Novel pyrimidin-2-yl sulfonamide derivatives and compositions containing the same, manufacturing process therefor and use thereof

Abstract

This invention relates to novel compounds having general formula I. R1, R2, R3, R4, X1, and X2 are as described herein, and the present invention also relates to compositions including such compounds and methods of using such compounds.

Description

Technical field

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

[0002] The present invention provides novel formula I compound I wherein R is H, halo, alkyl, alkoxy, alkoxyalkyl, alkoxyalkoxy, cyanoalkyl, haloalkyl, haloalkoxy group, thiolalkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxy or heterocycloalkyl; R2 is cyano, halo, alkyl, alkenyl, alkynyl, alkoxy, alkenyl ylalkyl, alkynylalkoxy, alkoxyalkyl, alkoxyalkoxy, haloalkyl, haloalkoxy, haloalkoxyalkyl, (haloalkoxy)alkoxy, cyanoalkyl, Cyanoalkoxy, Thiolalkyl, Halothiolalkyl, Halohydroxyalkoxy, Alkylsulfonylalkyl, Cycloalkyl, Cycloalkylalkyl, Cycloalkylalkoxy radical, cycloalkoxy, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkynyl or heterocycloalkylalkoxy; R3 is H, halo, alkyl, alkoxy, haloalkoxy or thiol alkyl; X1 is CR5 or N; X2 is NH, -N-R6, S, -S(O)- or -S(O2)-; R4 is H, halo, alkyl, hydroxyl Alkyl, thiolalkyl, cyanoalkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl or heterocycloalkyl; R5 is H, halo, cyano, alkyl, alkoxy , cyanoalkyl, cyanoalkoxy, N-alkyl, dialkylamino, haloalkyl, haloalkoxy, halothiolalkyl, alkylsulfinyl, alkylsulfonyl , alkyl 碸, thiol alkyl, hydroxyalkyl, alkoxycarbonyl, heterocycloalkyl, cycloalkyl or cycloalkoxy; or R4 and R5 are connected to form 5- or 6-membered cycloalkyl, hetero Cycloalkyl, substituted heterocycloalkyl or heteroaryl ring containing one or two substituents independently selected from alkyl and pendant oxy; R6 is H, alkyl, alkylhydroxyl or haloalkyl; and pharmaceutically acceptable salts.

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

Prior Technology

[0004] Myelination is a process that occurs strongly during development, and despite the presence of large numbers of oligodendritic glial precursor cells (OPCs) throughout the adult CNS, in chronic demyelination diseases, myelination The transformation of sheath oligodendritic glial cells and the production of restorative myelin around denuded axons are impaired. During development, myelination proceeds in a very orderly fashion, with OPCs characterized by markers such as neural / glial antigen 2 (NG2) and platelet-derived growth factor alpha (PDGFRα) differentiate into oligodendrites Glial cells that lose expression of NG2 and PDGFRα and gain 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 that are well known in the peripheral but not in the central nervous system (Macklin, W.B. (2010). Sci. Signal.3, pe32–pe32, "The myelin brake: When Enough Is Enough"). Myelination can also be controlled by internal brakes within oligodendrocytes themselves, by the transcription factor EB (TFEB)-PUMA axis, or by GPR17 antagonism (Chen, Y., et al. (2009) . Nat Neurosci 12, 1398–1406, “The oligodendrocyte-specific G protein-coupled receptor GPR17 is a cell-intrinsic timer of myelination”) (Sun, L.O., et al. (2018). Cell 175, 1811-1826.e21, "Spatiotemporal Control of CNS Myelination by Oligodendrocyte Programmed Cell Death through the TFEB-PUMA Axis"). Myelin not only serves to protect axons and facilitate neuronal transmission, but oligodendrocytes have also been shown to play an important role in axonal metabolism as well as 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").

[0005] GPR17 is a class A orphan G protein-coupled receptor (GPCR). GPCRs are seven-domain transmembrane proteins that transmit extracellular signals through intracellular signaling through their intracellular association with small heterotrimeric G protein complexes composed of Gα, Gβ, Gϒ subunits. Ligand coupling. It is the coupling of GPCRs to the Gα subunit that leads to downstream intracellular signaling pathways. GPR17 is known to directly couple Gαi / o, thereby inhibiting adenylate cyclase activity, resulting in decreased cyclic AMP production (cAMP). GPR17 was also shown to couple to Gq / 11 targeting phospholipase C. Activation of phospholipase C results in the cleavage of phosphatidylinositol 4,5-bisphosphate, yielding inositol triphosphate (IP3) and diacylglycerol (DAG). Thus, IP3 binds to the IP3 receptor on the endoplasmic reticulum and leads to an increase in intracellular calcium levels (Hanlon, C.D., and Andrew, D.J. (2015). J Cell Sci. 128, 3533-3542, "Outside-in signaling-a brief review of GPCR signaling with a focus on the Drosophila GPCR family”) (Inoue, A., et al. (2019), Cell 177, 1933-1947.e25, “Illuminating G-Protein-Coupling Selectivity of GPCRs”).

[0006] The role of GPR17 in myelination was first determined in an optic nerve screen in Olig1 knockout mice to identify genes that regulate myelination. GPR17 was found to be expressed only in myelinating cells of the CNS, but not in Schwann cells, the myelinating cells of the peripheral nervous system. Expression of GPR17 was found only in oligodendrocyte lineage cells and downregulated in myelinating oligodendrocytes (Chen, Y., et al. (2009)). Specifically, GPR17 was found to be present at low levels in early OPCs and increased 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 vivocell maturation and participation in acute trauma and chronic damage") (Dziedzic, A., et al. (2020). Int. J. Mol. Sci. 21, 1852, "The gpr17 receptor—a promising goal for therapy and a potential marker of the neurodegenerative process in multiple sclerosis") (Fumagalli, M. et al. (2011) , J Biol Chem 286, 10593–10604, "Phenotypic changes, signaling pathway, and functional correlates of GPR17-expressing neural precursor cells during oligodendrocyte differentiation"). GPR17 knockout animals were shown to exhibit premature myelination throughout the CNS, and conversely, in CNP-Cre (2', 3'-cyclic-nucleotide 3'-phosphodiesterase) promoter-less Transgenic mice overexpressing GPR17 in dendritic glial cells exhibit defects in myelination, consistent with expectations for a cell-intrinsic brake on the myelination process (Chen, Y., et al. (2009)). Furthermore, loss of GPR17 enhanced remyelination after lysophosphatidylcholine-induced demyelination (Lu, C., Dong, et al. (2018), Sci. Rep.8, 4502, "G-Protein- Coupled Receptor Gpr17 Regulates Oligodendrocyte Differentiation in Response to Lysolecithin-Induced Demyelination"). Thus, antagonism of GPR17, which promotes the differentiation of oligodendrocyte lineage cells into mature myelinating oligodendrocytes, would result in increased myelination following demyelination.

[0007] Multiple sclerosis (MS) is a chronic neurodegenerative disease characterized by the loss of myelin, the protective fatty lipid layer around axons, in the central nervous system (CNS). Prevention of myelination loss or remyelination of bare axons is thought to prevent axonal degeneration and thus disease progression (Franklin, R.J. (2002), Nat Rev Neurosci 3, 705–714, "Why does remyelination fail in multiple sclerosis? "). Due to the restorative effects of myelin repair on the central nervous system, this treatment would benefit all types of MS, namely relapsing remitting, secondary progressive, first progressive and progressive relapsing MS. Due to the neuroprotective effect of preserving axons, repairing the lost myelin sheath will reduce the neurological symptoms associated with MS.

[0008] Since myelination plays an important role in the function of the nervous system, promoting the differentiation of OPCs into oligodendroglial cells has the potential to affect a variety of diseases in which, due to the disease itself or inflammation, White matter defects / irregularities resulting from loss of oligodendrocytes or from blocked differentiation of OPCs into oligodendrocytes. This is in addition to disorders in which GPR17 expression itself is altered.

[0009] Diseases in which GPR17 antagonism can therefore be used to produce positive disease outcomes include, but are not limited to: Direct damage to myelin: - Metabolic conditions leading to central myelin destruction, such as central pontine myelolysis, hyponatremia due to too rapid correction Extrapontine myelolysis due to diseases such as but not limited to alcoholism, liver disease, post-transplant immunosuppression - carbon monoxide intoxication with oligodendritic glia dysfunction and regenerative failure reported in the deep white matter of the brain - leads to myeloid Loss of sheaths or nutritional deficiencies in which myelin is not produced correctly during development - Virus-induced demyelination Primary demyelination disorders - Multiple sclerosis (relapsing remitting, secondary progressive, first progressive, and progressive Relapsing MS) - Acute and multistage disseminated encephalomyelitis - Panneuromyelitis optica conditions including optic neuritis - Transverse myelitis - Leukodystrophy such as adrenoleukodystrophy, adrenomyeloneuropathy and others Hereditary leukodystrophy causing myelin loss CNS disorders with myelin loss: - Alzheimer's disease - Schizophrenia - Parkinson's disease - Huntington's disease Huntington's disease - amyotrophic lateralis - stroke-induced ischemia

[0010] Compounds of Formula I bind to and modulate GPR17 activity.

[0011] Accordingly, the compounds of formula I are particularly useful in the treatment of diseases associated with GPR17 antagonism. Compounds of formula I are particularly useful in the treatment or prevention of multiple sclerosis (MS), disorders associated with direct damage to the myelin sheath such as carbon monoxide poisoning or virus-induced demyelination, primary demyelination disorders such as Acute and multistage disseminated encephalomyelitis, and other central nervous system disorders associated with loss of myelin, such as Alzheimer's disease, schizophrenia, Parkinson's disease, and Huntington's disease.

Content of invention

[0013] The present invention provides novel formula I compound I wherein R is H, halo, alkyl, alkoxy, alkoxyalkyl, alkoxyalkoxy, cyanoalkyl, haloalkyl, haloalkoxy group, thiolalkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxy or heterocycloalkyl; R2 is cyano, halo, alkyl, alkenyl, alkynyl, alkoxy, alkenyl ylalkyl, alkynylalkoxy, alkoxyalkyl, alkoxyalkoxy, haloalkyl, haloalkoxy, haloalkoxyalkyl, (haloalkoxy)alkoxy, cyanoalkyl, Cyanoalkoxy, Thiolalkyl, Halothiolalkyl, Halohydroxyalkoxy, Alkylsulfonylalkyl, Cycloalkyl, Cycloalkylalkyl, Cycloalkylalkoxy radical, cycloalkoxy, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkynyl or heterocycloalkylalkoxy; R3 is H, halo, alkyl, alkoxy, haloalkoxy or thiol alkyl; X1 is CR5 or N; X2 is NH, -N-R6, S, -S(O)- or -S(O2)-; R4 is H, halo, alkyl, hydroxyl Alkyl, thiolalkyl, cyanoalkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl or heterocycloalkyl; R5 is H, halo, cyano, alkyl, alkoxy , cyanoalkyl, cyanoalkoxy, N-alkyl, dialkylamino, haloalkyl, haloalkoxy, halothiolalkyl, alkylsulfinyl, alkylsulfonyl , alkyl 碸, thiol alkyl, hydroxyalkyl, alkoxycarbonyl, heterocycloalkyl, cycloalkyl or cycloalkoxy; or R4 and R5 are connected to form 5- or 6-membered cycloalkyl, hetero Cycloalkyl, substituted heterocycloalkyl or heteroaryl ring containing one or two substituents independently selected from alkyl and pendant oxy; R6 is H, alkyl, alkylhydroxyl or haloalkyl; and pharmaceutically acceptable salts.

Implementation

[0014] The term "alkyl" means a monovalent straight or branched chain saturated hydrocarbon group of 1 to 6 carbon atoms. In some embodiments, if not stated otherwise, alkyl comprises 1 to 6 carbon atoms (C1-6-alkyl) or 1 to 4 carbon atoms (C1-4-alkyl). Examples of C1-6-alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl and pentyl. Particular alkyl groups include methyl, ethyl and propyl. When naming an alkyl residue having a certain number of carbon atoms, all geometric isomers with that number of carbon atoms are contemplated. Thus, for example, "butyl" may include n-butyl, di-butyl, isobutyl, and tert-butyl, and "propyl" may include n-propyl and isopropyl.

[0015] The term "alkoxy" means a group of formula -O-R', wherein R' is a C1-6-alkyl group. Examples of C1-6-alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Specific examples are methoxy and ethoxy.

[0016] The term "alkoxyalkyl" means an alkyl group in which at least one of the hydrogen atoms of the alkyl group has been replaced by an alkoxy group. Exemplary alkoxyalkyl groups include methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, methoxypropyl, and ethoxypropyl. Particular alkoxyalkyl groups include methoxymethyl and methoxyethyl.

[0017] The term "alkoxyalkoxy" refers to an alkoxy group in which at least one of the hydrogen atoms of the alkoxy group has been replaced by another alkoxy group. Examples of alkoxyalkoxy groups include methoxymethoxy, ethoxymethoxy, methoxyethoxy, ethoxyethoxy, methoxypropoxy, and ethoxypropoxy. Oxygen. A particular alkoxyalkoxy group is methoxyethoxy.

[0018] The term "alkoxycarbonyl" means a moiety of formula -C(O)-R', wherein R' is alkyl as defined herein. A specific example is methoxycarbonyl.

[0019] The term "alkenyl" refers to an unsaturated straight or branched monovalent hydrocarbon chain having at least one site of carbon-carbon double bond unsaturation (ie, having at least one moiety of formula C=C). In some embodiments, unless otherwise specified, alkenyl groups contain 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl. A particular alkenyl group is allyl.

[0020] The term "alkenylalkyl" means an alkyl group wherein at least one of the hydrogen atoms of the alkyl group is replaced by an alkenyl group.

[0021] The term "alkynyl" refers to an unsaturated straight or branched monovalent hydrocarbon chain having at least one site of acetylene unsaturation (ie, having at least one moiety of formula C≡C). In some embodiments, unless otherwise specified, the alkynyl group contains 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (or acetylenyl), prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl , but-2-ynyl and but-3-ynyl. A specific example is prop-1-ynyl.

[0022] The term "alkynylalkyl" means an alkyl group wherein at least one of the hydrogen atoms of the alkyl group is replaced by an alkynyl group.

[0023] The term "alkynylalkoxy" means an alkoxy group in which at least one of the hydrogen atoms of an alkyl group is replaced by an alkynyl group. A specific example is but-2-ynyloxy.

[0024] The term "alkylsulfonyl" or "alkylsulfonyl" means a straight-chain or branched lower alkylsulfonium having 1 to 4 carbon atoms, meaning a group of structure S(O)2 alkyl , wherein the alkyl moiety is a linear or branched alkyl group having 1 to 4 carbon atoms, and may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl. A specific example is methylsulfonyl.

[0025] The term "alkylsulfonylalkyl" means an alkyl group wherein at least one of the hydrogen atoms of the alkyl group is replaced by an alkylsulfonyl group. A specific example of alkylsulfonylalkyl is methylsulfonylethyl.

[0026] The term "alkylsulfinyl" means a group of formula -S(O)-R', wherein R' is an alkyl group. Examples of alkylsulfinyl groups include groups of the formula -S(O)-R', where R' is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or Tertiary butyl. Particular alkylsulfinyl groups include those of the formula -S(O)-R', where R' is methyl. A specific example of the alkylsulfinyl group is methylsulfinyl group.

[0027] The term "amino" means a -NH2 group.

[0028] The term "dialkylamino" refers to an amine group in which two hydrogen atoms of the amine group are replaced by two alkyl groups. A specific example is a dimethylamine group.

[0029] The term "cycloalkyl" means a monocyclic or polycyclic saturated or partially unsaturated non-aromatic hydrocarbon. In some embodiments, unless otherwise stated, the cycloalkyl group contains 3 to 8 carbon atoms, 3 to 6 carbon atoms, or 3 to 5 carbon atoms. In some embodiments, cycloalkyl is a saturated monocyclic or polycyclic hydrocarbon. In other embodiments, the cycloalkyl contains one or more double bonds (eg, a cycloalkyl fused to an aryl or heteroaryl ring or a monocyclic non-aromatic hydrocarbon containing one or two double bonds). Polycyclic cycloalkyl groups may include spiro, fused or bridged polycyclic moieties wherein each ring is a saturated or partially unsaturated non-aromatic hydrocarbon. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, octahydropentenyl, spiro[3.3]heptyl, and the like. Bicyclic means a ring system consisting of two saturated carbocyclic rings having two carbon atoms in common. Examples of monocyclic cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. A specific example is cyclopropyl.

[0030] The term "cycloalkylalkyl" means an alkyl group wherein at least one of the hydrogen atoms of the alkyl group is replaced by a cycloalkyl group. Examples of cycloalkylalkyl include cyclopropylmethyl.

[0031] The term "cycloalkoxy" means a group of formula -O-R', wherein R' is a cycloalkyl group. Examples of cycloalkoxy groups include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy. A particular cycloalkoxy group is cyclopropoxy.

[0032] The term "cycloalkylalkoxy" denotes an alkoxy group wherein at least one of the hydrogen atoms of the alkoxy group is replaced by a cycloalkyl group. Examples of cycloalkylalkoxy include cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, cycloheptylmethoxy and cyclooctylmethoxy.

[0033] The term "cyano" means a -C≡N group.

[0034] "Cyanoalkyl" means a moiety of formula -R'-R", wherein R' is alkyl as defined herein and R" is cyano or nitrile. Specific examples are cyanomethyl and cyanoethyl.

[0035] "Cyanoalkoxy" means a C1-6-alkoxy group, wherein at least one of the hydrogen atoms of the C1-6-alkoxy group has been replaced by a cyano group. A specific example is cyanomethoxy.

[0036] The terms "halogen," "halide," and "halo" are used interchangeably herein and mean fluorine, chlorine, bromine, or iodine. Particular halogens are fluorine, chlorine and bromine.

[0037] The term "haloalkyl" denotes a C1-6-alkyl group wherein at least one of the hydrogen atoms of the C1-6-alkyl group has been replaced by the same or a different halogen atom. Specific examples are fluoroethyl, fluoropropyl and difluoromethyl, difluoroethyl, difluoropropyl, trifluoromethyl, trifluoroethyl, trifluoropropyl and tetrafluoropropyl,

[0038] The term "haloalkoxy" denotes a C1-6-alkoxy group wherein at least one of the hydrogen atoms of the C1-6-alkoxy group has been replaced by the same or a different halogen atom. Specific examples are fluoromethoxy, fluoroethoxy, fluoropropoxy, difluoromethoxy, difluoroethoxy, difluoropropoxy, trifluoromethoxy, trifluoroethoxy, trifluoro Propoxy and tetrafluoroethoxy.

[0039] The term "haloalkoxyalkyl" means an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a haloalkoxy group. Examples of haloalkoxyalkyl include fluoromethoxymethyl, difluoromethoxymethyl, trifluoromethoxymethyl, fluoroethoxymethyl, difluoroethoxymethyl, trifluoroethoxy methyl, fluoromethoxyethyl, difluoromethoxyethyl, trifluoromethoxyethyl, fluoroethoxyethyl, difluoroethoxyethyl, trifluoroethoxyethyl, Fluoromethoxypropyl, difluoromethoxypropyl, trifluoromethoxypropyl, fluoroethoxypropyl, difluoroethoxypropyl and trifluoroethoxypropyl.

[0040] The term "haloalkoxyalkoxy" means an alkoxy group in which at least one of the hydrogen atoms of the alkoxy group has been replaced by a haloalkoxy group. Examples of haloalkoxyalkyl include fluoromethoxymethoxy, difluoromethoxymethoxy, trifluoromethoxymethoxy, fluoroethoxymethoxy, difluoroethoxymethoxy , trifluoroethoxymethoxy, fluoromethoxyethoxy, difluoromethoxyethoxy, trifluoromethoxyethoxy, fluoroethoxyethoxy, difluoroethoxyethyl Oxygen, trifluoroethoxyethoxy, fluoromethoxypropoxy, difluoromethoxypropoxy, trifluoromethoxypropoxy, fluoroethoxypropoxy, difluoroethoxy oxypropoxy and trifluoroethoxypropoxy. A specific example is difluoromethoxyethoxy.

[0041] The term "halohydroxyalkoxy" denotes an alkoxy group wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by the same or a different halogen atom, and one of the alkoxy groups At least one of the hydrogen atoms has been replaced by a hydroxyl group. A specific example is 1,1-difluoro-2-hydroxy-ethoxy.

[0042] The term "heterocycloalkyl" denotes a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of 4 to 9 ring atoms comprising 1, 2 or 3 ring heteroatoms selected from N, O and S , while the remaining ring atoms are carbon. Bicyclic means comprising two rings having two ring atoms in common, ie the bridge separating the two rings is a single bond or a chain of one or two ring atoms. Examples of monocyclic saturated heterocycloalkyl groups are oxetanyl, tetrahydroaziryl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazole Pyridyl, piperidyl, tetrahydropyranyl, tetrahydrothiopyranyl, or piperyl. Examples of partially unsaturated heterocycloalkyl are dihydrofuryl, imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridyl or dihydropyranyl. Specific examples of heterocycloalkyl groups are oxetane, "aper" linyl, tetrahydrofuranyl and tetrahydropyranyl.

[0043] The term "heterocycloalkoxy" means a group of formula —O—R', wherein R' is a heterocycloalkyl group. Examples of heterocycloalkoxy groups include tetrahydropyranyloxy, tetrahydrofuranyloxy and oxetanyloxy.

[0044] The term "heterocycloalkylalkoxy" refers to an alkoxy group wherein at least one of the hydrogen atoms of the alkoxy group is replaced by a heterocycloalkyl group. Examples of heterocycloalkylalkoxy groups include tetrahydropyranylmethoxy, tetrahydrofurylmethoxy, oxetanylmethoxy, tetrahydropyranylethoxy, tetrahydrofurylethoxy, and oxo Cyclobutanylethoxy. A specific example of heterocycloalkylalkoxy is oxetanylmethoxy.

[0045] "Heterocycloalkylalkyl" means a heterocycloalkyl moiety as defined above linked via an alkyl moiety (as defined above) to a parent core. Non-limiting examples of suitable heterocycloalkylalkyl groups include piperidinylmethyl, piperidinylmethyl and oxetanylmethyl. A specific example of heterocycloalkylalkyl is oxetanylethyl.

[0046] "Heterocycloalkylalkynyl" means a heterocycloalkyl moiety as defined above linked via an alkynyl moiety (as defined above) to a parent core. A specific example of heterocycloalkylalkynyl is oxetanylethynyl.

[0047] "Heteroaromatic ring" as used herein refers to a monocyclic or polycyclic group comprising at least one aromatic ring, wherein the aromatic ring comprises at least one ring heteroatom. In some embodiments, the heteroatoms are independently selected from the group consisting of N, O, and S. Unless otherwise stated, heteroaryl rings may contain 5, 6, 7, 8, 9, 10, 11, 12 ring atoms comprising 1, 2, 3 or 4 ring atoms selected from N, O and S A heteroatom, wherein ring atom refers to one or more rings (such as 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered or 12-membered heteroaryl) between carbon atoms and heteroatoms and. Examples of heteroaryl groups include pyrrolyl, furyl, oxazolyl, pyridyl, pyridyl, oxadiazolyl, isoxazole, pyrazole, triazolyl, and pyrimidinyl . Specific examples of heteroaryl rings include pyridine and thiazole.

[0048] The term "hydroxyl" means an -OH group.

[0049] The term "side oxy" means a double bonded oxygen (═O), ie a carbonyl group.

[0050] The term "hydroxyalkyl" refers to an alkyl group in which at least one of the hydrogen atoms of the alkyl group has been replaced by a hydroxy group. Examples of hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxymethylpropyl and dihydroxypropyl. A specific example is 1-hydroxy-1-methyl-ethyl.

[0051] A "thiolalkyl" group is an alkyl group as defined above in which the specified number of carbon atoms are covalently bonded to the group to which it is substituted by a sulfur bridge (-S-). A specific example is methylmercapto (-S-CH3).

[0052] A "halothiolalkyl" group is a thiolalkyl group in which at least one of the hydrogen atoms of the thiolalkyl group has been replaced by the same or a different halogen atom. A specific example is difluoromethylthio or difluoromethylthio.

[0053] The term "pharmaceutically acceptable salt" means a salt that retains the biological effect and free base or free acid properties and is not biologically or otherwise disadvantageous. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, in particular 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-acetyl hemi cystine. Furthermore, these salts can be prepared by adding an inorganic or organic base to the free acid. 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 resin. Compounds of formula I may also exist in zwitterionic form. Particularly preferred pharmaceutically acceptable salts of the compounds of formula I are the salts with formic acid and the salts with hydrochloric acid, resulting in the hydrochloride, dihydrochloride or trihydrochloride.

[0054] The abbreviation uM means micromole and is equivalent to the symbol µM.

[0055] The abbreviation uL means microliter and is equivalent to the symbol µL.

[0056] The abbreviation ug means microgram and is equivalent to the symbol µg.

[0057] The compounds of formula I described herein may contain several asymmetric centers and may be in the form of optically pure enantiomers, mixtures of enantiomers (such as racemates), optically pure non-enantiomers An isomer, a mixture of diastereomeric isomers, a diastereomeric racemate or a mixture of diastereomeric racemates.

[0058] According to the Cahn-Ingold-Prelog sequence rule, the asymmetric carbon atom can be in "R" or "S" configuration.

[0059] Furthermore, embodiments of the present invention provide compounds according to formula I described herein and pharmaceutically acceptable salts or esters thereof, specifically according to compounds of formula I described herein and pharmaceutically acceptable salts thereof Salts, more particularly compounds according to formula I as described herein.

[0060] Embodiments of the present invention provide compounds according to formula I described herein, wherein R is H, halo, haloalkyl, haloalkoxy, alkyl, alkoxy, alkoxyalkoxy, alkoxy Alkyl, thiolalkyl, cyanoalkyl, cycloalkoxy, cycloalkyl, cycloalkylalkyl or heterocycloalkyl.

[0061] Certain embodiments of the present invention provide compounds according to formula I described herein, wherein R1 is H, alkoxy, cycloalkyl or haloalkoxy.

[0062] Embodiments of the present invention provide compounds according to formula I described herein, wherein R is alkoxy, alkoxyalkoxy, alkoxyalkyl, alkylsulfonylalkyl, alkyl, alkene radical, alkynyl, alkynylalkoxy, cyano, cyanoalkyl, cycloalkyl, cycloalkoxy, cycloalkylalkyl, cyanoalkoxy, halo, haloalkoxy, (haloalkoxy group) alkoxy, thiolalkyl, halothiolalkyl, halohydroxyalkoxy, haloalkyl, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkynyl or hetero Cycloalkylalkoxy.

[0063] Specific embodiments of the present invention provide compounds according to formula I described herein, wherein R is alkyl, alkenyl, alkynyl, alkoxyalkyl, alkynyl, cyanoalkoxy, halo, haloalkane Oxy, haloalkyl or cycloalkyl.

[0064] Embodiments of the present invention provide compounds according to formula I described herein, wherein R3 is H or alkoxy.

[0065] Embodiments of the present invention provide compounds according to formula I described herein, wherein X2 is NH or S.

[0066] Embodiments of the present invention provide compounds according to formula I described herein, wherein R4 is H, halo, alkyl, alkoxy, thiol alkyl, cyanoalkyl, cycloalkyl, haloalkoxy radical, haloalkyl, heterocycloalkyl or hydroxyalkyl, and R5 is H, halo, haloalkyl, haloalkoxy, halothiolalkyl, alkoxy, alkoxycarbonyl, alkyl, hydroxy Alkyl, thiolalkyl, alkylsulfinate, alkylsulfo, cyano, cyanoalkyl, cyanoalkoxy, dialkylamino, cycloalkyl, cycloalkoxy or Heterocycloalkyl, or R4 and R5 are connected to form a 5-membered heterocycloalkyl containing a single O heteroatom, a 6-membered heterocycloalkyl containing a single N heteroatom substituted by pendant oxygen and alkyl, containing a N A 5‑membered heteroaryl ring with heteroatoms and an S heteroatom, or a 6‑membered heteroaryl ring with a single N heteroatom.

[0067] Embodiments of the present invention provide compounds according to formula I described herein, wherein R4 is halo, alkyl or haloalkyl, and R5 is H, halo, haloalkyl, haloalkoxy, halothiol Alkyl, alkoxy, alkyl, thiolalkyl, cyano, cyanoalkyl, cyanoalkoxy, dialkylamino, or cycloalkoxy, or R4 and R5 linked to form a A 5-membered heterocycloalkyl group of heteroatoms, or a 6-membered heteroaryl ring containing a single N heteroatom.

[0068] Embodiments of the present invention provide compounds according to formula I described herein, wherein R is H, halo, alkyl, alkoxy, thiol alkyl, cyanoalkyl, cycloalkyl, haloalkoxy group, haloalkyl, heterocycloalkyl or hydroxyalkyl.

[0069] Embodiments of the present invention provide compounds according to formula I described herein, wherein R4 is halo, alkyl or haloalkyl.

[0070] Specific embodiments of the present invention provide compounds according to formula I described herein, wherein R5 is H, halo, haloalkyl, haloalkoxy, halothiolalkyl, alkoxy, alkyl, hydroxyl Alkyl, alkoxycarbonyl, thiolalkyl, alkylsulfinate, alkylsulfonyl, cyano, cyanoalkyl, cyanoalkoxy, dialkylamino, cycloalkyl, Cycloalkoxy, heterocycloalkyl or heterocycloalkyl substituted by alkyl and pendant oxy.

[0071] Specific embodiments of the present invention provide compounds according to formula I described herein, wherein R5 is H, halo, haloalkyl, haloalkoxy, halothiolalkyl, alkoxy, alkyl, sulfur Alcoholalkyl, cyano, cyanoalkyl, cyanoalkoxy, dialkylamino or cycloalkoxy.

[0072] Embodiments of the present invention provide compounds according to formula I described herein, wherein R is H, halo, haloalkyl, haloalkoxy, alkyl, alkoxy, alkoxyalkoxy, alkoxy Alkyl, thiolalkyl, cyanoalkyl, cycloalkoxy, cycloalkyl, cycloalkylalkyl or heterocycloalkyl; R2 is alkoxy, alkoxyalkoxy, alkoxy Alkyl, alkylsulfonylalkyl, alkyl, alkenyl, alkynyl, alkynylalkoxy, cyano, cyanoalkyl, cycloalkyl, cycloalkoxy, cycloalkylalkyl, cyano Haloalkoxy, halo, haloalkoxy, (haloalkoxy)alkoxy, thiolalkyl, halothiolalkyl, halohydroxyalkoxy, haloalkyl, heterocycloalkyl, Heterocycloalkylalkyl, heterocycloalkylalkynyl or heterocycloalkylalkoxy; R3 is H, halo, alkyl, alkoxy, haloalkoxy or thiolalkyl; X1 is CR5 or N; X2 is NH or S; R4 is H, halo, alkyl, alkoxy, thiolalkyl, cyanoalkyl, cycloalkyl, haloalkoxy, haloalkyl, heterocycloalkyl, or hydroxy Alkyl, and R5 is H, halo, haloalkyl, haloalkoxy, halothiolalkyl, alkoxy, alkyl, alkoxycarbonyl, hydroxyalkyl, thiolalkyl, alkyl Sulfinic acid group, alkylsulfonyl group, cyano group, cyanoalkyl group, cyanoalkoxy group, dialkylamino group, cycloalkyl group, cycloalkoxy group or heterocycloalkyl group, or R4 and R5 are connected Form 5-membered heterocycloalkyl containing a single O heteroatom, 6-membered heterocycloalkyl containing a single N heteroatom substituted with alkyl and pendant oxy, 5-membered heterocycloalkyl containing a single N heteroatom and an S heteroatom A membered heteroaromatic ring or a 6‑membered heteroaromatic ring containing a single N heteroatom; and pharmaceutically acceptable salts.

[0073] Specific embodiments of the present invention provide compounds according to formula I described herein, wherein R1 is H, alkoxy, cycloalkyl or haloalkoxy; R2 is alkyl, alkenyl, alkynyl, alkoxy Alkyl, alkynyl, cyanoalkoxy, halo, haloalkoxy, haloalkyl or cycloalkyl; R3 is H or alkoxy; X1 is CR5 or N; X2 is NH or S; R4 is halo , alkyl or haloalkyl, and R5 is H, halo, haloalkyl, haloalkoxy, halothiolalkyl, alkoxy, alkyl, thiolalkyl, cyano, cyanoalkyl , cyanoalkoxy, dialkylamino or cycloalkoxy, or R4 and R5 are joined to form a 5-membered heterocycloalkyl containing a single O heteroatom, or a 6-membered heteroaryl containing a single N heteroatom ring; and pharmaceutically acceptable salts.

[0074] Embodiments of the present invention provide compounds according to formula I described herein, wherein R1 is H, alkyl, alkoxy or cycloalkyl.

[0075] Certain embodiments of the present invention provide compounds according to formula I described herein, wherein R1 is H, alkoxy or cycloalkyl.

[0076] Embodiments of the present invention provide compounds according to formula I described herein, wherein R is alkoxy, alkoxyalkoxy, alkyl, alkynyl, cyano, cycloalkyl, halo, haloalkoxy radical, (haloalkoxy)alkoxy or haloalkyl.

[0077] Specific embodiments of the present invention provide compounds according to formula I described herein, wherein R2 is alkyl, alkynyl, halo, haloalkoxy, haloalkyl.

[0078] Embodiments of the present invention provide compounds according to formula I described herein, wherein R3 is H, alkoxy or haloalkoxy.

[0079] Embodiments of the present invention provide compounds according to formula I described herein, wherein X2 is NH or S.

[0080] Embodiments of the present invention provide compounds according to formula I described herein, wherein R4 is halo.

[0081] Embodiments of the present invention provide compounds according to formula I described herein, wherein R5 is H, halo, haloalkyl or cycloalkoxy.

[0082] Particular embodiments of the present invention provide compounds according to formula I described herein, wherein R5 is H, halo or haloalkyl.

[0083] Embodiments of the present invention provide compounds according to formula I described herein, wherein R is H, halo, alkyl, alkoxy, alkoxyalkyl, alkoxyalkoxy, cyanoalkyl , haloalkyl, haloalkoxy, thiolalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy or heterocycloalkyl; R2 is cyano, halo, alkyl, alkynyl, Alkoxy, alkenylalkyl, alkoxyalkyl, alkoxyalkoxy, haloalkyl, haloalkoxy, haloalkoxyalkyl, (haloalkoxy)alkoxy, cyanoalkyl, thio Alcoholalkyl, halothiolalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, heterocycloalkyl, heterocycloalkylalkyl or heterocycloalkylalkoxy; R3 is H, halo, alkyl, alkoxy, haloalkoxy or thiol alkyl; X1 is CR5 or N; X2 is NH, -N-R6, S, -S(O)- or -S (O2)-; R4 is halo, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl or heterocycloalkyl; R5 is H, halo, cyano, alkyl, alkoxy, N-alkyl, haloalkyl, alkyl group, cycloalkyl or cycloalkoxy; or R4 is connected with R5 to form a 5- or 6-membered cycloalkyl, heterocycloalkyl or heteroaryl ring; R6 is H, alkyl, alkylhydroxy or haloalkyl; and pharmaceutically acceptable salts.

[0084] Embodiments of the present invention provide compounds according to formula I described herein, wherein R1 is H, alkyl, alkoxy or cycloalkyl; R2 is cyano, halo, alkyl, alkynyl, alkoxy group, alkoxyalkoxy, haloalkyl, haloalkoxy, (haloalkoxy) alkoxy or cycloalkyl; R3 is H, alkoxy or haloalkoxy; X1 is CR5 or N; X2 is NH or S; R4 is halo; R5 is H, halo, haloalkyl or cycloalkoxy; and pharmaceutically acceptable salts.

[0085] Specific embodiments of the present invention provide compounds according to formula I described herein, wherein R1 is H, alkoxy or cycloalkyl; R2 is alkyl, alkynyl, halo, haloalkoxy, haloalkyl; R3 is H, alkoxy or haloalkoxy; X1 is CR5 or N; X2 is NH or S; R4 is halo; R5 is H, halo or haloalkyl; and pharmaceutically acceptable salts.

[0086] Specific examples of compounds of formula I as described herein are selected from the group consisting of 6-chloro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-ind Indole-3-sulfonamide; 6-Chloro-7-fluoro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3- Sulfonamide; 6,7-Dichloro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6 -Chloro-7-(difluoromethyl)-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-7-(cyclopropoxy)-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide ; 6-chloro-N-(5-ethoxy-4-methoxy-pyrimidin-2-yl)-1H-indole-3-sulfonamide; 6-chloro-N-[4-methoxy -5-(2-methoxyethoxy)pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(difluoromethoxy)-4- Methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-[2-(difluoromethoxy)ethoxy]-4-methoxy Base-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl] -1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-chloro-N-(5-chloro-4,6-dimethoxy-pyrimidin-2-yl)-1H-ind Indole-3-sulfonamide; N-(5-bromo-4,6-dimethoxy-pyrimidin-2-yl)-6-chloro-1H-indole-3-sulfonamide; N-(5 -Bromo-4-ethoxy-6-methoxy-pyrimidin-2-yl)-6-chloro-1H-indole-3-sulfonamide; N-[5-bromo-4-(2-fluoro Ethoxy)-6-methoxy-pyrimidin-2-yl]-6-chloro-1H-indole-3-sulfonamide; 6-chloro-N-(5-ethyl-4-methoxy -pyrimidin-2-yl)-1H-indole-3-sulfonamide; 6-chloro-N-(5-ethyl-4,6-dimethoxy-pyrimidin-2-yl)-1H-indole Indole-3-sulfonamide; 6-Chloro-N-(4,6-dimethoxy-5-methyl-pyrimidin-2-yl)-1H-indole-3-sulfonamide; N-[ 5-bromo-4-(difluoromethoxy)-6-methoxy-pyrimidin-2-yl]-6-chloro-1H-indole-3-sulfonamide; 6-chloro-N-[4 -cyclopropyl-5-(2,2-difluoroethoxy)-6-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[ 5-(2,2-Difluoroethoxy)-4-methoxy-6-methyl-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[ 5-(3-fluoropropyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-(5-bromo-4-methoxy-pyrimidine-2 -yl)-6-chloro-1H-indole-3-sulfonamide; 6-chloro-N-(5-cyano-4-methoxy-pyrimidin-2-yl)-1H-indole-3 -sulfonamide; 6-chloro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]benzothiophene-3-sulfonamide; 6-bromo-N -[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-(4-methoxy- 5-methyl-pyrimidin-2-yl)-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidine-2 -yl]thieno[2,3-b]pyridine-3-sulfonamide; 6-chloro-N-(5-cyclopropyl-4-methoxy-pyrimidin-2-yl)-1H-indole -3-sulfonamide; 6-chloro-N-(4-methoxy-5-prop-1-ynyl-pyrimidin-2-yl)-1H-indole-3-sulfonamide; 6-bromo -N-(5-bromo-4,6-dimethoxy-pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; N-(5-bromo- 4,6-dimethoxy-pyrimidin-2-yl)-6-chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-chloro-N-(5-cyano -4,6-dimethoxy-pyrimidin-2-yl)-1H-indole-3-sulfonamide; and pharmaceutically acceptable salts thereof.

