New benzimidazole derivatives

Abstract

The present invention relates to a compound of formula (I) (wherein L, A 1 , R 1 , R 2 and R 3 as defined in the description and claims. The compounds of formula (I) can be used as pharmaceuticals. TIFF2026500715000111.tif38165

Description

[Technical Field]

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

[0002] The present invention relates in particular to compounds of formula (I) [ka] During the ceremony, R 1 is haloalkoxy, heterocycloalkylcarbonyl, heteroaryl, or heterocycloalkyl, and heterocycloalkylcarbonyl, heteroaryl, and heterocycloalkyl are R 4 optionally substituted with 1, 2, or 3 substituents individually selected from: R 2 is hydrogen, alkoxy, alkyl, halogen, haloalkoxy, dialkylaminocarbonylalkoxy, heterocycloalkyloxy, heterocycloalkylalkoxy, or alkylheteroarylamino; R 3 is hydrogen, cycloalkylcarbonyl, alkylcarbonyl, heterocycloalkylcarbonyl, heterocycloalkyl, or heteroaryl; heterocycloalkylcarbonyl, heterocycloalkyl, and heteroaryl are R 5 or R 2 and R 3 together with the carbon atom to which they are attached form a 4- to 6-membered heterocycloalkyl optionally substituted with alkylheteroaryl; R 4 each instance of is individually selected from alkyl, amino, alkylsulfonyl, cyano, halogen, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, dialkylaminocarbonyl, haloalkoxy, and haloalkyl; R 5each instance of is individually selected from alkyl, alkoxycarbonyl, heterocycloalkyl, cycloalkyl, (hydroxyl)(alkyl)heterocycloalkyl, dialkylaminocarbonyl, heterocycloalkylalkoxy, alkylheterocycloalkyl, alkylheterocycloalkyloxy, heterocycloalkylheterocycloalkyloxy, (haloalkyl)(alkyl)aminocarbonyl, dialkylaminocarbonylalkyl, hydroxyalkyl, and arylalkoxycarbonylaminoheterocycloalkyl; A 1 is -N- or -CH-, and L is absent, —O— or —NH—; The present invention relates to a compound, or a pharmaceutically acceptable salt thereof. [Background technology]

[0003] Salt-inducible kinases (SIKs) belong to a subfamily of AMP-activated protein kinases (AMPKs), known as AMPK-related kinases. Three members, designated SIK1, SIK2, and SIK3, exist and are widely expressed. Their primary biological role is to modify gene expression by controlling the phosphorylation and subcellular localization of two important classes of transcriptional regulators: CRTCs (cAMP-regulated transcriptional coactivators) and class IIa HDACs (histone deacetylases). Under basal conditions, both CRTCs and HDACs are phosphorylated by SIK kinases and sequestered in the cytoplasm through their interaction with the cytoplasmic chaperone 14-3-3. In response to extracellular cues that normally increase intracellular levels of cAMP, SIK kinase activity is inhibited, and CRTCs and HDACs are no longer phosphorylated and are therefore released from 14-3-3. Thus, they can translocate into the nucleus and regulate gene expression (reviewed in Wein et al., Trends Endocrinol Metab. 2018 Oct;29(10):723-735).

[0004] In macrophages, inhibition of SIK kinase results in 1) shuttling of CRTC3 to the nucleus and increased transcription of IL-10; and 2) translocation of HDAC4 / 5 to the nucleus and subsequent deacetylation of NF-κB, resulting in reduced transcription of pro-inflammatory cytokines (Clark et al., Proc Natl Acad Sci U S A. 2012 Oct 16;109(42):16986-91.).

[0005] Macrophages are important for maintaining tissue homeostasis, mediating inflammation, and promoting resolution of inflammation. To achieve this diversity of function, macrophages have the ability to "polarize" differently in response to environmental cues. The two extreme phenotypes along their activation state continuum are "M1" or "pro-inflammatory macrophages" and "M2" or "pro-resolution macrophages."

[0006] Surprisingly, inhibition of intracellular SIK kinase abolishes these extracellular macrophage-polarizing signals, driving them toward a pro-resolution phenotype. This is accompanied by an increase in IL-10 (by disrupting the SIK-CRTC3 pathway) and a concomitant decrease in TNF-α, IL-12, and IL-6 (by disrupting the SIK-HDAC4 / 5 and NF-κB pathways). High levels of IL-10 and low levels of pro-inflammatory cytokines upon SIK inhibition promote the resolution of inflammation. The SIK pathway was first explored in macrophages (Clark et al., Proc Natl Acad Sci US A. 2012 Oct 16;109(42):16986-91) and dendritic cells (Sundberg et al., Proc Natl Acad Sci US A. 2014 Aug 26;111(34):12468-73), and the therapeutic potential of pan-SIK inhibitors has been confirmed in mouse LPS (lipopolysaccharide) challenge models (Sundberg et al., ACS Chem Biol. 2016 Aug 19;11(8):2105-11) and colitis models (Fu et al., Inflamm Bowel Dis. 2021 Oct 20;27(11):1821-1831). SIK has since been shown to play an important role in the function of several immune cells, including mast cells (Darling et al., J Biol Chem. 2021 Jan-Jun;296:100428). Importantly, SIK1 is poorly expressed in macrophages, and one embodiment of the present invention is a SIK2 / 3 inhibitor that spares SIK1, thus limiting potential SIK1-associated toxicity.

[0007] SIK inhibitors have high therapeutic potential in 1) diseases characterized by the influx of pro-inflammatory macrophages into tissues and impaired tissue homeostasis and healing, or 2) diseases in which anti-TNF therapy is beneficial (partially or completely) or in which IL10 levels are insufficient. Diseases with an inflammatory macrophage signature include, for example, rheumatoid arthritis, juvenile rheumatoid arthritis, NASH, primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel disease ("IBD"), atherosclerosis, type 2 diabetes, and glomerulonephritis.

[0008] A disease with a proven association with IL-10 and TNF-α is IBD. Genetic alterations that reduce IL-10 function (e.g., SNPs in IL-10 or its receptor) are associated with an increased risk of IBD in humans. Furthermore, while anti-TNF therapy has been successful, only a subset of IBD patients respond, and much of this limited response is lost over time. The described dual effects of SIK inhibitors (increasing IL-10 and decreasing TNF-α) make them particularly suitable for the treatment of IBD.

[0009] All three SIK kinase isoforms are widely expressed in human tissues, with highest expression observed in skin and adipose tissue for SIK1, in adipose tissue for SIK2, and in testis and brain for SIK3. Similar to their role in macrophages, SIKs in these cells phosphorylate CRTCs and class II HDACs in response to extracellular signals, subsequently altering the expression of several cellular factors.

[0010] In addition to their physiological roles, reports have linked dysregulation of SIK expression to several diseases. For example, SIK2 has been described as a risk locus for primary sclerosing cholangitis, a fibrotic disease commonly associated with IBD. Furthermore, SIK2 and SIK3 expression is higher in ovarian and prostate cancer and correlates with poor survival (Miranda et al., Cancer Cell. 2016 Aug 8;30(2):273-289; Bon et al., Mol Cancer Res. 2015 Apr;13(4):620-635).

[0011] Currently, many diseases caused by dysregulation of the innate immune system lack effective treatment methods, and there is a high unmet medical need for new treatment methods.The present invention relates to novel compounds that are highly active SIK inhibitors for the treatment of inflammatory, allergic and autoimmune diseases.Therefore, in addition to inflammatory, allergic and autoimmune diseases, SIK inhibitors can potentially be related to cancer, metabolic diseases, bone density dysregulation diseases, pigment-related diseases or cosmetology, fibrotic diseases and depressive disorders. Summary of the Invention

[0012] As used herein, the term "alkyl," alone or in combination, refers to a straight-chain or branched-chain alkyl group having 1 to 8 carbon atoms, particularly a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, and more particularly a straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms. Examples of straight-chain and branched-chain C1-C8 alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, isomeric pentyls, isomeric hexyls, isomeric heptyls, and isomeric octyls, particularly methyl, ethyl, propyl, butyl, and pentyl. Particular examples of alkyl are methyl, ethyl, propyl, isopropyl, butyl, and isobutyl. Methyl, ethyl, propyl, and butyl, e.g., isobutyl, are further specific examples of "alkyl" in compounds of formula (I).

[0013] The term "heterocycloalkyl," alone or in combination, means a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of 4 to 12 ring atoms containing one, two, or three ring heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. Bicyclic means consisting of two rings that share one or two ring atoms in common. A "heterocycloylalkyl" can contain a carbonyl group, where the carbon is part of the ring system. The ring system can be attached to the rest of the compound through an atom selected from C, N, S, and O, particularly through an N atom ("N-heterocycloalkyl"). Examples of "heterocycloalkyl" and "heterocycloalkyl" include morpholino, morpholin-4-yl, pyrrolidinyl, pyrrolidin-1-yl, pyrrolidin-3-yl, piperidyl, 1-piperidyl, 3-piperidyl, 4-piperidyl, 2-oxopyrrolidin-1-yl, piperazinyl, piperazin-1-yl, azetidinyl, azetidin-1-yl, [3-oxo-piperazinyl]. (1,1-dioxo-1,2-thiazolidin-2-yl), (4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl), (3-oxo-1,5,6,8-tetrahydrooxazolo[3,4-a]pyrazin-7-yl), [rac-(3aR,6aS)-2,3,3a,5,6,6a-hexahydro-1H-pyrrolo[3,2-b]pyrrole-4 -yl][rac-(3aS,6aR)-2,3,3a,5,6,6a-hexahydro-1H-pyrrolo[3,2-b]pyrrol-4-yl], (4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-3-yl), (6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl), (4,7-diazaspiro[2.5]octan-7-yl), (2-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-3-yl), (6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl), (4,7-diazaspiro[2.5]octan-7-yl), sa-5,8-diazaspiro[3.5]nonan-8-yl), 3-azabicyclo[3.2.0]heptan-3-yl), (5-azaspiro[2.4]heptan-5-yl), (2-azabicyclo[2.2.1]heptan-2-yl), 2-azabicyclo[2.2.0]hexan-2-yl, 4-oxa-7-azaspiro[2.5]octan-7-yl, (3-azabicyclo[3.1.0]hexan-3-yl), (6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl), 2-oxa-7-azaspiro[3.4]octan-7-yl, (2-oxo-1-piperidyl), (2,3-dihydropyridazino[4,5-b][1,4]oxazin-8-yl), pyrrolidin-1-yl, 2-oxo-pyrimidin-4-yl, morpholinoethyl, 2-oxa-5-azaspiro[3.4]octan-5-yl, oxetan-3-yl, (2-oxo-1-piperidyl), 2-oxo-4-piperidyl, 5-oxo-pyrrolidine-3 -yl, 2-oxa-5-azaspiro[3.4]octan-5-yl, (7,8-dihydro-5H-pyrano[4,3-c]pyridazin-3-yl), [rac-(4aS,7aR)-4-methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-6-yl], [rac-(3aS,6aS)-6-oxo-2,3,3a,4,5,6a-hexahydropyrrolo[2,3-c]pyrrol-1-yl]diazaspiroheptanyl and 2,6-diazaspiro[3.3]heptanyl. Particular examples of "heterocycloalkyl" are diazaspiroheptanyl, tetrahydrofuranyl, piperidinyl, and oxetanyl, more particularly 2,6-diazaspiro[3.3]heptanyl, 6-tetrahydrofuran-3-yl, 4-piperidyl, and oxetan-3-yl. In certain embodiments, heterocycloalkyl is "N-heterocycloalkyl."

[0014] The term "heteroaryl," alone or in combination, means a fully aromatic or partially aromatic monocyclic or bicyclic ring system having 5 to 12 ring atoms, including 1, 2, 3, or 4 heteroatoms each independently selected from N, O, and S, with the remaining ring atoms being carbon. The ring system may be attached to the rest of the compound through an atom selected from C, N, S, and O, particularly through an N atom ("N-heteroaryl"). Examples of heteroaryl include pyrazolyl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyridinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridazinyl, pyridazin-3-yl, pyridazin-4-yl, pyrazinyl, pyrazin-2-yl, isoxazolyl, isoxazol-3-yl, isoxazol-4-yl, pyrimidinyl, pyrimidin-5-yl, benzotriazolyl, 1H-benzotriazol-4-yl, furanyl, furyl, 2-furyl, 3-furyl, [6-oxo-1H-pyridazin-5-yl], triazolyl, triazol-1-yl, triazol-2-yl, 2-oxo-4-pyridyl, pyrimidin-2-yl, pyrimidin-5-yl. yl, (1,3,4-oxadiazol-2-yl), (1,3,4-thiadiazol-2-yl), (1,2,4-triazin-3-yl), 2-oxo-pyrimidin-4-yl, (1-methyl-2-oxo-3-pyridyl), (2,3-dihydropyridazino[4,5-b][1,4]oxazin-8-yl), 1-methyl-6-oxo-pyridazin-3-yl, 2,3-dihydropyridazino[4,5-b][1,4]oxazin-8-yl, 6-oxo-pyrrolo[2,3-c]pyridazin-3-yl, 5,7-dihydropyrrolo[3,4-c]pyridazin-3-yl, pyridazin-3-yl and 5,6-dihydropyrrolo[2,3-c]pyridazin-7-yl. Particular examples of "heteroaryl" are pyrazolyl and pyridazinyl, more particularly pyrazol-1-yl, pyrazol-4-yl and pyridazin-3-yl. In certain embodiments, heteroaryl is "N-heteroaryl".

[0015] The term "cycloalkyl," alone or in combination, denotes a monovalent saturated monocyclic or bicyclic hydrocarbon radical containing 3 to 10 ring carbon atoms, particularly a monovalent saturated monocyclic hydrocarbon radical containing 3 to 8 ring carbon atoms. Bicyclic means consisting of two saturated carbocyclic rings having two carbon atoms in common, i.e., the bridge separating the two rings is either a single bond or a chain of one or two carbon atoms. Certain cycloalkyl groups are monocyclic. Examples of monocyclic cycloalkyls are cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl, or cycloheptyl. Examples of bicyclic cycloalkyls are bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, or adamantanyl.

[0016] The term "aryl," alone or in combination, refers to a monovalent aromatic carbocyclic monocyclic or bicyclic ring system containing 6 to 10 carbon ring atoms. Examples of aryl moieties include phenyl and naphthyl. A particular example of "aryl" is phenyl.

[0017] The terms "alkoxy" or "alkyloxy", alone or in combination, mean a radical of the formula alkyl-O-, wherein the term "alkyl" has the previously given meaning, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. Particular examples of "alkoxy" are methoxy and ethoxy.

[0018] The term "oxy", alone or in combination, signifies the group --O--.

[0019] The term "cyano", alone or in combination, means a carbon atom attached to a nitrogen atom through a triple bond. This group is also referred to as a carbonitrile group.

[0020] The term "sulfonyl", alone or in combination, signifies the -SO2- group.

[0021] The term "alkylsulfonyl" as used herein, alone or in combination, refers to a group of the formula alkyl-sulfonyl- in which the term "alkyl" has the meaning previously given.

[0022] The terms "halogen" or "halo," alone or in combination, mean fluorine, chlorine, bromine, or iodine, particularly fluorine, chlorine, or bromine, more particularly fluorine. The term "halo," in combination with another group, means substitution of the group with at least one halogen, particularly 1 to 5 halogens, and especially 1 to 4 halogens, i.e., 1, 2, 3, or 4 halogen substitution.

[0023] The term "haloalkyl," alone or in combination, refers to an alkyl group substituted with at least one halogen, particularly 1 to 5 halogens, particularly 1 to 3 halogens, and more particularly 2 to 3 halogens. Particular "haloalkyl" groups are fluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl, difluoromethyl, difluoroethyl, trifluoromethyl, and trifluoroethyl. More particularly, "haloalkyl" groups are difluoromethyl and trifluoroethyl.

[0024] The term "haloalkoxy," alone or in combination, refers to an alkoxy group substituted with at least one halogen, particularly substituted with 1 to 5 halogens, and especially substituted with 1 to 3 halogens. A particular "haloalkoxy" is difluoromethoxy.

[0025] The terms "hydroxyl" and "hydroxy," alone or in combination, refer to an --OH group.

[0026] The term "carbonyl", alone or in combination, signifies the -C(O)- group.

[0027] The term "heterocycloalkylcarbonyl," alone or in combination, means a "heterocycloalkyl" attached to a "carbonyl" group.

[0028] The term "heterocycloalkyloxy", alone or in combination, means a "heterocycloalkyl" group attached to an "oxy" group.

[0029] The term "heterocycloalkylalkoxy", alone or in combination, means a "heterocycloalkyl" group attached to an "alkoxy" group.

[0030] The term "heterocycloalkylalkoxy", alone or in combination, means a "heterocycloalkyl" group attached to an "alkoxy" group.

[0031] The term "amino," alone or in combination, means a primary amino group (-NH2), a secondary amino group (-NH-), or a tertiary amino group (-N-).

[0032] The term "alkylamino", alone or in combination, is an alkyl group attached to an -NH- group. The term "dialkylamino" means two alkyl groups attached to the -N- atom. An example of a "dialkylamino" group is e.g., dimethylamino.

[0033] The term "dialkylaminocarbonylalkoxy," alone or in combination, refers to a "dialkylamino" group attached to a "carbonyl" group, which is in turn attached to an "alkoxy" group.

[0034] The term "alkylheteroarylamino," alone or in combination, refers to an "alkyl" group bound to a "heteroaryl" group, which is in turn bound to an "amino" group.

[0035] The term "cycloalkylcarbonyl," alone or in combination, means a "cycloalkyl" group attached to a "carbonyl" group. Examples of cycloalkylcarbonyl include cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, and cyclohexylcarbonyl.

[0036] The term "cycloalkylalkyl," alone or in combination, refers to an "alkyl" group in which at least one of the alkyl group's hydrogen atoms has been replaced with a "cycloalkyl" group. Examples of cycloalkylalkyl include cyclopropylmethyl, cyclopropylethyl, cyclobutylpropyl, and cyclopentylbutyl.

[0037] The term "alkylcarbonyl", alone or in combination, means an "alkyl" group attached to a "carbonyl" group. Examples of alkylcarbonyl groups are, for example, methylcarbonyl, ethylcarbonyl, and propylcarbonyl.

[0038] The term "alkylheteroaryl," alone or in combination, refers to a "heteroaryl" in which at least one of the hydrogen atoms of the heteroaryl group has been replaced with an alkyl group. Examples of alkylheteroaryl include, for example, methylheteroaryl, ethylheteroaryl, and propylheteroaryl.

[0039] The term "alkoxyalkyl," alone or in combination, refers to an alkyl group in which at least one of the alkyl group's hydrogen atoms has been replaced by an alkoxy group. Exemplary alkoxyalkyl groups include 2-methoxyethyl, 3-methoxypropyl, 1-methyl-2-methoxyethyl, 1-(2-methoxyethyl)-3-methoxypropyl, and 1-(2-methoxyethyl)-3-methoxypropyl.

[0040] The term "dialkylaminocarbonyl," alone or in combination, means a "carbonyl" group attached to a "dialkylamino" group.

[0041] The term "alkoxycarbonyl", alone or in combination, means an "alkoxy" group attached to a "carbonyl" group.

[0042] The term "alkylheterocycloalkyl," alone or in combination, refers to a heterocycloalkyl group in which one of the hydrogen atoms has been replaced with an "alkyl" group. Examples of alkylheterocycloalkyl are, for example, methylheterocycloalkyl, ethylheterocycloalkyl, and propylheterocycloalkyl.

[0043] The term "alkylheterocycloalkyloxy", alone or in combination, means an "oxy" group attached to a "heterocycloalkyl" group in which one of the heterocycloalkyl's hydrogen atoms is replaced with an "alkyl" group.

[0044] The term "heterocycloalkylheterocycloalkyloxy," alone or in combination, refers to an "oxy" group attached to a "heterocycloalkyl" group, in which one of the hydrogen atoms of the "heterocycloalkyl" is replaced by a further "heterocycloalkyl" group.

[0045] The term "aminocarbonyl", alone or in combination, means an "amino" group attached to a "carbonyl" group.

[0046] The term "dialkylaminocarbonylalkyl", alone or in combination, refers to an "alkyl" group in which one of the alkyl's hydrogen atoms has been replaced by a dialkylamino group.

[0047] The term "hydroxyalkyl," alone or in combination, refers to an "alkyl" group in which at least one of the alkyl group's hydrogen atoms has been replaced by a "hydroxy" group. Examples of hydroxyalkyl include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, or 2-(hydroxymethyl)-3-hydroxypropyl.

[0048] The term "arylalkoxycarbonylaminoheterocycloalkyl," alone or in combination, refers to a "heterocycloalkyl" group in which a hydrogen atom of the heterocycloalkyl is replaced by a carbonylamino group bonded to an "alkoxy" group, and one of the hydrogens of the alkoxy is re-substituted by an "aryl" group.

[0049] The term "pharmaceutically acceptable salt" means a salt that is not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid and base addition salts. The term "pharmaceutically acceptable acid addition salts" refers to pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and the like, as well as organic acids selected from the aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. The term "pharmaceutically acceptable base addition salts" refers to pharmaceutically acceptable salts formed with organic or inorganic bases. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include 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, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, and polyamine resins.

[0050] The terms "compounds of this invention" and "compounds of the invention" refer to compounds of Formula (I) and their stereoisomers, tautomers, solvates, and salts (e.g., pharmaceutically acceptable salts).

[0051] It is to be understood that tautomers, ie structural isomers that interconvert with compounds of formula (I), particularly in solution, may exist in some cases and are included in the present invention.

[0052] If one of the starting materials or compounds of formula (I) of the present invention contains one or more functional groups that are not stable or reactive under the reaction conditions of one or more reaction steps, suitable protecting groups (e.g., as described in "Protective Groups in Organic Chemistry" by T.W. Greene and P.G.M. Buts, 3rd Ed., 1999, Wiley, New York) can be introduced before the critical step using methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature. Examples of protecting groups are tert-butoxycarbonyl (Boc), 9-fluorenylmethylcarbamate (Fmoc), 2-trimethylsilylethylcarbamate (Teoc), carbobenzyloxy (Cbz), and p-methoxybenzyloxycarbonyl (Moz).

[0053] The compounds of formula (I) may contain several asymmetric centers and may exist as optically pure enantiomers, mixtures of enantiomers, e.g. racemates, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates.

[0054] The term "asymmetric carbon atom" means a carbon atom bearing four different substituents. According to the Cahn-Ingold-Prelog rules, the asymmetric carbon atom can be of the "R" or "S" configuration.

[0055] Furthermore, the present invention includes, where applicable, all optical isomers of the compounds of formula (I), i.e., diastereomers, diastereomeric mixtures, racemic mixtures, all corresponding enantiomers and / or tautomers thereof, and solvates thereof.

[0056] If desired, racemic mixtures of the compounds of the present invention may be separated to isolate the individual enantiomers. Separation may be carried out by methods known in the art, such as coupling a racemic mixture of a compound to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods such as fractional recrystallization or chromatography.

[0057] In embodiments, when an optically pure enantiomer is provided, optically pure enantiomer means that the compound contains more than 90% by weight of the desired isomer, particularly more than 95% by weight of the desired isomer, or more particularly more than 99% by weight of the desired isomer, the weight percentages being based on the total weight of the isomers of the compound. Chirally pure or chirally enriched compounds can be prepared by chirally selective synthesis or by separation of enantiomers. Separation of enantiomers can be carried out on the final product or on a suitable intermediate.

[0058] Structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Specific examples of radioisotopes include: 2 H, 3 H, 13 C. 14 C and 18 F. For example, structures in which one or more hydrogen atoms are replaced by deuterium or tritium, or in which one or more carbon atoms are 13 C or 14 Structures replaced with C-enriched carbons are within the scope of the present invention.

[0059] Therefore, the present invention provides A compound according to the present invention, wherein said compound is of formula (I) [ka] During the ceremony, R 1is haloalkoxy, heterocycloalkylcarbonyl, heteroaryl, or heterocycloalkyl, and heterocycloalkylcarbonyl, heteroaryl, and heterocycloalkyl are R 4 optionally substituted with 1, 2, or 3 substituents individually selected from: R 2 is hydrogen, alkoxy, alkyl, halogen, dialkylaminocarbonylalkoxy, heterocycloalkyloxy, heterocycloalkylalkoxy, or alkylheteroarylamino; R 3 is hydrogen, cycloalkylcarbonyl, alkylcarbonyl, heterocycloalkylcarbonyl, heterocycloalkyl, or heteroaryl; heterocycloalkylcarbonyl, heterocycloalkyl, and heteroaryl are R 5 or R 2 and R 3 together with the carbon atom to which they are attached form a 4- to 6-membered heterocycloalkyl optionally substituted with alkylheteroaryl; R 4 each instance of is individually selected from alkyl, cyano, halogen, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, dialkylaminocarbonyl, haloalkoxy, and haloalkyl; R 5 each instance of is individually selected from alkyl, alkoxycarbonyl, heterocycloalkyl, cycloalkyl, (hydroxyl)(alkyl)heterocycloalkyl, dialkylaminocarbonyl, heterocycloalkylalkoxy, alkylheterocycloalkyl, alkylheterocycloalkyloxy, heterocycloalkylheterocycloalkyloxy, (haloalkyl)(alkyl)aminocarbonyl, dialkylaminocarbonylalkyl, hydroxyalkyl, and arylalkoxycarbonylaminoheterocycloalkyl; A 1 is -N- or -CH-, and L is absent, —O— or —NH—; a compound, or a pharmaceutically acceptable salt thereof; R 1 is haloalkoxy, azetidinylcarbonyl, pyrazolyl, triazolyl, or pyrrolidinyl, and azetidinylcarbonyl, pyrazolyl, triazolyl, and pyrrolidinyl are R 4 A compound according to the present invention optionally substituted with 1, 2 or 3 substituents individually selected from: R 1 is haloalkoxy, azetidinylcarbonyl, pyrazolyl, triazolyl, or pyrrolidinyl, and azetidinylcarbonyl, pyrazolyl, triazolyl, and pyrrolidinyl are R 4 A compound according to the present invention optionally substituted with one or two substituents individually selected from: R 1 is haloalkoxy, azetidinylcarbonyl, pyrazolyl, triazolyl, or pyrrolidinyl, and azetidinylcarbonyl, pyrazolyl, triazolyl, and pyrrolidinyl are R 4 The compound according to the present invention, optionally substituted with a substituent selected from: R 1 But R 4 A compound according to the present invention which is pyrazolyl optionally substituted with 1, 2 or 3 substituents individually selected from: R 1 But R 4 The compound according to the present invention is pyrazolyl optionally substituted with a substituent selected from: R 2 is hydrogen, alkoxy, alkyl, halogen, dialkylaminocarbonylalkoxy, oxetanyloxy, tetrahydropyranyloxy, pyrrolidinyloxy, morpholinylalkoxy, or alkylpyridazinylamino; or R 2 and R 3 together with the carbon atom to which they are attached to form a methylpyridazinyl substituted imidazolidin-2-one; R 2is hydrogen, methoxy, methyl, fluoro, dimethylaminocarbonylethoxy, oxetanyloxy, tetrahydropyranyloxy, pyrrolidinyloxy, morpholinylalkoxy, or alkylpyridazinylamino; or R 2 and R 3 together with the carbon atom to which they are attached to form a methylpyridazinyl substituted imidazolidin-2-one; R 2 is hydrogen, alkoxy, alkyl, halogen, haloalkoxy, dialkylaminocarbonylalkoxy, oxetanyloxy, tetrahydropyranyloxy, pyrrolidinyloxy, morpholinylalkoxy, or alkylpyridazinylamino; or R 2 and R 3 together with the carbon atom to which they are attached to form a methylpyridazinyl substituted imidazolidin-2-one; R 2 is hydrogen, methoxy, methyl, fluoro, difluoromethoxy, dimethylaminocarbonylethoxy, oxetanyloxy, tetrahydropyranyloxy, pyrrolidinyloxy, morpholinylalkoxy, or alkylpyridazinylamino; or R 2 and R 3 together with the carbon atom to which they are attached to form a methylpyridazinyl substituted imidazolidin-2-one; R 3is hydrogen, cyclopropylcarbonyl, piperidinylcarbonyl, diazaspiroheptanyl, piperidyl, dihydro-5H-pyrano[4,3-c]pyridazinyl, 1-methyl-6-oxo-pyridazinyl, dihydropyridazino[4,5-b][1,4]oxazinyl, 6-oxo-pyrrolo[2,3-c]pyridazinyl, 5,7-dihydropyrrolo[3,4-c]pyridazinyl, pyridazinyl or 5,6-dihydropyrrolo[2,3-c]pyridazinyl Certain compounds according to the present invention include piperidinylcarbonyl, diazaspiroheptanyl, piperidyl, dihydro-5H-pyrano[4,3-c]pyridazinyl, 1-methyl-6-oxo-pyridazinyl, dihydropyridazino[4,5-b][1,4]oxazinyl, 6-oxo-pyrrolo[2,3-c]pyridazinyl, 5,7-dihydropyrrolo[3,4-c]pyridazinyl, pyridazinyl, and 5,6-dihydropyrrolo[2,3-c]pyridazinyl. 5 and optionally substituted with 1, 2, or 3 substituents individually selected from R 5 Compounds substituted with one or two substituents individually selected from: R 3is hydrogen, cyclopropylcarbonyl, piperidinylcarbonyl, 2,6-diazaspiro[3.3]heptanyl, 4-piperidyl, 7,8-dihydro-5H-pyrano[4,3-c]pyridazin-3-yl, 1-methyl-6-oxo-pyridazin-3-yl, 2,3-dihydropyridazino[4,5-b][1,4]oxazin-8-yl, 6-oxo-pyrrolo[2,3-c]pyridazin-3-yl, 5,7-dihydropyrrolo[3,4-c]pyridazin-3-yl, pyridazin-3-yl or 5,6-dihydropyrrolo[2,3-c]pyridazin-7-yl; In certain compounds according to the present invention, piperidinylcarbonyl, 2,6-diazaspiro[3.3]heptanyl, 4-piperidyl, 7,8-dihydro-5H-pyrano[4,3-c]pyridazin-3-yl, 1-methyl-6-oxo-pyridazin-3-yl, 2,3-dihydropyridazino[4,5-b][1,4]oxazin-8-yl, 6-oxo-pyrrolo[2,3-c]pyridazin-3-yl, 5,7-dihydropyrrolo[3,4-c]pyridazin-3-yl, pyridazin-3-yl and 5,6-dihydropyrrolo[2,3-c]pyridazin-7-yl are R 5 and optionally substituted with 1, 2, or 3 substituents individually selected from R 5 Compounds substituted with one or two substituents individually selected from: R 3 R 5 The compound according to the present invention is pyridazin-3-yl substituted with R 4 is, at each instance, independently selected from cyano, methyl, amino, methylsulfonyl, fluoro, methoxyethyl, cyclopropylmethyl, dimethylaminocarbonyl, difluoromethoxy, (1R)-2,2-difluoro-1-methyl-ethoxy, difluoromethyl, trifluoromethyl, and trifluoroethyl; R 4is, at each instance, independently selected from cyano, methyl, fluoro, methoxyethyl, cyclopropylmethyl, dimethylaminocarbonyl, difluoromethoxy, (1R)-2,2-difluoro-1-methyl-ethoxy, difluoromethyl, trifluoromethyl, and trifluoroethyl; R 4 is amino or methylsulfonyl. R 5 and, in each instance, independently, tert-butyloxycarbonyl, methyl, ethyl, tetrahydrofuranyl, oxetanyl, 4-hydroxy-3-methyl-tetrahydrofuranyl, dimethylaminocarbonyl, 5-[rac-(1S,5R)-3-oxa-6-azabicyclo[3.1.1]heptanyl, 1-methyl-5-oxo-pyrrolidinyl, 2-morpholinoethoxy, (1-methyl-4-piperidyl)oxy, the compound according to the invention selected from (3R)-1-methyl-2-oxo-pyrrolidinyl, (3S)-1-methyl-2-oxo-pyrrolidinyl, 1-(oxetan-3-yl)-4-piperidyl]oxy, dimethylaminocarbonylmethyl, 5-(benzyloxycarbonylamino)-1,3-dioxan-2-yl, methyl(2,2,2-trifluoroethyl)carbamoyl and 1-methylazetidin-3-yl; R 5and in each instance independently represents tert-butyloxycarbonyl, methyl, ethyl, 6-tetrahydrofuran-3-yl, oxetan-3-yl, 4-hydroxy-3-methyl-tetrahydrofuran-3-yl, dimethylaminocarbonyl, 5-[rac-(1S,5R)-3-oxa-6-azabicyclo[3.1.1]heptan-6-yl, 1-methyl-5-oxo-pyrrolidin-2-yl, 2-morpholinoethoxy, (1-methyl-4-piperidin-2-yl), 2-methyl-4-pyrrolidin-2-yl, ... the compound according to the invention selected from: (3R)-1-methyl-2-oxo-pyrrolidin-3-yl, (3S)-1-methyl-2-oxo-pyrrolidin-3-yl, 1-(oxetan-3-yl)-4-piperidyl]oxy, dimethylaminocarbonylmethyl, 5-(benzyloxycarbonylamino)-1,3-dioxan-2-yl, methyl(2,2,2-trifluoroethyl)carbamoyl and 1-methylazetidin-3-yl; R 5 is alkyl, in particular methyl; A 1 The compound according to the present invention, wherein is -CH-; A 1 The compound according to the present invention, wherein is -N-; Compounds according to the present invention wherein L is -NH-; A compound according to the present invention, wherein L is absent; and Compounds according to the present invention wherein L is -O-; Regarding.

[0060] The present invention further comprises: 1-[3-(difluoromethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(2-morpholinoethoxy)benzimidazol-5-amine; 1-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[5-(difluoromethyl)-6-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 3-(Difluoromethyl)-1-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-N,N,5-trimethyl-pyrazole-4-carboxamide; 5-(Difluoromethoxy)-2-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-tetrahydrofuran-3-ylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 6-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]amino]-N,N-dimethyl-pyridazine-3-carboxamide; 3-[[1-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide; 1-[5-(difluoromethyl)-6-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 1-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine; 1-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-fluoro-pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[5-[(6-keto-5,5,7-trimethyl-pyrrolo[2,3-c]pyridazin-3-yl)amino]-6-methoxy-benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[5-[[6-(2-morpholinoethoxy)pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(Difluoromethyl)-6-[5-(7,8-dihydro-5H-pyrano[4,3-c]pyridazin-3-ylamino)-6-methoxy-benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]-6-tetrahydropyran-4-yloxy-benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-5-(difluoromethyl)-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine; 1-[6-[3,5-bis(difluoromethyl)pyrazol-1-yl]-5-(difluoromethyl)-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine; (3R,5S)-1-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrrolidine-3-carbonitrile; 1-[6-[5-[(7-cyclopropyl-6-keto-5,5-dimethyl-pyrrolo[2,3-c]pyridazin-3-yl)amino]-6-methoxy-benzimidazol-1-yl]-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[5-[(6-keto-1-methyl-pyridazin-3-yl)amino]-6-methoxy-benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-[(1-methyl-4-piperidyl)oxy]pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[5-(difluoromethyl)-6-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 1-[5-(difluoromethyl)-6-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 1-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-[[1-(oxetan-3-yl)-4-piperidyl]oxy]pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[6-methoxy-5-[(4-methyl-2,3-dihydropyridazino[4,5-b][1,4]oxazin-8-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[6-[1-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(difluoromethyl)-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 6-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]benzimidazol-5-yl]amino]-N,N,4-trimethyl-pyridazine-3-carboxamide; N-[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]benzimidazol-5-yl]cyclopropanecarboxamide; 1-[6-[1-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(difluoromethyl)-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 3-(Difluoromethoxy)-1-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-6,7-dihydropyrazolo[4,3-c]pyridin-4-one; 2-[3-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-5-yl]oxy-N,N-dimethyl-acetamide; 1-[5-(difluoromethyl)-6-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 1-[5-(difluoromethyl)-6-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 1-[5-(difluoromethyl)-6-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 1-[6-[1-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(difluoromethyl)-2-pyridyl]-6-fluoro-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 1-[3-(difluoromethyl)-6-[6-fluoro-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[6-methoxy-5-[[5-[(1S)-3-oxa-6-azabicyclo[3.1.1]heptan-6-yl]pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 3-[[1-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-5-(difluoromethyl)-2-pyridyl]-6-methyl-benzimidazol-5-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide; 1-[5-(difluoromethyl)-6-[(1R)-2,2-difluoro-1-methyl-ethoxy]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine; 1-[5-(difluoromethyl)-6-[(1S)-2,2-difluoro-1-methyl-ethoxy]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine; N-[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]-1-(oxetan-3-yl)piperidine-4-carboxamide; 1-[5-(difluoromethyl)-6-[3-(trifluoromethyl)-5,7-dihydro-4H-pyrano[3,4-c]pyrazol-1-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine; 2-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]-2-pyridyl]-3,5-dimethyl-4H-pyrrolo[3,4-c]pyrazol-6-one; 1-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-(1-methyl-5-oxo-pyrrolidin-2-yl)pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 3-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]amino]-N,N,5-trimethyl-pyridazine-4-carboxamide; 3-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]amino]-N,N,5,6-tetramethyl-pyridazine-4-carboxamide; 3-[[1-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]amino]-N,6-dimethyl-N-(2,2,2-trifluoroethyl)pyridazine-4-carboxamide; 2-[6-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]amino]pyridazin-3-yl]-N,N-dimethyl-acetamide; 1-[3-(difluoromethyl)-6-[6-methoxy-5-(3-methyl-5-methylol-5,6-dihydropyrrolo[2,3-c]pyridazin-7-yl)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[5-(difluoromethyl)-6-[2-methyl-5-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 1-[3-(difluoromethyl)-6-(6-methoxybenzimidazol-1-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[5-(difluoromethyl)-6-[1-methyl-5-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 1-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-[(3R)-1-methyl-2-oxo-pyrrolidin-3-yl]pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(Difluoromethyl)-6-[6-methoxy-5-[[6-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; Benzyl N-[2-[6-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]benzimidazol-5-yl]amino]pyridazin-3-yl]-1,3-dioxan-5-yl]carbamate; 1-[3-(Difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-4,6-dihydrofuro[3,4-c]pyrazole-3-carbonitrile; 1-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-2-pyridyl]-6-methoxy-N-[6-methyl-5-(1-methylazetidin-3-yl)pyridazin-3-yl]benzimidazol-5-amine; 1-[3-(Difluoromethyl)-6-[5-[(6-ethyl-5,7-dihydropyrrolo[3,4-c]pyridazin-3-yl)amino]-6-methoxy-benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; [3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-[2-(trifluoromethyl)azetidin-1-yl]methanone; 1-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-pyrrolidin-3-yloxy-benzimidazol-5-amine; 1-[3-(difluoromethyl)-6-[3-(6-methylpyridazin-3-yl)-2-oxo-1H-imidazo[4,5-f]benzimidazol-7-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(Difluoromethyl)-6-[1-(6-methylpyridazin-3-yl)-2-oxo-3H-imidazo[4,5-f]benzimidazol-7-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 6-[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester; 1-[6-[5-(2,6-diazaspiro[3.3]heptan-2-yl)-6-methoxy-benzimidazol-1-yl]-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[5-(difluoromethyl)-6-[1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 1-[3-(difluoromethyl)-6-[5-[[1-[(3R,4R)-4-hydroxy-3-methyl-tetrahydrofuran-3-yl]-4-piperidyl]amino]-6-methoxy-benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyrazin-2-yl]-5-methyl-pyrazole-3-carbonitrile; (3-aminoazetidin-1-yl)-[6-[6-(difluoromethoxy)-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-(difluoromethyl)-2-pyridyl]methanone; [6-[6-(difluoromethoxy)-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-(difluoromethyl)-2-pyridyl]-[2-(trifluoromethyl)azetidin-1-yl]methanone; [6-[6-(difluoromethoxy)-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-(difluoromethyl)-2-pyridyl]-[(2S,4S)-2,4-dimethylazetidin-1-yl]methanone; (3-aminoazetidin-1-yl)-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]methanone; [1-[5-(difluoromethyl)-6-(1-mesyl-3-piperidyl)-2-pyridyl]benzimidazol-5-yl]-(6-methylpyridazin-3-yl)amine; and 2-Azabicyclo[2.2.0]hexan-2-yl-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]methanone; or a pharmaceutically acceptable salt thereof.

