gel chromatography (silica gel, 0-45% ethyl acetate in petroleum ether) to give the crude product, which was further purified by preparative HPLC (Phenomenex Luna C8, 250 x 50 mm x 10 μm, water (0.1% formic acid) / acetonitrile) to give a second batch of product (2.0 g), which was combined with the first batch to give N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1-(p-tolylsulfonyl)pyrrole-3-sulfonamide (5.8 g, 76% yield) as an off-white solid. MS (ESI) m / z: 519.0 [M+H] + .

[0153] Step 2: N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrole-3-sulfonamide [ka] To a mixture of N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1-(p-tolylsulfonyl)pyrrole-3-sulfonamide (3.6 g, 6.94 mmol) in methanol (36 mL) was added sodium hydroxide (4 M in water, 8.7 mL, 34.7 mmol) under nitrogen at 20° C., and the mixture was stirred for 2 hours at 80° C. The reaction mixture was quenched by adding 1 M hydrochloric acid at 20° C. until pH=7, and then concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex Luna C8, 250 x 50 mm x 10 μm, water (0.1% formic acid) / acetonitrile) to give N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrole-3-sulfonamide (2.15 g, 84% yield) as a pale yellow solid. MS (ESI) m / z: 365.0 [M+H] + .

[0154] Step 3: 5-Bromo-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrole-3-sulfonamide [ka] To a mixture of N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrole-3-sulfonamide (1.03 g, 2.83 mmol) in tetrahydrofuran (20 mL) was added N-bromosuccinimide (503 mg, 2.83 mmol) at −78° C., and the reaction was stirred at −78° C. under nitrogen for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with saturated sodium chloride solution (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex Luna C8, 250 x 50 mm x 10 μm, water (0.1% formic acid) / acetonitrile) and lyophilized to give 5-bromo-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrole-3-sulfonamide (620 mg, 44% yield) as a pale yellow solid. MS (ESI) m / z: 443.0 [M+H] + .

[0155] Step 4: N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-3-sulfonamide [ka] To a mixture of 5-bromo-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrole-3-sulfonamide (1.64 g, 3.7 mmol), bis(pinacolato)diboron (1.41 g, 5.55 mmol), and potassium acetate (726 mg, 7.4 mmol) in 1,4-dioxane (30 mL), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (271 mg, 0.37 mmol, 0.1 equiv.) was added under nitrogen at 20 °C, and the mixture was stirred at 100 °C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0-60% ethyl acetate in petroleum ether solution) to give N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-3-sulfonamide (870 mg, 46% yield) as a pale yellow solid. MS(ESI) m / z: 491.1 [M+H] + .

[0156] Step 5: N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(2-methylthiazol-5-yl)-1H-pyrrole-3-sulfonamide [ka] To a mixture of N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-3-sulfonamide (50 mg, 0.1 mmol), 5-bromo-2-methyl-thiazole (18 mg, 0.1 mmol) and tripotassium phosphate (65 mg, 0.31 mmol) in n-butanol (2 mL) under nitrogen at 20° C. was added XPhos Pd G4 (8.8 mg, 0.01 mmol, 0.1 equiv., CAS 1599466-81-5), and the reaction was then stirred at 80° C. under nitrogen for 2 hours. The reaction mixture was filtered and purified by preparative HPLC (column Phenomenex Luna C18 150 x 25 mm x 10 um, water + 0.1% formic acid / acetonitrile) to give N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(2-methylthiazol-5-yl)-1H-pyrrole-3-sulfonamide (16 mg, 32% yield) as a white solid. MS (ESI) m / z: 462.0 [M+H] + .