[0087] Furthermore, specific examples of compounds of formula I as described herein are selected from N-(5-bromo-4,6-dimethyl-pyrimidin-2-yl)-6-chloro-1H-indole- 3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethoxy)pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N- [5-(2,2-Difluoroethoxy)-4-methylsulfanyl-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-(4- Methoxy-5-methylhydrogensulfanyl-pyrimidin-2-yl)-1H-indole-3-sulfonamide; 6-chloro-N-[5-(difluoromethylsulfanyl)-4- Methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(cyclopropoxy)-4-methoxy-pyrimidin-2-yl] -1H-indole-3-sulfonamide; 6-chloro-N-[5-(3,3-difluoropropoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole -3-sulfonamide; 6-chloro-N-[4-methoxy-5-(3,3,3-trifluoropropoxy)pyrimidin-2-yl]-1H-indole-3-sulfonate Amide; 6-Chloro-N-[4-methoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6 -Chloro-N-[5-(1,1-difluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N- [4-methoxy-5-(1,1,2,2-tetrafluoroethoxy)pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5 -(2-chloro-1,1,2-trifluoro-ethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N- (4-methoxy-5-propyl-pyrimidin-2-yl)-1H-indole-3-sulfonamide; 6-chloro-N-[5-(cyclopropylmethyl)-4-methyl Oxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidine-2 - Base] -1H-indole-3-sulfonamide; 6-chloro-N-[5-(3,3-difluoropropyl)-4-methoxy-pyrimidin-2-yl]-1H- Indole-3-sulfonamide; 6-Chloro-N-[4-methoxy-5-(2-methoxyethyl)pyrimidin-2-yl]-1H-indole-3-sulfonamide ; 6-chloro-N-[4-methoxy-5-(oxetane-3-yl)pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N- [5-(fluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(difluoromethane Oxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2-fluoroethoxy)-4 ,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethoxy)-4,6 -Dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[4,6-dimethoxy-5-(1,1,2-tri Fluoroethoxy)pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-(5-allyl-4,6-dimethoxy-pyrimidin-2-yl)-6- Chloro-1H-indole-3-sulfonamide; 6-chloro-N-(4,6-dimethoxy-5-prop-1-ynyl-pyrimidin-2-yl)-1H-indole- 3-sulfonamide; 6-chloro-N-(4,6-dimethoxy-5-propyl-pyrimidin-2-yl)-1H-indole-3-sulfonamide; 6-chloro-N -[5-(2-fluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2 ,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(3-fluoropropane base)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(3,3-difluoropropyl)- 4,6-Dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoropropyl)-4,6 -Dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[4,6-dimethoxy-5-(3,3,3-tri Fluoropropyl)pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[4,6-dimethoxy-5-(methoxymethyl)pyrimidine-2 -yl]-1H-indole-3-sulfonamide; 6-chloro-N-[4,6-dimethoxy-5-(2-methoxyethyl)pyrimidin-2-yl]-1H -Indole-3-sulfonamide; 6-Chloro-N-[5-(cyanomethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonyl Amide; 6-chloro-N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6- Chloro-N-(5-cyclopropyl-4,6-dimethoxy-pyrimidin-2-yl)-1H-indole-3-sulfonamide; N-[5-bromo-4-methoxy -6-(2-methoxyethoxy)pyrimidin-2-yl]-6-chloro-1H-indole-3-sulfonamide; N-[5-bromo-4-(cyclopropoxy) -6-methoxy-pyrimidin-2-yl]-6-chloro-1H-indole-3-sulfonamide; 6-chloro-N-[4-(difluoromethoxy)-6-methoxy Base-5-methyl-pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-(5-bromo-4-fluoro-6-methoxy-pyrimidin-2-yl)-6 -Chloro-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4-fluoro-6-methoxy-pyrimidin-2-yl ]-1H-indole-3-sulfonamide; 6-Chloro-N-(4-chloro-5,6-dimethoxy-pyrimidin-2-yl)-1H-indole-3-sulfonamide ; 6-chloro-N-[4-chloro-5-(2,2-difluoroethoxy)pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[ 5-(2,2-Difluoroethoxy)-4-ethyl-6-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[ 5-(2,2-Difluoroethyl)-4-methoxy-6-methyl-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[4 -Cyclopropyl-5-(2,2-difluoroethyl)-6-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-[5-bromo-4 -(cyclopropylmethyl)-6-methoxy-pyrimidin-2-yl]-6-chloro-1H-indole-3-sulfonamide; N-[5-bromo-4-methoxy- 6-(methoxymethyl)pyrimidin-2-yl]-6-chloro-1H-indole-3-sulfonamide; N-[5-bromo-4-(1,1-difluoroethyl) -6-methoxy-pyrimidin-2-yl]-6-chloro-1H-indole-3-sulfonamide; N-[5-bromo-4-(fluoromethoxy)-6-methoxy -pyrimidin-2-yl]-6-chloro-1H-indole-3-sulfonamide; N-[5-bromo-4-(difluoromethyl)-6-methoxy-pyrimidin-2-yl ]-6-chloro-1H-indole-3-sulfonamide; N-[5-bromo-4-(cyanomethyl)-6-methoxy-pyrimidin-2-yl]-6-chloro- 1H-indole-3-sulfonamide; 6-chloro-N-[5-(difluoromethoxy)-4-methoxy-6-methylhydrogensulfanyl-pyrimidin-2-yl]-1H -Indole-3-sulfonamide; N-[4,6-dimethoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-yl]-6-fluoro-1H- Indole-3-sulfonamide; 6-bromo-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonate Amide; 6-bromo-N-[5-(2-cyanoethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-bromo-N -[5-(Difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-bromo-N-[5-(2 -fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-bromo-N-[5-(2,2-difluoro Ethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-bromo-N-[5-(2-cyanoethyl)- 4,6-Dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidine -2-yl]-6-(difluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-(difluoromethyl)-N-[5-(2 -fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; N-[5-(2, 2-Difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfo Amide; 6-(difluoromethyl)-N-[4,6-dimethoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-yl]-1H-pyrrolo [2,3-b]pyridine-3-sulfonamide; 6-(difluoromethyl)-N-[5-(3,3-difluoropropyl)-4,6-dimethoxy-pyrimidine -2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; N-[5-(cyanomethoxy)-4,6-dimethoxy-pyrimidine-2 - Base] -6-(difluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-(difluoromethyl)-N-[4-methoxy- 5-(1,1,2-trifluoroethoxy)pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6- Dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4 ,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-1H-indole-3-sulfonamide; N-[5-(2-cyanoethyl)-4 ,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl) -4-methoxy-pyrimidin-2-yl]-6-(difluoromethoxy)-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2-cyanoethyl base)-4-methoxy-pyrimidin-2-yl]-7-(difluoromethylsulfanyl)-1H-indole-3-sulfonamide; 6-chloro-7-(difluoromethylthio Base)-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N- [5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(difluoromethylthio)-1H-indole-3-sulfonamide; 7-chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-bromo-N- [5-(2-Fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-bromo -N-[4,6-dimethoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3- Sulfonamide; 6-bromo-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b ]pyridine-3-sulfonamide; 6-bromo-N-[5-(3,3-difluoropropyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[ 2,3-b]pyridine-3-sulfonamide; 6-bromo-N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H- Pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-bromo-N-[5-(cyanomethoxy)-4,6-dimethoxy-pyrimidin-2-yl]- 1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidine- 2-yl]-7-(dimethylamino)-1H-indole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidine- 2-yl]-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide; N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidine- 2-yl]-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide; 6-chloro-N-(4,6-dimethoxy-5-methyl-pyrimidine-2- base)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-chloro-N-[5-(difluoromethoxy)-4-methoxy-pyrimidin-2-yl ]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy- Pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-chloro-N-[5-(3,3-difluoropropyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-chloro-N-[ 5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-chloro- N-[5-(2,2-difluoroethoxy)-4-methoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-chloro-N -[5-(2,2-Difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-chloro-N-[ 5-(Difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-chloro-N-[5- (Difluoromethoxy)-4-methoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-chloro-7-(cyclopropoxy)-N -[5-(2,2-Difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 7-bromo-N-[5-(2 ,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-6-fluoro-1H-indole-3-sulfonamide; 7-bromo-N-[5-(2,2 -Difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 7-chloro-N-[5-(2,2-difluoroethyl) -4-methoxy-pyrimidin-2-yl]-6-fluoro-1H-indole-3-sulfonamide; N-[5-(2-fluoroethoxy)-4,6-dimethoxy Base-pyrimidin-2-yl]-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4 ,6-dimethoxy-pyrimidin-2-yl]-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-chloro-N-[5-(2 ,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-"port" linyl-1H-indole-3-sulfonamide; 7-bromo-N -[5-(2,2-Difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5 -(2,2-Difluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(1,1 -Difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-(4-ethyl-6-methoxy-5 -Methyl-pyrimidin-2-yl)-1H-indole-3-sulfonamide; N-(5-bromo-4-methoxy-6-tetrahydropyran-4-yl-pyrimidine-2- base)-6-chloro-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl] Thieno[2,3-b]pyridine-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-6-fluoro- 1H-indole-3-sulfonamide; 7-bromo-6-chloro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole -3-sulfonamide; 7-bromo-6-chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3 -sulfonamide; 6-bromo-N-[5-(2,2-difluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-bromo-N-(4,6-dimethoxy-5-methyl-pyrimidin-2-yl)thieno[2,3-b]pyridine-3-sulfonamide; 6-bromo-N- [5-(2,2-Difluoroethoxy)-4-methoxy-pyrimidin-2-yl]thieno[2,3-b]pyridine-3-sulfonamide; 6-bromo-N- [5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]thieno[2,3-b]pyridine-3-sulfonamide; 6-bromo-N-[4- Methoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-yl]thieno[2,3-b]pyridine-3-sulfonamide; 6-bromo-N-[5 -(2,2-Difluoroethyl)-4-methoxy-pyrimidin-2-yl]thieno[2,3-b]pyridine-3-sulfonamide; 6-bromo-N-[5- (2-cyanoethyl)-4-methoxy-pyrimidin-2-yl]thieno[2,3-b]pyridine-3-sulfonamide; 6-bromo-N-[5-(2, 2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]thieno[2,3-b]pyridine-3-sulfonamide; 6-bromo-N-[5-( 2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]thieno[2,3-b]pyridine-3-sulfonamide; N-[5-(2,2- Difluoroethyl)-4-methoxy-pyrimidin-2-yl]-6-ethyl-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl) -4-methoxypyrimidin-2-yl]-6-propyl-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4 -methoxy-pyrimidin-2-yl]benzothiophene-3-sulfonamide; 6-chloro-N-[5-(3,3-difluoropropyl)-4-methoxy-pyrimidine-2 -yl]benzothiophene-3-sulfonamide; 6-chloro-N-[5-(2-cyanoethyl)-4-methoxy-pyrimidin-2-yl]benzothiophene-3-sulfonyl Amide; 6-bromo-N-[5-(2,2-difluoroethoxy)-4-methoxy-pyrimidin-2-yl]benzothiophene-3-sulfonamide; 6-bromo- N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]benzothiophene-3-sulfonamide; N-[5-(2-fluoroethoxy)- 4-methoxy-pyrimidin-2-yl]-6-methyl-benzothiophene-3-sulfonamide; 6-bromo-N-(4,6-dimethoxy-5-methyl-pyrimidine -2-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-bromo-N-[5-(2,2-difluoroethoxy)-4-methoxy Base-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4- Methoxy-pyrimidin-2-yl]-7-fluoro-benzothiophene-3-sulfonamide; 6-chloro-N-[5-(2-cyanoethyl)-4-methoxy-pyrimidine -2-yl]-7-fluoro-benzothiophene-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-6 ,7-difluoro-1H-indole-3-sulfonamide; 6-(difluoromethyl)-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidine-2- Base]thieno[2,3-b]pyridine-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-6- (Difluoromethyl)thieno[2,3-b]pyridine-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidine- 2-yl]-6-(difluoromethyl)thieno[2,3-b]pyridine-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6 -Dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4 ,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide; 6-chloro-N-[5-(2,2-two Fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-chloro-N-[4,6-di Methoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-bromo-N -[5-(Difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-chloro -N-(4-chloro-5-methoxy-pyrimidin-2-yl)-1H-indole-3-sulfonamide; 6-chloro-N-[5-(3-fluoropropoxy)- 4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-(5-but-2-ynyloxy-4-methoxy-pyrimidin-2-yl)- 6-chloro-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,3-difluoropropyl)-4-methoxy-pyrimidin-2-yl]-1H- Indole-3-sulfonamide; 6-Chloro-N-[4-methoxy-5-(2,2,2-trifluoroethyl)pyrimidin-2-yl]-1H-indole-3- Sulfonamide; 6-Chloro-N-[4-methoxy-5-(3,3,3-trifluoropropyl)pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6 -Chloro-N-[5-(2-cyanoethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[4- Methoxy-5-[2-(oxetane-3-yl)ethynyl]pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[4-methyl Oxy-5-[2-(oxetane-3-yl)ethyl]pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-[5-(2,2-two Fluoroethyl)-4-methoxy-pyrimidin-2-yl]-6-methyl-1H-indole-3-sulfonamide; 7-bromo-6-chloro-N-[5-(3, 3-Difluoropropyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-bromo-N-[5-(2,2-difluoroethyl )-4-methoxy-pyrimidin-2-yl]-7-methyl-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl) -4-methoxy-pyrimidin-2-yl]-7-methoxy-1H-indole-3-sulfonamide; 6-chloro-N-[5-(3,3-difluoropropyl) -4-methoxy-pyrimidin-2-yl]-7-methoxy-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl) -4-methoxy-pyrimidin-2-yl]-7-(difluoromethoxy)-1H-indole-3-sulfonamide; 6-bromo-N-[5-(difluoromethoxy )-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidine- 2-yl]-6-(trifluoromethyl)-1H-indole-3-sulfonamide; 6-bromo-N-[5-(2,2-difluoroethyl)-4-methoxy -pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidine -2-yl]-7-methyl-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl] -6-(methylthio)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidine-2- Base]-6-(difluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4-methyl Oxy-pyrimidin-2-yl]-6-(difluoromethyl)-1H-indole-3-sulfonamide; 6-bromo-N-[5-(2,2-difluoroethyl)- 4-methoxy-pyrimidin-2-yl]-7-methoxy-1H-indole-3-sulfonamide; 6-(cyanomethyl)-N-[5-(2,2-di Fluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4 -Methoxy-pyrimidin-2-yl]-7-(fluoromethoxy)-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl )-4-methoxy-pyrimidin-2-yl]-7-(difluoromethylsulfanyl)-1H-indole-3-sulfonamide; 6-bromo-N-[5-(2, 2-Difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-bromo-N-[5-( 3,3-Difluoropropyl)-4-methoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-bromo-N-[5 -(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6- Chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Chloro-N-[5-(3,3-difluoropropyl)-4-methoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonyl Amine; 6-chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3- Sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3- b] pyridine-3-sulfonamide; 6-chloro-N-[5-(3,3-difluoropropyl)-4-methoxy-pyrimidin-2-yl]-7-fluoro-1H-ind Indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-chloro-7-(difluoromethyl)-N-[5-(3, 3-difluoropropyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6,7-dichloro-N-[5-(2,2-di Fluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6,7-dichloro-N-[5-(3,3-difluoropropyl )-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-7-(cyclopropoxy)-N-[5-(3,3-two Fluoropropyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-bromo-7-fluoro-N-[5-(2-fluoroethoxy) -4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4-methoxy -pyrimidin-2-yl]-7-(difluoromethyl)-1H-indole-3-sulfonamide; 6-chloro-7-fluoro-N-[4-methoxy-5-(1, 1,2-Trifluoroethoxy)pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2-cyanoethyl)-4-methoxy Base-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethyl Oxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2-cyanoethyl)-4,6-dimethoxy Base-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-chloro-N-[5-(cyanomethoxy)-4,6-dimethoxy- Pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-chloro-N-[4-methoxy-5-(1,1,2-trifluoroethoxy) Pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-chloro-N-[5-(2-fluoroethoxy)-4,6-dimethyl Oxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4-methoxy -pyrimidin-2-yl]-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide; 6-chloro-7-cyano-N-[5-(2,2-difluoroethyl Base)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-7-cyano-N-[5-(difluoromethoxy)-4 ,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-7-cyano-N-[5-(2-fluoroethoxy)-4 ,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-7-cyano-N-[5-(2,2-difluoroethoxy )-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-7-cyano-N-[5-(2,2-difluoro Ethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4-methyl Oxy-pyrimidin-2-yl]-6,8-dihydro-1H-furo[3,4-g]indole-3-sulfonamide; N-[5-(2,2-difluoroethyl )-4,6-dimethoxy-pyrimidin-2-yl]-6,8-dihydro-1H-furo[3,4-g]indole-3-sulfonamide; 6-bromo-N- [5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-bromo-N- [4-methoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6- Chloro-7-(cyanomethyl)-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide ; 6-Chloro-7-cyclopropyl-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide ; 6-Chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-(methylthio)-1H-indole-3- Sulfonamide; 6-(Difluoromethyl)-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide ; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-1H-indole-3-sulf Amide; N-[5-(cyanomethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-1H-indole-3-sulfonyl Amine; 6-(difluoromethyl)-N-[4-methoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-yl]-1H-pyrrolo[2,3 -b]pyridine-3-sulfonamide; N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)- 1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-bromo-N-[5-(2-cyanoethyl)-4-methoxy-pyrimidin-2-yl]- 7-fluoro-1H-indole-3-sulfonamide; 6-bromo-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7- Fluoro-1H-indole-3-sulfonamide; 6-bromo-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]- 7-fluoro-1H-indole-3-sulfonamide; 6-bromo-N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7 -Fluoro-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(cyanomethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-fluoro -1H-indole-3-sulfonamide; 6-bromo-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H- Indole-3-sulfonamide; 6-Bromo-N-[5-(cyanomethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide Amide; 6-(difluoromethyl)-7-fluoro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3- Sulfonamide; N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-6-(difluoromethyl)-7-fluoro-1H-indole -3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-7-fluoro-1H -indole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl )-7-fluoro-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6 -(Difluoromethyl)-7-fluoro-1H-indole-3-sulfonamide; N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidine-2- base]-6-(difluoromethyl)-7-fluoro-1H-indole-3-sulfonamide; N-[5-(cyanomethoxy)-4,6-dimethoxy-pyrimidine -2-yl]-6-(difluoromethyl)-7-fluoro-1H-indole-3-sulfonamide; 6-cyclopropyl-N-[5-(2,2-difluoroethyl )-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 7-bromo-6-chloro-N-[5-(2-cyanoethyl)-4- Methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl] -6-fluoro-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6 -Fluoro-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-fluoro- 1H-indole-3-sulfonamide; N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-fluoro-1H-indole- 3-sulfonamide; 6-chloro-N-[5-(2,2-difluoropropyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[4-methoxy-5-(2,2,3,3-tetrafluoropropyl)pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro -N-[5-(Difluoromethoxymethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[4,6 -Dimethoxy-5-(oxetane-3-ylmethoxy)pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2 ,3-difluoropropyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(cyanomethoxy base)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[4-methoxy-5-(2,3, 3-trifluoropropyl)pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(cyanomethoxy)-4-methoxy-pyrimidine- 2-yl]-1H-indole-3-sulfonamide; 6-bromo-N-[5-(difluoromethoxy)-4-methoxy-pyrimidin-2-yl]benzothiophene-3 -sulfonamide; 6-bromo-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]thieno[2,3-b]pyridine-3- Sulfonamide; 6-Bromo-N-[5-(3,3-difluoropropyl)-4-methoxy-pyrimidin-2-yl]thieno[2,3-b]pyridine-3-sulfo Amide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]thieno[2,3-b]pyridine-3-sulfonyl Amine; N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-6-(oxetane-3-yl)-1H-indole-3 -sulfonamide; N-(4,6-dimethoxy-5-methyl-pyrimidin-2-yl)-6-methoxy-1H-indole-3-sulfonamide; N-[5 -(2,2-Difluoroethyl)-4-methoxy-pyrimidin-2-yl]-6-(1-hydroxy-1-methyl-ethyl)-1H-indole-3-sulfonyl Amine; 6-chloro-N-[5-(1,1-difluoro-2-hydroxy-ethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3 -sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-methylsulfinyl-1H-ind Indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-methylsulfonyl-1H- Indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-methylsulfinyl Base-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7 -Methylsulfinyl-1H-indole-3-sulfonamide; 6-Chloro-7-cyano-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidine- 2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[4,6-dimethoxy-5-(2-methylsulfonylethyl)pyrimidin-2-yl ]-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3 -e][1,2]benzothiazole-3-sulfonamide; 7-bromo-6-chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy -pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-[5-(cyanomethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6- Methyl-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidine- 2-yl]-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy -pyrimidin-2-yl]-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-(difluoromethyl)-N-[5-(2,3 -difluoropropyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-bromo-N-[5 -(2,3-Difluoropropyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-chloro -N-[5-(2,3-difluoropropyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonyl Amine; N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-8H-pyrrolo[2,3-e][1,3]benzothiazole -6-sulfonamide; 3-[[5-(2,2-Difluoroethyl)-4-methoxy-pyrimidin-2-yl]sulfamoyl]-6-methyl-1H-indole-7-carboxylic acid methyl ester; N-[5-(2 ,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-6-methyl-7-hydroxymethyl-1H-indole-3-sulfonamide; N-[5-( 2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-9-keto-8-methyl-6,7-dihydro-1H-pyrrole[3,2-h]isoquine Phenyl-3-sulfonamide; 6-Chloro-7-(cyanomethoxy)-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidine-2 -yl]-1H-indole-3-sulfonamide; and pharmaceutically acceptable salts thereof. ,

[0088] Further specific examples of formula I as described herein are selected from the group consisting of 6-chloro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-ind Indole-3-sulfonamide; 6-Chloro-7-fluoro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3- Sulfonamide; 6,7-Dichloro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6 -Chloro-7-(difluoromethyl)-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Chloro-N-(5-chloro-4,6-dimethoxy-pyrimidin-2-yl)-1H-indole-3-sulfonamide; N-(5-bromo-4,6-di Methoxy-pyrimidin-2-yl)-6-chloro-1H-indole-3-sulfonamide; 6-chloro-N-(5-ethyl-4,6-dimethoxy-pyrimidine-2 -yl)-1H-indole-3-sulfonamide; 6-chloro-N-(4,6-dimethoxy-5-methyl-pyrimidin-2-yl)-1H-indole-3- Sulfonamide; N-[5-bromo-4-(difluoromethoxy)-6-methoxy-pyrimidin-2-yl]-6-chloro-1H-indole-3-sulfonamide; 6 -Chloro-N-[4-cyclopropyl-5-(2,2-difluoroethoxy)-6-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(3-fluoropropyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5- (2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]benzothiophene-3-sulfonamide; 6-bromo-N-[5-(2-fluoroethoxy)-4 -Methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidine-2 -yl]thieno[2,3-b]pyridine-3-sulfonamide; 6-chloro-N-(4-methoxy-5-prop-1-ynyl-pyrimidin-2-yl)-1H -Indole-3-sulfonamide; 6-bromo-N-(5-bromo-4,6-dimethoxy-pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridine- 3-sulfonamide; N-(5-bromo-4,6-dimethoxy-pyrimidin-2-yl)-6-chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonyl amines; and pharmaceutically acceptable salts thereof.

[0089] Yet further specific examples of formula I as described herein are selected from the group consisting of 6-chloro-7-fluoro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl ]-1H-indole-3-sulfonamide; 6,7-dichloro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole Indole-3-sulfonamide; 6-Chloro-7-(difluoromethyl)-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H- Indole-3-sulfonamide; N-(5-bromo-4,6-dimethoxy-pyrimidin-2-yl)-6-chloro-1H-indole-3-sulfonamide; 6-chloro -N-(5-Ethyl-4,6-dimethoxy-pyrimidin-2-yl)-1H-indole-3-sulfonamide; 6-chloro-N-(4,6-dimethoxy -5-methyl-pyrimidin-2-yl)-1H-indole-3-sulfonamide; 6-chloro-N-[4-cyclopropyl-5-(2,2-difluoroethoxy )-6-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(3-fluoropropyl)-4-methoxy-pyrimidine -2-yl]-1H-indole-3-sulfonamide; 6-bromo-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H- Indole-3-sulfonamide; 6-bromo-N-(5-bromo-4,6-dimethoxy-pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3 -sulfonamide; 6-chloro-N-[4-methoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-yl]-1H-indole-3-sulfonamide ; 6-chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N -[5-(3,3-Difluoropropyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(two Fluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2-fluoroethoxy) -4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethoxy)-4 ,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[4,6-dimethoxy-5-(1,1,2 -Trifluoroethoxy)pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-(5-allyl-4,6-dimethoxy-pyrimidin-2-yl)- 6-chloro-1H-indole-3-sulfonamide; 6-chloro-N-(4,6-dimethoxy-5-prop-1-ynyl-pyrimidin-2-yl)-1H-indole Indole-3-sulfonamide; 6-chloro-N-(4,6-dimethoxy-5-propyl-pyrimidin-2-yl)-1H-indole-3-sulfonamide; 6-chloro -N-[5-(2-fluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5- (2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(3- Fluoropropyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(3,3-difluoropropyl )-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[4,6-dimethoxy-5-(3, 3,3-trifluoropropyl)pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[4,6-dimethoxy-5-(2-methoxy 6-Chloro-N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidine -2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-(5-cyclopropyl-4,6-dimethoxy-pyrimidin-2-yl)-1H-indole -3-sulfonamide; 6-chloro-N-[4-(difluoromethoxy)-6-methoxy-5-methyl-pyrimidin-2-yl]-1H-indole-3-sulfonate Amide; 6-bromo-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-bromo -N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-bromo-N-[5- (2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-bromo-N-[5-(2,2- Difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-bromo-N-[5-(2-cyanoethyl )-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6- Dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-(difluoromethyl)-N -[4,6-Dimethoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonyl Amine; 6-(difluoromethyl)-N-[5-(3,3-difluoropropyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2, 3-b]pyridine-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)- 1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethane base)-1H-indole-3-sulfonamide; N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl base)-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2-cyanoethyl)-4-methoxy-pyrimidin-2-yl]-7-(difluoro Methylthio)-1H-indole-3-sulfonamide; 6-Chloro-7-(difluoromethylthio)-N-[5-(2-fluoroethoxy)-4,6- Dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2-cyanoethyl)-4,6-dimethoxy- Pyrimidin-2-yl]-7-(difluoromethylthio)-1H-indole-3-sulfonamide; 6-bromo-N-[5-(2-fluoroethoxy)-4,6 -Dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-bromo-N-[4,6-dimethoxy-5- (1,1,2-trifluoroethoxy)pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-bromo-N-[5-(2 ,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-bromo-N- [5-(3,3-difluoropropyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6 -Bromo-N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonyl Amine; 6-bromo-N-[5-(cyanomethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3- Sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(dimethylamino)- 1H-indole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[3,2-h ]quinoline-3-sulfonamide; N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[3,2-h ]quinoline-3-sulfonamide; 6-chloro-N-(4,6-dimethoxy-5-methyl-pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridine -3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2, 3-b]pyridine-3-sulfonamide; 6-chloro-N-[5-(3,3-difluoropropyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H- Pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-chloro-N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl] -1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidine-2- base]-7-fluoro-1H-indole-3-sulfonamide; 6-chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl] -7-fluoro-1H-indole-3-sulfonamide; 6-chloro-7-(cyclopropoxy)-N-[5-(2,2-difluoroethyl)-4-methoxy -pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl] -6-Methyl-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidine-2 -yl]-6-fluoro-1H-indole-3-sulfonamide; 7-bromo-6-chloro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidine-2 -yl]-1H-indole-3-sulfonamide; 7-bromo-6-chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl ]-1H-indole-3-sulfonamide; 6-bromo-N-(4,6-dimethoxy-5-methyl-pyrimidin-2-yl)thieno[2,3-b]pyridine -3-sulfonamide; 6-bromo-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]thieno[2,3-b]pyridine- 3-sulfonamide; 6-bromo-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]thieno[2,3-b] Pyridine-3-sulfonamide; 6-bromo-N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]thieno[2,3-b] Pyridine-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]benzothiophene-3-sulfonamide; 6-bromo-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]benzothiophene-3-sulfonamide; 6-bromo-N-(4,6 -dimethoxy-5-methyl-pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; N-[5-(2,2-difluoroethane Oxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide; N-[5-(2,2- Difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide; 6-bromo-N-[5 -(Difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-chloro-N- [5-(2,3-Difluoropropyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2- Cyanoethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 7-bromo-6-chloro-N-[5-(3,3-difluoro Propyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-bromo-N-[5-(2,2-difluoroethyl)-4- Methoxy-pyrimidin-2-yl]-7-methyl-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4-methanol Oxy-pyrimidin-2-yl]-7-methoxy-1H-indole-3-sulfonamide; 6-chloro-N-[5-(3,3-difluoropropyl)-4-methanol Oxy-pyrimidin-2-yl]-7-methoxy-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4-methanol Oxy-pyrimidin-2-yl]-7-(difluoromethoxy)-1H-indole-3-sulfonamide; 6-bromo-N-[5-(2,2-difluoroethyl) -4-methoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4 -Methoxy-pyrimidin-2-yl]-7-methyl-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethyl Oxy-pyrimidin-2-yl]-6-(difluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-bromo-N-[5-(2, 2-Difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-methoxy-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2, 2-Difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-(fluoromethoxy)-1H-indole-3-sulfonamide; 6-chloro-N-[5- (2,2-Difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-(difluoromethylsulfanyl)-1H-indole-3-sulfonamide; 6-bromo-N- [5-(3,3-Difluoropropyl)-4-methoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-bromo- N-[5-(2,2-Difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonyl Amine; 6-Chloro-N-[5-(3,3-difluoropropyl)-4-methoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3- Sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine- 3-sulfonamide; 6-chloro-N-[5-(3,3-difluoropropyl)-4-methoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3- Sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-fluoro-1H-indole- 3-sulfonamide; 6,7-dichloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonate Amide; 6,7-dichloro-N-[5-(3,3-difluoropropyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-7-(cyclopropoxy)-N-[5-(3,3-difluoropropyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfo Amide; 6-bromo-7-fluoro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6 -Chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-(difluoromethyl)-1H-indole-3-sulfonyl Amine; 6-chloro-7-fluoro-N-[4-methoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-yl]-1H-indole-3-sulfonyl Amine; 6-chloro-N-[5-(2-cyanoethyl)-4-methoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6- Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6 -Chloro-N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6- Chloro-N-[5-(cyanomethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-chloro- N-[4-methoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfo Amide; 6-chloro-7-cyano-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonyl Amine; 6-chloro-7-cyano-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide ; 6-Chloro-7-cyano-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide ; 6-Chloro-7-cyano-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3- Sulfonamide; 6-chloro-7-cyano-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole- 3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6,8-dihydro-1H-fur[3 ,4-g] indole-3-sulfonamide; 6-bromo-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-pyrrolo[ 2,3-b]pyridine-3-sulfonamide; 6-bromo-N-[4-methoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-yl]-1H -pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-chloro-7-(cyanomethyl)-N-[5-(2,2-difluoroethyl)-4-methyl Oxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidine-2 - Base] -7-(methylthio)-1H-indole-3-sulfonamide; 6-(difluoromethyl)-N-[5-(2-fluoroethoxy)-4-methyl Oxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidine-2- Base]-6-(difluoromethyl)-1H-indole-3-sulfonamide; N-[5-(cyanomethoxy)-4,6-dimethoxy-pyrimidin-2-yl ]-6-(difluoromethyl)-1H-indole-3-sulfonamide; N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl ]-6-(difluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-bromo-N-[5-(2-cyanoethyl)-4- Methoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-bromo-N-[5-(difluoromethoxy)-4,6-dimethoxy Base-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-bromo-N-[5-(2,2-difluoroethoxy)-4,6-di Methoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-bromo-N-[5-(2-cyanoethyl)-4,6-dimethyl Oxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-bromo-N-[5-(cyanomethoxy)-4,6-dimethoxy -pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-bromo-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy Base-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-bromo-N-[5-(cyanomethoxy)-4,6-dimethoxy-pyrimidine-2- base]-1H-indole-3-sulfonamide; 6-(difluoromethyl)-7-fluoro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidine-2 -yl]-1H-indole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethane base)-7-fluoro-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl] -6-(Difluoromethyl)-7-fluoro-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy- Pyrimidin-2-yl]-6-(difluoromethyl)-7-fluoro-1H-indole-3-sulfonamide; N-[5-(2-cyanoethyl)-4,6-di Methoxy-pyrimidin-2-yl]-6-(difluoromethyl)-7-fluoro-1H-indole-3-sulfonamide; N-[5-(cyanomethoxy)-4, 6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-7-fluoro-1H-indole-3-sulfonamide; 7-bromo-6-chloro-N-[5 -(2-cyanoethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)- 4,6-Dimethoxy-pyrimidin-2-yl]-6-fluoro-1H-indole-3-sulfonamide; N-[5-(2-cyanoethyl)-4,6-di Methoxy-pyrimidin-2-yl]-6-fluoro-1H-indole-3-sulfonamide; 6-chloro-N-[5-(difluoromethoxymethyl)-4-methoxy -pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,3-difluoropropyl)-4,6-dimethoxy-pyrimidine- 2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(cyanomethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H -Indole-3-sulfonamide; 6-Chloro-N-[5-(cyanomethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide ; 7-Bromo-6-chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonyl Amine; 6-chloro-7-(cyanomethoxy)-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H- indole-3-sulfonamide; and pharmaceutically acceptable salts thereof. ,

[0090] Yet further specific examples of formula I as described herein are selected from the group consisting of 6-chloro-N-[4-methoxyl-5-(1,1,2-trifluoroethoxy)pyrimidin-2-yl ]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole -3-sulfonamide; 6-chloro-N-[5-(3,3-difluoropropyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide ; 6-chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N -[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-( 2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[4,6-di Methoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-(5-allyl-4,6- Dimethoxy-pyrimidin-2-yl)-6-chloro-1H-indole-3-sulfonamide; 6-chloro-N-(4,6-dimethoxy-5-prop-1-yne Base-pyrimidin-2-yl)-1H-indole-3-sulfonamide; 6-chloro-N-(4,6-dimethoxy-5-propyl-pyrimidin-2-yl)-1H- Indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide Amide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(3-fluoropropyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N- [5-(3,3-difluoropropyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[4, 6-dimethoxy-5-(3,3,3-trifluoropropyl)pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[4,6- Dimethoxy-5-(2-methoxyethyl)pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2-cyanoethyl )-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-(5-cyclopropyl-4,6-dimethoxy -pyrimidin-2-yl)-1H-indole-3-sulfonamide; 6-chloro-N-[4-(difluoromethoxy)-6-methoxy-5-methyl-pyrimidine-2 - Base] -1H-indole-3-sulfonamide; 6-bromo-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H- Indole-3-sulfonamide; 6-bromo-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonate Amide; 6-bromo-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6- Bromo-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-bromo- N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-[5-(2,2 -Difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonyl Amine; 6-(difluoromethyl)-N-[4,6-dimethoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-yl]-1H-pyrrolo[ 2,3-b]pyridine-3-sulfonamide; 6-(difluoromethyl)-N-[5-(3,3-difluoropropyl)-4,6-dimethoxy-pyrimidine- 2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidine-2- base]-6-(difluoromethyl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidine -2-yl]-6-(difluoromethyl)-1H-indole-3-sulfonamide; N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidine -2-yl]-6-(difluoromethyl)-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2-cyanoethyl)-4-methoxy- Pyrimidin-2-yl]-7-(difluoromethylthio)-1H-indole-3-sulfonamide; 6-chloro-7-(difluoromethylthio)-N-[5-( 2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2-cyanoethyl base)-4,6-dimethoxy-pyrimidin-2-yl]-7-(difluoromethylsulfanyl)-1H-indole-3-sulfonamide; 6-bromo-N-[5- (2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-bromo-N- [4,6-Dimethoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide ; 6-Bromo-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine- 3-sulfonamide; 6-bromo-N-[5-(3,3-difluoropropyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3 -b] pyridine-3-sulfonamide; 6-bromo-N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[ 2,3-b]pyridine-3-sulfonamide; 6-bromo-N-[5-(cyanomethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrole A[2,3-b]pyridine-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl ]-7-(dimethylamino)-1H-indole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl ]-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide; N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl ]-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide; 6-chloro-N-(4,6-dimethoxy-5-methyl-pyrimidin-2-yl)- 1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidine- 2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-chloro-N-[5-(3,3-difluoropropyl)-4,6-dimethyl Oxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-chloro-N-[5-(2-cyanoethyl)-4,6 -Dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl )-4-methoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-chloro-N-[5-(difluoromethoxy)-4,6 -Dimethoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-chloro-7-(cyclopropoxy)-N-[5-(2,2 -Difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6 -Dimethoxy-pyrimidin-2-yl]-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; N-[5-(2,2-difluoroethane Base)-4-methoxy-pyrimidin-2-yl]-6-fluoro-1H-indole-3-sulfonamide; 7-bromo-6-chloro-N-[5-(2-fluoroethoxy Base)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 7-bromo-6-chloro-N-[5-(2,2-difluoroethyl) -4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-bromo-N-(4,6-dimethoxy-5-methyl-pyrimidine-2- Base) Thieno[2,3-b]pyridine-3-sulfonamide; 6-bromo-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl ]thieno[2,3-b]pyridine-3-sulfonamide; 6-bromo-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidine-2 -yl]thieno[2,3-b]pyridine-3-sulfonamide; 6-bromo-N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidine-2 -yl]thieno[2,3-b]pyridine-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidine-2- Base] benzothiophene-3-sulfonamide; 6-bromo-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]benzothiophene-3-sulfonyl Amine; 6-bromo-N-(4,6-dimethoxy-5-methyl-pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; N -[5-(2,2-Difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[3,2-h]quinoline-3-sulfonyl Amine; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[3,2-h]quinoline-3- Sulfonamide; 6-bromo-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine- 3-sulfonamide; 6-chloro-N-[5-(2,3-difluoropropyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2-cyanoethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 7-bromo-6-chloro- N-[5-(3,3-difluoropropyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-bromo-N-[5-( 2,2-Difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-methyl-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2 ,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-methoxy-1H-indole-3-sulfonamide; 6-chloro-N-[5-(3 ,3-difluoropropyl)-4-methoxy-pyrimidin-2-yl]-7-methoxy-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2 ,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-(difluoromethoxy)-1H-indole-3-sulfonamide; 6-bromo-N-[ 5-(2,2-Difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-chloro-N-[5- (2,2-Difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-methyl-1H-indole-3-sulfonamide; N-[5-(2,2- Difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-methoxy-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-(fluoromethoxy)-1H-indole-3-sulfonate Amide; 6-chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-(difluoromethylsulfanyl)-1H- Indole-3-sulfonamide; 6-Bromo-N-[5-(3,3-difluoropropyl)-4-methoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3 -b]pyridine-3-sulfonamide; 6-bromo-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H- Pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Chloro-N-[5-(3,3-difluoropropyl)-4-methoxy-pyrimidin-2-yl]- 1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl ]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-chloro-N-[5-(3,3-difluoropropyl)-4-methoxy-pyrimidine-2 -yl]-7-fluoro-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidine -2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6,7-dichloro-N-[5-(2,2-difluoroethyl)-4-methoxy- Pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6,7-dichloro-N-[5-(3,3-difluoropropyl)-4-methoxy-pyrimidine-2 -yl]-1H-indole-3-sulfonamide; 6-chloro-7-(cyclopropyloxy)-N-[5-(3,3-difluoropropyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-bromo-7-fluoro-N-[5-(2-fluoroethyl Oxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4- Methoxy-pyrimidin-2-yl]-7-(difluoromethyl)-1H-indole-3-sulfonamide; 6-chloro-7-fluoro-N-[4-methoxy-5- (1,1,2-trifluoroethoxy)pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2-cyanoethyl)-4 -Methoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4,6 -Dimethoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2-cyanoethyl)-4,6- Dimethoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-chloro-N-[5-(cyanomethoxy)-4,6-dimethyl Oxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-chloro-N-[4-methoxy-5-(1,1,2-trifluoroethane Oxy)pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-chloro-N-[5-(2-fluoroethoxy)-4,6 -Dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-chloro-7-cyano-N-[5-(2,2 -Difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-7-cyano-N-[5-(difluoromethoxy yl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-7-cyano-N-[5-(2-fluoroethoxy base)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-7-cyano-N-[5-(2,2-di Fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-7-cyano-N-[5-(2, 2-Difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl) -4,6-dimethoxy-pyrimidin-2-yl]-6,8-dihydro-1H-furo[3,4-g]indole-3-sulfonamide; 6-bromo-N-[ 5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-bromo-N-[ 4-Methoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-chloro -7-(cyanomethyl)-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-(methylthio)-1H-indole-3-sulfo Amide; 6-(difluoromethyl)-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-[5-(2,2-Difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-1H-indole-3-sulfonyl Amine; N-[5-(cyanomethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-1H-indole-3-sulfonamide ; N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-1H-pyrrolo[2,3-b ]pyridine-3-sulfonamide; 6-bromo-N-[5-(2-cyanoethyl)-4-methoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3 -sulfonamide; 6-bromo-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonate Amide; 6-bromo-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3 -sulfonamide; 6-bromo-N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3- Sulfonamide; 6-Bromo-N-[5-(cyanomethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonyl Amine; 6-bromo-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6 -Bromo-N-[5-(cyanomethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-(difluoromethyl )-7-fluoro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-[5-( Difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-7-fluoro-1H-indole-3-sulfonamide; N-[ 5-(2,2-Difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-7-fluoro-1H-indole-3- Sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-7-fluoro-1H -Indole-3-sulfonamide; N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-7 -Fluoro-1H-indole-3-sulfonamide; N-[5-(cyanomethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl )-7-fluoro-1H-indole-3-sulfonamide; 7-bromo-6-chloro-N-[5-(2-cyanoethyl)-4-methoxy-pyrimidin-2-yl ]-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-fluoro-1H -indole-3-sulfonamide; N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-fluoro-1H-indole-3 -sulfonamide; 6-chloro-N-[5-(difluoromethoxymethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6- Chloro-N-[5-(2,3-difluoropropyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N -[5-(cyanomethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(cyano methoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 7-bromo-6-chloro-N-[5-(2,2-difluoro Ethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-7-(cyanomethoxy)-N-[5- (2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide and pharmaceutically acceptable salts thereof. ,

[0091] Processes for the preparation of compounds of formula I described herein are objects of the present invention.

