Novel imidazopyridine and pyrazolopyridine sulfonamide derivatives

Abstract

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

Description

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

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

[0003]

[0004] R 1 is alkyl, cyano, cyanoalkyl, cyclopropyl, halo, haloalkoxy, haloalkyl or

[0005] Oxetane;

[0006] R 2 is alkoxy, H or halo;

[0007] X 1 N, X 2 CR 12 , and X 3 CR 13 ,or

[0008] X 1 CR 11 , X 2 CR 12 , and X 3 CR 13 ,or

[0009] X 1 CR 11 , X 2 is N, and X 3 N or CR 13 ;

[0010] R 11 is alkoxy, H or halo;

[0011] R 12 is H or halogenated;

[0012] R 13 is alkoxy, H, halo or haloalkoxy;

[0013] W is selected from the ring systems A, B, C, D or E

[0014]

[0015]

[0016] Y 1 CR 4 or N;

[0017] R3 is alkoxy, alkyl, cyano, cyclopropyl, H, halo, haloalkoxy,

[0018] Halogenated alkyl,

[0019] Hydroxyalkyl, hydroxyoxetanyl or oxetanyl;

[0020] R 4 is alkoxy, alkyl, cyano, H or halo;

[0021] R 5 is alkyl, halo, haloalkyl, cyclopropyl or oxetanyl;

[0022] R 6 is H, cyano, alkyl, alkoxy or halo;

[0023] Y 2a CR 8a or O and Y 2b CR 8b or O, where Y 2a and Y 2b Only one of can be O;

[0024] n is 0 or 1;

[0025] R 7a and R 7b independently selected from H, alkyl, alkoxy or haloalkyl;

[0026] R 8a and R 8b Independently selected from H or alkyl;

[0027] Y 3 O or CH 2 ;

[0028] R 9a and R 9b independently selected from H, alkyl, alkoxy or haloalkyl;

[0029] Y 4 NR 10 ;

[0030] R 10 is an alkyl group or a halogenated alkyl group;

[0031] and pharmaceutically acceptable salts thereof.

[0032] Furthermore, the present invention includes all racemic mixtures, all corresponding enantiomers and / or optical isomers thereof. Background Art

[0033] Myelination is a process that occurs intensely during development, and although there are abundant oligodendrocyte precursor cells (OPCs) throughout the adult CNS, the transition to myelinating oligodendrocytes and the process of generating restorative myelin around denuded axons is impaired in chronic demyelinating diseases. During development, myelination proceeds in a very orderly manner, with OPCs characterized by the expression of markers such as neural / glial antigen 2 (NG2) and platelet-derived growth factor alpha (PDGFRα), differentiating into oligodendrocytes that lose NG2 and PDGFRα expression and gaining expression of markers such as myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG). Myelination by oligodendrocytes is a very tightly regulated process and in the CNS this can be controlled by interactions with axons, which is well understood in the peripheral nervous system but not in the central nervous system (Macklin, WB (2010). Sci. Signal. 3, pe32–pe32, “The myelin brake: When Enough Is Enough”). Myelination can also be controlled by internal brakes within the oligodendrocytes themselves through the transcription factor EB (TFEB)-PUMA axis or through GPR17 antagonism (Chen, Y. et al. (2009). Nat Neurosci 12, 1398-1406, "The oligodendrocyte-specific Gprotein-coupled receptor GPR17 is a cell-intrinsic timer of myelination") (Sun, LO et al. (2018). Cell 175, 1811--1826.e21, "Spatiotemporal Control of CNS Myelination by Oligodendrocyte Programmed Cell Death through the TFEB-PUMAAxis").Myelin not only serves to protect axons and promote neuronal transmission, but oligodendrocytes have also been shown to play an important role in axonal metabolism and maintaining electrolyte balance around axons (Schirmer, L. et al. (2014). Ann Neurol 75, 810-828, "Differential loss of KIR4.1 immunoreactivity in multiple sclerosis lesions")(Simons, M. and Nave, K.-A. (2015). Cold Spring Harb Perspect Biol. 22, "Oligodendrocytes: Myelination and Axonal Support").

[0034] GPR17 is a class A orphan G protein-coupled receptor (GPCR). GPCR is a 7-domain transmembrane protein that binds to G α , G β The intracellular association of a small heterotrimeric G protein complex composed of G and G subunits couples extracellular ligands to intracellular signals. α The coupling of the subunits confers consequences on downstream intracellular signaling pathways. GPR17 is known to directly bind to G αi / o This results in inhibition of adenylate cyclase activity, leading to a decrease in cyclic AMP production (cAMP). GPR17 has also been shown to bind to G q / 11 Activation of phospholipase C results in the cleavage of phosphatidylinositol 4,5-bisphosphate, which produces inositol triphosphate (IP 3 ) and diacylglycerol (DAG). IP 3 Then, IP 3 Receptor binding and leading to increased 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").

[0035] The role of GPR17 in myelination was first determined in a screen of the optic nerves of Olig1 knockout mice to identify genes that regulate myelination. GPR17 expression was found to be expressed only in myelinating cells of the CNS and not in Schwann cells (myelinating cells of the peripheral nervous system). GPR17 expression was found to be expressed only in oligodendrocyte lineage cells and downregulated in myelinating oligodendrocytes (Chen, Y. et al. (2009)). Specifically, GPR17 expression was found to be present at low levels in the early stages of OPCs and to increase in premyelinating oligodendrocytes before being downregulated in mature myelinating oligodendrocytes (Boda, E. et al. (2011), Glia 59, 1958-1973, “The GPR17 receptor in NG2 expressing cells: Focus on in vivo cell maturation and participation in acute trauma and chronic damage”) (Dziedzic, A. et al. (2020). Int. J. Mol. Sci. 21, 1852, “The gpr17 receptor—a promising goal for therapy and a potential marker of the neurodegenerative process in multiple sclerosis”) (Fumagalli, M. et al. (2011), J Biol Chem 286, 10593-10604, “Phenotypic changes, signaling pathway, and functional correlates of GPR17-expressing neural precursor cells during GPR17 knockout animals exhibit precocious myelination throughout the CNS, whereas transgenic mice overexpressing GPR17 in oligodendrocytes with the CNP-Cre (2',3'-cyclic nucleotide 3'-phosphodiesterase) promoter exhibit defects in myelination, consistent with the expectation of a cell-intrinsic brake on myelination (Chen, Y. et al. (2009)).Furthermore, loss of GPR17 enhances remyelination after demyelination in lysophosphatidylcholine-induced demyelination (Lu, C., Dong et al. (2018), Sci. Rep. 8, 4502, “G-Protein-Coupled Receptor Gpr17 Regulates Oligodendrocyte Differentiation in Response to Lysolecithin-Induced Demyelination”). Therefore, antagonism of GPR17, which promotes differentiation of oligodendrocyte lineage cells into mature myelin-forming oligodendrocytes, will lead to increased myelination after demyelination.

[0036] Multiple sclerosis (MS) is a chronic neurodegenerative disease characterized by the loss of myelin (the protective fatty lipid layer around the axons) in the central nervous system (CNS). Preventing myelin loss or remyelination of exposed axons is thought to prevent axonal degeneration, thereby preventing the progression of the disease (Franklin, RJ (2002), Nat Rev Neurosci 3, 705–714, “Why does remyelination fail in multiple sclerosis?”). Due to the restorative effect of myelin repair on the central nervous system, such treatment will benefit all types of MS, i.e., relapsing-remitting, secondary progressive, primary progressive, and progressive relapsing MS. Due to the neuroprotective effect of retaining axons, repairing lost myelin will alleviate the neurological symptoms associated with MS.

[0037] Since myelination plays an important role in nervous system function, promoting OPC differentiation into oligodendrocytes has the potential to impact a variety of diseases where white matter defects / irregularities due to loss of myelinating oligodendrocytes or blocked differentiation of OPC into oligodendrocytes have been observed, either due to the disease itself or inflammation. This is in addition to diseases where GPR17 expression itself is altered.

[0038] Therefore, diseases for which GPR17 antagonism could be used to produce positive disease results include, but are not limited to:

[0039] Direct damage to the myelin sheath:

[0040] - Metabolic disorders leading to central myelin destruction such as central pontine myelinolysis, extrapontine myelinolysis, due to too rapid correction of hyponatremia in cases such as, but not limited to, alcoholism, liver disease, post-transplant immunosuppression

[0041] - Carbon monoxide poisoning, oligodendrocyte dysfunction reported in deep white matter layers of the brain

[0042] Aplastic Disorders

[0043] -Nutrient deficiencies that lead to loss of myelin or failure to myelinate properly during development

[0044] - Virus-induced demyelination

[0045] Primary demyelinating diseases

[0046] -Multiple sclerosis (relapsing-remitting, secondary progressive, primary progressive, and progressive relapsing MS)

[0047] -Acute and multiphasic disseminated encephalomyelitis

[0048] - Neuromyelitis optica spectrum disorder, including optic neuritis

[0049] - Transverse myelitis

[0050] -Leukodystrophies such as adrenoleukodystrophy, adrenoleukodystrophy, and other hereditary leukodystrophies that cause loss of myelin

[0051] CNS diseases with associated myelin loss:

[0052] -Alzheimer's disease

[0053] - Schizophrenia

[0054] - Parkinson's disease

[0055] - Huntington's disease

[0056] -Amyotrophic lateral sclerosis

[0057] - Ischemia due to stroke

[0058] Other diseases:

[0059] - Inflammation in the CNS, eg, encephalitis, primary vasculitis, inflammation in the post-meningitis CNS The compounds of formula I bind to GPR17 and modulate its activity.

[0060] Therefore, the compounds of formula I are particularly useful for treating diseases associated with GPR17 antagonism.

[0061] The compounds of formula I are particularly useful for treating or preventing multiple sclerosis (MS), disorders associated with direct damage to the myelin sheath (such as carbon monoxide poisoning or virus-induced demyelination), primary demyelinating diseases (such as acute and multiphasic disseminated encephalomyelitis), and other CNS diseases associated with myelin loss (such as Alzheimer's disease, schizophrenia, Parkinson's disease and Huntington's disease). Summary of the invention

[0062] The present invention provides novel compounds of formula I,

[0063]

[0064] in,

[0065] R 1 is alkyl, cyano, cyanoalkyl, cyclopropyl, halo, haloalkoxy, haloalkyl or

[0066] Oxetane;

[0067] R 2 is alkoxy, H or halo;

[0068] X 1 N, X 2 CR 12 , and X 3 CR 13 ,or

[0069] X 1 CR 11 , X 2 CR 12 , and X 3 CR 13 ,or

[0070] X 1 CR 11 , X 2 is N, and X 3 N or CR 13 ;

[0071] R 11 is alkoxy, H or halo;

[0072] R 12 is H or halogenated;

[0073] R 13 is alkoxy, H, halo or haloalkoxy;

[0074] W is selected from the ring systems A, B, C, D or E

[0075]

[0076] Y 1 CR 4 or N;

[0077] R 3 is alkoxy, alkyl, cyano, cyclopropyl, H, halo, haloalkoxy,

[0078] Halogenated alkyl,

[0079] Hydroxyalkyl, hydroxyoxetanyl or oxetanyl;

[0080] R 4 is alkoxy, alkyl, cyano, H or halo;

[0081] R 5 is alkyl, halo, haloalkyl, cyclopropyl or oxetanyl;

[0082] R 6 is H, cyano, alkyl, alkoxy or halo;

[0083] Y 2a CR 8a or O and Y 2b CR 8b or O, where Y 2a and Y 2b Only one of can be O;

[0084] n is 0 or 1;

[0085] R 7a and R 7b independently selected from H, alkyl, alkoxy or haloalkyl;

[0086] R 8a and R 8b Independently selected from H or alkyl;

[0087] Y 3 O or CH 2 ;

[0088] R 9a and R 9b independently selected from H, alkyl, alkoxy or haloalkyl;

[0089] Y 4 NR 10 ;

[0090] R 10 is an alkyl group or a halogenated alkyl group;

[0091] and pharmaceutically acceptable salts thereof.

[0092] The term "alkyl" refers to a monovalent straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, if not otherwise specified, the alkyl group contains 1 to 6 carbon atoms (C 1-6 -alkyl) or 1 to 4 carbon atoms (C 1-4 -alkyl). 1-6Examples of -alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and amyl. Particular alkyl groups include methyl and ethyl. When an alkyl residue with a specific carbon number is indicated, all geometric isomers with that carbon number may be encompassed. Thus, for example, "butyl" may include n-butyl, sec-butyl, isobutyl and tert-butyl, and "propyl" may include n-propyl and isopropyl.

[0093] The term "alkoxy" refers to a group of formula -O-R', wherein R' is C 1-6 -alkyl group. 1-6 Examples of -alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Specific examples are methoxy and ethoxy.

[0094] The term "cyano" refers to a -C≡N group.

[0095] "Cyanoalkyl" means a moiety of the formula -R'-R" wherein R' is alkyl as defined herein and R" is cyano or nitrile. A specific example is cyanomethyl.

[0096] The terms "halogen", "halide" and "halo" are used interchangeably herein and refer to fluorine, chlorine, bromine or iodine. Specific halogens are fluorine, chlorine and bromine.

[0097] The term "haloalkyl" refers to a group in which C 1-6 -alkyl radicals wherein at least one hydrogen atom has been replaced by the same or different halogen atoms 1-6 -alkyl group. Specific examples are difluoromethyl, difluoroethyl, difluoropropyl and trifluoromethyl.

[0098] The term "haloalkoxy" refers to a group in which C 1-6 -alkoxy radicals wherein at least one hydrogen atom has been replaced by the same or different halogen atoms 1-6 -alkoxy groups. Specific examples are fluoroethoxy, difluoromethoxy and difluoroethoxy.

[0099] The term "hydroxy" refers to an -OH group.

[0100] The term "hydroxyalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group has been replaced by a hydroxyl group. Examples of hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxymethylpropyl and dihydroxypropyl. A specific example is 1-hydroxy-1-methyl-ethyl.

[0101] The term "pharmaceutical salt" refers to those salts that retain the biological effect and properties of free alkali or free acid, which are not undesirable in biology or other aspects. These salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid (particularly hydrochloric acid) and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine. In addition, these salts can be prepared by adding inorganic bases or organic bases to free acids. Salts derived from inorganic bases include but are not limited to sodium, potassium, lithium, ammonium, calcium, magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyamine resins). The compounds of formula I may also exist in the form of zwitterions. Particularly preferred pharmaceutically acceptable salts of the compounds of formula I are salts formed with formic acid and salts formed with hydrochloric acid to produce hydrochlorides, dihydrochlorides or trihydrochlorides.

[0102] The abbreviation uM means micromolar, and is equivalent to the symbol μM.

[0103] The abbreviation uL means microliter, and is equivalent to the symbol μL.

[0104] The abbreviation ug means microgram, and is equivalent to the symbol μg.

[0105] The compounds of formula I may contain several asymmetric centers and may exist as optically pure enantiomers, mixtures of enantiomers (eg racemates), optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates.

[0106] According to the Cahn-Ingold-Prelog convention, asymmetric carbon atoms can be in either the "R" or "S" configuration.

[0107] Another embodiment of the present invention provides a compound according to formula I as described herein and a pharmaceutically acceptable salt or ester thereof, in particular a compound according to formula I as described herein and a pharmaceutically acceptable salt thereof, more particularly a compound according to formula I as described herein.

[0108] One embodiment of the present invention provides a compound according to formula I as described herein, wherein Y 2a CH 2 And Y 2b CR 8b or O, where R 8b is H or alkyl.