[0061] The present invention further comprises: 1-[3-(difluoromethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(2-morpholinoethoxy)benzimidazol-5-amine; 1-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[5-(difluoromethyl)-6-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 3-(Difluoromethyl)-1-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-N,N,5-trimethyl-pyrazole-4-carboxamide; 5-(Difluoromethoxy)-2-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-tetrahydrofuran-3-ylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 6-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]amino]-N,N-dimethyl-pyridazine-3-carboxamide; 3-[[1-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide; 1-[5-(difluoromethyl)-6-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 1-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine; 1-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-fluoro-pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[5-[(6-keto-5,5,7-trimethyl-pyrrolo[2,3-c]pyridazin-3-yl)amino]-6-methoxy-benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[5-[[6-(2-morpholinoethoxy)pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(Difluoromethyl)-6-[5-(7,8-dihydro-5H-pyrano[4,3-c]pyridazin-3-ylamino)-6-methoxy-benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]-6-tetrahydropyran-4-yloxy-benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-5-(difluoromethyl)-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine; 1-[6-[3,5-bis(difluoromethyl)pyrazol-1-yl]-5-(difluoromethyl)-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine; (3R,5S)-1-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrrolidine-3-carbonitrile; 1-[6-[5-[(7-cyclopropyl-6-keto-5,5-dimethyl-pyrrolo[2,3-c]pyridazin-3-yl)amino]-6-methoxy-benzimidazol-1-yl]-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[5-[(6-keto-1-methyl-pyridazin-3-yl)amino]-6-methoxy-benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-[(1-methyl-4-piperidyl)oxy]pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[5-(difluoromethyl)-6-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 1-[5-(difluoromethyl)-6-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 1-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-[[1-(oxetan-3-yl)-4-piperidyl]oxy]pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[6-methoxy-5-[(4-methyl-2,3-dihydropyridazino[4,5-b][1,4]oxazin-8-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[6-[1-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(difluoromethyl)-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 6-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]benzimidazol-5-yl]amino]-N,N,4-trimethyl-pyridazine-3-carboxamide; N-[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]benzimidazol-5-yl]cyclopropanecarboxamide; 1-[6-[1-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(difluoromethyl)-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 3-(Difluoromethoxy)-1-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-6,7-dihydropyrazolo[4,3-c]pyridin-4-one; 2-[3-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-5-yl]oxy-N,N-dimethyl-acetamide; 1-[5-(difluoromethyl)-6-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 1-[5-(difluoromethyl)-6-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 1-[5-(difluoromethyl)-6-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 1-[6-[1-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(difluoromethyl)-2-pyridyl]-6-fluoro-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 1-[3-(difluoromethyl)-6-[6-fluoro-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[6-methoxy-5-[[5-[(1S)-3-oxa-6-azabicyclo[3.1.1]heptan-6-yl]pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 3-[[1-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-5-(difluoromethyl)-2-pyridyl]-6-methyl-benzimidazol-5-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide; 1-[5-(difluoromethyl)-6-[(1R)-2,2-difluoro-1-methyl-ethoxy]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine; 1-[5-(difluoromethyl)-6-[(1S)-2,2-difluoro-1-methyl-ethoxy]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine; N-[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]-1-(oxetan-3-yl)piperidine-4-carboxamide; 1-[5-(difluoromethyl)-6-[3-(trifluoromethyl)-5,7-dihydro-4H-pyrano[3,4-c]pyrazol-1-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine; 2-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]-2-pyridyl]-3,5-dimethyl-4H-pyrrolo[3,4-c]pyrazol-6-one; 1-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-(1-methyl-5-oxo-pyrrolidin-2-yl)pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 3-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]amino]-N,N,5-trimethyl-pyridazine-4-carboxamide; 3-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]amino]-N,N,5,6-tetramethyl-pyridazine-4-carboxamide; 3-[[1-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]amino]-N,6-dimethyl-N-(2,2,2-trifluoroethyl)pyridazine-4-carboxamide; 2-[6-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]amino]pyridazin-3-yl]-N,N-dimethyl-acetamide; 1-[3-(difluoromethyl)-6-[6-methoxy-5-(3-methyl-5-methylol-5,6-dihydropyrrolo[2,3-c]pyridazin-7-yl)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[5-(difluoromethyl)-6-[2-methyl-5-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 1-[3-(difluoromethyl)-6-(6-methoxybenzimidazol-1-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[5-(difluoromethyl)-6-[1-methyl-5-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 1-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-[(3R)-1-methyl-2-oxo-pyrrolidin-3-yl]pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(Difluoromethyl)-6-[6-methoxy-5-[[6-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; Benzyl N-[2-[6-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]benzimidazol-5-yl]amino]pyridazin-3-yl]-1,3-dioxan-5-yl]carbamate; 1-[3-(Difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-4,6-dihydrofuro[3,4-c]pyrazole-3-carbonitrile; 1-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-2-pyridyl]-6-methoxy-N-[6-methyl-5-(1-methylazetidin-3-yl)pyridazin-3-yl]benzimidazol-5-amine; 1-[3-(Difluoromethyl)-6-[5-[(6-ethyl-5,7-dihydropyrrolo[3,4-c]pyridazin-3-yl)amino]-6-methoxy-benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; [3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-[2-(trifluoromethyl)azetidin-1-yl]methanone; 1-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-pyrrolidin-3-yloxy-benzimidazol-5-amine; 1-[3-(difluoromethyl)-6-[3-(6-methylpyridazin-3-yl)-2-oxo-1H-imidazo[4,5-f]benzimidazol-7-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(Difluoromethyl)-6-[1-(6-methylpyridazin-3-yl)-2-oxo-3H-imidazo[4,5-f]benzimidazol-7-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 6-[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester; 1-[6-[5-(2,6-diazaspiro[3.3]heptan-2-yl)-6-methoxy-benzimidazol-1-yl]-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[5-(difluoromethyl)-6-[1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 1-[3-(difluoromethyl)-6-[5-[[1-[(3R,4R)-4-hydroxy-3-methyl-tetrahydrofuran-3-yl]-4-piperidyl]amino]-6-methoxy-benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; and 1-[3-(Difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyrazin-2-yl]-5-methyl-pyrazole-3-carbonitrile or a pharmaceutically acceptable salt thereof.

[0062] The present invention further comprises, in particular: 1-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(Difluoromethyl)-6-[5-(7,8-dihydro-5H-pyrano[4,3-c]pyridazin-3-ylamino)-6-methoxy-benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[6-[1-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(difluoromethyl)-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 1-[5-(difluoromethyl)-6-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 1-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-2-pyridyl]-6-methoxy-N-[6-methyl-5-(1-methylazetidin-3-yl)pyridazin-3-yl]benzimidazol-5-amine; and 1-[3-(Difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyrazin-2-yl]-5-methyl-pyrazole-3-carbonitrile or a pharmaceutically acceptable salt thereof.

[0063] The present invention further comprises, in particular: (3-aminoazetidin-1-yl)-[6-[6-(difluoromethoxy)-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-(difluoromethyl)-2-pyridyl]methanone; [6-[6-(difluoromethoxy)-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-(difluoromethyl)-2-pyridyl]-[2-(trifluoromethyl)azetidin-1-yl]methanone; [6-[6-(difluoromethoxy)-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-(difluoromethyl)-2-pyridyl]-[(2S,4S)-2,4-dimethylazetidin-1-yl]methanone; (3-aminoazetidin-1-yl)-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]methanone; [1-[5-(difluoromethyl)-6-(1-mesyl-3-piperidyl)-2-pyridyl]benzimidazol-5-yl]-(6-methylpyridazin-3-yl)amine; and 2-Azabicyclo[2.2.0]hexan-2-yl-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]methanone; or a pharmaceutically acceptable salt thereof.

[0064] One embodiment of the present invention is a compound of formula (IIa): [ka] In the formula, A 1 , L, R 2 and R 3 is as described herein; and R 4 is selected from cyano, haloalkyl and haloalkoxy, in particular cyano and difluoromethyl.

[0065] One embodiment of the present invention is a compound of formula (IIb): [ka] In the formula, L, R 2 and R 3 is as described herein; and R 4 is selected from cycloalkylalkyl and haloalkyl, in particular cyclopropylmethyl and trifluoroethyl.

[0066] One embodiment of the present invention is a compound of formula (III): [ka] In the formula, A 1 , L, R 1 , R 2, R 4 and R 5 is as described herein; and R 6 are, in each instance, individually selected from alkyl and alkylazetidinyl, particularly methyl and 1-methylazetidin-3-yl; or two R 6

[0023] This invention relates to compounds according to the present invention wherein the groups, taken together with the carbon to which they are attached, form a 5- to 7-membered heterocycloalkyl. DETAILED DESCRIPTION OF THE INVENTION

[0067] General synthetic scheme The synthesis of compounds of formula (I) can be achieved, for example, according to the non-exhaustive procedures described below in general schemes 1-4. In some embodiments, the order of the reaction steps can be changed, and the individual steps of the different schemes can be combined in different ways, as disclosed herein and in accordance with general knowledge. In general, the reaction conditions provided below and the reaction conditions described above can, in some cases, be further modified in accordance with the procedures described herein and general knowledge.

[0068] Scheme 1 Scheme 1 describes the synthesis of a compound of formula (Ia) or (I-a'). A compound of formula (Ia) is a compound of formula (I), wherein A 1 is C;R 1 is R 4 , R 4 ' and R 4 is a pyrazole optionally substituted with R 2 is selected from hydrogen, alkoxy, alkyl, halogen, dialkylaminocarbonylalkoxy, heterocycloalkyloxy, heterocycloalkylalkoxy, and alkylheteroarylamino; R 3 is methylpyridazinyl; L is -NH-; R 4 and R 4R is independently selected from alkyl, cyano, halogen, alkoxyalkyl, cycloalkylalkyl, haloalkoxy, and haloalkyl; and R is hydrogen or dialkylaminocarbonyl. Compounds of formula (I-a) are compounds of formula (I) wherein A 1 is C;R 1 is R 4 , R 4 ' and R 4 is a pyrazole optionally substituted with R 2 is methylpyridazinylamino; L is absent; R 3 is selected from hydrogen, alkoxy, alkyl, halogen, dialkylaminocarbonylalkoxy, heterocycloalkyloxy, heterocycloalkylalkoxy, and alkylheteroarylamino; R 4 and R 4 " is independently selected from alkyl, cyano, halogen, alkoxyalkyl, cycloalkylalkyl, haloalkoxy, and haloalkyl; R 4 is hydrogen or dialkylaminocarbonyl. In the schemes below, R2 / R3 means that the groups are selected from hydrogen, alkoxy, alkyl, halogen, dialkylaminocarbonylalkoxy, heterocycloalkyloxy, heterocycloalkylalkoxy and alkylheteroarylamino. [ka]

[0069] Step A: 2-chloro-6-fluoro-pyridine 1 can be reacted in the presence of a suitable base (such as LDA) in the presence of a suitable solvent (such as THF, MeTHF, or dioxane) at a temperature of about −78° C. to about 25° C., and the deprotonated intermediate can be reacted with DMF at a temperature of about −78° C. to about 25° C. to give intermediate 2.

[0070] Step B: 6-Chloro-2-fluoro-pyridine-3-carbaldehyde 2 can be reacted with substituted pyrazole 3 in the presence of a suitable organic or mineral base (such as DIPEA, DBU, K2CO3, Cs2CO3 or NaH) in a suitable polar solvent (such as DMF, DMA, NMP, DMSO or THF, MeTHF, etc.) at a temperature ranging from about -10°C to about 120°C to give intermediate 4.

[0071] Step C: Intermediate 4 can be reacted with a fluorinating reagent, such as DAST, in a suitable solvent, such as DCM or ACN, at a temperature ranging from about −30° C. to about 30° C. to provide intermediate 5.

[0072] Step D: Intermediates 5 and 6 can be reacted in the presence of a suitable organic or mineral base (such as DIPEA, DBU, K2CO3, Cs2CO3 or NaH) in a suitable polar solvent (such as DMF, DMA, NMP, DMSO or THF, MeTHF, etc.) at a temperature ranging from about 80°C to about 110°C to give regioisomeric compounds 7 and 7', which can be separated by flash column chromatography or preparative HPLC or preparative TLC or reacted in the next step as a regioisomeric mixture.

[0073] Step E: Introduction of the aminopyridazine can be achieved via Buchwald-Hartwig coupling using a suitable base such as, for example, CsCO, KCO, or KPO and a suitable palladium catalyst such as tBuXPhos Pd G3 or [tBuBrettPhos Pd(allyl)]OTf in a suitable solvent such as 1,4-dioxane at a temperature ranging from about 80° C. to about 100° C. to afford compounds Ia and I-a′, which can be separated by flash column chromatography or preparative HPLC or preparative TLC.

[0074] Scheme 2 Scheme 2 describes the synthesis of compounds of formula 6, where A is alkyl, dialkylaminoalkyl, heteroaryl, or heterocycloalkyl; where heteroaryl and heterocycloalkyl are optionally substituted with 1, 2, or 3 substituents individually selected from R5. [ka]

[0075] Step A: (4-Bromo-5-fluoro-2-nitro-phenyl)amine 8 can be reacted with alcohol 9 in the presence of a suitable organic or mineral base (such as NaH, CsCO, or DBU) in a suitable solvent (such as THF, MeTHF, or dioxane) at a temperature ranging from about −10° C. to about 120° C. to provide intermediate 10.

[0076] Step B: The nitro group of intermediate 10 can be reduced in the presence of a metal reducing agent (such as Zn or Fe), an acid (such as AcOH or HCl) in a suitable polar protic solvent (such as MeOH or EtOH) at a temperature ranging from about −10° C. to about 120° C. to provide diamino intermediate 11.

[0077] Alternatively, the nitro group of intermediate 10 can be reduced in the presence of hydrogen gas in the presence of a catalyst (such as Pd on charcoal) in a suitable polar protic solvent (such as MeOH or EtOH) at a temperature ranging from about −10° C. to about 65° C. to provide diamino intermediate 11.

[0078] Step C: Diamino intermediate 11 can be cyclized to provide benzimidazole intermediate 6 in the presence of an orthoformate (e.g., trimethyl orthoformate of triethyl orthoformate, etc.), which can be used as a reaction solvent, at a temperature of about 50°C to about 100°C.

[0079] Scheme 3 Scheme 3 describes the synthesis of compounds of formula (Ib) or (I-b'). Compounds of formula (Ib) are compounds of formula (I), wherein A 1is C;R 1 is methyl and R 4 ' is a pyrazole substituted with R 2 is selected from hydrogen, alkoxy and halogen; R 3 is methylpyridazinyl; L is -NH-; R 4 A' is 1,1,1-trifluoroethyl, methoxyethyl or cyclopropylmethyl. The compound of formula (I-b') is a compound of formula (I), wherein A 1 is C;R 1 is methyl and R 4 ' is a pyrazole substituted with R 2 is methylpyridazinylamino; R 3 is selected from hydrogen, alkoxy, and halogen; L is absent; R 4 ' is 1,1,1-trifluoroethyl, methoxyethyl or cyclopropylmethyl. In the schemes below, R2 / R3 means that the radicals are selected from hydrogen, alkoxy and halogen. [ka]

[0080] Step A: 2,6-dichloronicotinaldehyde 12 and ethane-1,2-diol can be reacted in the presence of a suitable organic or mineral acid (e.g., pTSOH) in a suitable solvent (e.g., toluene) at a temperature of about 80°C to about 110°C (reflux) with continuous removal of water using a Dean-Stark apparatus to provide intermediate 13.

[0081] Step B: Intermediates 13 and 14 can be reacted in the presence of a suitable organic or mineral base (such as DIPEA, DBU, K2CO3, Cs2CO3 or NaH) in a suitable polar solvent (such as DMF, DMA, NMP, DMSO or THF, MeTHF, etc.) at a temperature ranging from about -10°C to about 120°C to give regioisomeric compounds 15 and 15', which can be separated by flash column chromatography or preparative HPLC or preparative TLC or reacted in the next step as a regioisomeric mixture.

[0082] Step C: Palladium-catalyzed cross-coupling reaction (Suzuki-Miyaura) between intermediate 15 and the corresponding heteroaryl pinacolborane 16 using a Pd catalyst (e.g., a suitable Pd catalyst such as P(Ph3)4 or Pd(dppf)Cl2·CH2Cl2) and a suitable base (e.g., K3PO4, Cs2CO3, K2CO3, Na2CO3, etc.) in a suitable solvent (e.g., 1,4-dioxane or a mixture of 1,4-dioxane and water) heated (e.g., at a temperature between about 80°C and about 110°C, or at a temperature between about 80°C and about 120°C via microwave irradiation) provides regioisomeric compounds 17 and 17', which can be separated by flash column chromatography, preparative HPLC, or preparative TLC, or reacted in the next step as a regioisomeric mixture.

[0083] Step D: Intermediate 17 can be deprotected using an acid (e.g., HCl) in a suitable solvent (e.g., dioxane, THF, MeTHF, etc.) at a temperature between about 0°C and about 50°C to give regioisomeric compounds 18 and 18', which can be separated by flash column chromatography or preparative HPLC or preparative TLC, or reacted in the next step as a mixture of regioisomers.

[0084] Step E: Intermediate 18 can be reacted with a fluorinating reagent (such as DAST) in a suitable solvent (such as DCM) at a temperature of about −30° C. to about 30° C. to afford compounds of formula Ib or I-b′, which can be purified by flash column chromatography or preparative HPLC or preparative TLC.

[0085] Scheme 4 Scheme 3 describes the synthesis of compounds of formula (Ic). Compounds of formula (Ic) are compounds of formula (I), wherein A 1 is NH; L is -NH-; R 1 is a cyano- and methyl-substituted pyrazole; R 2 is alkoxy; R 3 is methylpyridazinyl. [ka]

[0086] Step A: 3,5-Dichloropyrazine-2-carbaldehyde 18 can be reacted with a fluorinating reagent (such as DAST) in a suitable solvent (such as DCM) at a temperature range of about -30°C to about 30°C to provide a compound of formula 20.

[0087] Step B: Intermediates 20 and 14 can be reacted in the presence of a suitable organic or mineral base (such as DIPEA, DBU, K2CO3, Cs2CO3 or NaH) in a suitable polar solvent (such as DMF, DMA, NMP, DMSO or THF, MeTHF, etc.) at a temperature ranging from about -10°C to about 120°C to afford compound 21, which can be purified by flash column chromatography or preparative HPLC or preparative TLC.

[0088] Step C: Intermediates 21 and 22 can be reacted in the presence of a suitable organic or mineral base (such as DIPEA, DBU, K2CO3, Cs2CO3 or NaH) in a suitable polar solvent (such as DMF, DMA, NMP, DMSO or THF, MeTHF, etc.) at a temperature ranging from about −10° C. to about 120° C. to afford compounds of formula (Ic), which can be purified by flash column chromatography or preparative HPLC or preparative TLC.

[0089] Therefore, the present invention also relates to a method for preparing a compound according to the present invention, comprising the following steps: (a) a compound of formula (B1) or (B2) [ka] or [ka] and a compound of formula (B3) [ka] in the presence of a suitable solvent and in the presence of a suitable base; (b) a compound of formula (C1) [ka] with a deoxofluorinating agent in the presence of a suitable solvent; or (c) A compound of formula (D1) [ka] and a compound of formula (D2) [ka] in the presence of a suitable solvent and in the presence of a suitable base, including one of the following; where X is halogen, OM or OT, in particular halogen; L, R 1 , R 2 , R 3 , R 4 and R 5 is as described herein, In step (a), the solvent may be, for example, toluene, xylene, 1,4-dioxane or a mixture thereof, in particular 1,4-dioxane; In step (a), the base may be, for example, Cs2CO3, K2CO3 or K3PO4, in particular K3PO4; In step (a), the catalyst can be a Pd catalyst such as tBuXPhos Pd G3 or [tBuBrettPhos Pd(allyl)]OTf; Advantageously, the reaction of step (a) is carried out at a temperature of from about 50°C to about 120°C, in particular from about 70°C to about 110°C, more in particular from about 80°C to about 100°C; Advantageously, the reaction of step (a) is carried out for a period of from about 1 hour to about 48 hours, in particular from about 2 hours to about 24 hours, more particularly from about 4 hours to about 18 hours, or from about 4 hours to about 16 hours; Conveniently, the reaction of step (a) is carried out in the presence of 1,4-dioxane, K3PO4, and tBuXPhos Pd G3 at a temperature range of about 70°C to about 110°C; Conveniently, the reaction of step (a) is carried out in the presence of 1,4-dioxane, Cs2CO3, and [tBuBrettPhos Pd(allyl)]OTf at a temperature range of about 70°C to about 110°C; In step (b), the solvent may be, for example, dichloromethane or diethyl ether, in particular dichloromethane; In step (b), the deoxofluorinating agent may be, for example, DAST, cesium fluoride, deoxofluor, or MOST, in particular DAST; Conveniently, the reaction of step (b) is carried out at a temperature ranging from about -30°C to about 30°C, particularly from about 0°C to about 30°C, more particularly from about 0°C to room temperature; Advantageously, the reaction of step (b) is carried out for a period of from about 30 minutes to about 48 hours, particularly from about 1 hour to about 24 hours, more particularly from about 2 hours to 12 hours; Conveniently, the reaction of step (b) is carried out in the presence of dichloromethane, in the presence of DAST, at a temperature range of about -30°C to about 30°C; In step (c), the solvent may be a polar solvent such as DMF, DMA, NMP, DMSO, THF, or 2-MeTHF, in particular DMSO; In step (c), the base may be an organic or inorganic base, such as DIPEA, DBU, K2CO3, Cs2CO3, NaH, etc., in particular DIPEA; Advantageously, the reaction of step (b) is carried out at a temperature of from about 60°C to about 140°C, in particular from about 70°C to about 130°C, more in particular from about 80°C to about 120°C; Advantageously, the reaction of step (c) is carried out for a period of from about 1 hour to about 48 hours, particularly from about 3 hours to about 30 hours, more particularly from about 3 hours to 18 hours; Conveniently, the reaction of step (c) is carried out in the presence of DMSO, in the presence of DIPEA, at a temperature range of about 80°C to about 120°C.

[0090] The present invention also relates, inter alia, to: A compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof for use as a therapeutically active substance; a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier; Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein for the treatment or prevention of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis, in particular inflammatory bowel disease (IBD); Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein for the preparation of a medicament for the treatment or prevention of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis, in particular inflammatory bowel disease (IBD); A compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis, in particular inflammatory bowel disease (IBD); and A method for the treatment or prevention of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis, comprising administering to a patient in need thereof an effective amount of a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof.

[0091] Pharmaceutical Composition Another embodiment of the present invention provides pharmaceutical compositions or medicaments containing a compound of the present invention and a therapeutically inert carrier, diluent, or excipient, and methods of using the compounds of the present invention to prepare such compositions and medicaments. In one example, a compound of Formula (I) may be formulated by mixing it with a physiologically acceptable carrier, i.e., a carrier that is not toxic to recipients at the dosages and concentrations used in herbal dosage forms, at an appropriate pH and desired purity, at ambient temperature. The pH of the formulation will depend primarily on the particular application and compound concentration, but is preferably in the range of about 3 to about 8. In one example, a compound of Formula (I) is formulated in an acetate buffer at pH 5. In another embodiment, the compound of Formula (I) is sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0092] The compositions are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to consider in this regard include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of drug delivery, the method of administration, the administration schedule, and other factors known to physicians.

[0093] 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, epidural, and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0094] The compounds of the present invention may be administered in any convenient dosage form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain ingredients typically found in pharmaceutical formulations, such as diluents, carriers, pH adjusters, sweeteners, bulking agents, and other active ingredients.

[0095] Typical formulations are prepared by mixing the compound of the present invention with carriers or excipients.Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, for example, Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricating agents, emulsifying agents, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, flavors, flavorings, diluents, and other known additives to present the drug (i.e., the compound of the present invention or a pharmaceutical composition thereof) aesthetically or to aid in the manufacture of a pharmaceutical product (i.e., a medicament).

[0096] The invention will now be illustrated by the following examples, which have no limiting character. [Example]

[0097] Abbreviation 2-MeTHF 2-methyltetrahydrofuran ACN Acetonitrile ATP adenosine triphosphate aq. aqueous solution BINAP [2,2'-bis(diphenylphosphino)-1,1'-binaphthyl] Boc tert-butyloxycarbonyl Boc(2)O di-tert-butyl dicarbonate BrettPhos Pd G4 Dicyclohexyl-[3,6-dimethoxy-2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane; Methanesulfonic acid; N-methyl-2-phenylaniline; Palladium (CAS#1599466-83-7) CAS Chemical Abstracts Service CDI Carbonyldiimidazole CH3CN Acetonitrile CO Carbon monoxide Cs2CO3 Cesium Carbonate DAST Diethylaminosulfur trifluoride dba Dibenzylideneacetone DBU 1,8-diazabicyclo(5.4.0)undec-7-ene DCE 1,2-dichloroethane DCM dichloromethane DIPEA N,N-Diisopropylethylamine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide dppf 1,1'-ferrocenediyl-bis(diphenylphosphine) eq. equivalent amount ESI electrospray ionization Et2O diethyl ether Et3N Triethylamine EtOAc ethyl acetate EtOH ethanol FA formic acid HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HCl Hydrogen chloride HPLC High Pressure Liquid Chromatography iPrOH Isopropyl Alcohol K3PO4 Tripotassium Phosphate KOH Potassium hydroxide LC-MS High-Performance Liquid Chromatography-Mass Spectrometry LiOH Lithium hydroxide MeOH Methanol MOST Morpholinosulfur trifluoride MsCl methanesulfonyl chloride MTBE Methyl tert-butyl ether N2 nitrogen NaH sodium hydride NBS N-Bromosuccinimide NH4OH Ammonium hydroxide NMP N-methylpyrrolidone NMR nuclear magnetic resonance NPLC normal phase liquid chromatography OMs O-mesylate OTs O-tosylate Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0) PdCl2(dppp) (1,3-bis(diphenylphosphino)propane)palladium(II) chloride (CAS#59831-02-6) PE Petroleum Ether psi pounds per square inch QphosPd(crotyl)Cl Chloro(crotyl)[1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene]palladium(II) (CAS#1252598-33-6) QToF quadrupole flight time RT room temperature RuPhos Pd G4 Methanesulfonato(2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (CAS#1599466-85-9) sat. saturation SEM-Cl 2-(trimethylsilyl)ethoxymethyl chloride sol. solution Sphos Pd G3 (2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]methanesulfonate palladium(II) (CAS#1445085-82-4) TBAF Tetrabutylammonium fluoride TBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tBuBrettPhos 2-(di-tert-butylphosphino)2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl (CAS#1160861-53-9) [tBuBrettPhos Pd(allyl)]Otf Allyl(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II) triflate (CAS#1798782-15-6) tBuXPhos Pd G3 [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]methanesulfonate palladium(II) (CAS#1447963-75-8) TEA Triethylamine Tf Trifle TFA trifluoroacetic acid TFAA Trifluoroacetic anhydride THF tetrahydrofuran TLC thin layer chromatography TMSCl Trimethylsilyl chloride TMSCN Trimethylsilyl cyanide Ts Tosil TsOH Tosylic acid Xantphos (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) XantPhos Pd G4 (6-Diphenylphosphanyl-10H-phenoxazin-4-yl)-diphenylphosphane; Methanesulfonic acid; N-methyl-2-phenylaniline; Palladium (CAS#1621274-19-8) Xphos 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0098] Example 1 1-[3-(Difluoromethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Step 1: 6-chloro-2-fluoro-nicotinaldehyde To a solution of diisopropylamine (16.7 g, 23.6 mL, 165.4 mmol, 1.45 eq.) in THF (110 mL) was added 1.6 M BuLi (92.7 mL, 148.2 mmol, 1.3 eq.) at −78°C over 20 min. The solution was cooled to −20°C and then recooled to −78°C. A solution of 2-chloro-6-fluoropyridine (15 g, 114.0 mmol, 1.0 eq.) in THF (220 mL) was added dropwise at −78°C over 30 min. The reaction mixture was stirred at −78°C for 1 h. DMF (10.0 g, 10.6 mL, 136.8 mmol, 1.2 eq.) was added dropwise at −78°C over 10 min. After stirring at -78 °C for 20 min, 4 M HCl in 1,4-dioxane (150 ml) was added until pH 1 was reached. The reaction mixture was poured into 400 mL of H2O. The layers were separated and the aqueous layer was washed with EtOAc. The organic layer was washed with H2O, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography eluting with EtOAc in heptane (0% to 100%) to give 6-chloro-2-fluoro-nicotinaldehyde (14.6 g, 80.0%) as a pale yellow solid. LC-ms: m / z = 156.06 [M+H] + ,ESI pos.

[0099] Step 2: 1-(6-chloro-3-formyl-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile Under an argon atmosphere, 6-chloro-2-fluoro-nicotinaldehyde (1.0 g, 6.27 mmol, 1.0 eq.) was dissolved in DMF (10 mL). 5-Methyl-1H-pyrazole-3-carbonitrile (738.5 mg, 6.9 mmol, 1.1 eq.) and K2CO3 (1.0 g, 7.5 mmol, 1.2 eq.) were added. The reaction mixture was stirred at room temperature for >1 h. The reaction mixture was partitioned between saturated aqueous NH4Cl and EtOAc, the product was extracted, the organic layer was dried over Na2SO4, and the volatiles were removed in vacuo. The crude product was triturated with EtOAc and a few drops of MeOH, filtered, washed with ether, and the solid was dried under high vacuum to give 1-(6-chloro-3-formyl-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile (590 mg, 22.9%) as an off-white solid. Flash column chromatography of the mother liquor using 0-30% EtOAc in heptane gave a second crop of 1-(6-chloro-3-formyl-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile (590 mg, 22.9%) as a white to pale yellow solid. LC-MS: m / z=247.0 [M+H] + ,ESI pos.

[0100] Step 3: 1-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile Under an argon atmosphere, 1-(6-chloro-3-formyl-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile (620 mg, 2.5 mmol, 1.0 eq.) was dissolved in DCM (11.8 mL). DAST (486.2 mg, 398.5 μL, 3.0 mmol, 1.2 eq.) was added at 0 °C, and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was partitioned between NaHCO3 solution and DCM, extracted, and the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography using 0-20% ethyl acetate as the eluent to give 1-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (597 mg, 88.4%) as a white solid. LC-MS: m / z=269.0 [M+H] + ,ESI pos.

[0101] Step 4: 1-[6-(5-bromobenzimidazol-1-yl)-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile Under an argon atmosphere, 1-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (820 mg, 3.1 mmol, 1.0 eq.) was dissolved in DMSO (23.4 mL). 5-Bromo-1H-benzimidazole (661.5 mg, 3.4 mmol, 1.1 eq.) and DBU (511.2 mg, 506.1 μL, 3.36 mmol, 1.1 eq.) were added, and the reaction mixture was stirred at 80 °C for 3 h. The reaction was cooled to room temperature and partitioned between HO and EtOAc. The product was extracted with EtOAc, and the organic layer was dried over NaSO and concentrated in vacuo. The crude product was purified by flash column chromatography using 0–4% MeOH in DCM as the eluent. A second flash column chromatography using 0-10% EtOAc in DCM separated the two regioisomeric products, affording 1-[6-(5-bromobenzimidazol-1-yl)-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (525 mg, 38.1%) and 1-[6-(6-bromobenzimidazol-1-yl)-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (497 mg, 36.0%) as white solids. LC-MS: m / z = 429.02 [M+H] + ,ESI pos.

[0102] Step 5: 1-[3-(difluoromethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; formic acid Under an argon atmosphere, 1-[6-(5-bromobenzimidazol-1-yl)-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (100 mg, 0.23 mmol, 1.0 eq.) was suspended in 1,4-dioxane (3 mL). (6-Methylpyridazin-3-yl)amine (50.9 mg, 0.47 mmol, 2.0 eq.) and Cs2CO3 (227.7 mg, 0.70 mmol, 3.0 eq.) were added. The reaction mixture was degassed with argon, and then [ tBuBrettPhos Pd(allyl)]OTf (18.2 mg, 0.023 mmol, 0.1 eq.) was added and the reaction mixture was stirred at 80° C. for more than 2 hours. t BuBrettPhos(Pd(allyl))]OTf (18.2 mg, 0.023 mmol, 0.1 eq.) was added, and the reaction mixture was stirred at 80 °C for 1 h or more to ensure complete reaction. The solvent was evaporated, and the crude product was purified by flash column chromatography using 0-5% MeOH in DCM. Further purification by reverse-phase chromatography with formic acid yielded an off-white lyophilized powder containing 1-[3-(difluoromethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; formic acid (25.0 mg, 21.3%). LC-MS: m / z = 458.2 [M+H] + ,ESI pos. 1-[3-(Difluoromethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; formate (15 mg, 12.8%) was also isolated as an off-white lyophilized powder. LC-MS: m / z=458.2 [M+H] + ,ESI pos.

[0103] Example 2 1-[3-(Difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] 1-[3-(Difluoromethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; formic acid (15 mg, 12.8%) was obtained as an off-white lyophilized powder in step 5 of Example 1. LC-MS: m / z=458.2 [M+H]+ ,ESI pos.

[0104] Example 3 1-[3-(Difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Step 1: 4-Bromo-5-methoxy-2-nitroaniline To a yellow suspension of 5-methoxy-2-nitroaniline (49.7 g, 295.6 mmol, 1.0 eq.) in CH3CN (750 mL) was added NBS (57.9 g, 325.2 mmol, 1.1 eq.) in portions. The mixture was stirred at 20 °C for 2 h. The reaction mixture was poured into saturated aqueous Na2SO3 (1 L) with stirring and then diluted with 2 L of HO. A yellow solid precipitated. The suspension was then filtered, and the filter cake was concentrated under reduced pressure to give the crude product. The crude product was triturated with MTBE (100 mL), and the resulting suspension was stirred for 30 min. The solid was collected by filtration and dried under reduced pressure to give 4-bromo-5-methoxy-2-nitroaniline (70.0 g, 95.5%) as a yellow solid. LC-MS: m / z = 247.0 / 249.0 [M + H]+,ESI pos. 1 H NMR(400MHz, CDCl3)δ=8.37(s,1H),6.26(brs,2H),6.19(s,1H),3.94(s,3H).

[0105] Step 2: 4-Bromo-5-methoxy-benzene-1,2-diamine To a yellow solution of 4-bromo-5-methoxy-2-nitroaniline (60.0 g, 242.87 mmol, 1.0 eq.) in THF (1.2 L) and MeOH (600 mL) was added NH4Cl (155.9 g, 2.9 mol, 12.0 eq.). The flask was purged with N2. To this mixture was added zinc (111.2 g, 1.7 mol, 7.0 eq.) in portions at 20 °C. After stirring for 2 h at 20 °C, the suspension was filtered, and the mother liquor was concentrated to give 4-bromo-5-methoxy-benzene-1,2-diamine (50.0 g, 94.9%) as a dark green solid. (The filter cake was dissolved in 2 L of 2 N HCl and stirred overnight to deactivate the residual zinc powder before discarding.) LC-MS: m / z = 216.8 / 218.8 [M+H] + ,ESI pos. 1 H NMR(400MHz, CDCl3)δ=6.91(s,1H),6.37(s,1H),3.82(s,3H),3.42-3.05(m,4H).

[0106] Step 3: 5-Bromo-6-methoxy-1H-benzimidazole 4-Bromo-5-methoxy-benzene-1,2-diamine (8.0 g, 36.86 mmol, 1.0 eq.) was dissolved in trimethyl orthoformate (39.1 g, 368.6 mmol, 10.0 eq.). Formic acid (6.95 mL, 184.3 mmol, 5.0 eq.) was added to the solution. The dark green solution was stirred at 90 °C for 2 h. The mixture was then quenched with saturated aqueous NaHCO (300 mL) and extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC (Phenomenex Luna C18 (250 mm x 70 mm, 10 μm), 10-30% CH3CN in HO (containing 0.225% HCOOH) for 15 min, flow rate: 140 mL / min) to give 5-bromo-6-methoxy-1H-benzimidazole (6.7 g, 72.1%) as a yellow solid. LC-MS: 227.0 / 229.0 [M+H] + ,ESI pos. 1H NMR(400MHz, CDCl3)δ=8.05(s,1H),7.89(s,1H),7.20(s,1H),3.97(s,3H).

[0107] Step 4: 1-[6-(5-bromo-6-methoxy-benzimidazol-1-yl)-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile To a solution of 1-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (300.0 mg, 1.1 mmol, 1.0 eq.) in DMSO (10 mL) was added 5-bromo-6-methoxy-1H-benzimidazole (278.9 mg, 1.2 mmol, 1.1 eq.) and DIPEA (0.55 mL, 3.35 mmol, 3.0 eq.). The reaction mixture was stirred at 120 °C for 30 h. The reaction was diluted with HO and EtOAc. The organic layer was washed with brine, dried over anhydrous NaSO, filtered, and concentrated to give a residue. The residue was purified by flash column chromatography using 40% to 60% EtOAc in PE as the eluent to give 1-[6-(6-bromo-5-methoxy-benzimidazol-1-yl)-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (110.0 mg, 21.5%) and 1-[6-(5-bromo-6-methoxy-benzimidazol-1-yl)-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (140.0 mg, 27.3%).

[0108] 1-[6-(6-Bromo-5-methoxy-benzimidazol-1-yl)-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile: LC-MS: m / z=458.8 [M+H] + , ESI pos. 1H NMR(400MHz,CDCl3)δ=8.40(s,1H),8.00(s,1H),7.71(d,J=8.50Hz,1H),7.53(s,1 H),7.26-6.98(m,1H),6.63(d,J=0.75Hz,1H),3.83(s,3H),2.47(d,J=0.63Hz,3H).

[0109] 1-[6-(5-Bromo-6-methoxy-benzimidazol-1-yl)-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile: LC-MS: m / z=458.8 [M+H] + , ESI pos. 1 H NMR(400MHz,CDCl3)δ=8.49(s,1H),8.37(d,J=8.50Hz,1H)8.21(s,1H),7.70(d,J=8.50H z,1H),7.32(s,1H),7.27-6.99(m,1H),6.64(d,J=0.75Hz,1H),3.92(s,3H),2.49(s,3H).

[0110] Step 5: 1-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile To a clear solution of 1-[6-(5-bromo-6-methoxy-benzimidazol-1-yl)-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (60.0 mg, 0.080 mmol, 1 eq.) in 1,4-dioxane (5 mL) was added 1-[6-(5-bromo-6-methoxy-benzimidazol-1-yl)-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (120.0 mg, 0.26 mmol, 1.0 eq.), [ tBuBrettPhos(Pd(allyl)]OTf (20.41 mg, 0.03 mmol, 0.1 eq.) and CsCO (255.41 mg, 0.78 mmol, 3.0 eq.) were added. The reaction mixture was stirred at 80 °C under a nitrogen atmosphere for 16 h. The mixture was diluted with HO and extracted with EtOAc. The organic layer was separated, dried over NaSO, and filtered. SiO-thiomet scavenger was added to the filtrate to remove palladium. The suspension was then filtered, and the filtrate was concentrated to give a residue. The residue was purified by preparative HPLC (Phenomenex Synergi C18 (50 × 25 mm, 10 μm), 14–44% CHCN (containing 0.225% HCOOH) in HO for 10 min, flow rate: 25 mL / min). After lyophilization, 1-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (20.9 mg, 16.4% yield) was obtained as a white solid. LC-MS: m / z=488.0 [M+H] + ,ESI pos. 1 H NMR(400MHz,DMSO-d6)δ=9.01(s,1H)8.80(s,1H)8.61-8.59(d,J=8.56Hz,1H)8.46(brd,J=1.10Hz,1H )8.37(d,J=8.44Hz,1H)7.83(s,1H)7.35(s,2H)7.25-6.98(m,2H)3.87(s,3H)2.51(s,3H)2.48(s,3H).

[0111] Example 4 1-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(2-morpholinoethoxy)benzimidazol-5-amine [ka] Step 1: 6-chloro-3-(difluoromethyl)-2-fluoro-pyridine To a solution of 6-chloro-2-fluoro-pyridine-3-carbaldehyde (2.0 g, 12.54 mmol, 1.0 eq.) in DCM (20 mL) was added DAST (5.0 mL, 37.6 mmol, 3.0 eq.) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was poured into saturated NaHCO3 solution with stirring and extracted with DCM. The combined extracts were concentrated in vacuo to give 6-chloro-3-(difluoromethyl)-2-fluoropyridine (2.0 g, 87.9%) as a yellow oil. LC-MS: m / z = 182.0 [M+H] + ,ESI pos. 1 H NMR(400MHz,DMSO-d6)δ=8.28(t,J=8.7Hz,1H),7.68(d,J=7.9Hz,1H),7.40-7.06(m,1H).

[0112] Step 2: 6-chloro-3-(difluoromethyl)-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine A solution of 6-chloro-3-(difluoromethyl)-2-fluoropyridine (900.0 mg, 5.0 mmol, 1.0 eq.), 3-(difluoromethyl)-5-methyl-1H-pyrazole (655.0 mg, 5.0 mmol, 1.0 eq.), and DIPEA (2.5 mL, 14.9 mmol, 3.0 eq.) in DMSO (10 mL) was stirred at 100 °C for 12 h. The reaction mixture was poured into HO and extracted with EtOAc. The organic phase was washed with brine, and the combined extracts were concentrated in vacuo to give a residue. The residue was purified by flash column chromatography using 10% EtOAc in PE as the eluent to give a mixture of regioisomers. The mixture was purified by preparative NPLC and concentrated under reduced pressure to give 6-chloro-3-(difluoromethyl)-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine (200.0 mg, 13.7%) as a white solid. LC-MS: m / z=294.1 [M+H] + ,ESI pos. 1H NMR(400MHz,CDCl3)δ=8.17(d,J=8.3Hz,1H),7.51(d,J=8.3Hz,1H),7.33-7.06(s,1H),6.83-6.52(m,1H),6.48(s,1H),2.53(s,3H).

[0113] Step 3: 4-[2-[6-bromo-3-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-2-pyridyl]benzimidazol-5-yl]oxyethyl]morpholine To a solution of 4-[2-[(6-bromo-3H-benzimidazol-5-yl)oxy]ethyl]morpholine (166.6 mg, 0.5 mmol, 1.0 eq.) in DMSO (4 mL) was added 6-chloro-3-(difluoromethyl)-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine (150.0 mg, 0.51 mmol, 1.0 eq.) and K2CO3 (211.78 mg, 1.53 mmol, 3.0 eq.). The reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was poured into 50 mL of H2O with stirring and extracted with EtOAc. The organic phase was washed with brine. The combined organic phase was concentrated in vacuo to give a residue. The residue was purified by preparative TLC and concentrated under reduced pressure to give a yellow solid as 4-[2-[6-bromo-1-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methylpyrazol-1-yl]-2-pyridyl]benzimidazol-5-yl]oxyethyl]morpholine (130.0 mg, 43.6%) and 4-[2-[6-bromo-3-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methylpyrazol-1-yl]-2-pyridyl]benzimidazol-5-yl]oxyethyl]morpholine (130.0 mg, 43.6%).

[0114] 4-[2-[6-Bromo-1-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-2-pyridyl]benzimidazol-5-yl]oxyethyl]morpholine: LC-MS: 585.1 [M+H] + ,ESI pos. 1H NMR(400MHz,DMSO-d6)δ=9.06(s,1H),8.59(d,J=8.7Hz,1H),8.30(d,J=8.6Hz,1H),8.04(s,1H),7.90(s,1H),7.34-6. 90(m,2H),6.70(s,1H),4.11(t,J=6.0Hz,2H),3.58-3.54(m,4H),2.74(t,J=6.1Hz,2H),2.52(brs,4H),2.47(brs,3H).