[0092] The compound of formula I of the present invention and its pharmaceutically acceptable salt can be prepared by methods known in the art, such as by the method described below, the method comprising a) making the compound of formula II and the compound of formula III

[0093] Reaction in the presence of a base selected from N,N-diisopropylethylamine or pyridine, to obtain formula I compound I wherein substituents R1, R2, R3, R4 and X1 and X2 are as defined above, or a ) reacting a compound of formula IV with a halogenating agent such as N-bromosuccinimide gives compound I of formula I wherein R2 is halogen, such as Br, and the other substituents are as defined above. b) make compound I of formula I wherein R2 is a halogen, react with a cyanating agent such as zinc cyanide in the presence of a palladium catalyst such as tetrakis (triphenylphosphine) palladium to obtain compound I of formula I wherein R2 is a cyano group, and other Substituents are as defined above.

[0094] general synthesis scheme

[0095] Compounds of formula I can be prepared according to the above method variants and Scheme 1 below. Starting materials are commercially available or can be prepared according to known methods.

[0096] Scheme 1

[0097] Compounds of general formula I can be prepared by reacting sulfonyl chloride II with 2-amino-pyrimidine III in the presence of a base such as N,N-diisopropylethylamine, pyridine, potassium phosphate or sodium hydride . II can be obtained from intermediate V in the presence of a chlorosulfonating agent such as chlorosulfonic acid or in the presence of a sulfonylating agent such as sulfur trioxide N,N-dimethylformamide complex, followed by chlorination Agents such as thionyl chloride chlorination intermediate sulfonic acid to prepare.

[0098] 2-Amino-pyrimidines of formula III are commercially available or can be prepared according to known methods or can be prepared according to process variants described in Schemes 2-7 below. Starting materials are commercially available or can be prepared according to known methods.

[0099] Scheme 2 wherein R2 is an alkoxy group 2-amino-pyrimidines of formula III can be prepared by deprotecting intermediate IX in the presence of an acid such as trifluoroacetic acid, wherein P1 is a protecting group such as p-methoxybenzyl, 3-4-dimethoxybenzyl or Boc group. IX can be obtained by alkylation of alcohol VIII in the presence of a base such as cesium or potassium carbonate or sodium or potassium hydroxide and an alkylating agent RX. Alcohols VIII can be prepared from dihalogenated starting materials VI by reacting VI with protected amines to give monohalogenated intermediates VII, which are first converted to boronate esters and then reacted with an oxidizing agent such as hydrogen peroxide. It is oxidized in the presence.

[0100] Scheme 3 wherein R1 is an alkoxy group or a thiolalkyl group. The 2-amino-pyrimidine of formula III can be prepared by halogenating the starting material X in alcohol or thiol and a base such as sodium hydride or III in which R1 is an alkoxy group can be prepared by alkylation of alcohol XI.

[0101] Scheme 4 2-Amino-pyrimidines of formula III wherein R1 and R3 are alkoxy groups can be prepared by reacting the dihalogenated starting material XII in the presence of an alcohol and a base such as sodium hydride.

[0102] Scheme 5 wherein R2 is alkyl, alkenylalkyl, alkynyl, cyanoalkyl, cycloalkyl, heterocycloalkyl The 2-amino-pyrimidine of formula III can be obtained by making intermediate IX in Prepared by deprotection in the presence of an acid such as trifluoroacetic acid, where P1 is a protecting group such as p-methoxybenzyl or Boc group. IX can be obtained from the monohalogenated intermediate VII under well-known metal-catalyzed cross-coupling reaction conditions.

[0103] Scheme 6 2-amino-pyrimidines of formula III wherein R3 is an alkoxy group can be prepared by reacting the halogenated starting material XV in the presence of an alcohol and a base such as sodium hydride. XV can be prepared from the keto-ester XIII by reacting it with guanidine-hydrochloride in the presence of a base such as sodium methoxide to give the alcohol intermediate XIV, which is then reacted with a halogenating agent such as phosphorus oxychloride.

[0104] Scheme 7 wherein R1 is an alkyl, cycloalkyl, heterocycloalkyl group 2-amino-pyrimidine of formula III can be obtained by making the halogenated starting material X under Suzuki reaction conditions in the boronic acid-ester and prepared by reaction in the presence of palladium catalyst.

[0105] Intermediates of formula V are commercially available or can be prepared according to known methods or according to process variants described in Schemes 8-9 below. Starting materials are commercially available or can be prepared according to known methods.

[0106] Scheme 8 Intermediates of formula V wherein X2 is NH can be prepared by reacting nitro starting material XVI under Bartoli reaction conditions in the presence of vinylmagnesium bromide.

[0107] Scheme 9 Intermediates of formula V wherein X2 is NH can be prepared following the Larock synthetic route starting from amine XVII which is converted to iodine intermediate XVIII in the presence of an iodinating agent such as N-iodosuccinimide. XVIII is then converted to the trimethylsilylated intermediate XIX in the presence of trimethylsilylacetylene, a palladium catalyst such as tetrakis(triphenylphosphine)palladium, and a base such as potassium carbonate. Reaction of XIX with tetrabutylammonium fluoride provides intermediates of formula V.

[0108] The present invention thus relates to compounds according to the invention prepared according to the process of the invention.

[0109] An embodiment of the present invention is a method for preparing a compound of formula I as defined above, the method comprising making a compound of II and a compound of formula III in the presence of a base selected from N,N-diisopropylethylamine or pyridine Reaction, wherein R1, R2, R3, R4, X1 and X2 are as defined above.

[0110] Another embodiment of the present invention provides pharmaceutical compositions or medicaments comprising the compounds of the present invention and therapeutically inert carriers, diluents or excipients, and methods of preparing such compositions and medicaments using the compounds of the present invention . In one example, a compound of formula I can be prepared by combining a compound of formula I with a physiologically acceptable carrier (i.e., nontoxic to recipients at the dosage and concentration employed) at an appropriate pH at ambient temperature, and at a desired degree of purity. carrier) to be formulated into a galenical administration form. The pH of the formulation depends largely on the particular use and concentration of the compound, but in any case a preferred range is from about 3 to about 8. In one example, the compound of formula I is formulated in ethyl acetate buffer (pH 5). In another embodiment, the compound of Formula I is sterile. Compounds can be stored, for example, as a solid or amorphous composition, as a lyophilized preparation, or as an aqueous solution.

[0111] The compositions will be formulated, dosed, and administered in a manner consistent with good medical practice. In such cases, considerations include the particular disorder being treated, the particular mammal being treated, the individual patient's clinical condition, the cause of the disorder, the site of delivery, the method of administration, the schedule of administration, and the health care practitioner's history. other known factors.

[0112] The compounds of the present invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, Intradermal, intrathecal and epidural and intranasal, and, if desired, for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.

[0113] The compounds of the present invention may be administered in any convenient administration form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches and the like. These compositions may contain conventional ingredients in pharmaceutical preparations, such as diluents, carriers, pH regulators, sweeteners, fillers and other active agents.

[0114] A typical formulation is prepared by admixing a compound of the invention with a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R. et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, penetrants, glidants, processing aids, colorants Agents, sweeteners, flavoring agents, flavoring agents, diluents and other known additives to provide good presentation of drugs (ie, compounds of the present invention or pharmaceutical compositions thereof) or to assist in the manufacture of drugs (ie, medicaments) .

[0115] The compound of formula I and its pharmaceutically acceptable salts can be processed together with pharmaceutically inert, inorganic or organic adjuvants for the manufacture of lozenges, coated tablets, dragees, hard gelatin capsules, injection solutions or topical For formulations, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used as such adjuvants for tablets, dragees and hard gelatin capsules.

[0116] Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols and the like.

[0117] Suitable adjuvants for producing solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, and the like.

[0118] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.

[0119] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols and the like.

[0120] Suitable adjuvants for topical ophthalmic formulations are, for example, cyclodextrins, mannitol, or many other carriers and excipients known in the art.

[0121] In addition, pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for changing the osmotic pressure, buffers, masking agents agents or antioxidants. They may also contain other therapeutically valuable substances.

[0122] The dosage may vary within wide limits and will, of course, be adapted to the individual requirements of each particular case. In general, in the case of oral administration, a daily dose of about 0.1 mg to 20 mg / kg body weight, preferably about 0.5 mg to 4 mg / kg body weight (eg about 300 mg per person) is preferably divided into 1 Up to 3 separate doses (which may consist, for example, of the same amount) should be appropriate. In the case of topical administration, the formulation may contain the drug at 0.001% to 15% by weight and the required dosage may be between 0.1 and 25 mg administered in single daily or weekly doses, or multiple daily doses. Doses (2 to 4 doses) are administered, or multiple doses are administered weekly, however, it will be apparent that the upper or lower limits given herein may be exceeded when indicated.

[0123] The present invention also particularly relates to: compounds of formula I for use as therapeutically active substances; compounds of formula I for the treatment of diseases regulated by GPR17;

[0124] Likewise, the subject of the invention is a pharmaceutical composition comprising a compound of formula I as described herein and a therapeutically inert carrier.

[0125] A use of a compound of formula I for treating or preventing diseases caused by direct myelin damage (including but not limited to pontine central and extrapontine myelin lysis, carbon monoxide poisoning, nutritional deficiency, and virus-induced demyelination myelin), demyelinating disorders (including but not limited to multiple sclerosis, acute and multistage disseminated encephalomyelitis, panneuromyelitis optica, and leukodystrophy), myelin-associated Central nervous system disorders (including but not limited to Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and stroke-induced ischemia) and such as encephalitis, primary Inflammation of the central nervous system following acute vasculitis, meningitis, and obesity.

[0126] An embodiment of the present invention is the use of the compound of formula I for the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease or Huntington's disease.

[0127] A particular embodiment of the present invention is the use of a compound of formula I for the treatment or prevention of multiple sclerosis.

[0128] A use of a compound of formula I for the preparation of a medicament for the treatment or prevention of conditions caused by: direct damage to the myelin sheath (including but not limited to pontine central and extrapontine myelin lysis, carbon monoxide poisoning, nutritional deficiency and virus-induced demyelination), demyelinating disorders (including but not limited to multiple sclerosis, acute and multistage disseminated encephalomyelitis, panneuromyelitis optica, and leukodystrophy), and Central nervous system disorders associated with loss of myelin sheath (including but not limited to Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and stroke-induced ischemia) and Examples include encephalitis, primary vasculitis, meningitis, and central nervous system inflammation following obesity.

[0129] An embodiment of the present invention is the use of a compound of formula I for the preparation of a medicament for the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease or Huntington's disease.

[0130] A specific embodiment of the present invention is the use of the compound of formula I for the preparation of a medicament for the treatment or prevention of multiple sclerosis.

[0131] A compound of formula I for use in the treatment or prevention of disorders caused by direct myelin damage (including but not limited to central and extrapontine myelin lysis, carbon monoxide poisoning, nutritional deficiency, and virus-induced demyelination ), demyelinating disorders (including but not limited to multiple sclerosis, acute and multistage disseminated encephalomyelitis, panneuromyelitis optica, and leukodystrophy), central nervous system disorders associated with myelin loss Systemic diseases (including but not limited to Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and stroke-induced ischemia) and such as encephalitis, primary vascular Inflammation of the central nervous system following inflammation, meningitis, and obesity.

[0132] An embodiment of the present invention is a compound of formula I for use in the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease or Huntington's disease.

[0133] A particular embodiment of the invention is a compound according to formula I for the treatment or prevention of multiple sclerosis.

[0134] A condition for the treatment or prevention of direct damage to myelin (including but not limited to central and extrapontine myelin lysis, carbon monoxide poisoning, nutritional deficiency and virus-induced demyelination), myelin demyelination Loss disorders (including but not limited to multiple sclerosis, acute and multistage disseminated encephalomyelitis, panneuromyelitis optica disorders, and leukodystrophy), central nervous system disorders associated with myelin loss (including but not limited to Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and stroke-induced ischemia) and such as encephalitis, primary vasculitis, meningitis and A method of central nervous system inflammation following obesity, the method comprising administering an effective amount of a compound of formula I to a patient in need thereof.

[0135] Embodiments of the present invention provide a method for treating or preventing multiple sclerosis, Alzheimer's disease, Parkinson's disease or Huntington's disease, the method comprising administering to a patient in need thereof an effective amount of a compound of formula I.

[0136] 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.

[0137] Furthermore, embodiments of the invention provide compounds of formula I as described herein when prepared according to any of the methods described.

[0138] Measuring procedure

[0139] GPR17 cAMP determination procedure:

[0140] At 37° C. / 5% CO Under conditions, in DMEM (Dulbecco's Modified Eagle Medium, Dulbecco's Modified Eagle Medium) supplemented with 10% fetal bovine serum and 400 μg / ml Geneticin: F-12 (1: 1) CHO-K1 cells stably expressing a vector containing the untagged human GPR17 short isoform (Roche) were cultured in medium.

[0141] Changes in intracellular cyclic adenosine monophosphate (cAMP) levels were quantified using the Nano-TRF Detection Assay Kit (Roche Diagnostics, Cat. No. 05214386001). This assay allows direct cAMP quantification in homogeneous solutions. Detection of cAMP is based on time-resolved fluorescence energy transfer (TR-FRET) and competitive binding of ruthenylated cAMP and endogenous cAMP to an anti-cAMP monoclonal antibody labeled with AlexaFluor-700. Ruthenium complexes act as FRET donors and transfer energy to AlexaFluor-700. FRET signal is inversely proportional to cAMP concentration.

[0142] CHO-GPR17S cells were separated with Accutase and resuspended in Hank's Balanced Salt Solution (HBSS), 10mM HEPES (4-(2-hydroxyethyl)piperone-1-ethanesulfonic acid solution) and 0.1% The assay buffer consisted of bovine serum albumin (pH 7.4). Cells were seeded in black 384-well plates (Corning) at a density of 10,000 cells / 20 µl in assay buffer until addition of compounds.

[0143] Test antagonist compounds were serially diluted in dimethylsulfoxide (DMSO) and spotted in 384-well plates. Then, the compound was added to MDL29,951 (3-(2-carboxy-4,6-dichloroindol-3-yl)propionic acid) (GPR17 agonist) supplemented with EC80 concentration plus 3-isobutyl- 1-Methylxanthine (IBMX) (0.5mM final concentration) was diluted in HBSS buffer and added to the cells at room temperature. Test compounds and cells were incubated for 30 minutes at room temperature, followed by the addition of Forskolin (15 μM final concentration) after 5 minutes. The assay was stopped by adding cAMP detection mix (containing detergent for cell lysis) for 90 min at room temperature.

[0144] Cellular cAMP was measured using a Paradigm reader (Molecular Devices). The FRET signal was calculated using the raw data based on the measured P-factor according to the cAMP kit instructions. Data were normalized to the maximum activity of the reference antagonist and dose response curves were fitted to the percent activity of the test compound using a sigmoidal dose response model (Genedata Screener).

[0145] The assay results of hGPR17 cAMP of the compound of formula I are provided in Table 1

[0146] Table 1: instance number hGPR17 cAMP IC50 [µM] 1 0.069 2 0.036 3 0.050 4 0.034 5 0.103 6 0.129 7 0.403 8 0.182 9 0.218 10 0.096 11 0.091 12 0.020 13 0.236 14 0.215 15 0.132 16 0.023 17 0.019 18 0.083 19 0.049 20 0.399 twenty one 0.012 twenty two 0.515 twenty three 0.256 twenty four 0.051 25 0.023 26 0.809 27 0.083 28 0.653 29 0.080 30 0.043 31 0.076 32 0.232 33 0.569 34 0.924 35 0.479 36 0.119 37 0.068 38 2.675 39 0.287 40 0.628 41 0.021 42 0.194 43 0.060 44 0.131 45 0.082 46 0.918 47 0.019 48 0.026 49 0.809 50 2.791 51 0.094 52 0.032 53 0.011 54 0.017 55 0.017 56 0.013 57 0.034 58 0.017 59 0.013 60 0.008 61 0.007 62 0.012 63 0.182 64 0.039 65 0.061 66 0.019 67 0.065 68 0.009 69 0.014 70 2.741 71 11.456 72 0.040 73 0.124 74 0.142 75 0.946 76 0.916 77 0.148 78 0.244 79 0.128 80 20.833 81 5.705 82 0.752 83 0.078 84 0.521 85 0.623 86 0.117 87 0.066 88 0.033 89 0.212 90 0.029 91 0.030 92 0.018 93 0.010 94 0.076 95 0.068 96 0.029 97 0.050 98 0.025 99 0.102 100 0.160 101 0.029 102 0.014 103 0.011 104 0.209 105 0.014 106 0.007 107 0.012 108 0.642 109 0.036 110 0.025 111 0.013 112 0.016 113 0.021 114 0.045 115 0.026 116 0.026 117 0.030 118 0.033 119 0.161 120 0.040 121 0.016 122 0.036 123 0.091 124 0.034 125 0.023 126 0.082 127 0.030 128 0.446 129 0.961 130 0.386 131 0.116 132 0.039 133 0.076 134 0.124 135 0.187 136 0.747 137 0.442 138 20.833 139 0.106 140 0.050 141 0.014 142 0.029 143 0.109 144 0.050 145 0.152 146 0.089 147 0.104 148 0.049 149 0.147 150 0.039 151 0.029 152 0.104 153 0.353 154 0.045 155 0.116 156 0.092 157 0.176 158 0.047 159 0.218 160 0.011 161 0.072 162 0.248 163 0.216 164 0.126 165 1.107 166 1.155 167 0.259 168 0.026 169 0.020 170 0.162 171 0.089 172 0.015 173 0.877 174 0.484 175 0.073 176 0.047 177 0.162 178 0.108 179 0.031 180 0.305 181 16.815 182 0.101 183 0.023 184 0.029 185 0.089 186 0.013 187 0.018 188 0.028 189 0.167 190 0.106 191 0.033 192 0.020 193 0.096 194 0.025 195 0.054 196 0.016 197 0.981 198 0.036 199 0.008 200 0.066 201 0.030 202 0.028 203 0.127 204 0.029 205 0.049 206 0.057 207 0.014 208 0.025 209 0.068 210 0.018 211 0.030 212 0.045 213 0.034 214 0.038 215 0.028 216 0.043 217 0.017 218 0.014 219 0.018 220 0.027 221 0.065 222 0.291 223 0.040 224 0.025 225 0.032 226 0.035 227 0.022 228 0.161 229 0.027 230 0.041 231 0.021 232 0.035 233 0.202 234 0.016 235 0.032 236 0.014 237 0.034 238 0.383 239 0.046 240 0.048 241 0.021 242 0.043 243 0.009 244 0.016 245 0.027 246 0.019 247 0.042 248 0.367 249 0.036 250 0.035 251 0.022 252 0.014 253 0.020 254 0.075 255 0.038 256 0.215 257 0.084 258 0.037 259 0.025 260 0.488 261 0.091 262 0.040 263 2.061 264 0.023 265 0.014 266 0.090 267 0.049 268 0.165 269 0.138 270 0.072 271 0.290 272 1.177 273 0.128 274 0.237 275 0.128 276 0.136 277 0.718 278 0.229 279 0.069 280 0.062 281 0.237 282 0.110 283 0.013 284 0.273 285 0.117 286 0.203 287 0.114 288 0.057 289 0.069 290 0.405 291 0.842 292 0.433 293 0.240 294 0.024

[0147] Microsomal clearance determination procedure:

[0148] Incubate with 1 mM test compound (0.5 mg / mL) in microsomes and the cofactor NADPH in 96-well plates at 37°C on a TECAN (Tecan Group Ltd, Switzerland) automated liquid handling system. During the incubation, the final concentration of the test compound was 1 microM. After 10 min pre-incubation of the test compound with the microsomes, the enzymatic reaction is started by adding cofactors. At 1, 3, 6, 9, 15, 25, 35, and 45 minutes, aliquots of the incubation were removed and quenched with 1:3 (v / v) acetonitrile containing an internal standard. The samples were then cooled and centrifuged, and the supernatant analyzed by LC-MS / MS.

[0149] Reference Examples RE-A, RE-B, RE-C, RE-D, RE-E and RE-F have been prepared as described herein.

[0150] Reference compounds were tested for microsomal clearance against exemplified compounds. The results are shown in Table 2 below.

[0151] Table 2. compound Microsomal clearance (µL / min / mg protein) for human, mouse, and rat Example 1 16, 10, 29 Example 123 10, 10, 10 Example 47 10, 10, 110 Instance 179 10, 10, 33 Example 48 10, 29 Example 22 10, 10, 10 RE-A 121, 77, 357 RE-B 11, 26, 65 RE-C 35, 81, 286 RE-D 103, 121, 869 RE-E 153,385 RE-F 29, 129, 166

[0152] The invention will now be illustrated by the following examples without limiting character.

[0153] If the preparation example is a mixture of enantiomers, the pure enantiomer can be obtained by the methods described herein or known to those skilled in the art, such as chiral chromatography or crystallization.

[0154] Example

[0155] If not stated otherwise, all examples and intermediates were prepared under nitrogen atmosphere.

[0156] Intermediate A

[0157] Intermediate A1: 6-chloro-1H-indole-3-sulfonyl chloride

[0158]

[0159] Intermediate A1 is commercially available (CAS: 1216060-79-5)

[0160] Intermediate A2: 6-bromo-1H-indole-3-sulfonyl chloride

[0161]

[0162] Intermediate A2 is commercially available (CAS: 2137914-35-1)

[0163] Intermediates A3-A9

[0164] Intermediates A3-A9 are known and have been prepared following the procedures described in the indicated patent applications: Intermediate number structure Name (CAS No.) Patent application number A3 6-Chlorobenzothiophene-3-sulfonyl chloride (1593831-66-3) WO2018122232 A4 6-Bromo-1H-pyrrolo[2,3-b]pyridine-3-sulfonyl chloride (2231234-27-6) WO2018122232 A5 6-Chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonyl chloride (2231234-21-0) WO2018122233 A6 6-Chloro-7-fluoro-1H-indole-3-sulfonyl chloride (2231234-36-7) WO2018122233 A7 6-Chloro-7-(difluoromethyl)-1H-indole-3-sulfonyl chloride (2404661-51-2) WO2019243398 A8 6,7-Dichloro-1H-indole-3-sulfonyl chloride (1780326-24-0) WO2019243398 A9 6-Chloro-7-(cyclopropoxy)-1H-indole-3-sulfonyl chloride (2404661-50-1) WO2019243398

[0165] Intermediate A10: 6-chlorothieno[2,3-b]pyridine-3-sulfonyl chloride

[0166]

[0167] 6-chlorothieno[2,3-b]pyridine (50 mg, 0.295 mmol, CAS: 62226-18-0) was dissolved in chlorosulfonic acid (708.12 mg, 406.97 uL, 5.9 mmol) at room temperature . The mixture was stirred at 60 °C for 2 h, then added to a stirred mixture of ice water (10 ml) / ethyl acetate (10 ml). The two layers separate quickly. The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound (80 mg, 96% yield) as a dark brown solid. MS (ESI): m / z=268.0 [M+H]+

[0168] intermediate A11-A20

[0169] Intermediates A11-A20 are known and have been prepared following the procedures described in the indicated patent applications: Intermediate number structure Name (CAS No.) Patent application number A11 6-Fluoro-1H-indole-3-sulfonyl chloride (1216026-07-1) WO2018122232 A12 6-Methyl-1H-indole-3-sulfonyl chloride (1367937-31-2) WO2018122232 A13 7-Bromo-6-chloro-1H-indole-3-sulfonyl chloride (2231234-40-3) WO2018122232 A14 6-Bromo-7-methyl-1H-indole-3-sulfonyl chloride (2231234-52-7) WO2018122232 A15 6-Chloro-5-fluoro-1H-indole-3-sulfonyl chloride (2231234-44-7) WO2018122232 A16 6-Chloro-7-methoxy-1H-indole-3-sulfonyl chloride (2231234-35-6) WO2018122232 A17 6-Cyclopropyl-1H-indole-3-sulfonyl chloride (2231234-20-9) WO2018122232 A18 6-(Difluoromethyl)-7-fluoro-1H-indole-3-sulfonyl chloride (2404661-52-3) WO2019243398 A19 6-Chloro-7-(difluoromethoxy)-1H-indole-3-sulfonyl chloride (2231234-59-4) WO2018122232 A20 6-(Trifluoromethyl)-1H-indole-3-sulfonyl chloride (1784173-91-6) WO2018122232

[0170] Intermediate A21-A31

[0171] Intermediates A21-A31 were prepared in a similar manner to sulfonyl chloride intermediate A10 by chlorosulfonylation of their respective non-sulfonylated precursors in the presence of chlorosulfonic acid. Precursors are commercially available or described in designated patent applications: Intermediate number structure name Non-sulfonylated starting material name (CAS number, patent application number) A21 6-Bromothieno[2,3-b]pyridine-3-sulfonyl chloride 6-Bromothieno[2,3-b]pyridine (CAS: 1836214-86-8, commercially available) A22 6-Bromo-7-fluoro-1H-indole-3-sulfonyl chloride 6-Bromo-7-fluoro-1H-indole (CAS: 936901-94-9, commercially available) A23 6-Chloro-7-methyl-1H-indole-3-sulfonyl chloride 6-Chloro-7-methyl-1H-indole (CAS: 57817-09-1, commercially available) A24 6-Ethyl-1H-indole-3-sulfonyl chloride 6-Ethyl-1H-indole (CAS: 4765-24-6, commercially available) A25 6-Methylmercapto-1H-indole-3-sulfonyl chloride 6-(Methylthio)-1H-indole (CAS: 202584-22-3, commercially available) A26 6-(Difluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonyl chloride 6-(Difluoromethyl)-1H-pyrrolo[2,3-b]pyridine (CAS: 1261488-22-5, WO2018122232) A27 6-(Difluoromethyl)-1H-indole-3-sulfonyl chloride 6-(Difluoromethyl)-1H-indole (CAS: 127956-27-8, commercially available) A28 6-Propyl-1H-indole-3-sulfonyl chloride 6-Propyl-1H-indole (CAS: 1043602-17-0, WO2015110092) A29 6-Bromo-7-methoxy-1H-indole-3-sulfonyl chloride 6-Bromo-7-methoxy-1H-indole (CAS:938061-65-5, US20070123527) A30 6-(Difluoromethoxy)-1H-indole-3-sulfonyl chloride 6-(Difluoromethoxy)-1H-indole (CAS: 200207-21-2, commercially available) A31 6-(cyanomethyl)-1H-indole-3-sulfonyl chloride 2-(1H-Indol-6-yl)acetonitrile (CAS:39689-57-1, WO2021111124)

[0172] Intermediate A32: 6-chloro-7-methylsulfanyl-1H-indole-3-sulfonyl chloride

[0173]

[0174] Step 1: 1-chloro-2-(methylthio)-3-nitro-benzene

[0175]

[0176] To 1-chloro-2-fluoro-3-nitrobenzene (600 mg, 402.68 uL, 3.42 mmol, commercially available) under argon in ultra-dry N,N-dimethylformamide (7 mL), NaSMe (311.44 mg, 4.44 mmol) was added. The brown reaction was stirred at room temperature for 3.5 h, and 0.5 eq of NaSMe was added. The reaction mixture was stirred for another 30 min, quenched with bleach and extracted 3 times 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 ethyl acetate / heptane 0%-5% to afford the title compound (311 mg, 44% yield) as an orange oil.

[0177] Step 2: 6-Chloro-7-methylsulfanyl-1H-indole

[0178]

[0179] Under argon, a solution of 1-chloro-2-(methylthio)-3-nitro-benzene (346 mg, 1.53 mmol) in ultra-dry THF (5 mL) was cooled to - 78°C. 1 M Vinylmagnesium bromide (4.59 mL, 4.59 mmol) was added over 8 min and the dark orange solution was stirred for 4.5 h. Add 1 M vinylmagnesium bromide (0.76 mL, 0.765 mmol). After 5.5 hours, the reaction mixture was quenched with saturated ammonium chloride solution. The aqueous phase was extracted twice with ethyl acetate, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-5% to afford the title compound (150 mg, 50% yield) as an orange oil. MS (ESI): m / z= 198.1 [M+H]+

[0180] Step 3: 6-chloro-7-methylsulfanyl-1H-indole-3-sulfonyl chloride

[0181]

[0182] The title compound was prepared as a pale yellow oil from 6-chloro-7-methylsulfanyl-1H-indole in a similar manner to Intermediate A10. MS (ESI): m / z= 294.0 [M+H]+

[0183] Intermediate A33: 6-chloro-7-(fluoromethoxy)-1H-indole-3-sulfonyl chloride

[0184]

[0185] Step 1: 1-chloro-2-(fluoromethoxy)-3-nitro-benzene

[0186]

[0187] To a solution of 2-chloro-6-nitrophenol (1.8 g, 10.37 mmol, commercially available) in DMF (40 mL) was added NaH (622.82 mg, 15.56 mmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 h and fluoro(iodo)methane (2.5 g, 15.56 mmol) was added. The reaction mixture was stirred at 25 °C for 12 h, quenched with water (50 mL), and extracted twice with ethyl acetate (50 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate / ether 0%-5% to afford the title compound (1.6 g, 75% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ = 7.79 (dd, J = 1.6, 8.2 Hz, 1H), 7.71 (dd, J = 1.6, 8.1 Hz, 1H), 7.32 (t, J = 8.2 Hz, 1H), 5.77 (s, 1H), 5.63 (s, 1H)

[0188] Step 2: 6-chloro-7-(fluoromethoxy)-1H-indole

[0189]

[0190] In a similar manner to Intermediate A32, Step 2, the title compound was prepared as a brown oil from 1-chloro-2-(fluoromethoxy)-3-nitro-benzene. 1H NMR (400 MHz, CDCl3) δ ppm 8.41 - 8.84 (m, 1 H) 7.39 - 7.43 (m, 1 H) 7.23 - 7.26 (m, 1 H) 7.10 - 7.14 (m, 1 H) 6.54 - 6.58 ( m, 1H) 5.67 - 5.85 (m, 2H)

[0191] Step 3: 6-chloro-7-(fluoromethoxy)-1H-indole-3-sulfonyl chloride

[0192]

[0193] The title compound was prepared as a gray oil from 6-chloro-7-(fluoromethoxy)-1H-indole in a similar manner to intermediate A10.

[0194] Intermediate A34: 6-chloro-7-(difluoromethylsulfanyl)-1H-indole-3-sulfonyl chloride

[0195]

[0196] Step 1: 2-chloro-6-nitro-thiophenol

[0197]

[0198] To a solution of 2,3-dichloronitrobenzene (20.0 g, 104.17 mmol, commercially available) in DMSO (300 mL) was added sodium sulfide (8.53 g, 109.38 mmol) at 25 °C. The mixture was stirred at 25°C for 18 hours. The reaction mixture was poured into water (1000 mL), and 3M HCl was added to the reaction mixture until the pH was adjusted to 4, extracted with ethyl acetate (3 x 300 mL), the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / ether 0%-30% to afford the title compound (12 g, 61% yield) as a brown solid.

[0199] Step 2: 1-Chloro-2-(difluoromethylsulfanyl)-3-nitro-benzene

[0200]

[0201] To a 30°C mixture of 2-chloro-6-nitro-thiophenol (6.0 g, 31.64 mmol) in acetonitrile (300 mL) was added KOH (17.75 g, 316.42 mmol) followed by (bromodi Diethyl fluoromethyl)phosphonate (33.8 g, 126.57 mmol). The reaction mixture was stirred at 30 °C for 12 h, poured into water (500 mL), and extracted with ethyl acetate (3x200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / ether 0%-30% to afford the title compound (5 g, 66% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ = 8.06 - 7.98 (m, 2H), 7.85 - 7.78 (m, 1H), 7.59 - 7.28 (m, 1H)

[0202] Step 3: 6-chloro-7-(fluoromethylsulfanyl)-1H-indole

[0203]

[0204] In a similar manner to Intermediate A32, Step 2, the title compound was prepared as a yellow oil from 1-chloro-2-(difluoromethylsulfanyl)-3-nitro-benzene. 1H NMR (400 MHz, DMSO-d6) δ = 11.50 (br s, 1H), 7.72 (d, J = 8.3 Hz, 1H), 7.54 - 7.36 (m, 2H), 7.25 (d, J = 8.4 Hz, 1H), 6.57 (dd, J = 1.9, 3.1 Hz, 1H)

[0205] Step 4: 6-chloro-7-(fluoromethylsulfanyl)-1H-indole-3-sulfonyl chloride

[0206]

[0207] The title compound was prepared as a pale red solid from 6-chloro-7-(fluoromethylsulfanyl)-1H-indole in a similar manner to intermediate A10.