[0109] One embodiment of the present invention provides a compound according to formula I as described herein, wherein R 9a or R 9b is alkyl and the other is H.

[0110] One embodiment of the present invention provides a compound according to formula I as described herein, wherein R 1 It is alkyl, cyanoalkyl, cyclopropyl, halo, haloalkoxy or haloalkyl.

[0111] One embodiment of the present invention provides a compound according to formula I as described herein, wherein R 2 is alkoxy or halogenated.

[0112] One embodiment of the present invention provides a compound according to formula I as described herein, wherein R 11 is alkoxy or H.

[0113] One embodiment of the present invention provides a compound according to formula I as described herein, wherein R 12 For H.

[0114] One embodiment of the present invention provides a compound according to formula I as described herein, wherein R 13 It is an alkoxy group.

[0115] One embodiment of the present invention provides a compound according to formula I as described herein, wherein W is selected from ring systems A, B or C.

[0116] One embodiment of the present invention provides a compound according to formula I as described herein, wherein R 3 is alkoxy, alkyl, cyclopropyl, halo, haloalkoxy, haloalkyl, hydroxyalkyl or oxetanyl.

[0117] One embodiment of the present invention provides a compound according to formula I as described herein, wherein R 4 is alkoxy, cyano, H or halo.

[0118] One embodiment of the present invention provides a compound according to formula I as described herein, wherein R 5 It is alkyl, halo or oxetanyl.

[0119] One embodiment of the present invention provides a compound according to formula I as described herein, wherein R 6 is cyano or H.

[0120] One embodiment of the present invention provides a compound according to formula I as described herein, wherein R 5 is halogenated and R 6 For H.

[0121] One embodiment of the present invention provides a compound according to formula I as described herein, wherein R10 It is an alkyl group.

[0122] One embodiment of the present invention provides a compound according to formula I as described herein, wherein when R 7a , R 7b , R 8a and R 8b When both are H, then X 1 is N and n is 1.

[0123] One embodiment of the present invention provides a compound according to formula I as described herein, wherein

[0124] R 1 is alkyl, cyano, cyanoalkyl, cyclopropyl, halo, haloalkoxy, haloalkyl or

[0125] Oxetane;

[0126] R 2 is alkoxy, H or halo;

[0127] X 1 N, X 2 CR 12 , and X 3 CR 13 ,or

[0128] X 1 CR 11 , X 2 CR 12 , and X 3 CR 13 ,or

[0129] X 1 CR 11 , X 2 is N, and X 3 N or CR 13 ;

[0130] R 11 is alkoxy, H or halo;

[0131] R 12 is H or halogenated;

[0132] R 13 is alkoxy, H, halo or haloalkoxy;

[0133] W is selected from the ring systems A, B, C, D or E

[0134]

[0135] Y 1 CR 4 or N;

[0136] R 3 is alkoxy, alkyl, cyano, cyclopropyl, H, halo, haloalkoxy, haloalkyl,

[0137] Hydroxyalkyl, hydroxyoxetanyl or oxetanyl;

[0138] R 4 is alkoxy, alkyl, cyano, H or halo;

[0139] R 5 is alkyl, halo or oxetanyl;

[0140] R 6 is cyano or H;

[0141] Y 2a CH 2 And Y 2b CR 8b or O, where R 8b is H or alkyl;

[0142] n is 0 or 1;

[0143] R 7a and R 7b independently selected from H, alkyl, alkoxy or haloalkyl;

[0144] Y 3 O or CH 2 ;

[0145] R 9a or R 9b is alkyl and the other is H;

[0146] Y 4 NR 10 ;

[0147] R 10 is an alkyl group;

[0148] and pharmaceutically acceptable salts thereof.

[0149] One embodiment of the present invention provides a compound according to formula I as described herein, wherein

[0150] R 1 is alkyl, cyano, cyanoalkyl, cyclopropyl, halo, haloalkoxy, haloalkyl or

[0151] Oxetane;

[0152] R 2 is alkoxy, H or halo;

[0153] X 1 N, X2 CR 12 , and X 3 CR 13 ,or

[0154] X 1 CR 11 , X 2 CR 12 , and X 3 CR 13 ,or

[0155] X 1 CR 11 , X 2 is N, and X 3 N or CR 13 ;

[0156] R 11 is alkoxy, H or halo;

[0157] R 12 is H or halogenated;

[0158] R 13 is alkoxy, H, halo or haloalkoxy;

[0159] W is selected from the ring systems A, B, C, D or E

[0160]

[0161] Y 1 CR 4 or N;

[0162] R 3 is alkoxy, alkyl, cyano, cyclopropyl, H, halo, haloalkoxy, haloalkyl,

[0163] Hydroxyalkyl, hydroxyoxetanyl or oxetanyl;

[0164] R 4 is alkoxy, alkyl, cyano, H or halo;

[0165] R 5 is alkyl, halo or oxetanyl;

[0166] R 6 is cyano or H;

[0167] Y 2a CH 2 And Y 2b CR 8b or O, where R 8b is H or alkyl;

[0168] n is 0 or 1;

[0169] R 7a and R 7b independently selected from H, alkyl, alkoxy or haloalkyl;

[0170] Y 3 O or CH 2 ;

[0171] R 9a or R 9b is alkyl and the other is H;

[0172] Y 4 NR 10 ;

[0173] R 10 is an alkyl group;

[0174] When R 7a , R 7b , R 8a and R 8b When both are H, then X 1 is N and n is 1;

[0175] and pharmaceutically acceptable salts thereof.

[0176] One embodiment of the present invention provides a compound according to formula I as described herein, wherein

[0177] R 1 is alkyl, cyanoalkyl, cyclopropyl, halo, haloalkoxy or haloalkyl;

[0178] R 2 is alkoxy or halogen;

[0179] X 1 N, X 2 CR 12 , and X 3 CR 13 ,or

[0180] X 1 CR 11 , X 2 CR 12 , and X 3 CR 13 ,or

[0181] X 1 CR 11 , X 2 is N, and X 3 N or CR 13 ;

[0182] R 11is alkoxy or H;

[0183] R 12 is H;

[0184] R 13 is alkoxy, halo or haloalkoxy;

[0185] W is selected from ring system A, B or C

[0186]

[0187] Y 1 CR 4 or N;

[0188] R 3 is alkoxy, alkyl, cyclopropyl, halo, haloalkoxy, haloalkyl, hydroxyalkyl or oxetanyl;

[0189] R 4 is alkoxy, cyano, H or halo;

[0190] R 5 is halogenated;

[0191] R 6 is H;

[0192] Y 2a CH 2 And Y 2b CR 8b or O, where R 8b is H or alkyl;

[0193] n is 1;

[0194] R 7a and R 7b independently selected from H, alkyl or haloalkyl;

[0195] and pharmaceutically acceptable salts thereof.

[0196] One embodiment of the present invention provides a compound according to formula I as described herein, wherein

[0197] R 1 is alkyl, cyanoalkyl, cyclopropyl, halo, haloalkoxy or haloalkyl;

[0198] R 2 is alkoxy or halogen;

[0199] X 1 N, X 2 CR 12 , and X 3 CR 13 ,or

[0200] X 1 CR 11 , X 2 CR 12 , and X 3 CR 13 ,or

[0201] X 1 CR 11 , X 2 is N, and X 3 N or CR 13 ;

[0202] R 11 is alkoxy or H;

[0203] R 12 is H;

[0204] R 13 is alkoxy, halo or haloalkoxy;

[0205] W is selected from ring system A, B or C

[0206]

[0207] Y 1 CR 4 or N;

[0208] R 3 is alkoxy, alkyl, cyclopropyl, halo, haloalkoxy, haloalkyl, hydroxyalkyl or oxetanyl;

[0209] R 4 is alkoxy, cyano, H or halo;

[0210] R 5 is halogenated;

[0211] R 6 is H;

[0212] Y 2a CH 2 And Y 2b CR 8b or O, where R 8b is H or alkyl;

[0213] n is 1;

[0214] R 7a and R 7b independently selected from H, alkyl or haloalkyl;

[0215] When R 7a , R 7b , R 8a and R8b When both are H, then X 1 is N and n is 1;

[0216] and pharmaceutically acceptable salts thereof.

[0217] Particular examples of compounds of formula I as described herein are selected from

[0218] 7-Bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0219] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide;

[0220] 7-Bromo-N-[4-(cyanomethyl)-5-fluoro-2-methoxy-phenyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0221] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-8-methoxy-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide;

[0222] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-(difluoromethoxy)imidazo[1,2-a]pyridine-3-sulfonamide;

[0223] 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0224] 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-8-fluoro-imidazo[1,2-a]pyridine-3-sulfonamide;

[0225] 7-bromo-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0226] 7-Chloro-N-[6-(3,3-difluoropropyl)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0227] 7-Bromo-N-[5-(2,2-difluoroethyl)-3-fluoro-6-methoxy-2-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0228] 7-Chloro-N-[6-(2,2-difluoroethyl)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0229] 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-8-methoxy-imidazo[1,2-a]pyridine-3-sulfonamide;

[0230] N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide;

[0231] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-(difluoromethyl)imidazo[1,2-a]pyridine-3-sulfonamide;

[0232] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-methoxy-imidazo[1,2-a]pyridine-3-sulfonamide;

[0233] 7-cyclopropyl-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyrimidine-3-sulfonamide;

[0234] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-ethyl-imidazo[1,2-a]pyridine-3-sulfonamide;

[0235] N-[4-(Cyanomethyl)-5-fluoro-2-methoxy-phenyl]-7-cyclopropyl-imidazo[1,2-a]pyrimidine-3-sulfonamide;

[0236] N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-8-methoxy-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide;

[0237] N-[4-(Cyanomethyl)-5-fluoro-2-methoxy-phenyl]-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide;

[0238] 7-bromo-N-[5-(cyanomethyl)-3-fluoro-6-methoxy-2-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0239] 7-Chloro-N-[6-(cyanomethyl)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0240] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-sulfonamide;

[0241] 7-Chloro-N-[5-(2,2-difluoroethyl)-3-fluoro-6-methoxy-2-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0242] 7-Chloro-N-(6-cyclopropyl-5-fluoro-2-methoxy-3-pyridinyl)imidazo[1,2-a]pyridine-3-sulfonamide;

[0243] 7-bromo-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0244] 8-cyano-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide;

[0245] 7-cyclopropyl-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyrimidine-3-sulfonamide;

[0246] N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-methoxy-imidazo[1,2-a]pyridine-3-sulfonamide;

[0247] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7,8-dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-sulfonamide;

[0248] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-(trifluoromethyl)imidazo[1,2-a]pyridine-3-sulfonamide;

[0249] N-[4-(Cyanomethyl)-2,5-difluoro-phenyl]-8-methoxy-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide;

[0250] 8-Cyano-7-cyclopropyl-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0251] 7-Bromo-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0252] N-[5-(Cyanomethyl)-3-fluoro-6-methoxy-2-pyridinyl]-7-methoxy-imidazo[1,2-a]pyridine-3-sulfonamide;

[0253] 7-cyclopropyl-N-[5-(2,2-difluoroethyl)-3-fluoro-6-methoxy-2-pyridinyl]imidazo[1,2-a]pyrimidine-3-sulfonamide;

[0254] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-methoxy-imidazo[1,2-a]pyrimidine-3-sulfonamide;

[0255] N-[2,6-bis(difluoromethoxy)-5-fluoro-3-pyridyl]-7-chloro-imidazo[1,2-a]pyridine-3-sulfonamide;

[0256] 7-Chloro-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0257] 7-Chloro-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0258] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-sulfonamide;

[0259] 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyrimidine-3-sulfonamide;

[0260] 8-cyano-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide;

[0261] 7-Chloro-N-(5-cyclopropyl-3-fluoro-6-methoxy-2-pyridinyl)imidazo[1,2-a]pyridine-3-sulfonamide;

[0262] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7,7-dimethyl-6,8-dihydro-5H-imidazo[1,2-a]pyridine-3-sulfonamide;

[0263] 7-Bromo-N-(5-bromo-4,6-dimethoxy-pyrimidin-2-yl)imidazo[1,2-a]pyridine-3-sulfonamide;

[0264] 7-Bromo-N-[3-fluoro-5-(2-fluoroethoxy)-6-methoxy-2-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0265] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-methyl-imidazo[1,2-a]pyrimidine-3-sulfonamide;

[0266] 7-cyclopropyl-N-[5-(2,2-difluoroethoxy)-3-fluoro-6-methoxy-2-pyridinyl]imidazo[1,2-a]pyrimidine-3-sulfonamide;

[0267] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-8-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-sulfonamide;

[0268] 7-Chloro-N-[5-(2,2-difluoroethoxy)-3-fluoro-6-methoxy-2-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0269] 7-Chloro-8-cyano-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0270] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-methyl-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine-3-sulfonamide;

[0271] N-(4,6-dimethoxy-5-methyl-pyrimidin-2-yl)-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide;

[0272] N-[4-(Cyanomethyl)-2,5-difluoro-phenyl]-7-methoxy-imidazo[1,2-a]pyridine-3-sulfonamide;

[0273] N-[2,6-bis(difluoromethoxy)-5-fluoro-3-pyridyl]-7-cyclopropyl-imidazo[1,2-a]pyrimidine-3-sulfonamide;

[0274] N-(4-bromo-2,5-difluoro-phenyl)-8-methoxy-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide;

[0275] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-8-keto-7-methyl-imidazo[1,2-a]pyrazine-3-sulfonamide;

[0276] 7-cyano-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0277] 8-cyano-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-methoxy-imidazo[1,2-a]pyridine-3-sulfonamide;

[0278] 7-Chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-8-methoxy-imidazo[1,2-a]pyridine-3-sulfonamide;

[0279] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-methoxy-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-sulfonamide;

[0280] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-sulfonamide;

[0281] 7-Chloro-N-(4-(cyanomethyl)-2,5-difluorophenyl)imidazo[1,2-a]pyridine-3-sulfonamide;

[0282] 8-cyano-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-(difluoromethoxy)imidazo[1,2-a]pyridine-3-sulfonamide;

[0283] N-[2,6-bis(difluoromethoxy)-5-fluoro-3-pyridinyl]-8-cyano-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide;

[0284] 8-Cyano-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide;

[0285] 7-Chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-8-fluoro-imidazo[1,2-a]pyridine-3-sulfonamide;

[0286] 8-cyano-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0287] 7-Chloro-N-[5-fluoro-2-methoxy-6-(oxetan-3-yl)-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0288] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-8-methyl-imidazo[1,2-a]pyridine-3-sulfonamide;

[0289] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-6-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-sulfonamide;

[0290] N-[4-(Cyanomethyl)-2,5-difluoro-phenyl]-7-methoxy-imidazo[1,2-a]pyrimidine-3-sulfonamide;

[0291] 7-Chloro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0292] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-sulfonamide;

[0293] N-[4-(Cyanomethyl)-2,5-difluoro-phenyl]-7-methyl-imidazo[1,2-a]pyrimidine-3-sulfonamide;

[0294] 6-Bromo-N-[6-(cyanomethyl)-5-fluoro-2-methoxy-3-pyridinyl]pyrazolo[1,5-a]pyridine-3-sulfonamide;

[0295] 6-Bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]pyrazolo[1,5-a]pyridine-3-sulfonamide;

[0296] 6-Bromo-N-[5-(cyanomethyl)-3-fluoro-6-methoxy-2-pyridinyl]pyrazolo[1,5-a]pyridine-3-sulfonamide;

