Novel imidazopyridine and pyrazolopyridine sulfonamide derivatives.

Abstract

The present invention relates to compounds of general formula I TIFF2025525574000082.tif51165 (In the formula, R 1 , R 2 , X1, X2, X3 and W are as described herein), compositions comprising said compounds, and methods of using said 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] R 1 is alkyl, cyano, cyanoalkyl, cyclopropyl, halo, haloalkoxy, haloalkyl, or oxetanyl; R 2 is alkoxy, H or halo; X1 is N and X2 is CR 12 and X 3 is CR 13 or X1 is CR 11 and X2 is CR 12 and X3 is CR 13 or X1 is CR 11 X2 is N, and X3 is N or CR 13 and R 11 is alkoxy, H, or halo; R 12 is H or halo, R 13 is alkoxy, H, halo, or haloalkoxy; W is selected from ring systems A, B, C, D or E; [ka] Y1 is CR 4 or N, R 3 is alkoxy, alkyl, cyano, cyclopropyl, H, halo, haloalkoxy, haloalkyl, hydroxyalkyl, hydroxyoxetanyl, or oxetanyl; R 4 is alkoxy, alkyl, cyano, H, or halo; R 5 is alkyl, halo, haloalkyl, cyclopropyl, or oxetanyl; R 6 is H, cyano, alkyl, alkoxy or halo; Y 2a But, CR 8a or O and Y 2b But, CR 8b or O and Y 2a and Y 2b Only one of the two can be O, n is 0 or 1, R 7a and R 7b is independently selected from H, alkyl, alkoxy, or haloalkyl; R 8a and R 8b is independently selected from H or alkyl; Y3 is O or CH2, R 9a and R 9b is independently selected from H, alkyl, alkoxy, or haloalkyl; Y4 is NR 10 and R 10 is alkyl or haloalkyl, and pharmaceutically acceptable salts thereof.

[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 despite the abundant presence of oligodendrocyte progenitor cells (OPCs) throughout the developing and adult CNS, and chronic demyelinating diseases impair their transition to myelinating oligodendrocytes and production of reparative myelin sheaths around demyelinated axons. During development, myelination proceeds in a highly orderly manner, with OPCs characterized by the expression of markers such as neural / glial antigen 2 (NG2) and platelet-derived growth factor alpha (PDGFRα) and differentiating into oligodendrocytes, which lose expression of NG2 and PDGFRα and acquire expression of markers such as myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG). The production of myelin 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, L.O. et al. (2018). Cell 175, 1811-1826, e21, "Spatiotemporal Control of CNS Myelination by Oligodendrocyte Programmed Cell Death through the TFEB-PUMA Axis"). Myelin not only helps protect axons and facilitate neuronal communication, 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 through intracellular association with small heterotrimeric G protein complexes composed of G subunits. The G subunits of GPCRs mediate downstream intracellular signaling pathways. α GPR17 is a conjugate for the G α i / o GPR17 is known to directly couple to G, which leads to inhibition of adenylate cyclase activity and a decrease in cyclic AMP production (cAMP). GPR17 also binds to G, which targets phospholipase C. q / 11It has been shown that phospholipase C binds to phosphoinositides. 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 in 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 of the CNS and absent from 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 expression is downregulated in mature myelinating oligodendrocytes (Boda, E. et al. (2011), Glia 59, 1958-1973, "The GPR17 receptor in NG2-expressing cells: Focus on in vivo cell maturation and participation in acute trauma and chronic damage") (Dziedzic, A. et al. (2020). Int. J. Mol. Sci. 21, 1852, "The gpr17 receptor - a promising goal for therapy and a potential marker of the neurodegenerative process in multiple sclerosis") (Fumagalli, M. et al. (2011), J Biol Chem 286, 10593-10604, "Phenotypic changes, signaling pathway, and functional correlates of GPR17-expressing neural precursor cells during oligodendrocyte differentiation'').GPR17 knockout animals have been shown to exhibit premature myelination throughout the CNS. Conversely, transgenic mice overexpressing GPR17 in oligodendrocytes with the CNP-Cre (2',3'-cyclic nucleotide 3'-phosphodiesterase) promoter exhibited myelinogenesis defects, consistent with a predicted 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"). Therefore, 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 demyelinated 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, namely, 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 preserving axons.

[0008] Due to the essential role that myelination plays in nervous system function, promoting OPC oligodendrocyte differentiation may have implications in multiple diseases in which white matter defects / irregularities resulting from either loss of myelinating oligodendrocytes or disruption of OPC 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 may be used to result in positive disease outcomes in this manner include, but are not limited to: Direct damage to the myelin sheath: - Central pontine myelinolysis and extrapontine myelinolysis due to overly rapid correction of hyponatremia in metabolic conditions resulting in destruction of central nervous system myelin, including, but not limited to, alcoholism, liver disease, and post-transplant immunosuppression -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 GPR17 and modulate GPR17 activity.

[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] (In the formula, R 1 is alkyl, cyano, cyanoalkyl, cyclopropyl, halo, haloalkoxy, haloalkyl or is oxetanyl, R 2 is alkoxy, H or halo; X1 is N and X2 is CR 12 and X 3 is CR 13 or X1 is CR 11 and X2 is CR 12 and X3 is CR 13 or X1 is CR 11 X2 is N, and X3 is N or CR 13 and R 11 is alkoxy, H, or halo; R 12is H or halo, R 13 is alkoxy, H, halo, or haloalkoxy; W is selected from ring systems A, B, C, D or E; [ka] Y1 is CR 4 or N, R 3 is alkoxy, alkyl, cyano, cyclopropyl, H, halo, haloalkoxy, haloalkyl, hydroxyalkyl, hydroxyoxetanyl, or oxetanyl; R 4 is alkoxy, alkyl, cyano, H, or halo; R 5 is alkyl, halo, haloalkyl, cyclopropyl, or oxetanyl; R 6 is H, cyano, alkyl, alkoxy or halo; Y 2a But, CR 8a or O and Y 2b But, CR 8b or O and Y 2a and Y 2b Only one of the two can be O, n is 0 or 1, R 7a and R 7b is independently selected from H, alkyl, alkoxy, or haloalkyl; R 8a and R 8b is independently selected from H or alkyl; Y3 is O or CH2, R 9a and R 9b is independently selected from H, alkyl, alkoxy, or haloalkyl; Y4 is NR 10 and R 10 is alkyl or haloalkyl) and pharmaceutically acceptable salts thereof.

[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. Specific alkyl groups include methyl and ethyl. 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. Particular examples are methoxy and ethoxy.

[0016] The term "cyano" refers to the group --C.ident.N.

[0017] "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 cyanomethyl.

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

[0019] 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. Particular examples are difluoromethyl, difluoroethyl, difluoropropyl and trifluoromethyl.

[0020] 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, difluoromethoxy, and difluoroethoxy.

[0021] The term "hydroxy" refers to an --OH group.

[0022] The term "hydroxyalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group has been replaced by a hydroxy group. Examples of hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxymethylpropyl, and dihydroxypropyl. A particular example is 1-hydroxy-1-methyl-ethyl.

[0023] 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 salts formed with hydrochloric acid to produce hydrochloride, dihydrochloride, or trihydrochloride.

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

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

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

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

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

[0029] Embodiments of the present invention also provide 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.

[0030] An embodiment of the present invention provides a compound according to formula I described herein, wherein Y 2a is CH2 and Y 2b is CR 8b or O and R 8b is H or alkyl.

[0031] Embodiments of the present invention provide compounds according to Formula I described herein, wherein R 9a or R 9b is alkyl and the other is H.

[0032] Embodiments of the present invention provide compounds according to Formula I described herein, wherein R 1 is alkyl, cyanoalkyl, cyclopropyl, halo, haloalkoxy or haloalkyl.

[0033] Embodiments of the present invention provide compounds according to Formula I described herein, wherein R 2 is alkoxy or halo.

[0034] Embodiments of the present invention provide compounds according to Formula I described herein, wherein R 11 is alkoxy or H.

[0035] Embodiments of the present invention provide compounds according to Formula I described herein, wherein R 12 is H.

[0036] Embodiments of the present invention provide compounds according to Formula I described herein, wherein R 13 is an alkoxy.

[0037] An embodiment of the present invention provides a compound according to Formula I described herein, wherein W is selected from ring systems A, B, or C.

[0038] Embodiments of the present invention provide compounds according to Formula I described herein, wherein R 3 is alkoxy, alkyl, cyclopropyl, halo, haloalkoxy, haloalkyl, hydroxyalkyl, or oxetanyl.

[0039] Embodiments of the present invention provide compounds according to Formula I described herein, wherein R 4 is alkoxy, cyano, H or halo.

[0040] Embodiments of the present invention provide compounds according to Formula I described herein, wherein R 5 is alkyl, halo, or oxetanyl.

[0041] Embodiments of the present invention provide compounds according to Formula I described herein, wherein R 6 is cyano or H.

[0042] Embodiments of the present invention provide compounds according to Formula I described herein, wherein R 5 is the halo and R 6 is H.

[0043] Embodiments of the present invention provide compounds according to Formula I described herein, wherein R 10 is alkyl.

[0044] Embodiments of the present invention provide compounds according to Formula I described herein, wherein R7a , R 7b , R 8a and R 8b are all H, then X1 is N and n is 1.

[0045] One embodiment of the present invention is a compound according to formula I described herein (In the formula, R 1 is alkyl, cyano, cyanoalkyl, cyclopropyl, halo, haloalkoxy, haloalkyl or is oxetanyl, R 2 is alkoxy, H or halo; X1 is N and X2 is CR 12 and X 3 is CR 13 or X1 is CR 11 and X2 is CR 12 and X3 is CR 13 or X1 is CR 11 X2 is N, and X3 is N or CR 13 and R 11 is alkoxy, H, or halo; R 12 is H or halo, R 13 is alkoxy, H, halo, or haloalkoxy; W is selected from ring systems A, B, C, D or E; [ka] Y1 is CR 4 or N, R 3 is alkoxy, alkyl, cyano, cyclopropyl, H, halo, haloalkoxy, haloalkyl, hydroxyalkyl, hydroxyoxetanyl, or oxetanyl; R 4 is alkoxy, alkyl, cyano, H, or halo; R 5 is alkyl, halo, or oxetanyl; R 6 is cyano or H, Y 2a is CH2 and Y 2b is CR 8b or O and R 8b is H or alkyl, n is 0 or 1, R 7a and R 7b is independently selected from H, alkyl, alkoxy, or haloalkyl; Y3 is O or CH2, R 9a or R 9b is alkyl and the other is H, Y4 is NR 10 and R 10 is alkyl) and pharmaceutically acceptable salts thereof.

[0046] One embodiment of the present invention is a compound according to formula I described herein (In the formula, R 1 is alkyl, cyano, cyanoalkyl, cyclopropyl, halo, haloalkoxy, haloalkyl or is oxetanyl, R 2 is alkoxy, H or halo; X1 is N and X2 is CR 12 and X 3 is CR 13 or X1 is CR 11 and X2 is CR 12 and X3 is CR 13 or X1 is CR 11 X2 is N, and X3 is N or CR 13 and R 11 is alkoxy, H, or halo; R12 is H or halo, R 13 is alkoxy, H, halo, or haloalkoxy; W is selected from ring systems A, B, C, D or E; [ka] Y1 is CR 4 or N, R 3 is alkoxy, alkyl, cyano, cyclopropyl, H, halo, haloalkoxy, haloalkyl, hydroxyalkyl, hydroxyoxetanyl, or oxetanyl; R 4 is alkoxy, alkyl, cyano, H, or halo; R 5 is alkyl, halo, or oxetanyl; R 6 is cyano or H, Y 2a is CH2 and Y 2b is CR 8b or O and R 8b is H or alkyl, n is 0 or 1, R 7a and R 7b is independently selected from H, alkyl, alkoxy, or haloalkyl; Y3 is O or CH2, R 9a or R 9b is alkyl and the other is H, Y4 is NR 10 and R 10 is alkyl, R 7a , R 7b , R 8a and R 8b If all are H, then X1 is N and n is 1) and pharmaceutically acceptable salts thereof.

[0047] One embodiment of the present invention is a compound according to formula I described herein (In the formula, R 1 is alkyl, cyanoalkyl, cyclopropyl, halo, haloalkoxy or haloalkyl; R 2 is alkoxy or halo; X1 is N and X2 is CR 12 and X 3 is CR 13 or X1 is CR 11 and X2 is CR 12 and X3 is CR 13 or X1 is CR 11 X2 is N, and X3 is N or CR 13 and R 11 is alkoxy or H, R 12 is H, R 13 is alkoxy, halo, or haloalkoxy; W is selected from ring systems A, B or C; [ka] Y1 is CR 4 or N, R 3 is alkoxy, alkyl, cyclopropyl, halo, haloalkoxy, haloalkyl, hydroxyalkyl, or oxetanyl; R 4 is alkoxy, cyano, H or halo; R 5 is the halo, R 6 is H, Y 2a is CH2 and Y 2b is CR 8b or O and R 8bis H or alkyl, n is 1, R 7a and R 7b are independently selected from H, alkyl, or haloalkyl and pharmaceutically acceptable salts thereof.

[0048] One embodiment of the present invention is a compound according to formula I described herein (In the formula, R 1 is alkyl, cyanoalkyl, cyclopropyl, halo, haloalkoxy or haloalkyl; R 2 is alkoxy or halo; X1 is N and X2 is CR 12 and X 3 is CR 13 or X1 is CR 11 and X2 is CR 12 and X3 is CR 13 or X1 is CR 11 X2 is N, and X3 is N or CR 13 and R 11 is alkoxy or H, R 12 is H, R 13 is alkoxy, halo, or haloalkoxy; W is selected from ring systems A, B or C; [ka] Y1 is CR 4 or N, R 3 is alkoxy, alkyl, cyclopropyl, halo, haloalkoxy, haloalkyl, hydroxyalkyl, or oxetanyl; R 4 is alkoxy, cyano, H or halo; R 5 is the halo, R 6 is H, Y 2a is CH2 and Y 2b is CR 8b or O and R 8b is H or alkyl, n is 1, R 7a and R 7b is independently selected from H, alkyl, or haloalkyl; R 7a , R 7b , R 8a and R 8b If all are H, then X1 is N and n is 1) and pharmaceutically acceptable salts thereof.

[0049] Specific examples of compounds of formula I described herein are: 7-Bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide; 7-Bromo-N-[4-(cyanomethyl)-5-fluoro-2-methoxy-phenyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-8-methoxy-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-(difluoromethoxy)imidazo[1,2-a]pyridine-3-sulfonamide; 7-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-8-fluoro-imidazo[1,2-a]pyridine-3-sulfonamide; 7-Bromo-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-chloro-N-[6-(3,3-difluoropropyl)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Bromo-N-[5-(2,2-difluoroethyl)-3-fluoro-6-methoxy-2-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-chloro-N-[6-(2,2-difluoroethyl)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-8-methoxy-imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-(difluoromethyl)imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methoxy-imidazo[1,2-a]pyridine-3-sulfonamide; 7-Cyclopropyl-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-ethyl-imidazo[1,2-a]pyridine-3-sulfonamide; N-[4-(cyanomethyl)-5-fluoro-2-methoxy-phenyl]-7-cyclopropyl-imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]-8-methoxy-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide; N-[4-(cyanomethyl)-5-fluoro-2-methoxy-phenyl]-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide; 7-Bromo-N-[5-(cyanomethyl)-3-fluoro-6-methoxy-2-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-chloro-N-[6-(cyanomethyl)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-sulfonamide; 7-chloro-N-[5-(2,2-difluoroethyl)-3-fluoro-6-methoxy-2-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-chloro-N-(6-cyclopropyl-5-fluoro-2-methoxy-3-pyridyl)imidazo[1,2-a]pyridine-3-sulfonamide; 7-Bromo-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 8-cyano-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide; 7-Cyclopropyl-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methoxy-imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7,8-dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-(trifluoromethyl)imidazo[1,2-a]pyridine-3-sulfonamide; N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-8-methoxy-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide; 8-cyano-7-cyclopropyl-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Bromo-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[5-(cyanomethyl)-3-fluoro-6-methoxy-2-pyridyl]-7-methoxy-imidazo[1,2-a]pyridine-3-sulfonamide; 7-Cyclopropyl-N-[5-(2,2-difluoroethyl)-3-fluoro-6-methoxy-2-pyridyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methoxy-imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[2,6-bis(difluoromethoxy)-5-fluoro-3-pyridyl]-7-chloro-imidazo[1,2-a]pyridine-3-sulfonamide; 7-chloro-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-chloro-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-sulfonamide; 7-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; 8-cyano-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide; 7-chloro-N-(5-cyclopropyl-3-fluoro-6-methoxy-2-pyridyl)imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7,7-dimethyl-6,8-dihydro-5H-imidazo[1,2-a]pyridine-3-sulfonamide; 7-Bromo-N-(5-bromo-4,6-dimethoxy-pyrimidin-2-yl)imidazo[1,2-a]pyridine-3-sulfonamide; 7-Bromo-N-[3-fluoro-5-(2-fluoroethoxy)-6-methoxy-2-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methyl-imidazo[1,2-a]pyrimidine-3-sulfonamide; 7-Cyclopropyl-N-[5-(2,2-difluoroethoxy)-3-fluoro-6-methoxy-2-pyridyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-8-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-sulfonamide; 7-chloro-N-[5-(2,2-difluoroethoxy)-3-fluoro-6-methoxy-2-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-chloro-8-cyano-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methyl-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine-3-sulfonamide; N-(4,6-dimethoxy-5-methyl-pyrimidin-2-yl)-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide; N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-7-methoxy-imidazo[1,2-a]pyridine-3-sulfonamide; N-[2,6-bis(difluoromethoxy)-5-fluoro-3-pyridyl]-7-cyclopropyl-imidazo[1,2-a]pyrimidine-3-sulfonamide; N-(4-bromo-2,5-difluoro-phenyl)-8-methoxy-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-8-keto-7-methyl-imidazo[1,2-a]pyrazine-3-sulfonamide; 7-cyano-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 8-cyano-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methoxy-imidazo[1,2-a]pyridine-3-sulfonamide; 7-chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-8-methoxy-imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methoxy-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-sulfonamide; 7-chloro-N-(4-(cyanomethyl)-2,5-difluorophenyl)imidazo[1,2-a]pyridine-3-sulfonamide; 8-cyano-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-(difluoromethoxy)imidazo[1,2-a]pyridine-3-sulfonamide; N-[2,6-bis(difluoromethoxy)-5-fluoro-3-pyridyl]-8-cyano-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide; 8-cyano-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide; 7-chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-8-fluoro-imidazo[1,2-a]pyridine-3-sulfonamide; 8-cyano-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-chloro-N-[5-fluoro-2-methoxy-6-(oxetan-3-yl)-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-8-methyl-imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-6-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-sulfonamide; N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-7-methoxy-imidazo[1,2-a]pyrimidine-3-sulfonamide; 7-chloro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-sulfonamide; N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-7-methyl-imidazo[1,2-a]pyrimidine-3-sulfonamide; 6-Bromo-N-[6-(cyanomethyl)-5-fluoro-2-methoxy-3-pyridyl]pyrazolo[1,5-a]pyridine-3-sulfonamide; 6-Bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]pyrazolo[1,5-a]pyridine-3-sulfonamide; 6-Bromo-N-[5-(cyanomethyl)-3-fluoro-6-methoxy-2-pyridyl]pyrazolo[1,5-a]pyridine-3-sulfonamide; 6-Bromo-N-[3-fluoro-5-(2-fluoroethoxy)-6-methoxy-2-pyridyl]pyrazolo[1,5-a]pyridine-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethoxy)-3-fluoro-6-methoxy-2-pyridyl]pyrazolo[1,5-a]pyridine-3-sulfonamide; 6-Bromo-N-(6-cyclopropyl-5-fluoro-2-methoxy-3-pyridyl)pyrazolo[1,5-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-sulfonamide; 7-cyano-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-6-methyl-pyrazolo[1,5-a]pyridine-3-sulfonamide; 6-Bromo-N-[4-(difluoromethoxy)-2,5-difluorophenyl]pyrazolo[1,5-a]pyridine-3-sulfonamide; 6-Bromo-N-(4-bromo-2,5-difluoro-phenyl)pyrazolo[1,5-a]pyridine-3-sulfonamide; 6-Bromo-N-[5-fluoro-2-methoxy-6-(oxetan-3-yl)-3-pyridyl]pyrazolo[1,5-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-6-methyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-3-sulfonamide; N-[4-(cyanomethyl)-5-fluoro-2-methoxy-phenyl]-7-cyclopropyl-imidazo[1,2-a]pyridine-3-sulfonamide; 7-Cyclopropyl-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Cyclopropyl-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[5-(cyanomethyl)-3-fluoro-6-methoxy-2-pyridyl]-7-cyclopropyl-imidazo[1,2-a]pyridine-3-sulfonamide; 7-Cyclopropyl-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; N-(4-cyano-2,5-difluoro-phenyl)-8-methoxy-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide; 6-Bromo-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridyl]pyrazolo[1,5-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-(oxetan-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide; N-[4-(cyanomethyl)-5-fluoro-2-methoxy-phenyl]-7-(oxetan-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide; N-[5-(2,2-difluoroethyl)-3-fluoro-6-methoxy-2-pyridyl]-7-(oxetan-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-(oxetan-3-yl)imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-6-(oxetan-3-yl)pyrazolo[1,5-a]pyridine-3-sulfonamide; 7-Bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-(1-hydroxy-1-methyl-ethyl)imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide, and pharmaceutically acceptable salts thereof.