[0208] Intermediate A35: 6-chloro-7-cyclopropyl-1H-indole-3-sulfonyl chloride

[0209]

[0210] Step 1: 6-chloro-7-cyclopropyl-1H-indole

[0211]

[0212] To 7-bromo-6-chloro-1H-indole (6.50 g, 28.2 mmol, commercially available) and cyclopropyl-boronic acid (3.63 g, 42.3 mmol, 3.59 mL) at 25°C under nitrogen in To a solution in dioxane (100 mL) and water (10.0 mL) were added PdCl2(dppf) (2.30 g, 2.80 mmol) and potassium phosphate (11.9 g, 56.4 mmol) in one portion. The mixture was stirred at 100°C for 16 hours. The mixture was filtered and concentrated in vacuo. The residue was extracted with dichloromethane (2x50 mL), and the combined organic phases were washed with brine (2x50.0 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase chromatography (column: YMC Triart C18 250 × 50 mm × 7 um) using gradient water (10 mM NH4HCO3) - ACN 48%-68% to give the title compound as a yellow solid ( 5 g, 92.6 % yield). MS (ESI): m / z= 191.9 [M+H]+

[0213] Step 2: 6-Chloro-7-methylsulfanyl-1H-indole-3-sulfonyl chloride

[0214]

[0215] The title compound was prepared as a white solid from 6-chloro-7-cyclopropyl-1H-indole in a similar manner to intermediate A10. MS (ESI): m / z= 288.1 [M+H]+

[0216] Intermediate A36: 6-chloro-7-(cyanomethyl)-1H-indole-3-sulfonyl chloride

[0217]

[0218] Step 1: 2-(6-Chloro-1H-indol-7-yl)acetonitrile

[0219]

[0220] 7-bromo-6-chloro-1H-indole (12.7 g, 55.1 mmol, commercially available) and 4-(4,4,5,5-tetramethyl- 1,3,2-Dioxaborolan-2-yl)isoxazole (13.9 g, 71.6 mmol, commercially available) was added in one portion in a mixture of DMSO (380 mL) and HO (190 mL) KF (9.60 g, 165 mmol, 3.87 mL), then Pd(dppf)Cl2 (8.06 g, 11.0 mmol) was added to the mixture. The mixture was slowly warmed to 120°C and stirred for 12 hours. The mixture was quenched with H2O (950 mL), extracted with ethyl acetate (3x100 mL). The combined organic phases were washed with brine (2x50.0 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / ether 0%-100% to afford the title compound (1.3 g, 12% yield) as a gray solid. MS (ESI): m / z= 191.0 [M+H]+

[0221] Step 2: 6-chloro-7-(cyanomethyl)-1H-indole-3-sulfonyl chloride

[0222]

[0223] The title compound was prepared as an off-white solid from 2-(6-chloro-1H-indol-7-yl)acetonitrile in a similar manner to Intermediate A10. MS (ESI): m / z= 287.1 [M-H]-

[0224] Intermediate A37: 6-bromobenzothiophene-3-sulfonyl chloride

[0225]

[0226] To a suspension of sulfur trioxide n,n-dimethylformamide complex (539.06 mg, 3.52 mmol) in 1,2-dichloroethane (2.5 mL) was added 6-Bromobenzothiophene (500 mg, 2.35 mmol, CAS: 17347-32-9), and stirred at 22°C for 1 hour, then heated to 70°C for 18 hours. The reaction mixture was cooled to room temperature and thionyl chloride (614.14 mg, 376.77 uL, 5.16 mmol) was added. The mixture was stirred at 22 °C for 30 min, heated to 80 °C for 1 h and concentrated. The residue was extracted twice with ethyl acetate and washed twice with water. The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using heptane as eluent to afford the title compound (282 mg, 38% yield) as an off-white solid. MS (ESI): m / z= 292.9 [M-H]-(sulfonic acid)

[0227] Intermediate A38: 6-methylbenzothiophene-3-sulfonyl chloride

[0228]

[0229] The title compound was prepared as an off-white solid from 6-methylbenzothiophene (CAS: 16587-47-6, commercially available) in a similar manner to Intermediate A37. MS (ESI): m / z= 227.1 [M-H]-(sulfonic acid)

[0230] Intermediate A39: 7-chloro-1H-indole-3-sulfonyl chloride

[0232]

[0233] Intermediate A39 is commercially available (CAS: 1369230-76-1)

[0234] Intermediate A40: 6-chloro-7-fluoro-benzothiophene-3-sulfonyl chloride

[0235]

[0236] Step 1: Methyl 6-chloro-7-fluoro-benzothiophene-2-carboxylate

[0237]

[0238] To a mixture of methyl thiolacetate (4.57 g, 43.05 mmol) in DMF (90 mL) was added 4-chloro-2,3-difluoro-benzaldehyde (7.6 g, 43.05 mmol, CAS: 1160573 -23-8) and potassium carbonate (11.87 g, 86.09 mmol). The mixture was stirred at 40 °C for 16 h, diluted with water and extracted 3 times 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 ethyl acetate / petroleum ether 0%-5% to afford the title compound (8.7 g, 83% yield) as a white solid. 1H NMR (400 MHz, chloroform-d) δ = 8.03 (d, J = 3.5 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.42 (dd, J = 6.6, 8.5 Hz, 1H), 3.97 (s, 4H)

[0239] Step 2: 6-Chloro-7-fluoro-benzothiophene-2-carboxylic acid

[0240]

[0241] To a mixture of methyl 6-chloro-7-fluoro-benzothiophene-2-carboxylate (8700.0 mg, 35.56 mmol) in methanol (100 mL) and tetrahydrofuran (50 mL) was added dropwise 5 M aqueous NaOH (50.0 mL, 250 mmol). The reaction mixture was stirred at 25°C for 16 hours. Add 5M HCl to the reaction mixture to adjust the pH to 1-2. The mixture was diluted with water and extracted three times with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (8 g, 98% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 8.13 (d, J = 3.7 Hz, 1H), 7.87 (d, J = 8.6 Hz, 1H), 7.63 (dd, J = 7.0, 8.5 Hz, 1H)

[0242] Step 3: 6-chloro-7-fluoro-benzothiophene

[0243]

[0244] To a mixture of 6-chloro-7-fluoro-benzothiophene-2-carboxylic acid (1.0 g, 4.34 mmol) in DMF (40 mL) was added copper(I) chloride (1697.88 mg, 17.34 mmol) ). The reaction mixture was stirred at 120 °C for 16 hours, diluted with water and extracted 3 times 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 / petroleum ether 0%-1% to afford the title compound (600 mg, 74% yield) as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ = 7.54 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 5.3 Hz, 1H), 7.41 - 7.32 (m, 2H)

[0245] Step 4: 6-chloro-7-fluoro-benzothiophene-3-sulfonyl chloride

[0246]

[0247] To a solution of 6-chloro-7-fluoro-benzothiophene (100 mg, 0.536 mmol) in ultra-dry acetonitrile (5 mL) was added dropwise chlorosulfonic acid (202.92 mg, 115.75 uL , 1.74 mmol​). The mixture was stirred overnight at 22 °C. Phosphorus oxychloride (361.5 mg, 219.75 uL, 2.36 mmol) was added and the mixture was stirred at 50°C for 2 hours and at 70°C for 22 hours. The mixture was dropped onto ice (25 mL) and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (152 mg, 100% yield) as a light brown solid. MS (ESI): m / z= 265.0 [M-H]-(sulfonic acid)

[0248] Intermediate A41: 6,7-difluoro-1H-indole-3-sulfonyl chloride

[0249]

[0250] The title compound was prepared as a red solid from 6,7-difluoro-1H-indole (CAS: 271780-84-8) in a similar manner to intermediate A10. MS (ESI): m / z= 250.0 [M-H]-

[0251] Intermediate A42: 6,8-dihydro-1H-furo[3,4-g]indole-3-sulfonyl chloride

[0252]

[0253] Step 1: 5,7-diiodo-1,3-dihydroisobenzofuran-4-amine

[0254]

[0255] To a stirred suspension of 1,3-dihydroisobenzofuran-4-amine (1 g, 7.18 mmol, CAS: 98475-10-6) in toluene (10 mL) was added acetic acid (452.52 mg , 430.97 uL, 7.54 mmol), then iodosuccinimide (1.75 g, 7.54 mmol) was added. The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was 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%-50%, followed by flash chromatography on a C18 RediSepRf gold column using a gradient of acetonitrile / water 10%-100% to give The title compound (273 mg, 10% yield) as an off-white solid. MS (ESI): m / z= 388.0 [M+H]+

[0256] Step 2: (5-iodo-6,8-dihydro-1H-furo[3,4-g]indol-2-yl)-trimethyl-silane

[0257]

[0258] In a sealed tube, combine 5,7-diiodo-1,3-dihydroisobenzofuran-4-amine (1 g, 2.58 mmol), potassium carbonate (721.53 mg, 5.17 mmol), tetra( Triphenylphosphine)palladium(0) (301.64 mg, 0.258 mmol), XPhos​ (246.39 mg, 0.517 mmol) and trimethylsilylacetylene (310.81 mg, 438.37 uL, 3.1 mmol) in THF (40 mL) The mixture was heated to 75°C and stirred for 15 hours. The reaction mixture was 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%, followed by flash chromatography on a C18 RediSepRf gold column using a gradient of acetonitrile / water 10%-100% to give The title compound (341 mg, 37% yield) as a white solid. MS (ESI): m / z= 358.0 [M+H]+

[0259] Step 3: 5-iodo-6,8-dihydro-1H-furo[3,4-g]indole

[0260]

[0261] To (5-iodo-6,8-dihydro-1H-fur[3,4-g]indol-2-yl)-trimethyl-silane (339 mg, 0.949 mmol) at room temperature To a stirred solution in tetrahydrofuran (7 mL) was added dropwise a solution of 1 M tetrabutylammonium fluoride in THF (4.74 mL, 4.74 mmol). The reaction mixture was heated to 50°C and stirred for 16 hours. The reaction mixture 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 triturated with dichloromethane, filtered and dried in vacuo to give 220 mg of the desired product. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-30% to afford 24 mg of the desired product. Overall, the method provided the title compound (244 mg, 90% yield) as an orange solid. MS (ESI): m / z= 286.0 [M+H]+

[0262] Step 4: 6,8-dihydro-1H-furo[3,4-g]indole

[0263]

[0264] 5-iodo-6,8-dihydro-1H-furo[3,4-g]indole (250 mg, 0.877 mmol) and triethylamine (97.61 mg, 134.45 uL, 0.965 mmol) in ethanol (15 mL) was degassed with argon and palladium on activated carbon (93.32 mg, 0.088 mmol) was added. The reaction mixture was stirred at room temperature under 1 atm of hydrogen for 1 h, filtered through a pad of celite and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-50% to afford the title compound (125 mg, 90% yield) as a white solid. MS (ESI): m / z= 160.1 [M+H]+

[0265] Step 5: 6,8-dihydro-1H-furo[3,4-g]indole-3-sulfonyl chloride

[0266]

[0267] A solution of 6,8-dihydro-1H-furo[3,4-g]indole (65 mg, 0.408 mmol) in acetonitrile (1.5 mL) was cooled to 0°C. Chlorosulfonic acid (123.71 mg, 71.1 uL, 1.06 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 30 min and at room temperature for 3 h. The reaction mixture was poured into ice / ethyl acetate and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (44 mg, 42% yield) as a light brown solid. MS (ESI): m / z= 256.0 [M+H]+

[0268] Intermediate A43: 6-chloro-7-cyano-1H-indole-3-sulfonyl chloride

[0269]

[0270] Step 1: 6-Chloro-1H-indole-7-carbonitrile

[0271]

[0272] 7-bromo-6-chloro-1H-indole (377 mg, 1.6 mmol, CAS: 1427439-04-0), (768.39 mg, 6.41 mmol) and tetrakis [triphenylphosphine] palladium (0 ) (333.04 mg, 0.285 mmol) in N,N-dimethylacetamide (10 mL) was heated in a microwave at 160°C for 20 min. The reaction mixture was diluted with ethyl acetate and washed twice with brine. 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 ethyl acetate / heptane 0%-20% to afford the title compound (233 mg, 82% yield) as an off-white solid. MS (ESI): m / z= 175.0 [M-H]-

[0273] Step 2: 6-chloro-7-cyano-1H-indole-3-sulfonyl chloride

[0274]

[0275] The title compound was prepared as an off-white solid from 6-chloro-1H-indole-7-carbonitrile in a similar manner to Intermediate A10. MS (ESI): m / z= 273.0 [M-H]-

[0276] Intermediate A44: 6-(difluoromethyl)thieno[2,3-b]pyridine-3-sulfonyl chloride

[0277]

[0278] Step 1: 7-Oxythieno[2,3-b]pyridin-7-ium

[0279]

[0280] Thieno[2,3-b]pyridine (2 g, 1.54 mL, 14.79 mmol, CAS: 272-23-4) in dichloromethane (20 mL) and ethyl acetate (20 mL) To the solution was added m-CPBA (4.38 g, 17.75 mmol) in portions within 20 minutes at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. Solvent was removed under reduced pressure. The residue was diluted with dichloromethane and washed 3 times with saturated NaHCO3. The combined aqueous layers were extracted twice with dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (2.2 g, 96% yield) as a yellow oil. MS (ESI): m / z= 152.1 [M+H]+

[0281] Step 2: 6-bromothieno[2,3-b]pyridine

[0282]

[0283] Under argon, 7-oxythieno[2,3-b]pyridin-7-ium (2.2 g, 14.13 mmol) was dissolved in ultra-dry N,N-dimethylformamide (12.54 mL ) and ethylene glycol dimethyl ether (75.24 mL). The stirred solution was cooled to 0 °C and tetrabutylammonium bromide (5.47 g, 16.96 mmol) was added in one portion. Methanesulfonic anhydride (4.92 g, 28.27 mmol) was added portionwise over 15 min at 0 °C. The brown solution was stirred at 0°C for 2 hours, then allowed to warm to room temperature and stirred for an additional 3 hours. Solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (80 mL) and water (40 mL). The pH of the mixture was carefully adjusted to 7 with 2 N NaOH. The aqueous layer was extracted three times with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-70% to give a mixture of regioisomers which were separated by SFC to give a pale yellow solid (900 mg, 29% yield). MS (ESI): m / z= 213.9 [M+H]+

[0284] Step 3: Thieno[2,3-b]pyridine-6-carbaldehyde

[0285]

[0286] 6-Bromothieno[2,3-b]pyridine (994 mg, 4.64 mmol) was placed in an autoclave and dissolved in acetonitrile (47.16 g, 60 mL, 1148.84 mmol). Add Pd(dppp)Cl2​ (758.35 mg, 0.929 mmol, CAS: 59831-02-6), triethylsilane (809.85 mg, 1.11 mL, 6.96 mmol) and sodium acetate (761.75 mg, 9.29 mmol). Close the reactor, flush it 5 times with 10 bar CO, then push it to 30 bar CO. The reaction mixture was stirred at 60 °C and 30 bar for 24 hours. The mixture was filtered, poured into water and a little brine and extracted 3 times 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 ethyl acetate / heptane 0%-20% to afford the title compound (473 mg, 52% yield) as a white solid. MS (ESI): m / z= 163.9 [M+H]+

[0287] Step 4: 6-(difluoromethyl)thieno[2,3-b]pyridine

[0288]

[0289] To a solution of thieno[2,3-b]pyridine-6-carbaldehyde (470 mg, 2.42 mmol) in ultra-dry dichloromethane (13.16 mL) was added dropwise Deoxo-fluor® at 0°C, 2.7M (50 wt.%) solution in toluene (1.34 mL, 3.63 mmol). The reaction mixture was stirred at 0 °C for 1 h, then allowed to warm to room temperature and stirred overnight. The mixture was diluted with saturated NaHCO3 and extracted 3 times with dichloromethane. 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 ethyl acetate / heptane 0%-40% to afford the title compound (185 mg, 41% yield) as a colorless liquid. MS (ESI): m / z= 186.0 [M+H]+

[0290] Step 5: 6-(difluoromethyl)thieno[2,3-b]pyridine-3-sulfonyl chloride

[0291]

[0292] The title compound was prepared as a light brown solid from 6-(difluoromethyl)thieno[2,3-b]pyridine in a similar manner to intermediate A10. MS (ESI): m / z= 283.9 [M+H]+

[0293] Intermediate A45: 6-chloro-7-(dimethylamino)-1H-indole-3-sulfonyl chloride

[0294]

[0295] Step 1: 6-chloro-N,N-dimethyl-1H-indole-7-amine

[0296]

[0297] Add (2-chloro-6-nitro-phenyl)-dimethyl-amine (600 mg, 2.99 mmol, CAS: 96994-75-1) in ultra-dry tetrahydrofuran (9.97 mL) at -78°C ), a solution of 1 M vinylmagnesium bromide in THF (11.96 mL, 11.96 mmol, 4 eq) was added dropwise. The reaction was stirred for 45 min, warmed to 0 °C, quenched by addition of saturated ammonium chloride solution and extracted 3 times with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-50% to afford the title compound (353.5 mg, 59% yield) as a yellow oil. MS (ESI): m / z= 195.0 [M+H]+

[0298] Step 2: 6-chloro-7-(dimethylamino)-1H-indole-3-sulfonyl chloride

[0299]

[0300] To a solution of 6-chloro-N,N-dimethyl-1H-indol-7-amine (100 mg, 0.514 mmol) in acetonitrile (2 mL) was added chlorosulfonic acid dropwise at 0°C (119.72 mg, 68.8 uL, 1.03 mmol). The reaction was stirred at 0 °C for 2 h, at room temperature for 1 h, at 60 °C for 2 h, then at 80 °C overnight. Phosphorus oxychloride (329 mg, 200 uL, 2.15 mmol) was added dropwise at room temperature. The reaction mixture was stirred overnight at 60 °C and cooled to room temperature. Add phosphorus oxychloride (329 mg, 200 uL, 2.15 mmol). The reaction mixture was stirred at 80 °C for 2 days, poured into ice / ethyl acetate and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (150 mg, 100% yield) as a dark brown solid. MS (ESI): m / z= 293.0 [M+H]+

[0301] Intermediate A46: 1H-pyrrolo[3,2-h]quinoline-3-sulfonyl chloride

[0302]

[0303] Intermediate A46 is known and has been prepared from 1H-pyrrolo[3,2-h]quinoline (CAS: 233-88-5) following the procedure described in WO2018122232.

[0304] Intermediate A47: 6-methyl-1H-pyrrolo[2,3-b]pyridine-3-sulfonyl chloride

[0305]

[0306] 6-Methyl-1H-pyrrolo[2,3-b]pyridine (0.500 g, 3.78 mmol, CAS: 824-51-1) was dissolved in ultra-dry acetonitrile (12.5 mL) at 0° C. Chlorosulfonic acid (1.43 g, 823.39 uL, 12.3 mmol​) was added dropwise to the solution. The mixture was stirred at 0 °C for 1 h and at room temperature for 2 h. Phosphorus oxychloride (2.55 g, 1.55 mL, 16.65 mmol) was added and the mixture was stirred at 70 °C overnight. The mixture was dropped into ice / ethyl acetate and extracted 3 times 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 ethyl acetate / heptane 0%-70% to afford the title compound (642 mg, 66% yield) as a white powder. MS (ESI): m / z= 231.0 [M+H]+

[0307] Intermediate A48: 7-chloro-6-fluoro-1H-indole-3-sulfonyl chloride

[0308]

[0309] Intermediate A48 is known and has been synthesized from 7-chloro-6-fluoro-1H-indole (CAS: 259860-04-3) following the procedure described in WO2018122232.

[0310] Intermediate A49: 7-bromo-6-fluoro-1H-indole-3-sulfonyl chloride

[0311]

[0312] To a solution of 7-bromo-6-fluoro-1H-indole (0.250 g, 1.17 mmol, CAS: 1000339-62-7) in ultra-dry acetonitrile (4 mL) was added chlorine dropwise at 0°C Sulfonic acid (442.33 mg, 254.21 uL, 3.25 mmol). The mixture was stirred at 0 °C for 1 h, at room temperature for 2 h, poured into ice / ethyl acetate and extracted three times with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (304 mg, 83% yield) as an off-white solid. MS (ESI): m / z= 312.0 [M+H]+

[0313] Intermediate A50: 7-bromo-1H-indole-3-sulfonyl chloride

[0314]

[0315] Intermediate A50 is commercially available (CAS: 2137914-27-1)

[0316] Intermediate A51: 6-Chloro-7-"port" linyl-1H-indole-3-sulfonyl chloride

[0317]

[0318] Step 1: 4-(2-Chloro-6-nitro-phenyl) "molo" line

[0319]

[0320] To a solution of morphine (744.45 mg, 744.45 uL, 8.55 mmolq) and triethylamine (1.15 g, 1.59 mL, 11.39 mmol) in tetrahydrofuran (20 mL) was added 1 -Chloro-2-fluoro-3-nitro-benzene (1 g, 666.67 uL, 5.7 mmol, CAS: 2106-49-2). The reaction mixture was then heated to 60 °C and stirred overnight. Add the morphine (248.15 mg, 248.15 uL, 2.85 mmol) again. The mixture was heated to reflux, and after a few hours, the morphine (248.15 mg, 248.15 uL, 2.85 mmol) and triethylamine (1.15 g, 1.59 mL, 11.39 mmol) were added again. The reaction was stirred overnight at 70 °C, cooled to room temperature, diluted with water and extracted three times with dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (1.36 g, 93% yield) as an orange solid. MS (ESI): m / z= 243.0 [M+H]+

[0321] Step 2: 4-(6-Chloro-1H-indol-7-yl) "Omo" morphine

[0322]

[0323] To a yellow solution of 4-(2-chloro-6-nitro-phenyl)"port"line (1.27 g, 5.22 mmol) in ultra-dry tetrahydrofuran (20 mL) at -78°C, A 1 M solution of vinylmagnesium bromide in THF (20.49 g, 20.89 mL, 20.89 mmol) was added dropwise. After 1 h, the mixture was warmed to 0 °C and quenched with saturated ammonium chloride solution. The aqueous layer was extracted three times 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 ethyl acetate / heptane 0%-70%, followed by flash chromatography on a C18 RediSepRf gold column using a gradient acetonitrile / water 10%-100% to give The title compound (120 mg, 9% yield) as a brown solid. MS (ESI): m / z= 237.1 [M+H]+

[0324] Step 3: 6-Chloro-7-"port" linyl-1H-indole-3-sulfonyl chloride

[0325]

[0326] To a stirred solution of 4-(6-chloro-1H-indol-7-yl)"port"line (120 mg, 0.492 mmol) in ultra-dry acetonitrile (2.4 mL) at 0°C, Chlorosulfonic acid (143.25 mg, 82.33 uL, 1.23 mmol) was added dropwise. After 30 minutes, the reaction was allowed to warm to room temperature. Phosphorus oxychloride (301.61 mg, 183.35 uL, 1.97 mmol) was added dropwise at room temperature. The mixture was heated to 70°C, stirred overnight, cooled to room temperature, poured into ice / ethyl acetate and extracted three times with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (164.8 mg, 100% yield) as a dark red waxy solid. MS (ESI): m / z= 335.0 [M+H]+

[0327] Intermediate A52: 3-chlorosulfonyl-6-methyl-1H-indole-7-carboxylic acid methyl ester

[0328]

[0329] Step 1: Methyl 6-methyl-1H-indole-7-carboxylate

[0330]

[0331] In a reaction vessel, 7-bromo-6-methyl-1H-indole (370 mg, 1.76 mmol, CAS: 1360885-93-3), [1,1'-bis(diphenylphosphine yl)ferrocene]dichloropalladium(II) (4.32 mg, 0.005 mol), 1,1'-bis(diphenylphosphino)ferrocene (8.95 mg, 0.016 mmol) and triethylamine (178.23 mg , 245 µl, 1.76 mmol) combined with methanol (7.4 ml). The reaction vessel was sealed and flushed with carbon monoxide (5 x 10 atm), pressurized with carbon monoxide (40 atm), placed in a shaker, heated to 130°C and shaken for 48 hours. The procedure was repeated twice. The reaction mixture was concentrated in vacuo, and the residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane to afford the title compound (210 mg, 49% yield) as a yellow solid. MS (ESI): m / z= 190.1 [M+H]+

[0332] Step 2: Methyl 3-chlorosulfonyl-6-methyl-1H-indole-7-carboxylate

[0333]

[0334] To a solution of methyl 6-methyl-1H-indole-7-carboxylate (187 mg, 0.939 mmol) in acetonitrile (6 mL) at 0°C was added chlorosulfonic acid (287.33 mg, 164.19 uL , 2.44 mmol). The mixture was stirred at 0 °C for 1 h, at room temperature for 30 min, poured into ice / ethyl acetate and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (221 mg, 82% yield) as an orange solid. MS (ESI): m / z= 285.9 [M-H]–

[0335] Intermediate A53: 8-methyl-9-oxo-6,7-dihydro-1H-pyrrolo[3,2-h]isoquinoline-3-sulfonyl chloride

[0336]

[0337] Step 1: 2-[2-(tertiary butoxycarbonylamino)ethyl]-6-nitro-benzoic acid methyl ester

[0338]

[0339] Methyl 2-bromo-6-nitro-benzoate (1.5 g, 5.65 mmol, CAS: 135484-76-3), (2-((tertiary butoxycarbonyl)amino)ethyl ) potassium trifluoroborate (2.24 g, 8.48 mmol), cesium carbonate (6.6 g, 20.07 mmol), palladium(II) acetate (76.15 mg, 0.339 mmol) and RuPhos (333.21 mg, 0.678 mmol) in toluene (30 mL) and water (10 mL) was heated to 95°C and stirred for 15 hours. The mixture was 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 ethyl acetate / heptane 0%-40% to afford the title compound (1.69 g, 87% yield) as a yellow viscous oil. MS (ESI): m / z= 225.1 [M+H-BOC]+

[0340] Step 2: 8-nitro-3,4-dihydro-2H-isoquinolin-1-one

[0341] To a stirred solution of methyl 2-[2-(tertiary butoxycarbonylamino)ethyl]-6-nitrobenzoate (1.69 g, 4.9 mmol) in dichloromethane (15 mL) Trifluoroacetic acid (5.58 g, 3.75 mL, 48.98 mmol) was added. The reaction mixture was stirred at room temperature for 30 min and concentrated in vacuo. The residue was diluted with 1,4-dioxane (40 mL) and n-ethyldiisopropylamine (6.46 g, 8.54 mL, 48.98 mmol) was added. The reaction mixture was heated to 80 °C, stirred for 15 hours and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-100% to afford the title compound (743 mg, 79% yield) as an off-white solid. MS (ESI): m / z= 193.0 [M+H]+

[0343] Step 3: 2-methyl-8-nitro-3,4-dihydroisoquinolin-1-one

[0344]

[0345] A solution of 8-nitro-3,4-dihydro-2H-isoquinolin-1-one (741 mg, 3.86 mmol) in N,N-dimethylformamide (20 mL) Cool to 0 °C. Sodium hydride (169.65 mg, 4.24 mmol) was added. After stirring at 0 °C for 30 min, iodomethane (656.77 mg, 289.33 uL, 4.63 mmol) was added. The reaction mixture was stirred at 0 °C for 30 min, quenched with saturated ammonium chloride solution, 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 ethyl acetate / heptane 0%-100% to afford the title compound (760 mg, 96% yield) as an off-white solid. MS (ESI): m / z= 207.1 [M+H]+

[0346] Step 4: 8-amino-2-methyl-3,4-dihydroisoquinolin-1-one

[0347]

[0348] A suspension of 2-methyl-8-nitro-3,4-dihydroisoquinolin-1-one (758 mg, 3.68 mmol) in ethyl acetate (24 mL) was purged with argon. gas, and palladium on activated carbon (391.2 mg, 0.368 mmol) was added. The reaction mixture was stirred at room temperature under 1 atm. of hydrogen for 4 hours, filtered through a pad of celite and concentrated in vacuo to afford the title compound (629 mg, 94% yield) as an off-white solid. MS (ESI): m / z= 177.0 [M+H]+

[0349] Step 5: 8-amino-5,7-diiodo-2-methyl-3,4-dihydroisoquinolin-1-one

[0350]

[0351] To 8-amino-2-methyl-3,4-dihydroisoquinolin-1-one (627 mg, 3.45 mmol) and acetic acid (455.97 mg, 434.25 uL, 7.59 mmol) in toluene (10 mL) was added iodosuccinimide (1.76 g, 7.59 mmol). The reaction mixture was stirred at room temperature for 15 h, diluted with ethyl acetate and washed once 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 ethyl acetate / heptane 0%-20% to afford the title compound (1.41 g, 95% yield) as a pale yellow solid. MS (ESI): m / z= 428.9 [M+H]+

[0352] Step 6: 5-iodo-8-methyl-2-trimethylsilyl-6,7-dihydro-1H-pyrrolo[3,2-h]isoquinolin-9-one

[0353]

[0354] In a sealed tube, combine 8-amino-5,7-diiodo-2-methyl-3,4-dihydroisoquinolin-1-one (1.4 g, 3.27 mmol), potassium carbonate ( 913.26 mg, 6.54 mmol), tetrakis(triphenylphosphine)palladium (381.8 mg, 0.327 mmol​), XPhos (321.51 mg, 0.654 mmol) and trimethylsilylacetylene (393.4 mg, 554.86 uL, 3.93 mmol) in The mixture in tetrahydrofuran (34 mL) was heated to 75°C and stirred for 15 hours. The reaction mixture was 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 ethyl acetate / heptane 0%-20% to afford the title compound (552 mg, 40% yield) as a yellow viscous oil. MS (ESI): m / z= 399.0 [M+H]+

[0355] Step 7: 5-iodo-8-methyl-6,7-dihydro-1H-pyrrolo[3,2-h]isoquinolin-9-one

[0356]

[0357] at room temperature to 5-iodo-8-methyl-2-trimethylsilyl-6,7-dihydro-1H-pyrrolo[3,2-h]isoquinolin-9-one ( 550 mg, 1.31 mmol) To a stirred solution in tetrahydrofuran (8 mL) was added 1 M tetrabutylammonium fluoride in THF (6.56 mL, 6.56 mmol). The reaction mixture was heated to 50 °C, stirred for 1 h, 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 ethyl acetate / heptane 0%-40% to afford the title compound (359 mg, 76% yield) as a yellow solid. MS (ESI): m / z= 327.0 [M+H]+

[0358] Step 8: 8-methyl-6,7-dihydro-1H-pyrrolo[3,2-h]isoquinolin-9-one

[0359]

[0360] 5-iodo-8-methyl-6,7-dihydro-1H-pyrrolo[3,2-h]isoquinolin-9-one (357 mg, 0.985 mmol) and triethylamine ( A suspension of 109.66 mg, 151.05 uL, 1.08 mmol) in ethanol (15 mL) was degassed with argon and palladium on activated carbon (104.84 mg, 0.099 mmol) was added. The reaction mixture was stirred at room temperature under 1 atm of hydrogen for 3.5 hours, filtered through a pad of celite and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate / heptane 0%-60%, followed by flash chromatography on a C18 RediSepRf gold column using a gradient of acetonitrile / water 10%-60% to give The title compound (150 mg, 76% yield) as a white solid. MS (ESI): m / z= 201.1 [M+H]+

[0361] Step 9: 8-methyl-9-oxo-6,7-dihydro-1H-pyrrolo[3,2-h]isoquinoline-3-sulfonyl chloride

[0362]

[0363] 8-Methyl-6,7-dihydro-1H-pyrrolo[3,2-h]isoquinolin-9-one (114 mg, 0.569 mmol) in acetonitrile (5 mL) The solution was cooled to 0 °C. Chlorosulfonic acid (174.22 mg, 99.39 uL, 1.48 mmol) was added and the reaction mixture was stirred at 0 °C for 30 minutes. Phosphorus oxychloride (436.47 mg, 264.53 uL, 2.85 mmol) was then added. The reaction mixture was heated to 70°C and stirred for 5.5 hours. The reaction mixture was poured into ice / ethyl acetate and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (232 mg, 100% yield) as a light red solid. MS (ESI): m / z= 298.9 [M+H]+

[0364] Intermediate A54: 6-chloro-7-(cyanomethoxy)-1H-indole-3-sulfonyl chloride

[0365]

[0366] Step 1: 2-Benzyloxy-1-chloro-3-nitro-benzene

[0367]

[0368] To a mixture of 2-chloro-6-nitrophenol (10 g, 57.6 mmol, CAS: 603-86-1) and potassium carbonate (15.927 g, 115.2 mmol) in dry acetonitrile (150 mL) was added Benzyl bromide (9.85 g, 6.85 mL, 57.6 mmol). The reaction mixture was stirred overnight at 70 °C, poured into water and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (15 g, 89% yield) as a brown waxy solid, which was used in the next step without further purification.

[0369] Step 2: 7-Benzyloxy-6-chloro-1H-indole

[0370]

[0371] A stirred solution of vinylmagnesium chloride (284.44 mL, 284.44 mmol) in dry tetrahydrofuran (500 mL) was cooled to -40°C and 2-benzyloxy-1-chloro-3-nitro-benzene (15.0 g, 56.89 mmol). The reaction mixture was stirred at this temperature for 30 min, quenched with saturated ammonium chloride solution, and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to afford the title compound (5.5 g, 36% yield) as a light brown waxy solid. 1H NMR (500 MHz, DMSO-d6) δ = 11.44 (br s, 1H), 7.59 (br d, J = 7.3 Hz, 2H), 7.44 - 7.30 (m, 5H), 7.01 (dd, J = 2.1, 8.4 Hz, 1H), 6.54 - 6.41 (m, 1H), 5.11 (s, 2H)

[0372] Step 3: 6-chloro-1H-indol-7-ol

[0373] A solution of 7-benzyloxy-6-chloro-1H-indole (4.0 g, 15.52 mmol) in dry ethyl acetate (100 mL) was degassed with argon and palladium on charcoal (350 mg). The reaction mixture was stirred at room temperature under 1 atm. of hydrogen overnight, filtered through a pad of celite and concentrated in vacuo to afford the title compound (3 g, 98% yield) as a brown oil. MS (ESI): m / z= 168.0 [M+H]+

[0375] Step 4: 2-[(6-Chloro-1H-indol-7-yl)oxy]acetonitrile

[0376]

[0377] To a stirred solution of 6-chloro-1H-indol-7-ol (4.0 g, 20.29 mmol) and potassium carbonate (5.61 g, 40.58 mmol) in dry acetonitrile (40 mL) was added bromoacetonitrile (2.68 g, 22.32 mmol). The reaction mixture was stirred overnight at room temperature. The precipitate was filtered off. The filtrate was concentrated in vacuo. The residue was diluted with water 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 TBME / hexanes to afford the title compound (1.9 g, 45% yield) as a light brown solid. MS (ESI): m / z= 207.0 [M+H]+

[0378] Step 5: 6-chloro-7-(cyanomethoxy)-1H-indole-3-sulfonyl chloride

[0379]

[0380] A solution of 2-[(6-chloro-1H-indol-7-yl)oxy]acetonitrile (100 mg, 0.484 mmol) in acetonitrile (4 mL) was cooled to 0°C. Chlorosulfonic acid (148.1 mg, 84.48 uL, 1.26 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 1 h and at room temperature for 16 h, poured into ice / ethyl acetate and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (123 mg, 83% yield) as a light red gum. MS (ESI): m / z= 302.9 [M-H]-

[0381] Intermediate B

[0382] Intermediate B1: 5-bromo-4-methoxy-pyrimidin-2-amine

[0383]

[0384] Intermediate B1 is commercially available (CAS: 36082-45-8)

[0385] Intermediate B2: 2-amino-4-methoxy-pyrimidine-5-carbonitrile

[0386]

[0387] Intermediate B2 is commercially available (CAS: 81066-95-7)

[0388] Intermediate B3: 5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-amine

[0389]

[0390] Step 1: (5-Bromo-4-methoxy-pyrimidin-2-yl)-bis(p-anisyl)amine

[0391]

[0392] 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-ethyl A suspension of diisopropylamine (858 uL, 4.92 mmol) in acetonitrile (20 mL) was heated at 70°C for 2 days. The resulting solution was poured into saturated aqueous sodium bicarbonate and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and dried in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-20% to afford the title compound (998 mg, 50% yield) as a colorless viscous oil. MS (ESI): m / z= 446.2 [M+H]+

[0393] Step 2: [4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl ]-bis(p-anisyl)amine

[0394]

[0395] (5-bromo-4-methoxy-pyrimidin-2-yl)-bis(p-anisyl)amine (500 mg, 1.13 mmol), bis(pinacol)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 silica gel column chromatography using a gradient ethyl acetate / heptane 0%-30% to afford the title compound (157 mg, 29% yield) as a colorless viscous oil. MS (ESI): m / z= 492.4 [M+H]+

[0396] Step 3: 2-[bis(p-anisyl)amino]-4-methoxy-pyrimidin-5-ol

[0397]

[0398] [4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidin-2-yl]- A solution of bis(p-anisyl)amine (130 mg, 0.265 mmol) in tetrahydrofuran (2.5 mL) was cooled to 0°C. Add hydrogen peroxide 35% (500 uL, 5.71 mmol). The reaction mixture was stirred at 0 °C for 15 min and at room temperature for 3 h. The reaction mixture was poured into cold 0.1 N sodium sulfite solution and extracted twice with EtOAc. The organic layer was washed twice with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (103 mg, 100% yield) as a pale yellow viscous oil. MS (ESI): m / z= 382.3 [M+H]+

[0399] Step 4: [5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-bis(p-anisyl)amine

[0400]

[0401] 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- A suspension of 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 ethyl acetate / heptane 0%-30% to afford the title compound (22 mg, 22% yield) as a colorless viscous oil. MS (ESI): m / z= 428.3 [M+H]+

[0402] Step 5: [5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]amine

[0403]

[0404] [5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-bis(p-anisyl)amine (87 mg, 0.204 mmol) in dichloromethane (500 uL ) in the solution was cooled to 0°C. Add trifluoroacetic acid (1.41 g, 944.56 uL, 12.21 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 16 hours and at 55 °C for an additional two hours. The resulting purple solution was poured into saturated aqueous sodium bicarbonate and extracted twice with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-100% to afford the title compound (27 mg, 71% yield) as an off-white solid. MS (ESI): m / z= 188.1 [M+H]+

[0405] Intermediate B4-B7

[0406] Intermediates B4-B7 have been converted to 2-[bis(p-anisyl)amino]-4-methoxy-pyrimidin-5-ol in a manner similar to Intermediate B3 by using a base and an alkylating agent Preparation by alkylation (Intermediate B3, Step 3) followed by deprotection of the bis(p-anisyl) protecting group with TFA (Intermediate B3, Step 5): Intermediate number structure name Alkylating agent alkali MS (ESI): m / z, [M+H] + B4 (5-Ethoxy-4-methoxy-pyrimidin-2-yl)amine Ethyl bromide K 2 CO 3 170.2 B5 [4-Methoxy-5-(2-methoxyethoxy)pyrimidin-2-yl]amine 1-Bromo-2-methoxyethane K 2 CO 3 200.2 B6 [5-(Difluoromethoxy)-4-methoxy-pyrimidin-2-yl]amine Sodium Chlorodifluoroacetate Cs 2 CO 3 192.1 B7 5-[2-(Difluoromethoxy)ethoxy]-4-methoxy-pyrimidin-2-amine 1-Bromo-2-(difluoromethoxy)ethane K 2 CO 3 236.2

[0407] Intermediate B8: (4-methoxy-5-prop-1-ynyl-pyrimidin-2-yl)amine

[0408]

[0409] Step 1: (4-methoxy-5-prop-1-ynyl-pyrimidin-2-yl)-bis(p-anisyl)amine

[0410]

[0411] (5-Bromo-4-methoxy-pyrimidin-2-yl)-bis(p-anisyl)amine (500 mg, 1.13 mmol, intermediate B3, step 1) was dissolved in N,N-di Methylformamide (5 mL), and triethylamine (455.48 mg, 627.39 uL, 4.5 mmol) was added at room temperature. The reaction mixture was purged with argon, and a solution of 1 M prop-1-yne 1M in DMF (1.35 mL, 1.35 mmol), bis(triphenylphosphine)palladium(II) chloride (78.99 mg, 0.113 mmol) and copper(I) iodide (32.15 mg, 0.169 mmol). The mixture was stirred at 50°C for 72 hours. The reaction mixture was diluted with saturated sodium bicarbonate solution and extracted twice with EtOAc. The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-100% to afford the title compound (130 mg, 24% yield) as a pale yellow oil. MS (ESI): m / z= 404.2 [M+H]+

[0412] Step 2: (4-methoxy-5-prop-1-ynyl-pyrimidin-2-yl)amine

[0413]

[0414] In a similar manner to intermediate B3 step 5, a light yellow solid form was prepared from (4-methoxy-5-prop-1-ynyl-pyrimidin-2-yl)-bis(p-anisyl)amine the title compound. MS (ESI): m / z= 164.1 [M+H]+

[0415] Intermediate B9: (5-ethyl-4-methoxy-pyrimidin-2-yl)amine

[0416]

[0417] Step 1: 2-Chloro-5-ethyl-4-methoxy-pyrimidine

[0418]

[0419] To a suspension of 2,4-dichloro-5-ethyl-pyrimidine (274.3 mg, 1.55 mmol, CAS: 34171-40-9) in MeOH (7 mL) was added NaH (65.07 mg, 1.63 mmol, 1.05 eq). The reaction mixture was stirred at room temperature for 1 h, and the solvent was removed under reduced pressure. The residue was dissolved in EtOAC and extracted 3 times. The combined organic layers were washed 3 times with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-50% to afford the title compound (154 mg, 57% yield) as a colorless oil. MS (ESI): m / z= 173.1 [M+H]+

[0420] Step 2: (5-Ethyl-4-methoxy-pyrimidin-2-yl)amine

[0421]