[0297] 6-Bromo-N-[3-fluoro-5-(2-fluoroethoxy)-6-methoxy-2-pyridinyl]pyrazolo[1,5-a]pyridine-3-sulfonamide;

[0298] 6-Bromo-N-[5-(2,2-difluoroethoxy)-3-fluoro-6-methoxy-2-pyridinyl]pyrazolo[1,5-a]pyridine-3-sulfonamide;

[0299] 6-Bromo-N-(6-cyclopropyl-5-fluoro-2-methoxy-3-pyridinyl)pyrazolo[1,5-a]pyridine-3-sulfonamide;

[0300] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-sulfonamide;

[0301] 7-cyano-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-6-methyl-pyrazolo[1,5-a]pyridine-3-sulfonamide;

[0302] 6-Bromo-N-[4-(difluoromethoxy)-2,5-difluoro-phenyl]pyrazolo[1,5-a]pyridine-3-sulfonamide;

[0303] 6-Bromo-N-(4-bromo-2,5-difluoro-phenyl)pyrazolo[1,5-a]pyridine-3-sulfonamide;

[0304] 6-Bromo-N-[5-fluoro-2-methoxy-6-(oxetan-3-yl)-3-pyridinyl]pyrazolo[1,5-a]pyridine-3-sulfonamide;

[0305] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-6-methyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-3-sulfonamide;

[0306] N-[4-(Cyanomethyl)-5-fluoro-2-methoxy-phenyl]-7-cyclopropyl-imidazo[1,2-a]pyridine-3-sulfonamide;

[0307] 7-cyclopropyl-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0308] 7-cyclopropyl-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0309] N-[5-(Cyanomethyl)-3-fluoro-6-methoxy-2-pyridinyl]-7-cyclopropyl-imidazo[1,2-a]pyridine-3-sulfonamide;

[0310] 7-cyclopropyl-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridinyl]imidazo[1,2-a]pyrimidine-3-sulfonamide;

[0311] N-(4-cyano-2,5-difluoro-phenyl)-8-methoxy-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide;

[0312] 6-Bromo-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridinyl]pyrazolo[1,5-a]pyridine-3-sulfonamide;

[0313] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-(oxetan-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide;

[0314] N-[4-(Cyanomethyl)-5-fluoro-2-methoxy-phenyl]-7-(oxetan-3-yl)imidazo

[0315] [1,2-a]pyridine-3-sulfonamide;

[0316] N-[5-(2,2-difluoroethyl)-3-fluoro-6-methoxy-2-pyridinyl]-7-(oxetan-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide;

[0317] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-(oxetan-3-yl)imidazo[1,2-a]pyrimidine-3-sulfonamide;

[0318] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-6-(oxetan-3-yl)pyrazolo[1,5-a]pyridine-3-sulfonamide;

[0319] 7-Bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyrimidine-3-sulfonamide;

[0320] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-(1-hydroxy-1-methyl-ethyl)imidazo[1,2-a]pyridine-3-sulfonamide;

[0321] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide;

[0322] and pharmaceutically acceptable salts thereof.

[0323] Preferred examples of compounds of formula I as described herein are selected from

[0324] 7-Bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0325] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide;

[0326] 7-Bromo-N-[4-(cyanomethyl)-5-fluoro-2-methoxy-phenyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0327] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-8-methoxy-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide;

[0328] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-(difluoromethoxy)imidazo[1,2-a]pyridine-3-sulfonamide;

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

[0330] 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-8-fluoro-imidazo[1,2-a]pyridine-3-sulfonamide;

[0331] 7-bromo-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0332] 7-Chloro-N-[6-(3,3-difluoropropyl)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0333] 7-Bromo-N-[5-(2,2-difluoroethyl)-3-fluoro-6-methoxy-2-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0334] 7-Chloro-N-[6-(2,2-difluoroethyl)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0335] 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-8-methoxy-imidazo[1,2-a]pyridine-3-sulfonamide;

[0336] N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide;

[0337] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-(difluoromethyl)imidazo[1,2-a]pyridine-3-sulfonamide;

[0338] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-methoxy-imidazo[1,2-a]pyridine-3-sulfonamide;

[0339] 7-cyclopropyl-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyrimidine-3-sulfonamide;

[0340] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-ethyl-imidazo[1,2-a]pyridine-3-sulfonamide;

[0341] N-[4-(Cyanomethyl)-5-fluoro-2-methoxy-phenyl]-7-cyclopropyl-imidazo[1,2-a]pyrimidine-3-sulfonamide;

[0342] N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-8-methoxy-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide;

[0343] N-[4-(Cyanomethyl)-5-fluoro-2-methoxy-phenyl]-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide;

[0344] 7-bromo-N-[5-(cyanomethyl)-3-fluoro-6-methoxy-2-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0345] 7-Chloro-N-[6-(cyanomethyl)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0346] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-sulfonamide;

[0347] 7-Chloro-N-[5-(2,2-difluoroethyl)-3-fluoro-6-methoxy-2-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0348] 7-Chloro-N-(6-cyclopropyl-5-fluoro-2-methoxy-3-pyridinyl)imidazo[1,2-a]pyridine-3-sulfonamide;

[0349] 7-bromo-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0350] 8-cyano-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide;

[0351] 7-cyclopropyl-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyrimidine-3-sulfonamide;

[0352] N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-methoxy-imidazo[1,2-a]pyridine-3-sulfonamide;

[0353] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7,8-dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-sulfonamide;

[0354] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-(trifluoromethyl)imidazo[1,2-a]pyridine-3-sulfonamide;

[0355] N-[4-(Cyanomethyl)-2,5-difluoro-phenyl]-8-methoxy-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide;

[0356] 8-Cyano-7-cyclopropyl-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0357] 7-Bromo-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[5-(cyanomethyl)-3-fluoro-6-methoxy-2-pyridinyl]-7-methoxy-imidazo[1,2-a]pyridine-3-sulfonamide;

[0358] 7-cyclopropyl-N-[5-(2,2-difluoroethyl)-3-fluoro-6-methoxy-2-pyridinyl]imidazo[1,2-a]pyrimidine-3-sulfonamide;

[0359] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-methoxy-imidazo[1,2-a]pyrimidine-3-sulfonamide;

[0360] N-[2,6-bis(difluoromethoxy)-5-fluoro-3-pyridyl]-7-chloro-imidazo[1,2-a]pyridine-3-sulfonamide;

[0361] 7-Chloro-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0362] 7-Chloro-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0363] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-sulfonamide;

[0364] 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyrimidine-3-sulfonamide;

[0365] 8-cyano-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide;

[0366] 7-Chloro-N-(5-cyclopropyl-3-fluoro-6-methoxy-2-pyridinyl)imidazo[1,2-a]pyridine-3-sulfonamide;

[0367] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7,7-dimethyl-6,8-dihydro-5H-imidazo[1,2-a]pyridine-3-sulfonamide;

[0368] 7-Bromo-N-(5-bromo-4,6-dimethoxy-pyrimidin-2-yl)imidazo[1,2-a]pyridine-3-sulfonamide;

[0369] 7-Bromo-N-[3-fluoro-5-(2-fluoroethoxy)-6-methoxy-2-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0370] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-methyl-imidazo[1,2-a]pyrimidine-3-sulfonamide;

[0371] 7-cyclopropyl-N-[5-(2,2-difluoroethoxy)-3-fluoro-6-methoxy-2-pyridinyl]imidazo[1,2-a]pyrimidine-3-sulfonamide;

[0372] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-8-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-sulfonamide;

[0373] 7-Chloro-N-[5-(2,2-difluoroethoxy)-3-fluoro-6-methoxy-2-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0374] 7-Chloro-8-cyano-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0375] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-methyl-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine-3-sulfonamide;

[0376] N-(4,6-dimethoxy-5-methyl-pyrimidin-2-yl)-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide;

[0377] 6-Bromo-N-(6-cyclopropyl-5-fluoro-2-methoxy-3-pyridinyl)pyrazolo[1,5-a]pyridine-3-sulfonamide;

[0378] N-[4-(Cyanomethyl)-5-fluoro-2-methoxy-phenyl]-7-cyclopropyl-imidazo[1,2-a]pyridine-3-sulfonamide;

[0379] 7-cyclopropyl-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0380] 7-cyclopropyl-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide;

[0381] N-[5-(Cyanomethyl)-3-fluoro-6-methoxy-2-pyridinyl]-7-cyclopropyl-imidazo[1,2-a]pyridine-3-sulfonamide;

[0382] 7-cyclopropyl-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridinyl]imidazo[1,2-a]pyrimidine-3-sulfonamide;

[0383] 6-Bromo-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridinyl]pyrazolo[1,5-a]pyridine-3-sulfonamide;

[0384] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-(oxetan-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide;

[0385] 7-Bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyrimidine-3-sulfonamide;

[0386] N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-(1-hydroxy-1-methyl-ethyl)imidazo[1,2-a]pyridine-3-sulfonamide;

[0387] and pharmaceutically acceptable salts thereof.

[0388] Processes for the manufacture of compounds of formula I as described herein are an object of the present invention.

[0389] The compounds of formula I and their pharmaceutically acceptable salts of the present invention can be prepared by methods known in the art, for example, by the following method, 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,

[0390]

[0391] Where R 1 , R 2 , X 1 , X 2 , X 3 and W as described above.

[0392] General synthetic scheme

[0393] Compounds of formula I can be prepared according to the above process variants and the following Scheme 1. The starting materials are either commercially available or can be prepared according to known methods.

[0394] Solution 1

[0395]

[0396] Compounds of formula Ia can be prepared by reacting sulfonyl chloride V with 2-amino-pyrimidine or 2-amino-pyridine or 3-amino-pyridine 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 (e.g., NCS) in aqueous solution. Intermediate IV can be prepared from intermediate III using a Buchwald-Hartwig type cross coupling using a palladium catalyst system (such as Pd(OAc) 2 or Pd2 (dba) 3 / xantphos or XPhos) and excess base (such as DIPEA or Cs 2 CO 3 ) is prepared at elevated temperature in a solvent such as dioxane or toluene. 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.

[0397] Compounds of formula VII can be prepared according to the above process variants and the following Scheme 2. The starting materials are either commercially available or can be prepared according to known methods.

[0398] Solution 2

[0399]

[0400] The compound of formula VII can be prepared by reacting sulfonyl chloride XI with 2-amino-pyrimidine or 2-amino-pyridine or 3-amino-pyridine 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 (e.g., NCS) in aqueous solution. Intermediate X can be prepared from intermediate IX using a Buchwald-Hartwig type cross coupling using a palladium catalyst system (such as Pd(OAc) 2 or Pd 2 (dba) 3 / xantphos or XPhos) and excess base (such as DIPEA or Cs 2 CO 3 ) is prepared at elevated temperature in a solvent such as dioxane or toluene. 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.

[0401] Compounds of formula XII can be prepared according to the above process variations and the following Scheme 3. The starting materials are either commercially available or can be prepared according to known methods.

[0402] Solution 3

[0403]

[0404] Compounds of formula XII can be prepared by reacting sulfonyl chloride XVI with 2-amino-pyrimidine or 2-amino-pyridine or 3-amino-pyridine 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 (e.g., NCS) in aqueous solution. Intermediate XV can be prepared from intermediate XIV using a Buchwald-Hartwig type cross coupling using a palladium catalyst system (such as Pd(OAc) 2 or Pd 2 (dba) 3 / xantpho or xphos) and excess base (such as DIPEA or Cs 2 CO 3 ) is prepared at elevated temperature in a solvent such as dioxane or toluene. 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.

[0405] Compounds of formula XVII can be prepared according to the above process variations and the following Scheme 4. The starting materials are either commercially available or can be prepared according to known methods.

[0406] Solution 4

[0407]

[0408] The compound of formula XVII can be prepared by reacting sulfonyl chloride XXI with 2-amino-pyrimidine or 2-amino-pyridine or 3-amino-pyridine 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 (e.g., NCS) in aqueous solution. Intermediate XX can be prepared from intermediate XIX using a Buchwald-Hartwig type cross coupling using a palladium catalyst system (such as Pd(OAc) 2 or Pd 2 (dba) 3 / xantpho or xphos) and excess base (such as DIPEA or Cs 2 CO 3 ) is prepared at elevated temperature in a solvent such as dioxane or toluene. 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.

[0409] Compounds of formula XXII can be prepared according to the above process variations and the following Scheme 5. The starting materials are either commercially available or can be prepared according to known methods.

[0410] Solution 5

[0411]

[0412] Compounds of formula XXII can be prepared by reacting sulfonyl chloride XXVI with 2-amino-pyrimidine or 2-amino-pyridine or 3-amino-pyridine or aniline VI in the presence of a base (e.g., pyridine). Sulfonyl chloride XXVI can be prepared from intermediate XXV in aqueous solution in the presence of a chlorinating agent (such as NCS). Intermediate XXV can be prepared from intermediate XXIV using a Buchwald-Hartwig type cross coupling using a palladium catalyst system (such as Pd(OAc) 2 or Pd 2 (dba) 3 / xantpho or xphos) and excess base (such as DIPEA or Cs 2 CO 3 ) is prepared at elevated temperature in a solvent such as dioxane or toluene. 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.

[0413] 2-Amino-pyrimidine or 2-amino-pyridine or 3-amino-pyridine or aniline VI is commercially available or can be prepared according to procedures described in the literature or in this patent. Starting materials are commercially available or can be prepared according to known methods.

[0414] Another embodiment of the present invention provides a pharmaceutical composition or medicine containing the compounds of this invention and a therapeutic inert carrier, diluent or excipient, and a method for preparing such compositions and medicines using the compounds of this invention. In one example, the compound of formula I can be formulated as a galenical administration form by mixing with a physiologically acceptable carrier (i.e., a carrier that is nontoxic to the recipient at the dosage and concentration used) at ambient temperature under appropriate pH and desired purity. The pH of the preparation depends primarily on the specific use and concentration of the compound, but is preferably in the range of about 3 to about 8. In one example, the compound of formula I is prepared in an acetate buffer at pH 5. In another example, the compound of formula I is sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized preparation, or as an aqueous solution.

[0415] The compositions are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the timing of administration, and other factors known to practitioners.

[0416] The compounds of the present invention can be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and (if necessary for local treatment) intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.

[0417] The compounds of the present invention can be administered in any convenient administration form, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain conventional components of pharmaceutical preparations, for example, diluents, carriers, pH adjusters, sweeteners, fillers and other active agents.

[0418] The usual formulations are prepared by mixing the compounds of the invention with carriers or excipients. Suitable carriers and excipients are well known to those skilled in the art and are described in, for example, Ansel, Howard C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams and Wilkins, 2004; Gennaro, Alfonso R. et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams and Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulation may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavoring agents, flavoring agents, diluents and other known additives to provide an aesthetically pleasing display of the drug (e.g., a compound of the present invention or a pharmaceutical composition thereof) or to facilitate the preparation of a pharmaceutical product (e.g., a drug).

[0419] The compounds of formula I and their pharmaceutically acceptable salts can be processed with pharmaceutically inert inorganic or organic adjuvants to produce tablets, coated tablets, dragees, hard gelatin capsules, injections or topical preparations. For example, lactose, corn starch or its derivatives, talcum powder, stearic acid or its salts, etc. can be used as such adjuvants for tablets, dragees and hard gelatin capsules.

[0420] Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid substances and liquid polyols and the like.

[0421] Suitable adjuvants for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like.

[0422] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.