[0115] 4-[2-[6-Bromo-3-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-2-pyridyl]benzimidazol-5-yl]oxyethyl]morpholine: LC-MS: 585.1 [M+H] + ,ESI pos. 1 H NMR(400MHz,DMSO-d6)δ=9.17(s,1H),8.56(d,J=8.7Hz,1H),8.46(s,1H),8.29(d,J=8.6Hz,1H),7.56(s,1H),7.29-6.91( m,2H),6.76(s,1H),4.25(t,J=5.6Hz,2H),3.62-3.54(m,4H),2.77(t,J=5.5Hz,2H),2.56-2.53(m,4H),2.49-2.49(m,3H)

[0116] Step 4: 1-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(2-morpholinoethoxy)benzimidazol-5-amine To a solution of 5-amino-2-methylpyridine (48.2 mg, 0.45 mmol, 2.0 eq.) and 4-[2-[6-bromo-3-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-2-pyridyl]benzimidazol-5-yl]oxyethyl]morpholine (130.0 mg, 0.22 mmol, 1.0 eq.) in 1,4-dioxane (4 mL) was added CsCO (217.82 mg, 0.67 mmol, 3.0 eq.). The flask was purged with N and [t BuBrettPhos(Pd(allyl)]OTf (17.41 mg, 0.02 mmol, 0.1 eq.) was added to the mixture and stirred at 80 °C for 4 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Phenomenex C18 (75 × 30 mm, 3 μm), 8–38% CH3CN (containing 0.225% HCOOH) in HO for 7 min, flow rate: 25 mL / min). The fractions were lyophilized to give a yellow solid as 1-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methylpyrazol-1-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(2-morpholinoethoxy)benzimidazol-5-amine (79.2 mg, 58.1%). LC-MS: m / z=612.2 [M+H] + ,ESI pos. 1 H NMR(400MHz,DMSO-d6)δ=9.01(s,1H),8.66(s,1H),8.57(d,J=8.6Hz,1H),8.33-8.26(m,2H),7.90(s,1H),7.37-7.32(m,1H),7.31-6. 94(m,3H),6.72(s,1H),4.16(t,J=6.1Hz,2H),3.56-3.52(m,4H),2.73(t,J=6.0Hz,2H),2.53(s,3H),2.49(s,3H),2.43-2.38(m,4H).

[0117] Example 5 1-[3-(Difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Step 1: 4-Bromo-2-nitro-5-(oxetan-3-yloxy)aniline To a mixture of oxetan-3-ol (473.0 mg, 6.4 mmol, 1.5 eq.) in THF (50 mL) was added 60% NaH in mineral oil (256.0 mg, 6.4 mmol, 1.5 eq.) portionwise at 0 °C. The reaction mixture was stirred at 0 °C for 30 min under a N atmosphere. Next, 4-bromo-5-fluoro-2-nitroaniline (1.0 g, 4.3 mmol, 1.0 eq.) was added, and the reaction mixture was further stirred at 25 °C for 12 h. The reaction was quenched with saturated aqueous NH Cl and extracted with EtOAc. The organic layer was dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography using 0-10% EtOAc in PE as the eluent to give 4-bromo-2-nitro-5-(oxetan-3-yloxy)aniline (1.1 g, 89.4%) as a white solid. LC-MS: m / z=289.1 [M+H] + ,ESI pos. 1 H NMR(400MHz,DMSO-d6)δ=8.15(s,1H),7.56(brs,2H),6.20(s,1H),5.31(brt,J=5.3Hz,1H),4.93(t,J=6.8Hz,2H),4.64-4.54(m,2H).

[0118] Step 2: 4-Bromo-5-(oxetan-3-yloxy)benzene-1,2-diamine To a solution of 4-bromo-2-nitro-5-(oxetan-3-yloxy)aniline (1.0 g, 3.5 mmol, 1.0 eq.) in EtOH (9 mL) was added iron (965.8 mg, 17.3 mmol, 5.0 eq.), NH4Cl (1.85 g, 34.6 mmol, 10.0 eq.), and HO (3 mL). The reaction mixture was stirred under N2 at 50 °C for 2 h. The reaction mixture was filtered, and the filtrate was poured into HO and extracted with EtOAc. The combined organic extracts were concentrated in vacuo to give 4-bromo-5-(oxetan-3-yloxy)benzene-1,2-diamine (800.0 mg, 89.3%) as a brown oil. LC-MS: m / z = 283.1 [M+H] + ,ESI pos.

[0119] Step 3: 5-Bromo-6-(oxetan-3-yloxy)-1H-benzimidazole To a solution of TsOH (47.5 mg, 0.3 mmol, 0.1 eq.) in EtOH (15 mL), 4-bromo-5-(oxetan-3-yloxy)benzene-1,2-diamine (800.0 mg, 3.1 mmol, 1.0 eq.) and trimethyl orthoformate (3.4 mL, 30.9 mmol, 10.0 eq.) were added, and the mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with NaHCO and extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography using 70% ethyl acetate as the eluent to give 5-bromo-6-(oxetan-3-yloxy)-1H-benzimidazole (600.0 mg, 72.2%) as a yellow oil. LC-MS: m / z = 271.0 [M+H] + ,ESI pos. 1 H NMR(400MHz, CDCl3)δ=8.02(s,1H),7.88(s,1H),6.78(s,1H),5.29(quin,J=5.6Hz,1H),5.04(t,J=6.8Hz,2H),4.91-4.88(m,2H).

[0120] Step 4: 1-[6-[5-bromo-6-(oxetan-3-yloxy)benzimidazol-1-yl]-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile To a solution of 5-bromo-6-(oxetan-3-yloxy)-1H-benzimidazole (300.5 mg, 1.12 mmol, 1.0 eq.) in DMSO (6 mL) was added 1-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (300.0 mg, 1.12 mmol, 1.0 eq.) and K2CO3 (462.98 mg, 3.35 mmol, 3.0 eq.). The reaction mixture was stirred at 50 °C for 4 h. The reaction mixture was poured into H2O and extracted with EtOAc. The organic layer was washed with brine, and the combined extracts were concentrated in vacuo. The residue was purified by flash column chromatography using ethyl acetate as a solvent to give 1-[6-[6-bromo-5-(oxetan-3-yloxy)benzimidazol-1-yl]-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (200.0 mg, 35.7%) as a white solid and 1-[6-[5-bromo-6-(oxetan-3-yloxy)benzimidazol-1-yl]-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (200.0 mg, 35.7%) as a yellow solid.

[0121] 1-[6-[6-bromo-5-(oxetan-3-yloxy)benzimidazol-1-yl]-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile: LC-MS: m / z=503.1 [M+H] + ,ESI pos. 1 H NMR(400MHz,DMSO-d6)δ=9.11(s,1H),8.64(d,J=8.6Hz,1H),8.35(d,J=8.5Hz,1H),8.09(s,1H),7.44(s,1H),7.23(s,1H),7.19( d,J=0.8Hz,1H),7.10(s,1H),6.96(s,1H),5.24(quin,J=5.4Hz,1H),4.74-4.67(m,2H),4.61(dd,J=5.0,7.4Hz,2H),2.42(s,3H).

[0122] 1-[6-[5-Bromo-6-(oxetan-3-yloxy)benzimidazol-1-yl]-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile: LC-MS: 503.1 [M+H] + ,ESI pos. 1 H NMR(400MHz,DMSO-d6)δ=9.18(s,1H),8.60(d,J=8.6Hz,1H),8.47(s,1H),8.35(d,J=8.6Hz,1H),7.22(s,1H),7.20(s,1H),7.17( s,1H),7.09(s,1H),6.95(s,1H),5.45(quin,J=5.4Hz,1H),5.02(t,J=6.7Hz,2H),4.60(dd,J=5.0,7.1Hz,2H),2.49-2.48(m,3H)

[0123] Step 5: 1-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile Prepared according to step 4 of example 4, 1-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (19.1 mg, 8.9%) was obtained as a yellow solid after purification by preparative HPLC. LC-MS: m / z=530.2 [M+H] + ,ESI pos. 1 H NMR(400MHz,DMSO-d6)δ=9.04(s,1H),8.84(s,1H),8.60(d,J=8.6Hz,1H),8.40-8.30(m,2H),7.38 -6.95(m,5H),5.24(quin,J=5.3Hz,1H),4.72(brd,J=5.5Hz,4H),2.53-2.51(m,3H),2.44(s,3H).

[0124] Example 6 1-[5-(difluoromethyl)-6-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine [ka] Step 1: 2,6-Dichloro-3-(1,3-dioxolan-2-yl)pyridine In a 250 mL three-neck flask equipped with a Dean-Stark trap, a strong condenser, and a thermometer, 2,6-dichloronicotinaldehyde (3.75 g, 19.2 mmol, 1.0 eq.) was dissolved in toluene (100 mL). Ethan-1,2-diol (1.8 g, 1.6 mL, 28.7 mmol, 1.5 eq.) and pTsOH (91.1 mg, 479 μmol, 0.025 eq.) were then added. The orange solution was heated at reflux overnight while azeotropically removing HO using a Dean-Stark trap. Once the mixture had cooled, it was concentrated in vacuo. The residual material was diluted with EtOAc and saturated aqueous NaHCO3. The organic layer was separated and washed with HO. The organic layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by flash column chromatography using 0–50% EtOAc in heptane as the eluent. The title compound, 2,6-dichloro-3-(1,3-dioxolan-2-yl)pyridine (3.85 g, 91.3%), was obtained as a pale yellow oil. LC-MS: m / z=220.1 [M+H] + ,ESI pos.

[0125] Step 2: 1-[6-chloro-5(1,3-dioxolan-2-yl)-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine (5.12 g, 22.72 mmol, 1.0 eq.), 2,6-dichloro-3-(1,3-dioxolan-2-yl)pyridine (5.0 g, 22.72 mmol, 1.0 eq.), KCO (6.28 g, 45.44 mmol, 2.0 eq.), and DMSO (50 mL) were mixed and stirred at 60 °C for 24 h. The filtrate was diluted with HO and extracted with ethyl acetate. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography using 10% MeOH in DCM to give 1-[6-chloro-5-(1,3-dioxolan-2-yl)-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (1.0 g, 10.8%) as a brown solid. LC-MS: m / z=409.1 [M+H] + ,ESI pos.

[0126] Step 3: 2-chloro-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbaldehyde To a solution of 1-[6-chloro-5-(1,3-dioxolan-2-yl)-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (600.0 mg, 1.5 mmol, 1.0 eq.) in HCl / dioxane (8.0 mL, 32.0 mmol, 21.8 eq.) was added HCl (8.0 mL, 48.0 mmol, 32.71 eq.) at 25° C., and the resulting mixture was stirred for 2 h at 25° C. The reaction mixture was filtered, and the filter cake was dissolved in HO and lyophilized to give a yellow solid, 2-chloro-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbaldehyde (530.0 mg, 99.0%). LC-MS: m / z=365.1 [M+H] + ,ESI pos.

[0127] Step 4: 1-[6-chloro-5-(difluoromethyl)-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine To a solution of 2-chloro-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbaldehyde (400.0 mg, 1.1 mmol, 1.0 eq.) in DCM (10 mL) was added DAST (2831.5 mg, 17.5 mmol, 16.0 eq.) at 25 °C, and the resulting mixture was stirred at 25 °C for 2 h. An additional DAST (530.9 mg, 3.29 mmol, 3.0 eq.) was added over 2 h. The reaction mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product 1-[6-chloro-5-(difluoromethyl)-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (300.0 mg, 70.7%) as a yellow solid. LC-MS: m / z=387.1 [M+H] + ,ESI pos. 1 H NMR(400MHz,DMSO-d6)δ=9.81(s,1H),9.10(s,1H),8.44-8.35(m,2H),8.31(d,J=8.8Hz,1H),8.16( d,J=8.4Hz,1H),7.64(d,J=9.2Hz,1H),7.52(dd,J=2.0,8.8Hz,1H),7.43-7.16(m,2H),2.55(s,3H).

[0128] Step 5: 4-Bromo-3-methyl-1-(2,2,2-trifluoroethyl)pyrazole 4-Bromo-3-methylpyrazole (15.0 g, 93.2 mmol, 1.0 eq.), 2,2,2-trifluoroethyltrifluoromethanesulfonate (22.7 g, 97.8 mmol, 1.05 eq.), and CsCO (25.3 g, 186.3 mmol, 2.0 eq.) were dissolved in DMF (150 mL) and stirred at 100 °C for 12 h. The reaction mixture was filtered, and the filtrate was diluted with HO and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography using a gradient of 11–17% EtOAc in PE as the eluent to give a mixture of 4-bromo-3-methyl-1-(2,2,2-trifluoroethyl)pyrazole and 4-bromo-5-methyl-1-(2,2,2-trifluoroethyl)pyrazole (19.5 g, 86.1%) as a colorless oil. LC-MS: m / z = 242.9 [M + H]+,ESI pos. 1 H NMR(400MHz,DMSO-d6)δ=8.00(s,1H),5.09-4.99(m,2H),2.14(s,3H).

[0129] Step 6: 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)pyrazole To a mixture of 4-bromo-3-methyl-1-(2,2,2-trifluoroethyl)pyrazole (11.0 g, 45.26 mmol, 1.0 eq.), 4-bromo-5-methyl-1-(2,2,2-trifluoroethyl)pyrazole, KOAc (5.7 mL, 90.5 mmol, 2.0 eq.), and bis(pinacolato)diboron (13.79 g, 54.3 mmol, 1.2 eq.) in 1,4-dioxane (200 mL), Pd(dppf)Cl CHCl (3.7 g, 4.53 mmol, 0.1 eq.) was added and stirred at 100 °C under a N atmosphere for 16 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography using 10-20% EtOAc in heptane as the eluent to give a yellow gummy mixture of 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)pyrazole and 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)pyrazole (18.0 g, >100% yield, crude). LC-MS: m / z = 291.1 [M+H] + ,ESI pos

[0130] Step 7: 1-[5-(difluoromethyl)-6-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine and 1-[5-(difluoromethyl)-6-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine A mixture of 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)pyrazole (45.0 mg, 0.16 mmol, 1.5 eq.) and 1-[6-chloro-5-(difluoromethyl)-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (40.0 mg, 0.1 mmol, 1.0 eq.) in THF (2 mL) and HO (0.5 mL) was added to Sphos Pd G3 (9.1 mg, 0.01 mmol, 0.1 eq.) and K3PO4 (43.9 mg, 0.21 mmol, 2.0 eq.) and stirred at 60 °C under N2 atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give 1-[5-(difluoromethyl)-6-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine and 1-[5-(difluoromethyl)-6-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (20.0 mg, 37.6%) as a yellow solid. LC-MS: m / z=515.3 [M+H] + ,ESI pos.

[0131] The mixture was separated into its two regioisomers using SFC (MeOH (0.1% NH4OH) dissolved in CO2 on a Daicel Chiralpak AS (250 mm × 30 mm, 10 μm)) to give 1-[5-(difluoromethyl)-6-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (9.5 mg, 16.1%) and 1-[5-(difluoromethyl)-6-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (3.5 mg, 17.5%) as white solids.

[0132] 1-[5-(difluoromethyl)-6-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine: LC-MS: m / z=515.2 [M+H] + ,ESI pos. 1 H NMR(400MHz,CD3OD)δ=8.92(s,1H),8.36(d,J=8.8Hz,1H),8.28-8.14(m,2H),8.01(s,1H),7.95(d,J=8.8Hz,1H),7.61(dd,J=2. 0,8.8Hz,1H),7.35(d,J=9.2Hz,1H),7.13(d,J=9.2Hz,1H),6.99-6.61(m,1H),5.00(q,J=8.8Hz,2H),2.53(s,3H),2.42(s,3H).

[0133] 1-[5-(difluoromethyl)-6-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine: LC-MS: m / z=515.2 [M+H] + ,ESI pos. 1 H NMR(400MHz,CD3OD)δ=8.91(s,1H),8.36(d,J=8.8Hz,1H),8.27-8.12(m,2H),7.95(d,J=8.4Hz,1H),7.80(s,1H),7.61(d d,J=2.0,9.2Hz,1H),7.35(d,J=9.2Hz,1H),7.12(d,J=9.2Hz,1H),7.01-6.67(m,1H),5.05(q,J=8.4Hz,2H),2.53(s,6H).

[0134] Example 7 3-(Difluoromethyl)-1-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-N,N,5-trimethyl-pyrazole-4-carboxamide [ka] Step 1: 1-[6-chloro-3-(difluoromethyl)-2-pyridyl]-3-(difluoromethyl)-N,N,5-trimethyl-pyrazole-4-carboxamide

[0135] To a solution of 6-chloro-3-(difluoromethyl)-2-fluoropyridine (68 mg, 0.375 mmol, 1.0 eq.) in DMF (0.6 mL) was added 3-(difluoromethyl)-N,N,5-trimethyl-1H-pyrazole-4-carboxamide (83.7 mg, 0.41 mmol, 1.1 eq.) and K2CO3 (51.8 mg, 0.375 mmol, 1.0 eq.). The reaction mixture was stirred at room temperature for more than 16 h. The filtrate was diluted with HO and extracted with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography using 0-50% EtOAc in heptane as the eluent to give 1-[6-chloro-3-(difluoromethyl)-2-pyridyl]-3-(difluoromethyl)-N,N,5-trimethyl-pyrazole-4-carboxamide (74.4 mg, 46.8%) as a pale yellow liquid. LC-MS: m / z=365.1 [M+H] + ,ESI pos.

[0136] Step 2: 3-(Difluoromethyl)-1-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-N,N,5-trimethyl-pyrazole-4-carboxamide 1-[6-chloro-3-(difluoromethyl)-2-pyridyl]-3-(difluoromethyl)-N,N,5-trimethyl-pyrazole-4-carboxamide (64.7 mg, 0.177 mmol, 1.0 eq.), (6-methoxy-1H-benzimidazol-5-yl)-(6-methylpyridazin-3-yl)amine (54.3 mg, 0.21 mmol, 1.2 eq.) and K3PO4 (113.0 mg, 0.53 mmol, 3.0 eq.) were added at room temperature. tThe mixture was dissolved in AmOH (1.36 mL) and purged with argon for 5 minutes. t BuXPhos Pd G3 (14.09 mg, 0.018 mmol, 0.100 eq.) was added, the vial was sealed, and the mixture was heated at 80 °C for 16 h. The reaction was cooled to 23 °C and extracted with DCM and HO. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using 0-10% MeOH in DCM to give a pale yellow solid: 3-(difluoromethyl)-1-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-N,N,5-trimethyl-pyrazole-4-carboxamide (36.1 mg, 33.2%). LC-MS: m / z = 584.3 [M+H] + ,ESI pos.

[0137] The isomeric 3-(difluoromethyl)-1-[3-(difluoromethyl)-6-[5-methoxy-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-N,N,5-trimethyl-pyrazole-4-carboxamide (45.8 mg, 42.0%) was also isolated as a pale yellow solid. LC-MS: m / z=584.3 [M+H] + ,ESI pos.

[0138] Example 8 5-(Difluoromethoxy)-2-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]pyrazole-3-carbonitrile [ka] Step 1: 3-(Difluoromethoxy)-1H-pyrazole-5-carboxamide To a stirred solution of 3-(difluoromethoxy)-1H-pyrazole-5-carboxylic acid (200 mg, 1.12 mmol, 1.0 eq.) in DMF (5.25 mL) at room temperature under an argon atmosphere was added CDI (236.7 mg, 1.5 mmol, 1.3 eq.). After stirring at room temperature for 3 h, NH4OH (2.25 g, 2.5 mL, 64.3 mmol, 20 eq.) was added and stirring was continued for 90 min. A second batch of CDI (236.73 mg, 1.46 mmol, 1.3 eq.) was added and the reaction mixture was stirred overnight. The filtrate was diluted with HO and extracted with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography using 20-100% EtOAc in heptane as the eluent to give 3-(difluoromethoxy)-1H-pyrazole-5-carboxamide (133.7 mg, 63.8%) as a white solid. LC-MS: m / z = 178.1 [M+H] + , ESI pos.

[0139] Step 2: 3-(Difluoromethoxy)-1H-pyrazole-5-carbonitrile To a stirred solution of 3-(difluoromethoxy)-1H-pyrazole-5-carboxamide (133.7 mg, 0.755 mmol, 1.0 eq.) and EtN (229.2 mg, 316 μL, 2.26 mmol, 3.0 eq.) in DCM (7.3 mL) at room temperature under an argon atmosphere, TFAA (475.7 mg, 320 μL, 2.26 mmol, 3.0 eq.) was carefully added. The mixture immediately became a clear, pale yellow solution, with white smoke emanating above it. Stirring was continued at room temperature for 30 min. The reaction mixture was concentrated with isolute and purified by flash column chromatography using 0-80% EtOAc in heptane as the eluent to give 3-(difluoromethoxy)-1H-pyrazole-5-carbonitrile (98.6 mg, 78.0%) as a colorless liquid. LC-MS: m / z = 160.0 [M+H] + ,ESI pos.

[0140] Step 3: 2-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-(difluoromethoxy)pyrazole-3-carbonitrile To a solution of 6-chloro-3-(difluoromethyl)-2-fluoropyridine (101.7 mg, 0.56 mmol, 1.0 eq.) in DMF (0.9 mL) was added 3-(difluoromethoxy)-1H-pyrazole-5-carbonitrile (98.0 mg, 0.62 mmol, 1.1 eq.) and K2CO3 (77.4 mg, 0.56 mmol, 1.000 eq.). The reaction mixture was heated to 50 °C and stirred for 4 h. The mixture was cooled to 20 °C, diluted with HO, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure.

[0141] The crude product was added to 1 g of isolute HM-N solute and purified by flash column chromatography using 0-50% EtOAc in heptane as the eluent to give 2-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-(difluoromethoxy)pyrazole-3-carbonitrile (138 mg, 76.6%) as a pale yellow solid. LC-MS: m / z = 320.0 [M] + ,ESI pos.

[0142] Step 4: 5-(Difluoromethoxy)-2-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]pyrazole-3-carbonitrile Prepared according to step 2 of example 7 to give 5-(difluoromethoxy)-2-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]pyrazole-3-carbonitrile (30.4 mg, 25.2%) as a yellow solid. LC-MS: m / z=540.3 [M+H] + ,ESI pos. The isomeric 5-(difluoromethoxy)-2-[3-(difluoromethyl)-6-[5-methoxy-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]pyrazole-3-carbonitrile (59.5 mg, 49.9%) was also isolated as a pale yellow solid. LC-MS: m / z = 540.3 [M+H] + , ESI pos.

[0143] Example 9 1-[3-(Difluoromethyl)-6-[6-methoxy-5-[(6-tetrahydrofuran-3-ylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Step 1: 1-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-tetrahydrofuran-3-ylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile Prepared according to step 4 of example 4 to give 1-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-tetrahydrofuran-3-ylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (32.0 mg, 50.8% yield) as a yellow solid. LC-MS: m / z=544.3 [M+H] + ,ESI pos.

[0144] Example 10 6-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]amino]-N,N-dimethyl-pyridazine-3-carboxamide [ka] Step 1: 6-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]amino]-N,N-dimethyl-pyridazine-3-carboxamide

[0145] Prepared according to step 4 of example 4 to give 6-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]amino]-N,N-dimethyl-pyridazine-3-carboxamide (27 mg, 43.7%) as an off-white solid. LC-MS: m / z=545.43 [M+H] + ,ESI pos.

[0146] Example 11 3-[[1-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide [ka] Step 1: 3-[[1-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide Prepared according to step 4 of Example 4, 3-[[1-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide (6.7 mg, 18.6%) was purified by preparative HPLC (Phenomenex C18 (150 × 25 mm, 10 μm), 29-59% CH3CN (containing 0.225% HCOOH) in HO for 10 min at a flow rate of 25 mL / min) as a yellow solid. LC-MS: m / z = 600.2 [M+H] + ,ESI pos. 1 H NMR(400MHz,DMSO-d6)δ=8.96(s,1H),8.84(s,1H),8.51(d,J=8.6Hz,1H),8.38(s,1H),8.22(d,J=8.5Hz,1H),7.8 4(s,1H),7.64-7.17(m,3H),6.27(s,1H),3.89(s,3H),3.03(brd,J=18.8Hz,6H),2.55(s,3H),2.53-2.52(m,3H).

[0147] Example 12 1-[5-(difluoromethyl)-6-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine [ka] 1-[5-(Difluoromethyl)-6-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (3.5 mg, 17.5% yield) was separated from its isomers by SFC as described in Step 7 of Example 6 and obtained as a white solid. LC-MS: m / z=515.2 [M+H] + ,ESI pos. 1H NMR(400MHz,CD3OD)δ=8.91(s,1H),8.36(d,J=8.8Hz,1H),8.27-8.12(m,2H),7.95(d,J=8.4Hz,1H),7.80(s,1H),7.61(d d,J=2.0,9.2Hz,1H),7.35(d,J=9.2Hz,1H),7.12(d,J=9.2Hz,1H),7.01-6.67(m,1H),5.05(q,J=8.4Hz,2H),2.53(s,6H).

[0148] Example 13 1-[5-(Difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine [ka] Step 1: 5-Bromo-1-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-2-pyridyl]-6-(oxetan-3-yloxy)benzimidazole A solution of 6-chloro-3-(difluoromethyl)-2-[3-(difluoromethyl)-5-methylpyrazol-1-yl]pyridine (360.0 mg, 1.23 mmol, 1.0 eq.), 5-bromo-6-(oxetan-3-yloxy)-1H-benzimidazole (329.89 mg, 1.23 mmol, 1.0 eq.), and KCO (508.3 mg, 3.68 mmol, 3.0 eq.) in DMSO (10 mL) was stirred at 50 °C for 16 h. The reaction mixture was cooled to 23 °C, diluted with HO (50 mL), and extracted with EtOAc (30 mL × 3). The organic layers were combined, washed with brine (50 mL × 3), and concentrated in vacuo. The residue was purified by flash column chromatography using 0-50% EtOAc in heptane as the eluent to give 5-bromo-1-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methylpyrazol-1-yl]-2-pyridyl]-6-(oxetan-3-yloxy)benzimidazole (300.0 mg, 46.5%) as a yellow solid. LC-MS: m / z=527.7 [M+H] + ,ESI pos. 1 H NMR(400MHz,CDCl3)δ=8.48(s,1H),8.46(d,J=8.4Hz,1H),8.11(s,1H),7.70(d,J=8.4Hz,1H),7.31(s,1H),7.17(t ,J=55.2Hz,1H),6.77(t,J=54.8Hz,1H),6.61(s,1H),5.16(quin,J=5.6Hz,1H),4.85(d,J=5.7Hz,4H),2.50(s,3H).

[0149] The isomeric 6-bromo-1-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-2-pyridyl]-5-(oxetan-3-yloxy)benzimidazole (300.0 mg, 46.5%) was also isolated as a white solid. LC-MS: m / z=527.7 [M+H] + ,ESI pos. 1H NMR(400MHz,CDCl3)δ=8.59(s,1H),8.44(brd,J=8.3Hz,1H),8.35(s,1H),7.73(brd,J=8.4Hz,1H),7.25(t,J=55.2Hz,1H),6.95(s,1 H),6.73(brt,J=54.8Hz,1H),6.57(s,1H),5.34(quin,J=5.4Hz,1H),5.08(brt,J=6.7Hz,2H),4.90(brt,J=6.1Hz,2H),2.58(s,3H).

[0150] Step 2: 1-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine Prepared according to step 4 of Example 4, 1-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine (106.7 mg, 0.19 mmol, 32.07% yield) was obtained as a yellow solid after purification by preparative HPLC (Phenomenex Synergi Max-RP (250x50 mm, 10 μm), 15-45% CHCN (containing HCOOH) in HO, 21 min, flow rate: 100 mL / min). LC-MS: m / z=555.2 [M+H] + ,ESI pos. 1 H NMR(400MHz,CDCl3)δ=8.51(s,1H),8.44(brd,J=8.1Hz,1H),8.35(s,1H),7.73(brd,J=8.2Hz,1H),7.32-7.28(m,2H),7.26-7.00 (m,2H),6.77(t,J=54.8Hz,1H),6.61(s,1H),5.22-5.16(m,1H),4.90-4.84(m,2H),4.83-4.76(m,2H),2.64(s,3H),2.51(s,3H).

[0151] Example 14 1-[3-(Difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-fluoro-pyrazole-3-carbonitrile [ka] Step 1: 1-(6-chloro-3-formyl-2-pyridyl)-5-fluoro-pyrazole-3-carboxylic acid ethyl ester Prepared according to step 2 of example 1 to give 1-(6-chloro-3-formyl-2-pyridyl)-5-fluoro-pyrazole-3-carboxylic acid ethyl ester (231 mg, 61.9%) as an off-white solid. LC-MS: m / z=298.1 [M+H] + ,ESI pos.

[0152] Step 2: 1-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-fluoro-pyrazole-3-carboxylic acid ethyl ester Prepared according to step 3 of example 1 to give 1-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-fluoro-pyrazole-3-carboxylic acid ethyl ester (280 mg, 82.8%) as a pale yellow oil. LC-MS: m / z=320.1 [M+H] + ,ESI pos.

[0153] Step 3: 1-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-fluoro-pyrazole-3-carboxylic acid Under an argon atmosphere, 1-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-fluoro-pyrazole-3-carboxylic acid ethyl ester (280 mg, 0.88 mmol, 1.0 eq.) was dissolved in THF (14.5 mL). At room temperature, 1 M LiOH in HO (1.31 mL, 1.31 mmol, 1.5 eq.) was added, and the reaction mixture was stirred at room temperature for 1.5 hours. To neutralize the reaction mixture, saturated aqueous NH4Cl was added, the volatiles were evaporated, and the crude product was purified by reverse-phase chromatography using formic acid to give 1-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-fluoro-pyrazole-3-carboxylic acid (255 mg, 99.8%) as a yellow lyophilized powder. LC-MS: m / z = 292.1 [M+H] + ,ESI pos.

[0154] Step 4: 1-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-fluoro-pyrazole-3-carboxamide Under an argon atmosphere, 1-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-fluoro-pyrazole-3-carboxylic acid (255 mg, 0.88 mmol, 1.0 eq.) was dissolved in DMF (4.13 mL). 25% aqueous NH4OH (65.5 mg, 83.3 μL, 0.96 mmol, 1.1 eq.), DIPEA (226.1 mg, 289.8 μL, 1.75 mmol, 2.0 eq.), and TBTU (505.4 mg, 1.6 mmol, 1.8 eq.) were added. The reaction mixture was stirred at room temperature for 2 hours. TBTU (505.4 mg, 1.6 mmol, 1.8 eq.) and 25% aqueous NH4OH (65.5 mg, 83.3 μL, 0.92 mmol, 1.1 eq.) were added again, and the reaction mixture was stirred at room temperature for 2 hours. A few drops of HO were added and the crude product was purified by reverse phase chromatography under neutral conditions to give 1-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-fluoro-pyrazole-3-carboxamide (224 mg, 42.3%) as an off-white lyophilized powder. LC-MS: m / z = 291.0 [M+H] + ,ESI pos.

[0155] Step 5: 1-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-fluoro-pyrazole-3-carbonitrile Under an argon atmosphere, 1-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-fluoro-pyrazole-3-carboxamide (224 mg, 0.77 mmol, 1.0 eq.) was dissolved in DCM (4.3 mL). TEA (234.0 mg, 322 μL, 2.31 mmol, 3.000 eq.) and TFAA (485.6 mg, 327 μL, 2.31 mmol, 3.0 eq.) were added, and the reaction mixture was stirred at room temperature for 3 h. The volatiles were evaporated, and the crude product was purified by reverse-phase chromatography under neutral conditions to give 1-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-fluoro-pyrazole-3-carbonitrile (140 mg, 60.9%) as a yellow oil. LC-MS: m / z = 272.9 [M+H] + ,ESI pos.

[0156] Step 6: 1-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-fluoro-pyrazole-3-carbonitrile Prepared according to step 2 of Example 7, and after purification on a reverse-phase flash chromatography column, 1-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-fluoro-pyrazole-3-carbonitrile (4.0 mg, 3.9%) was obtained as a white lyophilized powder. LC-MS: m / z=462.2 [M+H] + ,ESI pos.

[0157] Example 15 1-[3-(Difluoromethyl)-6-[5-[(6-keto-5,5,7-trimethyl-pyrrolo[2,3-c]pyridazin-3-yl)amino]-6-methoxy-benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Step 1: 3-(Benzhydrylideneamino)-5,5,7-trimethyl-pyrrolo[2,3-c]pyridazin-6-one In a sealed glass tube, 3-chloro-5,5,7-trimethyl-pyrrolo[2,3-c]pyridazin-6-one (94 mg, 0.44 mmol, 1.0 eq.), benzophenone imine (127.1 mg, 118 μL, 0.67 mmol, 1.5 eq.), and CsCO (289.4 mg, 0.89 mmol, 2.0 eq.) were added to 1,4-dioxane (1.8 mL), and the suspension was purged with argon. Next, BINAP (27.7 mg, 0.04 mmol, 0.1 eq.) and Pddba CHCl (23.0 mg, 0.022 mmol, 0.05 eq.) were added, the vial was sealed, and the mixture was heated to 100 °C for 20 h. The reaction mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography using 0-80% EtOAc in heptane as the eluent to give 3-(benzhydrylideneamino)-5,5,7-trimethyl-pyrrolo[2,3-c]pyridazin-6-one (131 mg, 78.6%) as an orange liquid. LC-MS: m / z = 357.3 [M+H] + ,ESI pos.

[0158] Step 2: 3-amino-5,5,7-trimethyl-pyrrolo[2,3-c]pyridazin-6-one; hydrogen chloride To a solution of 3-(benzhydrylideneamino)-5,5,7-trimethyl-pyrrolo[2,3-c]pyridazin-6-one (131 mg, 0.37 mmol, 1.0 eq.) in THF (5.3 mL) was added 2 M HCl in EtO (242.6 mg, 202 μL, 0.40 mmol, 1.1 eq.). The mixture immediately became cloudy and was stirred at 23 °C for 2 h. An additional 2 M HCl in EtO (121.3 mg, 101 μL, 0.20 mmol, 0.55 eq.) was added, and the reaction mixture was stirred overnight. The reaction mixture was filtered, washed with EtO, and the resulting solid was dried under vacuum to give 3-amino-5,5,7-trimethyl-pyrrolo[2,3-c]pyridazin-6-one; hydrogen chloride (61.7 mg, 69.7%) as a white solid. LC-MS: m / z=193.1 [M+H] + ,ESI pos.

[0159] Step 3: 1-[3-(difluoromethyl)-6-[5-[(6-keto-5,5,7-trimethyl-pyrrolo[2,3-c]pyridazin-3-yl)amino]-6-methoxy-benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile Prepared according to step 4 of example 4 to give 1-[3-(difluoromethyl)-6-[5-[(6-keto-5,5,7-trimethyl-pyrrolo[2,3-c]pyridazin-3-yl)amino]-6-methoxy-benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (21.3 mg, 27.6%) as a white solid. LC-MS: m / z=571.4 [M+H] + ,ESI pos.

[0160] Example 16 1-[3-(Difluoromethyl)-6-[5-[[6-(2-morpholinoethoxy)pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Step 1: 2-Morpholinoethanol To a solution of ethylene bromohydrin (9.15 mL, 129.13 mmol, 1.5 eq.) and K2CO3 (0.92 mL, 172.18 mmol, 2.0 eq.) in CH3CN (120 mL) was added morpholine (7.5 g, 86.1 mmol, 1.0 eq.). The yellow suspension was stirred at 80 °C overnight. The reaction mixture was filtered and concentrated. The crude product was purified by flash column chromatography eluting with 0-10% MeOH in DCM to give 2-morpholinoethanol (11.0 g, 97.4%) as a pale yellow oil. LC-MS: m / z = 132.0 [M+H] + ,ESI pos.

[0161] Step 2: 4-[2-(6-chloropyridazin-3-yl)oxyethyl]morpholine 2-Morpholinoethanol (1 g, 933 μL, 7.62 mmol, 1.0 eq.) was dissolved in THF (30 mL) and cooled to 0 °C. NaH 60% in mineral oil (320.2 mg, 8.0 mmol, 1.05 eq.) was added and stirred for 1 h. 3,6-Dichloropyridazine (1.25 g, 8.4 mmol, 1.1 eq.) was added and stirred at room temperature overnight. The reaction mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography eluting with 0–10% MeOH in DCM to give 4-[2-(6-chloropyridazin-3-yl)oxyethyl]morpholine (1.55 g, 83.4%) as a colorless oil. LC-MS: m / z = 244.2 [M+H] + ,ESI pos.

[0162] Step 3: N-[6-(2-morpholinoethoxy)pyridazin-3-yl]carbamic acid tert-butyl ester To a solution of 4-[2-(6-chloropyridazin-3-yl)oxyethyl]morpholine (1.55 g, 6.36 mmol, 1.0 eq.) in 1,4-dioxane (20 mL) was added tert-butyl carbamate (1.49 g, 12.7 mmol, 2.0 eq.), CsCO (4.14 g, 12.7 mmol, 2.00 eq.), Xantphos (736.1 mg, 1.3 mmol, 0.2 eq.), followed by Pddba (582.5 mg, 0.64 mmol, 0.1 eq.). The reaction mixture was heated to 90 °C for 3 h. The reaction mixture was diluted with HO and extracted with ethyl acetate. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography eluting with 0-8% MeOH in DCM to give N-[6-(2-morpholinoethoxy)pyridazin-3-yl]carbamic acid tert-butyl ester (1.4 g, 67.9%) as a yellow solid. LC-MS: m / z = 325.2 [M+H] + ,ESI pos.

[0163] Step 4: [6-(2-morpholinoethoxy)pyridazin-3-yl]amine; 2 2,2,2-trifluoroacetic acid N-[6-(2-morpholinoethoxy)pyridazin-3-yl]carbamic acid tert-butyl ester (500 mg, 1.54 mmol, 1.0 eq.) was dissolved in DCM (10 mL), TFA (1.76 g, 1.2 mL, 15.4 mmol, 10.0 eq.) was added, and the mixture was stirred for 2 h. The volatiles were removed under vacuum to give an orange oil. 10 mL of EtO was added, and the suspension was sonicated for 10 min. The solid was filtered, washed with ether, and dried under high vacuum to give [6-(2-morpholinoethoxy)pyridazin-3-yl]amine; 2 2,2,2-trifluoroacetic acid (675 mg, 96.8%) as a white solid. LC-MS: m / z = 225.1 [M+H] + ,ESI pos.

[0164] Step 5: 1-[3-(difluoromethyl)-6-[5-[[6-(2-morpholinoethoxy)pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile Prepared according to step 4 of example 4 to give 1-[3-(difluoromethyl)-6-[5-[[6-(2-morpholinoethoxy)pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (47 mg, 74%) as a white solid. LC-MS: m / z=617.4 [M+HCOO] - ,ESI neg.

[0165] Example 17 1-[3-(Difluoromethyl)-6-[5-(7,8-dihydro-5H-pyrano[4,3-c]pyridazin-3-ylamino)-6-methoxy-benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Step 1: Benzhydrylidene(7,8-dihydro-5H-pyrano[4,3-c]pyridazin-3-yl)amine Prepared according to step 1 of example 15 using 3-chloro-7,8-dihydro-5H-pyrano[4,3-c]pyridazine (340 mg, 1.9 mmol, 1.0 eq.) to give benzhydrylidene(7,8-dihydro-5H-pyrano[4,3-c]pyridazin-3-yl)amine (345 mg, 57.8%) as a yellow foam. LC-MS: m / z=316.2 [M+H] + ,ESI pos.

[0166] Step 2: 7,8-Dihydro-5H-pyrano[4,3-c]pyridazin-3-ylamine; 1:1 Hydrogen Chloride To a solution of benzhydrylidene(7,8-dihydro-5H-pyrano[4,3-c]pyridazin-3-yl)amine (345 mg, 1.1 mmol, 1.0 eq.) in THF (10 mL) was added 2 M HCl in EtO (602 μL, 1.2 mmol, 1.1 eq.). A precipitate formed immediately. After 2 h, 2 M HCl in ether (602 μL, 1.2 mmol, 1.1 eq.) was added again and stirred for another 2 h. Three drops of H2O were added and stirring was continued for 1 h. The solid was filtered, washed with Et2O, and dried under high vacuum to give 7,8-dihydro-5H-pyrano[4,3-c]pyridazin-3-ylamine; 1:1 hydrogen chloride (195 mg, 95%) as an off-white solid. LC-MS: m / z = 152.0 [M+H] + ,ESI pos.

[0167] Step 3: 1-[3-(difluoromethyl)-6-[5-(7,8-dihydro-5H-pyrano[4,3-c]pyridazin-3-ylamino)-6-methoxy-benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile Prepared according to step 4 of example 4 to give 1-[3-(difluoromethyl)-6-[5-(7,8-dihydro-5H-pyrano[4,3-c]pyridazin-3-ylamino)-6-methoxy-benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (34 mg, 65.5%) as a white solid. LC-MS: m / z=574.4 [M+HCOO] - ,ESI neg.

[0168] Example 18 1-[3-(Difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]-6-tetrahydropyran-4-yloxy-benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Step 1: 4-Bromo-2-nitro-5-tetrahydropyran-4-yloxyaniline To a mixture of tetrahydro-2H-pyran-4-ol (0.49 mL, 5.11 mmol, 1.2 eq.) in THF (15 mL) was added 60% NaH in mineral oil (400.0 mg, 10.0 mmol, 2.35 eq.) at 0 °C. The mixture was stirred at 0 °C for 30 min. Next, 4-bromo-5-fluoro-2-nitro-aniline (1.0 g, 4.26 mmol, 1.0 eq.) was added, and the mixture was stirred at 0 °C for 1.5 h, warmed to RT, and stirred overnight. The reaction mixture was diluted with saturated aqueous NH4Cl and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 4-bromo-2-nitro-5-tetrahydropyran-4-yloxy-aniline (603.0 mg, 42.7%) as a yellow oil. LC-MS: m / z = 317.1, 319.1 [M+H] + ,ESI pos.

[0169] Step 2: 4-Bromo-5-tetrahydropyran-4-yloxy-benzene-1,2-diamine A mixture of 4-bromo-2-nitro-5-tetrahydropyran-4-yloxy-aniline (600.0 mg, 1.9 mmol, 1.0 eq.), iron (528.3 mg, 9.5 mmol, 5.0 eq.), and NHCl (1.01 g, 18.9 mmol, 10.0 eq.) in EtOH (8 mL) and HO (2 mL) was stirred at 50 °C for 2 h. The mixture was filtered, purified by reverse-phase chromatography with formic acid, and lyophilized to give 4-bromo-5-tetrahydropyran-4-yloxy-benzene-1,2-diamine (370.0 mg, 57.9%) as a green oil. LC-MS: m / z = 287.1, 289.1 [M+H] + ,ESI pos.