[0422] Add 2-chloro-5-ethyl-4-methoxy-pyrimidine (130.4 mg, 0.77 mmol), sodium tertiary butoxide (82.33 mg, 0.8 mmol) and catalyst [Pd(allyl)(tBuBrettPhos)]OTf; (11.8 mg, 0.01.5 mmol) and 1,4-dioxane (3.26 mL). Close the autoclave and introduce ammonia (15 mmol) using an ammonia cylinder at room temperature. The reaction mixture was stirred at 100°C for 20 hours. The reaction mixture was filtered and washed with EtOAc, the solvent was removed under vacuum. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 30%-100% to afford the title compound (78 mg, 64% yield) as a white powder. MS (ESI): m / z= 154.1 [M+H]+

[0423] Intermediate B10: (4-methoxy-5-methyl-pyrimidin-2-yl)amine

[0424]

[0425] The title compound was prepared as a white solid from 2-chloro-4-methoxy-5-methyl-pyrimidine in a similar manner to Intermediate B9, Step 2. MS (ESI): m / z= 140.1 [M+H]+

[0426] Intermediate B11: (5-cyclopropyl-4-methoxy-pyrimidin-2-yl)amine

[0427]

[0428] Step 1: 5-cyclopropyl-4-methoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine

[0429]

[0430] In a glass tube, (5-bromo-4-methoxy-pyrimidin-2-yl)-bis(p-anisyl)amine (500 mg, 1.13 mmol, Intermediate B3, step 1), 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (945.49 mg, 5.63 mmol) and tripotassium phosphate (716.61 mg, 3.38 mmol ) in 1,4-dioxane (9.18 mL) and water (2.3 mL) was degassed. 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (93.03 mg, 0.113 mmol) was added, and the mixture was degassed with argon. The reaction mixture was stirred at 80 °C for 1 h. The reaction mixture was diluted with saturated sodium bicarbonate solution and extracted twice with EtOAc. The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-50% to afford the title compound (417 mg, 91 % yield) as a colorless oil. MS (ESI): m / z= 406.3 [M+H]+

[0431] Step 2: (5-cyclopropyl-4-methoxy-pyrimidin-2-yl)amine

[0432]

[0433] In a similar manner to intermediate B3 step 5, from 5-cyclopropyl-4-methoxyl-N, N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine The title compound was prepared as a white solid. MS (ESI): m / z= 166.1 [M+H]+

[0434] Intermediate B12: (5-chloro-4,6-dimethoxy-pyrimidin-2-yl)amine

[0435]

[0436] 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-chlorosuccinimide (109.65 mg, 0.821 mmol). The reaction mixture was stirred at room temperature, and the resulting pale yellow solution was diluted with EtOAc 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 ethyl acetate / heptane 0%-50% to afford the title compound (87 mg, 71% yield) as an off-white solid. MS (ESI): m / z= 190.1 [M+H]+

[0437] Intermediate B13: (5-bromo-4,6-dimethoxy-pyrimidin-2-yl)amine

[0438]

[0439] In a similar manner to intermediate B12, from (4,6-dimethoxypyrimidin-2-yl)amine (CAS: 36315-01-2) using N-bromosuccinimide as brominating agent to prepare the title compound. white solid. MS (ESI): m / z= 234.1 [M+H]+

[0440] Intermediate B14: (5-bromo-4-ethoxy-6-methoxy-pyrimidin-2-yl)amine

[0441]

[0442] Step 1: (5-bromo-4-chloro-6-methoxy-pyrimidin-2-yl)amine

[0443]

[0444] In a similar manner to intermediate B12, N-bromosuccinimide was used as bromine from (4-chloro-6-methoxy-pyrimidin-2-yl)amine (CAS: 5734-64-5) Reagent to prepare the title compound. white solid. MS (ESI): m / z= 238.1 [M+H]+

[0445] Step 2: (5-Bromo-4-ethoxy-6-methoxy-pyrimidin-2-yl)amine

[0446]

[0447] To a suspension of NaH (22.81 mg, 0.570 mmol) in 0.5 mL DMF was added ethanol (28.9 mg, 36.63 uL, 0.627 mmol) and stirred at room temperature for 15 minutes. To the reaction mixture was added a solution of (5-bromo-4-chloro-6-methoxy-pyrimidin-2-yl)amine (68 mg, 0.285 mmol) in 1 mL of DMF. The resulting reaction mixture was heated to 80 °C. After 1 hour, the reaction mixture was cooled to room temperature, quenched with saturated ammonium chloride solution, and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-15% to afford the title compound (30 mg, 30% yield) as a white solid. MS (ESI): m / z= 248.1 [M+H]+

[0448] Intermediate B15: 5-bromo-4-(2-fluoroethoxy)-6-methoxy-pyrimidin-2-amine

[0449]

[0450] In a similar manner to intermediate B14 step 2, from (5-bromo-4-chloro-6-methoxy-pyrimidin-2-yl)amine, using 2-fluoroethanol as alcohol and THF as solvent to prepare the title compound. white solid. 1H NMR (300 MHz, chloroform-d) δ = 4.86 - 4.72 (m, 3H), 4.69 - 4.58 (m, 2H), 4.55 - 4.48 (m, 1H), 3.94 (s, 3H); 19F NMR (282 MHz, chloroform-d) δ = -224.63 (s, 1F)

[0451] Intermediate B16: [5-bromo-4-(difluoromethoxy)-6-methoxy-pyrimidin-2-yl]amine

[0452]

[0453] Step 1: [4-(Difluoromethoxy)-6-methoxy-pyrimidin-2-yl]amine

[0454]

[0455] To a suspension of 2-amino-6-methoxy-pyrimidin-4-ol (20 mg, 0.135 mmol, CAS: 59081-28-6) in acetonitrile (1.5 mL) at 0°C Add 5 M potassium hydroxide (538.51 uL, 2.69 mmol) dropwise, then add bromodifluoromethyldiethylphosphonate (71.89 mg, 47.83 uL, 0.269 mmol) in acetonitrile (200 uL) dropwise at 0°C The solution. After stirring at 0 °C for 15 min, the reaction mixture was allowed to warm to room temperature and stirred for 2 h. The resulting yellow biphasic solution was quenched with water and extracted twice with EtOAc. The organic layer was washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-50% to afford the title compound (8 mg, 31 % yield) as a white solid. MS (ESI): m / z= 192.1 [M+H]+

[0456] Step 2: [5-bromo-4-(difluoromethoxy)-6-methoxy-pyrimidin-2-yl]amine

[0457]

[0458] In a similar manner to intermediate B12, from [4-(difluoromethoxy)-6-methoxy-pyrimidin-2-yl]amine using N-bromosuccinimide as brominating agent Preparation of the title compound. white solid. MS (ESI): m / z= 272.0 [M+H]+

[0459] Intermediate B17: 5-(3-fluoropropyl)-4-methoxy-pyrimidin-2-amine

[0460]

[0461] Step 1: (E)-ethyl 3-(2-amino-4-methoxy-pyrimidin-5-yl)acrylate

[0462]

[0463] In a sealed tube, (5-bromo-4-methoxy-pyrimidin-2-yl)amine (200 mg, 0.961 mmol, CAS: 36082-45-8), potassium tertiary butoxide (165 . mg, 1.44 mmol), tetrakis(triphenylphosphine)palladium(0) (112.14 mg, 0.096 mmol) and (E)-3-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl)ethyl acrylate (260.63 mg, 258.05 uL, 1.15 mmol) in 1,4-dioxane (4 mL) and water (4 mL) was heated to 90 °C and stirred for 15 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 ethyl acetate / heptane 0%-50% to afford the title compound (43 mg, 20% yield) as a pale yellow solid. MS (ESI): m / z= 224.2 [M+H]+

[0464] Step 2: Ethyl 3-(2-amino-4-methoxy-pyrimidin-5-yl)propionate

[0465]

[0466] A suspension of ethyl (E)-3-(2-amino-4-methoxy-pyrimidin-5-yl)acrylate (41 mg, 0.184 mmol) in methanol (2 mL) was washed with argon Air purge for 5 minutes. Palladium on activated carbon (19.55 mg, 0.018 mmol) was added. The reaction mixture was purged with hydrogen and stirred at room temperature under 1 atm. of hydrogen for 15 hours. The reaction mixture was filtered through a pad of celite and concentrated in vacuo to afford the title compound (36 mg, 74% yield) as a light gray solid. MS (ESI): m / z= 226.2 [M+H]+

[0467] Step 3: 3-(2-Amino-4-methoxy-pyrimidin-5-yl)propan-1-ol

[0468]

[0469] A solution of ethyl 3-(2-amino-4-methoxy-pyrimidin-5-yl)propanoate (35 mg, 0.132 mmol) in tetrahydrofuran (400 uL) was cooled to 0°C. Add a solution of 1 M LiAlH4 in THF (264.16 uL, 0.264 mmol) dropwise. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was carefully quenched with saturated ammonium chloride solution and extracted twice with EtOAc. 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%-100% and 10% MeOH to afford the title compound (11 mg, 46% yield) as a white solid. MS (ESI): m / z= 184.1 [M+H]+

[0470] Step 4: 5-(3-fluoropropyl)-4-methoxy-pyrimidin-2-amine

[0471]

[0472] A suspension of 3-(2-amino-4-methoxy-pyrimidin-5-yl)propan-1-ol (70 mg, 0.352 mmol) in dichloromethane (1.38 mL) was cooled to 0°C. A solution of Deoxo-fluor®, 2.7M (50 wt.%) in toluene (622.15 mg, 518.46 uL, 1.41 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 3 days. The resulting yellow solution was diluted with EtOAc and quenched carefully with saturated NaHCO3. The organic layer was separated and washed once with water, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-100% to afford the title compound (9 mg, 14% yield) as a pale yellow solid. MS (ESI): m / z= 186.1 [M+H]+

[0473] Intermediate B18: (5-ethyl-4,6-dimethoxy-pyrimidin-2-yl)amine

[0474]

[0475] (4,6-dichloro-5-ethyl-pyrimidin-2-yl)amine (100 mg, 0.521 mmol, CAS: 6343-68-6) and sodium methoxide (296.11 mg, 5.21 mmol) in The suspension in methanol (2.5 mL) was heated to 100 °C and stirred for 15 hours. Additional sodium methoxide (148.04 mg, 2.6 mmol) was added and stirring was continued at 100 °C for 20 hours. The reaction mixture was concentrated in vacuo. The residue was poured into water and extracted twice with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (88 mg, 90% yield) as a white solid. MS (ESI): m / z= 183.8 [M+H]+

[0476] Intermediate B19: (4,6-dimethoxy-5-methyl-pyrimidin-2-yl)amine

[0477]

[0478] In a similar manner to intermediate B18, the title compound was prepared as a white solid from (4,6-dichloro-5-methyl-pyrimidin-2-yl)amine (CAS: 7153-13-1). MS (ESI): m / z= 169.8 [M+H]+

[0479] Intermediate B20: [5-(2,2-difluoroethoxy)-4-methoxy-6-methyl-pyrimidin-2-yl]amine

[0480]

[0481] Step 1: (5-bromo-4-methoxy-6-methyl-pyrimidin-2-yl)amine

[0482]

[0483] In a similar manner to intermediate B12, from (4-methoxy-6-methyl-pyrimidin-2-yl)amine (CAS: 7749-47-5) using N-bromosuccinimide as Brominating reagents produced the title compound as a white solid. MS (ESI): m / z=218.0 [M+H]+

[0484] Step 2: (5-bromo-4-methoxy-6-methyl-pyrimidin-2-yl)amine

[0485]

[0486] (5-Bromo-4-methoxy-6-methyl-pyrimidin-2-yl)amine (700 mg, 3.21 mmol) in N,N-dimethylacetamide (8 mL) The solution was cooled to 0 °C. Sodium hydride (385.2 mg, 9.63 mmol) was added in portions (3x128 mg). Stirring was continued for 30 min at 0 °C. Add 4-methoxybenzyl chloride (1.03 g, 884.52 uL, 6.42 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 1.5 hours. The reaction mixture was carefully quenched with saturated ammonium chloride solution, 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 ethyl acetate / heptane 0%-20% to afford the title compound (1.24 g, 84% yield) as a white solid. MS (ESI): m / z= 460.2 [M+H]+

[0487] Step 3: 2-[bis(p-anisyl)amino]-4-methoxy-6-methyl-pyrimidin-5-ol

[0488]

[0489] To (5-bromo-4-methoxy-6-methyl-pyrimidin-2-yl)-bis(p-anisyl)amine (290 mg, 0.633 mmol) in tetrahydrofuran (2 mL) was added dropwise a 1.6 M solution of n-butyllithium in hexane (442.1 mg, 514.07 uL, 0.823 mmol). The resulting yellow solution was stirred at -78 °C for 30 min. Trimethylborate (98.62 mg, 105.81 uL, 0.949 mmol) was added dropwise and stirring was continued at -78°C for 1.5 hours. The reaction mixture was allowed to warm to 0 °C and acetic acid (75.99 mg, 72.42 uL, 1.27 mmol) was added dropwise followed by hydrogen peroxide 35% (92.23 mg, 83.09 uL, 0.949 mmol). Stirring was continued for 45 min at 0 °C. The resulting pale yellow suspension was poured into 0.1 N sodium sulfite and extracted twice with EtOAc. The organic layer was washed twice with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-30% to afford the title compound (104 mg, 42% yield) as a colorless gum. MS (ESI): m / z= 396.3 [M+H]+

[0490] Step 4: [5-(2,2-difluoroethoxy)-4-methoxy-6-methyl-pyrimidin-2-yl]-bis(p-anisyl)amine

[0491]

[0492] 2-[bis(p-anisyl)amino]-4-methoxy-6-methyl-pyrimidin-5-ol (46 mg, 0.116 mmol) and cesium carbonate (114.85 mg, 0.349 mmol) To a stirred suspension in N,N-dimethylformamide (1.5 mL) was added 2,2-difluoroethyl triflate (27.96 mg, 17.36 uL, 0.128 mmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was poured into water and extracted twice with EtOAc. The organic layer was washed twice with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (30 mg, 53% yield) as a pale yellow gum. MS (ESI): m / z= 460.4 [M+H]+

[0493] Step 5: [5-(2,2-difluoroethoxy)-4-methoxy-6-methyl-pyrimidin-2-yl]amine

[0494]

[0495] In a similar manner to intermediate B3 step 5, from [5-(2,2-difluoroethoxy)-4-methoxy-6-methyl-pyrimidin-2-yl]-bis( p-Anisyl)amine The title compound was prepared as a white solid. MS (ESI): m / z=220.2 [M+H]+

[0496] Intermediate B21: 4-cyclopropyl-5-(2,2-difluoroethoxy)-6-methoxy-pyrimidin-2-amine

[0497]

[0498] Step 1: (4-cyclopropyl-6-methoxy-pyrimidin-2-yl)amine

[0499]

[0500] In a sealed tube, (4-chloro-6-cyclopropyl-pyrimidin-2-yl)amine (300 mg, 1.77 mmol, CAS: 21573-09-1) and sodium methoxide (502.92 mg, 8.84 mmol) in methanol (10.39 mL) was heated at 85°C for 20 hours. The resulting pale yellow suspension was concentrated in vacuo. The residue was diluted with ethyl acetate. Water was added and the two layers were separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford the title compound (259 mg, 89% yield) as a pale yellow solid. MS (ESI): m / z= 282.1 [M-H]

[0501] Step 2: (5-bromo-4-cyclopropyl-6-methoxy-pyrimidin-2-yl)amine

[0502]

[0503] In a similar manner to Intermediate B20, Step 1, the title compound was prepared as a white solid from (4-cyclopropyl-6-methoxy-pyrimidin-2-yl)amine. MS (ESI): m / z=244.1 [M+H]+

[0504] Step 3: (5-bromo-4-cyclopropyl-6-methoxy-pyrimidin-2-yl)-bis(p-anisyl)amine

[0505]

[0506] In a similar manner to Intermediate B20, Step 2, the title compound was prepared as a white solid from (5-bromo-4-cyclopropyl-6-methoxy-pyrimidin-2-yl)amine. MS (ESI): m / z=486.3 [M+H]+

[0507] Step 4: 2-[bis(p-anisyl)amino]-4-cyclopropyl-6-methoxy-pyrimidin-5-ol

[0508]

[0509] In a similar manner to Intermediate B20, Step 3, a white solid was prepared from (5-bromo-4-cyclopropyl-6-methoxy-pyrimidin-2-yl)-bis(p-anisyl)amine form of the title compound. MS (ESI): m / z=422.3 [M+H]+

[0510] Step 5: [4-cyclopropyl-5-(2,2-difluoroethoxy)-6-methoxy-pyrimidin-2-yl]-bis(p-anisyl)amine

[0511] Preparation of white solid form from 2-[bis(p-anisyl)amino]-4-cyclopropyl-6-methoxy-pyrimidin-5-ol in a similar manner to Intermediate B20, Step 4 the title compound. MS (ESI): m / z=486.4 [M+H]+

[0513] Step 6: 4-cyclopropyl-5-(2,2-difluoroethoxy)-6-methoxy-pyrimidin-2-amine

[0514]

[0515] In a manner similar to intermediate B3, step 5, from [4-cyclopropyl-5-(2,2-difluoroethoxy)-6-methoxy-pyrimidin-2-yl]- Bis(p-anisyl)amine prepared the title compound as an off-white solid. MS (ESI): m / z=246.1 [M+H]+

[0516] Intermediate B22: 5-bromo-4,6-dimethyl-pyrimidin-2-amine

[0517]

[0518] Intermediate B22 is commercially available (CAS: 4214-57-7)

[0519] Intermediate B23: 4-chloro-5-methoxy-pyrimidin-2-amine

[0520]

[0521] Intermediate B23 is commercially available (CAS: 4763-36-4)

[0522] Intermediate B24: 5-(2,2-difluoroethoxy)pyrimidin-2-amine

[0523]

[0524] Step 1: 2-Chloro-5-(2,2-difluoroethoxy)pyrimidine

[0525]

[0526] To a stirred suspension of 2-chloropyrimidin-5-ol (100 mg, 0.776 mmol, CAS: 4983-28-2) and potassium carbonate (158.83 mg, 1.15 mmol) in acetone (2.7 mL) was added Tris 2,2-Difluoroethyl fluoromethanesulfonate (188.64 mg, 0.881 mmol). The reaction mixture was stirred at room temperature for 1.5 hours, then diluted with diethyl ether, filtered and concentrated in vacuo. Dichloromethane was added to the residue. The mixture was sonicated for 5 min, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-15% to afford the title compound (86 mg, 57% yield) as a white solid. MS (ESI): m / z= 195.1 [M+H]+

[0527] Step 2: 5-(2,2-difluoroethoxy)pyrimidin-2-amine

[0528]

[0529] In a glass tube, mix 2-chloro-5-(2,2-difluoroethoxy)pyrimidine (20 mg, 0.101 mmol), sodium tertiary butoxide (10.65 mg, 0.111 mmol) and [tBuBrettPhos The mixture of Pd(allyl)]Otf (2.36 mg, 0.003 mmol, CAS: 1798782-15-6) was flushed with argon, and a 0.5 M solution of ammonia in dioxane (2.42 mL, 1.21 mmol) was added. The reaction mixture was stirred at 30 °C for 2 h, then concentrated in vacuo. Dichloromethane was added to the residue. The mixture was filtered and concentrated in vacuo to give the title compound (23 mg, 100% yield) as a pale yellow oil. MS (ESI): m / z= 176.1 [M+H]+

[0530] Intermediate B25: 5-(2,2-difluoroethoxy)-4-methylsulfanyl-pyrimidin-2-amine

[0531]

[0532] Step 1: Ethyl 2-(2,2-difluoroethoxy)acetate

[0533]

[0534] To a mixture of sodium hydride (60% in oil (5.0 g, 208.33 mmol)) in tetrahydrofuran (500 mL) was added dropwise 2,2-difluoroethanol (12.96 mL, 204.75 mmol) at 0°C ). After 5 minutes, the reaction was allowed to warm to room temperature and ethyl bromoacetate (21.78 mL, 196.41 mmol) was added dropwise. After stirring at 22 °C for 24 h, the mixture was poured into aqueous NaHSO4 and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated carefully to give the title compound (32 g, 74% yield) as a dark brown oil. 1H NMR (400 MHz, DMSO-d6) δ = 6.12 (tt, J = 3.6, 54.9 Hz, 1H), 4.19 (s, 2H), 4.13 - 4.06 (m, 2H), 3.79 - 3.68 (m, 2H) , 1.16 (t, J = 1.0 Hz, 3H)

[0535] Step 2: (Z)-2-(2,2-difluoroethoxy)-3-(dimethylamino)prop-2-enoic acid ethyl ester

[0536]

[0537] 2-(2,2-difluoroethoxy) ethyl acetate (32 g, 190.32 mmol) and tertiary butoxy bis (dimethylamino) methane (168.8 g, 200 mL, 968.6 mmol) was heated to 140°C and stirred for 20 hours. The reaction mixture was concentrated in vacuo to afford the title compound (52 g, 86% yield) as a dark brown oil, which was used in the next step without further purification.

[0538] Step 3: 2-amino-5-(2,2-difluoroethoxy)-1H-pyrimidin-6-one

[0539]

[0540] To (Z)-2-(2,2-difluoroethoxy)-3-(dimethylamino) prop-2-enoic acid ethyl ester (52 g, 232.95 mmol) in N-form Guanidine carbonate (41.97 g, 232.95 mmol) and potassium carbonate (64.39 g, 465.91 mmol) were added to a stirred solution of phenyl-2-pyrrolidone (200 mL). The reaction mixture was stirred at 150 °C for 24 h, then concentrated in vacuo. The residue was purified by flash chromatography on silica gel to afford the title compound (16.3 g, 29% yield) as a white solid. MS (ESI): m / z= 192.0 [M+H]+

[0541] Step 4: 4-Chloro-5-(2,2-difluoroethoxy)pyrimidin-2-amine

[0542]

[0543] 2-Amino-5-(2,2-difluoroethoxy)-1H-pyrimidin-6-one (3.0 g, 15.7 mmol) was dissolved in phosphorus oxychloride (29.26 mL, 313.91 mmol) The solution was heated at reflux for 16 hours. Afterwards, the reaction mixture was evaporated to dryness and water (10 mL) was added. The resulting mixture was stirred at room temperature for 30 min, and 6% aqueous ammonium hydroxide (10 mL) was added. The resulting precipitate was filtered off. The filtrate was diluted with brine and extracted three times with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (2.5 g, 61% yield) as a brown solid. 1H NMR (500 MHz, DMSO-d6) δ = 8.21 (s, 1H), 6.33 (tt, J = 3.4, 54.3 Hz, 1H), 4.29 (dt, J = 3.5, 14.7 Hz, 2H)

[0544] Step 5: 5-(2,2-difluoroethoxy)-4-methylsulfanyl-pyrimidin-2-amine

[0545]

[0546] To 4-chloro-5-(2,2-difluoroethoxy) pyrimidin-2-amine (1.1 g, 5.25 mmol) at 0°C in N,N-dimethylformamide (30 mL) was added dropwise a 21% solution of sodium methylthiolate in water (2.63 mL, 2.63 g, 7.87 mmol). The reaction mixture was stirred at 0 °C for 1 h and at room temperature overnight, then poured into water and extracted twice with ethyl acetate. The organic layer was washed twice with brine, dried over sodium sulfate and concentrated in vacuo to give the title compound (330 mg, 23% yield) as an orange oil. MS (ESI): m / z= 222.0 [M+H]+

[0547] Intermediate B26: 4-methoxy-5-methylsulfanyl-pyrimidin-2-amine

[0548]

[0549] Step 1: 4-methoxy-N,N-bis[(4-methoxyphenyl)methyl]-5-methylsulfanyl-pyrimidin-2-amine

[0550]

[0551] To 5-bromo-4-methoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine (800.0 mg, 1.8 mmol, middle Compound B3, step 1) To a solution in tetrahydrofuran (10 mL) was added dropwise 2.5 M n-butyllithium in hexane (0.94 mL, 2.34 mmol). The mixture was stirred at -60 °C for 1 h, then methyl methanethiosulfonate (681.67 mg, 5.4 mmol) was added and the mixture was allowed to warm to room temperature. After stirring for 16 hours, the mixture was quenched with saturated ammonium chloride solution and concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to afford the title compound (117 mg, 16% yield). MS (ESI): m / z= 412.2 [M+H]+

[0552] Step 2: 4-methoxy-5-methylsulfanyl-pyrimidin-2-amine

[0553]

[0554] To 4-methoxy-N,N-bis[(4-methoxyphenyl)methyl]-5-methylhydrogensulfanyl-pyrimidin-2-amine (117.0 mg, 0.280 mmol) in To a solution in dichloromethane (10 mL) was added trifluoroacetic acid (1.95 g, 1.31 mL, 17.06 mmol). The mixture was heated at 50 °C for 15 h and concentrated in vacuo. The residue was dissolved in aqueous sodium carbonate and extracted with ethyl acetate. The organic phase was washed with water, brine, dried over sodium sulfate and concentrated in vacuo to give the title compound (42 mg, 86% yield). MS (ESI): m / z= 172.0 [M+H]+

[0555] Intermediate B27: 5-(difluoromethylsulfanyl)-4-methoxy-pyrimidin-2-amine

[0556]

[0557] Step 1: S-(2-Chloro-4-methoxy-pyrimidin-5-yl)thioglycolate

[0558]

[0559] 5-bromo-2-chloro-4-methoxy-pyrimidine (1 g, 4.39 mmol, CAS: 57054-92-9), tris(dibenzylideneacetone) dipalladium(0) (211.37 mg, 0.219 mmol), xanthene (258.94 mg, 0.439 mmol), n-ethyldiisopropylamine (1.74 g, 2.29 mL, 13.16 mmol) and potassium thioglycolate (766.65 mg, 6.58 mmol) in 1,4-bis The mixture in alkanes (20 mL) was heated in the microwave at 120 °C for 30 min. 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 ethyl acetate / heptane 0%-20% to afford the title compound (254 mg, 26% yield) as an orange oil. MS (ESI) m / z= 219.0 [M+H]+

[0560] Step 2: 2-Chloro-5-(difluoromethylsulfanyl)-4-methoxy-pyrimidine

[0561]

[0562] To a solution of S-(2-chloro-4-methoxy-pyrimidin-5-yl)thioacetate (190 mg, 0.869 mmol) in acetonitrile (2 mL) was added 5 M hydroxide A solution of potassium in water (3.48 mL, 17.38 mmol). The reaction mixture was stirred at room temperature for 2 hours. A solution of bromodifluoromethyldiethylphosphonate (464.02 mg, 308.73 uL, 1.74 mmol) in acetonitrile (600 uL) was added dropwise and stirring was continued at room temperature for 30 minutes. The reaction mixture was 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 ethyl acetate / heptane 0%-20% to afford the title compound (57 mg, 29% yield) as a colorless viscous oil. MS (ESI) m / z= 227.0 [M+H]+

[0563] Step 3: 5-(Difluoromethylsulfanyl)-4-methoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine

[0564]

[0565] 2-chloro-5-(difluoromethylsulfanyl)-4-methoxy-pyrimidine (68 mg, 0.300 mmol), bis(p-anisyl)amine (77.21 mg, 0.300 mmol) and A colorless solution of n-ethyldiisopropylamine (79.14 mg, 104.68 uL, 0.600 mmol) in N-methyl-2-pyrrolidone (1.4 mL) was heated to 80°C and stirred for 4.5 hours. The resulting light red solution was diluted with ethyl acetate and washed twice with brine. 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 ethyl acetate / heptane 0%-20% to afford the title compound (99 mg, 74% yield) as a colorless gum. MS (ESI) m / z= 448.3 [M+H]+

[0566] Step 4: 5-(Difluoromethylsulfanyl)-4-methoxy-pyrimidin-2-amine

[0567]

[0568] 5-(difluoromethylsulfanyl)-4-methoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine (98 mg, 0.219 mmol) in dichloromethane (300 uL) was cooled to 0 °C. Add trifluoroacetic acid (1.5 g, 1.01 mL, 13.14 mmol). The reaction mixture was stirred at 0 °C for 30 min, at room temperature for 2 days, at 60 °C for 40 h 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 ethyl acetate / heptane 0%-60% to afford the title compound (38 mg, 84% yield) as a pale yellow solid. MS (ESI) m / z= 208.1 [M+H]+

[0569] Intermediate B28: 5-(cyclopropoxy)-4-methoxy-pyrimidin-2-amine

[0570]

[0571] Step 1: 5-(cyclopropoxy)-4-methoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine

[0572]

[0573] 2-[bis(p-anisyl)amino]-4-methoxy-pyrimidin-5-ol (200 mg, 0.524 mmol, intermediate B3, step 3), cesium carbonate (341.68 mg, 1.05 mmol) and bromocyclopropane (317.17 mg, 210.05 uL, 2.62 mmol) in N-methyl-2-pyrrolidone (3 mL) was stirred at 130°C for 5 hours and at 140°C for 2.5 Hour. The reaction mixture was 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 preparative HPLC to afford the title compound (49 mg, 19% yield) as an orange viscous oil. MS (ESI) m / z= 422.4 [M+H]+

[0574] Step 2: 5-(cyclopropoxy)-4-methoxy-pyrimidin-2-amine

[0575]

[0576] To 5-(cyclopropoxy)-4-methoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine (48.9 mg, 0.116 mmol) in To a solution in dichloromethane (100 uL) was added trifluoroacetic acid (737 mg, 536.28 uL, 6.96 mmol). The reaction mixture was stirred at room temperature for 23 hours, then 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 ethyl acetate / heptane 0%-60% to afford the title compound (18 mg, 76% yield) as a white powder. MS (ESI) m / z= 182.1 [M+H]+

[0577] Intermediate B29: 5-(2,2-difluoroethoxy)-4-methoxy-pyrimidin-2-amine

[0578]

[0579] Step 1: 5-(2,2-difluoroethoxy)-4-methoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine

[0580]

[0581] To 2-[bis(p-anisyl)amino]-4-methoxy-pyrimidin-5-ol (120 mg, 0.315 mmol, intermediate B3, step 3) in N,N-dimethyl To a solution in formamide (3 mL), cesium carbonate (307.51 mg, 0.944 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (75.61 mg, 46.96 uL, 0.346 mmol) were added. The reaction mixture was stirred at room temperature for 15 min, poured into water and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (113 mg, 81% yield) as a light yellow viscous oil. MS (ESI) m / z= 446.3 [M+H]+

[0582] Step 2: 5-(2,2-difluoroethoxy)-4-methoxy-pyrimidin-2-amine

[0583]

[0584] 5-(2,2-difluoroethoxy)-4-methoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine (111 mg , 0.249 mmol) in dichloromethane (600 uL) was cooled to 0°C. Add trifluoroacetic acid (1.77 g, 1.19 mL, 15.36 mmol). After stirring at 0 °C for 30 min, the reaction mixture was allowed to warm to room temperature and stirring was continued for 2 days. The resulting red solution 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 ethyl acetate / heptane 0%-100% to afford the title compound (36 mg, 70% yield) as a white solid. MS (ESI) m / z= 206.1 [M+H]+

[0585] Intermediate B30: 5-(3-fluoropropoxy)-4-methoxy-pyrimidin-2-amine

[0586]

[0587] In a similar manner to intermediate B29, 2-[bis(p-anisyl)amino] Alkylation of 4-methoxy-pyrimidin-5-ol (Intermediate B3, step 3) followed by deprotection of the bis(p-anisyl) protecting group with TFA afforded the title compound as a yellow solid. MS (ESI): m / z= 202.1 [M+H]+

[0588] Intermediate B31: 5-but-2-ynyloxy-4-methoxy-pyrimidin-2-amine

[0589]

[0590] In a similar manner to intermediate B29, 2-[bis(p-anisyl)amino]-4-methanol was synthesized by using cesium carbonate as base and 1-bromobut-2-yne as alkylating agent Alkylation of oxy-pyrimidin-5-ol (intermediate B3, step 3) followed by deprotection of the bis(p-anisyl) protecting group with TFA afforded the title compound as a white solid. MS (ESI): m / z= 194.1 [M+H]+

[0591] Intermediate B32: 5-(3,3-difluoropropoxy)-4-methoxy-pyrimidin-2-amine

[0592]

[0593] Step 1: 3,3-Difluoropropyl 4-methylbenzenesulfonate

[0594]

[0595] To a solution of 3,3-difluoropropan-1-ol (1.3 g, 13.53 mmol) in dichloromethane (40 mL) was added triethylamine (3.42 g, 4.7 mL, 33.83 mmol), then p-toluenesulfonyl chloride (3.13 g, 16.24 mmol) was added. The reaction was stirred at room temperature for 4 hours, 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 residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-30% to afford the title compound (3 g, 84% yield) as a colorless liquid. 1H NMR (300 MHz, chloroform-d) δ = 7.79 (d, J = 7.7 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 5.89 (tt, J = 4.5, 56.0 Hz, 1H), 4.18 (t, J = 6.1 Hz, 2H), 2.46 (s, 3H), 2.29 - 2.13 (m, 2H)

[0596] Step 2: 5-(3,3-difluoropropoxy)-4-methoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine

[0597]

[0598] To 2-[bis(p-anisyl)amino]-4-methoxy-pyrimidin-5-ol (317 mg, 0.790 mmol, intermediate B3, step 3) in N,N-dimethyl To a solution in formamide (3.95 mL), cesium carbonate (771.73 mg, 2.37 mmol) was added. The mixture was stirred at room temperature for 30 minutes. 3,3-Difluoropropyl-4-methylbenzenesulfonate (310.49 mg, 0.868 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The mixture was poured into water, and extracted twice with ethyl acetate. The organic layer was washed twice with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-70% to afford the title compound (126 mg, 30% yield) as a yellow oil. MS (ESI) m / z= 460.3 [M+H]+

[0599] Step 3: 5-(3,3-difluoropropoxy)-4-methoxy-pyrimidin-2-amine

[0600]

[0601] To 5-(3,3-difluoropropoxy)-4-methoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine (126.2 mg , 0.233 mmol) To a stirred solution in dichloromethane (399 uL) was added trifluoroacetic acid (1.6 g, 1.08 mL, 14.01 mmol). The reaction mixture was stirred at 50 °C for 15 h, then concentrated in vacuo. The residue was poured into saturated NaHCO3 and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient of methanol / dichloromethane 0%-10% to afford the title compound (32 mg, 59% yield) as a white solid. MS (ESI) m / z= 220.1 [M+H]+

[0602] Intermediate B33: 4-methoxy-5-(3,3,3-trifluoropropoxy)pyrimidin-2-amine

[0603]

[0604] In a manner similar to intermediate B29, 2-[bis(p-anisyl )amino]-4-methoxy-pyrimidin-5-ol (intermediate B3, step 3) followed by deprotection of the bis(p-anisyl) protecting group with TFA to prepare the title as a pale yellow solid compound. MS (ESI): m / z= 238.1 [M+H]+

[0605] Intermediate B34: 4-methoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-amine

[0606]

[0607] Step 1: 5-(2,2-dichloro-1,1,2-trifluoro-ethoxy)-4-methoxy-N,N-bis[(4-methoxyphenyl )methyl]pyrimidin-2-amine

[0608]

[0609] 2-[bis(p-anisyl)amino]-4-methoxy-pyrimidin-5-ol (1100.0 mg, 2.62 mmol, intermediate B3, step 3), 1,1,2-tri A solution of a mixture of chlorotrifluoroethane (1081 mg, 5.80 mmol) and cesium carbonate (1409 mg, 4.3 mmol) in dimethylsulfoxide (25 mL) was heated to 50°C and stirred under nitrogen for 12 hours. The reaction mixture was poured into water, and extracted three times 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 / petroleum ether 0%-30% to afford the title compound (800 mg, 11% yield) as a yellow oil. MS (ESI) m / z= 498.2 [M+H]+

[0610] Step 2: 5-(2,2-dichloro-1,1,2-trifluoro-ethoxy)-4-methoxy-pyrimidin-2-amine

[0611]

[0612] 5-(2,2-dichloro-1,1,2-trifluoro-ethoxy)-4-methoxy-N,N-bis[(4-methoxyphenyl)methoxy A mixture of pyrimidin-2-amine (1200 mg, 2.25 mmol) in trifluoroacetic acid (55 mL) was stirred at 60°C for 12 hours. The reaction mixture was poured into saturated NaHCO3 to adjust the pH to 7-8 and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (660 mg, 100% yield) as a yellow semi-solid. MS (ESI) m / z= 291.6 [M+H]+

[0613] Step 3: 4-methoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-amine

[0614]

[0615] At room temperature under nitrogen, to 5-(2,2-dichloro-1,1,2-trifluoro-ethoxy)-4-methoxy-pyrimidin-2-amine (3000.0 mg, 10.27 mmol) To a stirred suspension in triethylsilane (40.0 mL) was added triethylamine (4.3 mL, 30.82 mmol) and a catalytic amount of palladium dichloride (182.16 mg, 1.03 mmol). The mixture was stirred at 80°C for 48 hours, poured into water and extracted four times with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to afford the title compound (790 mg, 34% yield) as an off-white solid. MS (ESI) m / z= 224.0 [M+H]+

[0616] Intermediate B35: 5-(1,1-difluoroethoxy)-4-methoxy-pyrimidin-2-amine

[0617]

[0618] Step 1: 5-[(Z)-1,2-dichlorovinyloxy]-4-methoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidine -2-amine

[0619]

[0620] To a solution of trichlorethylene (620.04 mg, 4.72 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (103.82 mg, 2.6 mmol) at 20 °C. The reaction mixture was stirred at 20 °C for 1 h. 2-[Bis(p-anisyl)amino]-4-methoxy-pyrimidin-5-ol (900.0 mg, 2.36 mmol, intermediate B3, step 3) in N,N-dimethylformamide (10 mL) was added to the reaction mixture. The mixture was stirred at 50 °C for 16 h and purified directly by flash chromatography on silica gel using a gradient of ethyl acetate / petroleum ether 0%-13% to afford the title compound (900 mg, 80% yield).