[0050] Preferred examples of compounds of formula I described herein are: 7-Bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide; 7-Bromo-N-[4-(cyanomethyl)-5-fluoro-2-methoxy-phenyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-8-methoxy-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-(difluoromethoxy)imidazo[1,2-a]pyridine-3-sulfonamide; 7-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-8-fluoro-imidazo[1,2-a]pyridine-3-sulfonamide; 7-Bromo-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-chloro-N-[6-(3,3-difluoropropyl)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Bromo-N-[5-(2,2-difluoroethyl)-3-fluoro-6-methoxy-2-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-chloro-N-[6-(2,2-difluoroethyl)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-8-methoxy-imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-(difluoromethyl)imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methoxy-imidazo[1,2-a]pyridine-3-sulfonamide; 7-Cyclopropyl-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-ethyl-imidazo[1,2-a]pyridine-3-sulfonamide; N-[4-(cyanomethyl)-5-fluoro-2-methoxy-phenyl]-7-cyclopropyl-imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]-8-methoxy-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide; N-[4-(cyanomethyl)-5-fluoro-2-methoxy-phenyl]-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide; 7-Bromo-N-[5-(cyanomethyl)-3-fluoro-6-methoxy-2-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-chloro-N-[6-(cyanomethyl)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-sulfonamide; 7-chloro-N-[5-(2,2-difluoroethyl)-3-fluoro-6-methoxy-2-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-chloro-N-(6-cyclopropyl-5-fluoro-2-methoxy-3-pyridyl)imidazo[1,2-a]pyridine-3-sulfonamide; 7-Bromo-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 8-cyano-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide; 7-Cyclopropyl-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methoxy-imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7,8-dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-(trifluoromethyl)imidazo[1,2-a]pyridine-3-sulfonamide; N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-8-methoxy-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide; 8-cyano-7-cyclopropyl-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Bromo-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[5-(cyanomethyl)-3-fluoro-6-methoxy-2-pyridyl]-7-methoxy-imidazo[1,2-a]pyridine-3-sulfonamide; 7-Cyclopropyl-N-[5-(2,2-difluoroethyl)-3-fluoro-6-methoxy-2-pyridyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methoxy-imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[2,6-bis(difluoromethoxy)-5-fluoro-3-pyridyl]-7-chloro-imidazo[1,2-a]pyridine-3-sulfonamide; 7-chloro-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-chloro-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-sulfonamide; 7-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; 8-cyano-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide; 7-chloro-N-(5-cyclopropyl-3-fluoro-6-methoxy-2-pyridyl)imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7,7-dimethyl-6,8-dihydro-5H-imidazo[1,2-a]pyridine-3-sulfonamide; 7-Bromo-N-(5-bromo-4,6-dimethoxy-pyrimidin-2-yl)imidazo[1,2-a]pyridine-3-sulfonamide; 7-Bromo-N-[3-fluoro-5-(2-fluoroethoxy)-6-methoxy-2-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methyl-imidazo[1,2-a]pyrimidine-3-sulfonamide; 7-Cyclopropyl-N-[5-(2,2-difluoroethoxy)-3-fluoro-6-methoxy-2-pyridyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-8-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-sulfonamide; 7-chloro-N-[5-(2,2-difluoroethoxy)-3-fluoro-6-methoxy-2-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-chloro-8-cyano-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methyl-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine-3-sulfonamide; N-(4,6-dimethoxy-5-methyl-pyrimidin-2-yl)-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide; 6-Bromo-N-(6-cyclopropyl-5-fluoro-2-methoxy-3-pyridyl)pyrazolo[1,5-a]pyridine-3-sulfonamide; N-[4-(cyanomethyl)-5-fluoro-2-methoxy-phenyl]-7-cyclopropyl-imidazo[1,2-a]pyridine-3-sulfonamide; 7-Cyclopropyl-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Cyclopropyl-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[5-(cyanomethyl)-3-fluoro-6-methoxy-2-pyridyl]-7-cyclopropyl-imidazo[1,2-a]pyridine-3-sulfonamide; 7-Cyclopropyl-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; 6-Bromo-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridyl]pyrazolo[1,5-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-(oxetan-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide; 7-Bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-(1-hydroxy-1-methyl-ethyl)imidazo[1,2-a]pyridine-3-sulfonamide, and pharmaceutically acceptable salts thereof.

[0051] The processes for the preparation of compounds of formula I described herein are an object of the present invention.

[0052] The present compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, such as the process described below, which comprises reacting a compound of formula V with a compound of formula VI in the presence of a base to provide a compound of formula I: [ka] In the formula, R 1 , R 2 , X1, X2, X3 and W are as described above.

[0053] General synthetic scheme Compounds of formula I can be prepared according to variations of the above process and the following Scheme 1. Starting materials are commercially available or can be prepared according to known methods.

[0054] Scheme 1 [ka] Compounds of general formula Ia can be prepared by reacting sulfonyl chloride V with 2-aminopyrimidine, 2-aminopyridine, 3-aminopyridine, or aniline VI in the presence of a base (e.g., pyridine). Sulfonyl chloride V can be prepared from intermediate II in the presence of a chlorosulfonylating agent (e.g., chlorosulfonic acid or trimethylsilyl chlorosulfonate). Alternatively, sulfonyl chloride V can be prepared from intermediate IV in the presence of a chlorinating agent such as NCS in aqueous solution. Intermediate IV can be prepared from intermediate III using a Buchwald-Hartwig cross-coupling reaction using a palladium catalyst system, such as Pd(OAc) or Pd(dba) / Xantphos or XPhos, and an excess of a base, such as DIPEA or CsCO, in a solvent such as dioxane or toluene at elevated temperatures. Intermediate III can be obtained from intermediate II in the presence of a brominating agent such as NBS in a solvent such as MeCN, EtOAc, or DMF.

[0055] Compounds of formula VII can be prepared according to variations of the above process and the following Scheme 2. Starting materials are commercially available or can be prepared according to known methods.

[0056] Scheme 2 [ka] Compounds of general formula VII can be prepared by reacting sulfonyl chloride XI with 2-aminopyrimidine, 2-aminopyridine, 3-aminopyridine, or aniline VI in the presence of a base (e.g., pyridine). Sulfonyl chloride XI can be prepared from intermediate VIII in the presence of a chlorosulfonylating agent (e.g., chlorosulfonic acid or trimethylsilyl chlorosulfonate). Alternatively, sulfonyl chloride XI can be prepared from intermediate X in the presence of a chlorinating agent such as NCS in aqueous solution. Intermediate X can be prepared from intermediate IX using a Buchwald-Hartwig cross-coupling reaction using a palladium catalyst system, such as Pd(OAc) or Pd(dba) / Xantphos or XPhos, and an excess of a base, such as DIPEA or CsCO, in a solvent such as dioxane or toluene at elevated temperatures. Intermediate IX can be obtained from intermediate VIII in the presence of a brominating agent such as NBS in a solvent such as MeCN, EtOAc, or DMF.

[0057] Compounds of formula XII can be prepared according to variations of the above process and the following Scheme 3. Starting materials are commercially available or can be prepared according to known methods.

[0058] Scheme 3 [ka] Compounds of general formula XII can be prepared by reacting sulfonyl chloride XVI with 2-aminopyrimidine, 2-aminopyridine, 3-aminopyridine, or aniline VI in the presence of a base (e.g., pyridine). Sulfonyl chloride XVI can be prepared from intermediate XIII in the presence of a chlorosulfonylating agent (e.g., chlorosulfonic acid or trimethylsilyl chlorosulfonate). Alternatively, sulfonyl chloride XVI can be prepared from intermediate XV in the presence of a chlorinating agent such as NCS in aqueous solution. Intermediate XV can be prepared from intermediate XIV using a Buchwald-Hartwig cross-coupling reaction using a palladium catalyst system, such as Pd(OAc) or Pd(dba) / Xantphos or XPhos, and an excess of a base, such as DIPEA or CsCO, in a solvent such as dioxane or toluene at elevated temperatures. Intermediate XIV can be obtained from intermediate XIII in the presence of a brominating agent such as NBS in a solvent such as MeCN, EtOAc or DMF.

[0059] Compounds of formula XVII can be prepared according to variations of the above process and the following Scheme 4. Starting materials are commercially available or can be prepared according to known methods.

[0060] Scheme 4 [ka] Compounds of general formula XVII can be prepared by reacting sulfonyl chloride XXI with 2-aminopyrimidine, 2-aminopyridine, 3-aminopyridine, or aniline VI in the presence of a base (e.g., pyridine). Sulfonyl chloride XXI can be prepared from intermediate XVIII in the presence of a chlorosulfonylating agent (e.g., chlorosulfonic acid or trimethylsilyl chlorosulfonate). Alternatively, sulfonyl chloride XXI can be prepared from intermediate XX in the presence of a chlorinating agent such as NCS in aqueous solution. Intermediate XX can be prepared from intermediate XIX using a Buchwald-Hartwig cross-coupling reaction using a palladium catalyst system, such as Pd(OAc) or Pd(dba) / Xantphos or XPhos, and an excess of a base, such as DIPEA or CsCO, in a solvent such as dioxane or toluene at elevated temperatures. Intermediate XIX can be obtained from intermediate XVIII in the presence of a brominating agent such as NBS in a solvent such as MeCN, EtOAc or DMF.

[0061] Compounds of formula XXII can be prepared according to variations of the above process and the following Scheme 5. Starting materials are commercially available or can be prepared according to known methods.

[0062] Scheme 5 [ka] Compounds of general formula XXII can be prepared by reacting sulfonyl chloride XXVI with 2-aminopyrimidine, 2-aminopyridine, 3-aminopyridine, or aniline VI in the presence of a base (e.g., pyridine). Sulfonyl chloride XXVI can be prepared from intermediate XXV in the presence of a chlorinating agent such as NCS in aqueous solution. Intermediate XXV can be prepared from intermediate XXIV using a Buchwald-Hartwig cross-coupling reaction using a palladium catalyst system, such as Pd(OAc) or Pd(dba) / Xantphos or XPhos, and an excess of a base, such as DIPEA or CsCO, in a solvent such as dioxane or toluene at elevated temperatures. Intermediate XXIV can be obtained from intermediate XXIII in the presence of a brominating agent such as NBS in a solvent such as MeCN, EtOAc, or DMF.

[0063] 2-Amino-pyrimidines or 2-amino-pyridines or 3-amino-pyridines or anilines VI are commercially available or can be prepared according to the literature or according to the procedures described in this patent. The starting materials are commercially available or can be prepared according to known methods.

[0064] 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.

[0065] The compositions are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to consider in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the dosing schedule, and other factors known to the medical profession.

[0066] The compounds of the present invention can be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, epidural, and intranasal, and, if desired for local treatment, intralesional administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0067] The compounds of the present invention may be administered in any convenient dosage form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain ingredients conventional in pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, fillers and additional active agents.

[0068] 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 drug product).

[0069] 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.

[0070] Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances, and liquid polyols.

[0071] Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose etc.

[0072] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

[0073] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols etc.

[0074] Suitable adjuvants for topical ophthalmic formulations are, for example, cyclodextrin, mannitol, or many other carriers and additives known in the art.

[0075] 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.

[0076] The dosage may vary widely and will, of course, be adapted to the individual requirements of each particular case. Generally, for oral administration, a daily dosage of about 0.1 mg to 20 mg per kg of body weight, preferably about 0.5 mg to 4 mg per kg of body weight (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.

[0077] 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.

[0078] 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.

[0079] Use of compounds of Formula I to treat or prevent conditions resulting from inflammation of the CNS, such as 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 after encephalitis, primary vasculitis, meningitis, and obesity.

[0080] One embodiment of the invention is the use of a compound of formula I to treat or prevent multiple sclerosis, Alzheimer's disease, Parkinson's disease, or Huntington's disease.

[0081] A particular embodiment of the invention is the use of a compound of formula I for treating or preventing multiple sclerosis.

[0082] Use of a compound of Formula I for the preparation of a medicament for the treatment or prevention of conditions resulting from inflammation of the CNS, such as 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.

[0083] One embodiment of the invention is the use of a compound of formula I for the preparation of a medicament for treating or preventing multiple sclerosis, Alzheimer's disease, Parkinson's disease, or Huntington's disease.

[0084] 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.

[0085] A compound according to formula I for use in the treatment or prevention of conditions resulting from inflammation of the CNS, such as 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 after encephalitis, primary vasculitis, meningitis, and obesity.

[0086] One embodiment of the invention is a compound of Formula I for use in the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease, or Huntington's disease.

[0087] A particular embodiment of the invention is a compound according to Formula I for use in the treatment or prevention of multiple sclerosis.

[0088] A method for treating or preventing symptoms resulting from inflammation of the CNS, for example, following encephalitis, primary vasculitis, meningitis, and obesity, including 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), comprising administering to a patient in need thereof an effective amount of a compound of Formula I.

[0089] 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, the method comprising administering to a patient in need thereof an effective amount of a compound of formula I.

[0090] A particular embodiment of the present invention is a method for treating or preventing multiple sclerosis, the method comprising administering an effective amount of a compound of formula I to a patient in need thereof.

[0091] Certain embodiments of the present invention also provide compounds of formula I as described herein when prepared according to any one of the methods described.

[0092] Assay procedure GPR17 cAMP Assay Protocol: CHO-K1 cells stably expressing a vector containing the untagged human GPR17 short isoform (Roche) were cultured at 37°C / 5% CO2 in DMEM (Dulbecco's modified Eagle's medium):F-12 (1:1) supplemented with 10% fetal bovine serum and 400 μg / ml Geneticin.

[0093] Changes in intracellular cyclic adenosine monophosphate (cAMP) levels were quantified using the Nano-TRF Detection Assay kit (Roche Diagnostics, catalog number 05214386001). This assay allows for direct cAMP quantification in homogeneous solution. cAMP is detected based on time-resolved fluorescence energy transfer (TR-FRET) and the competitive binding of ruthenium-labeled cAMP and endogenous cAMP to an anti-cAMP monoclonal antibody labeled with AlexaFluor-700. The ruthenium complex acts as a FRET donor, transferring energy to AlexaFluor-700. The FRET signal is inversely proportional to the cAMP concentration.

[0094] 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.

[0095] 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 MDL29,951 (3-(2-carboxy-4,6-dichloroindol-3-yl)propionic acid) (GPR17 agonist) + 3-isobutyl-1-methylxanthine (IBMX) (0.5 mM final concentration) at an EC80 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.

[0096] 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).

[0097] The results of the hGPR17 cAMP assay are provided for compounds of Formula I in Table 1. [Table 1] TIFF2025525574000017.tif115165

[0098] The invention will now be illustrated by the following examples, which have no limiting character.

[0099] Where preparations are obtained as mixtures of enantiomers, pure enantiomers can be obtained by methods described herein or known to those skilled in the art, such as chiral chromatography or crystallization. [Example]

[0100] Unless otherwise specified, all examples and intermediates were prepared under a nitrogen or argon atmosphere.

[0101] Intermediate A Intermediates are either commercially available or prepared according to procedures described in the indicated patent applications, or novel and the corresponding experimental procedures are listed at the end of the table. [Table 2] TIFF2025525574000019.tif225165 TIFF2025525574000020.tif214165 TIFF2025525574000021.tif34165

[0102] Intermediate A1: 2-(4-amino-2-fluoro-5-methoxyphenyl)acetonitrile [ka] To a stirred solution of (4-bromo-5-fluoro-2-methoxyphenyl)amine (2 g, 9.09 mmol, CAS: 330794-03-1), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (2.13 g, 10.91 mmol), and 1 M aqueous potassium fluoride (27.27 mL, 27.27 mmol) in N-methyl-2-pyrrolidinone under argon was added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (751.43 mg, 0.909 mmol).

[0103] The reaction mixture was stirred at 90° C. for 4 hours before another equivalent of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (1.77 g, 9.09 mmol) was added.