[0170] Step 3: 5-Bromo-6-tetrahydropyran-4-yloxy-1H-benzimidazole A mixture of 4-bromo-5-tetrahydropyran-4-yloxy-benzene-1,2-diamine (370.0 mg, 1.29 mmol, 1.0 eq.), trimethyl orthoformate (1367.4 mg, 12.89 mmol, 10.0 eq.), and pTsOH·HO (24.5 mg, 0.13 mmol, 0.1 eq.) in EtOH (8 mL) was stirred at 80 °C for 2 h. The mixture was purified by reverse-phase chromatography with formic acid and lyophilized to give 5-bromo-6-tetrahydropyran-4-yloxy-1H-benzimidazole (270.0 mg, 70.5%) as a yellow solid. LC-MS: m / z = 297.0, 299.0 [M+H] + ,ESI pos.

[0171] Step 4: 1-[6-(5-bromo-6-tetrahydropyran-4-yloxy-benzimidazol-1-yl)-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile Prepared according to step 3 of example 4, 1-[6-(6-bromo-5-tetrahydropyran-4-yloxy-benzimidazol-1-yl)-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (140.0 mg, 32.8%) and 1-[6-(5-bromo-6-tetrahydropyran-4-yloxy-benzimidazol-1-yl)-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (130.0 mg, 30.4% yield) were obtained as yellow solids after purification by flash column chromatography (15% EtOAc in PE to 25% MeOH in EtOAc).

[0172] 1-[6-(6-Bromo-5-tetrahydropyran-4-yloxy-benzimidazol-1-yl)-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile: LC-MS: m / z=529.1, 539.1 [M+H] + ,ESI pos. 1H NMR(400MHz,CD3OD)δ=8.93(s,1H),8.56(d,J=8.8Hz,1H),8.21(d,J=8.8Hz,1H),7.95(d,J=13.8Hz,2H),7.20-6.88 (m,2H),4.56-4.50(m,1H),4.02-3.95(m,2H),3.57-3.50(m,2H),2.48(s,3H),2.01-1.96(m,2H),1.84-1.77(m,2H).

[0173] 1-[6-(5-Bromo-6-tetrahydropyran-4-yloxy-benzimidazol-1-yl)-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile: LC-MS: m / z = 529.0, 539.0 [M+H] + ,ESI pos. 1 H NMR(400MHz,CD3OD)δ=8.97(s,1H),8.53(d,J=8.8Hz,1H),8.47(s,1H),8.18(d,J=8.8Hz,1H),7.44(s,1H),7.22-6.8 9(m,2H),4.78-4.71(m,1H),4.05-3.97(m,2H),3.67-3.60(m,2H),2.53(s,3H),2.12-2.05(m,2H),1.88-1.80(m,2H).

[0174] Step 5: 1-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]-6-tetrahydropyran-4-yloxy-benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile Prepared according to step 4 of Example 4, 1-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]-6-tetrahydropyran-4-yloxy-benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (14.1 mg, 10.3% yield) was obtained as a white solid after purification by preparative HPLC (Phenomenex C18 (75x30 mm, 3 μm), 18-48% CH3CN (containing 0.225% HCOOH) in HO for 7 min, flow rate: 25 mL / min). LC-MS: m / z = 558.3 ​​[M+H] + ,ESI pos. 1 H NMR(400MHz,DMSO-d6)δ=9.05(s,1H),8.68(s,1H),8.61(d,J=8.8Hz,1H),8.37(d,J=8.8Hz,1H),8.18(s,1H),7.89(s,1H),7.38-7.26(m,2H) ,7.25-6.93(m,2H),4.45-4.37(m,1H),3.90-3.82(m,2H),3.31-3.27( m,2H),2.48(s,3H),2.46(s,3H),1.96-1.89(m,2H),1.76-1.66(m,2H).

[0175] Example 19 1-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-5-(difluoromethyl)-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine [ka] Step 1: 5-Bromo-1-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-5-(difluoromethyl)-2-pyridyl]-6-(oxetan-3-yloxy)benzimidazole Prepared according to step 3 of example 4 to give 5-bromo-1-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-5-(difluoromethyl)-2-pyridyl]-6-(oxetan-3-yloxy)benzimidazole (110.0 mg, 31.4%) and 6-bromo-1-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-5-(difluoromethyl)-2-pyridyl]-5-(oxetan-3-yloxy)benzimidazole (100.0 mg, 28.6%) as white solids. LC-MS: m / z=544.0 [M+H] + ,ESI pos. 1 H NMR(400MHz,CD3OD)δ=8.96-8.91(m,1H),8.54-8.51(m,1H),8.50-8.43(m,1H),8.06-8.01(m,1H),7.41-6 .97(m,3H),6.20-6.11(m,1H),5.47-5.40(m,1H),5.15-5.09(m,2H),4.83-4.77(m,2H),2.57-2.47(m,3H).

[0176] Step 2: 1-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-5-(difluoromethyl)-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine Prepared according to step 4 of Example 4, 1-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-5-(difluoromethyl)-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine (37.0 mg, 35.2%) was obtained as a yellow solid after purification by preparative HPLC (Phenomenex luna C18 (150x40 mm, 15 μm), 18-48% CH3CN (containing 0.225% HCOOH) in HO for 7 min, flow rate: 25 mL / min). LC-MS: m / z = 571.1 [M+H] + ,ESI pos. 1H NMR(400MHz,DMSO-d6)δ=9.01-8.96(m,1H),8.86-8.80(m,1H),8.58-8.49(m,1H),8.28-8.27(m,1H),8.23-8.15(m,1H),7.65- 7.15(m,5H),6.35-6.27(m,1H),5.32-5.23(m,1H),4.82-4.78(m,2H),4.76-4.72(m,2H),2.52-2.52(m,3H),2.46-2.44(m,3H).

[0177] Example 20 1-[6-[3,5-bis(difluoromethyl)pyrazol-1-yl]-5-(difluoromethyl)-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine [ka] Step 1: 2-[3,5-bis(difluoromethyl)pyrazol-1-yl]-6-chloro-3-(difluoromethyl)pyridine Prepared according to step 1 of example 4 using 3,5-bis-(difluoromethyl)-1H-pyrazole (78.7 mg, 0.47 mmol, 1.0 eq.) at 50° C. to give 2-[3,5-bis(difluoromethyl)pyrazol-1-yl]-6-chloro-3-(difluoromethyl)pyridine (100.0 mg, 64.8%) as an off-white liquid. LC-MS: m / z=329.8 [M+H] + ,ESI pos. 1 H NMR(400MHz,CDCl3)δ=8.16-8.11(m,1H),7.54-7.38(m,2H),7.29(brd,J=8.0Hz,1H),6.97-6.93(m,1H),6.81-6.52(m,1H).

[0178] Step 2: 1-[6-[3,5-bis(difluoromethyl)pyrazol-1-yl]-5-(difluoromethyl)-2-pyridyl]-5-bromo-6-(oxetan-3-yloxy)benzimidazole Prepared according to step 3 of Example 4 using 5-bromo-6-(oxetan-3-yloxy)-1H-benzimidazole (81.6 mg, 0.3 mmol, 1.0 eq.) and 2-[3,5-bis(difluoromethyl)pyrazol-1-yl]-6-chloro-3-(difluoromethyl)pyridine (100.0 mg, 0.3 mmol, 1.0 eq.) at 50° C. to give 1-[6-[3,5-bis(difluoromethyl)pyrazole-1 -yl]-5-(difluoromethyl)-2-pyridyl]-5-bromo-6-(oxetan-3-yloxy)benzimidazole (80.0 mg, 46.9%) as a white solid, and 1-[6-[3,5-bis(difluoromethyl)pyrazol-1-yl]-5-(difluoromethyl)-2-pyridyl]-6-bromo-5-(oxetan-3-yloxy)benzimidazole (70.0 mg, 41.0%) as a yellow solid.

[0179] 1-[6-[3,5-bis(difluoromethyl)pyrazol-1-yl]-5-(difluoromethyl)-2-pyridyl]-5-bromo-6-(oxetan-3-yloxy)benzimidazole: LC-MS: m / z=564.0 [M+H] + ,ESI pos. 1 H NMR(400MHz,CD3OD)δ=8.91-8.88(m,1H),8.63-8.57(m,1H),8.18-8.13(m,1H),8.02-7 .99(m,1H),7.44-6.84(m,5H),5.32-5.25(m,1H),4.87-4.84(m,2H),4.78-4.73(m,2H).

[0180] Step 3: 1-[6-[3,5-bis(difluoromethyl)pyrazol-1-yl]-5-(difluoromethyl)-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine Prepared according to step 4 of Example 4, 1-[6-[3,5-bis(difluoromethyl)pyrazol-1-yl]-5-(difluoromethyl)-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine (7.0 mg, 7.8%) was obtained as a yellow solid after purification by preparative HPLC (Phenomenex luna C18 (150x40 mm, 15 μm), 22-52% CH3CN (containing 0.225% HCOOH) in HO for 7 min, flow rate: 25 mL / min). LC-MS: m / z = 591.2 [M+H] + ,ESI pos. 1 H NMR(400MHz,DMSO-d6)δ=8.99-8.95(m,1H),8.86-8.82(m,1H),8.64-8.59(m,1H),8.39-8.35(m,1H),8.32-8.27(m,1 H),7.60-7.32(m,5H),7.32-7.09(m,2H),5.31-5.24(m,1H),4.77-4.72(m,2H),4.71-4.67(m,2H),2.49-2.49(m,3H).

[0181] Example 21 (3R,5S)-1-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrrolidine-3-carbonitrile [ka] Step 1: tert-butyl (2S,4S)-2-methyl-4-methylsulfonyloxy-pyrrolidine-1-carboxylate To a solution of tert-butyl (2S,4S)-4-hydroxy-2-methyl-pyrrolidine-1-carboxylate (1000.0 mg, 4.97 mmol, 1.0 eq.) and TEA (3.46 mL, 24.87 mmol, 5.01 eq.) in DCM (16 mL) was added MsCl (0.88 mL, 11.34 mmol, 2.28 eq.) dropwise at 0 °C. The reaction mixture was stirred under N atmosphere at 0 °C for 3 h. HO (100 mL) was added and extracted with EtOAc (50 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a pale yellow oil. The crude product was purified by flash column chromatography using 0% to 30% EtOAc in PE to give tert-butyl (2S,4S)-2-methyl-4-methylsulfonyloxy-pyrrolidine-1-carboxylate (1.27 g, 91.5%) as a pale yellow oil. LC-MS: m / z=223 [M+H—C4H8] + ,ESI pos. 1 H NMR(400MHz,CDCl3)δ=5.22-5.13(m,1H),4.02(brd,J=5.3Hz,1H),3.83(brs,1H),3.55(brdd,J= 4.1,13.1Hz,1H),3.03(s,3H),2.44(brs,1H),1.92-1.80(m,1H),1.47(s,9H),1.29-1.25(m,3H).

[0182] Step 2: tert-butyl (2S,4R)-4-cyano-2-methyl-pyrrolidine-1-carboxylate To a clear brown solution of tert-butyl (2S,4S)-2-methyl-4-methylsulfonyloxy-pyrrolidine-1-carboxylate (1270.0 mg, 4.55 mmol, 1.0 eq.) in DMSO (13 mL) was added sodium cyanide (646.0 mg, 13.18 mmol, 2.9 eq.). The mixture was stirred at 80 °C for 20 h. The yellow suspension was cooled to 20 °C, and saturated NaHCO solution (300 mL) was added. The mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography using 0% to 30% EtOAc in PE to give tert-butyl (2S,4R)-4-cyano-2-methyl-pyrrolidine-1-carboxylate (820.0 mg, 85.8%) as a colorless oil. LC-MS: m / z=155 [M+H-C4H8] + ,ESI pos. 1 H NMR(400MHz,CDCl3)δ=3.92(brs,2H),3.53(dd,J=7.0,11.3Hz,1H),2.99(quin,J=7. 4Hz,1H),2.55-2.44(m,1H),1.95-1.87(m,1H),1.46(s,9H),1.35(brd,J=6.2Hz,3H).

[0183] Step 3: (3R,5S)-5-methylpyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid To a solution of tert-butyl (2S,4R)-4-cyano-2-methyl-pyrrolidine-1-carboxylate (820.0 mg, 3.9 mmol, 1.0 eq.) in DCM (10 mL) was added TFA (10.0 mL, 123.25 mmol, 31.6 eq.). The mixture was stirred at 25 °C for 2 h and concentrated to dryness to give (3R,5S)-5-methylpyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid (900.0 mg, yield) as a light brown oil. 1H NMR(400MHz,DMSO-d6)δ=9.53-9.29(m,1H),8.99(brs,1H),8.33-7.35(m,8H),3.63-3.4 5(m,4H),2.59-2.52(m,1H),1.81(ddd,J=8.9,10.4,12.9Hz,1H),1.32(d,J=6.6Hz,3H).

[0184] Step 4: (3R,5S)-1-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrrolidine-3-carbonitrile To a solution of (3R,5S)-5-methylpyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid (850.0 mg, 3.79 mmol, 1.0 eq.) in DMSO (20 mL) was added 6-chloro-3-(difluoromethyl)-2-fluoro-pyridine (689.0 mg, 3.8 mmol, 1.0 eq.). After stirring the mixture at 25 °C for 16 h, the clear yellow solution turned into a yellow suspension. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography using 0% to 2% EtOAc in PE to give (3R,5S)-1-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrrolidine-3-carbonitrile (340.0 mg, 33%) as a pale yellow oil. LC-MS: m / z = 272.2 [M+H] + ,ESI pos. 1 H NMR(400MHz,CDCl3)δ=7.78(d,J=8.1Hz,1H),6.92(d,J=8.0Hz,1H),6.73(t,J=54.9Hz,1H),4.44-4.33(m,1H) ,3.89-3.77(m,2H),3.11-2.99(m,1H),2.66-2.56(m,1H),1.98(td,J=9.5,12.4Hz,1H),1.28(d,J=6.0Hz,3H).

[0185] Step 5: (3R,5S)-1-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrrolidine-3-carbonitrile To a solution of (3R,5S)-1-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrrolidine-3-carbonitrile (320.0 mg, 1.18 mmol, 1.0 eq.) in t-amyl alcohol (15.0 mL) was added N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine (325.0 mg, 1.3 mmol, 1.1 eq.), KPO (750.0 mg, 3.54 mmol, 3.0 eq.) and HCl. tBuXPhos Pd G3 (94.0 mg, 0.12 mmol, 0.1 eq.) was added. The reaction mixture was heated to 100 °C and stirred under N2 atmosphere for 16 h. The brown suspension was cooled to 20 °C and quenched by adding saturated aqueous NH4Cl solution (100 mL). The mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was first purified by preparative HPLC (Phenomenex Luna C18 (150 mm × 40 mm, 15 μm), 17–47% CH3CN in HO (containing 0.225% HCOOH), 10 min, flow rate: 60 mL / min) to give a mixture of (3R,5S)-1-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrrolidine-3-carbonitrile and its regioisomer (3R,5S)-1-[3-(difluoromethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrrolidine-3-carbonitrile). The mixture was purified by SFC (Daicel Chiralcel OJ (250 mm × 30 mm, 10 μm), MeOH (0.1% NH OH) in CO ) to give (3R,5S)-1-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrrolidine-3-carbonitrile (70.0 mg, 30.9%) as a yellow solid. LC-MS: m / z = 461.2 [M+H] + ,ESI pos. 1H NMR(400MHz,CDCl3)δ=8.59(s,1H),8.06(d,J=8.3Hz,1H),8.00(d,J=8.8Hz,1H) ,7.76(d,J=1.5Hz,1H),7.47-7.42(m,1H),7.19-7.13(m,2H),7.10-7.05(m,1H), 6.99-6.68(m,2H),4.58-4.46(m,1H),4.00-3.89(m,2H),3.19-3.07(m,1H),2.7 7-2.67(m,1H),2.61(s,3H),2.08(td,J=9.5,12.7Hz,1H),1.38(d,J=6.0Hz,3H).

[0186] Example 22 1-[6-[5-[(7-cyclopropyl-6-keto-5,5-dimethyl-pyrrolo[2,3-c]pyridazin-3-yl)amino]-6-methoxy-benzimidazol-1-yl]-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Step 1: 3,6-Dichloro-N-cyclopropylpyridazin-4-amine In a 100 mL glass tube, 3,4,6-trichloropyridazine (5 g, 26.7 mmol, Eq: 1.00) was dissolved in THF (50.0 mL). Cyclopropanamine (15.6 g, 19.1 mL, 267 mmol, Eq: 10) was then added, resulting in a brown solution. The tube was sealed and heated at 50 °C for 3 h. The mixture was cooled to 20 °C. H2O and EtOAc were added. The mixture was extracted three times with EtOAc, and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The crude product was triturated with heptane / EtOAc = 9:1, collected by filtration, washed with heptane, and dried. 3,6-dichloro-N-cyclopropylpyridazin-4-amine (4.965 g) was obtained as an orange solid. LC-MS: m / z = 204.6 [M+H] + ,ESI pos. 1H NMR(300MHz,CDCl3)δ=6.91(s,1H),5.35(br.s.,1H),2.53(br.s.,1H),0.92-1.01(m,2H),0.64-0.72(m,2H).

[0187] Step 2: 5,8-Dichloro-1-cyclopropyl-7-isobutyryl-3,3-dimethyl-1,6,7-triazaspiro[3.5]nona-5,8-dien-2-one To a solution of 3,6-dichloro-N-cyclopropylpyridazin-4-amine (98 mg, 480 μmol, Eq: 1) in dry dichloromethane (1.96 mL) was added triethylamine (635 mg, 875 μL, 6.24 mmol, Eq: 13), pivaloyl chloride (591 mg, 603 μL, 4.8 mmol, Eq: 10), and isobutyryl chloride (115 mg, 113 μL, 1.06 mmol, Eq: 2.2) at 0°C to give a yellow solution. The mixture was stirred overnight at 20°C. The reaction mixture was diluted with DCM and saturated aqueous NaHCO3. The aqueous layer was extracted three times with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash column chromatography using 0% to 60% EtOAc in heptane to give 5,8-dichloro-1-cyclopropyl-7-isobutyryl-3,3-dimethyl-1,6,7-triazaspiro[3.5]nona-5,8-dien-2-one (100.8 mg) as a colorless oil. LC-MS: m / z = 240.1 [M+H] + ,ESI pos. 1 H NMR(300MHz,CDCl3)δ=5.24(d,J=0.6Hz,1H),3.49(spt,J=6.8Hz,1H),2.48-2.62( m,1H),1.22-1.27(m,6H),1.14-1.18(m,6H),0.99-1.12(m,1H),0.70-0.93(m,3H).

[0188] Step 3: 3-chloro-7-cyclopropyl-5,5-dimethyl-5H-pyrrolo[2,3-c]pyridazin-6(7H)-one In a 5 mL glass tube, 5,8-dichloro-1-cyclopropyl-7-isobutyryl-3,3-dimethyl-1,6,7-triazaspiro[3.5]nona-5,8-dien-2-one (98 mg, 285 μmol, Eq: 1.00) was dissolved in DMF (2.5 mL). Cs2CO3 (186 mg, 569 μmol, Eq: 2) was then added, resulting in a yellow suspension. The tube was closed and heated at 80 °C for 4 h. The mixture was filtered and concentrated in vacuo. The crude product was purified by preparative HPLC to give 3-chloro-7-cyclopropyl-5,5-dimethyl-5H-pyrrolo[2,3-c]pyridazin-6(7H)-one (67 mg) as a white solid. LC-MS: m / z = 238.1 [M + H]+,ESI pos. 1 H NMR(300MHz, CDCl3)δ=7.20(s,1H),2.95(s,1H),1.41(s,6H),1.10-1.14(m,4H).

[0189] Step 4: 3-(Benzhydrylideneamino)-7-cyclopropyl-5,5-dimethyl-pyrrolo[2,3-c]pyridazin-6-one In a sealed glass tube, 3-chloro-7-cyclopropyl-5,5-dimethyl-pyrrolo[2,3-c]pyridazin-6-one (786 mg, 3.31 mmol, 1.0 eq.), benzophenone imine (946.26 mg, 876.16 μL, 4.96 mmol, 1.5 eq.), and CsCO (2.15 g, 6.61 mmol, 2.0 eq.) were combined with 1,4-dioxane, extra dry (9.96 mL) and argon was bubbled through for 5 min. Next, BINAP (205.91 mg, 0.331 mmol, 0.1 eq.) and tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (171.14 mg, 0.165 mmol, 0.050 eq.) were added. The vial was sealed, and the mixture was heated to 100 °C and stirred for 16 h. The reaction mixture was cooled to 23 °C, 10 g of SiO2 was added, and concentrated in vacuo. The crude product was purified by flash column chromatography using 0% to 100% EtOAc in heptane to give 3-(benzhydrylideneamino)-7-cyclopropyl-5,5-dimethyl-pyrrolo[2,3-c]pyridazin-6-one (957 mg, 75.7%) as a dark red oil. LC-MS: m / z = 383.3 [M+H] + ,ESI pos.

[0190] Step 5: 3-amino-7-cyclopropyl-5,5-dimethyl-pyrrolo[2,3-c]pyridazin-6-one; 1:1 hydrogen chloride To a solution of 3-(benzhydrylideneamino)-7-cyclopropyl-5,5-dimethyl-pyrrolo[2,3-c]pyridazin-6-one (957 mg, 2.5 mmol, 1.0 eq.) in THF (10 mL) at 23 °C was added HCl 2 M in EtO (3.75 mL, 7.51 mmol, 3.0 eq.). A solid precipitated immediately. H2O (90.18 mg, 90.18 μL, 5 mmol, 2.0 eq.) was added, and the resulting solution was stirred for 1 h. The mixture was concentrated to dryness to give a brown oil, to which Et2O and a few drops of THF were added. A solid precipitated, collected by filtration, washed with Et2O, and dried. 3-Amino-7-cyclopropyl-5,5-dimethyl-pyrrolo[2,3-c]pyridazin-6-one; 1:1 hydrogen chloride (349 mg, 54.8%) was obtained as a light brown solid. LC-MS: m / z=219.1 [M+H] + ,ESI pos.

[0191] Step 6: 1-[6-[5-[(7-cyclopropyl-6-keto-5,5-dimethyl-pyrrolo[2,3-c]pyridazin-3-yl)amino]-6-methoxy-benzimidazol-1-yl]-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile Prepared according to step 4 of example 4 to give 1-[6-[5-[(7-cyclopropyl-6-keto-5,5-dimethyl-pyrrolo[2,3-c]pyridazin-3-yl)amino]-6-methoxy-benzimidazol-1-yl]-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (46 mg, 78.7%) as an off-white solid. LC-MS: m / z=641.4 [M+HCOO] - ,ESI neg.

[0192] Example 23 1-[3-(Difluoromethyl)-6-[5-[(6-keto-1-methyl-pyridazin-3-yl)amino]-6-methoxy-benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Step 1: 1-[3-(difluoromethyl)-6-[5-[(6-keto-1-methyl-pyridazin-3-yl)amino]-6-methoxy-benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile Prepared according to step 4 of example 4 to give 1-[3-(difluoromethyl)-6-[5-[(6-keto-1-methyl-pyridazin-3-yl)amino]-6-methoxy-benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (53 mg, 97.7%) as a pale yellow solid. LC-MS: m / z=504.2 [M+H] + ,ESI pos.

[0193] Example 24 1-[3-(Difluoromethyl)-6-[6-methoxy-5-[[6-[(1-methyl-4-piperidyl)oxy]pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Step 1: 3-chloro-6-[(1-methyl-4-piperidyl)oxy]pyridazine To a solution of 4-hydroxy-1-methylpiperidine (850.36 mg, 7.38 mmol, 1.1 eq.) in THF (20 mL) was added NaH (402.74 mg, 10.07 mmol, 1.5 eq.). The reaction was stirred at 0 °C for 0.5 h, after which 3,6-dichloropyridazine (1.0 g, 6.71 mmol, 1.0 eq.) was added, and stirring at 25 °C was continued for 4 h. The mixture was quenched with saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 3-chloro-6-[(1-methyl-4-piperidyl)oxy]pyridazine (1.3 g, 85.1%) as a white solid, which was used without further purification. LC-MS: m / z = 228.0 [M+H] + ,ESI pos.

[0194] Step 2: N-[6-[(1-methyl-4-piperidyl)oxy]pyridazin-3-yl]-1,1-diphenyl-methanimine To a solution of 3-chloro-6-[(1-methyl-4-piperidyl)oxy]pyridazine (400.0 mg, 1.76 mmol, 1.0 eq.) in toluene (4 mL) was added benzophenone imine (0.32 mL, 1.93 mmol, 1.1 eq.). CsCO (2289.43 mg, 7.03 mmol, 4.0 eq.), BINAP (218.61 mg, 0.35 mmol, 0.2 eq.), and Pd(dba) (160.94 mg, 0.18 mmol, 0.1 eq.) were added. The reaction mixture was stirred at 90 °C under a N atmosphere for 6 h. The mixture was cooled to 23 °C, diluted with HO (100 mL), and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (basic) to give N-[6-[(1-methyl-4-piperidyl)oxy]pyridazin-3-yl]-1,1-diphenyl-methanimine (240.0 mg, 36.7%) as a yellow gum. LC-MS: m / z=373.0 [M+H] + ,ESI pos.

[0195] Step 3: 6-[(1-methyl-4-piperidyl)oxy]pyridazin-3-amine A mixture of N-[6-[(1-methyl-4-piperidyl)oxy]pyridazin-3-yl]-1,1-diphenyl-methanimine (400.0 mg, 1.07 mmol, 1.0 eq) and 4 M HCl solution in dioxane (3.0 mL) was stirred at 25° C. for 1 h. The mixture was concentrated under reduced pressure. The residue was suspended in EtOAc (15 mL) and stirred for 15 min. The solid was collected by filtration and dried to give 6-[(1-methyl-4-piperidyl)oxy]pyridazin-3-amine (200.0 mg, 89.4%) as a brown solid. LC-MS: m / z=209.1 [M+H] + ,ESI pos.

[0196] Step 4: 1-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-[(1-methyl-4-piperidyl)oxy]pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile Prepared according to step 4 of Example 4, 1-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-[(1-methyl-4-piperidyl)oxy]pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (16.9 mg, 25.8%) was obtained as a white solid after purification by preparative HPLC (Waters Xbridge (150 mm × 25 mm, 5 μm), 40% to 70% CH CN (containing NH 4 HCO 3 ) in HO, 8 min, flow rate 25 mL / min). LC-MS: m / z=587.0 [M+H] + ,ESI pos. 1 H NMR(400MHz,CD3OD)δ=8.74(s,1H),8.59(s,1H),8.43(d,J=8.5Hz,1H),8.1 1(d,J=8.5Hz,1H),7.72-7.71(m,1H),7.26(d,J=9.5Hz,1H),7.11-6.91(t, 2H),6.84-6.83(m,1H),4.80(m,1H),3.84(s,3H),2.80(brs,2H),2.51-2.4 8(s,3H),2.46(brs,2H),2.34(s,3H),2.16-2.04(m,2H),1.93-1.80(m,2H).

[0197] Example 25 1-[5-(difluoromethyl)-6-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine [ka] Step 1: 1-(2-methoxyethyl)-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole 3-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.0 g, 14.42 mmol, 1.0 eq.), 2-bromoethyl methyl ether (5.85 mL, 62.29 mmol, 4.32 eq.), and potassium carbonate (4.42 g, 32.01 mmol, 2.22 eq.) in CHCN (40 mL) were stirred at 80° C. for 24 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography using 0% to 25% EtOAc in PE to give 1-(2-methoxyethyl)-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (3.0 g, 78.2%) as a colorless oil (2:1 mixture of regioisomers). LC-MS: m / z = 267.2 [M+H] + ,ESI pos.

[0198] Step 2: 1-[5-(1,3-dioxolan-2-yl)-6-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine To a mixture of 1-(2-methoxyethyl)-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (195.29 mg, 0.73 mmol, 1.5 eq.) and 1-[6-chloro-5-(1,3-dioxolan-2-yl)-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (200.0 mg, 0.49 mmol, 1.0 eq.) in THF (5 mL) and HO (0.5 mL) was added Sphos Pd G3 (42.82 mg, 0.05 mmol, 0.1 eq.) and K3PO4 (207.68 mg, 0.98 mmol, 2.0 eq.). The mixture was stirred at 60 °C under N2 atmosphere for 12 h. The reaction mixture was cooled to 23 °C and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (36% CHCN in H2O (containing 1% FA)) to give 1-[5-(1,3-dioxolan-2-yl)-6-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (200.0 mg, 79.8%) as a yellow solid (mixture of regioisomers). LC-MS: m / z = 513.2 [M+H] + ,ESI pos.

[0199] Step 3: 2-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbaldehyde To a solution of 1-[5-(1,3-dioxolan-2-yl)-6-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (250.0 mg, 0.49 mmol, 1.0 eq.) in a 4 M solution of HCl in dioxane (4.0 mL, 24.0 mmol, 32.8 eq.), 6 N HCl (4.0 mL, 24.0 mmol, 49.21 eq.) was added at 25° C. and the resulting mixture was stirred at 25° C. for 2 h. The reaction mixture was filtered and the filter cake was washed with HO (5 mL) and dried to give 2-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbaldehyde (180.0 mg, 98.5%) as a yellow solid (mixture of regioisomers). LC-MS: m / z = 469.2 [M+H] + ,ESI pos.

[0200] Step 4: 1-[5-(difluoromethyl)-6-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine To a solution of 2-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbaldehyde (60.0 mg, 0.13 mmol, 1.0 eq.) in DCM (5 mL) was added DAST (62.01 mg, 0.38 mmol, 3.0 eq.) at 0° C., and the resulting mixture was stirred for 12 h at 25° C. The reaction mixture was quenched by the addition of HO (3 mL) at 25° C., and DCM was removed under reduced pressure. The aqueous mixture was directly purified by reverse-phase HPLC (60% CHCN in HO (containing 1% FA)) to give 1-[5-(difluoromethyl)-6-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (20.0 mg, 31.8%) as a yellow solid (mixture of regioisomers). LC-MS: m / z = 491.3 [M+H] + ,ESI pos.

[0201] The mixture of regioisomers was purified by SFC (Daicel Chiralpak AD (250 mm × 30 mm, 10 μm), MeOH (0.1% NH OH) in CO ) to give 1-[5-(difluoromethyl)-6-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (5.4 mg, 26.2%) as a white solid. LC-MS: m / z = 491.3 [M+H] + ,ESI pos. 1H NMR(400MHz,DMSO-d6)δ=9.22(s,1H),9.04(s,1H),8.42(d,J=2.0Hz,1H),8.33(d, J=8.8Hz,1H),8.23(d,J=8.8Hz,1H),8.03(d,J=8.8Hz,1H),7.69(s,1H),7.52(dd,J =2.0,8.8Hz,1H),7.33(d,J=9.2Hz,1H),7.19(s,1H),7.13-7.03(m,2H),6.91(s,1H) ),4.34(t,J=5.2Hz,2H),3.76(t,J=5.2Hz,2H),3.28(s,3H),2.48(d,J=4.0Hz,6H).

[0202] Example 26 1-[5-(difluoromethyl)-6-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine [ka] In Step 4 of Example 25, 1-[5-(difluoromethyl)-6-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (8.1 mg, 0.02 mmol, 40.5% yield) was isolated as the second regioisomer and obtained as a white solid. LC-MS: m / z=491.3 [M+H] + ,ESI pos. 1H NMR(400MHz,DMSO-d6)δ=9.22(s,1H),9.02(s,1H),8.45(d,J=2.0Hz,1H),8.33(d,J=8.8 Hz,1H),8.21(d,J=8.8Hz,1H),8.01(d,J=8.8Hz,1H),7.94(s,1H),7.51(dd,J=2.0,8.8Hz ,1H),7.33(d,J=9.2Hz,1H),7.15(s,1H),7.09(d,J=9.2Hz,1H),7.01(s,1H),6.88(s,1H) ),4.31(t,J=5.3Hz,2H),3.74(t,J=5.2Hz,2H),3.28(s,3H),2.48(brs,3H),2.35(s,3H).

[0203] Example 27 1-[3-(Difluoromethyl)-6-[6-methoxy-5-[[6-[[1-(oxetan-3-yl)-4-piperidyl]oxy]pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Step 1: tert-butyl 4-(6-chloropyridazin-3-yl)oxypiperidine-1-carboxylate To a solution of 1-Boc-4-hydroxypiperidine (1621.1 mg, 8.05 mmol, 1.2 eq.) in THF (15 mL) was added NaH (537.0 mg, 13.43 mmol, 2.0 eq.) at 0 °C under a N atmosphere. The reaction mixture was stirred at 0 °C for 30 min. Next, 3,6-dichloropyridazine (1000.0 mg, 6.71 mmol, 1.0 eq.) was added to the mixture at 0 °C under a N atmosphere, and stirring was continued for 2 h. The reaction mixture was poured into saturated aqueous NH4Cl (100 mL) with stirring, which was then extracted with EtOAc (100 mL × 3). The combined organic extracts were concentrated in vacuo. The crude product was purified by flash column chromatography using 0% to 15% EtOAc in PE to give tert-butyl 4-(6-chloropyridazin-3-yl)oxypiperidine-1-carboxylate (1.8 g, 85.5%) as a white solid. LC-MS: m / z = 314.2 [M+H] + ,ESI pos. 1 H NMR(400MHz,CDCl3)δ=7.38(d,J=9.2Hz,1H),6.94(d,J=9.2Hz,1H),5.44(tt,J=3.9,8.1Hz,1 H),3.90-3.75(m,2H),3.31-3.22(m,2H),2.12-2.04(m,2H),1.83-1.68(m,2H),1.48(s,9H).

[0204] Step 2: 3-chloro-6-(4-piperidyloxy)pyridazine; hydrochloride To a solution of tert-butyl 4-(6-chloropyridazin-3-yl)oxypiperidine-1-carboxylate (1.5 g, 4.78 mmol, 1.0 eq.) in DCM (15 mL) was added a 4 M solution of HCl in dioxane (5.0 mL, 20.0 mmol, 4.18 eq.). The reaction mixture was stirred at 25° C. for 2 h. A white solid precipitated. The reaction mixture was concentrated to dryness to give 3-chloro-6-(4-piperidyloxy)pyridazine; hydrochloride (1.1 g, 92.0%) as a white solid. LC-MS: m / z=214.0 [M+H] + ,ESI pos. 1H NMR(400MHz,DMSO-d6)δ=9.25-8.94(m,2H),7.83(d,J=9.3Hz,1H),7.36(d,J=9.2Hz,1H),5.39(tt,J=3.7,7.8H z,1H),3.28-3.19(m,2H),3.11(brdd,J=3.2,7.2Hz,2H),2.20(ddd,J=3.4,6.9,10.1Hz,2H),2.05-1.90(m,2H).

[0205] Step 3: 3-chloro-6-[[1-(oxetan-3-yl)-4-piperidyl]oxy]pyridazine A solution of 3-chloro-6-(4-piperidyloxy)pyridazine (1.1 g, 5.15 mmol, 1.0 eq.) and 3-oxetanone (1.11 g, 15.45 mmol, 3.0 eq.) in MeOH (12 mL) was stirred at 20 °C for 10 min. Sodium cyanoborohydride (647.05 mg, 10.3 mmol, 2.0 eq.) was then added. Stirring at 20 °C was continued for 1 h. The reaction mixture was poured into HO (50 mL), which was extracted with EtOAc (50 mL × 3). The combined organic extracts were concentrated in vacuo. The crude product was purified by flash column chromatography using 0% to 100% EtOAc in PE to give 3-chloro-6-[[1-(oxetan-3-yl)-4-piperidyl]oxy]pyridazine (800.0 mg, 57.6%) as a white solid. LC-MS: m / z=270.0 [M+H] + ,ESI pos. 1 H NMR(400MHz,DMSO-d6)δ=7.78(d,J=9.2Hz,1H),7.31(d,J=9.3Hz,1H),5.16(td,J=4.2,8.3Hz,1H),4.56-4.51(m ,2H),4.43(t,J=6.1Hz,2H),3.42(quin,J=6.4Hz,1H),2.60-2.53(m,2H),2.14-2.03(m,4H),1.78-1.67(m,2H).

[0206] Step 4: N-[6-[[1-(oxetan-3-yl)-4-piperidyl]oxy]pyridazin-3-yl]-1,1-diphenylmethanimine To a solution of benzophenone imine (0.75 mL, 4.45 mmol, 1.5 eq.) and 3-chloro-6-[[1-(oxetan-3-yl)-4-piperidyl]oxy]pyridazine (800.0 mg, 2.97 mmol, 1.0 eq.) in 1,4-dioxane (10 mL), CsCO (1932.72 mg, 5.93 mmol, 2.0 eq.) and Xantphos Pd G (142.72 mg, 0.15 mmol, 0.05 eq.) were added under a N atmosphere at 20 °C. The mixture was stirred at 100 °C for 16 h. The reaction mixture was cooled to 23 °C and poured into HO (50 mL). It was extracted with EtOAc (50 mL × 3). The combined organic extracts were concentrated in vacuo. The crude product was purified by flash column chromatography using 0% to 100% EtOAc in PE to give N-[6-[[1-(oxetan-3-yl)-4-piperidyl]oxy]pyridazin-3-yl]-1,1-diphenyl-methanimine (700.0 mg, 56.9%) as a yellow solid. LC-MS: m / z = 270.0 [M+H] + ,ESI pos. 1 H NMR(400MHz,DMSO-d6)δ=7.70(d,J=7.2Hz,2H),7.58(d,J=7.2Hz,1H),7.55- 7.47(m,2H),7.37-7.32(m,3H),7.15(dd,J=2.8,6.5Hz,2H),7.11-7.06(m,1H ),7.04-6.98(m,1H),5.08-4.98(m,1H),4.52(t,J=6.4Hz,2H),4.44-4.39(m, 2H),3.42-3.37(m,1H),2.56(brs,2H),2.07-1.96(m,4H),1.70-1.57(m,2H).

[0207] Step 5: 6-[[1-(oxetan-3-yl)-4-piperidyl]oxy]pyridazin-3-amine To a solution of N-[6-[[1-(oxetan-3-yl)-4-piperidyl]oxy]pyridazin-3-yl]-1,1-diphenyl-methanimine (400.0 mg, 0.97 mmol, 1.0 eq.) in MeOH (8 mL) was added sodium acetate (0.18 mL, 2.41 mmol, 2.5 eq.) and hydroxylamine hydrochloride (134.12 mg, 1.93 mmol, 2.0 eq.). Stirring at 20 °C was continued for 0.5 h. The reaction mixture was purified by preparative TLC using 10% MeOH in DCM to give 6-[[1-(oxetan-3-yl)-4-piperidyl]oxy]pyridazin-3-amine (180.0 mg, 74.5%) as a white solid. LC-MS: m / z = 251.1 [M+H] + ,ESI pos. 1 H NMR(400MHz,DMSO-d6)δ=6.87-6.78(m,2H),5.85(s,2H),4.94(tt,J=4.1,8.5Hz,1H),4.55 -4.50(m,2H),4.42(t,J=6.1Hz,2H),2.10-1.94(m,4H),1.64(dtd,J=3.5,9.1,12.5Hz,2H).

[0208] Step 6: 1-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-[[1-(oxetan-3-yl)-4-piperidyl]oxy]pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile Prepared according to step 4 of Example 4, 1-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-[[1-(oxetan-3-yl)-4-piperidyl]oxy]pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (68.6 mg, 46.5%) was obtained as a brown solid after purification by preparative HPLC (Phenomenex Luna C18 (150 mm × 25 mm, 10 μm), 13-43% CH3CN in HO (containing 0.225% HCOOH) for 10 min, flow rate: 25 mL / min). LC-MS: m / z = 629.3 [M+H] + ,ESI pos. 1H NMR(400MHz,CD3OD)δ=8.80(s,1H),8.66(s,1H),8.49(brd,J=8.3Hz,1H),8.17(br d,J=8.4Hz,1H),7.78(s,1H),7.31(d,J=9.5Hz,1H),7.19-6.88(m,3H),5.16-5.06 (m,1H),4.74-4.66(m,2H),4.65-4.60(m,2H),3.90(s,3H),3.63-3.53(m,1H),2.7 4-2.63(m,2H),2.54(s,3H),2.28(brs,2H),2.19-2.11(m,2H),1.96-1.78(m,2H).

[0209] Example 28 1-[3-(Difluoromethyl)-6-[6-methoxy-5-[(4-methyl-2,3-dihydropyridazino[4,5-b][1,4]oxazin-8-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Step 1: 2-[(5,6-dichloropyridazin-4-yl)-methyl-amino]ethanol To a solution of 3,4,5-trichloropyridazine (11.0 g, 59.97 mmol, 1.0 eq.) in MeOH (80 mL) was added dropwise a solution of 2-(methylamino)ethanol (13.51 g, 179.91 mmol, 3.0 eq.) in MeOH (120 mL) at 20 °C. Stirring at 20 °C was continued for 16 h. The mixture was concentrated in vacuo. The crude product was purified by flash column chromatography using 0% to 16% MeOH in EtOAc to give 2-[(5,6-dichloropyridazin-4-yl)-methyl-amino]ethanol (9.7 g, 72.8%) as a yellow oil. LC-MS: m / z = 222.0 [M+H] + ,ESI pos. 1 H NMR(400MHz, CDCl3)δ=8.59(s,1H),3.94-3.88(m,2H),3.75-3.69(m,2H),3.21(s,3H).

[0210] Step 2: 8-chloro-4-methyl-2,3-dihydropyridazino[4,5-b][1,4]oxazine To a solution of 2-[(5,6-dichloropyridazin-4-yl)-methyl-amino]ethanol (3.0 g, 13.51 mmol, 1.0 eq.) in THF (270 mL) was added potassium tert-butoxide (1.82 g, 16.21 mmol, 1.2 eq.) at 80 °C. The mixture was stirred at 80 °C for 3 h. The reaction mixture was cooled to 23 °C and concentrated. The residue was treated with saturated aqueous NH4Cl (250 mL), which was extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over Na2SO4, filtered, and concentrated in vacuo to give chloro-4-methyl-2,3-dihydropyridazino[4,5-b][1,4]oxazine (2.2 g, 79.0%) as a light brown solid. LC-MS: m / z = 186.0 [M+H] + ,ESI pos. 1 H NMR(400MHz,DMSO-d6)δ=8.65(s,1H),4.41-4.36(m,2H),3.49-3.43(m,2H),3.02(s,3H).