[0621] Step 2: 5-ethynyloxy-4-methoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine

[0622]

[0623] Under a nitrogen atmosphere at -78°C, to 5-[(Z)-1,2-dichlorovinyloxy]-4-methoxy-N,N-bis[(4-methoxy To a solution of phenyl)methyl]pyrimidin-2-amine (630.0 mg, 1.32 mmol) in dry diethyl ether (30 mL) was added 2.5 M n-butyllithium solution (2.65 mL, 6.61 mmol). The mixture was stirred at -78 °C for 1 h. The mixture was then warmed to -40°C and stirred at -40°C for an additional 2 hours. The reaction mixture was quenched with saturated ammonium chloride solution and extracted three times 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 / petroleum ether 0%-15% to afford the title compound (89 mg, 17% yield) as a colorless oil. MS (ESI) m / z= 405.9 [M+H]+

[0624] Step 3: 5-(1,1-difluoroethoxy)-4-methoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine

[0625]

[0626] 5-Ethynyloxy-4-methoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine (130.0 mg, 0.320 mmol) was added to a Teflon flask and dissolved in dichloromethane (6 mL). The solution was cooled to -78 °C and stirred for 15 min. Add hydrogen fluoride-pyridine (220.0 mg, 1.44 mmol). The reaction mixture was stirred for 18 h, allowed to reach 25 °C, then poured into saturated NaHCO3 and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (142.3 mg, 100% yield) as a light brown oil. MS (ESI) m / z= 445.8 [M+H]+

[0627] Step 4: 5-(1,1-difluoroethoxy)-4-methoxy-pyrimidin-2-amine

[0628]

[0629] at 25 ℃ to 5-(1,1-difluoroethoxy)-4-methoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidine-2- Amine (150.0 mg, 0.340 mmol) To a mixture in dichloromethane (0.500 mL) was added trifluoroacetic acid (1.5 mL, 19.47 mmol). The reaction mixture was stirred at 60 °C for 5 h, then poured into saturated NaHCO3 and extracted three times 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 / petroleum ether 0%-80% to afford the title compound (50 mg, 72% yield) as an off-white semi-solid. MS (ESI) m / z= 206.0 [M+H]+

[0630] Intermediate B36: 4-methoxy-5-(1,1,2,2-tetrafluoroethoxy)pyrimidin-2-amine

[0631]

[0632] Step 1: 5-(2-bromo-1,1,2,2-tetrafluoro-ethoxy)-4-methoxy-N,N-bis[(4-methoxyphenyl) Methyl]pyrimidin-2-amine

[0633]

[0634] 2-[bis(p-anisyl)amino]-4-methoxy-pyrimidin-5-ol (400 mg, 1.05 mmol, intermediate B3, step 3), 1,2-dichlorotetra A mixture of fluoroethane (0.25 mL, 2.1 mmol) and cesium carbonate (512.52 mg, 1.57 mmol) in dimethylsulfoxide (10 mL) was heated to 50°C and stirred under nitrogen for 2 hours. The reaction mixture was extracted three times 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 / petroleum ether 0%-20% to afford the title compound (341 mg, 58% yield) as a colorless oil. MS (ESI) m / z= 559.9 [M+H]+

[0635] Step 2: 4-methoxy-5-(1,1,2,2-tetrafluoroethoxy)pyrimidin-2-amine

[0636]

[0637] 5-(2-bromo-1,1,2,2-tetrafluoro-ethoxy)-4-methoxy-N,N-bis[(4-methoxyphenyl)methyl ] A mixture of pyrimidin-2-amine (300 mg, 0.540 mmol) in methanol (30 mL) was purged with nitrogen. Palladium hydroxide (300 mg) was added. The mixture was purged with hydrogen, then stirred at 80°C under 2.7 atm of hydrogen for 16 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / petroleum ether 0%-100% to afford the title compound (50 mg, 38% yield) as a colorless oil. MS (ESI) m / z= 241.7 [M+H]+

[0638] Intermediate B37: 5-(2-Chloro-1,1,2-trifluoro-ethoxy)-4-methoxy-pyrimidin-2-amine

[0639]

[0640] Step 1: 5-(2-Chloro-1,1,2-trifluoro-ethoxy)-4-methoxy-N,N-bis[(4-methoxyphenyl)methyl ]pyrimidin-2-amine

[0641]

[0642] 2-[bis(p-anisyl)amino]-4-methoxy-pyrimidin-5-ol (1100 mg, 2.62 mmol, intermediate B3, step 3), 1,1,2-tri A solution of a mixture of chlorotrifluoroethane (1081 mg, 5.80 mmol) and cesium carbonate (1409 mg, 4.3 mmol) in dimethylsulfoxide (25 mL) was heated to 50°C and stirred under nitrogen for 12 hours. The reaction mixture was poured into water, and extracted three times 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 / petroleum ether 0%-30% to afford the title compound (800 mg, 11% yield) as a yellow oil. MS (ESI) m / z= 498.2 [M+H]+

[0643] Step 2: 5-(2-Chloro-1,1,2-trifluoro-ethoxy)-4-methoxy-pyrimidin-2-amine

[0644]

[0645] 5-(2-chloro-1,1,2-trifluoro-ethoxy)-4-methoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidine -2-Amine (720.0 mg, 1.45 mmol) in trifluoroacetic acid (7 mL) was stirred at 80°C for 12 hours. The reaction mixture was quenched by addition of saturated NaHCO3 and extracted three times with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (373 mg, 100% yield) as a dark brown solid. MS (ESI) m / z= 258.1 [M+H]+

[0646] Intermediate B38: 4-methoxy-5-propyl-pyrimidin-2-amine

[0647]

[0648] Step 1: 5-allyl-4-methoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine

[0649]

[0650] (5-bromo-4-methoxy-pyrimidin-2-yl)-bis(p-anisyl)amine (400 mg, 0.900 mmol, intermediate B3, step 1), 2-allyl- 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (302.56 mg, 338.43 uL, 1.8 mmol), potassium carbonate (373.27 mg, 2.7 mmol) and dichloro[1, 1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (22.06 mg, 0.027 mmol) in 1,4-dioxane (4.19 mL) and water (1.05 mL ) was heated to 90°C and stirred for 6 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-7% to afford the title compound (200 mg, 27% yield) as a colorless waxy solid. MS (ESI) m / z= 406.3 [M+H]+

[0651] Step 2: 4-methoxy-N,N-bis[(4-methoxyphenyl)methyl]-5-propyl-pyrimidin-2-amine

[0652]

[0653] 5-allyl-4-methoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine (200 mg, 0.493 mmol) in methanol (2 mL) and palladium on activated carbon (26.24 mg, 0.025 mmol) was stirred under 1 atm. of hydrogen at room temperature for 5 hours. The reaction mixture was filtered through a pad of celite and concentrated in vacuo to afford the title compound (200 mg, 80% yield) as a colorless waxy solid. MS (ESI) m / z= 408.3 [M+H]+

[0654] Step 3: 4-methoxy-5-propyl-pyrimidin-2-amine

[0655]

[0656] 4-methoxy-N, N-bis[(4-methoxyphenyl)methyl]-5-propyl-pyrimidin-2-amine (200 mg, 0.491 mmol) in trifluoroacetic acid (1.99 mL) was stirred at 50 °C for 17 h and concentrated in vacuo to afford the title compound (80 mg, 93% yield) as a colorless solid. MS (ESI) m / z=168.1 [M+H]+

[0657] Intermediate B39: 5-(cyclopropylmethyl)-4-methoxy-pyrimidin-2-amine

[0658]

[0659] Step 1: 5-bromo-N,N-bis[(2,4-dimethoxyphenyl)methyl]-4-methoxy-pyrimidin-2-amine

[0660]

[0661] 5-bromo-2-chloro-4-methoxy-pyrimidine (5.0 g, 22.38 mmol, CAS: 57054-92-9), n-ethyldiisopropylamine (8.68 g, 11.72 mL, 67.13 mmol ) and bis(2,4-dimethoxybenzyl)amine (10.65 g, 33.56 mmol) in acetonitrile (45 mL) was stirred at 80°C for 23 hours, then cooled to room temperature and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-25% to afford the title compound (9.18 g, 77% yield) as a pale yellow amorphous. MS (ESI) m / z= 506.2 [M+H]+

[0662] Step 2: 2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-4-methoxy-pyrimidine-5-carbaldehyde

[0663]

[0664] 5-bromo-N,N-bis[(2,4-dimethoxyphenyl)methyl]-4-methoxy-pyrimidin-2-amine (1.52 g, 2.86 mmol) in tetrahydrofuran (25 mL) was cooled to -72 °C. Add a 1.6 M solution of n-butyllithium in hexane (1.54 g, 1.79 mL, 2.86 mmol) dropwise. The reaction mixture was stirred at -72 °C for 15 min and N,N-dimethylformamide (313.9 mg, 332.17 uL, 4.29 mmol) was added. Stirring was continued for 45 min at -72 °C. The reaction mixture was quenched with saturated ammonium chloride solution and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-40% to afford the title compound (730 mg, 56% yield) as a colorless viscous oil. MS (ESI) m / z= 454.3 [M+H]+

[0665] Step 3: [2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-4-methoxy-pyrimidin-5-yl]-cyclopropyl-methanol

[0666]

[0667] A solution of 1 M cyclopropylmagnesium bromide in 2-methyltetrahydrofuran (441.02 uL, 0.441 mmol) was added dropwise to 2-[bis[(2,4-dimethoxybenzene In a solution of methyl]amino]-4-methoxy-pyrimidine-5-carbaldehyde (100 mg, 0.221 mmol) in tetrahydrofuran (4 mL). The reaction mixture was stirred at 0 °C for 15 min, then quenched with saturated ammonium chloride solution and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-50% to afford the title compound (94 mg, 86% yield) as a white solid. MS (ESI) m / z= 496.3 [M+H]+

[0668] Step 4: 5-(cyclopropylmethyl)-N,N-bis[(2,4-dimethoxyphenyl)methyl]-4-methoxy-pyrimidin-2-amine

[0669]

[0670] [2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-4-methoxy-pyrimidin-5-yl]-cyclopropyl-methanol (85 mg , 0.172 mmol) in dichloromethane (1 mL) was cooled to 0 °C. Triethylsilane (201.46 mg, 276.73 uL, 1.72 mmol) was added dropwise followed by trifluoroacetic acid (58.67 mg, 39.38 uL, 0.515 mmol). The reaction mixture was stirred at 0 °C for 20 min and at room temperature for 20 h, 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 residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-20% to afford the title compound (57 mg, 69% yield) as a white solid. MS (ESI) m / z= 480.3 [M+H]+

[0671] Step 5: 5-(cyclopropylmethyl)-4-methoxy-pyrimidin-2-amine

[0672]

[0673] 5-(cyclopropylmethyl)-N,N-bis[(2,4-dimethoxyphenyl)methyl]-4-methoxy-pyrimidin-2-amine (57 mg , 0.119 mmol) in dichloromethane (100 uL) was cooled to 0 °C. Add trifluoroacetic acid (813.14 mg, 545.73 uL, 7.13 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The resulting purple mixture was poured into saturated NaHCO3 and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (22 mg, 100% yield) as a white solid. MS (ESI) m / z= 180.2 [M+H]+

[0674] Intermediate B40: 5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-amine

[0675]

[0676] Step 1: 5-[(E)-2-ethoxyvinyl]-4-methoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidine-2- amine

[0677]

[0678] In a 250 mL round bottom flask, (5-bromo-4-methoxy-pyrimidin-2-yl)-bis(p-anisyl)amine (11.1 g, 23.73 mmol, Intermediate B3, step 1), 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.11 g, 30.85 mmol) , 1,4-dioxane (97 mL) / water (16 mL), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct ​(1.94 g, 2.37 mmol) and cesium carbonate (23.2 g, 71.2 mmol) (evacuated / argon filled after each addition). The reaction mixture was stirred at 110°C for 15 hours, then poured into water and extracted three times with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-30% to afford the title compound (4.2 g, 39 % yield) as a pale yellow oil. MS (ESI) m / z= 436.3 [M+H]+

[0679] Step 2: 2-[2-[bis[(4-methoxyphenyl)methyl]amino]-4-methoxy-pyrimidin-5-yl]acetaldehyde

[0680]

[0681] 5-[(E)-2-ethoxyvinyl]-4-methoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine ( A solution of 1 g, 2.3 mmol) in formic acid (3.17 g, 2.64 mL, 68.88 mmol) was stirred at 60°C for 30 minutes, then poured into saturated NaHCO3 under ice cooling, and extracted twice with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (1.01 g, 97% yield) as a pale yellow oil. MS (ESI) m / z= 408.3 [M+H]+

[0682] Step 3: 5-(2,2-difluoroethyl)-4-methoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine

[0683]

[0684] 2-[2-[bis[(4-methoxyphenyl)methyl]amino]-4-methoxy-pyrimidin-5-yl]acetaldehyde (1.01 g, 2.23 mmol​) The solution in ultra-dry dichloromethane (10 mL) was cooled to 0 °C. A solution of Deoxo-fluor®, 2.7M (50 wt.%) in toluene (1.98 g, 1.65 mL, 4.46 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 30 min, 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 residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-30% to afford the title compound (763 mg, 72% yield) as a colorless oil. MS (ESI) m / z= 430.3 [M+H]+

[0685] Step 4: 5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-amine

[0686]

[0687] To 5-(2,2-difluoroethyl)-4-methoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine (763 mg, 1.6 mmol) To a stirred solution in dichloromethane (8 mL) was added trifluoroacetic acid (10.94 g, 7.39 mL, 95.94 mmol). The reaction mixture was stirred at 50 °C for 2 days, then concentrated in vacuo. The residue was poured into saturated NaHCO3 and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-100% to afford the title compound (220 mg, 73% yield) as a pale yellow solid. MS (ESI) m / z= 190.1 [M+H]+

[0688] Intermediate B41: 5-(2,2-difluoropropyl)-4-methoxy-pyrimidin-2-amine

[0689]

[0690] Step 1: 1-[2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-4-methoxy-pyrimidin-5-yl]-2,2- Difluoro-propan-1-ol

[0691]

[0692] 5-bromo-N, N-bis[(2,4-dimethoxyphenyl) methyl]-4-methoxy-pyrimidin-2-amine (1.5 g, 2.97 mmol, Intermediate B39, step 1) To a solution in ultra-dry tetrahydrofuran (10 mL) was added 1.6 M n-butyllithium in hexane (2.42 mL, 3.87 mmol). After 1 hour, ethyl 2,2-difluoropropionate (2.05 g, 14.87 mmol) was added dropwise and the reaction mixture was stirred at -78°C for an additional 1 hour before warming to 0°C. After 45 min, methanol (2 mL) was added, followed by sodium borohydride (112.51 mg, 2.97 mmol). The reaction mixture was quenched with saturated ammonium chloride solution and extracted 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 ethyl acetate / heptane 0%-35% to afford the title compound (805 mg, 42% yield) as a white foam. MS (ESI) m / z= 520.4 [M+H]+

[0693] Step 2: 5-(2,2-difluoropropyl)-N,N-bis[(2,4-dimethoxyphenyl)methyl]-4-methoxy-pyrimidine-2 -amine

[0694]

[0695] 1-[2-[bis[(2,4-dimethoxyphenyl) methyl] amino]-4-methoxy-pyrimidin-5-yl]-2,2-difluoro -Propan-1-ol (580 mg, 1.12 mmol) and 1,1'-thiocarbonyldiimidazole (298.42 mg, 1.67 mmol) were mixed in tetrahydrofuran (8 mL) and stirred at 70°C for 5.5 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in toluene (11.6 mL) and degassed. Add 2,2'-azobis(2-methylpropionitrile) (36.66 mg, 0.223 mmol) and tri-n-butyltin hydride (1.62 g, 1.49 mL, 5.58 mmol). The reaction mixture was stirred at 85 °C for 3 hours, cooled to room temperature, placed on silica gel, concentrated in vacuo and purified by flash chromatography using a gradient ethyl acetate / heptane 0%-20% to give colorless Amorphous title compound (242 mg, 34% yield). MS (ESI) m / z= 504.4 [M+H]+

[0696] Step 3: 5-(2,2-difluoropropyl)-4-methoxy-pyrimidin-2-amine

[0697]

[0698] 5-(2,2-difluoropropyl)-N,N-bis[(2,4-dimethoxyphenyl)methyl]-4-methoxy-pyrimidin-2-amine (242 mg, 0.384 mmol) dissolved in trifluoroacetic acid (4.44 g, 3 mL, 38.94 mmol). The reaction mixture was stirred at room temperature for 15 hours and concentrated in vacuo. The residue was poured into saturated NaHCO3 and extracted 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 ethyl acetate / heptane 0%-70% to afford the title compound (52 mg, 63% yield) as a colorless solid. MS (ESI) m / z= 204.2 [M+H]+

[0699] Intermediate B42: 5-(3,3-difluoropropyl)-4-methoxy-pyrimidin-2-amine

[0700]

[0701] Step 1: N-(5-bromo-4-methoxy-pyrimidin-2-yl)-N-tertiary butoxycarbonyl-carbamic acid tertiary butyl ester

[0702]

[0703] Suspend (5-bromo-4-methoxy-pyrimidin-2-yl)amine (3 g, 14.7 mmol, CAS: 36082-45-8) in dichloromethane (72 mL), and add n-Ethyldiisopropylamine (2.28 g, 3.08 mL, 17.65 mmol). The mixture was cooled to 5 °C, and ditert-butyl dicarbonate (6.42 g, 6.83 mL, 29.41 mmol) in dichloromethane (36 mL) and 4-dimethylaminopyridine (179.64 mg, 1.47 mmol) were added dropwise. ) in the solution. After the addition, the cooling bath was removed and the mixture was stirred at room temperature for 5 hours, then poured into water and extracted three times with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-50% to afford the title compound (4.68 g, 79% yield) as a pale yellow oil. MS (ESI) m / z= 204.0 [M+H-2 BOC]+

[0704] Step 2: (E)-3-[2-[bis(tertiary butoxycarbonyl)amino]-4-methoxy-pyrimidin-5-yl]prop-2-enoic acid ethyl ester

[0705]

[0706] Add N-(5-bromo-4-methoxy-pyrimidin-2-yl)-N-tertiary butoxycarbonyl-carbamic acid tertiary butyl ester (4.68 g, 11.58 mmol), (e)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl acrylate (3.4 g, 3.37 mL, 15.05 mmol), ultra-dry 1,4-dioxane (30 mL), water (5 mL) and 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) ( 847.07 mg, 1.16 mmol) (3 vacuum-argon cycles after each addition). The reaction mixture was heated to 110 °C. After stirring at 110 °C for 1 hour, cesium carbonate (11.32 g, 34.73 mmol) was added. The reaction mixture was stirred at 110°C for 20 hours, then poured into water and extracted three times 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 ethyl acetate / heptane 0%-30% to afford the title compound (2.72 g, 55% yield) as a pale yellow oil. MS (ESI) m / z= 424.2 [M+H]+

[0707] Step 3: Ethyl 3-[2-[bis(tertiary butoxycarbonyl)amino]-4-methoxy-pyrimidin-5-yl]propionate

[0708] (E)-3-[2-[bis(tertiary butoxycarbonyl)amino]-4-methoxy-pyrimidin-5-yl]prop-2-enoic acid ethyl ester (2.72 g , 6.42 mmol) in ethyl acetate (24.8 mL) was purged with argon for 5 min. Palladium on activated carbon (683.56 mg, 0.642 mmol) was added. The reaction mixture was purged with hydrogen and stirred at room temperature for 2 hours under 1 atm. of hydrogen. The reaction mixture was filtered through a pad of celite and concentrated in vacuo to afford the title compound (2.54 g, 90% yield) as a light gray oil. MS (ESI): m / z= 426.2 [M+H]+

[0710] Step 4: Tertiary butyl N-tertiary butoxycarbonyl-N-[5-(3-hydroxypropyl)-4-methoxy-pyrimidin-2-yl]carbamate

[0711] 3-[2-[bis(tertiary butoxycarbonyl)amino]-4-methoxy-pyrimidin-5-yl]propanoic acid ethyl ester (2.54 g, 5.79 mmol) under argon Dissolve in ultra-dry tetrahydrofuran (25.62 mL). The solution was cooled to 0 °C and a solution of 1 M DIBAL-H in THF (11.58 mL, 11.58 mmol) was added dropwise. After the addition, the reaction mixture was allowed to warm to room temperature, stirred for 2 hours and carefully quenched by slow addition of saturated sodium tartrate solution at 0 °C. The mixture was then poured into water and extracted three times with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Dichloromethane was added to the residue, insolubles were filtered off, and the filtrate was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-60% to afford the title compound as a colorless oil ( 1.02 g, 44% yield). MS (ESI) m / z= 384.2 [M+H]+

[0713] Step 5: Tertiary butyl N-tertiary butoxycarbonyl-N-[4-methoxy-5-(3-oxopropyl)pyrimidin-2-yl]carbamate

[0714]

[0715] N-tertiary butyloxycarbonyl-N-[5-(3-hydroxypropyl)-4-methoxy-pyrimidin-2-yl]carbamate tertiary butyl ester (483 mg, 1.26 mmol) were dissolved in ultra-dry dichloromethane (3.91 mL). The mixture was degassed by sonication in an ultrasonic bath under an atmosphere of argon. 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benzodioxole-3-(1H)-one (641.12 mg, 1.51 mmol) was divided into Two parts are added. The mixture was stirred at room temperature for 1 h, then poured into saturated NaHCO3 and extracted 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 ethyl acetate / heptane 0%-60% to afford the title compound (419.3 mg, 86% yield) as a colorless oil. MS (ESI) m / z= 382.2 [M+H]+

[0716] Step 6: Tertiary butyl N-tertiary butoxycarbonyl-N-[5-(3,3-difluoropropyl)-4-methoxy-pyrimidin-2-yl]carbamate

[0717]

[0718] Under argon atmosphere, to N-tertiary butoxycarbonyl-N-[4-methoxy-5-(3-oxopropyl) pyrimidin-2-yl] carbamic acid at 0°C To a solution of tertiary butyl ester (419.3 mg, 1.08 mmol) in dichloromethane (4.73 mL) was added dropwise a solution of Deoxo-fluor®, 2.7M (50 wt.%) in toluene (399.01 uL, 1.08 mmol) . The reaction mixture was stirred at 0 °C for 2 h, then poured into saturated NaHCO3 and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (434.2 mg, 97% yield) as a yellow liquid. MS (ESI) m / z= 404.3 [M+H]+

[0719] Step 7: 5-(3,3-difluoropropyl)-4-methoxy-pyrimidin-2-amine

[0720]

[0721] N-tertiary butoxycarbonyl-N-[5-(3,3-difluoropropyl)-4-methoxy-pyrimidin-2-yl]carbamic acid tertiary butyl ester (434.2 mg, 1.04 mmol) and 4 M HCl in 1,4-dioxane (3.92 mL, 15.66 mmol) was stirred at room temperature for 15 hours, then poured into saturated NaHCO3 and extracted 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 ethyl acetate / heptane 0%-80% to afford the title compound (170.9 mg, 79% yield) as a pale yellow solid. MS (ESI) m / z= 203.9 [M+H]+

[0722] Intermediate B43: 5-(2,3-difluoropropyl)-4-methoxy-pyrimidin-2-amine

[0723]

[0724] Step 1: 5-allyl-4-methoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine

[0725]

[0726] To (5-bromo-4-methoxy-pyrimidin-2-yl)-bis(p-anisyl)amine (1000.0 mg, 2.25 mmol, intermediate B3, step 1) in 1,4-bis To a solution in alkane (20 mL) and water (4 mL), add allylboronic acid pinacol ester (567.29 mg, 3.38 mmol), cesium carbonate (1466.6 mg, 4.5 mmol) and 1,1'-bis (Diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (82.34 mg, 0.110 mmol). The mixture was evacuated and backfilled with nitrogen (three times), then stirred at 100 °C for 12 h. The reaction mixture was extracted three times 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 / petroleum ether 0%-10% to afford the title compound (700 mg, 77% yield) as a colorless oil. MS (ESI) m / z= 406.1 [M+H]+

[0727] Step 2: 3-[2-[bis[(4-methoxyphenyl)methyl]amino]-4-methoxy-pyrimidin-5-yl]propane-1,2-diol

[0728]

[0729] At room temperature, to 5-allyl-4-methoxyl-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine (630.0 mg, 1.55 mmol ) and to a solution of N-methyl"endo"line-N-oxide (364.03 mg, 3.11 mmol) in acetone (84 mL) and water (21 mL), add osmium tetroxide (40.0 mg, 0.160 mmol ) . The reaction mixture was stirred at room temperature for 12 hours. Sodium sulfite solution (50 mL) was added and stirring was continued for 1 h at room temperature. The reaction mixture was diluted with ethyl acetate and washed successively with water and brine. 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 ethyl acetate / petroleum ether 0%-100% to afford the title compound (500 mg, 73% yield) as a colorless oil. MS (ESI) m / z= 440.2 [M+H]+

[0730] Step 3: 5-(2,3-difluoropropyl)-4-methoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine

[0731]

[0732] 3-[2-[bis[(4-methoxyphenyl) methyl] amino]-4-methoxy-pyrimidin-5-yl] propane-1,2- To a solution of diol (300.0 mg, 0.680 mmol) in dichloromethane (6 mL) was added diethylaminosulfur trifluoride (0.45 mL, 3.41 mmol). The reaction mixture was allowed to warm to room temperature, stirred for 4 hours, then added slowly to ice / water. Adjust the pH to 7 with saturated NaHCO3. The mixture was 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 preparative TLC (eluent: ethyl acetate / petroleum ether 1 / 5) to afford the title compound (60 mg, 20% yield) as a white solid. MS (ESI) m / z= 444.1 [M+H]+

[0733] ​​Step 4: 5-(2,3-difluoropropyl)-4-methoxy-pyrimidin-2-amine

[0734]

[0735] 5-(2,3-difluoropropyl)-4-methoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine (60.0 mg, 0.140 mmol) in trifluoroacetic acid (2.0 mL, 26.93 mmol) was stirred at 60 °C for 2 hours, 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 residue was purified by preparative TLC (eluent: ethyl acetate / petroleum ether 1 / 2) to give the title compound (20 mg, 73% yield) as a colorless gum. MS (ESI) m / z= 203.9 [M+H]+

[0736] Intermediate B44: 4-methoxy-5-(2,2,2-trifluoroethyl)pyrimidin-2-amine

[0737]

[0738] Step 1: Dimethyl 2-(2,2,2-trifluoroethyl)malonate

[0739]

[0740] Dimethyl malonate (1 g, 869.57 uL, 7.42 mmol). After 20 minutes, 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.72 g, 1.07 mL, 7.42 mmol) was added at room temperature. The resulting pale yellow solution was heated to 50°C and stirred for 6 hours. 2,2,2-Trifluoroethyl triflate (1.72 g, 1.07 mL, 7.42 mmol) was added again and stirring was continued at 50 °C for 1 h. The reaction mixture was 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 to afford the title compound (1.19 g, 60% yield) as an orange solid, which was used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6) δ = 3.88 (t, J = 7.1 Hz, 1H), 3.71 (s, 6H), 2.87 (dq, J = 7.2, 11.0 Hz, 2H)

[0741] Step 2: 2-Amino-5-(2,2,2-trifluoroethyl)pyrimidine-4,6-diol

[0742]

[0743] To an orange solution of dimethyl 2-(2,2,2-trifluoroethyl)malonate (1.19 g, 4.45 mmol) in ethanol (11 mL) was added guanidine hydrochloride (424.7 mg, 4.45 mmol). The suspension was stirred at 75°C for 5 hours, then diluted with water (5 mL) and acetic acid (902.34 mg, 860.19 uL, 15.03 mmol). The mixture was heated at 80 °C for 10 min, cooled to room temperature, concentrated in vacuo and recrystallized from ethanol to afford the title compound (240 mg, 25% yield) as a brown solid. MS (ESI) m / z= 208.1 [M-H]-

[0744] Step 3: 4,6-dichloro-5-(2,2,2-trifluoroethyl)pyrimidin-2-amine

[0745]

[0746] 2-Amino-5-(2,2,2-trifluoroethyl)pyrimidine-4,6-diol (240 mg, 1.09 mmol) was suspended in phosphorus oxychloride (2.01 g, 1.22 mL , 13.08 mmol) and heated at 100°C for 16 hours. The reaction mixture was cooled to room temperature, poured into ice / water and extracted 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 ethyl acetate / heptane 0%-17% to afford the title compound (108 mg, 38% yield) as a light brown solid. MS (ESI) m / z= 246.1 [M+H]+

[0747] Step 4: 4-Chloro-6-methoxy-5-(2,2,2-trifluoroethyl)pyrimidin-2-amine

[0748]

[0749] 4,6-dichloro-5-(2,2,2-trifluoroethyl)pyrimidin-2-amine (108 mg, 0.439 mmol) and sodium methoxide (23.71 mg, 0.439 mmol) were dissolved in methanol ( 2 mL) was heated to 45°C and stirred for 23 hours. The reaction mixture was poured into water, and extracted 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 ethyl acetate / heptane 0%-20% to afford the title compound (83 mg, 74% yield) as a colorless solid. MS (ESI) m / z= 242.1 [M+H]+

[0750] Step 5: 4-methoxy-5-(2,2,2-trifluoroethyl)pyrimidin-2-amine

[0751]

[0752] 4-chloro-6-methoxy-5-(2,2,2-trifluoroethyl)pyrimidin-2-amine (83 mg, 0.326 mmol) and palladium on activated carbon (70 mg) in ethyl acetate The suspension in the ester (3 mL) was stirred under hydrogen and stirred at room temperature under 1 atm. of hydrogen for 9 hours. The reaction mixture was filtered through a pad of celite and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-80% to afford the title compound (35 mg, 49% yield) as a colorless solid. MS (ESI): m / z= 208.2 [M+H]+

[0753] Intermediate B45: 4-methoxy-5-(3,3,3-trifluoropropyl)pyrimidin-2-amine

[0754]

[0755] Step 1: 4-methoxy-N,N-bis[(4-methoxyphenyl)methyl]-5-(3,3,3-trifluoropropyl)pyrimidin-2-amine

[0756]

[0757] To (5-bromo-4-methoxy-pyrimidin-2-yl)-bis(p-anisyl)amine (200.0 mg, 0.450 mmol, intermediate B3, step 1) in 1,4-bis To a solution in alkane (10 mL) and water (2 mL), add 3,3,3-trifluoropropane-1-potassium trifluoroborate (459.04 mg, 2.25 mmol), cesium carbonate (1466.6 mg, 4.5 mmol ) and 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (16.47 mg, 0.020 mmol). The mixture was stirred at 100°C for 12 hours, then poured into water and extracted twice with ethyl acetate. The organic layer was washed successively with water and 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 / petroleum ether 0%-20% to afford the title compound (150 mg, 46% yield) as a colorless oil. MS (ESI) m / z= 462.1 [M+H]+

[0758] Step 2: 4-methoxy-5-(3,3,3-trifluoropropyl)pyrimidin-2-amine

[0759]

[0760] 4-methoxy-N, N-bis[(4-methoxyphenyl) methyl]-5-(3,3,3-trifluoropropyl) pyrimidin-2-amine (130.0 mg, 0.280 mmol) in trifluoroacetic acid (3.0 mL, 40.39 mmol) was stirred at 60 °C for 2 hours, then poured into saturated NaHCO3 and extracted twice with ethyl acetate. The organic layer was washed successively with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative TLC (eluent: ethyl acetate / petroleum ether 1 / 1) to afford the title compound (20 mg, 32% yield) as a white solid. MS (ESI) m / z= 222.4 [M+H]+

[0761] Intermediate B46: 5-(1,1-difluoroethyl)-4-methoxy-pyrimidin-2-amine

[0762]

[0763] Step 1: 1-(2-Chloro-4-methoxy-pyrimidin-5-yl)ethanone

[0764]

[0765] Under a nitrogen atmosphere, tributyl (1-ethoxyvinyl) tin (4.85 g, 13.43 mmol) and 5-bromo-2-chloro-4-methoxy-pyrimidine (3.0 g, 13.43 mmol, CAS: 57054-92-9) To a solution in N,N-dimethylformamide (50 mL), bis(triphenylphosphine)palladium(II) dichloride (0.94 g, 1.34 mmol). The mixture was stirred at 120 °C for 3 hours, then poured into water and extracted three times with ethyl acetate. The organic layer was concentrated in vacuo. Ethyl acetate (100 mL) and 2M HCl solution (200 mL) were added to the residue. The mixture was stirred at room temperature for 20 min and extracted three times 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 ethyl acetate / petroleum ether 0%-10% to afford the title compound (1.32 g, 53% yield) as a white solid. MS (ESI) m / z= 186.7 [M+H]+

[0766] Step 2: 2-Chloro-5-(1,1-difluoroethyl)-4-methoxy-pyrimidine

[0767]

[0768] To 1-(2-chloro-4-methoxy-pyrimidin-5-yl)ethanone (1.32 g, 7.07 mmol) in dichloromethane (20 mL) at -78°C under nitrogen atmosphere To the solution of diethylaminosulfur trifluoride (5.7 g, 35.37 mmol) was added. The reaction mixture was stirred at 20 °C for 12 h under nitrogen. Diethylaminosulfur trifluoride (5.7 g, 35.37 mmol) was added four times at -78°C under nitrogen, and the reaction mixture was stirred at 20°C under nitrogen for 12 hours. The reaction was then poured into saturated NaHCO3 and extracted twice with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / petroleum ether 0%-13% to afford the title compound (1 g, 68% yield) as a yellow oil. MS (ESI) m / z= 209.0 [M+H]+

[0769] Step 3: 5-(1,1-difluoroethyl)-4-methoxy-pyrimidin-2-amine

[0770]

[0771] 2-Chloro-5-(1,1-difluoroethyl)-4-methoxy-pyrimidine (300.0 mg, 1.44 mmol) and NH solution (5.0 mL, 25 mmol) in tetrahydrofuran The mixture was stirred at 60 °C for 16 hours and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate / petroleum ether 0%-43% to afford the title compound (100 mg, 26% yield) as a white solid. MS (ESI) m / z= 190.0 [M+H]+

[0772] Intermediate B47: 4-methoxy-5-(2,2,3,3-tetrafluoropropyl)pyrimidin-2-amine

[0773]

[0774] Step 1: 1-[2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-4-methoxy-pyrimidin-5-yl]-2,2, 3,3-Tetrafluoro-propan-1-ol

[0775]

[0776] 5-bromo-N, N-bis[(2,4-dimethoxyphenyl) methyl]-4-methoxy-pyrimidin-2-amine (1.8 g, 3.57 mmol, Intermediate B39, step 1) To a solution in tetrahydrofuran (12 mL) was added 1.6 M n-butyllithium in hexane (2.9 mL, 4.64 mmol). After 1 hour, ethyl 2,2,3,3-tetrafluoropropionate (1.86 g, 10.71 mmol) was added dropwise and the reaction mixture was stirred at -78°C for an additional 1 hour before warming to 0°C. After 20 minutes, methanol (2.4 mL) was added, followed by sodium borohydride (135.01 mg, 3.57 mmol). The reaction mixture was quenched with saturated ammonium chloride solution and extracted 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 ethyl acetate / heptane 0%-15% to afford the title compound (1.25 g, 54% yield) as a colorless solid. MS (ESI) m / z= 556.4 [M+H]+

[0777] Step 2: N,N-bis[(2,4-dimethoxyphenyl)methyl]-4-methoxy-5-(2,2,3,3-tetrafluoropropyl) Pyrimidin-2-amine

[0778]

[0779] 1-[2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-4-methoxy-pyrimidin-5-yl]-2,2,3, 3-Tetrafluoro-propan-1-ol (745 mg, 1.14 mmol) and 1,1'-thiocarbonyldiimidazole (304.72 mg, 1.71 mmol) were mixed in tetrahydrofuran (12.42 mL) and stirred at 70 °C for 5 Hour. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in toluene (8 mL) and 2,2'-azobis(2-methylpropionitrile) (37.44 mg, 0.228 mmol​), then tri-n-butyltin hydride (1.66 g, 1.52 mL, 5.7 mmol). The reaction mixture was stirred at 85 °C for 2 hours, cooled to room temperature, placed on silica gel, concentrated in vacuo and purified by flash chromatography using a gradient ethyl acetate / heptane 0%-22% to give colorless The title compound (99 mg, 16% yield) as a viscous oil. MS (ESI) m / z= 540.4 [M+H]+

[0780] Step 3: 4-methoxy-5-(2,2,3,3-tetrafluoropropyl)pyrimidin-2-amine

[0781]

[0782] N,N-bis[(2,4-dimethoxyphenyl)methyl]-4-methoxy-5-(2,2,3,3-tetrafluoropropyl)pyrimidine- 2-Amine (99 mg, 0.184 mmol) was dissolved in trifluoroacetic acid (2.96 g, 2 mL, 141.48 mmol). The reaction mixture was stirred at room temperature for 18 hours and concentrated in vacuo. The residue was poured into saturated NaHCO3 and extracted 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 ethyl acetate / heptane 0%-10% to afford the title compound (31 mg, 67% yield) as a colorless solid. MS (ESI) m / z= 240.2 [M+H]+

[0783] Intermediate B48: 3-(2-Amino-4-methoxy-pyrimidin-5-yl)propionitrile

[0784]

[0785] Step 1: 3-[2-[bis[(4-methoxyphenyl)methyl]amino]-4-methoxy-pyrimidin-5-yl]propionitrile

[0786]

[0787] To (5-bromo-4-methoxy-pyrimidin-2-yl)-bis(p-anisyl)amine (4000.0 mg, 9 mmol, intermediate B3, step 1) under nitrogen in methoxy 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)propionitrile (1955.78 mg , 10.8 mmol), cesium carbonate (8799.6 mg, 27.01 mmol) and cataCXium®A Pd G3 (655.63 mg, 0.9 mmol, CAS: 1651823-59-4). The mixture was purged three times with nitrogen, stirred at 90 °C for 12 hours, then poured into water and extracted three times 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 / petroleum ether 0%-30% to afford the title compound (3100 mg, 82% yield) as a yellow oil. MS (ESI) m / z= 418.9 [M+H]+

[0788] Step 2: 3-(2-Amino-4-methoxy-pyrimidin-5-yl)propionitrile

[0789]

[0790] 3-[2-[bis[(4-methoxyphenyl)methyl]amino]-4-methoxy-pyrimidin-5-yl]propionitrile (2000.0 mg, 4.78 mmol) in The mixture in trifluoroacetic acid (21 mL) was stirred at room temperature for 48 hours and concentrated in vacuo. The reaction mixture was quenched with saturated NaHCO3 and extracted three times 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 ethyl acetate / petroleum ether 0%-100% to afford the title compound (674 mg, 78% yield) as a yellow solid. MS (ESI) m / z= 179.0 [M+H]+

[0791] Intermediate B49: 4-methoxy-5-(2-methoxyethyl)pyrimidin-2-amine

[0792]

[0793] Step 1: 2-[2-[bis[(4-methoxyphenyl)methyl]amino]-4-methoxy-pyrimidin-5-yl]ethanol

[0794]

[0795] 2-[2-[bis[(4-methoxyphenyl)methyl]amino]-4-methoxy-pyrimidin-5-yl]acetaldehyde (1.07 g, 2.22 mmol, intermediate Compound B40, step 2) was dissolved in ultra-dry tetrahydrofuran (12 mL) under argon and cooled to -70 °C. A solution of 1 M DIBAL-H in THF (2.67 mL, 2.67 mmol) was added dropwise. After the addition, the reaction mixture was allowed to warm to 0 °C, stirred for 1 h and quenched by the addition of saturated aqueous sodium tartrate. The mixture was then poured into water and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-80% to afford the title compound (342 mg, 34% yield) as a pale yellow oil. MS (ESI) m / z= 410.3 [M+H]+

[0796] Step 2: 4-methoxy-5-(2-methoxyethyl)-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine

[0797]

[0798] 2-[2-[bis[(4-methoxyphenyl)methyl]amino]-4-methoxy-pyrimidin-5-yl]ethanol (342 mg, 0.835 mmol) in ultra-dry N,N-dimethylformamide (3 mL) was added dropwise to sodium hydride (36.75 mg, 0.919 mmol) in ultra-dry N,N-dimethylformamide (1 mL ) in suspension. The reaction mixture was stirred at 0 °C for 30 min. Iodomethane (130.4 mg, 57.19 uL, 0.919 mmol) was then added, and the reaction mixture was stirred at room temperature for 3 hours, 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 ethyl acetate / heptane 0%-80% to afford the title compound (225 mg, 61 % yield) as a colorless oil. MS (ESI) m / z= 424.3 [M+H]+