[0157] Example 43: N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-pyrimidin-2-yl-1H-pyrrole-3-sulfonamide [ka] To a mixture of N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-3-sulfonamide (80 mg, 0.16 mmol, preparation see Example 42), 2-bromopyrimidine (26 mg, 0.16 mmol), and tripotassium phosphate (104 mg, 0.49 mmol) in n-butanol (0.2 mL) was added [(di(1-adamantyl)-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (12 mg, 0.02 mmol, 0.1 equiv., CAS 1651823-59-4) under nitrogen at 20°C, and the reaction was stirred at 100°C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Xbridge 150 x 25 mm x 5 um, water (with ammonia hydroxide) / acetonitrile) to give the crude product (30 mg), which was further purified by preparative TLC (silica gel, SiO2, petroleum ether / ethyl acetate = 1:2) to give N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-pyrimidin-2-yl-1H-pyrrole-3-sulfonamide (6 mg, 8% yield) as a pale yellow solid. MS (ESI) m / z: 443.0 [M+H] + .

[0158] Example 44: N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(5-methylthiazol-2-yl)-1H-pyrrole-3-sulfonamide [ka] To a mixture of N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-3-sulfonamide (5.0 mg, 0.01 mmol, preparation see Example 42), 2-bromo-5-methylthiazole (1.8 mg, 0.01 mmol), potassium carbonate (4.23 mg, 0.03 mmol), and lithium chloride (1.3 mg, 0.03 mmol) in 1,4-dioxane (0.2 mL) and water (0.01 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (0.83 mg, 0.1 equiv.) at 20°C under nitrogen, and the reaction was then stirred at 90°C for 3 hours. The reaction mixture was filtered and purified by preparative HPLC (Phenomenex luna C18, 150 x 25 mm x 10 um, water (0.1% formic acid) / acetonitrile) to give N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(5-methylthiazol-2-yl)-1H-pyrrole-3-sulfonamide (4.6 mg, 98% yield) as a white solid. MS(ESI) m / z: 462.1 [M+H] + .

[0159] Example 45: N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-pyridazin-3-yl-1H-pyrrole-3-sulfonamide [ka] To a solution of N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-3-sulfonamide (80 mg, 0.16 mmol, preparation see Example 42), potassium carbonate (34 mg, 0.24 mmol), 3-bromopyridazine (26 mg, 0.16 mmol) in 1,4-dioxane (10 mL) and water (1.6 mL) under nitrogen was added tetrakis(triphenylphosphine)-palladium(0) (19 mg, 0.02 mmol, 0.1 equiv) and the reaction mixture was stirred at 100° C. for 3 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Phenomenex luna C18, 150 x 25 mm x 10 um, water (0.1% formic acid) / acetonitrile) to give N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-pyridazin-3-yl-1H-pyrrole-3-sulfonamide (11 mg, 15% yield) as a yellow solid. MS (ESI) m / z: 443.0 [M+H] + .

[0160] Example 46: 5-(3-chloro-2-pyridyl)-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrole-3-sulfonamide [ka] The title compound was prepared as a brown gum similar to Example 45 from 2-bromo-3-chloropyridine instead of 3-bromopyridazine. MS (ESI) m / z: 476.1 [M+H] + .

[0161] Example 47: N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-pyrimidin-4-yl-1H-pyrrole-3-sulfonamide [ka] The title compound was prepared as a pale yellow solid from 4-chloropyrimidine hydrochloride instead of 3-bromopyridazine in analogy to Example 45. MS (ESI) m / z: 443.0 [M+H] + .

[0162] Example 48: N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-pyrazin-2-yl-1H-pyrrole-3-sulfonamide [ka] To a mixture of N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-3-sulfonamide (80 mg, 0.16 mmol, preparation see Example 42), 2-bromopyrazine (26 mg, 0.16 mmol), and potassium phosphate tripotassium (104 mg, 0.49 mmol) in n-butanol (0.3 mL) was added XPhos Pd G4 (14 mg, 0.02 mmol, 0.1 equiv., CAS 1599466-81-5) under nitrogen at 20° C., and the mixture was stirred at 100° C. for 12 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Xbridge 150 x 25 mm x 5 um, water (with ammonium hydroxide) / acetonitrile) to give the crude product, which was further purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 1:2) to give N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-pyrazin-2-yl-1H-pyrrole-3-sulfonamide (15 mg, 20% yield) as a white solid. MS (ESI) m / z: 443.0 [M+H] + .