[0104] After an additional 5 hours at 90°C, 1 M aqueous potassium fluoride (9.09 mL, 9.09 mmol) was added and the reaction mixture was stirred at 90°C overnight. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a gradient of ethyl acetate / heptane 0-50% to give the title compound as a yellow oil (536 mg, 32%). MS (ESI): m / z = 181.1 [M+H] +

[0105] Intermediate A3: 2-(5-amino-3-fluoro-6-methoxy-2-pyridyl)acetonitrile [ka] Step 1: To a stirred solution of (6-bromo-5-fluoro-2-methoxy-3-pyridyl)amine (2.5 g, 10.75 mmol) in N,N-dimethylacetamide (25 mL) was added sodium hydride (1.29 g, 32.24 mmol) in 5 portions (258 mg) at 0 °C. After stirring at 0 °C for 30 min, 4-methoxybenzyl chloride (3.43 g, 2.99 mL, 21.49 mmol) was added, and the reaction mixture was stirred at room temperature for 30 min before being carefully quenched with saturated ammonium chloride solution, poured into water, and extracted twice with ethyl acetate. The organic layer was washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a gradient of 0-10% ethyl acetate / heptane to give (6-bromo-5-fluoro-2-methoxy-3-pyridyl)-bis(p-anisyl)amine (4.93 g, 99%) as a red viscous oil. 1H NMR (300 MHz, DMSO-d6) δ = 7.22-7.12 (m, 5H), 6.91-6.81 (m, 4H), 4.24 (s, 4H), 3.95 (s, 3H), 3.71 (s, 6H).

[0106] Step 2: A solution of (6-bromo-5-fluoro-2-methoxy-3-pyridyl)-bis(p-anisyl)amine (1 g, 2.17 mmol) in toluene (20 mL) was cooled to -78 °C, and 1.6 M n-butyllithium (1.75 g, 2.03 mL, 3.25 mmol) was added dropwise. The resulting dark blue solution was stirred at -78 °C for 30 minutes, after which N,N-dimethylformamide (396.11 mg, 419.17 uL, 5.42 mmol) was added. Stirring was continued at -78 °C for 30 minutes, after which the reaction mixture was allowed to warm to room temperature. Methanol (4 mL) was added, followed by sodium borohydride (82 mg, 2.17 mmol). After 15 minutes, the reaction mixture was quenched with saturated ammonium chloride solution and extracted twice with ethyl acetate. The organic layer was washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a gradient of 0-50% ethyl acetate / heptane to give [5-[bis(p-anisyl)amino]-3-fluoro-6-methoxy-2-pyridyl]methanol (297 mg, 32%) as a pale yellow viscous oil. MS (ESI): m / z = 413.3 [M+H] +

[0107] Step 3: To a stirred solution of [5-[bis(p-anisyl)amino]-3-fluoro-6-methoxy-2-pyridyl]methanol (144 mg, 0.342 mmol) in dichloromethane (1.5 mL) was added thionyl dichloride (81.41 mg, 49.64 μL, 0.684 mmol) dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 hour and then concentrated in vacuo to afford [6-(chloromethyl)-5-fluoro-2-methoxy-3-pyridyl]-bis(p-anisyl)amine (152 mg, 103%) as a light brown foam, which was used directly in the next step without further purification.

[0108] Step 4: To a stirred solution of [6-(chloromethyl)-5-fluoro-2-methoxy-3-pyridyl]-bis(p-anisyl)amine (152 mg, 0.353 mmol) in dichloromethane (700 μL) was added tetrabutylammonium bromide (11.49 mg, 0.035 mmol), followed by a solution of sodium cyanide (21.39 mg, 0.423 mmol) in water (130 μL). The reaction mixture was stirred at room temperature for 15 hours. Sodium cyanide (21.39 mg, 0.423 mmol) was added again, and stirring was continued at room temperature for another 15 hours. After that, the reaction mixture was diluted with dichloromethane and washed twice with water. The organic layer was washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a gradient of ethyl acetate / heptane 0-30% to give 2-[5-[bis(p-anisyl)amino]-3-fluoro-6-methoxy-2-pyridyl]acetonitrile (87 mg, 58%) as a colorless viscous oil. MS (ESI): m / z = 422.3 [M+H] +

[0109] Step 5: A solution of 2-[5-[bis(p-anisyl)amino]-3-fluoro-6-methoxy-2-pyridyl]acetonitrile (85 mg, 0.202 mmol) in dichloromethane (400 μL) was cooled to 0° C., and trifluoroacetic acid (1.38 g, 926.64 μL, 12.1 mmol) was added. The reaction mixture was stirred at 0° C. for 20 minutes and at room temperature for 4 hours, then poured into saturated NaHCO3 and extracted twice with ethyl acetate. The organic layer was washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a gradient of 0-40% ethyl acetate / heptane to give 2-(5-amino-3-fluoro-6-methoxy-2-pyridyl)acetonitrile (31 mg, 84%) as a pale yellow solid. MS (ESI): m / z = 182.1 [M+H] +

[0110] Intermediate A4: 5-(difluoromethoxy)-3-fluoro-6-methoxy-pyridin-2-amine [ka] Step 1: To a stirred solution of (5-bromo-3,6-difluoro-2-pyridyl)amine (2.45 g, 11.74 mmol) in N,N-dimethylacetamide (25 mL) was added sodium hydride (1.41 g, 35.21 mmol) in 5 portions (282 mg) at 0 °C. After stirring at 0 °C for 30 min, 4-methoxybenzyl chloride (3.75 g, 3.26 mL, 23.47 mmol) was added, and the reaction mixture was stirred at room temperature for an additional 30 min before being carefully quenched with saturated ammonium chloride solution, poured into water, and extracted twice with ethyl acetate. The organic layer was washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a gradient of ethyl acetate / heptane 0-10% to give (5-bromo-3,6-difluoro-2-pyridyl)-bis(p-anisyl)amine (4.9 g, 92%) as a pale yellow viscous oil. MS (ESI): m / z = 448.8 [M+H] +

[0111] Step 2: To a solution of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (1.27 g, 1.56 mmol), potassium acetate (2.92 mL, 46.74 mmol), and 5-bromo-3,6-difluoro-N,N-bis[(4-methoxyphenyl)methyl]pyridin-2-amine (7.0 g, 15.58 mmol) in 1,4-dioxane (70 mL) was added bis(pinacolato)diboron (5.93 g, 23.37 mmol) under a nitrogen atmosphere. The mixture was stirred at 100 °C for 16 h, filtered, diluted with water, and extracted twice with ethyl acetate. The organic layer was washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a gradient of ethyl acetate / petroleum ether 0-15% to give 3,6-difluoro-N,N-bis[(4-methoxyphenyl)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (4.2 g, 46%) as an off-white solid. MS (ESI): m / z = 497.0 [M+H] +

[0112] Step 3: To a solution of 3,6-difluoro-N,N-bis[(4-methoxyphenyl)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (3.70 g, 7.45 mmol) in THF (45 mL) was carefully added hydrogen peroxide (16.9 g, 149.09 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 15 minutes and at room temperature for an additional 2 hours, then poured into cold 0.1 N aqueous sodium thiosulfate solution (150 mL) and extracted twice with ethyl acetate. The organic layer was washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo (water bath temperature: 20 °C, do not evaporate to dryness) to give crude 6-[bis[(4-methoxyphenyl)methyl]amino]-2,5-difluoro-pyridin-3-ol (3.30 g, 114%). The crude material was used directly in the next step without further purification. MS (ESI): m / z=387.2 [M+H] +

[0113] Step 4: To a solution of 6-[bis[(4-methoxyphenyl)methyl]amino]-2,5-difluoro-pyridin-3-ol (3.30 g, 8.54 mmol) in acetonitrile (35 mL) was added aqueous potassium hydroxide (34.16 mL, 170.81 mmol) dropwise at 0 °C, followed by the addition of diethyl(bromodifluoromethyl)phosphonate (4.56 g, 17.08 mmol) in acetonitrile (10 mL). The resulting reaction mixture was stirred at 0 °C for 1 hour, then poured into water (200 mL) and extracted twice with ethyl acetate. The organic layer was washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a gradient of 0-20% ethyl acetate / petroleum ether to give 5-(difluoromethoxy)-3,6-difluoro-N,N-bis[(4-methoxyphenyl)methyl]pyridin-2-amine (3.31 g, 88%) as a pale yellow gum. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.81 (s, 6H) 4.59 (s, 4H) 6.27-6.66 (m, 1H) 6.85-6.89 (m, 4H) 7.19 (d, J = 8.56 Hz, 4H) 7.27-7.33 (m, 1H).

[0114] Step 5: A solution of 5-(difluoromethoxy)-3,6-difluoro-N,N-bis[(4-methoxyphenyl)methyl]pyridin-2-amine (3.30 g, 7.56 mmol) in dichloromethane (6 mL) and trifluoroacetic acid (31.46 mL, 408.34 mmol) was stirred at 0 °C for 1 h, then poured into saturated NaHCO solution (200 mL) and extracted twice with ethyl acetate. The organic layer was washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a gradient of 0-40% ethyl acetate / petroleum ether to afford 5-(difluoromethoxy)-3,6-difluoro-pyridin-2-amine (1.70 g, 114%) as a pale yellow oil. MS (ESI): m / z = 196.7 [M+H] +

[0115] Step 6: To a solution of 5-(difluoromethoxy)-3,6-difluoro-pyridin-2-amine (1.70 g, 8.67 mmol) in THF (40 mL) was added sodium methoxide (468 mg, 8.67 mmol, 1 equiv.) at room temperature. The reaction mixture was stirred at 60 °C for 6 hours, then poured into water (40 mL) and extracted twice with ethyl acetate. The organic layer was washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified twice by flash chromatography on silica gel using a gradient of 0-30% ethyl acetate / petroleum ether to give 5-(difluoromethoxy)-3-fluoro-6-methoxy-pyridin-2-amine (850 mg, 45%) as a pale yellow oil. MS (ESI): m / z = 208.7 [M+H] +

[0116] Intermediate A6: 5-(2,2-difluoroethyl)-3-fluoro-6-methoxy-pyridin-2-amine [ka] Step 1: A mixture of 5-bromo-3,6-difluoropyridin-2-amine (1.02 g, 4.88 mmol) and sodium methoxide (833 mg, 14.6 mmol) in THF (15 ml) was heated at 100 °C for 15 hours and then poured into saturated ammonium chloride solution. The pH was adjusted to approximately 7 with 1N aqueous HCl, and the reaction mixture was extracted twice with ethyl acetate. The organic layer was washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a gradient of 0-20% ethyl acetate / heptane to afford 5-bromo-3-fluoro-6-methoxypyridin-2-amine (893 mg, 83%) as a light brown solid. MS (ESI): m / z = 221.0 [M+H] +

[0117] Step 2: To a stirred solution of 5-bromo-3-fluoro-6-methoxypyridin-2-amine (200 mg, 0.905 mmol) in N,N-dimethylacetamide (3 mL) was added sodium hydride (108.57 mg, 2.71 mmol) at 0 °C. After stirring at 0 °C for 20 minutes, 4-methoxybenzyl chloride (289.2 mg, 251.48 µL, 1.81 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes before being carefully quenched with saturated ammonium chloride solution, poured into water, and extracted twice with ethyl acetate. The combined organic layers were washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a gradient of 0-20% ethyl acetate / heptane to give (5-bromo-3-fluoro-6-methoxy-2-pyridyl)-bis(p-anisyl)amine (270 mg, 64%) as a pale yellow viscous oil. MS (ESI): m / z = 463.2 [M+H] +

[0118] Step 3: To a solution of (5-bromo-3-fluoro-6-methoxy-2-pyridyl)-bis(p-anisyl)amine (1.27 g, 2.75 mmol) in tetrahydrofuran (80 mL) was added isopropylmagnesium chloride-lithium chloride complex (1.3 M in THF, 8.47 mL, 11.01 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 3 hours, then cooled to 0 °C, and N,N-dimethylformamide (1.61 g, 1.71 mL, 22.02 mmol) was added. After 30 minutes at room temperature, the reaction mixture was cooled to 0 °C, quenched with aqueous potassium bisulfate (1 N, 30 mL), and extracted with water and ethyl acetate. The combined organic layer was washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a gradient of ethyl acetate / heptane 0-30% to give the desired product (901 mg, 79%) as a colorless oil. MS (ESI): m / z=411.3 [M+H] +

[0119] Step 4: To a solution of 6-[bis(p-anisyl)amino]-5-fluoro-2-methoxy-nicotinaldehyde (933 mg, 2.16 mmol) in N,N-dimethylformamide (30 mL) was added triphenylphosphine (1.42 g, 5.4 mmol), and the reaction mixture was heated to 100 °C. Sodium chlorodifluoroacetate (823.1 mg, 5.4 mmol) was added to the reaction mixture in five portions of approximately 165 mg at 10 min intervals. The reaction mixture was allowed to cool to room temperature, quenched with water, and extracted twice with ethyl acetate. The combined organic layers were washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a gradient of 0-20% ethyl acetate / heptane to give the desired product (844 mg, 84%) as a pale yellow oil. MS (ESI): m / z = 445.3 [M+H] +

[0120] Step 5: To a solution of [5-(2,2-difluorovinyl)-3-fluoro-6-methoxy-2-pyridyl]-bis(p-anisyl)amine (836 mg, 1.88 mmol) in methanol (50 mL), palladium hydroxide on carbon (264.15 mg, 0.094 mmol, 0.050 equiv.) was added, and the reaction mixture was stirred at room temperature under hydrogen balloon pressure. After completion of the reaction, the reaction mixture was filtered through dicalite and washed with ethyl acetate. The combined organic layer was concentrated in vacuo and dried to give 5-(2,2-difluoroethyl)-3-fluoro-6-methoxy-pyridin-2-amine (390 mg, 80%) as a light brown oil. MS (ESI): m / z = 207.1 [M + H] +

[0121] Intermediate A7: 6-(2,2-difluoroethyl)-5-fluoro-2-methoxy-pyridin-3-amine [ka] Step 1: To a stirred solution of (6-bromo-5-fluoro-2-methoxy-3-pyridyl)amine (2.5 g, 10.75 mmol) in N,N-dimethylacetamide (25 mL) was added sodium hydride (1.29 g, 32.24 mmol) in 5 portions (258 mg) at 0 °C. After stirring at 0 °C for 30 min, 4-methoxybenzyl chloride (3.43 g, 2.99 mL, 21.49 mmol) was added, and the reaction mixture was stirred at room temperature for 30 min before being carefully quenched with saturated ammonium chloride solution, poured into water, and extracted twice with ethyl acetate. The organic layer was washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a gradient of 0-10% ethyl acetate / heptane to give (6-bromo-5-fluoro-2-methoxy-3-pyridyl)-bis(p-anisyl)amine (4.93 g, 99%) as a red viscous oil. 1H NMR (300 MHz, DMSO-d6) δ = 7.22-7.12 (m, 5H), 6.91-6.81 (m, 4H), 4.24 (s, 4H), 3.95 (s, 3H), 3.71 (s, 6H).

[0122] Step 2: To a solution of (6-bromo-5-fluoro-2-methoxy-3-pyridyl)-bis(p-anisyl)amine (1.33 g, 2.88 mmol) in tetrahydrofuran (25 mL) was added n-butyllithium (1.6 M in hexanes, 1.8 mL, 2.88 mmol) slowly at −78° C. After 15 minutes at −78° C., N,N-dimethylformamide (273.94 mg, 290.19 μL, 3.75 mmol) was added, and the mixture was stirred at −78° C. for an additional 5 minutes before warming to −20° C. When LCMS showed complete conversion, the reaction was quenched with saturated ammonium chloride solution at −78° C., warmed to room temperature, and extracted twice with ethyl acetate. The organic layer was washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a gradient of ethyl acetate / heptane 0-30% to give the desired product (807 mg, 65%) as a yellow foam. MS (ESI): m / z=411.3 [M+H] +

[0123] Step 3: To a solution of 5-[bis(p-anisyl)amino]-3-fluoro-6-methoxy-picolinaldehyde (805 mg, 1.96 mmol) in N,N-dimethylformamide (30 mL) was added triphenylphosphine (1.29 g, 4.9 mmol), and the reaction mixture was heated to 100 °C. Sodium chlorodifluoroacetate (747.55 mg, 4.9 mmol) was added to the reaction mixture in five approximately 150 mg portions at 10 min intervals. The reaction mixture was allowed to cool to room temperature, quenched with water, and extracted twice with ethyl acetate. The combined organic layers were washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a 0-20% gradient of ethyl acetate / heptane to afford the desired product (818 mg, 90%) as a colorless oil. MS (ESI): m / z = 445.3 [M+H] +

[0124] Step 5: To a solution of [6-(2,2-difluorovinyl)-5-fluoro-2-methoxy-3-pyridyl]-bis(p-anisyl)amine (812 mg, 1.74 mmol) in methanol (50 mL), palladium hydroxide on carbon (243.73 mg, 0.087 mmol, 0.050 equiv.) was added, and the reaction mixture was stirred at room temperature under hydrogen balloon pressure. After completion of the reaction, the reaction mixture was filtered through dicalite and washed with ethyl acetate. The combined organic layer was concentrated in vacuo and dried to give 6-(2,2-difluoroethyl)-5-fluoro-2-methoxy-pyridin-3-amine (355 mg, 89%) as a light brown oil. MS (ESI): m / z = 207.1 [M + H] +

[0125] Intermediate A10: 3-fluoro-5-(2-fluoroethoxy)-6-methoxypyridin-2-amine [ka] A solution of 3,6-difluoro-5-(2-fluoroethoxy)pyridin-2-amine (29 mg, 0.151 mmol, as described in WO2019243398) and sodium methoxide (25.75 mg, 0.453 mmol) in methanol (1 mL) was heated to 100 °C and stirred for 15 hours. Sodium methoxide (12.87 mg, 0.226 mmol) was added, and stirring was continued at 100 °C for 20 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was poured into water and extracted twice with ethyl acetate. The combined organic layers were washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give [3-fluoro-5-(2-fluoroethoxy)-6-methoxy-2-pyridyl]amine (26 mg, 81%) as a brown gum. MS (ESI): m / z = 205.1 [M+H] +

[0126] Intermediate A13: 6-(3,3-difluoropropyl)-5-fluoro-2-methoxy-pyridin-3-amine [ka] Step 1: To a solution of (6-bromo-5-fluoro-2-methoxy-3-pyridyl)amine (1.25 g, 5.66 mmol) in dichloromethane (30 mL) was added N,N-diisopropylethylamine (877.08 mg, 1.19 mL, 6.79 mmol) and 4-dimethylaminopyridine (34.55 mg, 0.283 mmol) and a solution of di-tert-butyl dicarbonate (1.36 g, 1.44 mL, 6.22 mmol) in dichloromethane (15 mL) at 0 °C. After stirring the reaction mixture at room temperature, additional di-tert-butyl dicarbonate (1.23 g, 1.31 mL, 5.66 mmol) was added after 3 hours, and stirring was continued at room temperature overnight. The reaction mixture was poured into water and extracted with dichloromethane. The combined organic layer was washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a gradient of ethyl acetate / heptane 0-30% to give the desired product (1.2 g, 40%) as a white semi-solid. MS (ESI): m / z=445.06 [M+H+Na] +

[0127] Step 2: To a solution of N-(6-bromo-5-fluoro-2-methoxy-3-pyridyl)-N-tert-butoxycarbonyl-carbamic acid tert-butyl ester (1.2 g, 2.85 mmol), (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylic acid ethyl ester (837.21 mg, 828.92 µL, 3.7 mmol), and cesium carbonate (2.78 g, 8.55 mmol) in 1,4-dioxane (6 mL) and water (1 mL) was added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (235.5 mg, 0.285 mmol). The reaction mixture was stirred at 100 °C for 2 hours. The residue was poured into water and extracted twice with ethyl acetate. The combined organic layers were washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was adsorbed onto ISOLUTE HM-N and purified by flash chromatography on silica gel using a gradient of 0-35% ethyl acetate / heptane to afford the desired product (747 mg, 56%) as a colorless oil. MS (ESI): m / z = 441.3 [M+H] +

[0128] Step 3: (E)-3-[5-[bis(tert-butoxycarbonyl)amino]-3-fluoro-6-methoxy-2-pyridyl]acrylic acid ethyl ester (740 mg, 1.68 mmol) was dissolved in ethyl acetate (30 mL) under argon. Palladium on activated carbon 10% (178.79 mg, 0.168 mmol) was added, and the flask was purged and filled with argon. The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours, after which it was filtered through decalite and washed with ethyl acetate. The filtrate was concentrated in vacuo to give the desired product (744 mg, 95%) as a colorless oil. MS (ESI): m / z = 443.3 [M+H] +

[0129] Step 4: In a 50 ml three-neck flask, 3-[5-[bis(tert-butoxycarbonyl)amino]-3-fluoro-6-methoxy-2-pyridyl]propionic acid ethyl ester (667 mg, 1.51 mmol) was dissolved in tetrahydrofuran (10 mL), and the colorless solution was cooled to −78° C. DIBAL-H (1 M in THF, 1.51 mL, 1.51 mmol) was added at −78° C., and the reaction mixture was stirred at this temperature for 1 h.