[0799] Step 3: 4-methoxy-5-(2-methoxyethyl)pyrimidin-2-amine

[0800]

[0801] To 4-methoxy-5-(2-methoxyethyl)-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine (225 mg, 0.510 mmol) To a stirred solution in ultra-dry dichloromethane (5 mL) was added trifluoroacetic acid (3.49 g, 2.36 mL, 30.6 mmol). The reaction mixture was stirred at 50 °C for 40 h 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 ethyl acetate / heptane 0%-100% to afford the title compound (48 mg, 51 % yield) as a white solid. MS (ESI) m / z= 184.1 [M+H]+

[0802] Intermediate B50: 5-(difluoromethoxymethyl)-4-methoxy-pyrimidin-2-amine

[0803]

[0804] Step 1: [2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-4-methoxy-pyrimidin-5-yl]methanol

[0805]

[0806] 5-bromo-N, N-bis[(2,4-dimethoxyphenyl) methyl]-4-methoxy-pyrimidin-2-amine (2.1 g, 4.16 mmol, Intermediate B39, step 1) To a solution in tetrahydrofuran (14 mL) was added 1.6 M n-butyllithium in hexane (3.38 mL, 5.41 mmol). After 1.5 hours, N,N-Dimethylformamide (1.52 g, 1.61 mL, 20.82 mmol) was added and the reaction mixture was stirred at -78°C for an additional 1 hour before warming to 0°C. After 15 minutes, methanol (2.8 mL) was added, followed by sodium borohydride (157.51 mg, 4.16 mmol). The reaction mixture was stirred at 0 °C for 15 min, quenched with saturated ammonium chloride solution, and extracted 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 ethyl acetate / heptane 0%-45% to afford the title compound as colorless amorphous (1.44 g, 72% yield). MS (ESI) m / z= 456.4 [M+H]+

[0807] Step 2: 5-(difluoromethoxymethyl)-N,N-bis[(2,4-dimethoxyphenyl)methyl]-4-methoxy-pyrimidine-2- amine

[0808]

[0809] [2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-4-methoxy-pyrimidin-5-yl]methanol (825 mg, 1.72 mmol) To a colorless solution in dichloromethane (7 mL) and water (7 mL), potassium acetate (1.01 g, 10.32 mmol) and (bromodifluoromethyl)trimethylsilane (698.92 mg , 533.53 uL, 3.44 mmol). Add (bromodifluoromethyl)trimethylsilane (698.92 mg, 533.53 uL, 3.44 mmol) 3 times. The reaction mixture was then quenched with saturated NaHCO3 and extracted three times 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 ethyl acetate / heptane 0%-25% to afford the title compound (107.7 mg, 12% yield) as a colorless viscous oil. MS (ESI) m / z= 506.3 [M+H]+

[0810] Step 3: 5-(Difluoromethoxymethyl)-4-methoxy-pyrimidin-2-amine

[0811]

[0812] to 5-(difluoromethoxymethyl)-N,N-bis[(2,4-dimethoxyphenyl)methyl]-4-methoxy-pyrimidin-2-amine ( 107.7 mg, 0.209 mmol) To a colorless solution in ultra-dry dichloromethane (2 mL) was added trifluoroacetic acid (2.96 g, 2 mL, 25.96 mmol). The pink solution was stirred at 50 °C for 50 min and concentrated in vacuo. The residue was poured into saturated NaHCO3 and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-37% to afford the title compound (29 mg, 64% yield) as a white solid. MS (ESI) m / z= 206.1 [M+H]+

[0813] Intermediate B51: 4-methoxy-5-(oxetane-3-yl)pyrimidin-2-amine

[0814]

[0815] [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 (8.25 mg, 0.007 mmol, CAS: 870987-63-6) was added to the reaction flask, followed by Sodium carbonate (154.4 mg, 1.47 mmol), (5-bromo-4-methoxy-pyrimidin-2-yl)amine (150 mg, 0.735 mmol, CAS: 36082-45-8), 3-bromooxetane alkane (201.42 mg, 122. uL, 1.47 mmol) and tris(trimethylsilyl)silane (244.98 mg, 303.95 uL, 0.985 mmol). Ultra-dry ethylene glycol dimethyl ether (11.86 mL) was added and the reaction mixture was degassed by bubbling argon through the mixture for 2 min. Finally, nickel(II) chloride ethylene glycol dimethyl ether complex (807.72 ug, 0.004 mmol, 0.005 eq) and 4,4'-bis(tertiary butyl)-2,2'-bipyridine (986.66 ug, 0.004 mmol, 0.005 eq) and the reaction was degassed again for 5 minutes. Place the vial in a photoreactor and irradiate with 450 nm for 14 h (stirring at 900 rpm, LED 100% power). The reaction mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-100% then methanol / ethyl acetate 0%-10% to afford the title compound as a light yellow solid (28.8 mg, 21 % yield). MS (ESI) m / z= 182.1 [M+H]+

[0816] Intermediate B52: 4-methoxy-5-[2-(oxetane-3-yl)ethynyl]pyrimidin-2-amine

[0817]

[0818] To 5-iodo-4-methoxy-pyrimidin-2-amine (300.0 mg, 1.2 mmol, CAS: 89322-66-7) and 3-ethynyl oxetane (117.74 mg , 1.43 mmol) To a solution in N,N-dimethylformamide (3 mL) was added bis(triphenylphosphine)palladium(II) dichloride (83.88 mg, 0.120 mmol), copper iodide ( I) (68.05 mg, 0.360 mmol) and triethylamine (362.79 mg, 3.59 mmol). The mixture was stirred at 30°C for 12 hours, poured into water and extracted three times 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 ethyl acetate / petroleum ether 0%-50% to afford the title compound (150 mg, 61 % yield) as a yellow solid. MS (ESI) m / z= 206.0 [M+H]+

[0819] Intermediate B53: 4-methoxy-5-[2-(oxetane-3-yl)ethyl]pyrimidin-2-amine

[0820]

[0821] To 4-methoxy-5-[2-(oxetane-3-yl)ethynyl]pyrimidin-2-amine (60 mg, 0.290 mmol, intermediate B52) in methanol (4 mL) Palladium on activated carbon (6 mg, 0.056 mmol) was added to the solution in . The reaction mixture was purged with hydrogen and stirred at room temperature for 12 hours under 1 atm. of hydrogen. The reaction mixture was filtered through a pad of celite and concentrated in vacuo to afford the title compound (30 mg, 34% yield) as a pale yellow solid. MS (ESI): m / z= 210.1 [M+H]+

[0822] Intermediate B54: 5-(fluoromethoxy)-4,6-dimethoxy-pyrimidin-2-amine

[0823]

[0824] Step 1: 5-bromo-4,6-dimethoxy-pyrimidin-2-amine

[0825]

[0826] 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 at room temperature Add a solution of N-bromosuccinimide (10.33 g, 57.48 mmol) in acetonitrile (100 mL). The reaction mixture was stirred at room temperature for 30 min. 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 afford the title compound (9.26 g, 87% yield) as a white solid. MS (ESI) m / z= 234.1 [M+H]+

[0827] Step 2: 5-bromo-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine

[0828]

[0829] A solution of 5-bromo-4,6-dimethoxy-pyrimidin-2-amine (517 mg, 2.21 mmol) in N,N-dimethylacetamide (9 mL) was cooled to 0 ℃. Sodium hydride (265.05 mg, 6.63 mmol) was added in portions (3 x 88 mg). Stirring was continued for 30 min at 0 °C. Add 4-methoxybenzyl chloride (706. mg, 608.62 uL, 4.42 mmol) dropwise. The reaction mixture was allowed to warm to room temperature, stirred for 1 h, 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 ethyl acetate / heptane 0%-20% to afford the title compound (1.11 g, 100% yield) as a white solid. MS (ESI) m / z= 476.2 [M+H]+

[0830] Step 3: 2-[bis[(4-methoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-ol

[0831]

[0832] 5-bromo-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine (500 mg, 1 mmol) to a colorless solution in tetrahydrofuran (3.5 mL) was added dropwise a 1.6 M solution of n-butyllithium in hexane (699.71 mg, 813.61 uL, 1.3 mmol). The resulting yellow solution was stirred at -78 °C for 30 min. Trimethylborate (156.08 mg, 167.47 uL, 1.5 mmol) was added dropwise and stirring was continued at -78 °C for 1.5 h. The reaction mixture was allowed to warm 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 for 1.5 h at 0 °C. The resulting pink suspension was poured into 0.1 N sodium thiosulfate solution and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-30% to afford the title compound (194 mg, 47% yield) as a pale yellow viscous oil. MS (ESI) m / z= 412.3 [M+H]+

[0833] Step 4: 5-(fluoromethoxy)-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine

[0834]

[0835] To 2-[bis[(4-methoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-alcohol (300.0 mg, 0.730 mmol) in N,N - To a solution in dimethylformamide (10 mL) was added sodium hydride (26.25 mg, 1.09 mmol) and the mixture was heated at 50 °C until gas evolution ceased (15 min). The reaction mixture was cooled to room temperature and fluoro(iodo)methane (233.22 mg, 1.46 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours, diluted with water and extracted with ethyl acetate. The organic layer was washed twice with water, once with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (250 mg, 77% yield) as a brown oil. MS (ESI) m / z= 444.4 [M+H]+

[0836] Step 5: 5-(fluoromethoxy)-4,6-dimethoxy-pyrimidin-2-amine

[0837]

[0838] 5-(fluoromethoxy)-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine (250.0 mg, 0.560 mmol) was dissolved in trifluoroacetic acid (2.61 mL, 33.82 mmol) and heated at 50°C for 15 hours. The mixture was concentrated in vacuo. The residue was poured into sodium carbonate solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (200 mg, 63% yield). MS (ESI) m / z= 204.2 [M+H]+

[0839] Intermediate B55: 5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-amine

[0840]

[0841] Step 1: 5-(difluoromethoxy)-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine

[0842]

[0843] 2-[bis[(4-methoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-ol (130 mg, 0.316 mmol, Intermediate B54, step 3) solution in acetonitrile (5 mL) was added dropwise with 5 M potassium hydroxide solution (1.26 mL, 6.32 mmol) followed by bromodifluoromethyldiethylphosphonate at 0 °C (168.72 mg, 112.26 uL, 0.632 mmol) in acetonitrile (1 mL). The reaction mixture was stirred at 0 °C for 10 min. The resulting pale yellow biphasic mixture was 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 ethyl acetate / heptane 0%-30% to afford the title compound (57 mg, 39% yield) as a white solid. MS (ESI) m / z= 462.3 [M+H]+

[0844] Step 2: 5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-amine

[0845]

[0846] To 5-(difluoromethoxy)-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine (56 mg, 0.121 mmol) To a stirred solution in dichloromethane (100 uL) was added trifluoroacetic acid (838.62 mg, 563.21 uL, 7.28 mmol). The reaction mixture was stirred at room temperature for 40 h, at 50 °C for 6 h, 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 ethyl acetate / heptane 0%-100% to afford the title compound (24 mg, 89% yield) as a white solid. MS (ESI) m / z= 222.1 [M+H]+

[0847] Intermediate B56: 5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-amine

[0848]

[0849] Step 1: 5-(2-fluoroethoxy)-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine

[0850]

[0851] 2-[bis[(4-methoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-ol (2 g, 4.52 mmol, intermediate B54, 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) The suspension 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 ethyl acetate / heptane 0%-30% to afford the title compound (1.79 g, 85% yield) as a white solid. MS (ESI) m / z= 458.3 [M+H]+

[0852] Step 2: 5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-amine

[0853]

[0854] To 5-(2-fluoroethoxy)-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine (1.79 g , 3.83 mmol) To a stirred solution 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 h, at room temperature for 15 h, 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 ethyl acetate / heptane 0%-60% to afford the title compound (885 mg, 100% yield) as an off-white solid. MS (ESI) m / z= 218.1 [M+H]+

[0855] Intermediate B57: 5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-amine

[0856]

[0857] Step 1: 5-(2,2-difluoroethoxy)-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidine-2 -amine

[0858]

[0859] To 2-[bis[(4-methoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-ol (100 mg, 0.214 mmol, intermediate B54, Step 3) Add 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 h, 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 ethyl acetate / heptane 0%-20% to afford the title compound (92 mg, 85% yield) as an off-white solid. MS (ESI) m / z= 476.2 [M+H]+

[0860] Step 1: 5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-amine

[0861]

[0862] to 5-(2,2-difluoroethoxy)-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidine at 0°C -2-Amine (92 mg, 0.193 mmol) To a stirred solution in dichloromethane (0.340 mL) was added trifluoroacetic acid (1.34 g, 897.97 uL, 11.61 mmol). 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 ethyl acetate / heptane 0%-30% to afford the title compound (41 mg, 87% yield) as a pale yellow solid. MS (ESI) m / z= 236.2 [M+H]+

[0863] Intermediate B58: 4,6-dimethoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-amine

[0864]

[0865] Step 1: 2-[2-[bis[(4-methoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-yl]oxyl-2, 2-Difluoro-ethyl acetate

[0866]

[0867] 2-[bis[(4-methoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-ol (1 g, 2.26 mmol, intermediate B54, Step 3), a mixture of potassium carbonate (946.62 mg, 6.78 mmol) and ethyl bromodifluoroacetate (1.42 g, 903.79 uL, 6.78 mmol) in N,N-dimethylformamide (20 mL) at 80 Stirred at °C for 20 hours, poured into brine and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-20% to afford the title compound (449 mg, 34% yield) as a colorless viscous oil. MS (ESI) m / z= 534.3 [M+H]+

[0868] Step 2: 2-[2-[bis[(4-methoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-yl]oxyl-2, 2-Difluoro-ethanol

[0869]

[0870] 2-[2-[bis[(4-methoxyphenyl) methyl] amino]-4,6-dimethoxy-pyrimidin-5-yl]oxygen-2,2- A solution of ethyl difluoro-acetate (447 mg, 0.771 mmol) in tetrahydrofuran (11 mL) was cooled to 0 °C. Add a solution of 1 M lithium aluminum hydride in THF (1.16 mL, 1.16 mmol) dropwise. The reaction mixture was stirred at 0 °C for 30 min, 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 ethyl acetate / heptane 0%-40% to afford the title compound (374 mg, 99% yield) as a colorless viscous oil. MS (ESI) m / z= 492.4 [M+H]+

[0871] Step 3: 4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]-5-(1,1,2-trifluoroethoxy)pyrimidine -2-amine

[0872]

[0873] to 2-[2-[bis[(4-methoxyphenyl) methyl] amino]-4,6-dimethoxy-pyrimidin-5-yl]oxygen-2,2- To a solution of difluoroethanol (372 mg, 0.757 mmol) in tetrahydrofuran (8 mL), triethylamine (919.09 mg, 1.27 mL, 9.08 mmol), perfluorobutanesulfonyl fluoride (914.61 mg, 531.75 uL, 3.03 mmol) and triethylamine trihydrogen fluoride (498.04 mg, 503.57 uL, 3.03 mmol). The reaction mixture was stirred at 60 °C for 56 h, cooled to room temperature, poured into saturated NaHCO3, and extracted 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 ethyl acetate / heptane 0%-20% to afford the title compound (110 mg, 28% yield) as an orange gum. MS (ESI) m / z= 494.4 [M+H]+

[0874] Step 4: 4,6-dimethoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-amine

[0875]

[0876] At room temperature, to 4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]-5-(1,1,2-trifluoroethoxy ) pyrimidin-2-amine (109 mg, 0.210 mmol) To a stirred solution in dichloromethane (400 uL) was added trifluoroacetic acid (1.44 g, 963.47 uL, 12.59 mmol) dropwise. The reaction mixture was stirred at room temperature for 15 h, at 60 °C for 4 h, 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 ethyl acetate / heptane 0%-50% to afford the title compound (53 mg, 100% yield) as a yellow solid. MS (ESI) m / z= 254.1 [M+H]+

[0877] Intermediate B59: 5-allyl-4,6-dimethoxy-pyrimidin-2-amine

[0878]

[0879] Under nitrogen, 5-bromo-4,6-dimethoxy-pyrimidin-2-amine (5000 mg, 21.4 mmol, intermediate B54, step 1), allylboronic acid pinacol ester ( 4307.8 mg, 25.64 mmol) and potassium carbonate (8857.47 mg, 64.09 mmol) in 1,4-dioxane (125 mL) and water (25 mL), add 1,1'-bis(diphenyl phosphino)ferrocene-dichloropalladium(II) dichloromethane complex (1743.22 mg, 2.14 mmol). The mixture was stirred at 110 °C for 12 hours and extracted three times with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC and lyophilized to afford the title compound (835 mg, 14% yield) as an off-white solid. MS (ESI) m / z= 195.8 [M+H]+

[0880] Intermediate B60: 4,6-dimethoxy-5-prop-1-ynyl-pyrimidin-2-amine

[0881]

[0882] Step 1: 5-iodo-4,6-dimethoxy-pyrimidin-2-amine

[0883]

[0884] To a solution of 2-amino-4,6-dimethoxypyrimidine (1.0 g, 6.45 mmol, CAS: 10272-07-8) in acetonitrile (20 mL) was added N-iodosuccinimide Amine (1.6 g, 7.09 mmol). The mixture was stirred at room temperature, diluted with 200 mL of water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (1.4 g, 77% yield).

[0885] Step 2: 4,6-dimethoxy-5-prop-1-ynyl-pyrimidin-2-amine

[0886]

[0887] Under argon, 5-iodo-4,6-dimethoxy-pyrimidin-2-amine (0.5 g, 1.78 mmol), triethylamine (0.74 mL, 5.34 mmol), 1-(tri Methylsilyl)-1-propyne (0.32 mL, 2.13 mmol), copper(I) iodide (67.76 mg, 0.360 mmol) and tetrakis(triphenylphosphine)palladium(0) (205.58 mg, 0.180 mmol) To a degassed mixture in N,N-dimethylformamide (25 mL) was added potassium fluoride (124.03 mg, 2.13 mmol) in one portion. The mixture was heated at 80 °C overnight under argon, poured into water and extracted with ethyl acetate. The organic layer was washed twice with water, once 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 chloroform / acetonitrile 0%-10% to afford the title compound (120 mg, 35% yield) as a light brown solid. MS (ESI) m / z= 194.2 [M+H]+

[0888] Intermediate B61: 4,6-dimethoxy-5-propyl-pyrimidin-2-amine

[0889]

[0890] To a solution of 5-allyl-4,6-dimethoxy-pyrimidin-2-amine (100.0 mg, 0.510 mmol, Intermediate B59) in methanol (2 mL) was added palladium on activated carbon ( 10 mg, 0.094 mmol). The reaction mixture was purged with hydrogen and stirred at room temperature for 4 hours under 1 atm. of hydrogen. The reaction mixture was filtered through a pad of celite and concentrated in vacuo to afford the title compound (100 mg, 99% yield) as a white solid. MS (ESI) m / z= 197.8 [M+H]+

[0891] Intermediate B62: 5-(2-fluoroethyl)-4,6-dimethoxy-pyrimidin-2-amine

[0892]

[0893] Step 1: N-(5-bromo-4,6-dimethoxy-pyrimidin-2-yl)-N-tertiary butoxycarbonyl-carbamic acid tertiary butyl ester

[0894]

[0895] 5-bromo-4,6-dimethoxy-pyrimidin-2-amine (8.9 g, 38.03 mmol, intermediate B54, step 1) was suspended in dichloromethane (200 mL) and N,N- Diisopropylethylamine (5.9 g, 7.97 mL, 45.63 mmol). The mixture was cooled to 5 °C, and a solution of ditert-butyl dicarbonate (9.13 g, 9.71 mL, 41.83 mmol) in dichloromethane (100 mL) was added dropwise. After the addition, the cooling bath was removed, and the mixture was stirred at room temperature for 2.5 hours. 4-Dimethylaminopyridine (464.56 mg, 3.8 mmol) was added and the reaction mixture was further stirred at room temperature for 2 hours. Add ditert-butyl dicarbonate (9.13 g, 9.71 mL, 41.83 mmol). The reaction mixture was stirred overnight at room temperature, poured into water and extracted twice with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-50% to afford the title compound (14.88 g, 86% yield) as a colorless oil. MS (ESI) m / z= 336.1 [M+H-BOC]+

[0896] Step 2: Tertiary butyl N-tertiary butoxycarbonyl-N-(4,6-dimethoxy-5-vinyl-pyrimidin-2-yl)carbamate

[0897]

[0898] Under argon, add N-(5-bromo-4,6-dimethoxy-pyrimidin-2-yl)-N-tertiary butoxycarbonyl-carbamic acid tertiary butyl ester (1.02 g, 2.35 mmol ), potassium vinyltrifluoroborate (440.45 mg, 3.29 mmol), isopropanol (4 mL), 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride ( II) Dichloromethane complex (95.9 mg, 0.117 mmol) and triethylamine (475.33 mg, 654.73 uL, 4.7 mmol). The reaction mixture was stirred at 100°C for 22 hours, poured into water and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-50% to afford the title compound (600 mg, 47% yield) as a colorless oil. MS (ESI) m / z= 382.3 [M+H]+

[0899] Step 3: Tertiary butyl N-[5-(2-hydroxyethyl)-4,6-dimethoxy-pyrimidin-2-yl]carbamate

[0900]

[0901] N-tertiary butoxycarbonyl-N-(4,6-dimethoxy-5-vinyl-pyrimidin-2-yl) carbamate tertiary butyl ester (598 mg , 1.57 mmol) in tetrahydrofuran (8 mL) was added dropwise a 0.5 M solution of 9-boronbicyclo[3.3.1]nonane in THF (5.02 mL, 2.51 mmol). The mixture was warmed to room temperature and stirred overnight. After cooling to 0 °C, water (508.54 mg, 508.54 uL, 28.22 mmol), 4 M NaOH solution (3.92 mL, 15.68 mmol) and hydrogen peroxide (1.83 g, 1.65 mL, 18.81 mmol) were added. The reaction mixture was stirred at 50°C for 2.5 hours, poured into water / sodium thiosulfate and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-50% to afford the title compound (213 mg, 43% yield) as a colorless oil. MS (ESI) m / z= 300.2 [M+H]+

[0902] Step 4: Tertiary butyl N-[5-(2-fluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]carbamate

[0903]

[0904] N-[5-(2-hydroxyethyl)-4,6-dimethoxy-pyrimidin-2-yl] tertiary butyl carbamate (213 mg, 0.712 mmol) in dichloromethane (6 mL) was cooled to 0 °C. Add diethylaminosulfur trifluoride (149.12 mg, 122.23 uL, 0.925 mmol). The reaction mixture was stirred further at 0 °C, poured carefully into saturated NaHCO3, stirred for 20 min and extracted twice with dichloromethane. 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 ethyl acetate / heptane 0%-30% to afford the title compound (78 mg, 35% yield) as a white semi-solid. MS (ESI) m / z= 302.2 [M+H]+

[0905] Step 5: 5-(2-fluoroethyl)-4,6-dimethoxy-pyrimidin-2-amine

[0906]

[0907] N-[5-(2-fluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]carbamate tertiary butyl ester (76 mg, 0.252 mmol) in dichloromethane (2 mL) was cooled to 0 °C. Add trifluoroacetic acid (230.08 mg, 155.46 uL, 2.02 mmol). The reaction mixture was stirred at 0 °C for 1 h and at room temperature for 6 h, poured into saturated NaHCO3, and extracted twice with dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (45 mg, 84% yield) as a white solid. MS (ESI) m / z= 202.1 [M+H]+

[0908] Intermediate B63: 5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-amine

[0909]

[0910] Step 1: Diethyl 2-(2,2-difluoroethyl)malonate

[0911]

[0912] Diethyl malonate (75.83 mL, 499.47 mmol) was combined with tetrahydrofuran (450 mL). Sodium ethoxide (prepared from ethanol (150 mL) and sodium (11.48 g, 499.47 mmol)) was added at room temperature, and the reaction mixture was stirred at room temperature for 15 minutes. A solution of 2,2-difluoroethyl trifluoromethanesulfonate (75.83 mL, 499.47 mmol) in tetrahydrofuran (10 mL) was slowly added. The reaction mixture was stirred at 20°C for 18 hours, then cooled to 0°C, quenched with saturated ammonium chloride solution and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (100.5 g, 90% yield). MS (ESI) m / z= 225.0 [M+H]+

[0913] Step 2: 2-amino-5-(2,2-difluoroethyl)pyrimidine-4,6-diol

[0914]

[0915] To a stirred solution of diethyl 2-(2,2-difluoroethyl)malonate (46.75 g, 208.52 mmol) in ethanol (5 mL) was added guanidine hydrochloride (19.92 g, 208.52 mmol) , then sodium ethoxide (prepared from ethanol and sodium (14.38 g, 625.56 mmol)) was added. The resulting orange suspension was heated to 80°C and stirred for 4 hours. The reaction mixture was concentrated by half and 50 mL of water was added followed by acetic acid (42.57 g, 708.97 mmol). The mixture was heated to 80 °C and stirred for 10 min, then cooled to room temperature. The solid product was filtered off and washed successively with water, ethanol and methyl tertiary butyl ether to obtain the title compound (22.3 g, 50% yield). MS (ESI) m / z= 192.0 [M+H]+

[0916] Step 3: 4,6-dichloro-5-(2,2-difluoroethyl)pyrimidin-2-amine

[0917]

[0918] Suspend 2-amino-5-(2,2-difluoroethyl)pyrimidine-4,6-diol (13.2 g, 69.06 mmol) in phosphorus oxychloride (80.46 mL, 863.24 mmol) . The reaction mixture was heated to 100 °C and stirred for 18 hours and concentrated in vacuo. The residue was diluted with ethyl acetate and poured carefully into ice / sat. NaHCO3. The resulting biphasic mixture was stirred at room temperature for 5 min 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 to afford the title compound (7.35 g, 47% yield). MS (ESI) m / z= 227.8 [M+H]+

[0919] Step 4: 5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-amine

[0920]

[0921] In a sealed tube, combine 4,6-dichloro-5-(2,2-difluoroethyl)pyrimidin-2-amine (7.6 g, 33.33 mmol) and sodium methoxide (made from methanol (50 mL ) in sodium (7662.33 mg, 333.29 mmol) prepared) was heated to 75 ℃ and stirred for 18 hours. The reaction mixture was quenched with water and extracted twice with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (6.604 g, 86% yield) as a pale yellow solid. MS (ESI) m / z= 220.0 [M+H]+

[0922] Intermediate B64: 5-(3-fluoropropyl)-4,6-dimethoxy-pyrimidin-2-amine

[0923]

[0924] Step 1: Diethyl 2-(3-fluoropropyl)malonate

[0925]

[0926] To a suspension of potassium carbonate (7719.77 mg, 55.86 mmol) in acetone (50 mL) was added diethyl malonate (2.04 mL, 13.41 mmol) followed by 1-fluoro-3 - Iodo-propane (2100.0 mg, 11.17 mmol). The mixture was then stirred at 25 °C for 24 h and extracted three times with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / petroleum ether 0%-30% to afford the title compound (2200 mg, 89% yield) as a yellow oil.

[0927] Step 2: 2-Amino-5-(3-fluoropropyl)pyrimidine-4,6-diol

[0928]

[0929] To a stirred solution of guanidine hydrochloride (858.83 mg, 8.99 mmol) in methanol (40 mL) was added 5 M sodium methoxide in methanol (3.76 mL, 18.8 mmol) at 25°C under nitrogen atmosphere, then Diethyl 2-(3-fluoropropyl)malonate (1800.0 mg, 8.17 mmol) was added. The reaction mixture was heated to 40°C and stirred for 2 hours. Methanol was evaporated and water (80 mL) was added to the residue. After stirring, the product was almost dissolved. The resulting mixture was then neutralized by dropwise addition of acetic acid, resulting in immediate and quantitative precipitation of the product as a fine solid. The mixture was then heated at reflux for 10 min and then cooled to 25 °C. The solid product was filtered off, washed with water and ethanol. The product was dried under high vacuum at 60 °C to afford the title compound (700 mg, 46% yield) as an off-white solid. MS (ESI) m / z= 187.7 [M+H]+

[0930] Step 3: 4,6-dichloro-5-(3-fluoropropyl)pyrimidin-2-amine

[0931]

[0932] To a solution of 2-amino-5-(3-fluoropropyl)pyrimidine-4,6-diol (330.0 mg, 1.76 mmol) in phosphoryl chloride (5.0 mL) was added triethylamine ( 0.75 mL, 5.38 mmol). The reaction mixture was stirred at 60 °C for 2 h, cooled to 25 °C and quenched by the addition of water (15 mL), and the pH was adjusted to 7-8 with 10% NaOH (aq, 35 mL). The mixture was then extracted three times with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (400 mg, 81% yield) as an off-white solid. MS (ESI) m / z= 223.7 [M+H]+

[0933] Step 4: 5-(3-fluoropropyl)-4,6-dimethoxy-pyrimidin-2-amine

[0934]

[0935] To a stirred suspension of 4,6-dichloro-5-(3-fluoropropyl)pyrimidin-2-amine (200.0 mg, 0.890 mmol) in tetrahydrofuran (5 mL) at 20°C under nitrogen atmosphere To the solution was added 5 M sodium methoxide in methanol (0.54 mL, 2.68 mmol). The reaction mixture was stirred at 30 °C for 3 h, at 60 °C for 6 h and at 80 °C for 1 h, then cooled to 25 °C, quenched by addition of saturated ammonium chloride solution (10 mL) and washed with ethyl acetate Esters were extracted three times. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (180 mg, 94% yield) as an off-white solid. MS (ESI) m / z= 216.4 [M+H]+

[0936] Intermediate B65: 5-(3,3-difluoropropyl)-4,6-dimethoxy-pyrimidin-2-amine

[0937]

[0938] Step 1: Diethyl 2-(3,3-difluoropropyl)malonate

[0939]

[0940] Sodium hydride (538.92 mg, 13.47 mmol) was suspended in ultra-dry tetrahydrofuran (30 mL), and the mixture was cooled to 0°C. Diethyl malonate (1.92 g, 1.83 mL, 11.99 mmol) was added slowly. The mixture was stirred at 0 °C for 10 min, then 3,3-difluoropropyl 4-methylbenzenesulfonate (3 g, 11.99 mmol, Intermediate B32, Step 1) in THF (5 mL) was added slowly solution. The reaction mixture was stirred at 0 °C for 5 min and at 60 °C for 20 h, then cooled to 0 °C and quenched with saturated ammonium chloride solution, poured into water and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-30% to afford the title compound (2.16 g, 50% yield) as a colorless liquid. MS (ESI) m / z= 239.2 [M+H]+

[0941] Step 2: 2-amino-5-(3,3-difluoropropyl)pyrimidine-4,6-diol

[0942]

[0943] Diethyl 2-(3,3-difluoropropyl)malonate (1.98 g, 8.31 mmol) was combined with ethanol (16 mL) to give a colorless solution. Guanidine hydrochloride (793.98 mg, 8.31 mmol) was added, followed by 21% sodium ethoxide in ethanol (8.08 g, 9.31 mL, 24.93 mmol), and the orange suspension was stirred at 75 °C for 4 hours. The reaction mixture was concentrated by half and 5 mL of water was added followed by acetic acid (1.69 g, 1.61 mL, 28.1 mmol). The mixture was heated at 80 °C for 10 min and then cooled to room temperature. The solid was filtered off and washed successively with water, ethanol and heptane to afford 460 mg of the product as a light brown solid. The filtrate was washed with ethyl acetate and concentrated by half. The precipitate was filtered off, washed successively with water, ethanol and heptane, combined with the previously obtained solid and dried under high vacuum to give the title compound (568 mg, 28% yield) as a light brown solid. MS (ESI) m / z= 206.1 [M+H]+

[0944] Step 3: 4,6-dichloro-5-(3,3-difluoropropyl)pyrimidin-2-amine

[0945]

[0946] Suspend 2-amino-5-(3,3-difluoropropyl)pyrimidine-4,6-diol (746 mg, 3.64 mmol) in phosphorus oxychloride (9.9 g, 6.02 mL, 64.54 mmol) and stirred at 100°C for 4 hours. Excess phosphorus oxychloride was removed under reduced pressure. The residue was diluted in dichloromethane, poured into ice-cold NaHCO3 solution and stirred at room temperature for 10 min. After extraction, the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-50% to afford the title compound (432 mg, 44% yield) as an off-white solid. MS (ESI) m / z= 242.1 [M+H]+

[0947] Step 4: 5-(3,3-difluoropropyl)-4,6-dimethoxy-pyrimidin-2-amine

[0948]

[0949] 4,6-Dichloro-5-(3,3-difluoropropyl)pyrimidin-2-amine (432 mg, 1.78 mmol) was dissolved in ultra-dry tetrahydrofuran (15 mL). Add 25% sodium methoxide in methanol (1.93 g, 2.04 mL, 8.92 mmol). The reaction mixture was stirred at 60°C for 5 hours, cooled to 0°C, quenched with saturated ammonium chloride solution and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-30% to afford the title compound (328 mg, 76% yield) as an off-white solid. MS (ESI) m / z= 234.2 [M+H]+

[0950] Intermediate B66: 5-(2,2-difluoropropyl)-4,6-dimethoxy-pyrimidin-2-amine

[0951]

[0952] Step 1: Dimethyl 2-(2,2-difluoropropyl)malonate

[0953]

[0954] A mixture of dimethyl acetonyl malonate (4.0 g, 21.26 mmol, CAS: 24889-15-4) and diethylaminosulfur trifluoride (13.71 g, 85.02 mmol) was heated at 40°C Stir for 72 hours, then cool to room temperature, pour slowly into ice / water and extract with ethyl acetate. The organic layer was washed successively with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as a dark brown oil which was used in the next step without further purification.

[0955] Step 2: 2-amino-5-(2,2-difluoropropyl)pyrimidine-4,6-diol

[0956]

[0957] Dimethyl 2-(2,2-difluoropropyl) malonate (1.1 g, 5.23 mmol), guanidine hydrochloride (0.5 g, 5.23 mmol) and potassium tertiary butoxide (1.17 g, 10.5 mmol) in dry 1,4-dioxane (15 mL) was stirred at 115 °C for 30 h, then concentrated in vacuo. Triturate the residue with tert-butyl methyl ether (20 mL). The precipitate was filtered, washed twice with acetonitrile (10 mL), poured into water (5 mL) and acidified to pH 4-5 with acetic acid. The resulting precipitate was filtered and dried in vacuo to afford the title compound (180 mg, 15% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ = 6.67 (br s, 2H), 2.82 - 2.65 (m, 2H), 1.48 (br t, J = 18.8 Hz, 3H)

[0958] Step 3: 4,6-dichloro-5-(2,2-difluoropropyl)pyrimidin-2-amine

[0959]

[0960] To a stirred solution of N,N-dimethylformamide (8.3 mL, 107.23 mmol) in dry chloroform (20 mL) was slowly added phosphorus oxychloride (11.99 mL, 128.68 mmol). The reaction mixture was stirred at room temperature for 1 hour. 2-Amino-5-(2,2-difluoropropyl)pyrimidine-4,6-diol (2.2 g, 10.72 mmol) was then added. The reaction mixture was stirred at 60 °C for 15 h, then concentrated in vacuo. The residue was diluted with ethanol (20 mL) and 12M aqueous HCl (5 mL), stirred at 50 °C for 2 hours and concentrated in vacuo. The residue was diluted with aqueous NaHCO3 (pH 8-9) and extracted three times with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (800 mg, 28% yield) as a brown solid. MS (ESI) m / z= 244.0 [M+H]+

[0961] Step 4: 5-(2,2-difluoropropyl)-4,6-dimethoxy-pyrimidin-2-amine

[0962]

[0963] Sodium (156.72 mg, 6.82 mmol) was dissolved in dry methanol (30 mL) and 4,6-dichloro-5-(2,2-difluoropropyl)pyrimidin-2-amine (750.0 mg , 3.1 mmol). The mixture was stirred at reflux for 15 h, then diluted with toluene (40 mL) and stirred at 100 °C overnight. The solvent was evaporated under reduced pressure and the residue was diluted with water and extracted three times with dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (250 mg, 35% yield) as a light brown semi-solid. MS (ESI) m / z= 234.1 [M+H]+

[0964] Intermediate B67: 4,6-dimethoxy-5-(3,3,3-trifluoropropyl)pyrimidin-2-amine

[0965]

[0966] Step 1: Diethyl 2-(3,3,3-trifluoropropyl)malonate

[0967]

[0968] Diethyl malonate (650.75 mg, 619.77 uL, 4.06 mmol) was combined with tetrahydrofuran (7 mL). 21% sodium ethoxide in ethanol (1.32 g, 1.52 mL, 4.06 mmol) was added at room temperature and the reaction mixture was stirred for 15 min. A solution of 3,3,3-trifluoropropyl trifluoromethanesulfonate (1 g, 4.06 mmol) in tetrahydrofuran (5 mL) was added slowly over 25 min. The reaction mixture was stirred at room temperature for 1 h, cooled to 0 °C, quenched with saturated ammonium chloride solution and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-30% to afford the title compound (645 mg, 59% yield) as a colorless liquid. MS (ESI) m / z= 257.2 [M+H]+

[0969] Step 2: 2-Amino-5-(3,3,3-trifluoropropyl)pyrimidine-4,6-diol

[0970]

[0971] Diethyl 2-(3,3,3-trifluoropropyl)malonate (1.05 g, 4.1 mmol) was combined with ethanol (10 mL) to give a colorless solution. Add guanidine hydrochloride (391.49 mg, 4.1 mmol) and 21% sodium ethoxide in ethanol (3.98 g, 4.59 mL, 12.29 mmol). The orange suspension was stirred at 75 °C for 4 h and concentrated by half. Add 5 mL of water, followed by acetic acid (839.2 mg, 800 uL, 13.98 mmol). The mixture was heated at 80 °C for 10 min and cooled to room temperature. The precipitate was filtered off, washed with water, ethanol and heptane, then dried under high vacuum to afford the title compound (386 mg, 40% yield) as an off-white solid. MS (ESI) m / z= 224.0 [M+H]+

[0972] Step 3: 4,6-dichloro-5-(3,3,3-trifluoropropyl)pyrimidin-2-amine

[0973]

[0974] 2-Amino-5-(3,3,3-trifluoropropyl)pyrimidine-4,6-diol (386 mg, 1.73 mmol) was added to phosphorus oxychloride (3.29 g, 2 mL , 21.46 mmol), and the mixture was stirred at 100°C for 7 hours. Excess phosphorus oxychloride was removed under reduced pressure. The residue was diluted with dichloromethane, poured into ice-cold NaHCO3 solution and stirred at room temperature for 10 min. After extraction, the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate / heptane 0%-100% to afford the title compound (250 mg, 50% yield) as an off-white solid. MS (ESI) m / z= 260.1 [M+H]+

[0975] Step 4: 4,6-dimethoxy-5-(3,3,3-trifluoropropyl)pyrimidin-2-amine

[0976]

[0977] 4,6-dichloro-5-(3,3,3-trifluoropropyl)pyrimidin-2-amine (250 mg, 0.961 mmol) was combined with tetrahydrofuran (5 mL) to give a light yellow solution . Add 25% sodium methoxide in methanol (1.04 g, 1.1 mL, 4.81 mmol). The reaction mixture was stirred at 60 °C for 2 hours, cooled to 0 °C, quenched with saturated ammonium chloride solution and extracted 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 ethyl acetate / heptane 0%-50% to afford the title compound (155 mg, 61 % yield) as a white solid. MS (ESI) m / z= 252.2 [M+H]+

[0978] Intermediate B68: 4,6-dimethoxy-5-(methoxymethyl)pyrimidin-2-amine

[0979]

[0980] Step 1: (2-amino-4,6-dimethoxy-pyrimidin-5-yl)methanol

[0981]

[0982] A suspension of (2-amino-4,6-dichloro-pyrimidin-5-yl)methanol (613 mg, 3.16 mmol, CAS: 850554-81-3) in methanol (1 mL) was cooled to 0°C. Add a 0.5 M solution of sodium methoxide in methanol (18.96 mL, 9.48 mmol) at this temperature. The ice bath was removed and the reaction mixture was stirred overnight at room temperature. Add 0.5M sodium methoxide in methanol (12.64 mL, 6.32 mmol) and continue stirring at room temperature for 4 hours. Add 25% sodium methoxide in methanol (2.73 g, 2.89 mL, 12.64 mmol). The reaction mixture was stirred at 60 °C for 6 h, poured into saturated ammonium chloride solution and extracted four times with dichloromethane / methanol 9:1. 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 ethyl acetate / heptane 30%-100% to afford the title compound (295 mg, 47% yield) as a white solid. MS (ESI) m / z= 186.1 [M+H]+

[0983] Step 2: 4,6-dimethoxy-5-(methoxymethyl)pyrimidin-2-amine

[0984]

[0985] To (2-amino-4,6-dimethoxy-pyrimidin-5-yl) methanol (83.1 mg, 0.422 mmol) and iodomethane (131.72 mg, 58.03 uL, 0.928 mmol) in tetrahydrofuran (2100 μL), sodium hydride (33.75 mg, 0.844 mmol) was added portionwise. The mixture was stirred at 23°C for 48 hours. Add iodomethane (131.72 mg, 58.03 uL, 0.928 mmol). The reaction mixture was stirred at 23°C for 7.5 hours, quenched with brine, poured into water and extracted three times 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 ethyl acetate / heptane 0%-100% to afford the title compound (40.3 mg, 46% yield) as a pale yellow solid. MS (ESI) m / z= 200.1 [M+H]+

[0986] Intermediate B69: 4,6-dimethoxy-5-(2-methoxyethyl)pyrimidin-2-amine

[0987]

[0988] Step 1: 2-amino-5-(2-methoxyethyl)pyrimidine-4,6-diol

[0989]

[0990] 1,3-diethyl 2-(2-methoxyethyl)malonate (6 g, 27.49 mmol, CAS: 6335-02-0) was combined with ethanol (60 mL) to give color solution. Guanidine hydrochloride (2.63 g, 27.49 mmol) and 21% sodium ethoxide in ethanol (26.73 g, 30.79 mL, 82.47 mmol) were added, and the orange suspension was stirred at 75°C for 5 hours and concentrated by half. 25 mL of water were added, followed by acetic acid (5.61 g, 5.35 mL, 93.47 mmol), and the mixture was concentrated in vacuo, diluted with toluene, and concentrated in vacuo until a precipitate appeared. The solid was filtered off and washed with toluene to afford the title compound (2.38 g, 37% yield) as a brown solid. MS (ESI) m / z= 186.1 [M+H]+

[0991] Step 2: 4,6-dichloro-5-(2-methoxyethyl)pyrimidin-2-amine

[0992]

[0993] 2-Amino-5-(2-methoxyethyl)pyrimidine-4,6-diol (1.6 g, 8.64 mmol) was carefully added to stirred phosphorus oxychloride (14.81 g, 9 mL, 96.56 mmol). The mixture was stirred at 100°C for 4 hours. Excess phosphorus oxychloride was removed under reduced pressure. The residue was diluted with dichloromethane, poured into ice-cold NaHCO3 solution and stirred at room temperature for 10 min. After extraction, the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated ...