[0163] Example 49: N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(3-methyl-2-pyridyl)-1H-pyrrole-3-sulfonamide [ka] The title compound was prepared as a yellow solid similar to Example 48 from 2-bromo-3-methylpyridine instead of 2-bromopyrazine. MS (ESI) m / z: 456.1 [M+H] + .

[0164] Example 50: 5-Cyclobutyl-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrole-3-sulfonamide [ka]

[0165] Step 1: 5-Cyclobutyl-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1-(p-tolylsulfonyl)pyrrole-3-sulfonamide [ka] To a mixture of [5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]amine (80 mg, 0.361 mmol, Intermediate B1) and 5-cyclobutyl-1-tosyl-pyrrole-3-sulfonyl chloride (198 mg, 0.40 mmol, Intermediate A4) was added pyridine (2 mL). The mixture was stirred at room temperature for 2 hours, then heated to 80 °C and stirred for 20 hours. The reaction mixture was concentrated in vacuo, and the residue was purified by flash chromatography (silica gel, 0% to 40% ethyl acetate in heptane) to give 5-cyclobutyl-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1-(p-tolylsulfonyl)pyrrole-3-sulfonamide (69 mg, 33% yield) as a colorless gum. MS (ESI) m / z: 559.1 [M+H] + .

[0166] Step 2: 5-Cyclobutyl-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrole-3-sulfonamide [ka] To a stirred solution of 5-cyclobutyl-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1-(p-tolylsulfonyl)pyrrole-3-sulfonamide (67 mg, 0.115 mmol) in methanol (1 mL) was added 5 M aqueous potassium hydroxide (185 μL, 0.92 mmol), and the mixture was stirred at 85 °C for 30 min. The reaction mixture was poured into water and extracted twice with ethyl acetate. The organic layer was dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0% to 50% ethyl acetate in heptane) to give 5-cyclobutyl-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrole-3-sulfonamide (23 mg, 48.5% yield) as a white solid. MS (ESI) m / z: 405.1 [M+H] + .

[0167] Example 51: 5-Cyclobutyl-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrole-3-sulfonamide [ka] The title compound was prepared as a white solid from Intermediate B4 instead of Intermediate B1 in Step 1, analogously to Example 50, MS (ESI) m / z: 419.1 [M+H] + .

[0168] Reference example Reference example RE-A: [ka] RE-A is Example 436 of WO2022254027 and was synthesized according to the procedure described therein.

[0169] Reference example RE-B: [ka] RE-B is Example 90 of WO2022254027 and was synthesized according to the procedure described therein.

[0170] Reference example RE-C: [ka] RE-C is Example 406 of WO2022254027 and was synthesized according to the procedure described therein.

[0171] Reference example RE-D: [ka] RE-D is Example 403 of WO2022254027 and was synthesized according to the procedure described therein.

[0172] Example A The compound of formula I can be used in a manner known per se as the active ingredient to produce tablets of the following composition: Per tablet Active ingredient 200mg Microcrystalline cellulose 155mg Cornstarch 25mg Talc 25mg Hydroxypropyl methylcellulose 20mg 425mg

[0173] Example B The compound of formula I can be used in a manner known per se as the active ingredient to produce capsules of the following composition: Per tablet Active ingredient 100.0mg Cornstarch 20.0mg Lactose 95.0mg Talc 4.5mg Magnesium stearate 0.5mg 220.0mg

Claims

1. Formula I: 【Chemical Formula 66】 [In the formula, 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 ４ is H, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl is optionally substituted with oxo, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, or cyano; R ５ is H, halo, alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein the aryl, heteroaryl, arylalkyl, or heteroarylalkyl is optionally substituted with halo, alkyl, haloalkyl, alkoxy, haloalkoxy, or cyano; R ６ is H or halo] and pharmaceutically acceptable salts thereof.