[0130] Additional DIBAL-H (1 M in THF, 1.51 mL, 1.51 mmol) was added at -78 °C, and the reaction mixture was stirred at room temperature. After 2 h, the reaction mixture was cooled to -78 °C, and water (120 μL) was added, followed by 15% aqueous NaOH (120 μL) and additional water (300 μL). The reaction mixture was warmed to room temperature and stirred for 30 min, then sodium sulfate was added. The reaction mixture was filtered through Celite and concentrated in vacuo. The crude material was adsorbed onto ISOLUTE HM-N and purified by flash chromatography on silica gel using a gradient of 0-50% ethyl acetate / heptane to give the desired product (423 mg, 56%) as a colorless oil. MS (ESI): m / z = 401.3 [M+H] +

[0131] Step 5: N-tert-Butoxycarbonyl-N-[5-fluoro-6-(3-hydroxypropyl)-2-methoxy-3-pyridyl]carbamic acid tert-butyl ester (416 mg, 1.04 mmol) was dissolved in dichloromethane (10 mL) and the solution was cooled to 0 ° C. 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benzodioxol-3-(1H)-one (Dess-Martin periodinane) (528.75 mg, 1.25 mmol) was added, the ice bath was removed, and the reaction mixture was stirred at room temperature for 45 minutes. The reaction mixture was poured into saturated NaHCO3 solution and extracted with dichloromethane. The combined organic layer was washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was adsorbed onto ISOLUTE HM-N and purified by flash chromatography on silica gel using a gradient of 0-50% ethyl acetate / heptane to give the desired product (359 mg, 84%) as a colorless oil. MS (ESI): m / z = 399.3 [M+H] +

[0132] Step 6: N-tert-Butoxycarbonyl-N-[5-fluoro-6-(3-ketopropyl)-2-methoxy-3-pyridyl]carbamic acid tert-butyl ester (355 mg, 0.891 mmol, 1 equiv.) was dissolved in dichloromethane (10 mL) and the solution was cooled to 0 °C. [Bis(2-methoxyethyl)amino]sulfur trifluoride (DeoxoFluor 2.7 M in toluene, 792 mg, 660 uL, 1.78 mmol) was added dropwise at 0 °C, and the reaction mixture was stirred at 0 °C and room temperature for 30 minutes. After 2 hours, the reaction mixture was poured into a saturated NaHCO / ice mixture and stirred for 10 minutes. The layers were separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was adsorbed onto ISOLUTE HM-N and purified by flash chromatography on silica gel using a gradient of 0-30% ethyl acetate / heptane to give the desired product (110 mg, 11%) as a colorless oil. MS (ESI): m / z = 421.3 [M+H] +

[0133] Step 7: A mixture of N-tert-butoxycarbonyl-N-[6-(3,3-difluoropropyl)-5-fluoro-2-methoxy-3-pyridyl]carbamic acid tert-butyl ester (107 mg, 0.255 mmol) and HCl (4 M in dioxane, 1.53 g, 1.27 mL, 5.09 mmol) was stirred at room temperature. After 2.5 h, the reaction mixture was poured into saturated NaHCO3 solution and extracted with ethyl acetate. The combined organic layers were washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was adsorbed onto ISOLUTE HM-N and purified by flash chromatography on silica gel using a gradient of 0-100% ethyl acetate / heptane to give the desired product (15 mg, 25%) as a colorless oil. MS (ESI): m / z = 221.1 [M+H] +

[0134] Intermediate A14: 2,6-bis(difluoromethoxy)-5-fluoro-pyridin-3-amine [ka] Step 1: To a solution of 4-methoxybenzyl alcohol (3.54 g, 25.61 mmol) in THF (120 mL) was added sodium bis(trimethylsilyl)amide (25.61 mL, 25.61 mmol) at −78°C. The resulting reaction mixture was stirred for 30 min, followed by the addition of a solution of 2,3,6-trifluoro-5-nitro-pyridine (4.8 g, 26.96 mmol) in THF (50 mL) at −78°C. After 1 h at −78°C, the reaction mixture was quenched with aqueous NHCl (125 mL) and extracted with ethyl acetate. The combined organic layers were washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a 0–10% gradient of ethyl acetate / petroleum ether to afford 2,5-difluoro-6-[(4-methoxyphenyl)methoxy]-3-nitro-pyridine (3.79 g, 47%) as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ=8.77(dd,J=7.5,8.8Hz,1H),7.45(d,J=8.7Hz,2H),7.03-6.91(m,2H),5.44(s,2H),3.76(s,3H).

[0135] Step 2: To a solution of 2,5-difluoro-6-[(4-methoxyphenyl)methoxy]-3-nitro-pyridine (3.98 g, 13.44 mmol) in THF (200 mL) was added sodium methoxide (2.69 g, 13.44 mmol), and the mixture was stirred at −20° C. for 2 hours. The mixture was quenched with aqueous NH4Cl (200 mL) and extracted with ethyl acetate. The combined organic layers were washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product, 5-fluoro-2-methoxy-6-[(4-methoxyphenyl)methoxy]-3-nitro-pyridine (4.04 g, 97%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 8.52 (d, J = 9.4 Hz, 1H), 7.45 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.7 Hz, 2H), 5.52 (s, 2H), 4.08 (s, 3H), 3.76 (s, 3H).

[0136] Step 3: To a solution of 5-fluoro-2-methoxy-6-[(4-methoxyphenyl)methoxy]-3-nitro-pyridine (5.88 g, 19.07 mmol) in dichloromethane (59 mL) was added trifluoroacetic acid (59.0 mL, 765.81 mmol) at 25 °C, and the reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue that was purified by flash chromatography on silica gel using a gradient of 0-50% ethyl acetate / petroleum ether to give 3-fluoro-6-methoxy-5-nitro-pyridin-2-ol (5.4 g, 78%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ = 8.41 (d, J = 9.5 Hz, 1H), 3.97 (s, 3H).

[0137] Step 4: To a solution of 3-fluoro-6-methoxy-5-nitro-pyridin-2-ol (1.0 g, 5.32 mmol) in acetonitrile (20 mL) was added a solution of KOH (2.98 g, 53.16 mmol) in water (3.5 mL) and diethyl (bromodifluoromethyl)phosphonate (8.52 g, 31.9 mmol) at 40 °C. The reaction mixture was stirred at 40 °C for 4 hours, then diluted with water and extracted with ethyl acetate. The combined organic layers were washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient of 0-3% ethyl acetate / petroleum ether to give 2-(difluoromethoxy)-3-fluoro-6-methoxy-5-nitro-pyridine (580 mg, 45%) as a yellow oil. 1H NMR (400MHz, DMSO-d6) δ=8.79(d,J=9.0Hz,1H),8.10-7.70(m,1H),4.04(s,3H).

[0138] Step 5: To a mixture of 2-(difluoromethoxy)-3-fluoro-6-methoxy-5-nitro-pyridine (1.7 g, 7.14 mmol) in dichloromethane (24 mL) was added BBr3 (3.34 mL, 35.7 mmol) at 0 °C, and the reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a 0-50% gradient of ethyl acetate / petroleum ether to give 6-(difluoromethoxy)-5-fluoro-3-nitro-pyridin-2-ol (1.48 g, 92%) as a yellow oil. 1H NMR(400MHz,CHLOROFORM-d)δ ppm 7.31-7.69(m,1H)8.33(d,J=7.70Hz,1H)11.35(br s,1H)

[0139] Step 6: To a solution of 6-(difluoromethoxy)-5-fluoro-3-nitro-pyridin-2-ol (1.48 g, 6.6 mmol) in acetonitrile (20 mL) and KOH (3705.78 mg, 66.04 mmol) in water (5 mL) was added diethyl(bromodifluoromethyl)phosphonate (10580.79 mg, 39.63 mmol) at 40 °C. After 1 h, the reaction mixture was cooled to room temperature and extracted with dichloromethane. The combined organic layers were washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a 0-20% gradient of ethyl acetate / petroleum ether to give 2,6-bis(difluoromethoxy)-3-fluoro-5-nitro-pyridine (2.38 g, 46%) as a pale yellow oil. 1H NMR(400MHz,DMSO-d6)δ ppm 7.64-8.12(m,2H)8.98(d,J=8.93Hz,1H)

[0140] Step 7: To a mixture of 2,6-bis(difluoromethoxy)-3-fluoro-5-nitro-pyridine (2.38 g, 3.04 mmol) in ethanol (24 mL) and water (6 mL) was added NHCl (805.34 mg, 15.2 mmol) and Fe (850.93 mg, 15.2 mmol) at 25 °C. The reaction mixture was stirred at 80 °C for 2 h, then cooled to room temperature and extracted with ethyl acetate. The combined organic layers were washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient of 0-30% ethyl acetate / petroleum ether to give 2,6-bis(difluoromethoxy)-5-fluoro-pyridin-3-amine (639.5 mg) as a light brown oil. MS (ESI): m / z = 244.7 [M+H] +

[0141] Intermediate A15: 5-Cyclopropyl-3-fluoro-6-methoxy-pyridin-2-amine [ka] Step 1: To a stirred solution of 3,6-difluoropyridin-2-amine (1.00 g, 7.69 mmol) in acetonitrile (15 ml) was added a suspension of N-bromosuccinimide (1.73 g, 9.61 mmol) in acetonitrile (10 ml). The reaction mixture was stirred at room temperature for 1 hour, then diluted with water and extracted with ethyl acetate. The combined organic layers were washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo (do not evaporate to dryness due to the formation of impurities!). The residue was purified by flash chromatography on silica gel using a gradient of 0-20% ethyl acetate / heptane to give 5-bromo-3,6-difluoropyridin-2-amine (1.44 g, 89%) as an orange solid. MS (ESI) m / z: 209.0 [M+H] +

[0142] Step 2: A mixture of 5-bromo-3,6-difluoropyridin-2-amine (1.02 g, 4.88 mmol) and sodium methoxide (833 mg, 14.6 mmol) in THF (15 ml) was heated to 100 °C. After 15 h, the reaction mixture was cooled to room temperature and poured into saturated NH₄Cl solution. The pH was adjusted to approximately 7 with 1 N HCl, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a gradient of 0-20% ethyl acetate / heptane to afford 5-bromo-3-fluoro-6-methoxypyridin-2-amine (893 mg, 82%) as a light brown solid. MS (ESI) m / z: 221.0 [M+H] +

[0143] Step 3: A mixture of (5-bromo-3-fluoro-6-methoxy-2-pyridyl)amine (100 mg, 0.452 mmol), cyclopropylboronic acid (77.73 mg, 0.905 mmol), tricyclohexylphosphine (13.08 mg, 0.045 mmol), palladium acetate (5.08 mg, 0.023 mmol), and tripotassium phosphate (346.52 mg, 1.58 mmol) in toluene (1.8 mL) and water (100 μL) was heated to 100 °C. After 6 h, the reaction mixture was poured into water and extracted twice with ethyl acetate. The combined organic layers were washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a gradient of ethyl acetate / heptane 0-20% to give (5-cyclopropyl-3-fluoro-6-methoxy-2-pyridyl)amine (55 mg, 65%) as an orange oil. MS (ESI) m / z: 183.1 [M+H] +

[0144] Intermediate A16: (5-Bromo-4,6-dimethoxy-pyrimidin-2-yl)amine [ka] To a stirred solution of (4,6-dimethoxypyrimidin-2-yl)amine (100 mg, 0.632 mmol, CAS: 36315-01-2) in acetonitrile (2 mL) was added N-bromosuccinimide (147.65 mg, 0.821 mmol) at room temperature. The reaction mixture was stirred at room temperature, and the resulting pale yellow solution was diluted with ethyl acetate and washed with water. 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 0-50% to give the title compound as an off-white solid (116 mg, 78%). MS (ESI): m / z = 234.1 [M+H] +

[0145] Intermediate A17: (4,6-Dimethoxy-5-methyl-pyrimidin-2-yl)amine [ka] A suspension of (4,6-dichloro-5-methyl-pyrimidin-2-yl)amine (100 mg, 0.551 mmol, CAS: 6343-68-6)) and sodium methoxide (156.53 mg, 2.75 mmol) in methanol (3 mL) was heated to 95° C. and stirred for 15 hours. Sodium methoxide (78.26 mg, 1.38 mmol) was added again. The reaction mixture was heated to 100° C. and stirred for 15 hours. The reaction mixture was concentrated in vacuo. The residue was poured into water and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give (4,6-dimethoxy-5-methyl-pyrimidin-2-yl)amine (91 mg, 97%) as a white solid. MS (ESI) m / z: 169.8 [M+H] +

[0146] Intermediate A20: 5-fluoro-2-methoxy-6-(oxetan-3-yl)pyridin-3-amine [ka] Step 1: To a stirred solution of (5-fluoro-2-methoxy-3-pyridyl)amine (900 mg, 6.33 mmol) in acetonitrile (30 mL) was added dropwise a solution of N-bromosuccinimide (1.13 g, 6.33 mmol) in acetonitrile (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes, then diluted with water and extracted with ethyl acetate. The combined organic layers were washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a gradient of 0-30% ethyl acetate / heptane to give the desired product (1.25 g, 87%) as a dark red solid. MS (ESI): m / z = 221.0 [M+H] +

[0147] Step 2: A stock solution of Ir catalyst (6.9 mg / mL in dichloromethane) and NiCl*glyme / dtbbpy (dimethoxyethane containing 2.7 mg Ni-Co-Cat / mL and 2.2 mg ligand / mL) was prepared.

[0148] A corresponding volume of Ir catalyst solution (7.61 mg, 0.007 mmol, 0.010 equiv.) of [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-n,n']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-n]phenyl-c]iridium(III) hexafluorophosphate (Ir[df(cf)ppy](dtbpy))pf6 was added to the reaction vial and the solvent was evaporated. Sodium carbonate (142.51 mg, 1.36 mmol, 2 equiv.), (6-bromo-5-fluoro-2-methoxy-3-pyridyl)amine (150 mg, 0.679 mmol, 1 equiv.), 3-bromooxetane (185.92 mg, 112.61 µL, 1.36 mmol, 2 equiv.), and tris(trimethylsilyl)silane (226.13 mg, 280.55 µL, 0.909 mmol, 1.34 equiv.) were then added. Additional dry ethylene glycol dimethyl ether (10.95 mL) was added, and the reaction mixture was degassed by bubbling argon through it for 2 min. The corresponding volumes of nickel(II) chloride ethylene glycol dimethyl ether complex in NiCl*glyme / dtbbpy solution (745.56 μg, 0.003 mmol, 0.005 equiv.) and 4,4'-bis(tert-butyl)-2,2'-bipyridine (910.72 μg, 0.003 mmol, 0.005 equiv.) were added, and the reaction was again degassed for 5 minutes. The vial was placed in a photoreactor and irradiated at 450 nm for 14 hours (stirring at 900 rpm, LED 100% power). The reaction mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography to give [5-fluoro-2-methoxy-6-(oxetan-3-yl)-3-pyridyl]amine (47 mg, 35%) as an off-white solid. (ESI): m / z = 199.1 [M+H] +

[0149] Intermediate A22: 5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-amine [ka] Step 1: A suspension of 5-bromo-2-chloro-4-methoxy-pyrimidine (1.02 g, 4.48 mmol, CAS: 57054-929), bis(p-anisyl)amine (1.29 g, 4.92 mmol), and n-ethyldiisopropylamine (858 uL, 4.92 mmol) in acetonitrile (20 mL) was heated at 70 °C for 2 days. The resulting solution was poured into saturated aqueous sodium bicarbonate and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and evaporated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate / heptane 0-20% to give the title compound (998 mg, 50%) as a colorless viscous oil. MS (ESI): m / z = 446.2 [M+H] +

[0150] Step 2: A suspension of (5-bromo-4-methoxy-pyrimidin-2-yl)-bis(p-anisyl)amine (500 mg, 1.13 mmol), bis(pinacolato)diboron (354 mg, 1.35 mmol), and potassium acetate (335 mg, 3.38 mmol) in 1,4-dioxane (10 mL) was purged with argon for 5 minutes. Dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (91.9 mg, 0.113 mmol) was added. The reaction mixture was heated to 90 °C and stirred for 16 hours. The resulting dark suspension was poured into ethyl acetate and washed once with saturated NaCl. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using a gradient of ethyl acetate / heptane 0-30% to give the title compound as a colorless viscous oil (157 mg, 29%). MS (ESI): m / z=492.4 [M+H] +

[0151] Step 3: A solution of [4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]-bis(p-anisyl)amine (130 mg, 0.265 mmol) in tetrahydrofuran (2.5 mL) was cooled to 0 °C. Hydrogen peroxide 35% (500 uL, 5.71 mmol) was added. The reaction mixture was stirred at 0 °C for 15 minutes, warmed to room temperature, and stirred for 3 hours. The reaction mixture was poured into cold 0.1 N sodium sulfite solution and extracted twice with EtOAc. The organic layer was washed twice with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound as a pale yellow viscous oil (103 mg, 100%). MS (ESI): m / z = 382.3 [M+H] +