Claims

1. A compound of formula I or a mirror isomer, non-mirror isomer, or pharmaceutically acceptable salt thereof, wherein R1 is H, a halogroup, C1-6-alkyl, C1-6-alkoxy, C1-6-alkoxyC1-6-alkyl, C1-6-alkoxyC1-6-alkoxy, cyanoC1-6-alkyl, haloC1-6-alkyl, haloC1-6-alkoxy, thiol-C1-6-alkyl, C3-8-cycloalkyl, C3-8-cycloalkylC1-6-alkyl, C3-8-cycloalkoxy, or heterocyclic alkyl; R2 The group can be cyano, halogen, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C1-6-alkoxy, C2-6-alkenylC1-6-alkyl, C2-6-alkynylC1-6-alkoxy, C1-6-alkoxyC1-6-alkyl, C1-6-alkoxyC1-6-alkoxy, halo-C1-6-alkyl, halo-C1-6-alkoxyC1-6-alkyl, (halogen-C1-6-alkoxy) C1-6-alkoxy, cyanoC1-6-alkyl, cyanoC1-6-alkoxy, thiol-C1-6-alkyl, halothiol-C1-6-alkyl, halohydroxy-C1-6-alkoxy, C1-4-alkylsulfonylC1-6-alkyl, C3-8-cycloalkyl, C3-8-cycloalkylC1-6-alkyl, C3-8-cycloalkylC1-6-alkoxy, C3-8-cycloalkoxy, heterocycloalkyl, heterocycloalkylC1-6-alkyl, heterocycloalkylC2-6-ynyl or heterocycloalkylC1-6-alkoxy; R3 is H, halogen, C1-6-alkyl, C1-6-alkoxy, haloC1-6-alkoxy or thiol-C1-6-alkyl; X1 is CR5 or N; X2 is NH, -N-R6, S, -S(O)- or -S(O2)-; R4 R5 is H, halogen, C1-6-alkyl, hydroxyC1-6-alkyl, thiolC1-6-alkyl, cyanoC1-6-alkyl, C1-6-alkoxy, haloC1-6-alkyl, haloC1-6-alkoxy, C3-8-cycloalkyl, or heterocyclic alkyl; C1-6-alkyl, diC1-6-alkylamino, haloC1-6-alkyl, haloC1-6-alkoxy, halothiol C1-6-alkyl, C1-4-alkylsulfinyl, C1-4-alkylsulfonyl, C1-4-alkyl guanidine, thiol C1-6-alkyl, hydroxy C1-6-alkyl, C1-6-alkoxycarbonyl, heterocyclic alkyl, C3-8-cycloalkyl or C3-8-cycloalkoxy; or R4 and R5 connected to form a 5- or 6-membered cycloalkyl, heterocyclic alkyl, substituted heterocyclic alkyl containing one or two substituents independently selected from C1-6-alkyl and side oxygen groups, or heteroaromatic ring;R6 is H, C1-6-alkyl, C1-6-alkylhydroxy, or halo-C1-6-alkyl; wherein the heterocyclic alkyl group has 4 to 9 ring atoms, including 1, 2, or 3 heterocyclic atoms selected from N, O, and S, and wherein the heteroaromatic ring has 5 to 12 ring atoms, including 1, 2, 3, or 4 heterocyclic atoms selected from N, O, and S.

2. The compound of claim 1 or its mirror isomer, non-mirror isomer, or pharmaceutically acceptable salt thereof, wherein R1 is H, a halogen, a halo-C1-6-alkyl, a halo-C1-6-alkoxy, C1-6-alkyl, C1-6-alkoxy-C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, thiol-C1-6-alkyl, cyano-C1-6-alkyl, C3-8-cycloalkoxy, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, or a heterocyclic alkyl.

3. A compound of claim 1 or 2 or a mirror isomer, non-mirror isomer or pharmaceutically acceptable salt thereof, wherein R1 is H, C1-6-alkoxy, C3-8-cycloalkyl or halo-C1-6-alkoxy.

4. A compound of claim 1 or 2, or its mirror-image isomers, non-mirror-image isomers, or pharmaceutically acceptable salts thereof, wherein R2 is C1-6-alkoxy, C1-6-alkoxy-C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, C1-4-alkylsulfonyl-C1-6-alkyl, C1-6-alkyl, C2-6-alkenyl, C2-6-ynyl, C2-6-ynyl-C1-6-alkoxy, cyano, cyano-C1-6-alkyl, C3-8-cycloalkyl, C3-8-cycloalkoxy, C3-8-cycloalkyl-C1-6-alkyl, cyano-C1-6-alkoxy, halogroup, halogenated C1-6-alkoxy, (halogenated C1-6-alkoxy) C1-6-alkoxy, thiol-C1-6-alkyl, halothiol-C1-6-alkyl, halohydroxy-C1-6-alkoxy, halo-C1-6-alkyl, heterocyclic alkyl, heterocyclic alkyl-C1-6-alkyl, heterocyclic alkyl-C2-6-ynyl or heterocyclic alkyl-C1-6-alkoxy.

5. A compound of claim 1 or 2 or a mirror isomer, non-mirror isomer, or pharmaceutically acceptable salt thereof, wherein R2 is a C1-6-alkyl, C2-6-alkenyl, C2-6-ynyl, C1-6-alkoxy-C1-6-alkyl, C2-6-ynyl, cyano-C1-6-alkoxy, halogen, halo-C1-6-alkoxy, halo-C1-6-alkyl, or C3-8-cycloalkyl.

6. A compound of claim 1 or 2 or a mirror isomer, non-mirror isomer or pharmaceutically acceptable salt thereof, wherein R3 is H or C1-6-alkoxy.

7. The compound of claim 1 or 2 or its mirror isomer, non-mirror isomer or pharmaceutically acceptable salt thereof, wherein X2 is NH or S.

8. A compound of claim 1 or 2 or its mirror isomer, non-mirror isomer, or pharmaceutically acceptable salt thereof, wherein R4 is H, a halogroup, C1-6-alkyl, C1-6-alkoxy, thioc1-6-alkyl, cyanoC1-6-alkyl, C3-8-cycloalkyl, haloC1-6-alkoxy, haloC1-6-alkyl, heterocyclic alkyl, or hydroxyC1-6-alkyl, and R5 It can be H, halogen, halogenated C1-6-alkyl, halogenated C1-6-alkoxy, halogenated thiol-C1-6-alkyl, C1-6-alkoxy, C1-6-alkoxycarbonyl, C1-6-alkyl, hydroxy C1-6-alkyl, thiol-C1-6-alkyl, C1-4-alkylsulfinic acid, C1-4-alkylsulfonyl, cyano, cyanoC1-6-alkyl, cyanoC1-6-alkoxy, diC1-6-alkylamino, C3-8-cycloalkyl, C3-8-cycloalkoxy, or heterocyclic alkyl, or R4 and R5 connected to form a 5-membered heterocyclic alkyl containing a single O heteroatom, a 6-membered heterocyclic alkyl containing a single N heteroatom substituted with a side oxygen and alkyl group, a 5-membered heteroaromatic ring containing one N heteroatom and one S heteroatom, or a 6-membered heteroaromatic ring containing a single N heteroatom.

9. A compound of claim 1 or 2 or a mirror isomer, non-mirror isomer, or pharmaceutically acceptable salt thereof, wherein R4 is a halogroup, C1-6-alkyl, or halo-C1-6-alkyl, and R5 is H, a halogroup, halo-C1-6-alkyl, halo-C1-6-alkoxy, halo-thiol-C1-6-alkyl, C1-6-alkoxy, C1-6-alkyl, thiol-C1-6-alkyl, cyano, cyano-C1-6-alkyl, cyano-C1-6-alkoxy, di-C1-6-alkylamino, or C3-8-cycloalkoxy, or R4 and R5 are connected to form a 5-membered heterocyclic alkyl containing a single O heteroatom or a 6-membered heteroaromatic ring containing a single N heteroatom.

10. A compound of claim 1 or 2 or a mirror isomer, non-mirror isomer, or pharmaceutically acceptable salt thereof, wherein R5 is H, a halogen, a halo-C1-6-alkyl, a halo-C1-6-alkoxy, a halo-thiol-C1-6-alkyl, a C1-6-alkoxy, a C1-6-alkyl, a thiol-C1-6-alkyl, a cyano, a cyano-C1-6-alkyl, a cyano-C1-6-alkoxy, a di-C1-6-alkylamino, or a C3-8-cycloalkoxy.

11. A compound of claim 1 or 2, or a mirror isomer, non-mirror isomer, or pharmaceutically acceptable salt thereof, wherein R1 is H, a halogroup, a halo-C1-6-alkyl, a halo-C1-6-alkoxy, C1-6-alkyl, C1-6-alkoxy-C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, a thiol-C1-6-alkyl, a cyano-C1-6-alkyl, a C3-8-cycloalkoxy, a C3-8-cycloalkyl, a C3-8-cycloalkyl-C1-6-alkyl, or a heterocyclic alkyl; R2 The following are C1-6-alkoxy, C1-6-alkoxy-C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, C1-4-alkylsulfonyl-C1-6-alkyl, C1-6-alkyl, C2-6-alkenyl, C2-6-ynyl, C2-6-ynyl-C1-6-alkoxy, cyano, cyano-C1-6-alkyl, C3-8-cycloalkyl, C3-8-cycloalkoxy, C3-8-cycloalkyl-C1-6-alkyl, cyano-C1-6-alkoxy, halogen, halogenated C1-6-alkoxy, (halogenated C1-6-alkoxy) C1-6-alkoxy, thiol-C1-6-alkyl, halothiol-C1-6-alkyl, halohydroxy-C1-6-alkoxy, haloC1-6-alkyl, heterocyclic alkyl, heterocyclic alkyl C1-6-alkyl, heterocyclic alkyl C2-6-ynyl, or heterocyclic alkyl C1-6-alkoxy; R3 is H, halogen, C1-6-alkyl, C1-6-alkoxy, haloC1-6-alkoxy, or thiol-C1-6-alkyl; X1 is CR5 or N; X2 is NH or S; R4 is H, halogen, C1-6-alkyl, C1-6-alkoxy, thiol-C1-6-alkyl, cyanoC1-6-alkyl, C3-8-cycloalkyl, haloC1-6-alkoxy, haloC1-6-alkyl, heterocyclic alkyl, or hydroxyC1-6-alkyl, and R5 It can be H, halogen, halogenated C1-6-alkyl, halogenated C1-6-alkoxy, halogenated thiol-C1-6-alkyl, C1-6-alkoxy, C1-6-alkyl, C1-6-alkoxycarbonyl, hydroxy C1-6-alkyl, thiol-C1-6-alkyl, C1-4-alkylsulfinic acid, C1-4-alkylsulfonyl, cyano, cyanoC1-6-alkyl, cyanoC1-6-alkoxy, diC1-6-alkylamino, C3-8-cycloalkyl, C3-8-cycloalkoxy, or heterocyclic alkyl, or R4 and R5 connected to form a 5-membered heterocyclic alkyl containing a single O heteroatom, a 6-membered heterocyclic alkyl containing a single N heteroatom substituted with alkyl and side oxygen, a 5-membered heteroaromatic ring containing one N heteroatom and one S heteroatom, or a 6-membered heteroaromatic ring containing a single N heteroatom.

12. A compound of claim 1 or 2, or a mirror-isomer, non-mirror-isomer, or pharmaceutically acceptable salt thereof, wherein R1 is H, C1-6-alkoxy, C3-8-cycloalkyl, or halo-C1-6-alkoxy; R2 is C1-6-alkyl, C2-6-alkenyl, C2-6-ynyl, C1-6-alkoxy-C1-6-alkyl, C2-6-ynyl, cyano-C1-6-alkoxy, halo, halo-C1-6-alkoxy, halo-C1-6-alkyl, or C3-8-cycloalkyl; R3 is H or C1-6-alkoxy; X1 is CR5 or N; X2 is NH or S; R4 is halo, C1-6-alkyl, or halo-C1-6-alkyl, and R5 It is H, a halogen, a halogenated C1-6-alkyl, a halogenated C1-6-alkoxy, a halogenated thiol-C1-6-alkyl, a C1-6-alkoxy, a C1-6-alkyl, a thiol-C1-6-alkyl, a cyano, a cyano-C1-6-alkyl, a cyano-C1-6-alkoxy, a di-C1-6-alkylamino, or a C3-8-cycloalkoxy, or R4 and R5 are connected to form a 5-membered heterocyclic alkyl containing a single O heteroatom or a 6-membered heteroaromatic ring containing a single N heteroatom.

13. A compound of claim 1 or 2, or a mirror-image isomer, non-mirror-image isomer, or pharmaceutically acceptable salt thereof, wherein the compound is selected from 6-chloro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-7-fluoro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6,7-dichloro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-7-(difluoromethyl)-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-7-(cyclopropoxy)-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-(5-ethoxy-4-methoxy-pyrimidin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[4-methoxy-5-(2-methoxyethoxy)pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-[2-(difluoromethoxy)ethoxy]-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Chloro-N-(5-chloro-4,6-dimethoxy-pyrimidin-2-yl)-1H-indole-3-sulfonamide; N-(5-bromo-4,6-dimethoxy-pyrimidin-2-yl)-6-chloro-1H-indole-3-sulfonamide; N-(5-bromo-4-ethoxy-6-methoxy-pyrimidin-2-yl)-6-chloro-1H-indole-3-sulfonamide; N-[5-bromo-4-(2-fluoroethoxy)-6-methoxy-pyrimidin-2-yl]-6-chloro-1H-indole-3-sulfonamide; 6-Chloro-N-(5-ethyl-4-methoxy-pyrimidin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(5-ethyl-4,6-dimethoxy-pyrimidin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4,6-dimethoxy-5-methyl-pyrimidin-2-yl)-1H-indole-3-sulfonamide; N-[5-bromo-4-(difluoromethoxy)-6-methoxy-pyrimidin-2-yl]-6-chloro-1H-indole-3-sulfonamide; 6-Chloro-N-[4-cyclopropyl-5-(2,2-difluoroethoxy)-6-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4-methoxy-6-methyl-pyrimidin-2-yl]-1H-indole-3-sulfonamide;6-Chloro-N-[5-(3-fluoropropyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-(5-bromo-4-methoxy-pyrimidin-2-yl)-6-chloro-1H-indole-3-sulfonamide; 6-chloro-N-(5-cyano-4-methoxy-pyrimidin-2-yl)-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]benzothiophene-3-sulfonamide; 6-bromo-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-(4-methoxy-5-methyl-pyrimidin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]thieno[2,3-b]pyridine-3-sulfonamide; 6-Chloro-N-(5-cyclopropyl-4-methoxy-pyrimidin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4-methoxy-5-prop-1-ynyl-pyrimidin-2-yl)-1H-indole-3-sulfonamide; 6-bromo-N-(5-bromo-4,6-dimethoxy-pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; N-(5-bromo-4,6-dimethoxy-pyrimidin-2-yl)-6-chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-chloro-N-(5-cyano-4,6-dimethoxy-pyrimidin-2-yl)-1H-indole-3-sulfonamide; N-(5-bromo-4,6-dimethyl-pyrimidin-2-yl)-6-chloro-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethoxy)pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethoxy)-4-methylhydrothio-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-(4-methoxy-5-methylhydrothiopyrimidin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethylthio)-4-methoxypyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(cyclopropoxy)-4-methoxypyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(3,3-difluoropropoxy)-4-methoxypyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[4-methoxy-5-(3,3,3-trifluoropropoxy)pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[4-methoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(1,1-difluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide;6-Chloro-N-[4-methoxy-5-(1,1,2,2-tetrafluoroethoxy)pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-chloro-1,1,2-trifluoro-ethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-(4-methoxy-5-propyl-pyrimidin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(cyclopropylmethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(3,3-difluoropropyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[4-methoxy-5-(2-methoxyethyl)pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[4-methoxy-5-(oxocyclobutane-3-yl)pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(fluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[4,6-dimethoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-(5-allyl-4,6-dimethoxy-pyrimidin-2-yl)-6-chloro-1H-indole-3-sulfonamide; 6-Chloro-N-(4,6-dimethoxy-5-prop-1-ynyl-pyrimidin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4,6-dimethoxy-5-propyl-pyrimidin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(3-fluoropropyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(3,3-difluoropropyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoropropyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide;6-Chloro-N-[4,6-dimethoxy-5-(3,3,3-trifluoropropyl)pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[4,6-dimethoxy-5-(methoxymethyl)pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[4,6-dimethoxy-5-(2-methoxyethyl)pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(cyanomethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-(5-cyclopropyl-4,6-dimethoxy-pyrimidin-2-yl)-1H-indole-3-sulfonamide; N-[5-bromo-4-methoxy-6-(2-methoxyethoxy)pyrimidin-2-yl]-6-chloro-1H-indole-3-sulfonamide; N-[5-bromo-4-(cyclopropoxy)-6-methoxy-pyrimidin-2-yl]-6-chloro-1H-indole-3-sulfonamide; 6-Chloro-N-[4-(difluoromethoxy)-6-methoxy-5-methyl-pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-(5-bromo-4-fluoro-6-methoxy-pyrimidin-2-yl)-6-chloro-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4-fluoro-6-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-(4-chloro-5,6-dimethoxy-pyrimidin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[4-chloro-5-(2,2-difluoroethoxy)pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4-ethyl-6-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-6-methyl-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[4-cyclopropyl-5-(2,2-difluoroethyl)-6-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-[5-bromo-4-(cyclopropylmethyl)-6-methoxy-pyrimidin-2-yl]-6-chloro-1H-indole-3-sulfonamide; N-[5-bromo-4-methoxy-6-(methoxymethyl)pyrimidin-2-yl]-6-chloro-1H-indole-3-sulfonamide; N-[5-bromo-4-(1,1-difluoroethyl)-6-methoxy-pyrimidin-2-yl]-6-chloro-1H-indole-3-sulfonamide; N-[5-bromo-4-(fluoromethoxy)-6-methoxy-pyrimidin-2-yl]-6-chloro-1H-indole-3-sulfonamide;N-[5-bromo-4-(difluoromethyl)-6-methoxy-pyrimidin-2-yl]-6-chloro-1H-indole-3-sulfonamide; N-[5-bromo-4-(cyanomethyl)-6-methoxy-pyrimidin-2-yl]-6-chloro-1H-indole-3-sulfonamide; 6-chloro-N-[5-(difluoromethoxy)-4-methoxy-6-methylhydrothio-pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-[4,6-dimethoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-yl]-6-fluoro-1H-indole-3-sulfonamide; 6-bromo-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2-cyanoethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-(difluoromethyl)-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-(difluoromethyl)-N-[4,6-dimethoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-(difluoromethyl)-N-[5-(3,3-difluoropropyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; N-[5-(cyanomethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-(difluoromethyl)-N-[4-methoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-1H-indole-3-sulfonamide;N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-1H-indole-3-sulfonamide; N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-6-(difluoromethoxy)-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2-cyanoethyl)-4-methoxy-pyrimidin-2-yl]-7-(difluoromethylthio)-1H-indole-3-sulfonamide; 6-Chloro-7-(difluoromethylthio)-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(difluoromethylthio)-1H-indole-3-sulfonamide; 7-Chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Bromo-N-[4,6-dimethoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Bromo-N-[5-(3,3-difluoropropyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Bromo-N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Bromo-N-[5-(cyanomethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(dimethylamino)-1H-indole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide; N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide; 6-Chloro-N-(4,6-dimethoxy-5-methylpyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide;6-Chloro-N-[5-(difluoromethoxy)-4-methoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Chloro-N-[5-(3,3-difluoropropyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Chloro-N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4-methoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4-methoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-Chloro-7-(cyclopropoxy)-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 7-bromo-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-6-fluoro-1H-indole-3-sulfonamide; 7-bromo-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 7-chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-6-fluoro-1H-indole-3-sulfonamide; N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-[[o-]-linyl-1H-indole-3-sulfonamide; 7-bromo-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(1,1-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide;6-Chloro-N-(4-ethyl-6-methoxy-5-methyl-pyrimidin-2-yl)-1H-indole-3-sulfonamide; N-(5-bromo-4-methoxy-6-tetrahydropiperan-4-yl-pyrimidin-2-yl)-6-chloro-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]thieno[2,3-b]pyridine-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-6-fluoro-1H-indole-3-sulfonamide; 7-bromo-6-chloro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 7-Bromo-6-chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Bromo-N-(4,6-dimethoxy-5-methyl-pyrimidin-2-yl)thieno[2,3-b]pyridine-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethoxy)-4-methoxy-pyrimidin-2-yl]thieno[2,3-b]pyridine-3-sulfonamide; 6-Bromo-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]thieno[2,3-b]pyridine-3-sulfonamide; 6-Bromo-N-[4-methoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-yl]thieno[2,3-b]pyridine-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]thieno[2,3-b]pyridine-3-sulfonamide; 6-Bromo-N-[5-(2-cyanoethyl)-4-methoxy-pyrimidin-2-yl]thieno[2,3-b]pyridine-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]thieno[2,3-b]pyridine-3-sulfonamide; 6-Bromo-N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]thieno[2,3-b]pyridine-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-6-ethyl-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-6-propyl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]benzothiophene-3-sulfonamide; 6-Chloro-N-[5-(3,3-difluoropropyl)-4-methoxy-pyrimidin-2-yl]benzothiophene-3-sulfonamide; 6-Chloro-N-[5-(2-cyanoethyl)-4-methoxy-pyrimidin-2-yl]benzothiophene-3-sulfonamide;6-Bromo-N-[5-(2,2-difluoroethoxy)-4-methoxy-pyrimidin-2-yl]benzothiophene-3-sulfonamide; 6-Bromo-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]benzothiophene-3-sulfonamide; N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-6-methyl-benzothiophene-3-sulfonamide; 6-Bromo-N-(4,6-dimethoxy-5-methyl-pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-fluoro-benzothiophene-3-sulfonamide; 6-Chloro-N-[5-(2-cyanoethyl)-4-methoxy-pyrimidin-2-yl]-7-fluoro-benzothiophene-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-6,7-difluoro-1H-indole-3-sulfonamide; 6-(difluoromethyl)-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]thieno[2,3-b]pyridine-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-6-(difluoromethyl)thieno[2,3-b]pyridine-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)thieno[2,3-b]pyridine-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Chloro-N-[4,6-dimethoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Bromo-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Chloro-N-(4-chloro-5-methoxy-pyrimidin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(3-fluoropropoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-(5-but-2-alkynoxy-4-methoxy-pyrimidin-2-yl)-6-chloro-1H-indole-3-sulfonamide;6-Chloro-N-[5-(2,3-difluoropropyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[4-methoxy-5-(2,2,2-trifluoroethyl)pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[4-methoxy-5-(3,3,3-trifluoropropyl)pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-cyanoethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[4-methoxy-5-[2-(oxocyclobutane-3-yl)ethynyl]pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[4-methoxy-5-[2-(oxocyclobutan-3-yl)ethyl]pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-6-methyl-1H-indole-3-sulfonamide; 7-bromo-6-chloro-N-[5-(3,3-difluoropropyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-bromo-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-methyl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-methoxy-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(3,3-difluoropropyl)-4-methoxy-pyrimidin-2-yl]-7-methoxy-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-(difluoromethoxy)-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(difluoromethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-6-(trifluoromethyl)-1H-indole-3-sulfonamide; 6-bromo-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-methyl-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-6-(methylthio)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-6-(difluoromethyl)-1H-indole-3-sulfonamide;6-Bromo-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-methoxy-1H-indole-3-sulfonamide; 6-(cyanomethyl)-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-(fluoromethoxy)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-(difluoromethylhydrothio)-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Bromo-N-[5-(3,3-difluoropropyl)-4-methoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Chloro-N-[5-(3,3-difluoropropyl)-4-methoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Chloro-N-[5-(3,3-difluoropropyl)-4-methoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-Chloro-7-(difluoromethyl)-N-[5-(3,3-difluoropropyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6,7-Dichloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6,7-Dichloro-N-[5-(3,3-difluoropropyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-7-(cyclopropoxy)-N-[5-(3,3-difluoropropyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-bromo-7-fluoro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide;6-Chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-(difluoromethyl)-1H-indole-3-sulfonamide; 6-Chloro-7-fluoro-N-[4-methoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-cyanoethyl)-4-methoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(cyanomethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-Chloro-N-[4-methoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide; 6-chloro-7-cyano-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-7-cyano-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-7-cyano-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-7-cyano-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-7-cyano-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-6,8-dihydro-1H-furan[3,4-g]indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6,8-dihydro-1H-furan[3,4-g]indole-3-sulfonamide; 6-Bromo-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Bromo-N-[4-methoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide;6-Chloro-7-(cyanomethyl)-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-7-cyclopropyl-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-(methylthio)-1H-indole-3-sulfonamide; 6-(difluoromethyl)-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-1H-indole-3-sulfonamide; N-[5-(cyanomethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-1H-indole-3-sulfonamide; 6-(difluoromethyl)-N-[4-methoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Bromo-N-[5-(2-cyanoethyl)-4-methoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(cyanomethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(cyanomethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-(difluoromethyl)-7-fluoro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-6-(difluoromethyl)-7-fluoro-1H-indole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-7-fluoro-1H-indole-3-sulfonamide;N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-7-fluoro-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-7-fluoro-1H-indole-3-sulfonamide; N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-7-fluoro-1H-indole-3-sulfonamide; N-[5-(cyanomethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-7-fluoro-1H-indole-3-sulfonamide; 6-Cyclopropyl-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 7-Bromo-6-chloro-N-[5-(2-cyanoethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-fluoro-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-fluoro-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-fluoro-1H-indole-3-sulfonamide; N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-fluoro-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoropropyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[4-methoxy-5-(2,2,3,3-tetrafluoropropyl)pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(difluoromethoxymethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[4,6-dimethoxy-5-(oxocyclobutane-3-ylmethoxy)pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,3-difluoropropyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(cyanomethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[4-methoxy-5-(2,3,3-trifluoropropyl)pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(cyanomethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(difluoromethoxy)-4-methoxy-pyrimidin-2-yl]benzothiophene-3-sulfonamide;6-Bromo-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]thieno[2,3-b]pyridine-3-sulfonamide; 6-Bromo-N-[5-(3,3-difluoropropyl)-4-methoxy-pyrimidin-2-yl]thieno[2,3-b]pyridine-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]thieno[2,3-b]pyridine-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-6-(oxocyclobutane-3-yl)-1H-indole-3-sulfonamide; N-(4,6-dimethoxy-5-methyl-pyrimidin-2-yl)-6-methoxy-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-6-(1-hydroxy-1-methyl-ethyl)-1H-indole-3-sulfonamide; 6-chloro-N-[5-(1,1-difluoro-2-hydroxy-ethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-methylsulfinyl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-methanesulfonyl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-methylsulfinyl-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-methylsulfinyl-1H-indole-3-sulfonamide; 6-Chloro-7-cyano-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[4,6-dimethoxy-5-(2-methylsulfonylurea-ethyl)pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-e][1,2]benzothiazol-3-sulfonamide; 7-bromo-6-chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-[5-(cyanomethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide;6-(difluoromethyl)-N-[5-(2,3-difluoropropyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-bromo-N-[5-(2,3-difluoropropyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-chloro-N-[5-(2,3-difluoropropyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-8H-pyrrolo[2,3-e][1,3]benzothiazole-6-sulfonamide; 3-[[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]aminesulfonyl]-6-methyl-1H-indole-7-carboxylic acid methyl ester; N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-6-methyl-7-hydroxymethyl-1H-indole-3-sulfonamide; N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-9-keto-8-methyl-6,7-dihydro-1H-pyrrole[3,2-h]isoquinoline-3-sulfonamide; 6-chloro-7-(cyanomethoxy)-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide.

14. A compound of claim 1 or 2, or a mirror-image isomer, non-mirror-image isomer, or pharmaceutically acceptable salt thereof, wherein the compound is selected from 6-chloro-7-fluoro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6,7-dichloro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-7-(difluoromethyl)-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-(5-bromo-4,6-dimethoxy-pyrimidin-2-yl)-6-chloro-1H-indole-3-sulfonamide; 6-Chloro-N-(5-ethyl-4,6-dimethoxy-pyrimidin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4,6-dimethoxy-5-methyl-pyrimidin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[4-cyclopropyl-5-(2,2-difluoroethoxy)-6-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(3-fluoropropyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-bromo-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Bromo-N-(5-Bromo-4,6-dimethoxy-pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Chloro-N-[4-methoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(3,3-difluoropropyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[4,6-dimethoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-(5-allyl-4,6-dimethoxy-pyrimidin-2-yl)-6-chloro-1H-indole-3-sulfonamide; 6-Chloro-N-(4,6-dimethoxy-5-prop-1-ynyl-pyrimidin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-(4,6-dimethoxy-5-propyl-pyrimidin-2-yl)-1H-indole-3-sulfonamide;6-Chloro-N-[5-(2-fluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(3-fluoropropyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(3,3-difluoropropyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[4,6-dimethoxy-5-(3,3,3-trifluoropropyl)pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[4,6-dimethoxy-5-(2-methoxyethyl)pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-(5-cyclopropyl-4,6-dimethoxy-pyrimidin-2-yl)-1H-indole-3-sulfonamide; 6-Chloro-N-[4-(difluoromethoxy)-6-methoxy-5-methyl-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-(difluoromethyl)-N-[4,6-dimethoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-(difluoromethyl)-N-[5-(3,3-difluoropropyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-1H-indole-3-sulfonamide;N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2-cyanoethyl)-4-methoxy-pyrimidin-2-yl]-7-(difluoromethylthio)-1H-indole-3-sulfonamide; 6-chloro-7-(difluoromethylthio)-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(difluoromethylthio)-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Bromo-N-[4,6-dimethoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Bromo-N-[5-(3,3-difluoropropyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Bromo-N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Bromo-N-[5-(cyanomethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-(dimethylamino)-1H-indole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide; N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide; 6-chloro-N-(4,6-dimethoxy-5-methyl-pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-chloro-N-[5-(3,3-difluoropropyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Chloro-N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide;6-Chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-Chloro-7-(cyclopropoxy)-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-6-fluoro-1H-indole-3-sulfonamide; 7-bromo-6-chloro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 7-bromo-6-chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-bromo-N-(4,6-dimethoxy-5-methyl-pyrimidin-2-yl)thieno[2,3-b]pyridine-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]thieno[2,3-b]pyridine-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]thieno[2,3-b]pyridine-3-sulfonamide; 6-Bromo-N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]thieno[2,3-b]pyridine-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]benzothieno-3-sulfonamide; 6-Bromo-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]benzothiophene-3-sulfonamide; 6-Bromo-N-(4,6-dimethoxy-5-methyl-pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide; 6-Bromo-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Chloro-N-[5-(2,3-difluoropropyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-cyanoethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide;7-Bromo-6-chloro-N-[5-(3,3-difluoropropyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-methyl-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-methoxy-1H-indole-3-sulfonamide; 6-chloro-N-[5-(3,3-difluoropropyl)-4-methoxy-pyrimidin-2-yl]-7-methoxy-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-(difluoromethoxy)-1H-indole-3-sulfonamide; 6-bromo-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-methyl-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-methoxy-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-(fluoromethoxy)-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-(difluoromethylhydrothio)-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(3,3-difluoropropyl)-4-methoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Chloro-N-[5-(3,3-difluoropropyl)-4-methoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Chloro-N-[5-(3,3-difluoropropyl)-4-methoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6,7-Dichloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide;6,7-Dichloro-N-[5-(3,3-difluoropropyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-7-(cyclopropoxy)-N-[5-(3,3-difluoropropyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-bromo-7-fluoro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-(difluoromethyl)-1H-indole-3-sulfonamide; 6-Chloro-7-fluoro-N-[4-methoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-cyanoethyl)-4-methoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-Chloro-N-[5-(cyanomethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-Chloro-N-[4-methoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Chloro-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-Chloro-7-cyano-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-7-cyano-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-7-cyano-N-[5-(2-fluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-7-cyano-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Chloro-7-cyano-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6,8-dihydro-1H-furan[3,4-g]indole-3-sulfonamide; 6-bromo-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide;6-Bromo-N-[4-methoxy-5-(1,1,2-trifluoroethoxy)pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-chloro-7-(cyanomethyl)-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,2-difluoroethyl)-4-methoxy-pyrimidin-2-yl]-7-(methylthio)-1H-indole-3-sulfonamide; 6-(difluoromethyl)-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-1H-indole-3-sulfonamide; N-[5-(cyanomethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-1H-indole-3-sulfonamide; N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide; 6-bromo-N-[5-(2-cyanoethyl)-4-methoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(cyanomethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-7-fluoro-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-Bromo-N-[5-(cyanomethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-(difluoromethyl)-7-fluoro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-7-fluoro-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-7-fluoro-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-7-fluoro-1H-indole-3-sulfonamide;N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-7-fluoro-1H-indole-3-sulfonamide; N-[5-(cyanomethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-6-(difluoromethyl)-7-fluoro-1H-indole-3-sulfonamide; 7-bromo-6-chloro-N-[5-(2-cyanoethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-fluoro-1H-indole-3-sulfonamide; N-[5-(2-cyanoethyl)-4,6-dimethoxy-pyrimidin-2-yl]-6-fluoro-1H-indole-3-sulfonamide; 6-chloro-N-[5-(difluoromethoxymethyl)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(2,3-difluoropropyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(cyanomethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-N-[5-(cyanomethoxy)-4-methoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 7-Bromo-6-chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide; 6-chloro-7-(cyanomethoxy)-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1H-indole-3-sulfonamide.

15. A compound that is 6-bromo-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide or a pharmaceutically acceptable salt thereof.

16. A compound that is 6-bromo-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide.

17. A method for preparing a compound of any one of claims 1 to 16 or a mirror isomer, non-mirror isomer, or pharmaceutically acceptable salt thereof, the method comprising reacting a compound of formula II with a compound of formula III in the presence of a base selected from N,N-diisopropylethylamine or pyridine, wherein R1, R2, R3, R4, X1, and X2 are as defined in claim 1.

18. The compound of claim 1 or 2 or its mirror isomer, non-mirror isomer or pharmaceutically acceptable salt thereof, used as a therapeutically active substance.

19. The compound of claim 1 or 2 or its mirror isomer, non-mirror isomer or pharmaceutically acceptable salt thereof, used to treat diseases regulated by GPR17.

20. A pharmaceutical composition comprising a compound of any one of claims 1 to 16 or a mirror isomer, non-mirror isomer, or pharmaceutically acceptable salt and therapeutically inert carrier thereof.

21. Use of a compound of any one of claims 1 to 16 or a mirror-isomer, non-mirror-isomer, or pharmaceutically acceptable salt thereof for the preparation of a medicament for treating conditions caused by: direct myelin damage, demyelination disorders, central nervous system disorders associated with myelin loss, and central nervous system inflammation.

22. As claimed in claim 21, wherein the demyelination condition is multiple sclerosis.

23. The compound of claim 1 or 2, used to treat conditions caused by: direct myelin damage, demyelination disorders, central nervous system disorders associated with myelin loss, and central nervous system inflammation.

24. The compound of claim 1 or 2 or its mirror isomer, non-mirror isomer or pharmaceutically acceptable salt thereof, used to treat multiple sclerosis.