Benzimidazole derivatives useful as SIK modulators

Abstract

The present invention relates to a compound of formula (I) (wherein L, R 1 , R 2 and R 3 as defined in the description and claims. The compounds of formula (I) can be used as medicines. TIFF2026500714000126.tif43161

Description

[Technical Field]

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

[0002] The present invention relates in particular to compounds of formula (I) [ka] During the ceremony, R 1 But R 4 heteroaryl optionally substituted with 1, 2, or 3 substituents individually selected from: R 2 is hydrogen, alkoxy, halogen, dialkylaminoalkoxy, heteroarylamino, or heterocycloalkyloxy; heteroarylamino and heterocycloalkyloxy are 5 optionally substituted with 1, 2, or 3 substituents individually selected from: R 3 is hydrogen, alkyl, dialkylaminoalkyl, heterocycloalkyl, or heteroaryl; heteroaryl and heterocycloalkyl are R 6 optionally substituted with 1, 2, or 3 substituents individually selected from: R 4 each instance of is individually selected from cyano, alkyl, alkoxy, halogen, haloalkoxy, and haloalkyl; R 5 each instance of is individually selected from alkyl and dialkylaminocarbonyl; R 6 each instance of is individually selected from alkyl, heterocycloalkyl, (heterocycloalkyl)heterocycloalkyloxy, (alkoxy)heterocycloalkylalkyl, and dialkylaminocarbonyl; 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, as well as 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" include morpholino, morpholin-4-yl, pyrrolidinyl, pyrrolidin-1-yl, pyrrolidin-3-yl, piperidinyl, 1-piperidyl, 4-piperidyl, 2-oxopyrrolidin-1-yl, piperazinyl, piperazin-1-yl, azetidinyl, azetidin-1-yl, [3-oxo-piperazin-1-yl], (1,1-dioxo-1,2-thiazolinyl), and the like. lysin-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]pyrrol-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-oxa-5,8-diazaspiro[3.5]nonan-8-yl), 3-azabicyclo[2,5]octan-7-yl, cyclo[3.2.0]heptan-3-yl), (5-azaspiro[2.4]heptan-5-yl), (2-azabicyclo[2.2.1]heptan-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-pyrrolidin-3-yl, 2-oxa-5-azaspiro[3.4]octan-5-yl Examples of heterocycloalkyl include, but are not limited to, 2,3,4,5,6,6-hexahydropyrrolo[2,3-c]pyrrol-1-yl, 2,3,4,5,6-hexahydropyrrolo[2,3-c]pyrrol-1-yl, and 2,3,4,5,6-hexahydropyrrolo[2,3-c]pyrrol-1-yl. Specific examples of "heterocycloalkyl" include piperidinyl and oxetanyl, more specifically 4-piperidyl and oxetan-3-yl. In certain embodiments, heterocycloalkyl is "N-heterocycloalkyl."

[0014] The term "heterocycloalkyloxy", alone or in combination, refers to an "oxy" group attached to a "heterocycloalkyl" group.

[0015] The term "heterocycloalkylalkyl", alone or in combination, refers to an "alkyl" group in which at least one hydrogen atom of the alkyl has been replaced by a "heterocycloalkyl" group.

[0016] The term "heteroaryl," alone or in combination, means an aromatic monocyclic or bicyclic ring system having 5 to 12 ring atoms containing 1, 2, 3, or 4 heteroatoms each independently selected from N, O, and S, with the remaining ring atoms being carbon. 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-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-1 Examples of "heteroaryl" include, but are not limited to, pyrazolyl, triazol-1-yl, triazol-2-yl, 2-oxo-4-pyridyl, pyrimidin-2-yl, pyrimidin-5-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), and (2,3-dihydropyridazino[4,5-b][1,4]oxazin-8-yl). Specific examples of "heteroaryl" include pyrazolyl and pyridazinyl, more specifically pyrazol-1-yl, pyrazol-4-yl, and pyridazin-3-yl. In one particular embodiment, heteroaryl is "N-heteroaryl."

[0017] The term "heteroarylamino", alone or in combination, means an "amino" group in which one of the amino's hydrogen atoms has been replaced by a "heteroaryl" group.

[0018] 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.

[0019] The term "oxy", alone or in combination, signifies the group --O--.

[0020] 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.

[0021] 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.

[0022] 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.

[0023] The term "haloalkoxy," alone or in combination, means 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.

[0024] The terms "hydroxyl" and "hydroxy," alone or in combination, refer to an --OH group.

[0025] The term "carbonyl", alone or in combination, signifies the -C(O)- group.

[0026] The term "amino," alone or in combination, means a primary amino group (-NH2), a secondary amino group (-NH-), or a tertiary amino group (-N-).

[0027] The term "alkylamino" refers to an alkyl group bonded to an -NH- group. The term "dialkylamino" refers to two alkyl groups bonded to an -N- atom. Examples of "dialkylamino" groups are, for example, dimethylamino, diethylamino, and (methyl)(ethyl)amino.

[0028] The term "dialkylaminocarbonyl," alone or in combination, means a "carbonyl" group attached to a "dialkylamino" group.

[0029] The term "dialkylaminoalkoxy", alone or in combination, refers to an "alkoxy" group wherein at least one hydrogen atom of the alkoxy has been replaced with a "dialkylamino" group.