2. R １ The compound of claim 1 , wherein is alkoxy.

3. R ２ 3. The compound of claim 1 or claim 2, wherein is cyclopropyl substituted with haloalkyl, haloalkoxy, cyanoalkyl, or cyano.

4. R ２ The compound of any one of claims 1 to 3, wherein is haloalkyl or haloalkoxy.

5. R ３ The compound of any one of claims 1 to 4, wherein is H or alkoxy.

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

7. R ４ is selected from cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl is optionally substituted with halo, alkyl, haloalkyl, alkoxy, haloalkoxy, or cyano.

8. R ４ but, i.H; ii. cyclobutyl; iii. 6-membered aryl; iv. a 5-membered heteroaryl containing one S heteroatom and one N heteroatom; v. 6-membered heteroaryl containing 1 or 2 N heteroatoms; vi. 6-membered aryl substituted with halo; vii. a 5-membered heteroaryl containing one S heteroatom and one N heteroatom substituted by alkyl; viii. a 6-membered heteroaryl containing one N heteroatom substituted with alkyl, halo, or both alkyl and oxy; The compound according to any one of claims 1 to 6, selected from:

9. R ４ but, i. 6-membered aryl; ii. a 5-membered heteroaryl containing one S heteroatom and one N heteroatom; iii. 6-membered heteroaryl containing one N heteroatom; iv. a 6-membered aryl substituted with halo; v. a 5-membered heteroaryl containing one S heteroatom and one N heteroatom substituted by alkyl; vi. 6-membered heteroaryl containing one N heteroatom substituted with alkyl or halo; The compound according to any one of claims 1 to 6, selected from:

10. R ４ is a 6-membered aryl or a 5- or 6-membered heteroaryl optionally substituted with halo and containing 1-2 heteroatoms independently selected from S and N.

11. R ５ 11. The compound of claim 10, wherein is H, arylalkyl, or arylalkyl substituted with halo.

12. R ５ The compound of any one of claims 1 to 11, wherein is H.

13. R ６ The compound of any one of claims 1 to 12, wherein is H.

14. 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 ４ is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl is optionally substituted with halo, alkyl, haloalkyl, alkoxy, haloalkoxy, or cyano; R ５ is H, halo, alkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein the aryl, heteroaryl, arylalkyl, or heteroarylalkyl is optionally substituted with halo, alkyl, haloalkyl, alkoxy, haloalkoxy, or cyano; R ６ is H or halo; 10. The compound of claim 1, and pharmaceutically acceptable salts thereof.

15. R １ is an alkoxy; R ２ is cyclopropyl substituted with haloalkyl, haloalkoxy, cyanoalkyl, or cyano; R ３ is H or alkoxy, R ４ but, i.H; ii. cyclobutyl; iii. 6-membered aryl; iv. a 5-membered heteroaryl containing one S heteroatom and one N heteroatom; v. 6-membered heteroaryl containing 1 or 2 N heteroatoms; vi. 6-membered aryl substituted with halo; vii. a 5-membered heteroaryl containing one S heteroatom and one N heteroatom substituted by alkyl; viii. a 6-membered heteroaryl containing one N heteroatom substituted with alkyl, halo, or both alkyl and oxy; and R ５ is H, arylalkyl, or arylalkyl substituted with halo; R ６ is H, 10. The compound of claim 1, and pharmaceutically acceptable salts thereof.

16. R １ is an alkoxy; R ２ is cyclopropyl substituted with haloalkyl, haloalkoxy, cyanoalkyl, or cyano; R ３ is an alkoxy; R ４ but, i. 6-membered aryl; ii. a 5-membered heteroaryl containing one S heteroatom and one N heteroatom; iii. 6-membered heteroaryl containing one N heteroatom; iv. a 6-membered aryl substituted with halo; v. a 5-membered heteroaryl containing one S heteroatom and one N heteroatom substituted by alkyl; vi. 6-membered heteroaryl containing one N heteroatom substituted with alkyl or halo; and R ５ is H, R ６ is H, 10. The compound of claim 1, and pharmaceutically acceptable salts thereof.