[0211] Step 3: Benzhydrylidene-(4-methyl-2,3-dihydropyridazino[4,5-b][1,4]oxazin-8-yl)amine In a glass tube, 8-chloro-4-methyl-2,3-dihydropyridazino[4,5-b][1,4]oxazine (250 mg, 1.35 mmol, 1.0 eq.), benzophenone imine (385.42 mg, 356.87 μL, 2.02 mmol, 1.5 eq.), and CsCO (877.7 mg, 2.69 mmol, 2.0 eq.) were combined with 1,4-dioxane, extra dry (4 mL) and argon was bubbled through for 5 min. Next, BINAP (83.87 mg, 0.135 mmol, 0.1 eq.) and tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (69.71 mg, 0.067 mmol, 0.05 eq.) were added. The vial was sealed, and the mixture was heated to 100 °C and stirred for 16 h. Additional benzophenone imine (385.42 mg, 356.87 μL, 2.02 mmol, 1.5 eq.), CsCO (877.7 mg, 2.69 mmol, 2.0 eq.), BINAP (83.87 mg, 0.135 mmol, 0.1 eq.), and tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (69.71 mg, 0.067 mmol, 0.05 eq.) were added. The mixture was stirred at 100 °C for 2 days. The reaction was cooled to 23 °C, 10 g of SiO was added, and the mixture was concentrated in vacuo. The crude product was purified by flash column chromatography using 0% to 100% EtOAc in heptane, then 20% EtOAc in MeOH to give benzhydrylidene-(4-methyl-2,3-dihydropyridazino[4,5-b][1,4]oxazin-8-yl)amine (188 mg, 39.7%) as a brown oil. LC-MS: m / z=331.2 [M+H] + ,ESI pos.

[0212] Step 4: (4-methyl-2,3-dihydropyridazino[4,5-b][1,4]oxazin-8-yl)amine dihydrochloride To a solution of benzhydrylidene-(4-methyl-2,3-dihydropyridazino[4,5-b][1,4]oxazin-8-yl)amine (188 mg, 0.535 mmol, 1.0 eq.) in THF (10 mL) was added EtO (2.67 mL, 5.35 mmol, 10.0 eq.) and HCl 2M in HO (9.64 mg, 9.64 μL, 0.535 mmol, 1.0 eq.). The mixture was stirred at 20 °C for 1 h. The precipitated solid was collected by filtration, washed with EtO, and dried to give (4-methyl-2,3-dihydropyridazino[4,5-b][1,4]oxazin-8-yl)amine dihydrochloride (100 mg, 78.2%) as a light brown solid. LC-MS: m / z = 167.0 [M+H] + ,ESI pos.

[0213] Step 5: 1-[3-(difluoromethyl)-6-[6-methoxy-5-[(4-methyl-2,3-dihydropyridazino[4,5-b][1,4]oxazin-8-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile According to Step 4 of Example 4, 1-[6-(5-bromo-6-methoxy-benzimidazol-1-yl)-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (50 mg, 0.098 mmol, 1.0 eq, prepared in Example 3, Step 4), (4-methyl-2,3-dihydropyridazino[4,5-b][1,4]oxazin-8-yl)amine; HCl (46.9 mg, 0.196 mmol, 2.0 eq) to give 1-[3-(difluoromethyl)-6-[6-methoxy-5-[(4-methyl-2,3-dihydropyridazino[4,5-b][1,4]oxazin-8-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (18 mg, 27.0%) as a light brown solid. LC-MS: m / z=589.3 [M+HCOO] - ,ESI neg.

[0214] Example 29 1-[6-[1-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(difluoromethyl)-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine [ka] Step 1: 1-(cyclopropylmethyl)-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole and 1-(cyclopropylmethyl)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole A solution of 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.0 g, 4.81 mmol, 1.0 eq.), (bromomethyl)cyclopropane (4.66 mL, 48.06 mmol, 10.0 eq.), and CsCO (3.13 g, 9.61 mmol, 2.0 eq.) in CHCN (10 mL) was stirred at 80 °C for 12 h. The reaction mixture was cooled to 23 °C and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Welch HPLC XB-CN (250 mm × 70 mm, 10 μm), gradient of EtOH in hexane).

[0215] 1-(Cyclopropylmethyl)-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (330 mg, 26.2%) was obtained as a colorless oil. LC-MS: m / z=263.1 [M+H] + ,ESI pos. 1 H NMR(400MHz,DMSO-d6)δ=7.80(s,1H),3.85(d,J=7.1Hz,2H),3.34(s,1H),2.23(s,3H),1.24(s,12H),0.49(brd,J=7.7Hz,2H),0.32(brd,J=4.6Hz,2H).

[0216] 1-(Cyclopropylmethyl)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (100 mg, 7.9%) was obtained as a colorless oil. LC-MS: m / z=263.1 [M+H] + ,ESI pos. 1 H NMR(400MHz,DMSO-d6)δ=7.45(s,1H),3.89(d,J=6.8Hz,2H),3.36(brs,1H),2.38(s,3H),1.24(s,12H),0.46(brd,J=7.8Hz,2H),0.31(brd,J=4.6Hz,2H).

[0217] Step 2: 1-[6-[1-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(1,3-dioxolan-2-yl)-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine Prepared according to the procedure of Example 25 to give 1-[6-[1-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(1,3-dioxolan-2-yl)-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (80.0 mg, 64.3%) as a yellow solid. LC-MS: m / z=509.3 [M+H] + ,ESI pos.

[0218] Step 3: 2-[1-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbaldehyde Prepared according to Example 25 to give 2-[1-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbaldehyde (80.0 mg, 87.6%) as a yellow solid. LC-MS: m / z=465.3 [M+H] + ,ESI pos.

[0219] Step 4: 1-[6-[1-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(difluoromethyl)-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; formic acid Prepared according to step 4 of example 25 to give 1-[6-[1-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(difluoromethyl)-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine, formic acid (31.0 mg, 36.1%) as a yellow solid. LC-MS: m / z=487.2 [M+H] + ,ESI pos. 1 H NMR(400MHz,CD3OD)δ=8.92(s,1H),8.34(d,J=8.8Hz,1H),8.29-8.19(m,2H), 7.93(s,1H),7.91(d,J=8.8Hz,1H),7.60(dd,J=2.0,8.8Hz,1H),7.41(d,J=9. 2Hz,1H),7.19(d,J=9.2Hz,1H),6.84(s,1H),4.05(d,J=7.2Hz,2H),2.54(s,3 H),2.42(s,3H),1.45-1.31(m,1H),0.72-0.59(m,2H),0.46(q,J=4.8Hz,2H).

[0220] Example 30 6-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]benzimidazol-5-yl]amino]-N,N,4-trimethyl-pyridazine-3-carboxamide [ka] Step 1: 6-Amino-4-methyl-pyridazine-3-carboxylic acid methyl ester In an autoclave under an inert atmosphere of argon, (6-chloro-5-methyl-pyridazin-3-yl)amine (5.4 g, 36.86 mmol, 1.0 eq.) was dissolved in MeOH (100 mL). PdCl2(dppp) (1.308 g, 1.83 mmol, 0.05 eq.) and NEt3 (11.18 g, 15.4 mL, 110.49 mmol, 3 eq.) were added to the mixture heated to 100 °C. The reaction mixture was stirred at 100 °C under a CO atmosphere (60 bar) for 18 h. The mixture was cooled to 20 °C and purged with argon. Brine was added to the mixture, and it was extracted several times with large amounts of EtOAc. Since a large amount of product was still present in the aqueous phase, further extractions were performed with DCM. All organic extracts were combined and concentrated to give a yellow solution. The crude material was purified by flash column chromatography in heptane 35% to 50% (EtOAc / EtOH / NH4OH = 75:25:2) to give 6-amino-4-methyl-pyridazine-3-carboxylic acid methyl ester (3.29 g, 51.8%) as a white solid. LC-MS: m / z = 168.1 [M+H] + ,ESI pos. 1 H NMR(300MHz, CDCl3)δ=6.56(d,J=1.0Hz,1H),5.06(brs,2H),3.99(s,3H),2.52(d,J=0.8Hz,3H).

[0221] Step 2: 6-amino-4-methyl-pyridazine-3-carboxylic acid Under an argon atmosphere, 6-amino-4-methyl-pyridazine-3-carboxylic acid methyl ester (300 mg, 1.79 mmol, 1.0 eq.) was suspended in THF (15 mL) at 20 °C. 1 M LiOH in HO (2.69 mL, 2.69 mmol, 1.5 eq.) was added and stirring was continued for 1 h. The reaction mixture was partitioned between HO and DCM. The aqueous layer was acidified to pH = 2 with 1 M HCl. After lyophilization, 6-amino-4-methyl-pyridazine-3-carboxylic acid (457 mg) was obtained as a solid and used without further purification. LC-MS: m / z = 154.0 [M+H] + ,ESI pos.

[0222] Step 3: 6-amino-N,N,4-trimethyl-pyridazine-3-carboxamide Under an argon atmosphere, 6-amino-4-methyl-pyridazine-3-carboxylic acid (167 mg, 0.654 mmol, 1.0 eq.) was suspended in DMF (1 mL) at 20 °C. 2 M dimethylamine in THF (436.75 mg, 490.73 μL, 0.981 mmol, 1.5 eq.) was added, and the reaction mixture became a solution. DIPEA (169.14 mg, 216.84 μL, 1.31 mmol, 2.0 eq.) and TBTU (252.1 mg, 0.785 mmol, 1.2 eq.) were added. The reaction mixture was stirred at 20 °C for 3 h 30 min. An additional 2 M dimethylamine in THF (981.45 μL, 1.96 mmol, 3.0 eq.) was added, and the reaction mixture was stirred at 20 °C for an additional 20 min. No further conversion was observed. Additional TBTU (252.1 mg, 0.785 mmol, 1.2 eq) and 2 M dimethylamine in THF (981.45 μL, 1.96 mmol, 3.0 eq.) were added, and the reaction mixture was stirred at 50 °C for 18 h. The mixture was cooled to 20 °C. HO was added, and the mixture was directly purified on a reverse-phase chromatography column to give 6-amino-N,N,4-trimethyl-pyridazine-3-carboxamide (777 mg, activated ester intermediate, contaminated with inorganic salts and DMF), which was used without further purification. LC-MS: m / z = 181.1 [M+H] + ,ESI pos.

[0223] Step 4: 6-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]benzimidazol-5-yl]amino]-N,N,4-trimethyl-pyridazine-3-carboxamide Prepared according to step 4 of example 4 to give 6-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]benzimidazol-5-yl]amino]-N,N,4-trimethyl-pyridazine-3-carboxamide (5.1 mg, 6.0%) as a white solid. LC-MS: m / z=529.3 [M+H] + ,ESI pos.

[0224] Example 31 N-[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]benzimidazol-5-yl]cyclopropanecarboxamide [ka] Step 1: Trimethyl-[2-[(5-nitrobenzimidazol-1-yl)methoxy]ethyl]silane To a solution of 5-nitrobenzimidazole (10.0 g, 61.3 mmol, 1.0 eq.) in DMF (50 mL) was added NaH 60% mineral oil dispersion (2.94 g, 73.56 mmol, 1.2 eq.) portionwise at 0 °C. The mixture was stirred at 20 °C for 1 h and then cooled to 0 °C again. 2-(Trimethylsilyl)ethoxymethyl chloride (15.19 mL, 85.82 mmol, 1.4 eq.) was added dropwise, the cooling bath was removed, and stirring at 20 °C was continued for 16 h. The mixture was poured into HO (200 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were concentrated under reduced pressure. The crude product was purified by flash column chromatography using 0% to 25% EtOAc in PE to give trimethyl-[2-[(5-nitrobenzimidazol-1-yl)methoxy]ethyl]silane (11.2 g, 62.3%) as a yellow oil (mixture of regioisomers). LC-MS: m / z = 294.2 [M+H] + ,ESI pos.

[0225] Step 2: 1-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine To a solution of trimethyl-[2-[(5-nitrobenzimidazol-1-yl)methoxy]ethyl]silane (2.4 g, 8.18 mmol, 1.0 eq.) (mixture of regioisomers) in EtOH (30 mL) and HO (10 mL) was added NH4Cl (4.38 g, 81.8 mmol, 10.0 eq.) and Fe (2.28 g, 40.9 mmol, 5.0 eq.). The mixture was stirred at 50 °C under a N2 atmosphere for 16 h. The suspension was cooled to 20 °C, filtered through a Celite pad, and the filter cake was washed with MeOH (50 mL × 5). The combined filtrates were concentrated under reduced pressure. The residue was treated with HO (300 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous NaSO, and concentrated under reduced pressure to give 1-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine (2.05 g, 85.6%) (mixture of regioisomers) as a brown oil. LC-MS: m / z = 264.0 [M+H] + ,ESI pos.

[0226] Step 3: N-[1-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]cyclopropanecarboxamide To a solution of cyclopropanecarboxylic acid (196.1 mg, 2.28 mmol, 1.2 eq.) and 1-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine (500 mg, 1.9 mmol, 1.0 eq.) (mixture of regioisomers) in DMF (5 mL) was added HATU (669.87 mg, 2.85 mmol, 1.5 eq.) and stirred at 25 °C for 0.5 h. DIPEA (736.02 mg, 5.69 mmol, 3.0 eq.) was added and stirring at 25 °C continued for an additional 0.5 h. The reaction mixture was quenched with HO (50 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by flash column chromatography using 0% to 50% EtOAc in PE to give N-[1-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]cyclopropanecarboxamide (350.0 mg, 50.1%) as a brown solid. LC-MS: m / z = 332.0 [M+H] + ,ESI pos. 1 H NMR(400MHz,CDCl3)δ=8.25(s,1H),7.94(s,1H),7.91(brs,1H),7.68(brd,J=8.7Hz,1H),7.05(brd,J=8.3Hz,1H),5.48(s,2H),3.51 (d,J=8.2Hz,2H),1.56(td,J=3.8,7.9Hz,1H),1.12-1.07(m,2H),0.90(d,J=8.3Hz,2H),0.85(brdd,J=3.1,7.7Hz,2H),-0.06(s,8H).

[0227] N-[3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]cyclopropanecarboxamide (200.0 mg, 28.6%) was also obtained as a brown solid. LC-MS: m / z=332.0 [M+H] + ,ESI pos. 1H NMR(400MHz,CDCl3)δ=7.99(s,1H),7.88(brs,1H),7.63(brs,1H),7.49(brd,J=8.7Hz,1H),5.53(s,2H),3.51( t,J=8.2Hz,2H),1.60-1.51(m,1H),1.16-1.11(m,2H),0.92(d,J=8.2Hz,2H),0.90-0.86(m,2H),-0.04(s,9H).

[0228] Step 4: N-(1H-benzimidazol-5-yl)cyclopropanecarboxamide; 2,2,2-trifluoroacetic acid A solution of N-[1-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl] in TFA (1 mL) was stirred at 25° C. for 1 h. The reaction mixture was concentrated to dryness to give N-(1H-benzimidazol-5-yl)cyclopropanecarboxamide; 2,2,2-trifluoroacetic acid (500.0 mg, 94.6%) as an orange oil. LC-MS: m / z=202.1 [M+H] + ,ESI pos. 1 H NMR(400MHz,CD3OD)δ=9.30(s,1H),8.46(d,J=1.3Hz,1H),7.78(d,J=8.9Hz,1H),7.59(d d,J=1.8,8.9Hz,1H),1.88-1.80(m,1H),1.03-0.99(m,2H),0.93(td,J=3.1,7.8Hz,2H).

[0229] Step 5: N-[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]benzimidazol-5-yl]cyclopropanecarboxamide A solution of 1-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (100.0 mg, 0.37 mmol, 1.0 eq) in t-amyl alcohol (5.0 mL, 45.89 mmol, 123.28 eq) was added with N-(1H-benzimidazol-5-yl)cyclopropanecarboxamide; 2,2,2-trifluoroacetic acid (129.08 mg, 0.41 mmol, 1.1 eq), K3PO4 (236.74 mg, 1.12 mmol, 3.0 eq) and t BuXPhos Pd G3 (29.56 mg, 0.04 mmol, 0.1 eq.) was added. The reaction mixture was heated to 100 °C and stirred under N2 atmosphere for 3 h. The mixture was cooled to 25 °C, quenched with HO (20 mL), and extracted with EtOAc (10 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (ACS-WH-GX-F, 37–67% CH3CN in HO (containing 0.225% HCOOH) for 10 min, flow rate: 25 mL / min) to give N-[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]benzimidazol-5-yl]cyclopropanecarboxamide (3.5 mg, 2.2%) as a white solid. LC-MS: m / z=434.2 [M+H] + ,ESI pos. 1 H NMR(400MHz,CD3OD)δ=8.99(s,1H),8.56(d,J=8.6Hz,1H),8.22(d,J=8.6Hz,1H),8.16(dd,J=3.5,5.2Hz,2H),7.57(dd,J=1.8,8 .9Hz,1H),7.08(t,J=54.7Hz,1H),6.91(d,J=0.6Hz,1H),2.53(s,3H),1.86-1.77(m,1H),1.03-0.97(m,2H),0.92-0.87(m,2H).

[0230] Example 32 1-[6-[1-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(difluoromethyl)-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine [ka] Step 1: 1-[6-chloro-5-(1,3-dioxolan-2-yl)-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine A solution of 6-methoxy-N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine (580.05 mg, 2.27 mmol, 1.0 eq.), 2,6-dichloro-3-(1,3-dioxolan-2-yl)pyridine (500.0 mg, 2.27 mmol, 1.0 eq.), and KCO (626.72 mg, 4.54 mmol, 2.0 eq.) in DMSO (8 mL) was stirred at 120 °C for 12 h. The reaction mixture was cooled to 23 °C, and HO (50 mL) was added. The insoluble material was collected by filtration and dried under reduced pressure. The crude material was purified by preparative HPLC (Welch μLtimate XB-CN (250 mm × 70 mm, 10 μm), EtOH gradient in hexane). The collected fractions were combined and concentrated to dryness. The residual solid was triturated with MeOH (5 mL) and the suspension was stirred at 25° C. for 30 min. The product was collected by filtration, washed with MeOH, and dewatered to give 1-[6-chloro-5-(1,3-dioxolan-2-yl)-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (80.0 mg, 8%) as a white solid. LC-MS: m / z=439.2 [M+H] + ,ESI pos. 1H NMR(400MHz,DMSO-d6)δ=8.89(s,1H),8.78(s,1H),8.39(s,1H),8.20(d,J=8.4Hz,1H),8.06(d,J=8.4Hz,1 H),7.98(s,1H),7.32(s,2H),6.07(s,1H),4.20-4.10(m,2H),4.08-4.02(m,2H),3.97(s,3H),2.48(s,3H).

[0231] Step 2: 1-[6-[1-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(1,3-dioxolan-2-yl)-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine To a solution of 1-[6-chloro-5-(1,3-dioxolan-2-yl)-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (100.0 mg, 0.23 mmol, 1.0 eq.) and 1-(cyclopropylmethyl)-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (71.68 mg, 0.27 mmol, 1.2 eq.) in THF (5 mL) was added KPO (0.46 mL, 0.68 mmol, 3.0 eq.) and Sphos Pd G (19.95 mg, 0.02 mmol, 0.1 eq.). Stirring at 60 °C was continued for 12 h. The reaction mixture was cooled to 23 °C and concentrated under reduced pressure. The crude product was purified by reverse-phase HPLC (50% CHCN in H2O (containing 0.1% HCOOH)) to give 1-[6-[1-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(1,3-dioxolan-2-yl)-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (100.0 mg, 81.5%) as a yellow solid. LC-MS: m / z = 539.3 [M+H] + ,ESI pos.

[0232] Step 3: 2-[1-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbaldehyde A solution of 1-[6-[1-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(1,3-dioxolan-2-yl)-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (100.0 mg, 0.19 mmol, 1.0 eq.) in a 4 M solution of HCl in dioxane (0.94 mL, 3.78 mmol, 20.34 eq.) was stirred at 25 °C for 2 h. The pH of the mixture was adjusted to 6 with saturated aqueous NaHCO . The precipitated solid was collected by filtration and dissolved in HO (5 mL). The solution was concentrated to dryness to give 2-[1-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbaldehyde (80.0 mg, 87.1%) as a yellow solid. LC-MS: m / z=495.3 [M+H] + ,ESI pos.

[0233] Step 4: 1-[6-[1-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(difluoromethyl)-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine To a solution of 2-[1-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbaldehyde (70.0 mg, 0.14 mmol, 1.0 eq.) in DCM (5 mL) was added DAST (114.22 mg, 0.71 mmol, 5.0 eq.) at 0° C., and the resulting mixture was stirred for 12 h at 25° C. The reaction mixture was quenched by the addition of HO (0.5 mL) at 25° C. and concentrated under reduced pressure to remove DCM. The remaining aqueous mixture was purified by preparative HPLC (Phenomenex Luna C18 (150 mm × 25 mm, 10 μm), CH3CN in HO (0.225% HCOOH)) to give 1-[6-[1-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(difluoromethyl)-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (10.0 mg, 13.4%) as a yellow solid. LC-MS: m / z = 517.3 [M+H] + ,ESI pos. 1 H NMR(400MHz,CD3OD)δ=8.81(s,1H),8.61(s,1H),8.33(d,J=8.8Hz,1H),8.04-7.82(m,3H),7.37(d,J=9.2Hz,1H),7.26(d,J=9.2Hz,1H),7 .09-6.65(m,1H),4.05(d,J=7.2Hz,2H),3.91(s,3H),2.54(s,3H),2.45(s,3H),1.47-1.30(m,1H),0.80-0.60(m,2H),0.50-0.40(m,2H).

[0234] Example 33 3-(Difluoromethoxy)-1-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-6,7-dihydropyrazolo[4,3-c]pyridin-4-one [ka] Step 1: 5-Methyl-1,2,6,7-tetrahydropyrazolo[4,3-c]pyridine-3,4-quinone To a solution of 2,4-diketo-1-methyl-nipecotic acid ethyl ester (570 mg, 2.86 mmol, 1.0 eq.) and AcOH (336.79 mg, 321.05 μL, 5.61 mmol, 1.96 eq.) in EtOH (23.83 mL) was added a 1 M solution of hydrazine in THF (4.27 g, 4.18 mL, 4.18 mmol, 1.46 eq.) in one portion in a microwave tube. The tube was sealed, and the mixture was stirred at 23 °C for 20 h. The resulting reaction mixture was stirred at 100 °C under microwave irradiation for 1 h. The reaction mixture was cooled to 23 °C and concentrated to dryness. The residue was triturated with a mixture of MeOH (3 mL) and DCM (5 mL). The solid was collected by filtration, washed with DCM, and dried. 5-Methyl-1,2,6,7-tetrahydropyrazolo[4,3-c]pyridine-3,4-quinone (414 mg, 82.2% yield) was obtained as a white solid. LC-MS: m / z=168.1 [M+H] + ,ESI pos.

[0235] Step 2: 3-Hydroxy-4-keto-5-methyl-6,7-dihydropyrazolo[4,3-c]pyridine-1-carboxylic acid tert-butyl ester To a mixture of 5-methyl-1,2,6,7-tetrahydropyrazolo[4,3-c]pyridine-3,4-quinone (155 mg, 0.927 mmol, 1.0 eq.) in DCM (0.909 mL) was added EtN (103.21 mg, 142.16 μL, 1.02 mmol, 1.1 eq.) and (Boc)O (202.36 mg, 215.28 μL, 0.927 mmol, 1.0 eq.). The reaction mixture was stirred at 23 °C for 16 h and evaporated to dryness to give 3-hydroxy-4-keto-5-methyl-6,7-dihydropyrazolo[4,3-c]pyridine-1-carboxylic acid tert-butyl ester (247 mg, 94.7%) as a white solid. LC-MS: m / z = 268.2 [M+H] + ,ESI pos.

[0236] Step 3: 3-(Difluoromethoxy)-4-keto-5-methyl-6,7-dihydropyrazolo[4,3-c]pyridine-1-carboxylic acid tert-butyl ester To a solution of 3,4-diketo-5-methyl-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-1-carboxylic acid tert-butyl ester (247.77 mg, 0.927 mmol, 1.0 eq.) in DMF (8.43 mL) was added KCO (384.36 mg, 2.78 mmol, 3.0 eq.) and sodium chlorodifluoroacetate (212 mg, 1.39 mmol, 1.5 eq.). The mixture was heated to 80 °C and stirred for 30 min. The reaction mixture was cooled to 23 °C, diluted with HO, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO, filtered, and concentrated in vacuo to give 3-(difluoromethoxy)-4-keto-5-methyl-6,7-dihydropyrazolo[4,3-c]pyridine-1-carboxylic acid tert-butyl ester (184 mg, 37.5%) as an orange liquid, which was used without further purification. LC-MS: m / z=318.2 [M+H] + ,ESI pos.

[0237] Step 4: 3-(Difluoromethoxy)-5-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-4-one; 1:1 Hydrogen Chloride To a solution of 3-(difluoromethoxy)-4-keto-5-methyl-6,7-dihydropyrazolo[4,3-c]pyridine-1-carboxylic acid tert-butyl ester (183.39 mg, 0.578 mmol, 1.0 eq.) in 1,4-dioxane (2.64 mL), a 4 M solution of HCl in dioxane (5.2 g, 4.34 mL, 17.34 mmol, 30.0 eq.) was added, and the mixture was stirred at 23 °C for 16 h. The reaction mixture was concentrated to dryness to give 3-(difluoromethoxy)-5-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-4-one 1:1 hydrochloride (131 mg, 71.5%) as a pale yellow solid. LC-MS: m / z = 218.1 [M+H] + ,ESI pos.

[0238] Step 5: 6-chloro-2-[3-(difluoromethoxy)-4-keto-5-methyl-6,7-dihydropyrazolo[4,3-c]pyridin-1-yl]nicotinaldehyde To a solution of 6-chloro-2-fluoro-nicotinaldehyde (74.99 mg, 0.470 mmol, 1.0 eq.) in DMF (0.750 mL) was added 3-(difluoromethoxy)-5-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-4-one; hydrochloride (131.13 mg, 0.517 mmol, 1.1 eq.) and K2CO3 (194.88 mg, 1.41 mmol, 3.000 eq.). The reaction mixture was stirred at 23 °C for 1 h. The reaction mixture was diluted with HO and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (first using 0% to 100% EtOAc in heptane and then 20% to 80% EtOAc in heptane) to give 6-chloro-2-[3-(difluoromethoxy)-4-keto-5-methyl-6,7-dihydropyrazolo[4,3-c]pyridin-1-yl]nicotinaldehyde (115 mg, 63.6%) as a white solid. LC-MS: m / z = 357.1 [M+H] + ,ESI pos.

[0239] Step 6: 1-[6-chloro-3-(difluoromethyl)-2-pyridyl]-3-(difluoromethoxy)-5-methyl-6,7-dihydropyrazolo[4,3-c]pyridin-4-one To a solution of 6-chloro-2-[3-(difluoromethoxy)-4-keto-5-methyl-6,7-dihydropyrazolo[4,3-c]pyridin-1-yl]nicotinaldehyde (57.07 mg, 0.160 mmol, 1.0 eq.) in DCMe (0.255 mL) was added DAST (77.37 mg, 63.42 μL, 0.480 mmol, 3.0 eq.) at 0° C. The reaction mixture was stirred at 0° C. for 2.5 h, poured into saturated aqueous NaHCO3, and extracted with DCM. The organic layer was washed with brine, dried over MgSO, filtered, and concentrated in vacuo to give 1-[6-chloro-3-(difluoromethyl)-2-pyridyl]-3-(difluoromethoxy)-5-methyl-6,7-dihydropyrazolo[4,3-c]pyridin-4-one (60.5 mg, 90.9%) as a pale yellow solid. LC-MS: m / z=379.1 [M+H] + ,ESI pos.

[0240] Step 7: 3-(Difluoromethoxy)-1-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-6,7-dihydropyrazolo[4,3-c]pyridin-4-one

[0241] Prepared according to Example 7, step 2 to give 3-(difluoromethoxy)-1-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-6,7-dihydropyrazolo[4,3-c]pyridin-4-one (19.8 mg, 20.5%) as a yellow solid. LC-MS: m / z=598.2 [M+H] + ,ESI pos.

[0242] Example 34 2-[3-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-5-yl]oxy-N,N-dimethyl-acetamide [ka] Step 1: 2-(5-amino-2-bromo-4-nitro-phenoxy)-N,N-dimethyl-acetamide To a solution of 2-hydroxy-N,N-dimethyl-acetamide (1.0 g, 9.7 mmol, 1.14 eq.) in THF (20 mL) was added 60% NaH dispersion in mineral oil (680.82 mg, 17.02 mmol, 2.0 eq.). The mixture was stirred at 0 °C for 1 h. 4-Bromo-5-fluoro-2-nitro-aniline (2.0 g, 8.51 mmol, 1.0 eq.) was added and stirring was continued at 25 °C for 12 h. The reaction mixture was diluted with HO (40 mL) and extracted with EtOAc. A solid precipitated. It was collected by filtration and dried to give 2-(5-amino-2-bromo-4-nitro-phenoxy)-N,N-dimethyl-acetamide (300.0 mg, 10%) as an orange solid. LC-MS: m / z = 317.8 [M+H] + ,ESI pos. 1 H NMR (400 MHz, DMSO-d6) δ = 8.13 (s, 1H), 7.56 (s, 2H), 6.38 (s, 1H), 4.98 (s, 2H), 3.00 (s, 3H), 2.86 (s, 3H). The layers from the biphasic filtrate were separated, and the organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography using 80% EtOAc in PE to give a second crop of 2-(5-amino-2-bromo-4-nitro-phenoxy)-N,N-dimethyl-acetamide (700.0 mg, 23.3%) as a yellow solid. LC-MS: m / z = 317.8 [M+H] + ,ESI pos. 1 H NMR(400MHz, CDCl3)δ=8.28(s,1H),6.29(s,1H),4.73(s,2H),3.07(s,3H),2.91(s,3H).

[0243] Step 2: 2-(4,5-diamino-2-bromo-phenoxy)-N,N-dimethyl-acetamide To a solution of 2-(5-amino-2-bromo-4-nitro-phenoxy)-N,N-dimethyl-acetamide (1.0 g, 3.14 mmol, 1.0 eq.) in EtOH (20 mL) was added Fe (877.66 mg, 15.72 mmol, 5.0 eq.), NH4Cl (1681.44 mg, 31.43 mmol, 10.0 eq.), and HO (5 mL). The mixture was stirred under N2 at 50 °C for 2 h. The reaction mixture was concentrated under reduced pressure, and a mixture of DCM / MeOH 10:1 (50 mL) was added. Stirring at 50 °C was continued for 1 h. The mixture was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC in DCM / MeOH 10:1 to give 2-(4,5-diamino-2-bromo-phenoxy)-N,N-dimethyl-acetamide (500.0 mg, 49.7%) as a grey solid. LC-MS: m / z=288.0 [M+H] + ,ESI pos. 1 H NMR(400MHz,CD3OD)δ=6.87(s,1H),6.46(s,1H),4.67(s,2H),3.13(s,3H),2.99(s,3H).

[0244] Step 3: 2-[(6-bromo-3H-benzimidazol-5-yl)oxy]-N,N-dimethyl-acetamide To a solution of 2-(4,5-diamino-2-bromo-phenoxy)-N,N-dimethyl-acetamide (500.0 mg, 1.74 mmol, 1.0 eq.) in EtOH (1 mL), trimethyl orthoformate (1841.47 mg, 17.35 mmol, 10.0 eq.) and TsOH (26.69 mg, 0.17 mmol, 0.1 eq.) were added. The mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography using 0% to 10% MeOH in EtOAc to give 2-[(6-bromo-3H-benzimidazol-5-yl)oxy]-N,N-dimethyl-acetamide (500.0 mg, 87%) as a brown solid. LC-MS: m / z = 299.8 [M+H] + ,ESI pos. 1H NMR(400MHz,CD3OD)δ=8.13(s,1H),7.84(s,1H),7.24(s,1H),4.91(s,2H),3.18(s,3H),3.01(s,3H).

[0245] Step 4: 2-[6-bromo-3-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]benzimidazol-5-yl]oxy-N,N-dimethyl-acetamide To a solution of 2-[(6-bromo-3H-benzimidazol-5-yl)oxy]-N,N-dimethyl-ethanamine (200.0 mg, 0.7 mmol, 1.0 eq.) in DMSO (2 mL) was added 1-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (189.09 mg, 0.7 mmol, 1.0 eq.) and K2CO3 (291.84 mg, 2.11 mmol, 3.0 eq.) and stirring was continued at 50 °C for 1 h. The reaction mixture was diluted with HO (10 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were washed with brine (5 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC using DCM / MeOH 10:1 to give 2-[6-bromo-3-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]benzimidazol-5-yl]oxy-N,N-dimethyl-acetamide (80.0 mg, 19.3%) as a white solid. LC-MS: m / z=531.7 [M+H] + ,ESI pos. 1 H NMR(400MHz,CDCl3)δ=8.58(s,1H),8.46(d,J=8.4Hz,1H),8.31(s,1H),7.79(d,J=8.4Hz,1H),7.42(s,1H) ,7.36(s,1H),7.23(s,1H),7.09(s,1H),6.73(s,1H),4.88(s,2H),3.18(s,3H),3.03(s,3H),2.58(s,3H).

[0246] Also, 2-[6-bromo-1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]benzimidazol-5-yl]oxy-N,N-dimethyl-acetamide (80.0 mg, 19.3%) was obtained as a white solid. LC-MS: m / z=531.7 [M+H] + ,ESI pos. 1 H NMR(400MHz,CDCl3)δ=8.57(s,1H),8.53(d,J=8.6Hz,1H),8.10(s,1H),7.85(d,J=8.3Hz,1H),7.80(s,1H),7.3 3(s,1H),7.19(s,1H),7.06(s,1H),6.71(d,J=0.6Hz,1H),4.84(s,2H),3.18(s,3H),2.96(s,3H),2.56(s,3H).

[0247] Step 5: 2-[3-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-5-yl]oxy-N,N-dimethyl-acetamide Prepared according to step 4 of Example 4, 2-[3-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-5-yl]oxy-N,N-dimethyl-acetamide (12.1 mg, 13.9%) was obtained as an off-white solid after purification by preparative HPLC (ACS-WH-GX-F, 10-40% CHCN in HO (containing HCOOH), 10 min, flow rate: 25 mL / min). LC-MS: m / z=559.3 [M+H] + ,ESI pos. 1H NMR(400MHz,DMSO-d6)δ=9.03(s,1H),8.85(s,1H),8.81(s,1H),8.59(d,J=8.7Hz,1H),8.34(d,J=8.6Hz,1H),7.78(s,1H), 7.37-7.33(m,1H),7.30-7.26(m,1H),7.22-6.92(m,2H),4.95(s,2H),2.90(s,3H),2.83(s,3H),2.55(s,3H),2.46(s,3H).

[0248] Example 35 1-[5-(difluoromethyl)-6-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine [ka] Step 1: 4-Bromo-5-methoxy-2-nitroaniline To a solution of 5-methoxy-2-nitroaniline (10.0 g, 59.47 mmol, 1.0 eq.) in acetonitrile (150 mL), NBS (11.6 g, 65.42 mmol, 1.1 eq.) was added portionwise at room temperature under N2, and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was poured into saturated aqueous Na2SO3 (300 mL) with vigorous stirring, and HO (500 mL) was added. The resulting precipitate was filtered, and the filter cake was dried to give 4-bromo-5-methoxy-2-nitroaniline (13.0 g, 52.62 mmol, 88% yield) as a yellow solid. ESI pos[M+H] + 249.1. 1 H NMR(400MHz,CDCl3)δ=8.36(s,1H),6.25(brs,2H),6.18(s,1H),3.92(s,3H)

[0249] Step 2: 4-Bromo-5-methoxy-benzene-1,2-diamine To a solution of 4-bromo-5-methoxy-2-nitro-aniline (13.0 g, 52.6 mmol, 1.0 eq.) in a mixture of DCM (260 mL) and MeOH (260 mL), saturated NH4Cl (520 mL, 1052 mmol, 20.0 eq.) was added at room temperature, and N2 was bubbled through the mixture for 10 min. Zn (34.4 g, 527 mmol, 10.0 eq.) was added portionwise at room temperature, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was dissolved in DCM (600 mL) and washed with brine (3 × 200 mL). The combined organic phases were concentrated to give 4-bromo-5-methoxy-benzene-1,2-diamine (11.0 g, 50.68 mmol, 96% yield) as a black solid, which was used without further purification. ESI pos[M+H] + 217.0. 1 H NMR(400MHz,DMSO-d6)δ=6.66(s,1H),6.34(s,1H),4.79-4.13(m,4H),3.63(s,3H).

[0250] Step 3: 5-Bromo-6-methoxy-1H-benzimidazole To a solution of 4-bromo-5-methoxy-benzene-1,2-diamine (11.0 g, 50.7 mmol, 1.0 eq.) in trimethyl orthoformate (200 mL, 507 mmol, 10.0 eq.) was added formic acid (10.0 mL, 265 mmol, 5.2 eq.), and the mixture was stirred at 90 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (400 mL) and washed with saturated NaHCO (300 mL). The organic phase was then washed with brine (3 × 100 mL), dried over NaSO, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, EtOAc) to give 5-bromo-6-methoxy-1H-benzimidazole (9.6 g, 42.3 mmol, 83% yield) as a yellow solid. ESI pos[M+H] + 227.0. 1H NMR(400MHz,DMSO-d6)δ=12.53-12.20(m,1H),8.14(brs,1H),7.90-7.68(m,1H),7.40-7.09(m,1H),3.86(s,3H).

[0251] Step 4: 2-[(5-bromo-6-methoxy-benzimidazol-1-yl)methoxy]ethyl-trimethyl-silane and 2-[(6-bromo-6-methoxy-benzimidazol-1-yl)methoxy]ethyl-trimethyl-silane To a solution of 2-(trimethylsilyl)ethoxymethyl chloride (3.27 mL, 18.5 mmol, 1.4 eq.) in DMF (60 mL) was added sodium hydride (60% in oil) (635 mg, 15.9 mmol, 1.2 eq.) portionwise at 0 °C. After the addition, the mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was cooled to 0 °C, and 5-bromo-6-methoxy-1H-benzimidazole (3.0 g, 13.2 mmol, 1.0 eq.) was added. The mixture was allowed to warm to room temperature and stirred for 16 h. The mixture was poured into saturated aqueous NH4Cl (300 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0% to 20% EtOAc in petroleum ether) to give a mixture of 2-[(5-bromo-6-methoxy-benzimidazol-1-yl)methoxy]ethyl-trimethylsilane and 2-[(6-bromo-5-methoxy-benzimidazol-1-yl)methoxy]ethyl-trimethylsilane (2.8 g, 7.84 mmol, 59% yield) as a yellow oil. ESI pos[M+H] + 357.0.

[0252] Step 5: 6-Methoxy-N-(6-methylpyridazin-3-yl)-1-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine and 6-Methoxy-N-(6-methylpyridazin-3-yl)-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine A solution of a mixture of 2-[(5-bromo-6-methoxybenzimidazol-1-yl)methoxy]ethyl-trimethylsilane and 2-[(6-bromo-5-methoxybenzimidazol-1-yl)methoxy]ethyl-trimethylsilane (2.8 g, 7.84 mmol, 1.0 eq.), 3-amino-6-methylpyridazine (1.71 g, 15.7 mmol, 2.0 eq.), and CsCO (7.66 g, 23.5 mmol, 3.0 eq.) in 1,4-dioxane (50 mL) was bubbled with N for 10 min. [tBuBrettPhos Pd(allyl)]OTf (613 mg, 0.78 mmol, 0.1 eq.) was added, and the mixture was stirred at 80 °C under N atmosphere for 4 h. The mixture was poured into saturated aqueous NH4Cl (300 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0% to 100% EtOAc in petroleum ether) to give a mixture of 6-methoxy-N-(6-methylpyridazin-3-yl)-1-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine and 6-methoxy-N-(6-methylpyridazin-3-yl)-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine (3.0 g, 7.78 mmol, 94% yield) as a yellow oil. ESI pos[M+H] + 386.1.

[0253] Step 6: 6-Methoxy-N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine A solution of 6-methoxy-N-(6-methylpyridazin-3-yl)-1-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine and 6-methoxy-N-(6-methylpyridazin-3-yl)-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine (3.0 g, 7.39 mmol, 1.0 eq.) in trifluoroacetic acid (10 mL, 130 mmol, 18 eq.) was stirred at room temperature for 3 h. The mixture was concentrated, and the resulting gum was dissolved in MeOH (10 mL). Aqueous NH3 (10%) (10 mL) was carefully added until the pH reached 7, and the resulting yellow precipitate was filtered. The filter cake was washed with PE (3 × 10 mL) and dried to give 6-methoxy-N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine (1.0 g, 3.92 mmol, 52% yield) as a yellow solid. The combined filtrates were concentrated, and the resulting residue was purified by preparative HPLC (Kromasil Eternity XT 10 μm, 250 mm × 80 mm, 0.1% NH₄HCO₃ in water-ACN) to give 6-methoxy-N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine (0.5 g, 1.96 mmol, 26% yield) as a yellow solid. ESI pos[M+H] + 256.1. 1 H NMR(400MHz,CD3OD)δ=8.61(s,1H),8.36(s,1H),7.41(d,J=9.3Hz,1H),7.33-7.28(m,1H),7.26(s,1H),3.98(s,3H),2.54(s,3H).

[0254] Step 7: 6-Methoxy-N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine A solution of 6-methoxy-N-(6-methylpyridazin-3-yl)-1-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine (10.6 g, 27.49 mmol, 1.0 eq.) in TFA (20.0 mL, 259.6 mmol, 9.44 eq.) was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (CHCN in HO (containing 0.1% NHOH)) to give 6-methoxy-N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine (10.0 g, 99.7% yield) as a brown solid. LC-MS: m / z = 256.0 [M+H] + ,ESI pos.