[0152] Step 4: A suspension of 2-[bis(p-anisyl)amino]-4-methoxy-pyrimidin-5-ol (100 mg, 0.236 mmol), potassium carbonate (98.82 mg, 0.708 mmol), and 1-bromo-2-fluoroethane (61.14 mg, 35.75 uL, 0.472 mmol) in acetonitrile (2.5 mL) was stirred at room temperature for 15 minutes and at 80 °C for 6 hours. The reaction mixture was poured into water and extracted twice with EtOAc. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate / heptane 0-30% to give the title compound (22 mg, 22%) as a colorless viscous oil. MS (ESI): m / z = 428.3 [M+H] +

[0153] Step 5: A solution of [5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-bis(p-anisyl)amine (87 mg, 0.204 mmol) in dichloromethane (500 uL) was cooled to 0 °C. Trifluoroacetic acid (1.41 g, 944.56 uL, 12.21 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 16 hours and at 55 °C for an additional 2 hours. The resulting purple solution was poured into saturated aqueous sodium bicarbonate and extracted twice with EtOAc. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate / heptane 0-100% to give the title compound as an off-white solid (27 mg, 71%). MS (ESI): m / z = 188.1 [M+H] +

[0154] Intermediate A23: 5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidin-2-amine [ka] Step 1: 5-Bromo-4,6-dimethoxy-pyrimidin-2-amine [ka] To a stirred solution of (4,6-dimethoxypyrimidin-2-yl)amine (7 g, 44.22 mmol, CAS: 36315-01-2) in acetonitrile (100 mL) was added dropwise a solution of N-bromosuccinimide (10.33 g, 57.48 mmol) in acetonitrile (100 mL) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes. The resulting white suspension was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered, diluted with heptane, and concentrated in vacuo. The precipitate was filtered off and washed with heptane to give the title compound as a white solid (9.26 g, 87% yield). MS (ESI) m / z = 234.1 [M+H] +

[0155] Step 2: 5-Bromo-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine [ka] A solution of 5-bromo-4,6-dimethoxy-pyrimidin-2-amine (517 mg, 2.21 mmol) in N,N-dimethylacetamide (9 mL) was cooled to 0 °C. Sodium hydride (265.05 mg, 6.63 mmol) was added in portions (3 × 88 mg). Stirring was continued at 0 °C for 30 minutes. 4-Methoxybenzyl chloride (706 mg, 608.62 µL, 4.42 mmol) was added dropwise. The reaction mixture was warmed to room temperature, stirred for 1 hour, carefully quenched with saturated ammonium chloride solution, poured into water, and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate / heptane 0-20% to give the title compound as a white solid (1.11 g, 100% yield). MS(ESI) m / z=476.2[M+H] +

[0156] Step 3: 2-[bis[(4-methoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-ol [ka] To a colorless solution of 5-bromo-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine (500 mg, 1 mmol) in tetrahydrofuran (3.5 mL) was added dropwise 1.6 M n-butyllithium in hexane (699.71 mg, 813.61 µL, 1.3 mmol) at -78 °C. The resulting yellow solution was stirred at -78 °C for 30 minutes. Trimethyl borate (156.08 mg, 167.47 µL, 1.5 mmol) was added dropwise, and stirring was continued at -78 °C for 1.5 hours. The reaction mixture was warmed to 0 °C, and acetic acid (120.27 mg, 114.62 µL, 2 mmol) was added dropwise, followed by 35% hydrogen peroxide (145.98 mg, 131.51 µL, 1.5 mmol). Stirring was continued at 0° C. for 1.5 hours. The resulting pink suspension was poured into 0.1 N sodium thiosulfate solution and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0-30% to give the title compound as a pale yellow viscous oil (194 mg, 47% yield). MS (ESI) m / z=412.3 [M+H] +

[0157] Step 4: 5-(2,2-difluoroethoxy)-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine [ka] To a solution of 2-[bis[(4-methoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-ol (100 mg, 0.214 mmol) in N,N-dimethylformamide (1.75 mL) was added potassium carbonate (88.68 g, 0.642 mmol) and 1,1-difluoro-2-iodoethane (123.16 mg, 56.5 μL, 0.642 mmol). The reaction mixture was stirred at 80° C. for 1.5 hours, cooled to room temperature, poured into water, and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate / heptane 0-20% to give the title compound as an off-white solid (92 mg, 85% yield). MS (ESI) m / z = 476.2 [M+H] +

[0158] Step 5: 5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-amine [ka] To a stirred solution of 5-(2,2-difluoroethoxy)-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine (92 mg, 0.193 mmol) in dichloromethane (0.340 mL) was added trifluoroacetic acid (1.34 g, 897.97 μL, 11.61 mmol) at 0° C. The reaction mixture was stirred at room temperature for 18 hours and at 50° C. for 4 hours. The resulting red solution was concentrated in vacuo, poured into saturated NaHCO3, and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate / heptane 0-30% to give the title compound as a pale yellow solid (41 mg, 87% yield). MS (ESI) m / z = 236.2 [M+H] +

[0159] Intermediate A24: 5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-amine [ka] Step 1: 5-(2-fluoroethoxy)-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine [ka] A suspension of 2-[bis[(4-methoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-ol (2 g, 4.52 mmol, Intermediate A23, Step 3), potassium carbonate (1.89 g, 13.56 mmol), and 1-bromo-2-fluoroethane (1.76 g, 1.03 mL, 13.56 mmol) in N,N-dimethylformamide (45 mL) was heated to 80 °C and stirred for 2.5 h. 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 on silica gel using a gradient of ethyl acetate / heptane 0-30% to give the title compound as a white solid (1.79 g, 85% yield). MS (ESI) m / z = 458.3 [M+H] +

[0160] Step 2: 5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-amine [ka] To a stirred solution of 5-(2-fluoroethoxy)-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine (1.79 g, 3.83 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (26.23 g, 17.62 mL, 230.06 mmol). The reaction mixture was stirred at 50 °C for 3 hours, at room temperature for 15 hours, and concentrated in vacuo. The residue was poured into saturated NaHCO 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 (885 mg, 100% yield). MS (ESI) m / z = 218.1 [M+H] +

[0161] Intermediate B [Table 3] TIFF2025525574000045.tif237165 TIFF2025525574000046.tif214165 TIFF2025525574000047.tif208165 TIFF2025525574000048.tif221165 TIFF2025525574000049.tif212165

[0162] Method A A solution of imidazolo or pyrazolo derivative II, VIII, XIII, XVIII, or XXIII (1 equivalent) in chlorosulfonic acid (12 equivalents) was stirred at 110° C. until LCMS indicated complete conversion. The reaction mixture was allowed to cool to room temperature, poured into ice / ethyl acetate, and extracted with ethyl acetate. The combined organic layers were washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the corresponding sulfonyl chloride B. If sulfonyl chloride B was stable on silica gel, the crude material was purified by flash chromatography on silica gel using a gradient of ethyl acetate / heptane.

[0163] Method B To a solution of imidazolo or pyrazolo derivative II, VIII, XIII, XVIII, or XXIII (1 equivalent) in 1,2-dichloroethane was added trimethylsilyl chlorosulfonate (3 equivalents). The mixture was stirred at 90°C until complete conversion to the sulfonic acid. The reaction mixture was cooled to room temperature, and triethylamine (2 equivalents) and phosphorus oxychloride (3 equivalents) were added. The reaction mixture was stirred at 100°C until LCMS showed complete conversion. The reaction mixture was cooled to room temperature, poured into saturated NaHCO3 / ice solution, and extracted with ethyl acetate. The combined organic layers were washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the corresponding sulfonyl chloride B. If sulfonyl chloride B was stable on silica gel, the crude material was purified by flash chromatography on silica gel using a gradient of ethyl acetate / heptane.

[0164] Method C Step 1: To a solution of imidazolo or pyrazolo derivative III or IX or XIV or XIX or XXIV (1 equiv.) in 1,4-dioxane (5 mL) under nitrogen at room temperature, benzyl mercaptan (1.1 equiv.), N-ethyldiisopropylamine (2 equiv.), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.050 equiv.), and tris(dibenzylideneacetone)dipalladium (0.030 equiv.) were added. The reaction mixture was stirred at 90 °C until complete conversion, then cooled to room temperature and poured into water. Ethyl acetate was added, and the mixture was filtered. Both layers were separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a gradient of ethyl acetate / heptane to give the corresponding benzyl thioether.

[0165] Step 2: To a solution of the benzyl thioether derivative (1 equivalent) in acetic acid / water (10:1) was added n-chlorosuccinimide (3 equivalents) under nitrogen at room temperature. The reaction mixture was stirred at room temperature until complete conversion. The reaction mixture was diluted with ice water and ethyl acetate. Both layers were separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. If sulfonyl chloride B was stable on silica gel, the crude material was purified by flash chromatography on silica gel using a gradient of ethyl acetate / heptane.

[0166] Synthesis of precursor I or III of sulfonyl chloride intermediate B Precursor B1-I: 7-Cyclopropylimidazo[1,2-a]pyridine In a 25 mL round-bottom flask were added 7-bromoimidazo[1,2-a]pyridine (1 g, 5.08 mmol), cyclopropylboronic acid (566.77 mg, 6.6 mmol), 1,4-dioxane (24 mL), PdCl(dppf)-CHCl (828.95 mg, 1.02 mmol), and cesium carbonate (4.96 g, 15.23 mmol). The reaction mixture was stirred at 90 °C for 2 h, then poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was adsorbed onto ISOLUTE HM-N and purified by flash chromatography on silica gel using a gradient of 0-100% ethyl acetate / heptane to afford 7-cyclopropylimidazo[1,2-a]pyridine (613 mg, 65%) as a light brown oil. MS (ESI): m / z = 159.1 [M+H] +

[0167] Precursor B2-I: 7-Bromoimidazo[1,2-a]pyridine Commercially available CAS 808744-34-5

[0168] Precursor B3-I: 7-methylimidazo[1,2-a]pyridine Commercially available CAS 874-39-5

[0169] Precursor B4-I: 8-Methoxy-7-methyl-imidazo[1,2-a]pyridine To (3-methoxy-4-methyl-2-pyridyl)amine (0.500 g, 3.62 mmol) in ethanol (15 mL) was added 50% aqueous chloroacetaldehyde (5.68 g, 4.6 mL, 36.19 mmol) at room temperature. The reaction mixture was stirred at reflux for 16 hours, then cooled to room temperature and concentrated. The residue was dissolved in saturated NaHCO3 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a gradient of methanol / dichloromethane 0-10% to give 8-methoxy-7-methyl-imidazo[1,2-a]pyridine (478 mg, 77%) as a light brown oil. MS (ESI): m / z = 163.0 [M+H] +

[0170] Precursor B5-I: 7-(difluoromethoxy)imidazo[1,2-a]pyridine To a solution of 4-(difluoromethoxy)pyridin-2-amine (20.0 mg, 0.120 mmol) in ethanol (1 mL) was added chloroacetaldehyde (51.48 mg, 0.260 mmol). The mixture was stirred at 90 °C for 16 hours and then concentrated under reduced pressure. The mixture was triturated with 5 mL of acetonitrile to give 7-(difluoromethoxy)imidazo[1,2-a]pyridine (30 mg, 100%, 80% purity) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.67 (br d, J = 7.0 Hz, 1H), 8.00 (s, 1H), 7.94 (s, 1H), 7.79 (s, 1H), 7.19 (br d, J = 5.4 Hz, 1H), 7.11-6.66 (m, 1H).

[0171] Precursor B6-III: 3-Bromo-7-chloro-imidazo[1,2-a]pyridine Commercially available CAS 342613-67-6

[0172] Precursor B7-I: 7-chloro-8-fluoro-imidazo[1,2-a]pyridine Commercially available CAS 628691-87-2

[0173] Precursor B8-I: 7-chloro-8-methoxy-imidazo[1,2-a]pyridine To a mixture of (4-chloro-3-methoxy-2-pyridyl)amine (200 mg, 1.26 mmol) in ethanol (1 mL) was added 2-chloroacetaldehyde (296.99 mg, 239.51 uL, 1.89 mmol). The reaction mixture was heated to 150 °C in a sand bath for 90 minutes, then cooled to room temperature and concentrated in vacuo. The residue was treated with diethyl ether and filtered to give 7-chloro-8-methoxy-imidazo[1,2-a]pyridine (247.5 mg, 104%) as a light brown solid. MS (ESI): m / z = 183.0 [M+H] +

[0174] Precursor B9-I: 7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine To a solution of 7-methylimidazo[1,2-a]pyridine (1 g, 7.57 mmol) in 1-butanol (20.0 mL) was added Raney Ni (1.4 g). The reaction mixture was purged with hydrogen gas several times, and the reaction mixture was stirred under a hydrogen atmosphere (50 psi) at 65 °C until LCMS showed complete conversion. The reaction mixture was filtered and concentrated under reduced pressure to give 7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (614 mg, 58%) as a pale yellow oil. MS (ESI): m / z = 137.2 [M+H] +

[0175] Precursor B10-I: 7-(difluoromethyl)imidazo[1,2-a]pyridine To a solution of imidazo[1,2-a]pyridine-7-carboxaldehyde (500 mg, 3.42 mmol) in dichloromethane (20 mL) was added diethylaminosulfur trifluoride (1.93 g, 11.97 mmol) at −78° C. The mixture was stirred at 30° C. After 12 h, LCMS indicated that approximately 80% of the starting material remained. Diethylaminosulfur trifluoride (3.58 g, 22.24 mmol) was added to the reaction mixture, which was stirred at 30° C. for an additional 12 h before being quenched with saturated NaHCO3 solution and extracted with dichloromethane / MeOH (10:1 V / V). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a gradient of ethyl acetate / petroleum ether 0-50% to give 7-(difluoromethyl)imidazo[1,2-a]pyridine (180 mg, 31%) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.23 (d, J = 7.0 Hz, 1H), 7.82-7.60 (m, 3H), 6.96 (d, J = 7.0 Hz, 1H), 6.86-6.47 (m, 1H).

[0176] Precursor B11-I: 7-Methoxyimidazo[1,2-a]pyridine Commercially available CAS 342613-71-2

[0177] Precursor B12-I: 7-Cyclopropylimidazo[1,2-a]pyrimidine To a solution of (4-cyclopropylpyrimidin-2-yl)amine (1 g, 7.4 mmol) in ethanol (28.26 mL) was added 50% aqueous chloroacetaldehyde (11.61 g, 9.4 mL, 73.98 mmol) at room temperature. The reaction mixture was stirred at reflux for 16 hours, then cooled to room temperature and concentrated in vacuo. The residue was dissolved in saturated NaHCO3 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a gradient of dichloromethane / methanol 0-7.5% to give 7-cyclopropylimidazo[1,2-a]pyrimidine (670 mg, 51%) as a pale red solid. MS (EI): m / z = 158.1 [M−H] +

[0178] Precursor B13-I: 7-Ethylimidazo[1,2-a]pyridine To a solution of (4-ethyl-2-pyridyl)amine (500 mg, 3.97 mmol) in ethanol (16 mL) was added 50% aqueous 2-chloroacetaldehyde (6.23 g, 5.03 mL, 39.7 mmol), and the resulting yellow solution was stirred at 80 °C for 5 h. The reaction mixture was cooled to room temperature, diluted with saturated NaHCO solution, extracted twice with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a 0-5% gradient of dichloromethane / methanol to afford 7-ethylimidazo[1,2-a]pyridine (313 mg, 49%) as a yellow oil. MS (ESI): m / z = 147.1 [M+H] +

[0179] Precursor B14-III: 3-Bromo-7-methyl-imidazo[1,2-a]pyridine-8-carbonitrile To a solution of 7-methylimidazo[1,2-a]pyridine-8-carbonitrile (750 mg, 4.77 mmol) in acetonitrile (12 mL), N-bromosuccinimide (849.3 mg, 4.77 mmol) was added portionwise, and the resulting reaction mixture was stirred at 22 °C until complete conversion. Saturated NaHCO solution was added to the reaction mixture, which was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 3-bromo-7-methyl-imidazo[1,2-a]pyridine-8-carbonitrile (990 mg, 88%) as an orange solid. MS (ESI): m / z = 236.0 [M+H] +

[0180] Precursor B15-I: 7,8-dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine A reaction mixture of 7,8-dimethylimidazo[1,2-a]pyridine (550 mg, 4 mmol) and 4.5% palladium and 0.5% rhodium on carbon (770 mg, 3.4 mol%) in ethanol (11 mL) was heated at 80 °C and 50 bar hydrogen atmosphere until complete conversion. The reaction mixture was filtered and the crude material concentrated in vacuo to give 7,8-dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (469 mg, 63%) as a pale yellow oil. MS (ESI): m / z = 150.9 [M+H] +

[0181] Precursor B16-III: 3-Bromo-7-(trifluoromethyl)imidazo[1,2-a]pyridine To a stirred solution of 7-(trifluoromethyl)imidazo[1,2-a]pyridine (650 mg, 3.49 mmol) in acetic acid (8 mL) at room temperature was added bromine (558.09 mg, 178.93 μL, 3.49 mmol). The clear yellow solution was stirred at room temperature for 1 hour, and then 4N NaOH was added at 0° C. until a pH >10 was reached. The reaction mixture was extracted with dichloromethane / methanol 95:5. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 3-bromo-7-(trifluoromethyl)imidazo[1,2-a]pyridine (810 mg, 70%) as a pale yellow solid. MS (ESI): m / z = 265.1 [M+H] +

[0182] Precursor B17-III: 3-Bromo-7-cyclopropyl-imidazo[1,2-a]pyridine-8-carbonitrile Step 1: To a solution of 2-amino-4-bromo-nicotinonitrile (300 mg, 1.52 mmol), cyclopropylboronic acid (260.27 mg, 3.03 mmol) in toluene (6 mL) and water (0.3 mL) was added tricyclohexylphosphine (84.97 mg, 0.303 mmol), palladium acetate (34.01 mg, 0.152 mmol), and potassium phosphate triphosphate (1.13 g, 5.3 mmol). The reaction mixture was stirred at 110 °C for 15 h and then concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a gradient heptane / ethyl acetate 0-100% to give 2-amino-4-cyclopropyl-nicotinonitrile (124 mg, 51%) as a yellow solid. MS (ESI): m / z = 160.1 [M+H] +

[0183] Step 2: To a yellow solution of 2-amino-4-cyclopropyl-nicotinonitrile (124 mg, 0.779 mmol) in ethanol (6.18 mL) was added chloroacetaldehyde (183.44 mg, 147.93 uL, 2.34 mmol). The reaction mixture was stirred at 150 °C for 4 hours and then concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a 0-50% gradient of methanol / ethyl acetate to afford 7-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile (155 mg, 97%) as a light brown solid. MS (ESI): m / z = 184.1 [M+H] +