17. R １ is an alkoxy; R ２ is haloalkyl or haloalkoxy; R ３ is an alkoxy; R ４ is a 6-membered aryl or a 5- or 6-membered heteroaryl optionally substituted with halo and containing 1-2 heteroatoms independently selected from S and N; R ５ is H, R ６ is H, 10. The compound of claim 1, and pharmaceutically acceptable salts thereof.

18. below: N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-phenyl-1H-pyrrole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-phenyl-1H-pyrrole-3-sulfonamide; N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-phenyl-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-thiazol-2-yl-1H-pyrrole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(3-fluoro-2-pyridyl)-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-(3-fluoro-2-pyridyl)-1H-pyrrole-3-sulfonamide; N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(3-fluoro-2-pyridyl)-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(3-fluoro-2-pyridyl)-1H-pyrrole-3-sulfonamide; and pharmaceutically acceptable salts thereof.

19. below: N-[5-(2,2-difluoroethoxy)-4-methoxy-pyrimidin-2-yl]-5-thiazol-2-yl-1H-pyrrole-3-sulfonamide; N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-thiazol-2-yl-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-isothiazol-3-yl-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-phenyl-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-thiazol-2-yl-1H-pyrrole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-thiazol-2-yl-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-thiazol-4-yl-1H-pyrrole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-thiazol-4-yl-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-(2-pyridyl)-1H-pyrrole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(2-pyridyl)-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(2-pyridyl)-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-(4-methylthiazol-2-yl)-1H-pyrrole-3-sulfonamide; 4-benzyl-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrole-3-sulfonamide; 4-benzyl-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrole-3-sulfonamide; N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-(3-fluoro-2-pyridyl)-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-5-(3-fluoro-2-pyridyl)-1H-pyrrole-3-sulfonamide; N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-thiazol-4-yl-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-thiazol-4-yl-1H-pyrrole-3-sulfonamide; N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(2-pyridyl)-1H-pyrrole-3-sulfonamide; 4-benzyl-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrole-3-sulfonamide; 4-[dideuterio-(3-fluorophenyl)methyl]-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrole-3-sulfonamide; 4-benzyl-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrole-3-sulfonamide; N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(4-methylthiazol-2-yl)-1H-pyrrole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(4-methylthiazol-2-yl)-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(4-methylthiazol-2-yl)-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-5-thiazol-2-yl-1H-pyrrole-3-sulfonamide; N-[5-(2-cyanocyclopropyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-thiazol-2-yl-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-thiazol-5-yl-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-(2-fluorophenyl)-1H-pyrrole-3-sulfonamide; N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(2-fluorophenyl)-1H-pyrrole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(2-fluorophenyl)-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(2-fluorophenyl)-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(2-keto-1-methyl-3-pyridyl)-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(2-methylthiazol-5-yl)-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-pyrimidin-2-yl-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(5-methylthiazol-2-yl)-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-pyridazin-3-yl-1H-pyrrole-3-sulfonamide; 5-(3-chloro-2-pyridyl)-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-pyrimidin-4-yl-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-pyrazin-2-yl-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(3-methyl-2-pyridyl)-1H-pyrrole-3-sulfonamide; 5-cyclobutyl-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrole-3-sulfonamide; 5-cyclobutyl-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrole-3-sulfonamide; 18. The compound according to any one of claims 1 to 17, selected from: and pharmaceutically acceptable salts thereof.