[0255] Step 8: 1-[5-(1,3-dioxolan-2-yl)-6-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine Prepared according to step 7 of example 6 to give 1-[5-(1,3-dioxolan-2-yl)-6-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (180.0 mg, 72.8%) as a yellow solid (mixture of regioisomers in pyrazole). LC-MS: m / z=543.3 [M+H] + ,ESI pos.

[0256] Step 8: 2-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbaldehyde Prepared according to step 3 of Example 32 to give 2-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbaldehyde (160.0 mg, 96.7%) as a yellow solid (mixture of regioisomers in pyrazole). LC-MS: m / z=499.2 [M+H] + ,ESI pos.

[0257] Step 10: 1-[5-(difluoromethyl)-6-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine Prepared according to step 4 of Example 32, 1-[5-(difluoromethyl)-6-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (60.0 mg, 33.8%) was obtained as a yellow oil (mixture of regioisomers in pyrazole) after purification by preparative HPLC (Welch μLtimate XB-CN (250 mm × 50 mm, 10 μm), gradient of EtOH in hexane). LC-MS: m / z = 521.3 [M + H] + ,ESI pos. This regioisomeric mixture was purified by SFC (Daicel Chiralpak AS (250 mm × 30 mm, 10 μm), EtOH (0.1% NH4OH) in CO2) to give 1-[5-(difluoromethyl)-6-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (17.1 mg, 28.5%) as a yellow solid. LC-MS: m / z = 521.3 [M+H] + ,ESI pos. 1H NMR(400MHz,CD3OD)δ=8.81(s,1H),8.63(s,1H),8.33(d,J=8.8Hz,1H),7.98(s,1H),7.93-7.83(m,2H),7.35(d,J=9.2Hz,1H),7.23( d,J=9.2Hz,1H),7.01-6.64(m,1H),4.34(t,J=5.2Hz,2H),3.91(s,3H),3.79(t,J=5.2Hz,2H),3.37(s,2H),2.53(s,3H),2.45(s,3H).

[0258] Example 36 1-[5-(Difluoromethyl)-6-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine [ka] 1-[5-(difluoromethyl)-6-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (14.2 mg, 23.4%) obtained in Step 4 of Example 35 was obtained as a yellow solid. LC-MS: m / z=521.3 [M+H] + ,ESI pos. 1 H NMR(400MHz,CD3OD)δ=8.93-8.31(m,2H),8.23(d,J=8.4Hz,1H),8.00-7.75(m,2H),7.63(s,1H),7.40-7.10(m,2H),6. 96-6.47(m,1H),4.27(t,J=5.2Hz,2H),3.82(s,3H),3.71(t,J=5.2Hz,2H),3.25-3.23(m,3H),2.43(d,J=10.4Hz,6H).

[0259] Example 37 1-[5-(difluoromethyl)-6-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine [ka] Step 1: 1-[5-(1,3-dioxolan-2-yl)-6-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine and 1-[5-(1,3-dioxolan-2-yl)-6-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine

[0260] Prepared according to step 2 of Example 32 to give 1-[5-(1,3-dioxolan-2-yl)-6-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine and 1-[5-(1,3-dioxolan-2-yl)-6-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (250.0 mg, 96.8%) as a yellow solid. LC-MS: m / z=567.2 [M+H] + ,ESI pos.

[0261] Step 2: 6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridine-3-carbaldehyde and 6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridine-3-carbaldehyde Prepared according to step 3 of Example 35 to give 6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridine-3-carbaldehyde and 6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridine-3-carbaldehyde (190.0 mg, 82.4%) as a yellow solid. LC-MS: m / z=523.2 [M+H] + ,ESI pos.

[0262] Step 3: 1-[5-(difluoromethyl)-6-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine Prepared according to step 3 of example 35 to give 1-[5-(difluoromethyl)-6-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (4.6 mg, 15.1%) as a yellow solid. LC-MS: m / z=523.2 [M+H] + ,ESI pos. 1H NMR(400MHz,CD3OD)δ=8.84(s,1H),8.66(s,1H),8.35(d,J=8.4Hz,1H),8.01(d,J=15.6Hz,2H),7.96(d,J=8.4Hz,1H),7. 35(d,J=9.2Hz,1H),7.24(d,J=9.2Hz,1H),6.98-6.62(m,1H),5.04-4.98(m,2H),3.90(s,3H),2.53(s,3H),2.44(s,3H).

[0263] Example 38 1-[6-[1-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(difluoromethyl)-2-pyridyl]-6-fluoro-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine [ka] Step 1: 2-[(5-bromo-6-fluoro-benzimidazol-1-yl)methoxy]ethyl-trimethylsilane To a solution of 5-bromo-6-fluoro-1H-benzimidazole (5.0 g, 23.25 mmol, 1.0 eq.) and tetrabutylammonium bromide (0.75 g, 2.33 mmol, 0.1 eq.) in DCM (40 mL) was added a solution of KOH (2.6 g, 23.25 mmol, 1.0 eq.) in HO (20 mL). SEM-Cl (4.63 g, 27.9 mmol, 1.2 eq.) was added at 0 °C, and the resulting mixture was stirred for 1 h, then at 25 °C for 1 h. Saturated aqueous NaCl (100 mL) was added, and the reaction mixture was extracted with EtOAc (50 mL × 3). The combined organic extracts were concentrated under reduced pressure. The residue was purified by flash column chromatography using 10% to 50% EtOAc in PE to give 2-[(5-bromo-6-fluoro-benzimidazol-1-yl)methoxy]ethyl-trimethylsilane (8.4 g, 94.2%) as a brown oil. LC-MS: m / z = 347.0 [M+H] + ,ESI pos.

[0264] Step 2: 6-fluoro-N-(6-methylpyridazin-3-yl)-1-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine A mixture of 2-[(5-bromo-6-fluoro-benzimidazol-1-yl)methoxy]ethyl-trimethylsilane (8.0 g, 23.17 mmol, 1.0 eq.), 3-amino-6-methylpyridazine (3.03 g, 27.8 mmol, 1.2 eq.), [Pd(allyl)(tBuBrettPhos)]OTf (0.91 g, 1.16 mmol, 0.05 eq.) and CsCO (22.65 g, 69.51 mmol, 3.0 eq.) in 1,4-dioxane (100 mL) was stirred at 100 °C for 12 h under N atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give 6-fluoro-N-(6-methylpyridazin-3-yl)-1-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine (11.0 g, 95.3%) as a brown oil. LC-MS: m / z=374.2 [M+H] + ,ESI pos.

[0265] Step 3: 6-fluoro-N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine; formic acid A mixture of 6-fluoro-N-(6-methylpyridazin-3-yl)-1-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine (11.0 g, 29.45 mmol, 1.0 eq.) and TFA (32.0 mL) was stirred at 25 °C for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (10% CHCN in H2O (containing 0.1% FA)) to give 6-fluoro-N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine; formate (9.0 g, 89.8%) as a yellow solid. LC-MS: m / z = 244.0 [M+H] + ,ESI pos.

[0266] Step 4: 1-[6-chloro-5(1,3-dioxolan-2-yl)-2-pyridyl]-6-fluoro-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine Prepared according to Step 1 of Example 32 to afford 1-[6-chloro-5-(1,3-dioxolan-2-yl)-2-pyridyl]-6-fluoro-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (300.0 mg, 9.6%) as a white solid. LC-MS: m / z=426.8 [M+H] + ,ESI pos. 1 H NMR(400MHz,DMSO-d6)δ=9.06(s,1H),8.89(s,1H),8.69(d,J=7.8Hz,1H),8.22-8.14(m,2H),8.07( d,J=8.3Hz,1H),7.38-7.33(m,1H),7.29-7.24(m,1H),6.05(s,1H),4.16-4.01(m,4H),2.48(s,3H).

[0267] Step 5: 1-[6-[1-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(1,3-dioxolan-2-yl)-2-pyridyl]-6-fluoro-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine Prepared according to step 2 of example 35 to give 1-[6-[1-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(1,3-dioxolan-2-yl)-2-pyridyl]-6-fluoro-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (90.0 mg, 72.9%) as a white solid. LC-MS: m / z=527.3 [M+H] + ,ESI pos.

[0268] Step 6: 2-[1-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-6-[6-fluoro-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbaldehyde Prepared according to step 3 of example 35 to give 2-[1-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-6-[6-fluoro-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbaldehyde (80.0 mg, 97.0%) as a yellow solid. LC-MS: m / z=483.3 [M+H] + ,ESI pos.

[0269] Step 7: 1-[6-[1-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(difluoromethyl)-2-pyridyl]-6-fluoro-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine Prepared according to Example 35, step 4 to give 1-[6-[1-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(difluoromethyl)-2-pyridyl]-6-fluoro-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (17.7 mg, 24.8%) as a white solid. LC-MS: m / z=505.3 [M+H] + ,ESI pos. 1 H NMR(400MHz,CD3OD)δ=8.95(s,1H),8.55(d,J=7.6Hz,1H),8.34(d,J=8.8Hz,1H),8.20(d,J=11.6Hz,1H),8.03-7.85(m,2H),7.40(d,J=9.2Hz,1H),7. 23(d,J=9.2Hz,1H),7.01-6.60(m,1H),4.05(d,J=7.2Hz,2H),2.54(s,3H) ,2.42(s,3H),1.47-1.31(m,1H),0.74-0.61(m,2H),0.46(q,J=5.2Hz,2H).

[0270] Example 39 1-[3-(Difluoromethyl)-6-[6-fluoro-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Step 1: 1-[3-(difluoromethyl)-6-[6-fluoro-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile 1-[6-Chloro-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (100 mg, 0.372 mmol, 1.0 eq.) was dissolved in t-amyl alcohol (2.67 mL). (6-Fluoro-1H-benzimidazol-5-yl)-(6-methylpyridazin-3-yl)amine (99.6 mg, 0.409 mmol, 1.1 eq.) and potassium phosphate tripotassium (237.04 mg, 1.12 mmol, 3.0 eq.) were added at 23 °C. The suspension was purged with argon, and then tBuXPhosPdG (29.57 mg, 0.037 mmol, 0.1 eq.) was added. The vial was closed under argon, and the reaction mixture was heated to 80 °C and stirred overnight. The reaction mixture was cooled to 23 °C, diluted with HO, and extracted with EtOAc (2x). The combined organic layers were dried over MgSO4, filtered, and concentrated to dryness. The crude product was purified by flash column chromatography using 0% to 5% MeOH in DCM to give 1-[3-(difluoromethyl)-6-[6-fluoro-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (58.4 mg, 32.9%) as a white solid. LC-MS: m / z=476.2 [M+H] + ,ESI pos.

[0271] Example 40 1-[3-(Difluoromethyl)-6-[6-methoxy-5-[[5-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl]pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Step 1: 6-(6-chloropyridazin-4-yl)-3-oxa-6-azabicyclo[3.1.1]heptane To a mixture of 3,5-dichloropyridazine (274.12 mg, 1.84 mmol, 1.0 eq.) and KCO (762.92 mg, 5.52 mmol, 3.0 eq.) in CHCN (4.35 mL) was added 3-oxa-6-azabicyclo[3.1.1]heptane hydrochloride (299.38 mg, 2.21 mmol, 1.2 eq.). The mixture was stirred at 60 °C for 16 h, cooled to 23 °C, and concentrated under reduced pressure. The residue was purified by flash column chromatography using 20% ​​to 100% EtOAc in heptane to give 6-(6-chloropyridazin-4-yl)-3-oxa-6-azabicyclo[3.1.1]heptane as a pale yellow liquid (213 mg, 51.9%). LC-MS: m / z = 212.2 [M+H] + ,ESI pos.

[0272] Step 2: N-[5-[3-oxa-6-azabicyclo[3.1.1]heptan-6-yl]pyridazin-3-yl]carbamic acid tert-butyl ester To a mixture of 6-(6-chloropyridazin-4-yl)-3-oxa-6-azabicyclo[3.1.1]heptane (160 mg, 0.756 mmol, 1.0 eq.) in 1,4-dioxane (2.38 mL) was added tert-butyl carbamate (177.12 mg, 1.51 mmol, 2.0 eq.), CsCO (492.62 mg, 1.51 mmol, 2.0 eq.), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (87.48 mg, 0.151 mmol, 0.2 eq.), and tris(dibenzylideneacetone)dipalladium(0) chloroform complex (78.25 mg, 0.076 mmol, 0.1 eq.). The vial was sealed, and the mixture was heated to 90 °C and stirred for 3 h. The reaction mixture was cooled to 23 °C, diluted with HO, and extracted with DCM. The organic layer was washed with brine, dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using 0% to 100% DCM in DCM (DCM / MeOH 9:1) to give N-[5-[3-oxa-6-azabicyclo[3.1.1]heptan-6-yl]pyridazin-3-yl]carbamic acid tert-butyl ester as an orange solid (64.1 mg, 26.1%). LC-MS: m / z = 293.2 [M+H] + ,ESI pos.

[0273] Step 3: [5-[3-oxa-6-azabicyclo[3.1.1]heptan-6-yl]pyridazin-3-yl]amine; 2,2,2-trifluoroacetic acid N-[5-[3-oxa-6-azabicyclo[3.1.1]heptan-6-yl]pyridazin-3-yl]carbamic acid tert-butyl ester (64.1 mg, 0.219 mmol, 1.0 eq.) was dissolved in DCM (1.42 mL), TFA (250.01 mg, 168.93 μL, 2.19 mmol, 10.0 eq.) was added, and stirring was continued at 23 °C for 18 h. The solution was evaporated to dryness. The residue was triturated with 3 mL of EtO, and the resulting suspension was stirred for 30 min. The product was collected by filtration, washed with EtO, and dried to give [5-[3-oxa-6-azabicyclo[3.1.1]heptan-6-yl]pyridazin-3-yl]amine; 2,2,2-trifluoroacetic acid as an orange solid (52.3 mg, 62.3%). LC-MS: m / z=193.2 [M+H] + ,ESI pos.

[0274] Step 4: 1-[3-(difluoromethyl)-6-[6-methoxy-5-[[5-[3-oxa-6-azabicyclo[3.1.1]heptan-6-yl]pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile Prepared according to step 4 of example 4 to give 1-[3-(difluoromethyl)-6-[6-methoxy-5-[[5-[3-oxa-6-azabicyclo[3.1.1]heptan-6-yl]pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile as a yellow solid (35.6 mg, 50.9%). LC-MS: m / z=571.2 [M+H] + ,ESI pos.

[0275] Example 41 3-[[1-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-5-(difluoromethyl)-2-pyridyl]-6-methyl-benzimidazol-5-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide [ka] Step 1: Ethyl 3-(benzhydrylideneamino)-6-methyl-pyridazine-4-carboxylate Prepared according to step 4 of example 27 to give 3-(benzhydrylideneamino)-6-methyl-pyridazine-4-carboxylate (1200.0 mg, 69.7%) as a brown oil. LC-MS: m / z=346.1 [M+H] + ,ESI pos.

[0276] Step 2: 3-(Benzhydrylideneamino)-6-methyl-pyridazine-4-carboxylate; lithium salt To a mixture of 3-(benzhydrylideneamino)-6-methyl-pyridazine-4-carboxylate (1200.0 mg, 3.47 mmol, 1.0 eq.) in THF (6 mL), MeOH (6 mL), and HO (6 mL) was added LiOH (249.11 mg, 10.42 mmol, 3.0 eq.), and the reaction mixture was stirred at 30 °C for 12 h, turning into a clear solution. The mixture was concentrated in vacuo to give 3-(benzhydrylideneamino)-6-methyl-pyridazine-4-carboxylate; lithium salt (1000.0 mg, 89%) as a yellow solid. LC-MS: m / z = 318.1 [M+H] + ,ESI pos.

[0277] Step 3: 3-(Benzhydrylideneamino)-N,N,6-trimethyl-pyridazine-4-carboxamide To a suspension of dimethylamine hydrochloride (323.75 mg, 3.97 mmol, 1.5 eq.) in DMF (10 mL) was added DIPEA (1025.98 mg, 7.94 mmol, 3.0 eq.), 3-(benzhydrylideneamino)-6-methyl-pyridazine-4-carboxylic acid (840.0 mg, 2.65 mmol, 1.0 eq.), and HATU (934.12 mg, 3.97 mmol, 1.5 eq.). The reaction mixture was heated to 30 °C and stirred for 1 h. The reaction mixture was diluted with HO (50 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography using 30% to 40% EtOAc in PE to give 3-(benzhydrylideneamino)-N,N,6-trimethyl-pyridazine-4-carboxamide (400.0 mg, 39.5%) as a white solid. LC-MS: m / z = 345.2 [M + H]+,ESI pos. 1 H NMR(400MHz,CDCl3)δ=7.84-7.22(m,11H),3.06(s,3H),3.02(s,3H),2.61(s,3H).

[0278] Step 4: 3-amino-N,N,6-trimethyl-pyridazine-4-carboxamide To a colorless solution of 3-(benzhydrylideneamino)-N,N,6-trimethyl-pyridazine-4-carboxamide (400.0 mg, 1.16 mmol, 1.0 eq.) in MeOH (20 mL) was added hydroxylamine hydrochloride (161.41 mg, 2.32 mmol, 2.0 eq.) and sodium acetate (0.22 mL, 2.9 mmol, 2.5 eq.), and the resulting colorless solution was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was taken up in HO (20 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc) to give 3-amino-N,N,6-trimethyl-pyridazine-4-carboxamide (220.0 mg, 94.6%) as a brown solid. LC-MS: m / z=181.1 [M+H] + ,ESI pos. 1 H NMR(400MHz,CDCl3)δ=6.92(s,1H),5.42(brs,2H),3.04(brs,3H),2.94(brs,3H),2.50(s,3H).

[0279] Step 5: 5-Bromo-1-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-5-(difluoromethyl)-2-pyridyl]-6-methyl-benzimidazole To a solution of 5-bromo-6-methyl-1H-benzimidazole (143.47 mg, 0.68 mmol, 1.0 eq.) in DMSO (3 mL) was added 6-chloro-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-3-(difluoromethyl)pyridine (210.0 mg, 0.68 mmol, 1.0 eq.) and K2CO3 (281.18 mg, 2.03 mmol, 3.0 eq.). The reaction mixture was stirred at 50 °C for 12 h. The reaction mixture was cooled to 23 °C, diluted with HO (10 mL), and extracted with EtOAc (5 mL × 3). The combined organic layer was washed with brine (5 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography using 20% ​​to 50% EtOAc in PE to give 5-bromo-1-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-5-(difluoromethyl)-2-pyridyl]-6-methyl-benzimidazole (70.0 mg, 19.2%) as a white solid. LC-MS: m / z = 486.0 [M+H] + ,ESI pos. 1 H NMR(400MHz,CDCl3)δ=8.53(s,1H),8.40(d,J=8.4Hz,1H),8.08(s,1H),7.91(s,1H),7.65(d,J=8.4Hz,1H ),7.46(s,1H),7.32(s,1H),7.18(s,1H),6.93(t,J=72.9Hz,1H),6.00(s,1H),2.57(s,3H),2.54(s,3H).

[0280] The regioisomer 6-bromo-1-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-5-(difluoromethyl)-2-pyridyl]-5-methyl-benzimidazole (110.0 mg, 30.2%) was also obtained as a white solid. LC-MS: m / z=486.0 [M+H] + ,ESI pos. 1H NMR(400MHz,CDCl3)δ=8.55(s,1H),8.39(d,J=8.4Hz,1H),8.27(s,1H),7.75(s,1H),7.64(d,J=8. 4Hz,1H),7.46(s,1H),7.32(s,1H),7.18(s,1H),6.93(t,J=72.9Hz,1H),6.00(s,1H),2.55(s,6H).

[0281] Step 6: 3-[[1-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-5-(difluoromethyl)-2-pyridyl]-6-methyl-benzimidazol-5-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide Prepared according to step 4 of Example 4, 3-[[1-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-5-(difluoromethyl)-2-pyridyl]-6-methyl-benzimidazol-5-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide (7.9 mg, 15.9%) was obtained as a white solid after purification by preparative HPLC (ACS-WH-GX-F, 28-58% CH3CN in HO (containing 0.225% HCOOH) for 10 min, flow rate: 25 mL / min). LC-MS: m / z = 584.2 [M+H] + ,ESI pos. 1 H NMR(400MHz,CDCl3)δ=8.61(brs,1H),8.40(d,J=8.4Hz,1H),8.33(brs,1H),8.15-8.00(m,1H),7.88(s,1H),7.72(brd,J=8.3Hz,1H),7.4 7(s,1H),7.33(s,1H),7.19(s,1H),7.16-6.76(m,2H),6.01(s,1H),3.14(brs,3H),3.07(brs,3H),2.66(s,3H),2.56(s,3H),2.48(s,3H).

[0282] Example 42 1-[5-(Difluoromethyl)-6-[(1R)-2,2-difluoro-1-methyl-ethoxy]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine [ka] Step 1: 1,1-difluoropropan-2-ol To a solution of 1,1-difluoropropan-2-one (20.0 g, 212.63 mmol, 1.0 eq.) in EtO (200 mL) was added NaBH (8.04 g, 212.63 mmol, 1.0 eq.) at 0 °C. The mixture was then stirred at 15 °C for 1 h. The reaction mixture was slowly added to saturated aqueous NH Cl (500 mL). The resulting mixture was stirred at 15 °C for 10 min. The layers were separated. The organic phase was dried over Na SO and filtered. The organic phase was evaporated at atmospheric pressure to remove the solvent. The residue was then distilled under reduced pressure (30 mmHg, 29 °C) to give 1,1-difluoropropan-2-ol (7.3 g, 28.6%) as a colorless oil. 1 H NMR(400MHz, CDCl3)δ=5.79-5.44(m,1H),4.03-3.84(m,1H),2.13(brs,1H),1.30(d,J=6.6Hz,3H).

[0283] Step 2: 6-chloro-3-(difluoromethyl)-2-(2,2-difluoro-1-methyl-ethoxy)pyridine To a colorless solution of 1,1-difluoropropan-2-ol (58.22 mg, 0.61 mmol, 1.1 eq.) in THF (10 mL) was added NaH (33.05 mg, 0.83 mmol, 1.5 eq.) under N2 atmosphere at 0 °C and stirring was continued for 1 h. 6-Chloro-3-(difluoromethyl)-2-fluoro-pyridine (100.0 mg, 0.55 mmol, 1.0 eq.) was added and stirring was continued for 12 h at 25 °C under N2 atmosphere. The reaction mixture was diluted with HO (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated in vacuo to give 6-chloro-3-(difluoromethyl)-2-(2,2-difluoro-1-methyl-ethoxy)pyridine (130.0 mg, 0.5 mmol, 91.6% yield) as a yellow oil. LC-MS: m / z=258.0 [M+H] + ,ESI pos. 1 H NMR(400MHz,CDCl3)δ=7.87(d,J=7.8Hz,1H),7.09(d,J=7.8Hz,1H),6.83(t,J=55.0 Hz,1H),5.94(ddd,J=3.2,54.8,56.3Hz,1H),5.58-5.42(m,1H),1.37-1.16(m,3H).

[0284] Step 3: 4-Bromo-2-nitro-5-(oxetan-3-yloxy)aniline To a solution of oxetan-3-ol (4.26 g, 57.46 mmol, 1.5 eq.) in THF (90 mL) cooled to 0 °C under a N atmosphere, sodium hydride (60% in oil) (2.3 g, 57.61 mmol, 1.5 eq.) was added portionwise, and the mixture was stirred at 0 °C for 30 min. 4-Bromo-5-fluoro-2-nitro-aniline (9.0 g, 38.3 mmol, 1.0 eq.) was added, and the reaction mixture was warmed to RT and stirred at room temperature for 12 h. The reaction was quenched with HO (100 mL), resulting in the formation of a precipitate. The mixture was filtered, and the filter cake was dried under reduced pressure to give 4-bromo-2-nitro-5-(oxetan-3-yloxy)aniline (4.0 g, 13.84 mmol, 36% yield). The filtrate was extracted with EtOAc (3 × 250 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was triturated with a mixture of petrol ether / EtOAc (10:1, 30 mL) for 30 minutes. The mixture was filtered, and the filter cake was dried under reduced pressure to give 4-bromo-2-nitro-5-(oxetan-3-yloxy)aniline (7.0 g, 24.21 mmol, 63% yield) as a yellow solid. ESI pos[M+H] + 289.0. 1 H NMR(400MHz,DMSO-d6)δ=8.16(s,1H),7.56(s,2H),6.21(s,1H),5.31(q,J=5.4Hz,1H),4.93(t,J=6.8Hz,2H),4.59(dd,J=5.2,7.6Hz,2H).

[0285] Step 4: 4-Bromo-5-(oxetan-3-yloxy)benzene-1,2-diamine To a solution of 4-bromo-2-nitro-5-(oxetan-3-yloxy)aniline (10.5 g, 36.32 mmol, 1.0 eq.) in EtOH (120 mL) under a N atmosphere was added Fe (10.14 g, 181.61 mmol, 5.0 eq.), NH4Cl (19.43 g, 363.22 mmol, 10.0 eq.), and HO (40 mL). The reaction mixture was stirred at 50 °C under N2 for 12 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with HO (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were concentrated to give 4-bromo-5-(oxetan-3-yloxy)benzene-1,2-diamine (9.4 g, 36.28 mmol, quantitative yield) as a black solid. ESI pos[M+H] + 259.0.

[0286] Step 5: 5-Bromo-6-(oxetan-3-yloxy)-1H-benzimidazole; formic acid A solution of 4-bromo-5-(oxetan-3-yloxy)benzene-1,2-diamine (9.0 g, 34.74 mmol, 1.0 eq.) and formic acid (8.0 mL, 41463.19 mmol, 1193.68 eq.) in triethyl orthoformate (80 mL) was stirred at 80 °C for 12 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by preparative HPLC (Phenomenex Luna C18 10 μm, 150 mm × 40 mm, water + 0.1% FA-ACN) to give 5-bromo-6-(oxetan-3-yloxy)-1H-benzimidazole (8.6 g, 31.96 mmol, 91% yield) as a white solid. ESI pos [M+H] + 270.9. 1 H NMR(400MHz, CDCl3)δ=8.16(s,1H),8.05(s,1H),7.88(s,1H),6.80(s,1H),5.29(td,J=5.6,11.2Hz,1H),5.04(t,J=6.8Hz,2H),4.95-4.84(m,2H).

[0287] Step 6: 5-Bromo-1-[5-(difluoromethyl)-6-(2,2-difluoro-1-methyl-ethoxy)-2-pyridyl]-6-(oxetan-3-yloxy)benzimidazole [ka] To a yellow solution of 6-chloro-3-(difluoromethyl)-2-(2,2-difluoro-1-methyl-ethoxy)pyridine (310.0 mg, 1.2 mmol, 1.0 eq.) and 5-bromo-6-(oxetan-3-yloxy)-1H-benzimidazole (prepared similarly to the procedure described in Example 18, Step 3) (323.81 mg, 1.2 mmol, 1.0 eq.) in DMSO (10 mL) was added KCO (498.94 mg, 3.61 mmol, 3.0 eq.). The resulting yellow suspension was stirred at 80 °C for 16 h. The reaction mixture was cooled to 23 °C, poured into HO (50 mL), and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using 0% to 100% EtOAc in PE to give 5-bromo-1-[5-(difluoromethyl)-6-(2,2-difluoro-1-methyl-ethoxy)-2-pyridyl]-6-(oxetan-3-yloxy)benzimidazole (200.0 mg, 33.9%) as a colorless oil. LC-MS: m / z = 492.0 [M+H] + ,ESI pos. 1 H NMR(400MHz,CDCl3)δ=8.40(s,1H),8.17(brd,J=7.9Hz,1H),8.12(d,J=1.5Hz,1H),7.22(brd,J=8.0Hz,1H),7.19(s,1H),6.94(brt,J=54.9Hz, 1H),6.14-5.81(m,1H),5.70-5.55(m,1H),5.40-5.26(m,1H),5.05-4.9 8(m,2H),4.96-4.90(m,1H),4.89-4.83(m,1H),1.56(brd,J=6.5Hz,3H).

[0288] The regioisomer 6-bromo-1-[5-(difluoromethyl)-6-(2,2-difluoro-1-methyl-ethoxy)-2-pyridyl]-5-(oxetan-3-yloxy)benzimidazole (260.0 mg, 0.53 mmol, 44.07% yield) was also obtained as a yellow solid. LC-MS: m / z = 492.0 [M+H] + ,ESI pos. 1 H NMR(400MHz,CDCl3)δ=8.42(s,1H),8.23(s,1H),8.05(d,J=8.0Hz,1H),7.17(s,1H),7.00-6.65(m,2H),5.90(dt,J=3.2,5 5.4Hz,1H),5.56-5.41(m,1H),5.30-5.20(m,1H),4.99(t,J=6.7Hz,2H),4.82(brt,J=5.9Hz,2H),1.50(brd,J=6.4Hz,3H).

[0289] Step 7: 1-[5-(difluoromethyl)-6-(2,2-difluoro-1-methyl-ethoxy)-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine Prepared according to step 4 of Example 4, 1-[5-(difluoromethyl)-6-(2,2-difluoro-1-methyl-ethoxy)-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine (85.0 mg, 37.4%) was obtained as a yellow solid after purification by preparative HPLC (Phenomenex Luna C18 (75 mm × 30 mm, 3 μm), 27-47% CH3CN (containing TFA) in HO for 9 min, flow rate: 25 mL / min). LC-MS: m / z = 519.2 [M+H] + ,ESI pos.

[0290] Step 8: 1-[5-(difluoromethyl)-6-[(1R)-2,2-difluoro-1-methyl-ethoxy]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine 1-[5-(difluoromethyl)-6-(2,2-difluoro-1-methyl-ethoxy)-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine (85.0 mg, 0.16 mmol, 1.0 eq.) was added to a chiral SFC (Daicel Chiralpak Purification on an AD (250 mm x 30 mm, 10 μm) with EtOH (0.1% NHOH) in CO over 6.5 min (flow rate 70 mL / min) gave 1-[5-(difluoromethyl)-6-[(1R)-2,2-difluoro-1-methyl-ethoxy]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine (23.2 mg, 27.3%) as a white solid. LC-MS: m / z = 519.2 [M+H] + ,ESI pos. 1 H NMR(400MHz,CD3OD)δ=8.74(s,1H),8.60(s,1H),8.23(d,J=7.9Hz,1H),7.56(d,J=7 .9Hz,1H),7.43-7.37(m,2H),7.33-7.26(m,1H),7.02(t,J=55.1Hz,1H),6.18(dt,J =3.5,55.3Hz,1H),5.79-5.65(m,1H),5.48(quin,J=5.4Hz,1H),5.10-5.01(m,2H), 4.85-4.81(m,1H),4.79(dd,J=5.2,7.0Hz,1H),2.57(s,3H),1.56(d,J=6.6Hz,3H).

[0291] Example 43 1-[5-(Difluoromethyl)-6-[(1S)-2,2-difluoro-1-methyl-ethoxy]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine [ka] Step 1: 1-[5-(difluoromethyl)-6-[(1S)-2,2-difluoro-1-methyl-ethoxy]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine In Step 5 of Example 42, after chiral SFC purification, 1-[5-(difluoromethyl)-6-[(1S)-2,2-difluoro-1-methyl-ethoxy]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine (24.7 mg, 29.1%) was obtained as a white solid. LC-MS: m / z=519.2 [M+H] + ,ESI pos. 1 H NMR(400MHz,CD3OD)δ=8.74(s,1H),8.60(s,1H),8.23(d,J=7.9Hz,1H),7.56(d,J=7 .9Hz,1H),7.43-7.37(m,2H),7.33-7.26(m,1H),7.02(t,J=55.1Hz,1H),6.18(dt,J =3.5,55.3Hz,1H),5.79-5.65(m,1H),5.48(quin,J=5.4Hz,1H),5.10-5.01(m,2H), 4.85-4.81(m,1H),4.79(dd,J=5.2,7.0Hz,1H),2.57(s,3H),1.56(d,J=6.6Hz,3H).

[0292] Example 44 N-[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]-1-(oxetan-3-yl)piperidine-4-carboxamide [ka] Step 1: Methyl 1-(oxetan-3-yl)piperidine-4-carboxylate A solution of methyl 4-piperidinecarboxylate (1.0 g, 6.98 mmol, 1.0 eq.) and 3-oxetanone (1.51 g, 20.95 mmol, 3.0 eq.) in MeOH (10 mL) was stirred at 20 °C for 10 min. NaBHCN (877.78 mg, 13.97 mmol, 2.0 eq.) was then added. The mixture was stirred at 20 °C for 1 h. The mixture was concentrated in vacuo to remove MeOH. To the residue was added HO (20 mL), and the mixture was extracted with EtOAc (20 mL × 2). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness to give methyl 1-(oxetan-3-yl)piperidine-4-carboxylate (1000.0 mg, 71.9%) as a colorless oil. LC-MS: m / z = 200.2 [M+H] + ,ESI pos.

[0293] Step 2: 1-(oxetan-3-yl)piperidine-4-carboxylic acid To a solution of methyl 1-(oxetan-3-yl)piperidine-4-carboxylate (1000.0 mg, 5.02 mmol, 1.0 eq.) in THF (2 mL) and HO (2 mL) was added LiOH hydrate (526.47 mg, 12.55 mmol, 2.5 eq.). The mixture was stirred at 20 °C for 2 h and concentrated in vacuo to remove THF. The pH of the remaining aqueous mixture was adjusted to 7 by adding 1 N HCl. The mixture was directly purified by preparative HPLC (Waters Atlantis T3 (150 mm × 30 mm, 5 μm), CHCN in HO (containing TFA)) to give 1-(oxetan-3-yl)piperidine-4-carboxylic acid (380.0 mg, 40.9%) as a white solid. LC-MS: m / z = 186.1 [M+H] + ,ESI pos. 1 H NMR(400MHz,DMSO-d6)δ=4.53-4.48(m,2H),4.40(t,J=6.1Hz,2H),3.36-3.32(m,1H) ,2.60(brd,J=11.3Hz,2H),2.24-2.16(m,1H),1.84-1.73(m,4H),1.59-1.48(m,2H).

[0294] Step 3: 1-[6-(5-amino-6-methoxy-benzimidazol-1-yl)-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile Prepared according to step 4 of example 4 to give 1-[6-(5-amino-6-methoxy-benzimidazol-1-yl)-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (15 mg, 13.5%) as a yellow solid. LC-MS: m / z=396.1, [M+H] + ,ESI pos. 1 H NMR(400MHz,CDCl3)δ=8.44-8.37(m,2H),7.75(d,J=8.4Hz,1H),7.47(s,1H),7.29(s ,1H),7.27(s,1H),7.16(s,1H),7.02(s,1H),6.69(s,1H),3.87(s,3H),2.54(s,3H).

[0295] Step 4: N-[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]-1-(oxetan-3-yl)piperidine-4-carboxamide To a pale yellow solution of 1-[6-(5-amino-6-methoxy-benzimidazol-1-yl)-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (15.0 mg, 0.040 mmol, 1 eq.) in DMF (1 mL) was added DIPEA (9.1 mg, 0.070 mmol, 2 eq.) and 1-(oxetan-3-yl)piperidine-4-carboxylic acid (7.84 mg, 0.040 mmol, 1.2 eq.) at 25 °C. HATU (12.45 mg, 0.050 mmol, 1.5 eq.) was added portionwise to give a brown solution. The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with NH4Cl (10 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified using preparative HPLC (Waters Xbridge (150 mm x 25 mm, 5 μm), 32% to 62% CH3CN (containing NH4HCO3) in H2O, 8 min, flow rate 25 mL / min) to give N-[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]-1-(oxetan-3-yl)piperidine-4-carboxamide (4.7 mg, 21.1%) as a white solid. LC-MS: m / z = 563.1 [M+H] + ,ESI pos. 1 H NMR(400MHz,CD3OD)δ=8.88-8.81(m,1H),8.57-8.48(m,1H),8.44-8.39(m,1H),8.24-8.13(m, 1H),7.85-7.77(m,1H),7.20(brd,J=5.9Hz,1H),7.06(brd,J=5.9Hz,1H),6.91(brs,1H),6.89( s,1H),4.75-4.69(m,2H),4.68-4.62(m,2H),3.91-3.86(m,3H),3.70-3.61(m,1H),2.98(brd, J=11.5Hz,2H),2.67-2.57(m,1H),2.53(d,J=5.1Hz,3H),2.18-2.09(m,2H),2.02-1.89(m,4H).

[0296] Example 45 1-[5-(Difluoromethyl)-6-[3-(trifluoromethyl)-5,7-dihydro-4H-pyrano[3,4-c]pyrazol-1-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine [ka] Step 1: 3,6-Dihydro-2H-pyran-5-yloxy(trimethyl)silane To a solution of dihydro-2H-pyran-3(4H)-one (1.0 g, 9.99 mmol, 1.0 eq.) in THF (20 mL) was added TMSCl (3.2 mL, 24.97 mmol, 2.5 eq.) at 25 °C, and the mixture was stirred for 0.2 h. TEA (3.75 mL, 26.97 mmol, 2.7 eq.) was then added dropwise at 25 °C. The resulting mixture was stirred at 70 °C for 12 h. The reaction mixture was cooled to 23 °C and concentrated under reduced pressure. The residue was triturated with PE (20 mL), and the resulting suspension was stirred at 25 °C for 10 min. The solid was filtered, and the filtrate was concentrated under reduced pressure to give 3,6-dihydro-2H-pyran-5-yloxy(trimethyl)silane (1.7 g, 98.8%) as a yellow gum. 1 H NMR(400MHz,CDCl3)δ=4.96(t,J=4.0Hz,1H),3.90(d,J=1.6Hz,2H),3.70(t,J=5.4Hz,2H),2.21-2.13(m,2H),0.21(s,9H).

[0297] Step 2: 3-(trifluoromethyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole To a solution of 4-(2,2,2-trifluoroacetyl)tetrahydropyran-3-one (1.0 g, 5.1 mmol, 1.0 eq.) in THF (10 mL) was added dropwise methyllithium (3.19 mL, 5.1 mmol, 1.0 eq.) at 25 °C under a N atmosphere. After stirring for 1 h, the mixture was cooled to -78 °C, and 4-(2,2,2-trifluoroacetyl)tetrahydropyran-3-one (1.0 g, 5.1 mmol, 1.0 eq.) was added. The mixture was allowed to warm slowly to 25 °C over 12 h. The reaction mixture was quenched by the addition of saturated aqueous NH Cl (5 mL), diluted with HO (15 mL), and extracted with EtOAc (25 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (50 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 4-(2,2,2-trifluoroacetyl)tetrahydropyran-3-one (600.0 mg). To a solution of 4-(2,2,2-trifluoroacetyl)tetrahydropyran-3-one (600.0 mg, 3.06 mmol, 1 eq.) in EtOH (10 mL) solution, hydrazine hydrate (510.74 mg, 10.2 mmol, 2.0 eq.) was added at 25 °C, and the reaction mixture was stirred at 70 °C for 12 hours. The reaction mixture was cooled to 25 °C and concentrated under reduced pressure. The residue was purified by preparative HPLC (Welch HPLC XB-SiOH (250 mm × 50 mm, 10 μm), gradient of EtOH (containing 0.1% NH4OH) in hexane) to give 3-(trifluoromethyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole (270.0 mg, 45.0%) as a white solid. No analysis.

[0298] Step 3: 1-[6-chloro-3-(difluoromethyl)-2-pyridyl]-3-(trifluoromethyl)-5,7-dihydro-4H-pyrano[3,4-c]pyrazole To a solution of 6-chloro-3-(difluoromethyl)-2-fluoro-pyridine (236.21 mg, 1.3 mmol, 1.0 eq.) in DMSO (5 mL) was added 3-(trifluoromethyl)-1,4,5,7-tetrahydropyrano[3,4-c]pyrazole (250.0 mg, 1.3 mmol, 1.0 eq.) and DIPEA (0.66 mL, 3.9 mmol, 3.0 eq.). The mixture was stirred at 70 °C for 12 h. The reaction mixture was purified by reverse-phase HPLC (CHCN in HO (containing 0.1% FA)) to give 1-[6-chloro-3-(difluoromethyl)-2-pyridyl]-3-(trifluoromethyl)-5,7-dihydro-4H-pyrano[3,4-c]pyrazole (180.0 mg, 0.51 mmol, 39.11% yield) as a white solid. LC-MS: m / z=354.1 [M+H] + ,ESI pos. 1 H NMR(400MHz,CDCl3)δ=8.19(d,J=8.0Hz,1H),7.94-7.58(m,1H),7.40(d,J=8.0Hz,1H),5.12(s,2H),3.96(t,J=5.6Hz,2H),2.81(t,J=5.2Hz,2H).

[0299] Step 4: 1-[6-[5-bromo-6-(oxetan-3-yloxy)benzimidazol-1-yl]-3-(difluoromethyl)-2-pyridyl]-3-(trifluoromethyl)-5,7-dihydro-4H-pyrano[3,4-c]pyrazole To a pale yellow solution of 1-[6-chloro-3-(difluoromethyl)-2-pyridyl]-3-(trifluoromethyl)-5,7-dihydro-4H-pyrano[3,4-c]pyrazole (155.0 mg, 0.44 mmol, 1.0 eq.) in DMF (5 mL) was added 5-bromo-6-(oxetan-3-yloxy)-1H-benzimidazole (117.93 mg, 0.44 mmol, 1.0 eq.). The brown solution was treated with KCO (181.71 mg, 1.31 mmol, 3.0 eq.) and stirred at 20 °C for 12 h. The mixture was poured into HO (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL × 3), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (EtOAc) to give 1-[6-[5-bromo-6-(oxetan-3-yloxy)benzimidazol-1-yl]-3-(difluoromethyl)-2-pyridyl]-3-(trifluoromethyl)-5,7-dihydro-4H-pyrano[3,4-c]pyrazole (55.0 mg, 21.4%) as a yellow solid. LC-MS: m / z=586.0 [M+H] + ,ESI pos. 1 H NMR(400MHz,CD3OD)δ=8.89(s,1H),8.56(d,J=8.5Hz,1H),8.41(s,1H),8.00(d,J=8.5Hz,1H),7.59(t,J=55.0Hz,1H),7.05(s,1H) ,5.50-5.40(m,1H),5.11(t,J=7.0Hz,2H),5.06(s,2H),4.80(dd,J=4.9,7.8Hz,2H),3.99(t,J=5.6Hz,2H),2.84(t,J=5.3Hz,2H).