[0184] Step 3: To a suspension of 7-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile (155 mg, 0.761 mmol) in acetonitrile (2 mL) was added a suspension of N-bromosuccinimide (135 mg, 0.761 mmol) in acetonitrile (1 mL) at 0 °C. The resulting reaction mixture was stirred at 0 °C for 1 hour, then poured into saturated NaHCO solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by reverse-phase HPLC to give 3-bromo-7-cyclopropyl-imidazo[1,2-a]pyridine-8-carbonitrile (153 mg, 63%) as a pale yellow solid. MS (ESI): m / z = 262.1 [M+H] +

[0185] Precursor B18-I: 7-Methoxyimidazo[1,2-a]pyrimidine To a solution of (4-methoxypyrimidin-2-yl)amine (1 g, 7.83 mmol) in ethanol (29.4 mL) was added 50% aqueous chloroacetaldehyde (12.3 g, 9.95 mL, 78.32 mmol) at room temperature, and the reaction mixture was stirred at reflux for 16 hours. The reaction mixture was cooled to room temperature, diluted with saturated NaHCO3 solution, extracted twice with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a 0-7.5% gradient of dichloromethane / methanol to give 7-methoxyimidazo[1,2-a]pyrimidine (742 mg, 63%) as a white solid. MS (ESI): m / z = 150.0 [M+H] +

[0186] Precursor B19-I: 7-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine A reaction mixture of 7-(trifluoromethyl)imidazo[1,2-a]pyridine (75 mg, 0.4 mmol) and 5% platinum on carbon (7.5 mg) in ethanol (2 mL) was heated at 80 °C and 50 bar hydrogen atmosphere until complete conversion. The reaction mixture was filtered and the crude material was concentrated in vacuo to give 7-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (72 mg, 73%) as a colorless solid. MS (EI+): m / z = 190.1 [M] +

[0187] Precursor B20-I: 7,7-dimethyl-6,8-dihydro-5H-imidazo[1,2-a]pyridine Step 1: A solution of 4,4-dimethyl-2-piperidone (1 g, 7.86 mmol, 1 equiv.) and Lawesson's reagent (1.74 g, 4.31 mmol) in tetrahydrofuran (13.35 mL) was stirred at 70° C. for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered, and concentrated to dryness. The crude compound was purified by flash chromatography on silica gel using a gradient of 0-30% dichloromethane / methanol to give 4,4-dimethylpiperidine-2-thione (700 mg, 59%) as a white solid. MS (ESI): m / z = 144.1 [M+H] +

[0188] Step 2: 4,4-Dimethylpiperidine-2-thione (255 mg, 1.78 mmol) was dissolved in 1-butanol (8.9 mL), followed by the addition of 2,2-diethoxyethylamine (355 mg, 388.25 uL, 2.67 mmol) and p-toluenesulfonic acid monohydrate (507 mg, 2.67 mmol). The mixture was stirred at 130 °C for 16 h. After complete conversion, the solvent was removed and the mixture was poured into dichloromethane and saturated NaHCO3 solution. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by flash chromatography on silica gel using a gradient of 0 to 30% methanol in dichloromethane (stained with KMnO) to give 7,7-dimethyl-6,8-dihydro-5H-imidazo[1,2-a]pyridine (67 mg, 24%) as a pale yellow oil. MS (ESI): m / z = 151.1 [M+H] +

[0189] Precursor B21-I: 7-methylimidazo[1,2-a]pyrimidine To a solution of (4-methylpyrimidin-2-yl)amine (3 g, 27.49 mmol) in ethanol (120 mL) was added chloroacetaldehyde, 50% aqueous solution (43.16 g, 34.92 mL, 274.9 mmol) at room temperature. The reaction mixture was stirred at reflux for 16 hours. The reaction mixture was cooled to room temperature, diluted with saturated NaHCO3 solution, extracted twice with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a gradient of dichloromethane / methanol 0-10% to give a regioisomeric mixture, which was separated by SFC. 7-Methylimidazo[1,2-a]pyrimidine (466 mg, 12%) was obtained as a pale yellow solid. MS (ESI): m / z = 134.0 [M+H] +

[0190] Precursor B22-I: 8-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine Step 1: A solution of 3-methyl-2-piperidone (1 g, 8.84 mmol) and Lawesson's reagent (1.96 g, 4.84 mmol) in tetrahydrofuran (15 mL) was stirred at 70° C. for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered, and concentrated to dryness. The crude material was purified by flash chromatography on silica gel using a gradient of 0-30% dichloromethane / methanol to give 3-methylpiperidine-2-thione (532 mg, 44%) as a white solid. MS (ESI): m / z=130.1 [M+H] +

[0191] Step 2: 3-Methylpiperidine-2-thione (308 mg, 2.38 mmol) was dissolved in toluene (10 mL), followed by the addition of 2,2-dimethoxyethylamine (250.6 mg, 259.69 uL, 2.38 mmol) and p-toluenesulfonic acid monohydrate (453.4 mg, 2.38 mmol). The reaction mixture was stirred at 130 °C for 72 hours. After complete conversion, the reaction mixture was poured into dichloromethane and saturated aqueous NaHCO3. The layers were separated, and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and concentrated to dryness to afford 8-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (215 mg, 39%) as a brown solid, which was used without further purification. MS (ESI): m / z = 137.1 [M+H] +

[0192] Precursor B23-III: 3-Bromo-7-chloro-imidazo[1,2-a]pyridine-8-carbonitrile

[0193] Step 1: A mixture of 2,4-dibromonicotinonitrile (2 g, 7.64 mmol) and ammonia (0.4 M in THF) (62.96 g, 80 mL, 32 mmol) was stirred at 100 °C for 16 h. After complete conversion, the reaction mixture was concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a gradient of heptane / ethyl acetate 0-100% to give 2-amino-4-bromo-nicotinonitrile (140.2 mg, 8%) as a white solid. MS (GS): m / z = 196.9 [M] +

[0194] Step 2: To a mixture of 2-amino-4-methoxy-nicotinonitrile (2.03 g, 13.61 mmol) in ethanol (5.1 mL) was added 2-chloroacetaldehyde (3.2 g, 2.59 mL, 20.41 mmol). The reaction mixture was subjected to microwave heating at 150 °C for 45 minutes. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was treated with diethyl ether to give a solid precipitate. The solid was filtered off, washed with ethyl acetate, and dried under reduced pressure to give 7-hydroxyimidazo[1,2-a]pyridine-8-carbonitrile (802 mg, 33%) as a brown powder: MS (ESI): m / z = 160.0 [M+H] +

[0195] Step 3: A suspension of 7-hydroxyimidazo[1,2-a]pyridine-8-carbonitrile (200 mg, 1.13 mmol) in phosphoryl chloride (888.3 mg, 540 μL, 5.79 mmol) was heated to 140 °C for 2 h. The reaction mixture was concentrated in vacuo, and the residue was treated with saturated aqueous NaHCO3 and extracted twice with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated to dryness to give 7-chloroimidazo[1,2-a]pyridine-8-carbonitrile (162 mg, 80%) as a yellow solid. MS (ESI): m / z = 178.1 [M+H] +

[0196] Step 4: A suspension of 7-chloroimidazo[1,2-a]pyridine-8-carbonitrile (142 mg, 0.800 mmol) in acetonitrile (7 mL) was cooled to 0 °C. A solution of N-bromosuccinimide (143 mg, 0.800 mmol) in acetonitrile (1.5 mL) was added dropwise. The reaction mixture was stirred at 0 °C for 25 min, then poured into saturated aqueous NaHCO3 and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The crude material was purified by flash chromatography on silica gel using a gradient of 0-60% heptane / ethyl acetate to give 3-bromo-7-chloro-imidazo[1,2-a]pyridine-8-carbonitrile (169 mg, 73%) as a pale yellow solid. MS (ESI): m / z = 258.0 [M+H] +

[0197] Precursor B24-I: 7-methyl-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine A mixture of 2-chloro-1H-imidazole (1.1 g, 10.73 mmol), potassium carbonate (2.97 g, 21.46 mmol), and 4-bromobutan-2-ol (1.64 g, 10.73 mmol) in acetonitrile (22 mL) was stirred at 60° C. overnight. The solid was filtered off, washed with acetonitrile, and the filtrate was concentrated in vacuo. The residue was dissolved in tetrahydrofuran (22 mL), sodium hydride (429 mg, 10.73 mmol) was added at 0° C., and the resulting reaction mixture was stirred at 70° C. overnight. The reaction mixture was quenched with acetic acid (644.31 mg, 614.22 μL, 10.73 mmol) and concentrated in vacuo. The crude material was purified by silica gel flash using a gradient of heptane / ethyl acetate 0-100% to give 7-methyl-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine as a colorless semi-solid. MS(EI+): m / z=138.0 [M] +

[0198] Precursor B25-III: 3-Bromo-7-methyl-imidazo[1,2-a]pyrazin-8-one A suspension of 3-bromo-7H-imidazo[1,2-a]pyrazin-8-one (350 mg, 1.64 mmol, CAS: 689297-67-4) in N,N-dimethylformamide (7 mL) was cooled to 8-10 °C, and sodium hydride (78.5 mg, 1.96 mmol) was added portionwise. After stirring at 20 °C for 15 min, iodomethane (255.34 mg, 112.48 µL, 1.8 mmol) was added, and the reaction mixture was stirred at room temperature. After 1 h, the suspension was cooled to 0 °C, and methanol (2 mL) was added slowly. After stirring for 10 min, the mixture was concentrated in vacuo. The crude compound was purified by flash chromatography on silica gel using a gradient of 0-15% dichloromethane / methanol to give 3-bromo-7-methyl-imidazo[1,2-a]pyrazin-8-one (280 mg, 75%) as a white solid. MS (ESI): m / z = 230.1 [M+H] +

[0199] Precursor B26-III: 3-Bromoimidazo[1,2-a]pyridine-7-carbonitrile Commercially available CAS 1392210-94-4

[0200] Precursor B27-III: 3-Bromo-7-methoxy-imidazo[1,2-a]pyridine-8-carbonitrile Commercially available CAS 1072944-45-6

[0201] Precursor B28-III: 3-Bromo-7-methoxy-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine Step 1: A reaction mixture of 7-methoxyimidazo[1,2-a]pyridine (1.9 g, 13 mmol) and 4.5% palladium and 0.5% rhodium on carbon (1 g, 13 mol%) in ethanol (70 mL) was heated at 80 °C and 50 bar hydrogen atmosphere until complete conversion. The reaction mixture was filtered and the crude material was concentrated in vacuo to give 7-methoxy-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (2 g, 82%) as a pale yellow oil. MS (ESI): m / z = 153.1 [M+H] + Step 2: A mixture of 7-methoxy-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (380 mg, 2 mmol) and N-bromosuccinimide (355 mg, 2 mmol) in acetonitrile (5 mL) was stirred at room temperature. After 1 h, the reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude compound was purified by flash chromatography on silica gel using a gradient of 0-10% dichloromethane / methanol to give 3-bromo-7-methoxy-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (257 mg, 54%) as a colorless oil. MS (EI+): m / z = 230.0 [M] +

[0202] Precursor B29-I: 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine Commercially available CAS 34167-66-3

[0203] Precursor B30-III: 3-Bromo-7-(difluoromethoxy)imidazo[1,2-a]pyridine-8-carbonitrile Step 1: A mixture of 2-amino-4-methoxy-nicotinonitrile (1 g, 6.57 mmol) and 2-chloroacetaldehyde solution, approximately 50% by weight in water (1.55 g, 1.25 mL, 9.85 mmol) in ethanol (2.5 mL) was heated to 150 °C and stirred for 5 hours. The reaction mixture was concentrated in vacuo. The residue was triturated with ethyl acetate and filtered through a sintered glass filter. The solid was washed with diethyl ether and dried in vacuo to give 7-hydroxyimidazo[1,2-a]pyridine-8-carbonitrile (1.23 g, 94%) as a light brown solid. MS (ESI): m / z = 160.1 [M+H] +

[0204] Step 2: A mixture of 7-hydroxyimidazo[1,2-a]pyridine-8-carbonitrile (400 mg, 2.51 mmol), cesium carbonate (1.24 g, 3.77 mmol), chlorodifluoroacetic acid sodium salt (997 mg, 6.28 mmol), and water (600 μL) in N,N-dimethylformamide (6 mL) was heated to 100 °C. After 1 h, the reaction mixture was poured into water and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude material was purified by flash filtration on silica gel using a gradient of 0-100% heptane / ethyl acetate to give 7-(difluoromethoxy)imidazo[1,2-a]pyridine-8-carbonitrile (126 mg, 23%) as a yellow solid. MS (ESI): m / z = 210.0 [M+H] +

[0205] Step 3: A solution of 7-(difluoromethoxy)imidazo[1,2-a]pyridine-8-carbonitrile (36 mg, 0.172 mmol) in acetonitrile (1.5 mL) was cooled to 0 °C. A solution of N-bromosuccinimide (31 mg, 0.172 mmol) in acetonitrile (300 μL) was added dropwise. The reaction mixture was stirred at 0 °C for 35 minutes, then poured into saturated NaHCO and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash on silica gel using a gradient of 0-100% heptane / ethyl acetate to give 3-bromo-7-(difluoromethoxy)imidazo[1,2-a]pyridine-8-carbonitrile (37 mg, 74%) as a pale yellow solid. MS (ESI): m / z = 290.0 [M+H] +

[0206] Precursor B31-III: 3-Bromoimidazo[1,2-a]pyridine-8-carbonitrile Commercially available CAS 1383718-53-3

[0207] Precursor B32-I: 6-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole Step 1: After stirring a solution of 4-methyl-2-pyrrolidone (500 mg, 5.04 mmol) and Lawesson's reagent (1.12 g, 2.76 mmol) in tetrahydrofuran (10 mL) at 70 °C for 2 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered, and concentrated to dryness. The crude compound was purified by flash chromatography on silica gel using a gradient of dichloromethane / methanol 0-10% to afford 4-methylpyrrolidine-2-thione (390 mg, 63%) as an off-white solid. MS (ESI): m / z = 116.0 [M+H] +

[0208] Step 2: A solution of 4-methylpyrrolidine-2-thione (390 mg, 3.22 mmol) and iodomethane (2.5 g, 1.1 mL, 17.59 mmol) in dichloromethane (12.14 mL) was stirred at 23 °C for 16 h. The reaction mixture was diluted with saturated Na2CO3 solution and extracted with dichloromethane. The combined organic layers were washed with water, brine, dried over sodium sulfate, and concentrated to dryness to give 4-methyl-2-(methylthio)-1-pyrroline (342 mg, 82%) as a pale yellow gum. MS (ESI): m / z = 130.0 [M+H] +

[0209] Step 3: A solution of 4-methyl-2-(methylthio)-1-pyrroline (342 mg, 2.65 mmol) and 2,2-dimethoxyethylamine (417 mg, 432.54 uL, 3.97 mmol) in ethanol (3.63 mL) was stirred at 90 °C for 24 h. All volatiles were removed in vacuo to give 2,2-dimethoxyethyl-(4-methyl-1-pyrrolin-2-yl)amine (487 mg, 98%) as an off-white gum. MS (ESI): m / z = 187.2 [M+H] +

[0210] Step 4: A solution of 2,2-dimethoxyethyl-(4-methyl-1-pyrrolin-2-yl)amine (100 mg, 0.537 mmol) in HCl (846 mg, 705.44 uL, 8.59 mmol) and methanol (1 mL) with a few drops of water was stirred at 90 °C for 24 hours. The solvent was evaporated, and the crude compound was treated with saturated NaHCO and extracted with dichloromethane. The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered, and concentrated to dryness to give 6-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (41 mg, 62%) as a light brown gum. MS (ESI): m / z = 123.1 [M+H] +

[0211] Precursor B33-I: 7-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole Step 1: A solution of 3-methyl-2-pyrrolidone (500 mg, 5.04 mmol) and Lawesson's reagent (1.12 g, 2.76 mmol) in tetrahydrofuran (10 mL) was stirred at 70 °C for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered, and concentrated to dryness. The crude compound was purified by flash chromatography on silica gel using a gradient of dichloromethane / methanol 0-10% to give 3-methylpyrrolidine-2-thione (422 mg, 71%) as a white solid. MS (ESI): m / z = 116.0 [M+H] +

[0212] Step 2: A solution of 3-methylpyrrolidine-2-thione (422.4 mg, 3.59 mmol) and iodomethane (2.72 g, 1.2 mL, 19.19 mmol) in dichloromethane (7 mL) was stirred at 23 °C for 16 hours. The reaction mixture was quenched with saturated Na2CO3 solution and extracted with dichloromethane. The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered, and concentrated to dryness to give 3-methyl-2-(methylthio)-1-pyrroline (233 mg, 49%) as a pale yellow oil. MS (ESI): m / z = 130.0 [M+H] +

[0213] Step 3: A solution of 3-methyl-2-(methylthio)-1-pyrroline (220 mg, 1.67 mmol) and 2,2-dimethoxyethylamine (210.37 mg, 218 μL, 2 mmol) in ethanol (2.2 mL) was stirred at 90° C. for 16 hours. The reaction mixture was concentrated to dryness to give 2,2-dimethoxyethyl-(3-methyl-1-pyrrolin-2-yl)amine (309 mg, 94%) as a colorless oil. MS (ESI): m / z = 187.1 [M+H] +

[0214] Step 4: A solution of 2,2-dimethoxyethyl-(3-methyl-1-pyrrolin-2-yl)amine (100 mg, 0.510 mmol) and p-toluenesulfonic acid monohydrate (19.4 mg, 0.102 mmol) in toluene (1 mL) was stirred at 130 °C for 4 h. The reaction mixture was quenched with saturated NaHCO solution and extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to dryness to give 7-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (30 mg, 43%) as a brown gum. MS (ESI): m / z = 123.1 [M+H] +

[0215] Precursor B34-I: 6-Bromopyrazolo[1,5-a]pyridine Commercially available CAS 1264193-11-4

[0216] Precursor B35-I: 6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine Step 1: A solution of 6-bromopyrazolo[1,5-a]pyridine (400 mg, 2.03 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (509 mg, 566.32 µL, 4.06 mmol), potassium carbonate (308 mg, 2.23 mmol) in water (0.7 mL) and PdCl(dppf)-CHCl adduct (82 mg, 0.102 mmol) in 1,4-dioxane (6.5 mL) was heated at 90 °C. After 16 h, the reaction was cooled to room temperature, ethyl acetate was added, and the reaction mixture was filtered. All volatiles were removed in vacuo, and the residue was purified by flash filtration on silica gel using a gradient of 0-60% heptane / ethyl acetate to afford 6-methylpyrazolo[1,5-a]pyridine (187 mg, 59%) as a pale yellow oil. MS (ESI): m / z = 133.0 [M+H] +