[0423] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols and the like.

[0424] Suitable adjuvants for topical ophthalmic preparations are, for example, cyclodextrins, mannitol or numerous other carriers and excipients known in the art.

[0425] In addition, the pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying the osmotic pressure, buffer masking agents or antioxidants. They may also contain other therapeutically valuable substances.

[0426] Dosage can vary over a wide range, and will certainly be suitable for various requirements in each particular case. Generally speaking, in the case of oral administration, a daily dose of about 0.1 mg to 20 mg per kg body weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g., about 300 mg per person) should be suitable, and it is preferably divided into 1 to 3 separate doses (which may be composed of, for example, the same amount). In the case of topical administration, the formulation may include 0.001% to 15% of the drug by weight, and the desired dose may be 0.1 mg to 25 mg, a single application every day or every week, or multiple applications every day (2 to 4 times), or multiple applications every week. However, it is apparent that, when shown as applicable, the upper or lower limits given herein may be exceeded.

[0427] The present invention also particularly relates to:

[0428] Compounds of formula I for use as therapeutically active substances;

[0429] A compound of formula I for use in treating a disease regulated by GPR17;

[0430] 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.

[0431] The use of compounds of formula I for treating or preventing conditions caused by direct damage to the myelin sheath (including but not limited to central and extrapontine myelinolysis, carbon monoxide poisoning, nutritional deficiencies and virally induced demyelination), demyelinating diseases (including but not limited to multiple sclerosis, acute and multiphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorders and leukodystrophy), CNS diseases associated with myelin loss (including but not limited to Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and ischemia caused by stroke) and inflammation in the CNS such as encephalitis, primary vasculitis, meningitis and inflammation in the CNS following obesity.

[0432] An embodiment of the invention is the use of a compound of formula I for the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease or Huntington's disease.

[0433] A particular embodiment of the invention is the use of a compound of formula I for the treatment or prevention of multiple sclerosis.

[0434] The use of a compound of formula I for the manufacture of a medicament for treating or preventing conditions caused by direct damage to the myelin sheath (including but not limited to central and extrapontine myelinolysis, carbon monoxide poisoning, nutritional deficiencies and virus-induced demyelination), demyelinating diseases (including but not limited to multiple sclerosis, acute and multiphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorders and leukodystrophy), CNS diseases associated with myelin loss (including but not limited to Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and ischemia caused by stroke) and inflammation in the CNS such as encephalitis, primary vasculitis, meningitis and inflammation in the CNS following obesity.

[0435] An embodiment of the invention is the use of a compound of formula I for the manufacture of a medicament for the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease or Huntington's disease.

[0436] A particular embodiment of the invention is the use of a compound of formula I for the preparation of a medicament for the treatment or prevention of multiple sclerosis.

[0437] According to the compounds of formula I, they are used to treat or prevent conditions caused by direct damage to the myelin sheath (including but not limited to central and extrapontine myelinolysis, carbon monoxide poisoning, nutritional deficiencies and viral-induced demyelination), demyelinating diseases (including but not limited to multiple sclerosis, acute and multiphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorders and leukodystrophy), CNS diseases associated with myelin loss (including but not limited to Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and ischemia caused by stroke) and inflammation in the CNS such as encephalitis, primary vasculitis, meningitis and inflammation in the CNS following obesity.

[0438] An embodiment of the invention is a compound of formula I for use in the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease or Huntington's disease.

[0439] A particular embodiment of the invention is a compound according to formula I for use in the treatment or prevention of multiple sclerosis.

[0440] A method for treating or preventing conditions caused by direct damage to the myelin sheath (including but not limited to central and extrapontine myelinolysis, carbon monoxide poisoning, nutritional deficiencies and virus-induced demyelination), demyelinating diseases (including but not limited to multiple sclerosis, acute and multiphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorders and leukodystrophy), CNS diseases associated with myelin loss (including but not limited to Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and ischemia caused by stroke) and inflammation in the CNS such as encephalitis, primary vasculitis, meningitis and inflammation in the CNS following obesity, the method comprising administering to a patient in need thereof an effective amount of a compound of formula I.

[0441] An embodiment of the present invention is a method for treating or preventing multiple sclerosis, Alzheimer's disease, Parkinson's disease or Huntington's disease, comprising administering an effective amount of a compound of formula I to a patient in need thereof.

[0442] A specific embodiment of the invention is a method for treating or preventing multiple sclerosis, comprising administering an effective amount of a compound of formula I to a patient in need thereof.

[0443] Another embodiment of the present invention provides a compound of formula (I) as described herein, prepared according to any of the methods described herein.

[0444] Determination procedure

[0445] GPR17 cAMP Assay Protocol:

[0446] CHO-K1 cells stably expressing untagged human GPR17 (Roche) were cultured in DMEM (Dulbecco's Modified Eagle's Medium):F-12 (1:1) supplemented with 10% fetal bovine serum and 400 μg / ml Geneticin at 37° C. / 5% CO 2 .

[0447] Nano-TRF detection analysis kit (Roche Diagnostics, catalog number 05214386001) is used to quantify the changes in intracellular cyclic adenosine monophosphate (cAMP) levels. This assay allows direct quantification of cAMP in a homogenous solution. cAMP is detected based on time-resolved fluorescence energy transfer (TR-FRET) and competitive binding of ruthenium cAMP and endogenous cAMP with anti-cAMP monoclonal antibodies labeled with AlexaFluor-700. Ruthenium complex acts as a FRET donor and transfers energy to AlexaFluor-700. FRET signal is inversely proportional to cAMP concentration.

[0448] CHO-GPR17S cells were detached with Accutase and resuspended in an assay buffer consisting of Hank's balanced salt solution (HBSS), 10 mM HEPES (4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid solution) and 0.1% bovine serum albumin (pH 7.4). The cells were seeded in a black 384-well plate (Corning) at a density of 10'000 cells / 20 μl assay buffer per well until the addition of compounds.

[0449] Test antagonist compounds were serially diluted in dimethyl sulfoxide (DMSO) and spotted in 384-well plates. Compounds were then diluted in HBSS buffer supplemented with EC80 concentrations of MDL29,951 (3-(2-carboxy-4,6-dichloroindol-3-yl) propionic acid) (GPR17 agonist) and 3-isobutyl-1-methylxanthine (IBMX) (0.5 mM final concentration) and added to cells at room temperature. Forskolin (15 μM final concentration) was added 5 minutes after the test compounds, and the cells were incubated at room temperature for 30 minutes. The assay was stopped by adding cAMP detection mix (containing detergent for cell lysis) for 90 minutes at room temperature.

[0450] Cellular cAMP was measured using a Paradigm reader (Molecular Devices). Raw data were used to calculate the FRET signal based on the measured P factor according to the instructions of the cAMP kit. Data were normalized to the maximum activity of the reference antagonist, and the dose-response curve was fitted to the activity percentage of the test compound using a sigmoidal dose-response model (Genedata Screener).

[0451] The hGPR17 cAMP assay results for compounds of Formula I are provided in Table 1

[0452] Table 1:

[0453]

[0454]

[0455]

[0456] The invention will now be illustrated by the following examples, which are not limiting.

[0457] If preparations are obtained as mixtures of enantiomers, the pure enantiomers may be obtained by methods described herein or by methods known to those skilled in the art such as, for example, chiral chromatography or crystallization.

[0458] Examples

[0459] If not stated otherwise, all examples and intermediates were prepared under nitrogen or argon atmosphere.

[0460] Intermediate A

[0461] The intermediates are either commercially available or have been prepared following the procedures described in the indicated patent applications or the novel and corresponding experimental procedures described at the end of the table:

[0462]

[0463]

[0464]

[0465]

[0466] Intermediate A1: 2-(4-Amino-2-fluoro-5-methoxy-phenyl)acetonitrile

[0467]

[0468] To a stirred solution of (4-bromo-5-fluoro-2-methoxy-phenyl)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 solution (27.27 mL, 27.27 mmol) in N-methyl-2-pyrrolidone was added 1,1′-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (751.43 mg, 0.909 mmol) under argon.

[0469] The reaction mixture was stirred at 90 °C for 4 hours, then another equivalent of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (1.77 g, 9.09 mmol) was added.

[0470] After an additional 5 hours at 90 ° C, 1M aqueous potassium fluoride solution (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 provide the title compound (536 mg, 32%) as a yellow oil. MS (ESI): m / z=181.1 [M+H] +

[0471] Intermediate A3: 2-(5-Amino-3-fluoro-6-methoxy-2-pyridinyl)acetonitrile

[0472]

[0473] Step 1: To a stirred solution of (6-bromo-5-fluoro-2-methoxy-3-pyridinyl)amine (2.5 g, 10.75 mmol) in N,N-dimethylacetamide (25 mL) at 0°C was added sodium hydride (1.29 g, 32.24 mmol) in portions (5 x 258 mg). After stirring at 0°C for 30 minutes, 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 minutes, then 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 (6-bromo-5-fluoro-2-methoxy-3-pyridinyl)-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)

[0474] 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, and then N,N-dimethylformamide (396.11 mg, 419.17 uL, 5.42 mmol) was added. Stirring was continued at -78 °C for 30 minutes. The reaction mixture was then 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 ethyl acetate / heptane 0-50% to give [5-[bis(p-anisyl)amino]-3-fluoro-6-methoxy-2-pyridinyl]methanol (297 mg, 32%) as a light yellow viscous oil. MS (ESI): m / z = 413.3 [M+H] +

[0475] Step 3: To a stirred solution of [5-[bis(p-anisyl)amino]-3-fluoro-6-methoxy-2-pyridinyl]methanol (144 mg, 0.342 mmol) in dichloromethane (1.5 mL) was added thionyl chloride (81.41 mg, 49.64 uL, 0.684 mmol) dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 hour and then concentrated in vacuo to give [6-(chloromethyl)-5-fluoro-2-methoxy-3-pyridinyl]-bis(p-anisyl)amine (152 mg, 103%) as a light brown foam, which was used directly in the next step without further purification.

[0476] Step 4: To a stirred solution of [6-(chloromethyl)-5-fluoro-2-methoxy-3-pyridinyl]-bis(p-anisyl)amine (152 mg, 0.353 mmol) in dichloromethane (700 uL) was added tetrabutylammonium bromide (11.49 mg, 0.035 mmol) followed by a solution of sodium cyanide (21.39 mg, 0.423 mmol) in water (130 uL). 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, then 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-pyridinyl]acetonitrile (87 mg, 58%) as a colorless viscous oil. MS (ESI): m / z = 422.3 [M+H] +

[0477] Step 5: A solution of 2-[5-[bis(p-anisyl)amino]-3-fluoro-6-methoxy-2-pyridinyl]acetonitrile (85 mg, 0.202 mmol) in dichloromethane (400 uL) was cooled to 0 ° C and trifluoroacetic acid (1.38 g, 926.64 uL, 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 ethyl acetate / heptane 0-40% to give 2-(5-amino-3-fluoro-6-methoxy-2-pyridinyl)acetonitrile (31 mg, 84%) as a light yellow solid. MS (ESI): m / z=182.1[M+H] +

[0478] Intermediate A4:5-(Difluoromethoxy)-3-fluoro-6-methoxy-pyridin-2-amine

[0479]

[0480] Step 1: To a stirred solution of (5-bromo-3,6-difluoro-2-pyridinyl)amine (2.45 g, 11.74 mmol) in N,N-dimethylacetamide (25 mL) at 0°C was added sodium hydride (1.41 g, 35.21 mmol) in portions (5 x 282 mg). After stirring at 0°C for 30 minutes, 4-methoxybenzyl chloride (3.75 g, 3.26 mL, 23.47 mmol) was added and the reaction mixture was stirred at room temperature for another 30 minutes 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-pyridinyl)-bis(p-anisyl)amine (4.9 g, 92%) as a light yellow viscous oil. MS (ESI): m / z = 448.8 [M+H] +

[0481] Step 2: To a solution of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (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 nitrogen atmosphere. The mixture was stirred at 100°C for 16 hours, then 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 afford 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] +

[0482] 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 another 2 hours before it was 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, not evaporated to dryness) to give crude material 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] +

[0483] 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 dropwise potassium hydroxide aqueous solution (34.16 mL, 170.81 mmol) 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 ethyl acetate / petroleum ether 0-20% to give 5-(difluoromethoxy)-3,6-difluoro-N,N-bis[(4-methoxyphenyl)methyl]pyridin-2-amine (3.31 g, 88%) as a light 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)

[0484] 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 hour, then poured into a saturated NaHCO3 (200 mL) 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 ethyl acetate / petroleum ether 0-40% to give 5-(difluoromethoxy)-3,6-difluoro-pyridin-2-amine (1.70 g, 114%) as a light yellow oil. MS (ESI): m / z=196.7[M+H] +

[0485] Step 6: Sodium methoxide (468 mg, 8.67 mmol, 1 eq) was added to a solution of 5-(difluoromethoxy)-3,6-difluoro-pyridine-2-amine (1.70 g, 8.67 mmol) in THF (40 mL) 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 ethyl acetate / petroleum ether 0-30% to give 5-(difluoromethoxy)-3-fluoro-6-methoxy-pyridine-2-amine (850 mg, 45%) as a light yellow oil. MS (ESI): m / z=208.7 [M+H] +

[0486] Intermediate A6: 5-(2,2-Difluoroethyl)-3-fluoro-6-methoxy-pyridin-2-amine

[0487]

[0488] Step 1: A mixture of 5-bromo-3,6-difluoropyridine-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 a saturated ammonium chloride solution. The pH was adjusted to about 7 with 1N HCl aqueous solution, 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 ethyl acetate / heptane 0-20% to give 5-bromo-3-fluoro-6-methoxypyridine-2-amine (893 mg, 83%) as a light brown solid. MS (ESI): m / z=221.0[M+H]+

[0489] Step 2: Sodium hydride (108.57 mg, 2.71 mmol) was added to a stirred solution of 5-bromo-3-fluoro-6-methoxypyridin-2-amine (200 mg, 0.905 mmol) in N,N-dimethylacetamide (3 mL) at 0°C. After stirring at 0°C for 20 minutes, 4-methoxybenzyl chloride (289.2 mg, 251.48 uL, 1.81 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes, then 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 over silica gel using a gradient of ethyl acetate / heptane 0-20% to give (5-bromo-3-fluoro-6-methoxy-2-pyridinyl)-bis(p-anisyl)amine (270 mg, 64%) as a light yellow viscous oil. MS (ESI): m / z = 463.2 [M + H] +

[0490] 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 and quenched with aqueous potassium hydrogen sulfate (1N, 30 ml), extracted with water and 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 over 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] +

[0491] 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 5 portions (about 165 mg each) at 10 minute intervals. The reaction mixture was cooled 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 over silica gel using a gradient of ethyl acetate / heptane 0-20% to give the desired product (844 mg, 84%) as a light yellow oil. MS (ESI): m / z=445.3[M+H] +

[0492] Step 5: Palladium hydroxide / carbon (264.15 mg, 0.094 mmol, 0.050 eq) was added to [5-(2,2-difluorovinyl)-3-fluoro-6-methoxy-2-pyridinyl]-bis(p-anisyl)amine (836 mg, 1.88 mmol) dissolved in methanol (50 mL), and the reaction mixture was stirred at room temperature under hydrogen balloon pressure. After the reaction was completed, the reaction mixture was filtered through celite and washed with ethyl acetate. The combined organic layers were concentrated and dried in vacuo 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] +

[0493] Intermediate A7: 6-(2,2-Difluoroethyl)-5-fluoro-2-methoxy-pyridin-3-amine

[0494]