[0300] The regioisomer 1-[6-[6-bromo-5-(oxetan-3-yloxy)benzimidazol-1-yl]-3-(difluoromethyl)-2-pyridyl]-3-(trifluoromethyl)-5,7-dihydro-4H-pyrano[3,4-c]pyrazole (40.0 mg, 15.6%) was also obtained as a brown gum. LC-MS: m / z=586.0 [M+H] + ,ESI pos. 1H NMR(400MHz,CD3OD)δ=8.83(s,1H),8.58(d,J=8.4Hz,1H),8.41-8.32(m,1H),8.05-7.96(m,2H),7.85-7.78(m,1H),7.54(t,J=54.9Hz,1H) ,7.35(s,1H),5.44-5.32(m,1H),5.05(s,2H),3.98(t,J=5.6Hz,2H),3.88(t,J=5.6Hz,1H),2.85(brt,J=5.3Hz,2H),2.70(t,J=5.9Hz,1H).

[0301] Step 5: 1-[5-(difluoromethyl)-6-[3-(trifluoromethyl)-5,7-dihydro-4H-pyrano[3,4-c]pyrazol-1-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine Prepared according to step 4 of Example 4, 1-[5-(difluoromethyl)-6-[3-(trifluoromethyl)-5,7-dihydro-4H-pyrano[3,4-c]pyrazol-1-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine (20.5 mg, 32.5%) was obtained as a yellow solid after purification by preparative HPLC (Phenomenex Luna C18 (150 mm × 25 mm, 10 μm), 24-54% CH3CN in HO (containing 0.225% FA) for 10 min, flow rate: 25 mL / min). LC-MS: m / z = 615.1 [M+H] + ,ESI pos. 1 H NMR(400MHz,DMSO-d6)δ=8.86(d,J=15.8Hz,2H),8.58(d,J=8.5Hz,1H),8.38(s,1H),8.12(d,J=8.4Hz,1H),7.62-7.31(m,3H),7.27(s,1H), 5.41(quin,J=5.6Hz,1H),5.04(s,2H),4.84(t,J=6.6Hz,2H),4.78-4.70(m,2H),3.93(brt,J=5.5Hz,2H),2.79(brs,2H),2.50-2.49(m,3H).

[0302] Example 46 2-[3-(Difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]-2-pyridyl]-3,5-dimethyl-4H-pyrrolo[3,4-c]pyrazol-6-one [ka] Step 1: Methyl 5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate In a 500 mL three-necked round-bottom flask (dried under vacuum with a heat gun), methyl 5-methyl-1H-pyrazole-3-carboxylate (5.0 g, 35.68 mmol, 1.0 eq.) was dissolved in DMF (100 mL). NaH (60% dispersion in mineral oil) (1712.0 mg, 42.8 mmol, 1.2 eq.) was added portionwise at 0 °C under a N atmosphere. The reaction mixture was stirred at 0 °C for 0.5 h to give a white suspension. Next, 2-trimethylsilyl)ethoxymethyl chloride (9.47 mL, 53.52 mmol, 1.5 eq.) was added dropwise via syringe at 0 °C. The reaction mixture was stirred at 0 °C for 2 h to give a yellow suspension. The mixture was carefully quenched under a N stream by the addition of NH Cl (600 mL). EtOAc (400 mL) was added, and the layers were separated. The aqueous phase was back-extracted with EtOAc (400 mL x 2). The combined organic extracts were washed with brine (600 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using 30% EtOAc in PE to give methyl 5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (4.0 g, 41.5%) as a colorless oil. LC-MS: m / z = 271.2 [M+H] + ,ESI pos. 1 H NMR(400MHz,CDCl3)δ=6.63(s,1H),5.49(s,2H),3.92(s,3H),3.56(t,J=8.1Hz,2H),2.39(s,3H),0.88(t,J=8.2Hz,2H),-0.03(s,9H).

[0303] The regioisomer, methyl 5-methyl-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (4.0 g, 41.5%), was also obtained as a colorless oil. LC-MS: m / z = 271.2 [M+H] + ,ESI pos. 1 H NMR(400MHz,CDCl3)δ=6.68(s,1H),5.78(s,2H),3.88(s,3H),3.63-3.53(m,2H),2.30(s,3H),0.93-0.87(m,2H),-0.04(s,9H).

[0304] Step 2: 4-bromo-5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate methyl To a solution of methyl 5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (4.0 g, 14.79 mmol, 1 eq.) in CH3CN (40 mL) was added NBS (3949.7 mg, 22.19 mmol, 1.5 eq.) under a N2 atmosphere at 20 °C. The reaction mixture was stirred at 20 °C for 3 h. SiO2 (6 g) was added to the orange solution. The mixture was concentrated to dryness at 23 °C, and the residual yellow solid was purified by flash column chromatography using 0% to 20% EtOAc in PE to give 4-bromo-5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (4.5 g, 87.1%) as a colorless oil. LC-MS: m / z = 290.9 [M+H] + ,ESI pos. 1 H NMR(400MHz,CDCl3)δ=5.49(s,2H),3.94(s,3H),3.54(t,J=8.3Hz,2H),2.38(s,3H),0.87(t,J=8.3Hz,2H),-0.03(s,9H).

[0305] Step 3: methyl 4-[(tert-butoxycarbonylamino)methyl]-5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate To a suspension of methyl 4-bromo-5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (3.0 g, 8.59 mmol, 1.0 eq.) and potassium N-BOC-aminomethyltrifluoroborate (5.09 g, 21.47 mmol, 2.5 eq.) in 1,4-dioxane (30 mL) was added CsCO (6.99 g, 21.47 mmol, 2.5 eq.), Pd(OAc) (385.64 mg, 1.72 mmol, 0.2 eq.), XPhos (1637.73 mg, 3.44 mmol, 0.4 eq.), and HO (3 mL). The suspension was degassed and back-filled with N three times. The mixture was then heated to 110 °C and stirred for 16 h. The resulting dark suspension was cooled to 23 °C. The precipitate was filtered off. The filtrate was diluted with H2O (150 mL) and extracted with EtOAc (100 mL x 3). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using 20% ​​EtOAc in PE to give methyl 4-[(tert-butoxycarbonylamino)methyl]-5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (1.5 g, 43.7%) as a colorless oil. LC-MS: m / z = 400.2 [M+H] + ,ESI pos. 1 H NMR(400MHz,CDCl3)δ=5.47(s,2H),4.29(d,J=6.4Hz,2H),3.96(s,3H),3.6 0-3.52(m,2H),2.44(s,3H),1.42(s,9H),0.91-0.85(m,2H),-0.03(s,9H).

[0306] Step 4: 4-(aminomethyl)-5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate methyl To a solution of methyl 4-[(tert-butoxycarbonylamino)methyl]-5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (1.8 g, 4.5 mmol, 1.0 eq.) in DCM (18 mL) was added TFA (1.8 mL). The reaction mixture was stirred at 25 °C for 4 h. The mixture was quenched by careful addition of saturated aqueous NaHCO (50 mL). DCM (20 mL) was added and the layers were separated. The aqueous phase was back-extracted with DCM (20 mL × 2). The combined organic extracts were dried over NaSO, filtered, and concentrated in vacuo to give methyl 4-(aminomethyl)-5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (1.2 g, 89.0%) as a yellow oil, which was used without further purification. LC-MS: m / z = 300.1 [M+H] + ,ESI pos.

[0307] Step 5: 4-(aminomethyl)-5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylic acid To a solution of methyl 4-(aminomethyl)-5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (1.2 g, 4.01 mmol, 1.0 eq.) in a mixed solvent of THF (10 mL), MeOH (10 mL), and HO (1 mL) was added LiOH hydrate (420.79 mg, 10.02 mmol, 2.5 eq.). The mixture was stirred at 25 °C for 1 h. The pH was adjusted to 7 with 1 M HCl, and the mixture was concentrated under reduced pressure to give 4-(aminomethyl)-5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylic acid (1.0 g, 87.4%) as a yellow oil, which was used without further purification. LC-MS: m / z = 286.2 [M+H] + ,ESI pos.

[0308] Step 6: 3-methyl-2-(2-trimethylsilylethoxymethyl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6-one To a solution of 4-(aminomethyl)-5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylic acid (1.0 g, 3.5 mmol, 1.0 eq.) in DMF (50 mL) was added DIPEA (0.52 mL, 10.51 mmol, 3.0 eq.) and HATU (989.17 mg, 4.2 mmol, 1.2 eq.). The reaction mixture was stirred at 25 °C for 12 h, diluted with HO (200 mL), and extracted with EtOAc (150 mL × 2). The combined organic extracts were washed with brine (300 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (DCM / MeOH = 10:1) and concentrated in vacuo to give the crude product (200 mg, 50% purity). The crude product was purified by reverse-phase flash column chromatography to give 3-methyl-2-(2-trimethylsilylethoxymethyl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6-one (50.0 mg, 5.3%) as a white solid. LC-MS: m / z = 268.2 [M+H] + ,ESI pos.

[0309] Step 7: 3,5-dimethyl-2-(2-trimethylsilylethoxymethyl)-4H-pyrrolo[3,4-c]pyrazol-6-one To a solution of 3-methyl-2-(2-trimethylsilylethoxymethyl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6-one (50.0 mg, 0.19 mmol, 1.0 eq.) in DMF (3 mL) was added 60% NaH dispersion in mineral oil (12.0 mg, 0.3 mmol, 1.6 eq.) in portions. The mixture was stirred at 0 °C for 30 min. Then, iodomethane (0.12 mL, 1.87 mmol, 10.0 eq.) was added dropwise. The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was poured into saturated aqueous NH4Cl (40 mL). The mixture was extracted with EtOAc (30 mL × 2). The combined organic extracts were washed with brine (60 mL), dried over NaSO, filtered, and concentrated in vacuo to give 3,5-dimethyl-2-(2-trimethylsilylethoxymethyl)-4H-pyrrolo[3,4-c]pyrazol-6-one (40.0 mg, 76.0%) as a colorless oil, which was used without further purification. LC-MS: m / z=282.2 [M+H] + ,ESI pos.

[0310] Step 8: 3,5-Dimethyl-2,4-dihydropyrrolo[3,4-c]pyrazol-6-one 3,5-Dimethyl-2-(2-trimethylsilylethoxymethyl)-4H-pyrrolo[3,4-c]pyrazol-6-one (40.0 mg, 0.14 mmol, 1.0 eq.) was dissolved in TFA (1.0 mL) and stirred at 50 °C for 12 h. The reaction mixture was cooled to 23 °C and concentrated under reduced pressure. The residue was dissolved in DCM (5 mL) and treated with saturated aqueous NaHCO (pH adjusted to ∼7). The mixture was concentrated to dryness. The residue was taken up in a mixture of DCM (5 mL) and MeOH (1 mL). The resulting suspension was stirred at 20 °C for 10 min. The solid was filtered, and the filtrate was concentrated under reduced pressure to give 3,5-dimethyl-2,4-dihydropyrrolo[3,4-c]pyrazol-6-one (15.0 mg, 69.8%) as a yellow oil, which was used without further purification. LC-MS: m / z=152.1 [M+H] + ,ESI pos.

[0311] Step 9: 2-[6-chloro-3-(difluoromethyl)-2-pyridyl]-3,5-dimethyl-4H-pyrrolo[3,4-c]pyrazol-6-one To a solution of 6-chloro-3-(difluoromethyl)-2-fluoro-pyridine (20.0 mg, 0.110 mmol, 1 eq.) and 3,5-dimethyl-2,4-dihydropyrrolo[3,4-c]pyrazol-6-one (16.65 mg, 0.110 mmol, 1 eq.) in DMSO (1 mL) was added KCO (0.04 mL, 0.220 mmol, 2 eq.). The reaction mixture was stirred at 30 °C for 1 h. The reaction mixture was diluted with HO (10 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (30 mL × 3) and concentrated in vacuo. The residue was purified by preparative TLC using 20% ​​EtOAc in PE to give 2-[6-chloro-3-(difluoromethyl)-2-pyridyl]-3,5-dimethyl-4H-pyrrolo[3,4-c]pyrazol-6-one (20.0 mg, 58.1%) as a white solid. LC-MS: m / z=313.0 [M+H] + ,ESI pos. 1 H NMR(400MHz,CDCl3)δ=8.16(d,J=8.2Hz,1H),7.57-7.29(t,1H),7.50(d,J=8.2Hz,1H),4.30(s,2H),3.20(s,3H),2.53(s,3H).

[0312] Step 10: 2-[6-[5-bromo-6-(oxetan-3-yloxy)benzimidazol-1-yl]-3-(difluoromethyl)-2-pyridyl]-3,5-dimethyl-4H-pyrrolo[3,4-c]pyrazol-6-one [ka] To a solution of 2-[6-chloro-3-(difluoromethyl)-2-pyridyl]-3,5-dimethyl-4H-pyrrolo[3,4-c]pyrazol-6-one (20.0 mg, 0.06 mmol, 1.0 eq.) and 5-bromo-6-(oxetan-3-yloxy)-1H-benzimidazole (21.0 mg, 0.08 mmol, 1.22 eq.) in DMSO (1 mL) was added KCO (26.52 mg, 0.19 mmol, 3.0 eq.) at 20 °C. The reaction mixture was stirred at 40 °C for 12 h. The reaction mixture was cooled to 23 °C. EtOAc (10 mL) and HO (10 mL) were added, and the layers were separated. The aqueous phase was back-extracted with EtOAc (10 mL × 2). The combined organic extracts were washed with brine (20 mL x 3), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative TLC using 10% MeOH to give 2-[6-[5-bromo-6-(oxetan-3-yloxy)benzimidazol-1-yl]-3-(difluoromethyl)-2-pyridyl]-3,5-dimethyl-4H-pyrrolo[3,4-c]pyrazol-6-one (15.0 mg, 43.0%). LC-MS: m / z = 545.1 [M+H] + ,ESI pos. 1 H NMR(400MHz,DMSO-d6)δ=9.09(s,1H),8.61(d,J=8.6Hz,1H),8.29(d,J=8.5Hz,1H),8.09(s,1H),7.48(s,1H),7.33-7.0 1(m,1H),5.25(t,J=5.6Hz,1H),4.75-4.67(m,2H),4.61(dd,J=5.2,7.3Hz,2H),4.40(s,2H),3.09(s,3H),2.46(s,3H).

[0313] The regioisomer 2-[6-[6-bromo-5-(oxetan-3-yloxy)benzimidazol-1-yl]-3-(difluoromethyl)-2-pyridyl]-3,5-dimethyl-4H-pyrrolo[3,4-c]pyrazol-6-one (10.0 mg, 28.7 g) was also isolated as a yellow oil. LC-MS: m / z = 545.1 [M+H] + ,ESI pos. 1H NMR(400MHz,DMSO-d6)δ=9.16(s,1H),8.57(d,J=8.7Hz,1H),8.50(s,1H),8.30(d,J=8.4Hz,1H),7.19(s,1H),7.25-6.98( m,1H),5.48-5.40(m,1H),5.02(t,J=6.7Hz,2H),4.61(dd,J=5.1,7.0Hz,2H),4.42(s,2H),3.08(s,3H),2.52-2.51(m,3H).

[0314] Step 11: 2-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]-2-pyridyl]-3,5-dimethyl-4H-pyrrolo[3,4-c]pyrazol-6-one Prepared according to step 4 of Example 4, 2-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]-2-pyridyl]-3,5-dimethyl-4H-pyrrolo[3,4-c]pyrazol-6-one (2.65 mg, 15.1% yield) was purified by preparative HPLC (Phenomenex C18 (75 mm × 30 mm, 3 μm), 8-38% CH3CN in HO (containing 0.225% FA), 7 min, flow rate: 25 mL / min) to obtain a white solid. LC-MS: m / z = 574.3 [M+H] + ,ESI pos. 1 H NMR(400MHz,CD3OD)δ=8.91(brs,1H),8.64(brs,1H),8.53(brd,J=8.5Hz,1H),8.17(brd,J=8.3Hz,1H),7.49(brs,1H),7.39 (brs,1H),7.29-7.01(m,2H),5.25(brd,J=3.8Hz,1H),4.79(brd,J=4.8Hz,4H),4.50(s,2H),3.23(s,3H),2.61-2.48(m,6H).

[0315] Example 47 1-[3-(Difluoromethyl)-6-[6-methoxy-5-[[6-(1-methyl-5-oxo-pyrrolidin-2-yl)pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Step 1: tert-butyl N-(6-formylpyridazin-3-yl)carbamate To a solution of tert-butyl N-(6-vinylpyridazin-3-yl)carbamate (500.0 mg, 2.26 mmol, 1.0 eq.) in MeOH (5 mL) and HO (2 mL) was added OsO (58.49 mg, 0.23 mmol, 0.1 eq.). After stirring for 5 min, NaIO (1.45 g, 6.78 mmol, 3.0 eq.) was added, and stirring was continued at 20 °C for 2 h. The reaction mixture was poured into HO (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were concentrated in vacuo. The residue was purified by flash column chromatography using 30% EtOAc in PE to give N-(6-formylpyridazin-3-yl)tert-butylcarbamate (250.0 mg, 49.6%) as a white solid. LC-MS: m / z=167.8 [M+H-56] + ,ESI pos.

[0316] Step 2: 4-[6-(tert-butoxycarbonylamino)pyridazin-3-yl]-4-oxobutanoic acid methyl ester To a solution of methyl acrylate (578.48 mg, 6.72 mmol, 1.5 eq.) in THF (10 mL) at 23 °C, 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide (241.63 mg, 0.9 mmol, 0.2 eq.) and TEA (1.87 mL, 13.44 mmol, 3.0 eq.) were added, followed by tert-butyl N-(6-formylpyridazin-3-yl)carbamate (1.0 g, 4.48 mmol, 1.0 eq.), and stirring was continued at 70 °C for 2 h. The reaction mixture was poured into HO (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using 30% EtOAc in PE to give methyl 4-[6-(tert-butoxycarbonylamino)pyridazin-3-yl]-4-oxobutanoate (400.0 mg, 28.9%) as a white solid. LC-MS: m / z=310.1 [M+H] + ,ESI pos.

[0317] Step 3: tert-butyl N-[6-(1-methyl-5-oxo-pyrrolidin-2-yl)pyridazin-3-yl]carbamate To a solution of methyl 4-[6-(tert-butoxycarbonylamino)pyridazin-3-yl]-4-oxobutanoate (400.0 mg, 1.29 mmol, 1.0 eq.) in MeOH (5 mL) was added HOAc (7.77 mg, 0.13 mmol, 0.1 eq.) and a 2 M solution of methylamine in THF (3.23 mL, 6.47 mmol, 5.0 eq.). The reaction mixture was stirred at 30 °C for 12 h. NaBHCN (243.79 mg, 3.88 mmol, 3.0 eq.) was added and stirring was continued at 30 °C for 12 h. The reaction mixture was poured into HO (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative TLC using 10% MeOH in DCM to give tert-butyl N-[6-(1-methyl-5-oxo-pyrrolidin-2-yl)pyridazin-3-yl]carbamate (80.0 mg, 21.2%) as a brown solid. LC-MS: m / z=292.9 [M+H] + ,ESI pos.

[0318] Step 4: 5-(6-aminopyridazin-3-yl)-1-methyl-pyrrolidin-2-one A 4 M solution of tert-butyl N-[6-(1-methyl-5-oxo-pyrrolidin-2-yl)pyridazin-3-yl]carbamate (80.0 mg, 0.27 mmol, 1.0 eq.) in dioxane (1.0 mL) was stirred at 40 °C for 1 h. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (Phenomenex Luna C18 (150 mm × 40 mm, 15 μm), 4% to 30% CH3CN in HO (containing 0.225% FA) for 10 min, flow rate: 20 mL / min) to give 5-(6-aminopyridazin-3-yl)-1-methyl-pyrrolidin-2-one (40.0 mg, 76.0%) as a brown solid. LC-MS: m / z = 193.0 [M+H] + ,ESI pos.

[0319] Step 5: 1-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-(1-methyl-5-oxo-pyrrolidin-2-yl)pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile Prepared according to step 4 of example 4 to give, after purification by preparative HPLC, 1-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-(1-methyl-5-oxo-pyrrolidin-2-yl)pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (6.0 mg, 11.7%) as a yellow solid. LC-MS: m / z=571.1 [M+H] + ,ESI pos. 1H NMR(400MHz,DMSO-d6)δ=9.07-8.98(m,1H),8.84-8.72(m,1H),8.70-8.53(m,2H),8.48-8.29(m,1H),7.91-7.81(m,1H),7.49-7.3 7(m,2H),7.08(m,2H),4.86-4.69(m,1H),3.92-3.84(m,3H),3.30(brs,3H),2.56(brs,3H),2.42-2.31(m,3H),1.98-1.86(m,1H).

[0320] Example 48 3-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]amino]-N,N,5-trimethyl-pyridazine-4-carboxamide [ka] Step 1: 3-chloro-N,N,5-trimethyl-pyridazine-4-carboxamide A suspension of 6-keto-4-methyl-1H-pyridazine-5-carboxylic acid (500 mg, 3.24 mmol, 1.0 eq.) in phosphorus oxychloride (8.23 g, 5 mL, 53.64 mmol, 16.5 eq.) was stirred at 90 °C for 2 h. The mixture was cooled to 23 °C and concentrated. The residue was dissolved in DCM, and the solution was added dropwise to a 2 M solution of dimethylamine in THF containing molecular sieves (16.22 mL, 32.44 mmol, 10 eq.). The reaction mixture was stirred at 23 °C for 30 min. The mixture was concentrated to dryness, and the residue was purified by flash column chromatography using 0% to 10% MeOH in DCM to give 3-chloro-N,N,5-trimethyl-pyridazine-4-carboxamide (338 mg, 44.4%) as a red oil. LC-MS: m / z = 200.0 [M+H] + ,ESI pos.

[0321] Step 2: 3-(Benzhydrylideneamino)-N,N,5-trimethyl-pyridazine-4-carboxamide 3-Chloro-N,N,5-trimethyl-pyridazine-4-carboxamide (175 mg, 0.877 mmol, 1.0 eq.), benzophenone imine (250.84 mg, 232.25 μL, 1.31 mmol, 1.5 eq.), and CsCO (571.21 mg, 1.75 mmol, 2.0 eq.) were combined in 1,4-dioxane (2.6 mL) and argon was bubbled through for 5 min. Next, BINAP (54.58 mg, 0.088 mmol, 0.1 eq.) and tris(dibenzylideneacetone)dipalladium(0) (45.37 mg, 0.044 mmol, 0.05 eq.) were added to a glass tube, and the reaction mixture was stirred at 100 °C overnight. The mixture was cooled to 23 °C and concentrated. The residue was purified by flash column chromatography using 50% to 100% EtOAc in heptane to give 3-(benzhydrylideneamino)-N,N,5-trimethyl-pyridazine-4-carboxamide (217 mg, 70.7%) as a yellow viscous oil. LC-MS: m / z=345.1 [M+H] + ,ESI pos.

[0322] Step 3: 3-amino-N,N,5-trimethyl-pyridazine-4-carboxamide To a solution of 3-(benzhydrylideneamino)-N,N,5-trimethyl-pyridazine-4-carboxamide (207 mg, 0.601 mmol, 1.0 eq.) in tetrahydrofuran (11.24 mL) was added a 2 M solution of HCl in EtO (3.01 mL, 6.01 mmol, 10.0 eq.) and HO (10.83 mg, 10.83 μL, 0.601 mmol, 1.0 eq.). The reaction mixture was stirred overnight at 23 °C. An additional 2 M solution of HCl in EtO (1.5 mL, 3.01 mmol, 5.0 eq.) was added, and stirring was continued for an additional 4 h. The solid was collected by filtration, washed with EtO, and dried to give 3-amino-N,N,5-trimethyl-pyridazine-4-carboxamide (76.5 mg, 70.6%) as a white solid. LC-MS: m / z=181.0 [M+H] + ,ESI pos.

[0323] Step 4: 3-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]amino]-N,N,5-trimethyl-pyridazine-4-carboxamide Prepared according to step 4 of Example 4 to afford, after purification by flash column chromatography using 0% to 10% MeOH in DCM, 3-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]amino]-N,N,5-trimethyl-pyridazine-4-carboxamide (19.9 mg, 31.1%) as an off-white solid. LC-MS: m / z=557.2 [MH] - ,ESI neg.

[0324] Example 49 3-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]amino]-N,N,5,6-tetramethyl-pyridazine-4-carboxamide [ka] Step 1: 3-chloro-5,6-dimethyl-pyridazine-4-carboxylic acid Under an argon atmosphere, 3-chloro-5,6-dimethyl-pyridazine-4-carboxylic acid ethyl ester (300 mg, 1.33 mmol, 1.0 eq.) was dissolved in THF (9 mL) at 23 °C. 1 M aqueous LiOH (1.99 mL, 1.99 mmol, 1.5 eq.) was added, and the dark reaction mixture was stirred at 70 °C overnight. The mixture was cooled to 23 °C and treated with HCOOH (244.46 mg, 203.72 μL, 5.31 mmol, 4 eq.) to adjust the pH to 3. The mixture was concentrated to dryness. The residue was purified by flash column chromatography using a gradient of DCM (DCM / MeOH / HCOOH = 8:2:1) to give 3-chloro-5,6-dimethyl-pyridazine-4-carboxylic acid (140.8 mg, 55.7%) as a light brown solid. LC-MS: m / z=187.0 [M+H] + ,ESI pos.

[0325] Step 2: 3-chloro-N,N,5,6-tetramethyl-pyridazine-4-carboxamide Under an argon atmosphere, 3-chloro-5,6-dimethyl-pyridazine-4-carboxylic acid (132 mg, 0.707 mmol, 1.0 eq.) was suspended in dry DCM (1.32 mL). Dry DMF (5.17 mg, 5.48 μL, 0.071 mmol, 0.1 eq.), pyridine (123.1 mg, 125.87 μL, 1.56 mmol, 2.2 eq.), and thionyl chloride (100.99 mg, 61.96 μL, 0.849 mmol, 1.2 eq.) were added. The dark mixture was stirred at 23 °C for 45 min. A 2 M solution of dimethylamine in THF (1.57 g, 1.77 mL, 3.54 mmol, 5.0 eq.) was added to the reaction mixture, which was then stirred at 23 °C for 45 min. A 2M solution of dimethylamine in THF (1.57 g, 1.77 mL, 3.54 mmol, 5.0 eq.) was added to the reaction mixture and stirred at 23 °C for an additional 30 min. The reaction mixture was concentrated. The residue was purified by flash column chromatography using 0% to 10% MeOH in DCM to give 3-chloro-N,N,5,6-tetramethyl-pyridazine-4-carboxamide (128 mg, 84.4%) as a brown solid. LC-MS: m / z = 214.1 [M+H] + ,ESI pos.

[0326] Step 3: 3-(Benzhydrylideneamino)-N,N,5,6-tetramethyl-pyridazine-4-carboxamide Prepared according to step 2 of example 48 to afford 3-(benzhydrylideneamino)-N,N,5,6-tetramethyl-pyridazine-4-carboxamide (129.8 mg, 65.5%) as a yellow viscous oil after purification by flash column chromatography using 50% to 100% EtOAc in heptane. LC-MS: m / z=359.2 [M+H] + ,ESI pos.

[0327] Step 4: 3-amino-N,N,5,6-tetramethyl-pyridazine-4-carboxamide Prepared according to step 3 of example 48 to give 3-amino-N,N,5,6-tetramethyl-pyridazine-4-carboxamide (53 mg, 86.1%) as a white solid. LC-MS: m / z=183.0 [M+H] + ,ESI pos.

[0328] Step 5: 3-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]amino]-N,N,5,6-tetramethyl-pyridazine-4-carboxamide Prepared according to step 4 of example 4 to give 3-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]amino]-N,N,5,6-tetramethyl-pyridazine-4-carboxamide (50.0 mg, 68.7%) as an off-white solid. LC-MS: m / z=573.2 [M+H] + ,ESI pos.

[0329] Example 50 3-[[1-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]amino]-N,6-dimethyl-N-(2,2,2-trifluoroethyl)pyridazine-4-carboxamide [ka] Step 1: 2-[(5-bromo-6-methoxy-benzimidazol-1-yl)methoxy]ethyl-trimethylsilane To a mixture of 5-bromo-6-methoxy-1H-benzimidazole (7.0 g, 30.83 mmol, 1.0 eq.) and NaH (3.4 mL, 61.66 mmol, 2.0 eq.) in DMF (70 mL) at 0 °C, SEM-Cl (7.71 g, 46.24 mmol, 1.5 eq.) was added. The reaction mixture was stirred at 0 °C for 0.5 h. The mixture was quenched by the addition of saturated aqueous NH4Cl (200 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using 20% ​​to 50% EtOAc in PE to give 2-[(5-bromo-6-methoxy-benzimidazol-1-yl)methoxy]ethyl-trimethylsilane (10.0 g, 90.8%) as a yellow oil (mixture of regioisomers). LC-MS: m / z = 359.0 [M+H] + ,ESI pos.

[0330] Step 2: 3-[[6-Methoxy-1-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]amino]-6-methyl-pyridazine-4-carboxylic acid Prepared according to step 5 of example 46 to give 3-[[6-methoxy-1-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]amino]-6-methyl-pyridazine-4-carboxylic acid (90.0 mg, 95.9%) as a yellow solid (mixture of regioisomers). LC-MS: m / z=430.1 [M+H] + ,ESI pos.

[0331] Step 3: 3-[[6-methoxy-1-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]amino]-N,6-dimethyl-N-(2,2,2-trifluoroethyl)pyridazine-4-carboxamide To a mixture of 3-[[6-methoxy-1-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]amino]-6-methyl-pyridazine-4-carboxylic acid (70.0 mg, 0.160 mmol, 1 eq.), methyl-(2,2,2-trifluoro-ethyl)-amine hydrochloride (48.74 mg, 0.330 mmol, 2 eq.), and DIPEA (0.09 mL, 0.490 mmol, 3 eq.) in DMF (3 mL) was added HATU (115.02 mg, 0.490 mmol, 3 eq.) at 30 °C. The mixture was stirred at 30 °C for 2 h. The reaction mixture was diluted with HO (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic extracts were washed with brine (60 mL × 3), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by reverse-phase flash chromatography (column: Spherical C18 20-45 μm, 120 g; 30%-40% CH3CN in HO (containing 0.1% FA) for 25 min at a flow rate of 50 mL / min) to give 3-[[6-methoxy-1-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]amino]-N,6-dimethyl-N-(2,2,2-trifluoroethyl)pyridazine-4-carboxamide (80.0 mg, 93.5%) as a yellow solid (mixture of regioisomers). LC-MS: m / z = 525.3 [M+H] + ,ESI pos.

[0332] Step 4: 3-[(6-methoxy-1H-benzimidazol-5-yl)amino]-N,6-dimethyl-N-(2,2,2-trifluoroethyl)pyridazine-4-carboxamide; 2,2,2-trifluoroacetic acid 3-[[6-Methoxy-1-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]amino]-N,6-dimethyl-N-(2,2,2-trifluoroethyl)pyridazine-4-carboxamide (100.0 mg, 0.19 mmol, 1.0 eq.) was dissolved in TFA (1.0 mL). The resulting yellow solution was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in a mixture of CH3CN (1 mL) and HO (15 mL), and the solution was lyophilized to give 3-[(6-methoxy-1H-benzimidazol-5-yl)amino]-N,6-dimethyl-N-(2,2,2-trifluoroethyl)pyridazine-4-carboxamide; 2,2,2-trifluoroacetic acid (65.0 mg, 67.1%) as a yellow solid. LC-MS: m / z=395.1 [M+H] + ,ESI pos.

[0333] Step 5: 3-[[1-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]amino]-N,6-dimethyl-N-(2,2,2-trifluoroethyl)pyridazine-4-carboxamide [ka] Prepared according to step 5 of example 31, 3-[[1-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]amino]-N,6-dimethyl-N-(2,2,2-trifluoroethyl)pyridazine-4-carboxamide (6.23 mg, 6.5%) was obtained as a yellow solid after purification by preparative TLC using 10% MeOH in DCM. LC-MS: m / z=668.3 [M+H] + ,ESI pos. 1H NMR(400MHz,CD3OD)δ=8.88(brs,1H),8.83(s,1H),8.48(brd,J=8.3Hz,1H),8.07(d,J=8.3Hz,1H),7.88(s,1H),7.45(brs,1H),7.39(s,1H),7.32( s,1H),7.25(s,1H),7.14(s,1H),7.11(s,1H),6.96(s,1H),6.12(s,1H), 4.48-4.17(m,2H),3.93(s,3H),3.19(brs,3H),2.62(s,3H),2.54(s,3H).

[0334] The regioisomer 3-[[3-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]amino]-N,6-dimethyl-N-(2,2,2-trifluoroethyl)pyridazine-4-carboxamide (19.72 mg, 21.0%) was also isolated as a yellow solid. LC-MS: m / z=668.3 [M+H] + ,ESI pos. 1 H NMR(400MHz,CD3OD)δ=9.35(brs,1H),8.79(s,1H),8.53(brd,J=8.4Hz,1H),8.04(brd,J=8.4Hz,1H),7.46(brs,1H),7.43(s,1H),7.36(brs,1H),7.31 (s,1H),7.29(s,1H),7.15(s,1H),7.13(s,1H),6.95(s,1H),6.03(s,1H),4 .48-4.24(m,2H),4.00(s,3H),3.18(brs,3H),2.63(s,3H),2.51(brs,3H).

[0335] Example 51 2-[6-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]amino]pyridazin-3-yl]-N,N-dimethyl-acetamide [ka] Step 1: Diethyl 2-(6-chloropyridazin-3-yl)propanedioate To a colorless solution of 3,6-dichloropyridazine (2.0 g, 13.42 mmol, 1.0 eq.) and diethyl malonate (3.06 mL, 20.14 mmol, 1.5 eq.) in DMSO (20 mL) was added CsCO (8.75 g, 26.85 mmol, 2.0 eq.). The mixture was heated to 110 °C and stirred for 1 h. The reaction mixture was cooled to 23 °C, diluted with HO (100 mL), and extracted with EtOAc (40 mL × 3). The combined organic layers were washed with brine (40 mL × 3), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using 10% to 30% EtOAc in PE to give diethyl 2-(6-chloropyridazin-3-yl)propanedioate (3.3 g, 81.1%) as a yellow oil. LC-MS: m / z=273.0 [M+H] + ,ESI pos. 1 H NMR(400MHz, CDCl3)δ=7.85(d,J=8.9Hz,1H),7.58(d,J=9.0Hz,1H),5.28(s,1H),4.33-4.24(m,4H),1.31(t,J=7.1Hz,6H).

[0336] Step 2: Diethyl 2-[6-(tert-butoxycarbonylamino)pyridazin-3-yl]propanedioate To a solution of diethyl 2-(6-chloropyridazin-3-yl)propanedioate (2.7 g, 9.9 mmol, 1.0 eq.) and tert-butyl carbamate (1.74 g, 14.85 mmol, 1.5 eq.) in 1,4-dioxane (30 mL) was added CsCO (6.45 g, 19.8 mmol, 2.0 eq.), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (1.15 g, 1.98 mmol, 0.2 eq.), and tris(dibenzylideneacetone)dipalladium(0) (0.91 g, 0.99 mmol, 0.1 eq.). The mixture was degassed and back-filled with N three times, then heated to 90 °C and stirred for 12 h. The resulting brown suspension was cooled to 23 °C and filtered. The filtrate was diluted with HO (100 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrous NaSO, filtered, concentrated under reduced pressure, and purified by flash column chromatography using 20% ​​to 40% EtOAc in PE. The isolated material was purified by preparative HPLC (ACS-WH-GX-S, 35% to 65% CHCN (containing NHCO) in HO for 10 min at a flow rate of 60 mL / min) to give diethyl 2[6(tert-butoxycarbonylamino)pyridazin-3-yl]propanedioate (200.0 mg, 5.7%) as a white solid. LC-MS: m / z = 354.0 [M+H] + ,ESI pos. 1 H NMR(400MHz, CDCl3)δ=8.27(d,J=9.3Hz,1H),7.79-7.73(m,2H),5.17(s,1H),4.30-4.20(m,4H),1.55(s,9H),1.28(t,J=7.2Hz,6H).

[0337] Step 3: 2-[6-(tert-butoxycarbonylamino)pyridazin-3-yl]acetic acid To a suspension of diethyl 2-[6-(tert-butoxycarbonylamino)pyridazin-3-yl]propanedioate (160.0 mg, 0.45 mmol, 1.0 eq.) in a mixture of MeOH (2 mL) and HO (1 mL) was added LiOH monohydrate (38.0 mg, 0.91 mmol, 2.0 eq.). The reaction mixture was then heated to 30 °C and stirred for 12 h. The reaction mixture was concentrated to dryness to give 2-[6-(tert-butoxycarbonylamino)pyridazin-3-yl]acetic acid (110.0 mg, 86.3%) as a white solid. LC-MS: m / z = 254.1 [M+H] + ,ESI pos.

[0338] Step 4: tert-butyl N-[6-[2-(dimethylamino)-2-oxo-ethyl]pyridazin-3-yl]carbamate To a suspension of dimethylamine hydrochloride (77.27 mg, 0.95 mmol, 2.0 eq.) in DMF (2 mL) was added DIPEA (244.98 mg, 1.9 mmol, 4.0 eq.), HATU (222.96 mg, 0.95 mmol, 2.0 eq.), and 2-[6-(tert-butoxycarbonylamino)pyridazin-3-yl]acetic acid (120.0 mg, 0.47 mmol, 1.0 eq.). The mixture was heated to 30 °C and stirred for 12 h. The reaction mixture was diluted with HO (20 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC using 10% MeOH in DCM to give tert-butyl N-[6-[2-(dimethylamino)-2-oxo-ethyl]pyridazin-3-yl]carbamate (20 mg, 96.4%) as a white solid. LC-MS: m / z=225.1 [M+H] + ,ESI pos. 1 H NMR(400MHz,CDCl3)δ=8.19(d,J=9.3Hz,1H),7.58(d,J=9.3Hz,2H),4.03(s,2H),3.14(s,3H),2.97(s,3H),1.54(s,9H).

[0339] Step 5: 2-(6-aminopyridazin-3-yl)-N,N-dimethyl-acetamide A 4 M solution of tert-butyl N-[6-[2-(dimethylamino)-2-oxo-ethyl]pyridazin-3-yl]carbamate (60.0 mg, 0.21 mmol, 1.0 eq.) in dioxane (1.0 mL) was stirred at 40° C. for 13 hours. The resulting white suspension was concentrated to dryness, and the residue was lyophilized to give 2-(6-aminopyridazin-3-yl)-N,N-dimethyl-acetamide (40.0 mg, 93.3%) as a white solid. LC-MS: m / z=225.1 [M+H] + ,ESI pos.

[0340] Step 6: 2-[6-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]amino]pyridazin-3-yl]-N,N-dimethyl-acetamide Prepared according to step 4 of Example 4, 2-[6-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]amino]pyridazin-3-yl]-N,N-dimethyl-acetamide (5.5 mg, 21.5%) was obtained as a white solid after purification by preparative HPLC (ACS-WH-GX-F, 17% to 47% CH3CN in HO (containing FA), 10 min, flow rate: 25 mL / min). LC-MS: m / z=560.3 [M+H] + ,ESI pos. 1 H NMR(400MHz,DMSO-d6)δ=9.00(s,1H),8.80(s,1H),8.60(d,J=8.7Hz,1H),8.47(s,1H),8.37(d,J=8.6Hz,1H),7.83 (s,1H),7.37-7.29(m,2H),7.26-6.97(m,2H),3.90(s,2H),3.87(s,3H),3.09(s,3H),2.85(s,3H),2.53(brs,3H).

[0341] Example 52 1-[3-(Difluoromethyl)-6-[6-methoxy-5-(3-methyl-5-methylol-5,6-dihydropyrrolo[2,3-c]pyridazin-7-yl)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Step 1: 3,6-Dichloro-4-(oxetan-3-yl)pyridazine A mixture of 3,6-dichloro-1,2,4,5-tetrazine (919.31 mg, 6.09 mmol, 1.0 eq.) and 3-ethynyloxetane (710 mg, 8.65 mmol, 1 eq.) in toluene (7.04 mL) was placed in a sealed tube and heated to 140 °C. Stirring was continued for 2 h. The reaction mixture was cooled to 23 °C and concentrated. The residue was purified by flash column chromatography using 0% to 30% EtOAc in cyclohexane to give 3,6-dichloro-4-(oxetan-3-yl)pyridazine (897 mg, 71.8%) as a pink solid. LC-MS: m / z = 205.0 [M+H] + ,ESI pos.

[0342] Step 2: 3-chloro-6-methyl-4-(oxetan-3-yl)pyridazine To a solution of 3,6-dichloro-4-(oxetan-3-yl)pyridazine (342 mg, 1.67 mmol, 1.0 eq.) in a mixture of dry 1,4-dioxane (2.78 mL), HO (2.78 mL), and 2 M aqueous NaCO (150 μL, 0.30 mmol, 0.180 eq.), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (209.38 mg, 233.16 μL, 1.67 mmol, 1.0 eq.) was added. Argon was bubbled through the mixture for 5 min. Next, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (137.89 mg, 0.167 mmol, 0.1 eq.) was added, and the mixture was heated to 90 °C. Stirring was continued for 4.5 h. The mixture was cooled to 23 °C and concentrated. The residue was purified by flash column chromatography using 0% to 3.5% MeOH in DCM to give a mixture of regioisomers, which was further purified by reverse-phase preparative HPLC to give 3-chloro-6-methyl-4-(oxetan-3-yl)pyridazine (61 mg, 19.2%) as a pale red solid. LC-MS: m / z = 185.0 [M+H] + ,ESI pos.