20. below: N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-phenyl-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-thiazol-2-yl-1H-pyrrole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(3-fluoro-2-pyridyl)-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-(3-fluoro-2-pyridyl)-1H-pyrrole-3-sulfonamide; N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(3-fluoro-2-pyridyl)-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(3-fluoro-2-pyridyl)-1H-pyrrole-3-sulfonamide; N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-thiazol-2-yl-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-isothiazol-3-yl-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-phenyl-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-thiazol-2-yl-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-(2-pyridyl)-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(2-pyridyl)-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-(4-methylthiazol-2-yl)-1H-pyrrole-3-sulfonamide; N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-(3-fluoro-2-pyridyl)-1H-pyrrole-3-sulfonamide; N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(2-pyridyl)-1H-pyrrole-3-sulfonamide; N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(4-methylthiazol-2-yl)-1H-pyrrole-3-sulfonamide; N-[5-(2-cyanocyclopropyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-thiazol-2-yl-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-thiazol-5-yl-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-5-(2-fluorophenyl)-1H-pyrrole-3-sulfonamide; N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(2-fluorophenyl)-1H-pyrrole-3-sulfonamide; 5-(3-chloro-2-pyridyl)-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-5-(3-methyl-2-pyridyl)-1H-pyrrole-3-sulfonamide; 20. The compound according to any one of claims 1 to 19, selected from: and pharmaceutically acceptable salts thereof.

21. 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; 【Transformation 67】 [In the formula, R １ , R ２ , R ３ , R ３ , R ４ , R ５ and R ６ is as above] A process for preparing a compound according to any one of claims 1 to 20.

22. A compound according to any one of claims 1 to 20 for use as a therapeutically active substance.

23. A compound according to any one of claims 1 to 20 for use in the treatment of a disease modulated by GPR17.

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

25. 21. Use of a compound according to any one of claims 1 to 20 for the treatment or prevention of direct damage to the myelin sheath (including but not limited to centropontine and extrapontine myelinolysis, carbon monoxide poisoning, nutritional deficiencies, and viral-induced demyelination), demyelinating disorders (including but not limited to multiple sclerosis, acute and multiphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorders, and leukodystrophies), 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 conditions resulting from inflammation of the CNS, for example following encephalitis, primary vasculitis, meningitis, and obesity.

26. Use of a compound according to any one of claims 1 to 20 for treating or preventing multiple sclerosis.

27. 21. Use of a compound according to any one of claims 1 to 20 for the preparation of a medicament for the treatment or prevention of direct damage to the myelin sheath (including but not limited to centropontine and extrapontine myelinolysis, carbon monoxide poisoning, nutritional deficiencies, and viral-induced demyelination), demyelinating disorders (including but not limited to multiple sclerosis, acute and multiphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorders, and leukodystrophies), 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 conditions resulting from inflammation of the CNS, for example following encephalitis, primary vasculitis, meningitis, and obesity.

28. 21. A compound according to any one of claims 1 to 20 for use in the treatment or prevention of direct damage to the myelin sheath (including but not limited to centropontine and extrapontine myelinolysis, carbon monoxide poisoning, nutritional deficiencies, and viral-induced demyelination), demyelinating disorders (including but not limited to multiple sclerosis, acute and multiphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorders, and leukodystrophies), 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 conditions resulting from inflammation of the CNS, for example following encephalitis, primary vasculitis, meningitis, and obesity.

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

30. 21. A method for treating or preventing direct damage to the myelin sheath (including but not limited to centropontine and extrapontine myelinolysis, carbon monoxide poisoning, nutritional deficiencies, and viral-induced demyelination), demyelinating disorders (including but not limited to multiple sclerosis, acute and multiphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorders, and leukodystrophies), 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 conditions resulting from inflammation of the CNS, for example, after encephalitis, primary vasculitis, meningitis, and obesity, comprising administering to a patient in need thereof an effective amount of a compound of any one of claims 1 to 20.

31. 21. A method for treating or preventing multiple sclerosis, comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 20.

32. A compound according to any one of claims 1 to 20 when produced according to the process of claim 21.

33. The invention as hereinbefore described.

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