[0495] Step 1: To a stirred solution of (6-bromo-5-fluoro-2-methoxy-3-pyridinyl)amine (2.5 g, 10.75 mmol) in N,N-dimethylacetamide (25 mL) at 0°C was added sodium hydride (1.29 g, 32.24 mmol) in portions (5 x 258 mg). After stirring at 0°C for 30 minutes, 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 minutes, then 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 (6-bromo-5-fluoro-2-methoxy-3-pyridinyl)-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)

[0496] Step 2: To a solution of (6-bromo-5-fluoro-2-methoxy-3-pyridinyl)-bis(p-anisyl)amine (1.33 g, 2.88 mmol) in tetrahydrofuran (25 mL) was slowly added n-butyllithium (1.6 M in hexanes, 1.8 mL, 2.88 mmol) at -78°C. After 15 minutes at -78°C, N,N-dimethylformamide (273.94 mg, 290.19 uL, 3.75 mmol) was added and the mixture was stirred at -78°C for another 5 minutes and then warmed to -20°C. When LCMS indicated 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] +

[0497] Step 3: To a solution of 5-[bis(p-anisyl)amino]-3-fluoro-6-methoxy-pyridinecarboxaldehyde (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 5 portions (about 150 mg each) at 10 minute intervals. The reaction mixture was cooled 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 over silica gel using a gradient of ethyl acetate / heptane 0-20% to give the desired product (818 mg, 90%) as a colorless oil. MS (ESI): m / z=445.3[M+H] +

[0498] Step 5: Palladium hydroxide / carbon (243.73 mg, 0.087 mmol, 0.050 eq) was added to [6-(2,2-difluorovinyl)-5-fluoro-2-methoxy-3-pyridinyl]-bis(p-anisyl)amine (812 mg, 1.74 mmol) dissolved in methanol (50 mL), and the reaction mixture was stirred at room temperature under hydrogen balloon pressure. After the reaction was completed, the reaction mixture was filtered through celite and washed with ethyl acetate. The combined organic layers were concentrated and dried in vacuo 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] +

[0499] Intermediate A10 :3-Fluoro-5-(2-fluoroethoxy)-6-methoxy-pyridin-2-amine

[0500]

[0501] 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-pyridinyl] amine (26 mg, 81%) as a brown gum. MS (ESI): m / z=205.1[M+H] +

[0502] Intermediate A13: 6-(3,3-Difluoropropyl)-5-fluoro-2-methoxy-pyridin-3-amine

[0503]

[0504] Step 1: To a solution of (6-bromo-5-fluoro-2-methoxy-3-pyridinyl)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. The reaction mixture was stirred 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 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 0-30% to give the desired product (1.2 g, 40%) as a white semi-solid. MS (ESI): m / z = 445.06 [M+H+Na] +

[0505] Step 2: To a solution of tert-butyl N-(6-bromo-5-fluoro-2-methoxy-3-pyridyl)-N-tert-butoxycarbonyl-carbamate (1.2 g, 2.85 mmol), ethyl (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (837.21 mg, 828.92 uL, 3.7 mmol) and cesium carbonate (2.78 g, 8.55 mmol) in 1,4-dioxane (6 mL), water (1 mL) was added 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) 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 over silica gel using a gradient of ethyl acetate / heptane 0-35% to give the desired product (747 mg, 56%) as a colorless oil. MS (ESI): m / z=441.3 [M+H] +

[0506] Step 3: (E)-3-[5-[bis(tert-butoxycarbonyl)amino]-3-fluoro-6-methoxy-2-pyridyl]acrylate (740 mg, 1.68 mmol) was dissolved in ethyl acetate (30 mL) under argon. Palladium / activated carbon 10% (178.79 mg, 0.168 mmol) was added, and the flask was purged and backfilled with argon. The reaction mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere, then filtered on celite 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] +

[0507] Step 4: In a 50 ml three-necked flask, ethyl 3-[5-[bis(tert-butoxycarbonyl)amino]-3-fluoro-6-methoxy-2-pyridinyl]propanoate (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 hour.

[0508] Additional DIBAL-H (1M in THF, 1.51 mL, 1.51 mmol) was added at -78 °C, and the reaction mixture was stirred at room temperature. After 2 hours, the reaction mixture was cooled to -78 °C, water (120 uL) was added, followed by 15% aqueous NaOH solution (120 uL) and additional water (300 uL). The reaction mixture was warmed to room temperature and stirred for 30 minutes, then sodium sulfate was added. The reaction mixture was filtered through celite and concentrated in vacuo. The crude material was adsorbed on ISOLUTE HM-N and purified by flash chromatography over silica gel using a gradient of ethyl acetate / heptane 0-50% to give the desired product (423 mg, 56%) as a colorless oil. MS (ESI): m / z=401.3[M+H] +

[0509] Step 5: tert-Butyl N-tert-butoxycarbonyl-N-[5-fluoro-6-(3-hydroxypropyl)-2-methoxy-3-pyridinyl]carbamate (416 mg, 1.04 mmol) was dissolved in dichloromethane (10 mL) and the solution was cooled to 0 ° C. 1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benzodioxole-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 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 ethyl acetate / heptane 0-50% to give the desired product (359 mg, 84%) as a colorless oil. MS (ESI): m / z = 399.3 [M+H] +

[0510] Step 6: Dissolve tert-butyl N-tert-butoxycarbonyl-N-[5-fluoro-6-(3-ketopropyl)-2-methoxy-3-pyridyl]carbamate (355 mg, 0.891 mmol, 1 eq) in dichloromethane (10 mL) and cool the solution to 0°C. Add [bis(2-methoxyethyl)amino]sulfur trifluoride (DeoxoFluor 2.7M in toluene, 792.mg, 660 uL, 1.78 mmol) dropwise at 0°C and stir the reaction mixture at 0°C for 30 minutes and at room temperature. After 2 hours, pour the reaction mixture into a saturated NaHCO3 / ice mixture and stir for 10 minutes. Separate the layers and extract the aqueous layer with dichloromethane. Wash the combined organic layers twice with brine, dry over anhydrous sodium sulfate, filter and concentrate in vacuo. The crude material was adsorbed on ISOLUTE HM-N and purified by flash chromatography on silica gel using a gradient of ethyl acetate / heptane 0-30% to give the desired product (110 mg, 11%) as a colorless oil. MS (ESI): m / z = 421.3 [M+H] +

[0511] Step 7: A mixture of tert-butyl N-tert-butoxycarbonyl-N-[6-(3,3-difluoropropyl)-5-fluoro-2-methoxy-3-pyridinyl]carbamate (107 mg, 0.255 mmol) and HCl (4M in dioxane, 1.53 g, 1.27 mL, 5.09 mmol) was stirred at room temperature. After 2.5 hours, 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 on ISOLUTE HM-N and purified by flash chromatography over silica gel using a gradient of ethyl acetate / heptane 0-100% to give the desired product (15 mg, 25%) as a colorless oil. MS (ESI): m / z=221.1 [M+H] +

[0512] Intermediate A14: 2,6-Bis(difluoromethoxy)-5-fluoro-pyridin-3-amine

[0513]

[0514] Step 1: Sodium bis(trimethylsilyl)amide (25.61 mL, 25.61 mmol) was added to a solution of 4-methoxybenzyl alcohol (3.54 g, 25.61 mmol) in THF (120 mL) at -78 ° C, and the resulting reaction mixture was stirred for 30 minutes and then added to 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 hour at -78 ° C, the reaction mixture was quenched with NH4Cl aqueous solution (125 mL) and extracted with ethyl acetate. The combined organic layer was washed twice with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography over silica gel using gradient ethyl acetate / petroleum ether 0-10% to obtain 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).

[0515] 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). The mixture was stirred at -20 °C for 2 hours. The mixture was quenched with aqueous NH4Cl solution (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).

[0516] 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 hours. The reaction mixture was concentrated under reduced pressure to give a residue and purified by flash chromatography on silica gel using a gradient of ethyl acetate / petroleum ether 0-50% 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).

[0517] Step 4: To a solution of 3-fluoro-6-methoxy-5-nitro-pyridine-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 layer was 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 ethyl acetate / petroleum ether 0-3% to obtain 2-(difluoromethoxy)-3-fluoro-6-methoxy-5-nitro-pyridine (580 mg, 45%) as a yellow oil. 1HNMR (400MHz, DMSO-d6) δ = 8.79 (d, J = 9.0Hz, 1H), 8.10-7.70 (m, 1H), 4.04 (s, 3H).

[0518] Step 5: Add BBr3 (3.34 mL, 35.7 mmol) to a mixture of 2-(difluoromethoxy)-3-fluoro-6-methoxy-5-nitro-pyridine (1.7 g, 7.14 mmol) in dichloromethane (24 mL) at 0 ° C and stir the reaction mixture at 20 ° C for 1 hour. The reaction mixture is poured into water and extracted with ethyl acetate. The combined organic layer is washed twice with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica gel using a gradient of ethyl acetate / petroleum ether 0-50% to obtain 6-(difluoromethoxy)-5-fluoro-3-nitro-pyridine-2-ol (1.48 g, 92%) as a yellow oil. 1H NMR (400MHz, chloroform-d) δppm 7.31-7.69 (m, 1H) 8.33 (d, J=7.70Hz, 1H) 11.35 (br s, 1H)

[0519] Step 6: To a solution of 6-(difluoromethoxy)-5-fluoro-3-nitro-pyridine-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 hour, 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 gradient of ethyl acetate / petroleum ether 0-20% to give 2,6-bis(difluoromethoxy)-3-fluoro-5-nitro-pyridine (2.38 g, 46%) as a light yellow oil. 1HNMR(400MHz,DMSO-d6)δppm7.64-8.12(m,2H)8.98(d,J=8.93Hz,1H)

[0520] 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 NH4Cl (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 hours. It was 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 ethyl acetate / petroleum ether 0-30% to give 2,6-bis(difluoromethoxy)-5-fluoro-pyridine-3-amine (639.5 mg) as a light brown oil. MS (ESI): m / z=244.7 [M+H] +

[0521] Intermediate A15: 5-Cyclopropyl-3-fluoro-6-methoxy-pyridin-2-amine

[0522]

[0523] Step 1: To a stirred solution of 3,6-difluoropyridine-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 as impurities will form!). The residue was purified by flash chromatography over silica gel using a gradient of ethyl acetate / heptane 0-20% to give 5-bromo-3,6-difluoropyridine-2-amine (1.44 g, 89%) as an orange solid. MS (ESI) m / z: 209.0 [M+H] +

[0524] Step 2: A mixture of 5-bromo-3,6-difluoropyridine-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 hours, the reaction mixture was cooled to room temperature and poured into a saturated NH4Cl solution. The pH was adjusted to about 7 with 1N 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 over silica gel using a gradient of ethyl acetate / heptane 0-20% to give 5-bromo-3-fluoro-6-methoxypyridine-2-amine (893 mg, 82%) as a light brown solid. MS (ESI) m / z: 221.0 [M+H] +

[0525] Step 3: A mixture of (5-bromo-3-fluoro-6-methoxy-2-pyridinyl)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 uL) was heated to 100 ° C. After 6 hours, 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-pyridinyl)amine (55 mg, 65%) as an orange oil. MS (ESI) m / z: 183.1 [M+H] +

[0526] Intermediate A16:(5-Bromo-4,6-dimethoxy-pyrimidin-2-yl)amine

[0527]

[0528] 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 obtained light 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 provide the title compound (116 mg, 78%) as an off-white solid. MS (ESI): m / z=234.1 [M+H] +

[0529] Intermediate A17: (4,6-Dimethoxy-5-methyl-pyrimidin-2-yl)amine

[0530]

[0531] 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] +

[0532] Intermediate A20: 5-Fluoro-2-methoxy-6-(oxetan-3-yl)pyridin-3-amine

[0533]

[0534] 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 over silica gel using a gradient of ethyl acetate / heptane 0-30% to give the desired product (1.25 g, 87%) as a dark red solid. MS (ESI): m / z=221.0 [M+H] +

[0535] Step 2: Prepare stock solutions of Ir-catalyst (6.9 mg / mL in dichloromethane) and NiCl2*glyme / dtbbpy (2.7 mg Ni-Co-Cat / mL and 2.2 mg ligand / mL in dimethoxyethane).

[0536] The corresponding volume of Ir-catalyst solution of [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-n1,n1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl-n]phenyl-c]iridium(III)hexafluorophosphate-(Ir[df(cf3)ppy]2(dtbpy))pf6 (7.61 mg, 0.007 mmol, 0.010 eq) was added into the reaction flask and the solvent was evaporated. Then sodium carbonate (142.51 mg, 1.36 mmol, 2 eq), (6-bromo-5-fluoro-2-methoxy-3-pyridinyl)amine (150 mg, 0.679 mmol, 1 eq), 3-bromooxetane (185.92 mg, 112.61 uL, 1.36 mmol, 2 eq) and tris(trimethylsilyl)silane (226.13 mg, 280.55 uL, 0.909 mmol, 1.34 eq) were added. Ultra-dry ethylene glycol dimethyl ether (10.95 mL) was added and the reaction mixture was degassed by bubbling argon through the mixture for 2 minutes. The corresponding volume of nickel chloride (II) glycol dimethyl ether complex NiCl2*glyme / dtbbpy solution (745.56ug, 0.003mmol, 0.005eq) and 4,4'-bis(tert-butyl)-2,2'-bipyridine (910.72ug, 0.003mmol, 0.005eq) were added, and the reactants were degassed again for 5 minutes. The vial was placed in a photoreactor and irradiated with 450nm for 14 hours (stirred at 900rpm, LED 100% power). The reaction mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography to obtain [5-fluoro-2-methoxy-6-(oxetanes-3-yl)-3-pyridyl] amine (47mg, 35%) as an off-white solid. (ESI): m / z=199.1[M+H] +

[0537] Intermediate A22: 5-(2-Fluoroethoxy)-4-methoxy-pyrimidin-2-amine

[0538]

[0539] 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 a saturated aqueous sodium bicarbonate solution and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and dried in vacuo. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate / heptane 0-20% to provide the title compound (998 mg, 50%) as a colorless viscous oil. MS (ESI): m / z=446.2[M+H] +

[0540] 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 over silica gel using a gradient of ethyl acetate / heptane 0-30% to provide the title compound (157 mg, 29%) as a colorless viscous oil. MS (ESI): m / z = 492.4 [M + H] +

[0541] 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 a cold 0.1N 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 provide the title compound (103 mg, 100%) as a light yellow viscous oil. MS (ESI): m / z=382.3[M+H] +

[0542] 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 provide the title compound (22 mg, 22%) as a colorless viscous oil. MS (ESI): m / z=428.3[M+H] +

[0543] 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 stirred at 55 °C for another two hours. The resulting purple solution was poured into saturated aqueous sodium bicarbonate solution 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 provide the title compound (27 mg, 71%) as an off-white solid. MS (ESI): m / z=188.1 [M+H] +

[0544] Intermediate A23: 5-(2,2-Difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-amine

[0545]

[0546] Step 1: 5-Bromo-4,6-dimethoxy-pyrimidin-2-amine

[0547]

[0548] 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 provide the title compound (9.26 g, 87% yield) as a white solid. MS (ESI) m / z=234.1 [M+H] +

[0549] Step 2: 5-Bromo-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine

[0550]