[0343] Step 3: Benzhydrylidene-[6-methyl-4-(oxetan-3-yl)pyridazin-3-yl]amine 3-Chloro-6-methyl-4-(oxetan-3-yl)pyridazine (61 mg, 0.321 mmol, 1.0 eq.), benzophenone imine (87.13 mg, 80.67 μL, 0.481 mmol, 1.5 eq.), and CsCO (208.85 mg, 0.641 mmol, 2.0 eq.) were combined with dry 1,4-dioxane (1.6 mL) in a glass tube, and argon was bubbled through the mixture for 5 min. Next, BINAP (19.96 mg, 0.032 mmol, 0.10 eq.) and tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (16.59 mg, 0.016 mmol, 0.050 eq.) were added, the vial was sealed, and the mixture was heated to 100 °C. Stirring was continued for 16 h. The mixture was cooled to 23°C and concentrated. The residue was purified by flash column chromatography using 0% to 35% EtOAc in heptane followed by 0% to 7.5% MeOH in DCM to give benzhydrylidene-[6-methyl-4-(oxetan-3-yl)pyridazin-3-yl]amine (93 mg, 86.3%) as a pale yellow oil. LC-MS: m / z = 330.2 [M+H] + ,ESI pos.

[0344] Step 4: (3-methyl-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-7-ium-5-yl)methanol; 2,2,2-trifluoroacetate TFA (630.95 mg, 426.32 μL, 5.53 mmol, 20.0 eq) was added dropwise to a solution of benzhydrylidene-[6-methyl-4-(oxetan-3-yl)pyridazin-3-yl]amine (93 mg, 0.277 mmol, 1.0 eq) in DCM (1.84 mL) and HO (14.96 mg, 14.96 μL, 0.830 mmol, 3.0 eq), and the mixture was stirred at 23 °C for 1 h. The mixture was diluted with HO and washed three times with DCM. The aqueous layer was evaporated to dryness to give (3-methyl-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-7-ium-5-yl)methanol; 2,2,2-trifluoroacetate (65 mg, 75.7%) as dark green crystals. LC-MS: m / z=166.0 [M+H] + ,ESI pos.

[0345] Step 5: 1-[3-(difluoromethyl)-6-[6-methoxy-5-(3-methyl-5-methylol-5,6-dihydropyrrolo[2,3-c]pyridazin-7-yl)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile Prepared according to Step 4 of Example 4 to give the title compound as a white lyophilized solid (14.8 mg, 16.4%). LC-MS: m / z=544.2 [M+H] + ,ESI pos.

[0346] Example 53 1-[5-(difluoromethyl)-6-[2-methyl-5-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine [ka] Step 1: N-amino-3-(difluoromethyl)pyridine-2-carboxamidine A mixture of 3-(difluoromethyl)pyridine-2-carbonitrile (5.0 g, 32.44 mmol, 1.0 eq.) and hydrazine hydrate (31.47 mL, 648.85 mmol, 20.0 eq.) was stirred at 20 °C for 2 h. The reaction mixture was poured into HO (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using 0% to 50% EtOAc in PE to give N-amino-3-(difluoromethyl)pyridine-2-carboxamidine (5.3 g, 87.8%) as a yellow solid. LC-MS: m / z = 187.0 [M+H] + ,ESI pos. 1 H NMR(400MHz,CDCl3)δ=8.67-8.62(m,1H),8.16-8.11(m,1H),8.00-7.71(m,1H),7.43-7.38(m,1H).

[0347] Step 2: N-[(Z)-[amino-[3-(difluoromethyl)-2-pyridyl]methylene]amino]-3,3,3-trifluoro-propanamide To a solution of 3,3,3-trifluoropropionic acid (4.37 g, 34.16 mmol, 1.2 eq) in DMF (50 mL) was added N'-amino-3-(difluoromethyl)pyridine-2-carboxamidine (5.3 g, 28.47 mmol, 1.0 eq), HATU (10.05 g, 42.71 mmol, 1.5 eq), and DIPEA (9.92 mL, 56.94 mmol, 2.0 eq), and the reaction mixture was stirred at 30 °C for 1 h. The reaction mixture was poured into HO (200 mL) and extracted with EtOAc (200 mL × 3). The organic phase was washed with saturated brine (200 mL × 3), and the combined organic phase was dried over anhydrous NaSO and concentrated in vacuo. The residue was purified by flash column chromatography using 100% EtOAc to give N-[(Z)-[amino-[3-(difluoromethyl)-2-pyridyl]methylene]amino]-3,3,3-trifluoro-propanamide (6.0 g, 71.1%) as a white solid. LC-MS: m / z=297.0 [M+H] + ,ESI pos. 1 H NMR(400MHz,CDCl3)δ=8.64-8.60(m,1H),8.66-8.59(m,1H),7.63-7.33(m,2H),3.63-3.54(m,2H).

[0348] Step 3: 3-(Difluoromethyl)-2-[3-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl]pyridine A solution of N-[(Z)-[amino-[3-(difluoromethyl)-2-pyridyl]methylene]amino]-3,3,3-trifluoro-propanamide (5.0 g, 16.88 mmol, 1.0 eq.) in ethylene glycol (10.48 g, 168.8 mmol, 10.0 eq.) was stirred at 180° C. for 1 h. The reaction mixture was cooled to 23° C., poured into HO (300 mL), and extracted with EtOAc (300 mL×3). The combined organic layers were washed with brine (300 mL×3), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using 33% EtOAc in PE to give 3-(difluoromethyl)-2-[3-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl]pyridine (3.0 g, 63.9%) as a white solid. LC-MS: m / z=279.1 [M+H] + ,ESI pos.

[0349] Step 4: 3-(Difluoromethyl)-2-[2-methyl-5-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-yl]pyridine To a solution of 3-(difluoromethyl)-2-[3-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl]pyridine (3.0 g, 10.78 mmol, 1.0 eq.) in DMF (20 mL) was added KCO (2.25 g, 16.18 mmol, 1.5 eq.) and iodomethane (2.3 g, 16.18 mmol, 1.5 eq.). The resulting clear solution was stirred at 30 °C for 2 h. The reaction mixture was cooled to 23 °C, poured into HO (200 mL), and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (200 mL × 3), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography with EtOAc to give 3-(difluoromethyl)-2-[2-methyl-5-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-yl]pyridine (1.5 g, 47.6%) as a yellow solid. LC-MS: m / z=293.0 [M+H] + ,ESI pos. 1H NMR(400MHz,CDCl3)δ=8.86-8.78(m,1H),8.27-8.17(m,1H),7.85-7.57(m,1H),7.57-7.48(m,1H),4.21-4.18(m,3H),4.16-4.10(m,2H).

[0350] 3-(Difluoromethyl)-2-[1-methyl-5-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-yl]pyridine (1.4 g, 44.3%) was also isolated as a white solid. LC-MS: m / z=293.0 [M+H] + ,ESI pos.

[0351] Step 5: 3-(difluoromethyl)-2-[2-methyl-5-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-yl]-1-oxide-pyridin-1-ium To a solution of 3-(difluoromethyl)-2-[2-methyl-5-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-yl]pyridine (1.5 g, 5.13 mmol, 1.0 eq.) in hydrogen peroxide (10.49 mL, 102.67 mmol, 20.0 eq.) was added acetic acid (5.0 mL, 25.67 mmol, 5.0 eq.). The reaction mixture was heated to 85 °C and stirred for 3 h. The mixture was cooled to 23 °C and quenched by the addition of saturated aqueous Na2SO3 (200 mL). The mixture was stirred for 1 h and then extracted with EtOAc (200 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography using 10% MeOH in EtOAc to give 3-(difluoromethyl)-2-[2-methyl-5-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-yl]-1-oxide-pyridin-1-ium (1.5 g, 94.8%) as a white solid. LC-MS: m / z=309.0 [M+H] + ,ESI pos.

[0352] Step 6: 1-[5-(difluoromethyl)-6-[2-methyl-5-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine Prepared according to Step 5 of Example 31 to initially obtain a mixture of regioisomers (100.0 mg, 29.94%) as a yellow solid. After purification by reverse-phase preparative HPLC, LC-MS: m / z=546.0 [M+H] + ,ESI pos. This mixture was further purified by chiral SFC to give 1-[5-(difluoromethyl)-6-[2-methyl-5-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (40.0 mg, 25.9%) as a white solid. LC-MS: m / z=546.2 [M+H] + ,ESI pos. 1 H NMR(400MHz,DMSO-d6)δ=9.27(s,1H),8.99-8.92(m,1H),8.58-8.51(m,1H),8.49-8.40(m,1H),8.25-8.20(m,1H),7.71-7.6 7(m,1H),7.58-7.53(m,1H),7.33-7.26(m,2H),4.14-4.08(m,3H),4.00-3.95(m,3H),3.94-3.85(m,2H),2.47-2.41(m,3H).

[0353] The regioisomer 3-[5-(difluoromethyl)-6-[2-methyl-5-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (74.0 mg, 47.8%) was also isolated as a white solid. LC-MS: m / z = 546.2 [M+H] + ,ESI pos. 1H NMR(400MHz,DMSO-d6)δ=9.00-8.93(m,1H),8.85(s,1H),8.57-8.51(m,1H),8.36(brs,1H),8.35-8.28(m,1H),7.84 -7.76(m,1H),7.71-7.40(m,1H),7.37(brd,J=3.9Hz,2H),4.23-4.13(m,3H),3.98-3.87(m,5H),2.49-2.48(m,3H).

[0354] Example 54 1-[3-(difluoromethyl)-6-(6-methoxybenzimidazol-1-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Step 1: 1-[3-(difluoromethyl)-6-(6-methoxybenzimidazol-1-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile In a glass tube, 1-[6-(5-bromo-6-methoxy-benzimidazol-1-yl)-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (50 mg, 0.109 mmol, 1.0 eq.) (obtained in Example 15, Step 3) was dissolved in 1,4-dioxane (1 mL) under argon. 2-(oxetan-3-yl)-2,6-diazaspiro[3.3]heptane, tosylic acid (81.43 mg, 0.163 mmol, 1.5 eq.), CsCO (177.37 mg, 0.544 mmol, 5.0 eq.), and HO (30.47 mg, 30.47 μL, 1.69 mmol, 15.53 eq.) were added. The reaction mixture was purged with argon, QphosPd(crotyl)Cl (7.91 mg, 0.009 mmol, 0.08 eq.) was added, the vial was sealed, and the reaction mixture was stirred at 80 °C for 18 h. The reaction mixture was cooled to 23 °C and concentrated. The residue was purified by flash column chromatography using 0% to 50% DCM (DCM / MeOH = 9:1) to give 1-[3-(difluoromethyl)-6-(6-methoxybenzimidazol-1-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (5 mg, 12.1%) as a white powder (a by-product from the reaction). LC-MS: m / z = 381.1 [M+H] + ,ESI pos.

[0355] Example 55 1-[5-(difluoromethyl)-6-[1-methyl-5-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine [ka] Step 1: 1-[5-(difluoromethyl)-6-[1-methyl-5-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine Prepared according to Step 6 of Example 53, 1-[5-(difluoromethyl)-6-[1-methyl-5-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (20.0 mg, 5.7%) was purified by preparative HPLC (Phenomenex Luna C18 (150 mm × 40 mm, 15 μm), 2-22% CH3CN in HO (containing 0.225% FA) for 10 min, flow rate: 25 mL / min) as a yellow solid. LC-MS: m / z = 546.3 [M+H] + ,ESI pos. 1 H NMR(400MHz,CD3OD)δ=8.69-8.62(m,1H),8.52-8.41(m,2H),8.17-8.09(m,1H),8.05-7.72(m,2H),7.42-7 .35(m,1H),7.29-7.21(m,1H),4.05-3.99(m,2H),3.98-3.96(m,3H),3.96-3.92(m,3H),2.59-2.53(m,3H).

[0356] The regioisomer 3-[5-(difluoromethyl)-6-[1-methyl-5-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (43.0 mg, 11.6%) was also isolated as a yellow solid. LC-MS: m / z = 546.3 [M+H] + ,ESI pos. 1 H NMR(400MHz,CD3OD)δ=9.27-9.22(m,1H),9.01-8.95(m,1H),8.47-8.39(m,1H),8.05-7.73(m,2H ),7.37-7.21(m,3H),4.09-4.02(m,2H),4.01-3.99(m,3H),3.98-3.95(m,3H),2.57-2.48(m,3H).

[0357] Example 56 1-[3-(Difluoromethyl)-6-[6-methoxy-5-[[6-[(3R)-1-methyl-2-oxo-pyrrolidin-3-yl]pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Step 1: Benzyl 1-methyl-2-oxo-pyrrolidine-3-carboxylate A solution of NMP (4.86 mL, 50.44 mmol, 1 eq) (extra dry) in THF (75 mL) was cooled to −78 °C under N2, and LDA (53.0 mL, 106 mmol, 2.1 eq) was added slowly at −78 °C. After the addition was complete, stirring was continued at −78 °C for 30 min. Benzyl chloroformate (8.6 g, 50.44 mmol, 1 eq) was then added dropwise over 15 min under N2, resulting in a green suspension. The reaction mixture was stirred at −75 °C for an additional 1 h. The reaction mixture was poured into saturated aqueous NH4Cl (300 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography using 0% to 35% EtOAc in PE to give benzyl 1-methyl-2-oxo-pyrrolidine-3-carboxylate (8 g, mmol, 68%) as a dark brown oil. LC-MS: m / z=234.1 [M+H] + ,ESI pos. 1 H NMR(400MHz,CDCl3)δ=7.47-7.27(m,5H),5.20(s,2H),3.53-3.44(m,2H),3. 34(dt,J=5.8,8.9Hz,1H),2.87(s,3H),2.45-2.35(m,1H),2.32-2.20(m,1H).

[0358] Step 2: Benzyl 3-(6-chloropyridazin-3-yl)-1-methyl-2-oxo-pyrrolidine-3-carboxylate To a solution of 3,6-dichloropyridazine (7.68 g, 51.55 mmol, 1.5 eq) in DMSO (100 mL) was added CsCO (22.4 g, 68.75 mmol, 2.0 eq) and benzyl 1-methyl-2-oxo-pyrrolidine-3-carboxylate (8.0 g, 34.3 mmol, 1.0 eq) at 23 °C. The reaction mixture was stirred at 110 °C under N for 2 h. The reaction mixture was cooled to 23 °C, filtered, and the filter cake was washed with DMSO (10 mL × 3). The filtrate was poured into saturated aqueous NHCl (1 L), which was extracted with EtOAc (500 mL × 3). The combined organic layers were washed with brine (500 mL × 3), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using 0% to 50% EtOAc in PE to give benzyl 3-(6-chloropyridazin-3-yl)-1-methyl-2-oxo-pyrrolidine-3-carboxylate (3.0 g, 23.0%) as a colorless oil. LC-MS: m / z = 346.0 [M+H] + ,ESI pos.

[0359] Step 3: 3-(6-chloropyridazin-3-yl)-1-methyl-pyrrolidin-2-one To a solution of benzyl 3-(6-chloropyridazin-3-yl)-1-methyl-2-oxo-pyrrolidine-3-carboxylate (3.0 g, 8.68 mmol, 1 eq) in EtOH (180 mL) was added 1 N NaOH (60.0 mL, 60 mmol, 6.92 eq) at 20 °C. The reaction mixture was stirred at 20 °C for 2 h. The mixture was diluted with HO (200 mL) and extracted with DCM (100 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography using 0% to 100% EtOAc in PE followed by 15% MeOH in EtOAc to give 3-(6-chloropyridazin-3-yl)-1-methyl-pyrrolidin-2-one (1.8 g, 98.0%) as a purple solid. LC-MS: m / z=212.0 [M+H] + ,ESI pos. 1H NMR(400MHz,CDCl3)δ=7.72(d,J=8.9Hz,1H),7.48(d,J=8.9Hz,1H),3.95(t,J=8.5Hz,1H),3.61(dt,J= 4.3,9.2Hz,1H),3.55-3.46(m,1H),2.91(s,3H),2.88-2.80(m,1H),2.55(dtd,J=4.3,8.7,13.0Hz,1H).

[0360] Step 4: tert-butyl N-[6-(1-methyl-2-oxo-pyrrolidin-3-yl)pyridazin-3-yl]carbamate To a solution of 3-(6-chloropyridazin-3-yl)-1-methyl-pyrrolidin-2-one (400.0 mg, 1.88 mmol, 1 eq) in 1,4-dioxane (40 mL) was added tert-butyl carbamate (661.31 mg, 5.64 mmol, 3 eq), CSO (1.84 g, 5.64 mmol, 3 eq), Pd(dba) (344.72 mg, 0.380 mmol, 0.200 eq), and XantPhos (435.79 mg, 0.750 mmol, 0.4 eq). The reaction mixture was purged with N before heating to 100 °C. Stirring was then continued for 2 h. The mixture was cooled to 23 °C, poured into saturated aqueous NH Cl (200 mL), and extracted with EtOAc (100 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography using 0% to 100% EtOAc in PE, followed by 10% MeOH in EtOAc to give tert-butyl N-[6-(1-methyl-2-oxo-pyrrolidin-3-yl)pyridazin-3-yl]carbamate (250 mg, 45.5%) as a brown gum. LC-MS: m / z = 293.1 [M+H] + ,ESI pos.

[0361] Step 5: 3-(6-aminopyridazin-3-yl)-1-methyl-pyrrolidin-2-one; Hydrochloride tert-Butyl N-[6-(1-methyl-2-oxo-pyrrolidin-3-yl)pyridazin-3-yl]carbamate (240.0 mg, 0.820 mmol, 1 eq.) was dissolved in a 4 M solution of HCl in dioxane (10.0 mL, 40 mmol, 48.72 eq.) and stirred at 30 °C for 16 h. The reaction mixture was diluted with HO and extracted with EtOAc (10 mL × 3). The combined organic layers were concentrated under reduced pressure to give 3-(6-aminopyridazin-3-yl)-1-methyl-pyrrolidin-2-one; hydrochloride salt (158.0 mg, 84.2%) as a brown gum. LC-MS: m / z = 193.0 [M+H] + ,ESI pos.

[0362] Step 6: 1-[3-(Difluoromethyl)-6-[6-methoxy-5-[[6-[rac-(3R)-1-methyl-2-oxo-pyrrolidin-3-yl]pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Prepared according to Step 4 of Example 4, triturated with DMSO (2 mL) and purified by preparative HPLC (Phenomenex Luna C18 (150 mm × 25 mm, 10 μm), 22-52% CH3CN (0.225% FA) in HO dropwise over 10 min, flow rate: 25 mL / min) to give a racemic mixture of 1-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-[rac-1-methyl-2-oxo-pyrrolidin-3-yl]pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]5-methyl-pyrazole-3-carbonitrile (60 mg total). This racemic mixture was then purified using chiral SFC (REGIS(S,S)WHELK-O1 (250 mm x 25 mm, 10 μm), 70% CO in MeOH (containing 0.1% NH OH), 4.5 min, flow rate: 80 mL / min) to obtain 1-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-[(3R)-1-methyl-2-oxo-pyrrolidin-3-yl]pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (or enantiomer) (11.7 mg, 3.6% yield, 87% ee) as a yellow solid (absolute stereochemistry not determined). LC-MS: m / z = 571.1 [M+H] + ,ESI pos. 1 H NMR(400MHz,DMSO-d6)δ=9.00(s,1H),8.79(s,1H),8.60(d,J=8.7Hz,1H),8.52(s,1H),8.37(d,J=8.6Hz,1H),7.83(s,1H),7. 43-7.33(m,2H),7.27-6.95(m,2H),3.87(s,3H),3.84(s,1H),3.54-3.42(m,2H),2.79(s,3H),2.53(s,3H),2.45-2.37(m,2H).

[0363] Example 57 1-[3-(Difluoromethyl)-6-[6-methoxy-5-[[6-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Step 1: 1-[3-(Difluoromethyl)-6-[6-methoxy-5-[[6-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile The title compound was obtained from the racemic mixture described in Example 56 after separation of the enantiomers by chiral SFC (REGIS(S,S)WHELK-O1 (250 mm × 25 mm, 10 μm), 70% CO in MeOH (containing 0.1% NH OH), 4.5 min, flow rate: 80 mL / min), followed by a second chiral purification using the same conditions to give 1-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (or enantiomer, absolute stereochemistry not determined; 11.6 mg, 3.6% yield, 89% ee) as a yellow solid as the second eluting enantiomer. LC-MS: m / z=571.1 [M+H] + ,ESI pos. 1 H NMR(400MHz,DMSO-d6)δ=9.00(s,1H),8.79(s,1H),8.60(d,J=8.7Hz,1H),8.52(s,1H),8.37(d,J=8.6Hz,1H),7.83(s,1H),7. 43-7.33(m,2H),7.27-6.95(m,2H),3.87(s,3H),3.84(s,1H),3.54-3.42(m,2H),2.79(s,3H),2.53(s,3H),2.45-2.37(m,2H).

[0364] Example 58 Benzyl N-[2-[6-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]benzimidazol-5-yl]amino]pyridazin-3-yl]-1,3-dioxan-5-yl]carbamate [ka] Step 1: Benzyl N-[2-(6-chloropyridazin-3-yl)-1,3-dioxan-5-yl]carbamate To a solution of 6-chloropyridazine-3-carbaldehyde (1.0 g, 7.02 mmol, 1.0 eq.) in toluene (30 mL) was added benzyl N-[2-hydroxy-1-(hydroxymethyl)ethyl]carbamate (3.16 g, 14.03 mmol, 2.0 eq.) and TosOH (175.61 mg, 0.7 mmol, 0.1 eq.). The reaction was heated to 130 °C and stirred for 16 h using a Dean-Stark trap. The reaction mixture was cooled to 23 °C, poured into saturated aqueous NaHCO (100 mL), and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using 0% to 80% EtOAc in PE to give N-[2-(6-chloropyridazin-3-yl)-1,3-dioxan-5-yl]benzylcarbamate (460.0 mg, 18.7%) as a brown solid. LC-MS: m / z = 350.0 [M+H] + ,ESI pos. 1 H NMR(400MHz,CD3OD)δ=7.81(brs,1H),7.64-7.57(m,1H),7.36(brs,2H),7.27-7.18(m,2H),6.88(brd,J=5.4H z,1H),6.23(brs,1H),5.17-5.08(m,2H),4.30(brd,J=5.3Hz,2H),4.25-4.19(m,1H),3.79(brd,J=9.6Hz,2H).

[0365] Step 2: 1-[6-(5-aminobenzimidazol-1-yl)-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile To a solution of 1-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (300.0 mg, 1.12 mmol, 1.0 eq) in DMSO (100 mL) was added 5-aminobenzimidazole (148.69 mg, 1.12 mmol, 1.0 eq) and K2CO3 (462.98 mg, 3.35 mmol, 3.0 eq). The reaction mixture was heated to 80 °C and stirred for 5 h. The mixture was cooled to 23 °C, diluted with HO (100 mL), and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative TLC using 10% MeOH in EtOAc to give 1-[6-(5-aminobenzimidazol-1-yl)-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (200.0 mg, 49.0%) as a yellow solid. LC-MS: m / z=365.9 [M+H] + ,ESI pos. 1 H NMR(400MHz,CD3OD)δ=8.99-8.85(m,1H),8.62-8.50(m,1H),8.27-8.13(m,1H),8 .05-7.94(m,1H),7.27-6.97(m,2H),6.90(brd,J=10.8Hz,2H),2.60-2.54(m,3H).

[0366] Step 3: Benzyl N-[2-[6-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]benzimidazol-5-yl]amino]pyridazin-3-yl]-1,3-dioxan-5-yl]carbamate To a solution of 1-[6-(5-aminobenzimidazol-1-yl)-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (30.0 mg, 0.08 mmol, 1.0 eq.) in 2-methyl-2-butanol (2.0 mL, 0.08 mmol, 1.0 eq.), benzyl N-[2-(6-chloropyridazin-3-yl)-1,3-dioxan-5-yl]carbamate (43.08 mg, 0.12 mmol, 1.5 eq.), CsCO (80.26 mg, 0.25 mmol, 3.0 eq.), and RuPhos Pd G (3.49 mg, 0.0 mmol, 0.05 eq.) was added. The reaction was heated to 100 °C and stirred under a N atmosphere for 3 h. The reaction mixture was cooled to 23 °C, poured into HO (50 mL), and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Phenomenex Luna C18 (150 mm × 40 mm, 15 μm), 5–12% CHCN in HO (containing 0.225% FA), 10 min, flow rate 25 mL / min) to give benzyl N-[2-[6-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]benzimidazol-5-yl]amino]pyridazin-3-yl]-1,3-dioxan-5-yl]carbamate (10.0 mg, 16.7% yield) as a yellow solid. LC-MS: m / z=679.2 [M+H] + ,ESI pos. 1 H NMR(400MHz,CD3OD)δ=9.02-8.93(m,1H),8.61-8.49(m,1H),8.33-8.24(m,1H),8.23-8.12(m,2H),7.81-7.70(m,1H),7.66-7.58(m,1H),7.44- 7.29(m,5H),7.24-7.06(m,2H),6.95-6.87(m,1H),5.82-5.69(m,1H),5 .19-5.13(m,2H),4.32-4.23(m,2H),3.69-3.61(m,1H),2.50(brs,3H).

[0367] Example 59 1-[3-(Difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-4,6-dihydrofuro[3,4-c]pyrazole-3-carbonitrile [ka] Step 1: 4,6-Dihydro 1H-furo[3,4-c]pyrazole-3-carboxamide To a stirred solution of 4,6-dihydro-1H-furo[3,4-c]pyrazole-3-carboxylic acid (500 mg, 3.24 mmol, 1.0 eq.) in DMF (16.22 mL) at 20 °C under an argon atmosphere was added CDI (683.87 mg, 4.22 mmol, 1.3 eq.). After stirring for 3 h, ammonium hydroxide (2.27 g, 2.53 mL, 64.88 mmol, 20.0 eq.) was added and stirring was continued over the weekend. The mixture was diluted with HO and washed with EtOAc. The aqueous layer was concentrated to dryness to give 4,6-dihydro-1H-furo[3,4-c]pyrazole-3-carboxamide (700 mg, 42.3%) as a brown semi-solid. LC-MS: m / z = 152.0 [M−H] - ,ESI neg. This product was used in the next step without further purification.

[0368] Step 2: 4,6-Dihydro-1H-furo[3,4-c]pyrazole-3-carbonitrile To a stirred mixture of 4,6-dihydro-1H-furo[3...

Claims

1. Formula (I) 【Chemistry 1】 (In the formula, R １ is haloalkoxy, heterocycloalkylcarbonyl, heteroaryl, or heterocycloalkyl, where heterocycloalkylcarbonyl, heteroaryl, and heterocycloalkyl are R ４ optionally substituted with 1, 2, or 3 substituents individually selected from: R ２ is hydrogen, alkoxy, alkyl, halogen, haloalkoxy, dialkylaminocarbonylalkoxy, heterocycloalkyloxy, heterocycloalkylalkoxy or alkylheteroarylamino; R ３ is hydrogen, cycloalkylcarbonyl, alkylcarbonyl, heterocycloalkylcarbonyl, heterocycloalkyl, or heteroaryl, where heterocycloalkylcarbonyl, heterocycloalkyl, and heteroaryl are R ５ optionally substituted with 1, 2, or 3 substituents individually selected from: ２ and R ３ together with the carbon atom to which they are attached form a 4- to 6-membered heterocycloalkyl optionally substituted with alkylheteroaryl; R ４ are individually selected from alkyl, amino, alkylsulfonyl, cyano, halogen, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, dialkylaminocarbonyl, haloalkoxy, and haloalkyl; R ５ is individually selected from alkyl, alkoxycarbonyl, heterocycloalkyl, cycloalkyl, (hydroxyl)(alkyl)heterocycloalkyl, dialkylaminocarbonyl, heterocycloalkylalkoxy, alkylheterocycloalkyl, alkylheterocycloalkyloxy, heterocycloalkylheterocycloalkyloxy, (haloalkyl)(alkyl)aminocarbonyl, dialkylaminocarbonylalkyl, hydroxyalkyl, and arylalkoxycarbonylaminoheterocycloalkyl; A １ is —N— or —CH—, L is absent, —O— or —NH—. or a pharmaceutically acceptable salt thereof.

2. R １ is haloalkoxy, azetidinylcarbonyl, pyrazolyl, triazolyl, or pyrrolidinyl, and azetidinylcarbonyl, pyrazolyl, triazolyl, and pyrrolidinyl are R ４ 10. The compound of claim 1, optionally substituted with 1, 2, or 3 substituents individually selected from:

3. R １ But, R ４ 3. The compound of claim 1 or 2, which is pyrazolyl optionally substituted with 1, 2 or 3 substituents individually selected from:

4. R ２ is hydrogen, alkoxy, alkyl, halogen, haloalkoxy, dialkylaminocarbonylalkoxy, oxetanyloxy, tetrahydropyranyloxy, pyrrolidinyloxy, morpholinylalkoxy, or alkylpyridazinylamino; or R ２ and R ３ together with the carbon atom to which they are attached to form a methylpyridazinyl substituted imidazolidin-2-one.

5. R ２ is hydrogen, methoxy, methyl, fluoro, difluoromethoxy, dimethylaminocarbonylethoxy, oxetanyloxy, tetrahydropyranyloxy, pyrrolidinyloxy, morpholinylalkoxy, or alkylpyridazinylamino; or R ２ and R ３ together with the carbon atom to which they are attached to form a methylpyridazinyl substituted imidazolidin-2-one.

6. R ３ is hydrogen, cyclopropylcarbonyl, piperidinylcarbonyl, diazaspiroheptanyl, piperidyl, dihydro-5H-pyrano[4,3-c]pyridazinyl, 1-methyl-6-oxo-pyridazinyl, dihydropyridazino[4,5-b][1,4]oxazinyl, 6-oxo-pyrrolo[2,3-c]pyridazinyl, 5,7-dihydropyrrolo[3,4-c]pyridazinyl, pyridazinyl or 5,6-dihydropyrrolo[2,3-c]pyridazinyl; piperidinylcarbonyl, diazaspiroheptanyl, piperidyl, dihydro-5H-pyrano[4,3-c]pyridazinyl, 1-methyl-6-oxo-pyridazinyl, dihydropyridazino[4,5-b][1,4]oxazinyl, 6-oxo-pyrrolo[2,3-c]pyridazinyl, 5,7-dihydropyrrolo[3,4-c]pyridazinyl, pyridazinyl and 5,6-dihydropyrrolo[2,3-c]pyridazinyl are R ５ optionally substituted with 1, 2 or 3 substituents individually selected from The compound according to any one of claims 1 to 5.

7. R ３ is hydrogen, cyclopropylcarbonyl, piperidinylcarbonyl, 2,6-diazaspiro[3.3]heptanyl, 4-piperidyl, 7,8-dihydro-5H-pyrano[4,3-c]pyridazin-3-yl, 1-methyl-6-oxo-pyridazin-3-yl, 2,3-dihydropyridazino[4,5-b][1,4]oxazin-8-yl, 6-oxo-pyrrolo[2,3-c]pyridazin-3-yl, 5,7-dihydropyrrolo[3,4-c]pyridazin-3-yl, pyridazin-3-yl or 5,6-dihydropyrrolo[2,3-c]pyridazin-7-yl; piperidinylcarbonyl, 2,6-diazaspiro[3.3]heptanyl, 4-piperidyl, 7,8-dihydro-5H-pyrano[4,3-c]pyridazin-3-yl, 1-methyl-6-oxo-pyridazin-3-yl, 2,3-dihydropyridazino[4,5-b][1,4]oxazin-8-yl, 6-oxo-pyrrolo[2,3-c]pyridazin-3-yl, 5,7-dihydropyrrolo[3,4-c]pyridazin-3-yl, pyridazin-3-yl and 5,6-dihydropyrrolo[2,3-c]pyridazin-7-yl are R ５ 7. The compound of any one of claims 1 to 6, optionally substituted with 1, 2 or 3 substituents individually selected from:

8. R ４ is, at each occurrence, independently selected from cyano, methyl, amino, methylsulfonyl, fluoro, methoxyethyl, cyclopropylmethyl, dimethylaminocarbonyl, difluoromethoxy, (1R)-2,2-difluoro-1-methyl-ethoxy, difluoromethyl, trifluoromethyl, and trifluoroethyl.

9. R ５ in each case tert-butyloxycarbonyl, methyl, ethyl, tetrahydrofuranyl, oxetanyl, 4-hydroxy-3-methyl-tetrahydrofuranyl, dimethylaminocarbonyl, 5-[rac-(1S,5R)-3-oxa-6-azabicyclo[3.1.1]heptanyl, 1-methyl-5-oxo-pyrrolidinyl, 2-morpholinoethoxy, (1-methyl-4-piperidyl)oxy, (3R)-1- 9. The compound of any one of claims 1 to 8, independently selected from methyl-2-oxo-pyrrolidinyl, (3S)-1-methyl-2-oxo-pyrrolidinyl, 1-(oxetan-3-yl)-4-piperidyl]oxy, dimethylaminocarbonylmethyl, 5-(benzyloxycarbonylamino)-1,3-dioxan-2-yl, methyl(2,2,2-trifluoroethyl)carbamoyl, and 1-methylazetidin-3-yl.

10. R ５ in each case tert-butyloxycarbonyl, methyl, ethyl, 6-tetrahydrofuran-3-yl, oxetan-3-yl, 4-hydroxy-3-methyl-tetrahydrofuran-3-yl, dimethylaminocarbonyl, 5-[rac-(1S,5R)-3-oxa-6-azabicyclo[3.1.1]heptan-6-yl, 1-methyl-5-oxo-pyrrolidin-2-yl, 2-morpholinoethoxy, (1-methyl-4-piperidyl)oxy, 10. The compound of any one of claims 1 to 9, independently selected from (3R)-1-methyl-2-oxo-pyrrolidin-3-yl, (3S)-1-methyl-2-oxo-pyrrolidin-3-yl, 1-(oxetan-3-yl)-4-piperidyl]oxy, dimethylaminocarbonylmethyl, 5-(benzyloxycarbonylamino)-1,3-dioxan-2-yl, methyl(2,2,2-trifluoroethyl)carbamoyl, and 1-methylazetidin-3-yl.

11. A １ The compound of any one of claims 1 to 10, wherein is -CH-.

12. The compound of any one of claims 1 to 11, wherein L is -NH-.

13. 1-[3-(difluoromethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(2-morpholinoethoxy)benzimidazol-5-amine; 1-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[5-(difluoromethyl)-6-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 3-(difluoromethyl)-1-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-N,N,5-trimethyl-pyrazole-4-carboxamide; 5-(difluoromethoxy)-2-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-tetrahydrofuran-3-ylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 6-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]amino]-N,N-dimethyl-pyridazine-3-carboxamide; 3-[[1-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide; 1-[5-(difluoromethyl)-6-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 1-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine; 1-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-fluoro-pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[5-[(6-keto-5,5,7-trimethyl-pyrrolo[2,3-c]pyridazin-3-yl)amino]-6-methoxy-benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[5-[[6-(2-morpholinoethoxy)pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[5-(7,8-dihydro-5H-pyrano[4,3-c]pyridazin-3-ylamino)-6-methoxy-benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]-6-tetrahydropyran-4-yloxy-benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-5-(difluoromethyl)-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine; 1-[6-[3,5-bis(difluoromethyl)pyrazol-1-yl]-5-(difluoromethyl)-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine; (3R,5S)-1-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrrolidine-3-carbonitrile; 1-[6-[5-[(7-cyclopropyl-6-keto-5,5-dimethyl-pyrrolo[2,3-c]pyridazin-3-yl)amino]-6-methoxy-benzimidazol-1-yl]-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[5-[(6-keto-1-methyl-pyridazin-3-yl)amino]-6-methoxy-benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-[(1-methyl-4-piperidyl)oxy]pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[5-(difluoromethyl)-6-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 1-[5-(difluoromethyl)-6-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 1-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-[[1-(oxetan-3-yl)-4-piperidyl]oxy]pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[6-methoxy-5-[(4-methyl-2,3-dihydropyridazino[4,5-b][1,4]oxazin-8-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[6-[1-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(difluoromethyl)-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 6-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]benzimidazol-5-yl]amino]-N,N,4-trimethyl-pyridazine-3-carboxamide; N-[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]benzimidazol-5-yl]cyclopropanecarboxamide; 1-[6-[1-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(difluoromethyl)-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 3-(difluoromethoxy)-1-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-6,7-dihydropyrazolo[4,3-c]pyridin-4-one; 2-[3-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-5-yl]oxy-N,N-dimethyl-acetamide; 1-[5-(difluoromethyl)-6-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 1-[5-(difluoromethyl)-6-[1-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 1-[5-(difluoromethyl)-6-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 1-[6-[1-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(difluoromethyl)-2-pyridyl]-6-fluoro-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 1-[3-(difluoromethyl)-6-[6-fluoro-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[6-methoxy-5-[[5-[(1S)-3-oxa-6-azabicyclo[3.1.1]heptan-6-yl]pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 3-[[1-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-5-(difluoromethyl)-2-pyridyl]-6-methyl-benzimidazol-5-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide; 1-[5-(difluoromethyl)-6-[(1R)-2,2-difluoro-1-methyl-ethoxy]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine; 1-[5-(difluoromethyl)-6-[(1S)-2,2-difluoro-1-methyl-ethoxy]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine; N-[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]-1-(oxetan-3-yl)piperidine-4-carboxamide; 1-[5-(difluoromethyl)-6-[3-(trifluoromethyl)-5,7-dihydro-4H-pyrano[3,4-c]pyrazol-1-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine; 2-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]-2-pyridyl]-3,5-dimethyl-4H-pyrrolo[3,4-c]pyrazol-6-one; 1-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-(1-methyl-5-oxo-pyrrolidin-2-yl)pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 3-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]amino]-N,N,5-trimethyl-pyridazine-4-carboxamide; 3-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]amino]-N,N,5,6-tetramethyl-pyridazine-4-carboxamide; 3-[[1-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]amino]-N,6-dimethyl-N-(2,2,2-trifluoroethyl)pyridazine-4-carboxamide; 2-[6-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]amino]pyridazin-3-yl]-N,N-dimethyl-acetamide; 1-[3-(difluoromethyl)-6-[6-methoxy-5-(3-methyl-5-methylol-5,6-dihydropyrrolo[2,3-c]pyridazin-7-yl)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[5-(difluoromethyl)-6-[2-methyl-5-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 1-[3-(difluoromethyl)-6-(6-methoxybenzimidazol-1-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[5-(difluoromethyl)-6-[1-methyl-5-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 1-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-[(3R)-1-methyl-2-oxo-pyrrolidin-3-yl]pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; benzyl N-[2-[6-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]benzimidazol-5-yl]amino]pyridazin-3-yl]-1,3-dioxan-5-yl]carbamate; 1-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-4,6-dihydrofuro[3,4-c]pyrazole-3-carbonitrile; 1-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-2-pyridyl]-6-methoxy-N-[6-methyl-5-(1-methylazetidin-3-yl)pyridazin-3-yl]benzimidazol-5-amine; 1-[3-(difluoromethyl)-6-[5-[(6-ethyl-5,7-dihydropyrrolo[3,4-c]pyridazin-3-yl)amino]-6-methoxy-benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; [3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-[2-(trifluoromethyl)azetidin-1-yl]methanone; 1-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-pyrrolidin-3-yloxy-benzimidazol-5-amine; 1-[3-(difluoromethyl)-6-[3-(6-methylpyridazin-3-yl)-2-oxo-1H-imidazo[4,5-f]benzimidazol-7-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[1-(6-methylpyridazin-3-yl)-2-oxo-3H-imidazo[4,5-f]benzimidazol-7-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 6-[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester; 1-[6-[5-(2,6-diazaspiro[3.3]heptan-2-yl)-6-methoxy-benzimidazol-1-yl]-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[5-(difluoromethyl)-6-[1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 1-[3-(difluoromethyl)-6-[5-[[1-[(3R,4R)-4-hydroxy-3-methyl-tetrahydrofuran-3-yl]-4-piperidyl]amino]-6-methoxy-benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyrazin-2-yl]-5-methyl-pyrazole-3-carbonitrile 13. The compound of formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, selected from:

14. 1-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[5-(7,8-dihydro-5H-pyrano[4,3-c]pyridazin-3-ylamino)-6-methoxy-benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[6-[1-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(difluoromethyl)-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 1-[5-(difluoromethyl)-6-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; 1-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-2-pyridyl]-6-methoxy-N-[6-methyl-5-(1-methylazetidin-3-yl)pyridazin-3-yl]benzimidazol-5-amine; 1-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyrazin-2-yl]-5-methyl-pyrazole-3-carbonitrile; (3-aminoazetidin-1-yl)-[6-[6-(difluoromethoxy)-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-(difluoromethyl)-2-pyridyl]methanone; [6-[6-(difluoromethoxy)-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-(difluoromethyl)-2-pyridyl]-[2-(trifluoromethyl)azetidin-1-yl]methanone; [6-[6-(difluoromethoxy)-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-(difluoromethyl)-2-pyridyl]-[(2S,4S)-2,4-dimethylazetidin-1-yl]methanone; (3-aminoazetidin-1-yl)-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]methanone; [1-[5-(difluoromethyl)-6-(1-mesyl-3-piperidyl)-2-pyridyl]benzimidazol-5-yl]-(6-methylpyridazin-3-yl)amine; and 2-Azabicyclo[2.2.0]hexan-2-yl-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]methanone 14. The compound of formula (I) according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, selected from:

15. The following steps: (a) Formula (B1) or (B2) 【Chemistry 2】 and a compound of formula (B3) 【Transformation 3】 in the presence of a suitable solvent or in the presence of a suitable base; (b) Formula (C1) 【Chemistry 4】 with a deoxofluorinating agent in the presence of a suitable solvent; or (c) Formula (D1) 【Transformation 5】 and a compound of formula (D2) 【Transformation 6】 in the presence of a suitable solvent and in the presence of a suitable base wherein X is halogen, OM or OT, in particular halogen, and L, R １ , R ２ , R ３ , R ４ and R ５ is as defined in any one of claims 1 to 12) 15. A method for preparing a compound according to any one of claims 1 to 14, comprising one of the following steps:

16. A compound according to any one of claims 1 to 14 when produced according to the method of claim 15.

17. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14 for use as a therapeutically active substance.

18. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier.

19. Use of a compound of formula (I) according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof for treating or preventing rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis.

20. Use of a compound of formula (I) according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prevention of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis.

21. 15. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14 for use in the treatment or prevention of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis.

22. 16. A method for treating or preventing rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis, comprising administering to a patient in need thereof an effective amount of a compound of formula (I) according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof.

23. The invention as hereinbefore described.

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