[0217] Step 2: 6-Methylpyrazolo[1,5-a]pyridine (187 mg, 1.2 mmol) was dissolved in methanol (9 mL) and acetic acid (0.100 mL), platinum dioxide (27.31 mg, 0.120 mmol) was added, and the reaction mixture was stirred under hydrogen at 35 °C. After complete conversion, the reaction mixture was filtered and washed with diethyl ether. The organic phase was diluted with diethyl ether, washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo (30 °C / 200 mbar). The residue was diluted with diethyl ether and crystallized at 4 °C to give 6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (45 mg, containing acetic acid). The mother liquor was removed under vacuum to give 6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (135 mg) as an oil containing ethyl acetate / acetic acid. MS (ESI): m / z = 137.2 [M+H] +

[0218] Precursor B36-III: 3-Bromo-6-methyl-pyrazolo[1,5-a]pyridine-7-carbonitrile Step 1: A solution of 6-bromo-3-methyl-picolinonitrile (2 g, 10.15 mmol) was dissolved in N,N-dimethylformamide (20 mL) and trimethylsilylacetylene (1.2 g, 1.69 mL, 12.18 mmol), and triphenylphosphine (532 mg, 2.03 mmol), bis(triphenylphosphine)palladium(II) chloride (712 mg, 1.02 mmol), triethylamine (3.08 g, 4.24 mL, 30.45 mmol), and copper(I) iodide (386 mg, 2.03 mmol) were added. The mixture was stirred at 80 °C. After 16 h, the solvent was removed under reduced pressure and the crude material purified by silica gel flash using a gradient of heptane / ethyl acetate 0-100% to give 3-methyl-6-(2-trimethylsilylethynyl)picolinonitrile (1.32 g, 59%) as a pink solid. MS (ESI): m / z = 215.1 [M+H] +

[0219] Step 2: 3-Methyl-6-(2-trimethylsilylethynyl)picolinonitrile (1.32 g, 6.16 mmol) was dissolved in dichloromethane (16 mL) and the resulting solution was cooled to 0° C. 2,4,6-Trimethylbenzenesulfonic acid amino ester (2.39 g, 11.09 mmol) in dichloromethane (8 mL) was added dropwise, and the mixture was stirred at 23° C. for 20 hours. Upon completion, most of the solvent was removed under reduced pressure. Diethyl ether was added to the residue, and a precipitate formed. The solid was isolated by filtration to give the desired product (1.24 g). The mother liquor was partitioned between water and diethyl ether. The layers were separated, and the ether phase was washed twice with water. The combined aqueous layers were dried on a lyophilizer to give additional product. MS (ESI): m / z = 230.2 [M+H] +

[0220] Step 3: A mixture of 1-amino-3-methyl-6-(2-trimethylsilylethynyl)pyridin-1-ium-2-carbonitrile, 1:1 2,4,6-trimethylbesylate (942 mg, 2.19 mmol), and K2CO3 (303 mg, 2.19 mmol) in N,N-dimethylformamide (15 mL) was stirred at 23 °C for 16 h. The solvent was removed under reduced pressure, and the residue was partitioned between ethyl acetate and water. The layers were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash filtration on silica gel using a gradient of 0-60% heptane / ethyl acetate to give 6-methylpyrazolo[1,5-a]pyridine-7-carbonitrile (42 mg, 12%) as a pale yellow solid. MS (ESI): m / z = 158.1 [M+H] +

[0221] Step 4: To a solution of 6-methylpyrazolo[1,5-a]pyridine-7-carbonitrile (18.3 mg, 0.114 mmol) in N,N-dimethylformamide (0.571 mL) was added N-bromosuccinimide (20.31 mg, 0.114 mmol). The resulting mixture was stirred at 25 °C for 2.5 hours and then partitioned between ethyl acetate and water. The layers were separated, and the organic layer was washed twice with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash filtration on silica gel using a gradient of 0-100% heptane / ethyl acetate to give 3-bromo-6-methyl-pyrazolo[1,5-a]pyridine-7-carbonitrile (19 mg, 69%) as a colorless solid. MS (ESI): m / z = 236.0 [M+H] +

[0222] Example Example 1: 7-Bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide [ka] To a mixture of 7-bromoimidazo[1,2-a]pyridine-3-sulfonyl chloride (Intermediate B2, 56 mg, 0.185 mmol) and [6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]amine (Intermediate A2, 41 mg, 0.185 mmol) was added pyridine (1 mL). The reaction mixture was stirred at room temperature. After complete conversion, the reaction mixture was concentrated in vacuo. The crude material was purified by flash filtration on silica gel using a gradient of 0-60% heptane / ethyl acetate to give 7-bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide (55 mg, 62%) as an off-white solid. MS (ESI): m / z = 483.1 [M+H] +

[0223] The following Examples 2-88 were prepared in a similar manner to Example 1 by coupling the sulfonyl chloride intermediate B and amine intermediate A as shown. [Table 4] TIFF2025525574000052.tif230167 TIFF2025525574000053.tif224167 TIFF2025525574000054.tif235167 TIFF2025525574000055.tif229167 TIFF2025525574000056.tif233167 TIFF2025525574000057.tif234167 TIFF2025525574000058.tif224167 TIFF2025525574000059.tif242167 TIFF2025525574000060.tif224167 TIFF2025525574000061.tif238167 TIFF2025525574000062.tif114167

[0224] Example 93: N-[4-(cyanomethyl)-5-fluoro-2-methoxy-phenyl]-7-cyclopropyl-imidazo[1,2-a]pyridine-3-sulfonamide [ka] A solution of 7-bromo-N-[4-(cyanomethyl)-5-fluoro-2-methoxy-phenyl]imidazo[1,2-a]pyridine-3-sulfonamide (60 mg, 0.137 mmol), cyclopropylboronic acid (15 mg, 0.178 mmol), PdCl(dppf)-CHCl(11 mg, 0.014 mmol), and cesium carbonate (133 mg, 0.410 mmol) in 1,4-dioxane (2.8 mL) was stirred at 90 °C overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash on silica gel using a gradient heptane / ethyl acetate 0-100% to give N-[4-(cyanomethyl)-5-fluoro-2-methoxy-phenyl]-7-cyclopropyl-imidazo[1,2-a]pyridine-3-sulfonamide (2.8 mg, 5%) as an off-white solid. MS (ESI): m / z = 401.2 [M+H]

[0225] In analogy to Example 89, the following Examples 90-92 were prepared by Pd-mediated Suzuki cross-coupling reaction of bromo-imidazosulfonamides with cyclopropylboronic acid. [Table 5]

[0226] Example 97: 7-Cyclopropyl-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridyl]imidazo[1,2-a]pyrimidine-3-sulfonamide [ka] A solution of [5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridyl]amine (30 mg, 0.144 mmol) in N,N-dimethylformamide (500 μL) was cooled to 0° C. Sodium hydride (6.92 mg, 0.173 mmol) was added, and the reaction mixture was stirred at 0° C. for 10 minutes. 7-Cyclopropylimidazo[1,2-a]pyrimidine-3-sulfonyl chloride (40.86 mg, 0.159 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 1.5 hours. The resulting dark purple mixture was quenched with water, poured into brine, and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash on silica gel using a gradient heptane / ethyl acetate 0-60% to give 7-cyclopropyl-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridyl]imidazo[1,2-a]pyrimidine-3-sulfonamide (3.3 mg, 5%) as a light brown solid. MS (ESI): m / z = 430.1 [M+H]

[0227] The following Examples 94 and 95 were prepared in a similar manner to Example 93 by coupling the sulfonyl chloride intermediate B and amine intermediate A shown. [Table 6]

[0228] Example 100: N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-(oxetan-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide [ka] To a 15 mL vial equipped with a stir bar was added 7-bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide (30.0 mg, 0.060 mmol), 3-bromooxetane (11.1 mg, 0.080 mmol), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (0.7 mg), NiCl2·dtbbpy (0.12 mg), tris(trimethylsilyl)silane (0.02 mL, 0.060 mmol), sodium carbonate (13.21 mg, 0.120 mmol) in dimethoxyethane (1 mL). The vial was sealed and placed under nitrogen. The reaction was stirred and irradiated with a 34W blue LED lamp (7cm distance) and the reaction temperature was maintained at 25°C using a cooling fan. After 14 hours, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (conditions: water (0.225% FA)-ACN, column: Phenomenex Gemini-NX C18 75*30mm*3um) and lyophilized to give N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-(oxetan-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide (14mg, 47%) as an orange solid. MS(ESI): m / z=458.8[M+H] +

[0229] Example 101: N-[4-(cyanomethyl)-5-fluoro-2-methoxy-phenyl]-7-(oxetan-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide [ka] A stock solution of Ir[dF(CF3)ppy]2(dtbpy)(PF6) (255.41 μg, 2.277 E-04 mmol) in dichloromethane was added to a reaction vial, and the solvent was evaporated. Sodium carbonate (4.83 mg, 0.046 mmol), 7-bromo-N-[4-(cyanomethyl)-5-fluoro-2-methoxyphenyl]imidazo[1,2-a]pyridine-3-sulfonamide (10 mg, 0.023 mmol), 3-bromooxetane (4.05 mg, 2.46 μL, 0.030 mmol), tris(trimethylsilyl)silane (7.59 mg, 9.41 μL, 0.031 mmol), and ethylene glycol dimethyl ether (0.367 mL) were then added. The reaction mixture was degassed by bubbling argon through it for 5 min. Subsequently, a corresponding volume of a stock solution of 4,4''-di-tert-butyl-2,2''-dipyridyl (30.55 μg, 1.138E-04 mmol) and nickel(II) ethylene glycol dimethyl chloride (25.01 μg, 1.138E-04 mmol) in dimethoxyethane was added after sonication of the pastel green suspension. Finally, the mixture was degassed again by bubbling argon through it for 10 minutes. The mixture was placed in a photoreactor and irradiated at 450 nm for 1 hour (stirring at 900 rpm, 100% LED power). LCMS showed complete conversion. The mixture was then filtered and concentrated in vacuo. The crude orange product was purified by flash chromatography on silica gel using a gradient heptane / ethyl acetate 0-100% to give N-[4-(cyanomethyl)-5-fluoro-2-methoxy-phenyl]-7-(oxetan-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide (3 mg, 28%) as an off-white solid. MS (ESI): m / z = 417.1 [M+H] +

[0230] Example 102: N-[5-(2,2-difluoroethyl)-3-fluoro-6-methoxy-2-pyridyl]-7-(oxetan-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide [ka] A stock solution of Ir[dF(CF3)ppy]2(dtbpy)(PF6) (771.67 µg, 0.000688 mmol) in dichloromethane was added to a reaction vial, and the solvent was evaporated. Then, sodium carbonate (14.58 mg, 0.138 mmol), 7-bromo-N-[5-(2,2-difluoroethyl)-3-fluoro-6-methoxy-2-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide (32 mg, 0.069 mmol), 3-bromooxetane (12.25 mg, 7.42 µL, 0.089 mmol), tris(trimethylsilyl)silane (22.92 mg, 28.43 µL, 0.092 mmol), and ethylene glycol dimethyl ether (1.11 mL) were added. The reaction mixture was degassed by bubbling argon through for 5 minutes. Subsequently, a corresponding volume of a stock solution of 4,4''-di-tert-butyl-2,2''-dipyridyl (92.3 μg, 3.439E-04 mmol) and nickel(II) ethylene glycol dimethyl chloride (75.56 μg, 3.439E-04 mmol) in dimethoxyethane was added after sonication of the pastel green suspension. Finally, the mixture was degassed again by bubbling argon through for 10 minutes. The mixture was placed in a photoreactor and irradiated at 450 nm for 15 minutes (stirring at 900 rpm, 100% LED power). LCMS showed the product and the desbromo byproduct. The mixture was filtered and evaporated. The residue was purified by flash chromatography using a gradient heptane / ethyl acetate 0-100% followed by a C18 flash chromatography RediSepRf Gold column (C18, 5.5 g, acetonitrile in water 10%-100%) to give N-[5-(2,2-difluoroethyl)-3-fluoro-6-methoxy-2-pyridyl]-7-(oxetan-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide (4 mg, 11%) as an off-white solid. MS (ESI): m / z = 443.3 [M+H] +

[0231] Example 103: N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-(oxetan-3-yl)imidazo[1,2-a]pyrimidine-3-sulfonamide [ka] The reaction was carried out on a 10 mg scale (four runs). To a vial was added Ir[dF(CF3)ppy]2(dtbpy)(PF6) (902.68 µg, 8.046E-04 mmol), sodium carbonate (17.06 mg, 0.161 mmol), 7-bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyrimidine-3-sulfonamide (38.8 mg, 0.080 mmol), 3-bromooxetane (14.33 mg, 8.68 µL, 0.105 mmol), and tris(trimethylsilyl)silane (26.81 mg, 33.26 µL, 0.108 mmol). Ethylene glycol dimethyl ether (1.3 mL) was added, and the mixture was degassed for 5 min. Nickel(II) chloride ethylene glycol dimethyl ether complex (88.39 μg, 4.023E-04 mmol) and 4,4′′-di-tert-butyl-2,2′′-dipyridyl (107.98 μg, 4.023E-04 mmol) (as a stock solution in dimethoxyethane) were then added. The mixture was again degassed for 10 minutes. The reaction mixture was irradiated at 450 nm in a photoreactor (100% LED output, 900 rpm stirring) for 15 hours. The reaction mixture was filtered and concentrated in vacuo. The orange residue was purified by flash chromatography using a heptane / ethyl acetate gradient (0-100%) to give N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-(oxetan-3-yl)imidazo[1,2-a]pyrimidine-3-sulfonamide (4 reactions combined: 4 mg, 8%) as a yellow solid. MS (ESI): m / z = 460.2 [M+H] +

[0232] Example 104: N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-6-(oxetan-3-yl)pyrazolo[1,5-a]pyridine-3-sulfonamide [ka] To a vial was added Ir[dF(CF3)ppy]2(dtbpy)(PF6) (2.1 mg, 0.002 mmol), sodium carbonate (39.64 mg, 0.374 mmol), 6-bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]pyrazolo[1,5-a]pyridine-3-sulfonamide (90 mg, 0.187 mmol), 3-bromooxetane (51.24 mg, 31.05 µL, 0.374 mmol), and tris(trimethylsilyl)silane (62.32 mg, 77.31 µL, 0.251 mmol). Ethylene glycol dimethyl ether (3.02 mL) was added, and the mixture was degassed for 5 min. Nickel(II) chloride ethylene glycol dimethyl ether complex (205.46 μg, 9.351E-04 mmol) and 4,4′′-di-tert-butyl-2,2′′-dipyridyl (250.97 μg, 9.351E-04 mmol) (as a stock solution in dimethoxyethane) were then added. The mixture was again degassed for 10 minutes. The reaction mixture was irradiated at 450 nm in a photoreactor (100% LED power, 900 rpm stirring) for 14 hours. The reaction mixture was concentrated, dissolved in dichloromethane, filtered, and purified by flash chromatography on silica gel using a gradient heptane / ethyl acetate 0-100%, followed by preparative HPLC and SFC to give N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-6-(oxetan-3-yl)pyrazolo[1,5-a]pyridine-3-sulfonamide (4.3 mg, 4.5%) as a pale yellow solid. MS (ESI): m / z = 459.2 [M+H] +

[0233] Example 105: 7-Bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyrimidine-3-sulfonamide [ka] To an orange-brown suspension of 7-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyrimidine-3-sulfonamide (62.9 mg, 0.144 mmol) in propionitrile (2.37 g, 3 mL, 43.1 mmol) and bromotrimethylsilane (329.94 mg, 284.44 µL, 2.16 mmol) was added. The reaction mixture was heated to 50 °C. After 5 hours, the reaction mixture was slowly added to a stirred solution of NaOH 2N / ice and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient heptane / ethyl acetate 0-100% to give 7-bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyrimidine-3-sulfonamide (38.8 mg, 56%) as an off-white solid. MS (ESI): m / z = 484.1 [M+H] +

[0234] Example 106: N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-(1-hydroxy-1-methyl-ethyl)imidazo[1,2-a]pyridine-3-sulfonamide [ka] A solution of 3-[[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]sulfamoyl]imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (10 mg, 0.022 mmol) in tetrahydrofuran (100 μL) was cooled to 0 °C. 3 M methylmagnesium bromide in diethyl ether (37.47 mg, 36.2 μL, 0.109 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 1 h, then quenched with saturated NH4Cl and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using a gradient heptane / ethyl acetate 0-100% to give N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-(1-hydroxy-1-methyl-ethyl)imidazo[1,2-a]pyridine-3-sulfonamide (5.6 mg, 56%) as a colorless solid. MS (ESI): m / z=461.1 [M+H] +

[0235] Example 107: N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide [ka] To a stirred solution of 7-bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide (43 mg, 0.089 mmol) in tetrahydrofuran (860 µL) was added 1.3 M Turbo Grignard (196.09 mg, 206.2 µL, 0.268 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour, and then oxetan-3-one (19.32 mg, 15.7 µL, 0.268 mmol) was added. The reaction mixture was stirred at room temperature for 90 minutes, then quenched with saturated NH4Cl 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 preparative HPLC to give N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide (3 mg, 6%) as a colorless solid. MS(ESI): m / z=475.1 [M+H] +

[0236] Example 108 and Example 109: (7R)—N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-sulfonamide and (7S)—N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-sulfonamide [ka] [ka] Example 23 was subjected to chiral separation using SFC (Column: Chiralpak IC-3 50 x 4.6 mm ID, 3 um mobile phase: Phase A for CO, Phase B for IPA (0.05% DEA); Gradient elution: IPA in CO (0.05% DEA) from 5% to 40%, flow rate: 3 mL / min; Detector: PDA, Column temperature: 35°C; Back pressure: 100 bar") (Run time = 2.109) to give both enantiomers as off-white solids.

[0237] 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

[0238] 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 capsule Active ingredient 100.0mg Cornstarch 20.0mg Lactose 95.0mg Talc 4.5mg Magnesium stearate 0.5mg 220.0mg

Claims

1. Compound of formula I 【Chemistry 1】 (In the formula, R １ These are alkyl, cyano, cyanoalkyl, cyclopropyl, halo, haloalkoxy, haloalkyl or oxetanyl, R ２ is an alkoxy, H or halo, X １ is N, X ２ CR １２ X ３ CR １３ is, or X １ is CR １１ and X ２ is CR １２ and X ３ is CR １３ or X １ CR １１ X ２ is N, X ３ is N or CR １３ And, R １１ is an alkoxy, H, or halo, R １２ is H or halo, R １３ is an alkoxy, H, halo, or haloalkoxy, W is selected from ring systems A, B, C, D, or E. 【Chemistry 2】 Y １ CR ４ or N, R ３ alkoxy, alkyl, cyano, cyclopropyl, H, halo, haloalkoxy, haloalkyl, It is a hydroxyalkyl, hydroxyoxetanyl, or oxetanyl, R ４ is an alkoxy, alkyl, cyano, H, or halo, R ５ These are alkyl, halo, haloalkyl, cyclopropyl, or oxetanyl. R ６ is H, cyano, alkyl, alkoxy or halo, Y ２ａ CR ８ａ or O, Y ２ｂ CR ８ｂ or O, Y ２ａ and Y ２ｂ Only one of them can be O, n is either 0 or 1, R ７ａ and R ７ｂ These are independently selected from H, alkyl, alkoxy, or haloalkyl, R ８ａ and R ８ｂ These are independently selected from H or alkyl, Y ３ is O or CH ２ And, R ９ａ and R ９ｂ These are independently selected from H, alkyl, alkoxy, or haloalkyl, Y ４ NR １０ And, R １０ (It is alkyl or haloalkyl.) and its pharmaceutically acceptable salts.