[0551] A solution of 5-bromo-4,6-dimethoxy-pyrimidine-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 batches (3 x 88 mg). Stirring was continued at 0 ° C for 30 minutes. 4-methoxybenzyl chloride (706. mg, 608.62 uL, 4.42 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature, stirred for 1 hour, carefully quenched with saturated ammonium chloride solution, poured into water and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate / heptane 0-20% to provide the title compound (1.11 g, 100% yield) as a white solid. MS (ESI) m / z=476.2[M+H] +

[0552] Step 3: 2-[Bis[(4-methoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-ol

[0553]

[0554] 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 1.6 M n-butyl lithium / hexane (699.71 mg, 813.61 uL, 1.3 mmol) dropwise at -78°C. The resulting yellow solution was stirred at -78°C for 30 minutes. Trimethyl borate (156.08 mg, 167.47 uL, 1.5 mmol) was added dropwise and stirring was continued at -78°C for 1.5 hours. The reaction mixture was warmed to 0°C and acetic acid (120.27 mg, 114.62 uL, 2 mmol) was added dropwise, followed by hydrogen peroxide 35% (145.98 mg, 131.51 uL, 1.5 mmol). Stirring was continued at 0°C for 1.5 hours. The resulting pink suspension was poured into 0.1 N sodium thiosulfate solution and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate / heptane 0-30% to provide the title compound (194 mg, 47% yield) as a light yellow viscous oil. MS (ESI) m / z=412.3 [M+H]+

[0555] Step 4: 5-(2,2-difluoroethoxy)-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidine- 2-Amine

[0556]

[0557] 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 uL, 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 provide the title compound (92 mg, 85% yield) as an off-white solid. MS (ESI) m / z=476.2[M+H] +

[0558] Step 5: 5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-amine

[0559]

[0560] 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 uL, 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 provide the title compound (41 mg, 87% yield) as a light yellow solid. MS (ESI) m / z=236.2[M+H] +

[0561] Intermediate A24: 5-(2-Fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-amine

[0562]

[0563] Step 1: 5-(2-fluoroethoxy)-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine

[0564]

[0565] 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 hours. The reaction mixture was poured into brine and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate / heptane 0-30% to provide the title compound (1.79 g, 85% yield) as a white solid. MS (ESI) m / z=458.3[M+H] +

[0566] Step 2: 5-(2-Fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-amine

[0567]

[0568] 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 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 0-60% to provide the title compound (885 mg, 100% yield) as an off-white solid. MS (ESI) m / z=218.1[M+H] +

[0569] Intermediate B

[0570]

[0571]

[0572]

[0573]

[0574]

[0575]

[0576]

[0577] Method A

[0578] A solution of imidazo or pyrazolo derivative II or VIII or XIII or XVIII or XXIII (1 eq) in chlorosulfonic acid (12 eq) was stirred at 110°C until LCMS indicated complete conversion. The reaction mixture was cooled 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 the sulfonyl chloride B is stable on silica gel, the crude material was purified by flash chromatography over silica gel using a gradient of ethyl acetate / heptane.

[0579] Method B

[0580] To a solution of imidazo or pyrazolo derivative II or VIII or XIII or XVIII or XXIII (1 eq) in 1,2-dichloroethane is added trimethylsilyl chlorosulfonate (3 eq). The mixture is stirred at 90 ° C until it is completely converted into sulfonic acid. The reaction mixture is cooled to room temperature, triethylamine (2 eq) and phosphorus oxychloride (3 eq) are added. The reaction mixture is stirred at 100 ° C until LCMS shows complete conversion. The reaction mixture is cooled to room temperature and poured into a saturated NaHCO3 / ice solution and extracted with ethyl acetate. The combined organic layer is washed twice with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain the corresponding sulfonyl chloride B. If the sulfonyl chloride B is stable on silica gel, the crude material is purified by flash chromatography over silica gel using a gradient of ethyl acetate / heptane.

[0581] Method C

[0582] Step 1: To a solution of the imidazo or pyrazolo derivative III or IX or XIV or XIX or XXIV (1 eq) in 1,4-dioxane (5 mL) was added benzyl mercaptan (1.1 eq), N-ethyldiisopropylamine (2 eq), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.050 eq) and tris(dibenzylideneacetone)dipalladium (0.030 eq) at room temperature under nitrogen. 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. The two 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 over silica gel using a gradient of ethyl acetate / heptane to give the corresponding benzyl sulfide.

[0583] Step 2: under nitrogen at room temperature to a solution of benzyl thioether derivative (1eq) in acetic acid / water (10: 1) add n-chlorosuccinimide (3eq). The reaction mixture is stirred at room temperature until complete conversion. The reaction mixture is diluted with ice water and ethyl acetate. The two layers are separated and the aqueous phase is extracted twice with ethyl acetate. The combined organic layer is washed twice with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. If sulfonyl chloride B is stable on silica gel, the crude material is purified by flash chromatography over silica gel using gradient ethyl acetate / heptane.

[0584] Synthesis of Precursor I or III of Sulfonyl Chloride Intermediate B

[0585] Precursor B1-I: 7-cyclopropylimidazo[1,2-a]pyridine

[0586] In a 25 ml round-bottom flask, 7-bromoimidazo[1,2-a]pyridine (1 g, 5.08 mmol), cyclopropylboronic acid (566.77 mg, 6.6 mmol), 1,4-dioxane (24 mL), PdCl2(dppf)-CH 2 Cl 2 (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 hours, then poured into water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was adsorbed on ISOLUTE HM-N and purified by flash chromatography on silica gel using a gradient of ethyl acetate / heptane 0-100% to give 7-cyclopropylimidazo[1,2-a]pyridine (613 mg, 65%) as a light brown oil. MS (ESI): m / z=159.1[M+H] +

[0587] Precursor B2-I: 7-bromoimidazo[1,2-a]pyridine

[0588] Commercially available CAS 808744-34-5

[0589] Precursor B3-I: 7-methylimidazo[1,2-a]pyridine

[0590] Commercially available CAS 874-39-5

[0591] Precursor B4-I: 8-methoxy-7-methyl-imidazo[1,2-a]pyridine

[0592] To (3-methoxy-4-methyl-2-pyridyl)amine (0.500 g, 3.62 mmol) in ethanol (15 mL) was added 50% aqueous chloroacetaldehyde solution (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] +

[0593] Precursor B5-I: 7-(difluoromethoxy)imidazo[1,2-a]pyridine

[0594] 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)

[0595] Precursor B6-III: 3-bromo-7-chloro-imidazo[1,2-a]pyridine

[0596] Commercially available CAS 342613-67-6

[0597] Precursor B7-I: 7-chloro-8-fluoro-imidazo[1,2-a]pyridine

[0598] Commercially available CAS 628691-87-2

[0599] Precursor B8-I: 7-chloro-8-methoxy-imidazo[1,2-a]pyridine

[0600] 2-Chloroacetaldehyde (296.99 mg, 239.51 uL, 1.89 mmol) was added to a mixture of (4-chloro-3-methoxy-2-pyridyl)amine (200 mg, 1.26 mmol) in ethanol (1 mL). 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 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] +

[0601] Precursor B9-I: 7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine

[0602] 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 several times and then stirred at 65 ° C under a hydrogen atmosphere (50 psi) 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 light yellow oil. MS (ESI): m / z=137.2[M+H] +

[0603] Precursor B10-I: 7-(difluoromethyl)imidazo[1,2-a]pyridine

[0604] Diethylaminosulfur trifluoride (1.93 g, 11.97 mmol) was added to a solution of imidazo [1,2-a] pyridine -7- carbaldehyde (500 mg, 3.42 mmol) in dichloromethane (20 mL) at -78 ° C. The mixture was stirred at 30 ° C. After 12 hours, LCMS showed that about 80% of the starting material remained. Diethylaminosulfur trifluoride (3.58 g, 22.24 mmol) was added to the reaction mixture and stirred for another 12 hours at 30 ° C, then quenched with saturated NaHCO3 solution and extracted with dichloromethane / MeOH (10: 1 V / V). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography over silica gel using a gradient of ethyl acetate / petroleum ether 0-50% to obtain 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)

[0605] Precursor B11-I: 7-methoxyimidazo[1,2-a]pyridine

[0606] Commercially available CAS 342613-71-2

[0607] Precursor B12-I: 7-cyclopropylimidazo[1,2-a]pyrimidine

[0608] To a solution of (4-cyclopropylpyrimidin-2-yl)amine (1 g, 7.4 mmol) in ethanol (28.26 mL) was added 50% aqueous chloroacetaldehyde solution (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 over silica gel using a gradient of dichloromethane / methanol 0-7.5% to give 7-cyclopropylimidazo[1,2-a]pyrimidine (670 mg, 51%) as a light red solid. MS (EI): m / z=158.1 [MH] + Precursor B13-I: 7-ethylimidazo[1,2-a]pyridine

[0609] To a solution of (4-ethyl-2-pyridyl)amine (500 mg, 3.97 mmol) in ethanol (16 mL) was added 50% aqueous 2-chloroacetaldehyde solution (6.23 g, 5.03 mL, 39.7 mmol), and the resulting yellow solution was stirred at 80 ° C for 5 hours. The reaction mixture was cooled to room temperature and 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 0-5% to give 7-ethylimidazo[1,2-a]pyridine (313 mg, 49%) as a yellow oil. MS (ESI): m / z=147.1[M+H] +

[0610] Precursor B14-III: 3-bromo-7-methyl-imidazo[1,2-a]pyridine-8-carbonitrile

[0611] N-bromosuccinimide (849.3 mg, 4.77 mmol) was added in batches to a solution of 7-methylimidazo[1,2-a]pyridine-8-carbonitrile (750 mg, 4.77 mmol) in acetonitrile (12 mL), and the resulting reaction mixture was stirred at 22 ° C until complete conversion. Saturated NaHCO3 solution was added to the reaction mixture and 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] +

[0612] Precursor B15-I: 7,8-dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine

[0613] A reaction mixture of 7,8-dimethylimidazo[1,2-a]pyridine (550 mg, 4 mmol) and 4.5% palladium and 0.5% rhodium / 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 was concentrated in vacuo to give 7,8-dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (469 mg, 63%) as a light yellow oil. MS (ESI): m / z=150.9 [M+H] +

[0614] Precursor B16-III: 3-bromo-7-(trifluoromethyl)imidazo[1,2-a]pyridine

[0615] To a stirred solution of 7-(trifluoromethyl)imidazo[1,2-a]pyridine (650 mg, 3.49 mmol) in acetic acid (8 mL) was added bromine (558.09 mg, 178.93 uL, 3.49 mmol) at room temperature. The clear yellow solution was stirred at room temperature for 1 hour, and then 4N NaOH was added at 0°C until 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 light yellow solid. MS (ESI): m / z=265.1[M+H] +

[0616] Precursor B17-III: 3-bromo-7-cyclopropyl-imidazo[1,2-a]pyridine-8-carbonitrile

[0617] 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 tripotassium phosphate (1.13 g, 5.3 mmol). The reaction mixture was stirred at 110 ° C for 15 hours and then 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-cyclopropyl-nicotinonitrile (124 mg, 51%) as a yellow solid. MS (ESI): m / z=160.1 [M+H] +

[0618] 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 gradient of methanol / ethyl acetate 0-50% to give 7-cyclopropylimidazo[1,2-a]pyridine-8-carbonitrile (155 mg, 97%) as a light brown solid. MS (ESI): m / z=184.1[M+H] +

[0619] 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 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 a saturated NaHCO3 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 light yellow solid. MS (ESI): m / z=262.1[M+H] +

[0620] Precursor B18-I: 7-methoxyimidazo[1,2-a]pyrimidine

[0621] To a solution of (4-methoxypyrimidin-2-yl)amine (1 g, 7.83 mmol) in ethanol (29.4 mL) was added 50% aqueous chloroacetaldehyde solution (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 and 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 over silica gel using a gradient of dichloromethane / methanol 0-7.5% to give 7-methoxyimidazo[1,2-a]pyrimidine (742 mg, 63%) as a white solid. MS (ESI): m / z=150.0[M+H] +

[0622] Precursor B19-I: 7-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine

[0623] The reaction mixture of 7-(trifluoromethyl)imidazo[1,2-a]pyridine (75 mg, 0.4 mmol) and 5% platinum / 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] +

[0624] Precursor B20-I: 7,7-dimethyl-6,8-dihydro-5H-imidazo[1,2-a]pyridine

[0625] Step 1: A solution of 4,4-dimethyl-2-piperidone (1 g, 7.86 mmol, 1 eq) 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 in vacuo.

[0626] The crude compound was purified by flash chromatography on silica gel using a gradient of dichloromethane / methanol 0-30% to give 4,4-dimethylpiperidine-2-thione (700 mg, 59%) as a white solid. MS (ESI): m / z = 144.1 [M+H] +

[0627] Step 2: 4,4-dimethylpiperidine-2-thione (255 mg, 1.78 mmol) was dissolved in 1-butanol (8.9 mL), and then 2,2-diethoxyethylamine (355 mg, 388.25 uL, 2.67 mmol) and p-toluenesulfonic acid monohydrate (507 mg, 2.67 mmol) were added. The mixture was stirred at 130 ° C for 16 hours. 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 in vacuo. The crude material was purified by flash chromatography on silica gel using a gradient of 0-30% methanol / dichloromethane (stained with KMnO4) to give 7,7-dimethyl-6,8-dihydro-5H-imidazo[1,2-a]pyridine (67 mg, 24%) as a light yellow oil. MS (ESI): m / z = 151.1 [M+H] +

[0628] Precursor B21-I: 7-methylimidazo[1,2-a]pyrimidine

[0629] To a solution of (4-methylpyrimidin-2-yl)amine (3g, 27.49mmol) in ethanol (120mL) was added 50% aqueous chloroacetaldehyde solution (43.16g, 34.92mL, 274.9mmol) at room temperature. The reaction mixture was stirred at reflux for 16 hours. The reaction mixture was cooled to room temperature and 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 mixture of regioisomers, which were separated by SFC. 7-Methylimidazo[1,2-a]pyrimidine (466mg, 12%) was obtained as a light yellow solid. MS (ESI): m / z=134.0[M+H] +

[0630] Precursor B22-I: 8-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine

[0631] 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 in vacuo.

[0632] The crude material was purified by flash chromatography on silica gel using a gradient of dichloromethane / methanol 0-30% to give 3-methylpiperidine-2-thione (532 mg, 44%) as a white solid. MS (ESI): m / z = 130.1 [M+H] +

[0633] 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 onto 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 give 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] +

[0634] Precursor B23-III: 3-bromo-7-chloro-imidazo[1,2-a]pyridine-8-carbonitrile

[0635] 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 hours. 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] +

[0636] 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 heated in a microwave oven at 150 ° C for 45 minutes. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was treated with ether to precipitate a solid. 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] +

[0637] Step 3: A suspension of 7-hydroxyimidazo[1,2-a]pyridine-8-carbonitrile (200 mg, 1.13 mmol) in phosphorus oxychloride (888.3 mg, 540 uL, 5.79 mmol) was heated to 140 ° C for 2 hours. 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] +

[0638] 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 minutes, then poured into a saturated aqueous NaHCO3 solution 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 heptane / ethyl acetate 0-60% to give 3-bromo-7-chloro-imidazo[1,2-a]pyridine-8-carbonitrile (169 mg, 73%) as a light yellow solid. MS (ESI): m / z=258.0[M+H] +

[0639] Precursor B24-I: 7-methyl-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

[0640] A mixture of 2-chloro-1H-imidazole (1.1 g, 10.73 mmol), potassium carbonate (2.97 g, 21.46 mmol) and 4-bromobutane-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 uL, 10.73 mmol) and concentrated in vacuo. The crude material was purified by rapid, silica gel, using a gradient of heptane / ethyl acetate 0-100% to obtain 7-methyl-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine as a colorless semisolid. MS (EI+): m / z = 138.0 [M] +

[0641] Precursor B25-III: 3-bromo-7-methyl-imidazo[1,2-a]pyrazin-8-one

[0642] A suspension of 3-bromo-7H-imidazo[1,2-a]pyrazine-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 in batches. After stirring at 20 ° C for 15 minutes, iodomethane (255.34 mg, 112.48 uL, 1.8 mmol) was added, and the reaction mixture was stirred at room temperature. After 1 hour, the suspension was cooled to 0 ° C, methanol (2 ml) was slowly added and stirred for 10 minutes, and then concentrated in vacuo. The crude compound was purified by flash chromatography on silica gel using a gradient of dichloromethane / methanol 0-15% to obtain 3-bromo-7-methyl-imidazo[1,2-a]pyrazine-8-one (280 mg, 75%) as a white solid. MS (ESI): m / z = 230.1 [M + H] +

[0643] Precursor B26-III: 3-bromoimidazo[1,2-a]pyridine-7-carbonitrile

[0644] Commercially available CAS1392210-94-4

[0645] Precursor B27-III: 3-bromo-7-methoxy-imidazo[1,2-a]pyridine-8-carbonitrile

[0646] Commercially available CAS1072944-45-6

[0647] Precursor B28-III: 3-bromo-7-methoxy-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine

[0648] 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 / 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 light yellow oil. MS (ESI): m / z=153.1 [M+H] +

[0649] 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 hour, 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 over silica gel using a gradient of dichloromethane / methanol 0-10% 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] +

[0650] Precursor B29-I: 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine

[0651] Commercially available CAS 34167-66-3

[0652] Precursor B30-III: 3-bromo-7-(difluoromethoxy)imidazo[1,2-a]pyridine-8-carbonitrile

[0653] Step 1: A mixture of 2-amino-4-methoxy-nicotinonitrile (1 g, 6.57 mmol) and about 50 wt.% of 2-chloroacetaldehyde aqueous solution (1.55 g, 1.25 mL, 9.85 mmol) in ethanol (2.5 mL) was heated to 150 ° C and stirred for 5 hours, and the reaction mixture was concentrated in vacuo. The residue was triturated with ethyl acetate and filtered through sintered glass. The solid was washed with 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] +

[0654] 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), sodium chlorodifluoroacetate (997 mg, 6.28 mmol) and water (600 uL) in N,N-dimethylformamide (6 mL) was heated to 100 ° C. After 1 hour, 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, over silica gel, using a gradient of heptane / ethyl acetate 0-100% 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] +

[0655] 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 uL) was added dropwise. The reaction mixture was stirred at 0°C for 35 minutes, then poured into saturated NaHCO3 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 heptane / ethyl acetate 0-100% to give 3-bromo-7-(difluoromethoxy)imidazo[1,2-a]pyridine-8-carbonitrile (37 mg, 74%) as a light yellow solid. MS (ESI): m / z=290.0 [M+H] +

[0656] Precursor B31-III: 3-bromoimidazo[1,2-a]pyridine-8-carbonitrile

[0657] Commercially available CAS1383718-53-3

[0658] Precursor B32-I: 6-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole

[0659] Step 1: 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) was stirred at 70 ° C for 2 hours, then the reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layer was washed with water, 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 dichloromethane / methanol 0-10% to give 4-methylpyrrolidine-2-thione (390 mg, 63%) as an off-white solid. MS (ESI): m / z=116.0[M+H] +

[0660] 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 hours. 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 light yellow gum. MS (ESI): m / z=130.0 [M+H] +

[0661] 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 hours. 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] +

[0662] 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 NaHCO3 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 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] +

[0663] Precursor B33-I: 7-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole

[0664] 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 layer was washed with water, 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 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] +

[0665] 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 light yellow oil. MS (ESI): m / z=130.0 [M+H] +

[0666] Step 3: A solution of 3-methyl-2-(methylthio)-1-pyrroline (220 mg, 1.67 mmol) and 2,2-dimethoxyethylamine (210.37 mg, 218 uL, 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] +

[0667] 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 hours. The reaction mixture was quenched with saturated NaHCO3 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] +

[0668] Precursor B34-I: 6-bromopyrazolo[1,5-a]pyridine

[0669] Commercially available CAS1264193-11-4

[0670] Precursor B35-I: 6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine

[0671] 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 uL, 4.06 mmol), potassium carbonate (308 mg, 2.23 mmol) in water (0.7 mL) and PdCl2(dppf)-CH2Cl2 adduct (82 mg, 0.102 mmol) in 1,4-dioxane (6.5 mL) was heated at 90 °C. After 16 hours, the reaction was cooled to room temperature, ethyl acetate was added and the reaction mixture was filtered. All volatiles were removed under vacuum and the residue was purified by flash over silica gel using a gradient of heptane / ethyl acetate 0-60% to give 6-methylpyrazolo[1,5-a]pyridine (187 mg, 59%) as a light yellow oil. MS (ESI): m / z = 133.0 [M + H] +

[0672] 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 at 35 ° C under hydrogen. After complete conversion, the reaction mixture was filtered and washed with diethyl ether. The organic phase was diluted with diethyl ether and 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 obtain 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] +

[0673] Precursor B36-III: 3-bromo-6-methyl-pyrazolo[1,5-a]pyridine-7-carbonitrile

[0674] Step 1: To 6-bromo-3-methyl-picolinonitrile (2 g, 10.15 mmol) dissolved in N,N-dimethylformamide (20 mL) was added trimethylsilyl acetylene (1.2 g, 1.69 mL, 12.18 mmol), triphenylphosphine (532 mg, 2.03 mmol), bis(triphenylphosphine)palladium(II) dichloride (712 mg, 1.02 mmol), triethylamine (3.08 g, 4.24 mL, 30.45 mmol) and copper(I) iodide (386 mg, 2.03 mmol). The mixture was stirred at 80 °C. After 16 hours, the solvent was removed under reduced pressure and the crude material was purified by flash chromatography over silica gel 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] +

[0675] Step 2: 3-methyl-6-(2-trimethylsilylethynyl)pyridine carbonitrile (1.32 g, 6.16 mmol) was dissolved in dichloromethane (16 mL), and the resulting solution was cooled at 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. After completion, most of the solvent was removed under reduced pressure. Ether was added to the residue and a precipitate was formed. The solid was separated by filtration to provide the desired product (1.24 g). The mother liquor was distributed between water and diethyl ether. The layers were separated and the ether phase was washed twice with water. The combined water layer was dried on a freeze dryer to obtain additional product. MS (ESI): m / z=230.2[M+H] +

[0676] Step 3: A mixture of 1-amino-3-methyl-6-(2-trimethylsilylethynyl)pyridin-1-ium-2-carbonitrile .1:1 2,4,6-trimethylbenzenesulfonate (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 hours. The solvent was removed under reduced pressure and the residue was distributed 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, over silica gel, using a gradient of heptane / ethyl acetate 0-60% to give 6-methylpyrazolo[1,5-a]pyridine-7-carbonitrile (42 mg, 12%) as a light yellow solid. MS (ESI): m / z=158.1[M+H] +

[0677] 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, over silica gel, using a gradient of heptane / ethyl acetate 0-100% 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] +

[0678] Examples

[0679] Example 1: 7-bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide

[0680]

[0681] Pyridine (1 mL) was added 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). The reaction mixture was stirred at room temperature. After complete conversion, the reaction mixture was concentrated in vacuo. The crude material was purified by rapid, silica gel, using a gradient of heptane / ethyl acetate 0-60% 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] +

[0682] The following Examples 2 to 88 were prepared analogously to Example 1 by coupling the sulfonyl chloride intermediate B with the amine intermediate A as shown.

[0683]

[0684]

[0685]

[0686]

[0687]

[0688]

[0689]

[0690]

[0691]

[0692]

[0693]

[0694]

[0695]

[0696]

[0697] Example 93: N-[4-(Cyanomethyl)-5-fluoro-2-methoxy-phenyl]-7-cyclopropyl-imidazo[1,2-a]pyridine-3-sulfonamide

[0698]

[0699] 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), PdCl2(dppf)-CH2Cl2 (11 mg, 0.014 mmol) and cesium carbonate (133 mg, 0.410 mmol) in 1,4-dioxane (2.8 mL). The reaction mixture 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 chromatography on silica gel using a gradient of heptane / ethyl acetate 0-100% to afford 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]+

[0700] The following Examples 90 to 92 were prepared in analogy to Example 89 by Pd-mediated Suzuki cross-coupling reaction between bromo-imidazosulfonamide and cyclopropylboronic acid.

[0701]

[0702] Example 97: 7-Cyclopropyl-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridinyl]imidazo[1,2-a]pyrimidine-3-sulfonamide

[0703]

[0704] A solution of [5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridinyl]amine (30 mg, 0.144 mmol) in N,N-dimethylformamide (500 uL) 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 allowed to warm 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 chromatography on silica gel using a gradient of heptane / ethyl acetate 0-60% to give 7-cyclopropyl-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridinyl]imidazo[1,2-a]pyrimidine-3-sulfonamide (3.3 mg, 5%) as a light brown solid. MS (ESI): m / z = 430.1 [M+H]+

[0705] The following Examples 94 and 95 were prepared in analogy to Example 93 by coupling the sulfonyl chloride intermediate B with the amine intermediate A as shown.

[0706]

[0707] Example 100: N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-(oxetan-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide

[0708]

[0709] 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 34 W blue LED lamp (7 cm away) while the reaction temperature was maintained at 25 °C with 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 freeze-dried to give N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-(oxetane-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide (14 mg, 47%) as an orange solid. MS (ESI): m / z=458.8[M+H] +

[0710] Example 101: N-[4-(Cyanomethyl)-5-fluoro-2-methoxy-phenyl]-7-(oxetan-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide

[0711]

[0712] The corresponding volume of Ir[dF(CF3)ppy]2(dtbpy)(PF6) (255.41ug, 2.277E-04mmol) in dichloromethane stock solution was added to the reaction flask and the solvent was evaporated. Then, sodium carbonate (4.83mg, 0.046mmol), 7-bromo-N-[4-(cyanomethyl)-5-fluoro-2-methoxy-phenyl]imidazo[1,2-a]pyridine-3-sulfonamide (10mg, 0.023mmol), 3-bromooxetane (4.05mg, 2.46uL, 0.030mmol), tris(trimethylsilyl)silane (7.59mg, 9.41uL, 0.031mmol) and ethylene glycol dimethyl ether (0.367mL) were added. The reaction mixture was degassed by bubbling argon for 5 minutes. Subsequently, after sonication of the light green suspension, the corresponding volumes of 4,4"-di-tert-butyl-2,2"-bipyridyl (30.55 ug, 1.138E-04 mmol) and nickel(II) chloride ethylene glycol dimethyl (25.01 ug, 1.138E-04 mmol) stock solutions in dimethoxyethane were added. Finally, the mixture was degassed again by bubbling argon through for 10 minutes. The mixture was placed in a photoreactor and irradiated with 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 of 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] +

[0713] Example 102: N-[5-(2,2-difluoroethyl)-3-fluoro-6-methoxy-2-pyridinyl]-7-(oxetan-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide

[0714]

[0715] The corresponding volume of Ir[dF(CF3)ppy]2(dtbpy)(PF6) (771.67ug, 0.000688mmol) in dichloromethane stock solution was added to the reaction flask and the solvent was evaporated. Then, sodium carbonate (14.58mg, 0.138mmol), 7-bromo-N-[5-(2,2-difluoroethyl)-3-fluoro-6-methoxy-2-pyridyl]imidazo[1,2-a]pyridine-3-sulfonamide (32mg, 0.069mmol), 3-bromooxetane (12.25mg, 7.42uL, 0.089mmol), tris(trimethylsilyl)silane (22.92mg, 28.43uL, 0.092mmol) and ethylene glycol dimethyl ether (1.11mL) were added. The reaction mixture was degassed by bubbling argon for 5 minutes. Subsequently, after sonication of the light green suspension, the corresponding volumes of 4,4"-di-tert-butyl-2,2"-bipyridyl (92.3 ug, 3.439E-04 mmol) and nickel(II) chloride ethylene glycol dimethyl (75.56 ug, 3.439E-04 mmol) stock solutions in dimethoxyethane were added. Finally, the mixture was degassed again by bubbling argon through for 10 minutes. The mixture was placed in a photoreactor and irradiated with 450 nm for 15 minutes (stirring at 900 rpm, 100% LED power). LCMS showed product and debrominated byproducts. The mixture was filtered and evaporated. The residue was purified by flash chromatography using a gradient of heptane / ethyl acetate 0-100%, followed by C18 flash chromatography RediSepRf Gold column (C18, 5.5 g, acetonitrile in water 10% to 100%) to give N-[5-(2,2-difluoroethyl)-3-fluoro-6-methoxy-2-pyridinyl]-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] +

[0716] Example 103: N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-(oxetan-3-yl)imidazo[1,2-a]pyrimidine-3-sulfonamide

[0717]

[0718] The reaction was carried out on a 10 mg scale (4 times). In a vial, Ir[dF(CF3)ppy]2(dtbpy)(PF6) (902.68ug, 8.046E-04mmol), sodium carbonate (17.06mg, 0.161mmol), 7-bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]imidazo[1,2-a]pyrimidine-3-sulfonamide (38.8mg, 0.080mmol), 3-bromooxetane (14.33mg, 8.68uL, 0.105mmol) and tris(trimethylsilyl)silane (26.81mg, 33.26uL, 0.108mmol) were added. Ethylene glycol dimethyl ether (1.3mL) was added and the mixture was degassed for 5 minutes. Then, nickel(II) chloride ethylene glycol dimethyl ether complex (88.39ug, 4.023E-04mmol) and 4,4"-di-tert-butyl-2 2"-bipyridine (107.98ug, 4.023E-04mmol) (as a stock solution in dimethoxyethane) were added. The mixture was degassed again for 10 minutes. The reaction mixture was irradiated with 450nm for 15 hours in a photoreactor (100% LED power, 900rpm stirring). The reaction mixture was filtered and concentrated in vacuo. The orange residue was purified by flash chromatography using a gradient of heptane / ethyl acetate 0-100% to give N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-7-(oxetane-3-yl)imidazo[1,2-a]pyrimidine-3-sulfonamide (4 reactions combined: 4mg, 8%) as a yellow solid. MS (ESI): m / z = 460.2 [M + H] +

[0719] Example 104: N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-6-(oxetan-3-yl)pyrazolo[1,5-a]pyridine-3-sulfonamide

[0720]

[0721] In a vial, 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 uL, 0.374 mmol) and tris(trimethylsilyl)silane (62.32 mg, 77.31 uL, 0.251 mmol) were added. Ethylene glycol dimethyl ether (3.02 mL) was added and the mixture was degassed for 5 minutes. Then, nickel(II) chloride ethylene glycol dimethyl ether complex (205.46 ug, 9.351E-04 mmol) and 4,4"-di-tert-butyl-2,2"-bipyridyl (250.97 ug, 9.351E-04 mmol) (as stock solutions in dimethoxyethane) were added. The mixture was degassed again for 10 minutes. The reaction mixture was irradiated with 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 of heptane / ethyl acetate 0-100%, followed by preparative HPLC and SFC to give N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-6-(oxetan-3-yl)pyrazolo[1,5-a]pyridine-3-sulfonamide (4.3 mg, 4.5%) as a light yellow solid. MS (ESI): m / z=459.2[M+H] +

[0722] Example 105: 7-Bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyrimidine-3-sulfonamide

[0723]

[0724] 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) was added bromotrimethylsilane (329.94 mg, 284.44 uL, 2.16 mmol). 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 of heptane / ethyl acetate 0-100% to give 7-bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyrimidine-3-sulfonamide (38.8 mg, 56%) as an off-white solid. MS (ESI): m / z=484.1 [M+H] +

[0725] Example 106: N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-(1-hydroxy-1-methyl-ethyl)imidazo[1,2-a]pyridine-3-sulfonamide

[0726]

[0727] 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 solution (10 mg, 0.022 mmol) in tetrahydrofuran (100 uL) was cooled to 0 ° C. 3M methylmagnesium bromide / ether (37.47 mg, 36.2 uL, 0.109 mmol) was added dropwise. The reaction mixture was stirred at 0 ° C for 1 hour, 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 of heptane / ethyl acetate 0-100% to give N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-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] +

[0728] Example 107: N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide

[0729]

[0730] 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 uL) was added 1.3 M Turbo Grignard reagent (196.09 mg, 206.2 uL, 0.268 mmol) at 0°C. The reaction mixture was stirred at 0°C for 1 hour, and then oxetane-3-one (19.32 mg, 15.7 uL, 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-pyridinyl]-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] +

[0731] Example 108 and Example 109: (7R)-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-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-pyridinyl]-7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-sulfonamide

[0732]

[0733] Example 23 was chirally separated using SFC (column: Chiralpak IC-3 50×4.6 mm ID, 3 um mobile phase: phase A is CO2, and phase B is IPA (0.05% DEA); gradient elution: IPA (0.05% DEA) / CO2, 5% to 40%, flow rate: 3 mL / min; detector: PDA, column temperature: 35°C; back pressure: 100 Bar") (run time = 2.109) to give two enantiomers as off-white solids.