2. Y ２ａ ga CH ２ Y ２ｂ CR ８ｂ or O, R ８ｂ The compound according to claim 1, wherein is H or alkyl.

3. R ９ａ or R ９ｂ The compound according to claim 1, wherein one is alkyl and the other is H.

4. R １ The compound according to any one of claims 1 to 3, wherein the compound is alkyl, cyanoalkyl, cyclopropyl, halo, haloalkoxy, or haloalkyl.

5. R ２ The compound according to claim 1, wherein the compound is an alkoxy or a halo.

6. R １１ The compound according to claim 1, wherein the compound is an alkoxy or H.

7. R １２ The compound according to claim 1, wherein is H.

8. R １３ The compound according to claim 1, wherein is an alkoxy.

9. The compound according to claim 1, wherein W is selected from ring systems A, B, or C.

10. R ３ The compound according to claim 1, wherein the compound is an alkoxy, alkyl, cyclopropyl, halo, haloalkoxy, haloalkyl, hydroxyalkyl, or oxetanyl.

11. R ４ The compound according to claim 1, wherein the compound is an alkoxy, cyano, H, or halo.

12. R ５ That is Haro, R ６ The compound according to claim 1, wherein is H.

13. R ７ａ , R ７ｂ , R ８ａ and R ８ｂ If all are H, then X １ The compound according to claim 1, wherein is N and n is 1.

14. R １ However, these are alkyl, cyano, cyanoalkyl, cyclopropyl, halo, haloalkoxy, haloalkyl or oxetanyl, R ２ However, it is an alkoxy, H or halo, X １ N is X ２ CR １２ X ３ CR １３ is, or X １ CR １１ X ２ CR １２ X ３ CR １３ is, or X １ CR １１ X ２ N is X ３ is N or CR １３ And, R １１ However, it is an alkoxy, H, or halo. R １２ is H or halo, R １３ However, it is an alkoxy, H, halo, or haloalkoxy, W is selected from ring systems A, B, C, D, or E. 【Transformation 3】 Y １ However, CR ４ or N, R ３ However, it is alkoxy, alkyl, cyano, cyclopropyl, H, halo, haloalkoxy, haloalkyl, hydroxyalkyl, hydroxyoxetanyl, or oxetanyl. R ４ is alkoxy, alkyl, cyano, H, or halo, and R ５ However, it is alkyl, halo, or oxetanyl, R ６ However, it is cyano or H, Y ２ａ is CH ２ and Y ２ｂ is CR ８ｂ or O, and R ８ｂ is H or alkyl n is 0 or 1, R ７ａ and R ７ｂ However, independently selected from H, alkyl, alkoxy, or haloalkyl, Y ３ However, O or CH ２ And, R ９ａ or R ９ｂ One is alkyl, and the other is H. Y ４ NR １０ And, R １０ It is alkyl, R ７ａ , R ７ｂ , R ８ａ and R ８ｂ If all are H, then X １ A compound according to claim 1, wherein n is N and n is 1, and a pharmaceutically acceptable salt thereof.

15. R １ However, these are alkyl, cyanoalkyl, cyclopropyl, halo, haloalkoxy or haloalkyl, R ２ However, it is an alkoxy or halo, X １ N is X ２ CR １２ X ３ CR １３ is, or X １ CR １１ X ２ CR １２ X ３ CR １３ is, or X １ CR １１ X ２ N is X ３ is N or CR １３ And, R １１ However, it is an alkoxy or H, R １２ H is, R １３ However, it is an alkoxy, halo, or haloalkoxy, W is selected from ring systems A, B, or C. 【Chemistry 4】 Y １ However, CR ４ or N, R ３ However, these are alkoxy, alkyl, cyclopropyl, halo, haloalkoxy, haloalkyl, hydroxyalkyl, or oxetanyl. R ４ However, it is an alkoxy, cyano, H or halo, R ５ That is Haro, R ６ H is, Y ２ａ ga CH ２ Y ２ｂ CR ８ｂ or O, R ８ｂ is H or alkyl, n is 1, R ７ａ and R ７ｂ However, independently selected from H, alkyl, or haloalkyl, R ７ａ , R ７ｂ , R ８ａ and R ８ｂ If all are H, then X １ A compound according to claim 1, wherein n is N and n is 1, and a pharmaceutically acceptable salt thereof.

16. 7-Bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methylimidazo[1,2-a]pyridine-3-sulfonamide; 7-Bromo-N-[4-(cyanomethyl)-5-fluoro-2-methoxyphenyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-8-methoxy-7-methylimidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-(difluoromethoxy)imidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-8-fluoroimidazo[1,2-a]pyridine-3-sulfonamide; 7-Bromo-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-[6-(3,3-difluoropropyl)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Bromo-N-[5-(2,2-difluoroethyl)-3-fluoro-6-methoxy-2-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethyl)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-8-methoxyimidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methylimidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-(difluoromethyl)imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methoxy-imidazo[1,2-a]pyridine-3-sulfonamide; 7-Cyclopropyl-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-ethyl-imidazo[1,2-a]pyridine-3-sulfonamide; N-[4-(cyanomethyl)-5-fluoro-2-methoxyphenyl]-7-cyclopropyl-imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]-8-methoxy-7-methylimidazo[1,2-a]pyridine-3-sulfonamide; N-[4-(cyanomethyl)-5-fluoro-2-methoxyphenyl]-7-methylimidazo[1,2-a]pyridine-3-sulfonamide; 7-Bromo-N-[5-(cyanomethyl)-3-fluoro-6-methoxy-2-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-[6-(cyanomethyl)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-[5-(2,2-difluoroethyl)-3-fluoro-6-methoxy-2-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-(6-cyclopropyl-5-fluoro-2-methoxy-3-pyridyl)imidazo[1,2-a]pyridine-3-sulfonamide; 7-Bromo-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 8-Cyano-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methylimidazo[1,2-a]pyridine-3-sulfonamide; 7-Cyclopropyl-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methoxy-imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7,8-dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-(trifluoromethyl)imidazo[1,2-a]pyridine-3-sulfonamide; N-[4-(cyanomethyl)-2,5-difluorophenyl]-8-methoxy-7-methylimidazo[1,2-a]pyridine-3-sulfonamide; 8-Cyano-7-Cyclopropyl-N-[6-(2,2-Difluoroethoxy)-5-Fluoro-2-Methoxy-3-Pyridyl]Imidazou[1,2-a]Pyridine-3-Sulfonamide; 7-Bromo-N-[4-(cyanomethyl)-2,5-difluorophenyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[5-(cyanomethyl)-3-fluoro-6-methoxy-2-pyridyl]-7-methoxy-imidazo[1,2-a]pyridine-3-sulfonamide; 7-Cyclopropyl-N-[5-(2,2-difluoroethyl)-3-fluoro-6-methoxy-2-pyridyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methoxy-imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[2,6-bis(difluoromethoxy)-5-fluoro-3-pyridyl]-7-chloroimidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; 8-Cyano-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methylimidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-(5-cyclopropyl-3-fluoro-6-methoxy-2-pyridyl)imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7,7-dimethyl-6,8-dihydro-5H-imidazo[1,2-a]pyridine-3-sulfonamide; 7-Bromo-N-(5-bromo-4,6-dimethoxypyrimidine-2-yl)imidazo[1,2-a]pyridine-3-sulfonamide; 7-Bromo-N-[3-Fluoro-5-(2-Fluorethoxy)-6-Methoxy-2-Pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methyl-imidazo[1,2-a]pyrimidine-3-sulfonamide; 7-Cyclopropyl-N-[5-(2,2-difluoroethoxy)-3-fluoro-6-methoxy-2-pyridyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-8-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-[5-(2,2-difluoroethoxy)-3-fluoro-6-methoxy-2-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-8-cyano-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methyl-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine-3-sulfonamide; N-(4,6-dimethoxy-5-methylpyrimidine-2-yl)-7-methylimidazo[1,2-a]pyridine-3-sulfonamide; N-[4-(cyanomethyl)-2,5-difluorophenyl]-7-methoxyimidazo[1,2-a]pyridine-3-sulfonamide; N-[2,6-bis(difluoromethoxy)-5-fluoro-3-pyridyl]-7-cyclopropyl-imidazo[1,2-a]pyrimidine-3-sulfonamide; N-(4-bromo-2,5-difluorophenyl)-8-methoxy-7-methylimidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-8-keto-7-methylimidazo[1,2-a]pyrazine-3-sulfonamide; 7-Cyano-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 8-Cyano-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methoxyimidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-[4-(cyanomethyl)-2,5-difluorophenyl]-8-methoxyimidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methoxy-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-(4-(cyanomethyl)-2,5-difluorophenyl)imidazo[1,2-a]pyridine-3-sulfonamide; 8-Cyano-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-(difluoromethoxy)imidazo[1,2-a]pyridine-3-sulfonamide; N-[2,6-bis(difluoromethoxy)-5-fluoro-3-pyridyl]-8-cyano-7-methylimidazo[1,2-a]pyridine-3-sulfonamide; 8-Cyano-N-[4-(cyanomethyl)-2,5-difluorophenyl]-7-methylimidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-[4-(cyanomethyl)-2,5-difluorophenyl]-8-fluoroimidazo[1,2-a]pyridine-3-sulfonamide; 8-Cyano-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-[5-fluoro-2-methoxy-6-(oxetan-3-yl)-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-8-methylimidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-6-methyl-6,7-dihydro-5H-pyrrole[1,2-a]imidazole-3-sulfonamide; N-[4-(cyanomethyl)-2,5-difluorophenyl]-7-methoxyimidazo[1,2-a]pyrimidine-3-sulfonamide; 7-Chloro-N-[5-(2-fluoroethoxy)-4-methoxypyrimidine-2-yl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methyl-6,7-dihydro-5H-pyrrole[1,2-a]imidazole-3-sulfonamide; N-[4-(cyanomethyl)-2,5-difluorophenyl]-7-methylimidazo[1,2-a]pyrimidine-3-sulfonamide; 6-bromo-N-[6-(cyanomethyl)-5-fluoro-2-methoxy-3-pyridyl]pyrazolo[1,5-a]pyridine-3-sulfonamide; 6-Bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]pyrazolo[1,5-a]pyridine-3-sulfonamide; 6-bromo-N-[5-(cyanomethyl)-3-fluoro-6-methoxy-2-pyridyl]pyrazolo[1,5-a]pyridine-3-sulfonamide; 6-bromo-N-[3-fluoro-5-(2-fluoroethoxy)-6-methoxy-2-pyridyl]pyrazolo[1,5-a]pyridine-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethoxy)-3-fluoro-6-methoxy-2-pyridyl]pyrazolo[1,5-a]pyridine-3-sulfonamide; 6-Bromo-N-(6-cyclopropyl-5-fluoro-2-methoxy-3-pyridyl)pyrazolo[1,5-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-sulfonamide; 7-Cyano-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-6-methyl-pyrazolo[1,5-a]pyridine-3-sulfonamide; 6-bromo-N-[4-(difluoromethoxy)-2,5-difluorophenyl]pyrazolo[1,5-a]pyridine-3-sulfonamide; 6-Bromo-N-(4-bromo-2,5-difluorophenyl)pyrazolo[1,5-a]pyridine-3-sulfonamide; 6-Bromo-N-[5-Fluoro-2-methoxy-6-(oxetan-3-yl)-3-pyridyl]pyrazolo[1,5-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-6-methyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-3-sulfonamide; : N-[4-(cyanomethyl)-5-fluoro-2-methoxyphenyl]-7-cyclopropyl-imidazo[1,2-a]pyridine-3-sulfonamide; 7-Cyclopropyl-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Cyclopropyl-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[5-(cyanomethyl)-3-fluoro-6-methoxy-2-pyridyl]-7-cyclopropyl-imidazo[1,2-a]pyridine-3-sulfonamide; 7-Cyclopropyl-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; N-(4-cyano-2,5-difluorophenyl)-8-methoxy-7-methylimidazo[1,2-a]pyridine-3-sulfonamide; 6-bromo-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridyl]pyrazolo[1,5-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-(oxetan-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide; N-[4-(cyanomethyl)-5-fluoro-2-methoxyphenyl]-7-(oxetan-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide; N-[5-(2,2-difluoroethyl)-3-fluoro-6-methoxy-2-pyridyl]-7-(oxetan-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-(oxetan-3-yl)imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-6-(oxetan-3-yl)pyrazolo[1,5-a]pyridine-3-sulfonamide; 7-Bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-(1-hydroxy-1-methyl-ethyl)imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide A compound according to claim 1, selected from the above, and a pharmaceutically acceptable salt thereof.

17. 7-Bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methylimidazo[1,2-a]pyridine-3-sulfonamide; 7-Bromo-N-[4-(cyanomethyl)-5-fluoro-2-methoxyphenyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-8-methoxy-7-methylimidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-(difluoromethoxy)imidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-8-fluoroimidazo[1,2-a]pyridine-3-sulfonamide; 7-Bromo-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-[6-(3,3-difluoropropyl)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Bromo-N-[5-(2,2-difluoroethyl)-3-fluoro-6-methoxy-2-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethyl)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-8-methoxyimidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methylimidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-(difluoromethyl)imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methoxy-imidazo[1,2-a]pyridine-3-sulfonamide; 7-Cyclopropyl-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-ethyl-imidazo[1,2-a]pyridine-3-sulfonamide; N-[4-(cyanomethyl)-5-fluoro-2-methoxyphenyl]-7-cyclopropyl-imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]-8-methoxy-7-methylimidazo[1,2-a]pyridine-3-sulfonamide; N-[4-(cyanomethyl)-5-fluoro-2-methoxyphenyl]-7-methylimidazo[1,2-a]pyridine-3-sulfonamide; 7-Bromo-N-[5-(cyanomethyl)-3-fluoro-6-methoxy-2-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-[6-(cyanomethyl)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-[5-(2,2-difluoroethyl)-3-fluoro-6-methoxy-2-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-(6-cyclopropyl-5-fluoro-2-methoxy-3-pyridyl)imidazo[1,2-a]pyridine-3-sulfonamide; 7-Bromo-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 8-Cyano-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methylimidazo[1,2-a]pyridine-3-sulfonamide; 7-Cyclopropyl-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methoxy-imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7,8-dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-(trifluoromethyl)imidazo[1,2-a]pyridine-3-sulfonamide; N-[4-(cyanomethyl)-2,5-difluorophenyl]-8-methoxy-7-methylimidazo[1,2-a]pyridine-3-sulfonamide; 8-Cyano-7-Cyclopropyl-N-[6-(2,2-Difluoroethoxy)-5-Fluoro-2-Methoxy-3-Pyridyl]Imidazou[1,2-a]Pyridine-3-Sulfonamide; 7-Bromo-N-[4-(cyanomethyl)-2,5-difluorophenyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[5-(cyanomethyl)-3-fluoro-6-methoxy-2-pyridyl]-7-methoxy-imidazo[1,2-a]pyridine-3-sulfonamide; 7-Cyclopropyl-N-[5-(2,2-difluoroethyl)-3-fluoro-6-methoxy-2-pyridyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methoxy-imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[2,6-bis(difluoromethoxy)-5-fluoro-3-pyridyl]-7-chloroimidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; 8-Cyano-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methylimidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-(5-cyclopropyl-3-fluoro-6-methoxy-2-pyridyl)imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7,7-dimethyl-6,8-dihydro-5H-imidazo[1,2-a]pyridine-3-sulfonamide; 7-Bromo-N-(5-bromo-4,6-dimethoxypyrimidine-2-yl)imidazo[1,2-a]pyridine-3-sulfonamide; 7-Bromo-N-[3-Fluoro-5-(2-Fluorethoxy)-6-Methoxy-2-Pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methyl-imidazo[1,2-a]pyrimidine-3-sulfonamide; 7-Cyclopropyl-N-[5-(2,2-difluoroethoxy)-3-fluoro-6-methoxy-2-pyridyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-8-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-[5-(2,2-difluoroethoxy)-3-fluoro-6-methoxy-2-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-8-cyano-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-methyl-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine-3-sulfonamide; N-(4,6-dimethoxy-5-methylpyrimidine-2-yl)-7-methylimidazo[1,2-a]pyridine-3-sulfonamide; 6-Bromo-N-(6-cyclopropyl-5-fluoro-2-methoxy-3-pyridyl)pyrazolo[1,5-a]pyridine-3-sulfonamide; : N-[4-(cyanomethyl)-5-fluoro-2-methoxyphenyl]-7-cyclopropyl-imidazo[1,2-a]pyridine-3-sulfonamide; 7-Cyclopropyl-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Cyclopropyl-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[5-(cyanomethyl)-3-fluoro-6-methoxy-2-pyridyl]-7-cyclopropyl-imidazo[1,2-a]pyridine-3-sulfonamide; 7-Cyclopropyl-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; 6-bromo-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridyl]pyrazolo[1,5-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-(oxetan-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide; 7-Bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-(1-hydroxy-1-methyl-ethyl)imidazo[1,2-a]pyridine-3-sulfonamide A compound according to claim 1, selected from the above, and a pharmaceutically acceptable salt thereof.

18. To provide a compound of formula I by reacting a compound of formula V with a compound of formula VI in the presence of a base. 【Transformation 5】 (In the formula, R １ , R ２ , X １ , X ２ , X ３ A method for producing the compound according to claim 1, comprising W as described above.

19. The compound according to claim 1 for use as a therapeutically active substance.

20. The compound according to claim 1, for use in the treatment of diseases regulated by GPR17.

21. A pharmaceutical composition comprising the compound described in claim 1 and a therapeutically inert carrier.

22. The pharmaceutical composition according to claim 21 for use in treating or preventing direct damage to the myelin sheath (including, but not limited to, central and extrapontine myelin lysis, carbon monoxide poisoning, malnutrition, and virus-induced demyelination), demyelinating disorders (including, but not limited to, multiple sclerosis, acute and polyphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorder, and leukodystrophy), CNS disorders associated with myelin loss (including, but not limited to, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and ischemia due to stroke), as well as symptoms resulting from inflammation of the CNS, for example, after encephalitis, primary vasculitis, meningitis, and obesity.

23. The pharmaceutical composition according to claim 21, for use in the treatment or prevention of multiple sclerosis.

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

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

26. The compound according to claim 1, for use in the treatment or prevention of multiple sclerosis.

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