[0734] Example A

[0735] The compounds of formula I can be used in a manner known per se as active ingredients for the production of tablets of the following composition:

[0736]

[0737] Example B

[0738] The compounds of formula I can be used in a manner known per se as active ingredient for the production of capsules of the following composition:

[0739]

Claims

1. A compound of formula I, in, R 1 is alkyl, cyano, cyanoalkyl, cyclopropyl, halo, haloalkoxy, haloalkyl or oxetanyl; R 2 is alkoxy, H or halo; X1 is N, X2 is CR 12 , and X 3 CR 13 ,or X1 for CR 11 , X2 is CR 12 , and X3 is CR 13 ,or X1 for CR 11 , X2 is N, and X3 is N or CR 13 ; R 11 is alkoxy, H or halo; R 12 is H or halogenated; R 13 is alkoxy, H, halo or haloalkoxy; W is selected from the ring systems A, B, C, D or E 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 CR 8a or O and Y 2b CR 8b or O, where Y 2a and Y 2b Only one of can be O; n is 0 or 1; R 7a and R 7b independently selected from H, alkyl, alkoxy or haloalkyl; R 8a and R 8b Independently selected from H or alkyl; Y3 is O or CH2; R 9a and R 9b independently selected from H, alkyl, alkoxy or haloalkyl; Y4 is NR 10 ; R 10 is an alkyl group or a halogenated alkyl group; and pharmaceutically acceptable salts thereof.

2. The compound according to claim 1, wherein Y 2a is CH2 and Y 2b CR 8b or O, where R 8b is H or alkyl.

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

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

5. A compound according to any one of claims 1 to 4, wherein R 2 is alkoxy or halogenated.

6. A compound according to any one of claims 1 to 5, wherein R 11 is alkoxy or H.

7. A compound according to any one of claims 1 to 6, wherein R 12 For H.

8. A compound according to any one of claims 1 to 7, wherein R 13 It is an alkoxy group.

9. The compound according to any one of claims 1 to 8, wherein W is selected from ring systems A, B or C.

10. A compound according to any one of claims 1 to 9, wherein R 3 is alkoxy, alkyl, cyclopropyl, halo, haloalkoxy, haloalkyl, hydroxyalkyl or oxetanyl.

11. A compound according to any one of claims 1 to 10, wherein R 4 is alkoxy, cyano, H or halo.

12. A compound according to any one of claims 1 to 11, wherein R 5 is halogenated and R 6 For H.

13. A compound according to any one of claims 1 to 12, wherein when R 7a , R 7b , R 8a and R 8b When both are H, then X1 is N and n is 1.

14. The compound according to claim 1, wherein R 1 is alkyl, cyano, cyanoalkyl, cyclopropyl, halo, haloalkoxy, haloalkyl or oxetanyl; R 2 is alkoxy, H or halo; X1 is N, X2 is CR 12 , and X 3 CR 13 ,or X1 for CR 11 , X2 is CR 12 , and X3 is CR 13 ,or X1 for CR 11 , X2 is N, and X3 is N or CR 13 ; R 11 is alkoxy, H or halo; R 12 is H or halogenated; R 13 is alkoxy, H, halo or haloalkoxy; W is selected from the ring systems A, B, C, D or E 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 CR 8b or O, where R 8b is H or alkyl; n is 0 or 1; R 7a and R 7b 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 ; R 10 is an alkyl group; When R 7a , R 7b , R 8a and R 8b When both are H, then X1 is N and n is 1; and pharmaceutically acceptable salts thereof.

15. The compound according to claim 1, wherein R 1 is alkyl, cyanoalkyl, cyclopropyl, halo, haloalkoxy or haloalkyl; R 2 is alkoxy or halogenated; X1 is N, X2 is CR 12 , and X 3 CR 13 ,or X1 for CR 11 , X2 is CR 12 , and X3 is CR 13 ,or X1 for CR 11 , X2 is N, and X3 is N or CR 13 ; R 11 is alkoxy or H; R 12 is H; R 13 is alkoxy, halo or haloalkoxy; W is selected from ring system A, B or C 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 halogenated; R 6 is H; Y 2a is CH2 and Y 2b CR 8b or O, where R 8b is H or alkyl; n is 1; R 7a and R 7b independently selected from H, alkyl or haloalkyl; When R 7a , R 7b , R 8a and R 8b When both are H, then X1 is N and n is 1; and pharmaceutically acceptable salts thereof.

16. A compound according to any one of claims 1 to 15, selected from 7-Bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-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-pyridinyl]-8-methoxy-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-(difluoromethoxy)imidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-8-fluoro-imidazo[1,2-a]pyridine-3-sulfonamide; 7-bromo-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-[6-(3,3-difluoropropyl)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Bromo-N-[5-(2,2-difluoroethyl)-3-fluoro-6-methoxy-2-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethyl)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-8-methoxy-imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-(difluoromethyl)imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-methoxy-imidazo[1,2-a]pyridine-3-sulfonamide; 7-cyclopropyl-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-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-pyridinyl]-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-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-[6-(cyanomethyl)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-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-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-(6-cyclopropyl-5-fluoro-2-methoxy-3-pyridinyl)imidazo[1,2-a]pyridine-3-sulfonamide; 7-bromo-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide; 8-cyano-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide; 7-cyclopropyl-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-methoxy-imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7,8-dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-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-pyridinyl]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-pyridinyl]-7-methoxy-imidazo[1,2-a]pyridine-3-sulfonamide; 7-cyclopropyl-N-[5-(2,2-difluoroethyl)-3-fluoro-6-methoxy-2-pyridinyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-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-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-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-pyridinyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; 8-cyano-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-(5-cyclopropyl-3-fluoro-6-methoxy-2-pyridinyl)imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-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-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-methyl-imidazo[1,2-a]pyrimidine-3-sulfonamide; 7-cyclopropyl-N-[5-(2,2-difluoroethoxy)-3-fluoro-6-methoxy-2-pyridinyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-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-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-8-cyano-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-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-pyridinyl]-8-keto-7-methyl-imidazo[1,2-a]pyrazine-3-sulfonamide; 7-cyano-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide; 8-cyano-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-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-pyridinyl]-7-methoxy-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-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-pyridinyl]-7-(difluoromethoxy)imidazo[1,2-a]pyridine-3-sulfonamide; N-[2,6-bis(difluoromethoxy)-5-fluoro-3-pyridinyl]-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-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-[5-fluoro-2-methoxy-6-(oxetan-3-yl)-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-8-methyl-imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-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-pyridinyl]-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-pyridinyl]pyrazolo[1,5-a]pyridine-3-sulfonamide; 6-Bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]pyrazolo[1,5-a]pyridine-3-sulfonamide; 6-Bromo-N-[5-(cyanomethyl)-3-fluoro-6-methoxy-2-pyridinyl]pyrazolo[1,5-a]pyridine-3-sulfonamide; 6-Bromo-N-[3-fluoro-5-(2-fluoroethoxy)-6-methoxy-2-pyridinyl]pyrazolo[1,5-a]pyridine-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethoxy)-3-fluoro-6-methoxy-2-pyridinyl]pyrazolo[1,5-a]pyridine-3-sulfonamide; 6-Bromo-N-(6-cyclopropyl-5-fluoro-2-methoxy-3-pyridinyl)pyrazolo[1,5-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-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-pyridinyl]-6-methyl-pyrazolo[1,5-a]pyridine-3-sulfonamide; 6-Bromo-N-[4-(difluoromethoxy)-2,5-difluoro-phenyl]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-pyridinyl]pyrazolo[1,5-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-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-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-cyclopropyl-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[5-(Cyanomethyl)-3-fluoro-6-methoxy-2-pyridinyl]-7-cyclopropyl-imidazo[1,2-a]pyridine-3-sulfonamide; 7-cyclopropyl-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridinyl]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-pyridinyl]pyrazolo[1,5-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-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-pyridinyl]-7-(oxetan-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-(oxetan-3-yl)imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-6-(oxetan-3-yl)pyrazolo[1,5-a]pyridine-3-sulfonamide; 7-Bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-(1-hydroxy-1-methyl-ethyl)imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-(3-hydroxyoxetan-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide; and pharmaceutically acceptable salts thereof.

17. A compound according to any one of claims 1 to 16, selected from 7-Bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-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-pyridinyl]-8-methoxy-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-(difluoromethoxy)imidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-8-fluoro-imidazo[1,2-a]pyridine-3-sulfonamide; 7-bromo-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-[6-(3,3-difluoropropyl)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Bromo-N-[5-(2,2-difluoroethyl)-3-fluoro-6-methoxy-2-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethyl)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-8-methoxy-imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-(difluoromethyl)imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-methoxy-imidazo[1,2-a]pyridine-3-sulfonamide; 7-cyclopropyl-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-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-pyridinyl]-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-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-[6-(cyanomethyl)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-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-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-(6-cyclopropyl-5-fluoro-2-methoxy-3-pyridinyl)imidazo[1,2-a]pyridine-3-sulfonamide; 7-bromo-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide; 8-cyano-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide; 7-cyclopropyl-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-methoxy-imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7,8-dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-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-pyridinyl]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-pyridinyl]-7-methoxy-imidazo[1,2-a]pyridine-3-sulfonamide; 7-cyclopropyl-N-[5-(2,2-difluoroethyl)-3-fluoro-6-methoxy-2-pyridinyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-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-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-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-pyridinyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; 8-cyano-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-methyl-imidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-N-(5-cyclopropyl-3-fluoro-6-methoxy-2-pyridinyl)imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-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-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-methyl-imidazo[1,2-a]pyrimidine-3-sulfonamide; 7-cyclopropyl-N-[5-(2,2-difluoroethoxy)-3-fluoro-6-methoxy-2-pyridinyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-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-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-Chloro-8-cyano-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-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-pyridinyl)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-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide; 7-cyclopropyl-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyridine-3-sulfonamide; N-[5-(Cyanomethyl)-3-fluoro-6-methoxy-2-pyridinyl]-7-cyclopropyl-imidazo[1,2-a]pyridine-3-sulfonamide; 7-cyclopropyl-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridinyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; 6-Bromo-N-[5-(difluoromethoxy)-3-fluoro-6-methoxy-2-pyridinyl]pyrazolo[1,5-a]pyridine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-(oxetan-3-yl)imidazo[1,2-a]pyridine-3-sulfonamide; 7-Bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]imidazo[1,2-a]pyrimidine-3-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridinyl]-7-(1-hydroxy-1-methyl-ethyl)imidazo[1,2-a]pyridine-3-sulfonamide; and pharmaceutically acceptable salts thereof.

18. A process for preparing a compound according to any one of claims 1 to 17, comprising 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, Where R 1 , R 2 , X1, X2, X3 and W are as described above.

19. Compounds according to any one of claims 1 to 17 for use as therapeutically active substances.

20. A compound according to any one of claims 1 to 17 for use in the treatment of a disease modulated by GPR17.

21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17 and a therapeutically inert carrier.

22. Use of a compound according to any one of claims 1 to 17 for the treatment or prevention of conditions caused by direct damage to the myelin sheath (including but not limited to central and extrapontine myelinolysis, carbon monoxide poisoning, nutritional deficiencies and virally induced demyelination), demyelinating diseases (including but not limited to multiple sclerosis, acute and multiphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorders and leukodystrophy), CNS diseases associated with myelin loss (including but not limited to Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and ischemia caused by stroke) and inflammation in the CNS such as encephalitis, primary vasculitis, meningitis and inflammation in the CNS following obesity.

23. Use of a compound according to any one of claims 1 to 17 for the treatment or prevention of multiple sclerosis.

24. The use of a compound according to any one of claims 1 to 17 for the preparation of a medicament for the treatment or prevention of a condition caused by direct damage to the myelin sheath (including but not limited to central and extrapontine myelinolysis, carbon monoxide poisoning, nutritional deficiencies, and virally induced demyelination), demyelinating diseases (including but not limited to multiple sclerosis, acute and multiphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorders, and leukodystrophy), CNS diseases associated with myelin loss (including but not limited to ischemia caused by Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and stroke), and inflammation in the CNS such as inflammation in the CNS following encephalitis, primary vasculitis, meningitis, and obesity.

25. A compound according to any one of claims 1 to 17 for use in the treatment or prevention of conditions caused by direct damage to the myelin sheath (including but not limited to central and extrapontine myelinolysis, carbon monoxide poisoning, nutritional deficiencies and virally induced demyelination), demyelinating diseases (including but not limited to multiple sclerosis, acute and multiphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorders and leukodystrophy), CNS diseases associated with myelin loss (including but not limited to Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and ischemia caused by stroke) and inflammation in the CNS such as encephalitis, primary vasculitis, meningitis and inflammation in the CNS following obesity.

26. A compound according to any one of claims 1 to 17 for use in the treatment or prevention of multiple sclerosis.

27. A method for treating or preventing conditions caused by direct damage to the myelin sheath (including but not limited to central and extrapontine myelinolysis, carbon monoxide poisoning, nutritional deficiencies and virally induced demyelination), demyelinating diseases (including but not limited to multiple sclerosis, acute and multiphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorders and leukodystrophy), CNS diseases associated with myelin loss (including but not limited to Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and ischemia caused by stroke), and inflammation in the CNS such as encephalitis, primary vasculitis, meningitis and inflammation in the CNS following obesity, the method comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 17.

28. A method for treating or preventing multiple sclerosis, the method comprising administering an effective amount of a compound according to any one of claims 1 to 17 to a patient in need thereof.

29. The compound according to any one of claims 1 to 17, which is manufactured according to the method of claim 18.

30. The invention as hereinbefore described.

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