[0030] The term "dialkylaminoalkyl", alone or in combination, means an "alkyl" group in which at least one hydrogen atom of the alkyl has been replaced with a "dialkylamino" group.

[0031] The term "pharmaceutically acceptable salt" refers to a salt that is not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid addition salts and base addition salts. The term "pharmaceutically acceptable acid addition salt" 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, and 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 salt" refers to a pharmaceutically acceptable salt formed with an organic or inorganic base. 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, piperidine, N-ethylpiperidine, and polyamine resins. A particular pharmaceutically acceptable salt of the compounds of the invention is the salt formed with formic acid.

[0032] The terms "compound(s) of this invention" and "compound(s) of the present invention" refer to compounds of formula (I) and their stereoisomers, tautomers, solvates, and salts (e.g., pharmaceutically acceptable salts).

[0033] 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.

[0034] 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).

[0035] 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 diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.

[0036] 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.

[0037] Furthermore, the present invention includes, where applicable, all optical isomers of the compounds of formula (I), i.e., diastereoisomers, diastereomeric mixtures, racemic mixtures, all corresponding enantiomers and / or tautomers thereof, and solvates thereof.

[0038] 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.

[0039] 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.

[0040] 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 structures in which one or more carbon atoms are replaced by 13 C or 14 Structures replaced with C-enriched carbons are within the scope of the present invention.

[0041] Therefore, the present invention provides R 1is selected from pyrazolyl and pyridinyl, and pyrazolyl and pyridinyl are selected from R 4 A compound according to the present invention optionally substituted with 1, 2 or 3 substituents individually 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 2 is hydrogen, alkoxy, halogen, dialkylaminoalkoxy, pyridazinylamino, or oxetanyloxy; pyridazinylamino and oxetanyloxy are R 5 A compound according to the present invention optionally substituted with 1, 2 or 3 substituents individually selected from: R 2 is hydrogen, methoxy, fluoro, dimethylaminoethoxy, pyridazinylamino or oxetanyloxy; pyridazinylamino and oxetanyloxy are R 5 A compound according to the present invention optionally substituted with 1, 2 or 3 substituents individually selected from: R 3 is hydrogen, alkyl, dialkylaminoalkyl, piperidyl, oxetanyl, or pyridazinyl; piperidyl, oxetanyl, and pyridazinyl are R 6 A compound according to the present invention optionally substituted with 1, 2 or 3 substituents individually selected from: R 3 is hydrogen, methyl, dimethylaminoethyl, piperidyl, oxetanyl, or pyridazinyl; piperidyl, oxetanyl, and pyridazinyl are R 6 A compound according to the present invention optionally substituted with 1, 2 or 3 substituents individually selected from: R 4 is, at each instance, independently selected from cyano, alkyl, haloalkoxy, and haloalkyl; R 4 is independently selected at each instance from cyano, methyl, difluoromethoxy, difluoromethyl, and trifluoroethyl; R 5 is, in each instance, independently selected from methyl and dimethylaminocarbonyl; R 6 is, in each instance, individually selected from alkyl, oxetanyl, (oxetanyl)piperidinyloxy, (methoxy)azetidinylethyl, and dialkylaminocarbonyl; R 6 is, at each instance, individually selected from methyl, oxetanyl, (oxetanyl)piperidinyloxy, (methoxy)azetidinylethyl, and dimethylaminocarbonyl; A compound according to the present invention, wherein L is -NH-; A compound according to the present invention, wherein L is absent; Compounds according to the present invention wherein L is -O-; A compound according to the present invention, wherein the compound of formula (I) is present as a free base; and The present invention relates to pharmaceutically acceptable salts of the compounds according to formula (I) described herein.

[0042] The present invention further comprises: 2-(3-cyano-5-methyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[2-(dimethylamino)ethoxy]-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[2-(dimethylamino)ethoxy]-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; 6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile; 6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile; 3-[[3-[5-cyano-6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-2-pyridyl]benzimidazol-5-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide; 3-[[1-[5-cyano-6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-2-pyridyl]benzimidazol-5-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide; 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]-5-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-fluoro-5-[[6-[[1-(oxetan-3-yl)-4-piperidyl]oxy]pyridazin-3-yl]amino]benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-fluoro-5-[[6-[2-(3-methoxyazetidin-1-yl)ethyl]pyridazin-3-yl]amino]benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]-5-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[5-methoxy-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-(3-methyloxetan-3-yl)oxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[2-(difluoromethoxy)-5-methyl-4-pyridyl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[5-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile; and 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[[1-(oxetan-3-yl)-4-piperidyl]amino]benzimidazol-1-yl]pyridine-3-carbonitrile; or a pharmaceutically acceptable salt thereof.

[0043] The present invention further comprises, in particular: 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; 6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile; 6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile; 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; and 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-(3-methyloxetan-3-yl)oxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; or a pharmaceutically acceptable salt thereof.

[0044] One embodiment of the present invention is a compound of formula (IIa) [ka] In the formula, L, R 2 and R 3 is, as described herein, R 4 is selected from cyano, haloalkyl and haloalkoxy, in particular cyano, difluoromethoxy, difluoromethyl and trifluoroethyl.

[0045] 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, R 4 is selected from cyano, haloalkyl and haloalkoxy, in particular cyano, difluoromethoxy, difluoromethyl and trifluoroethyl.

[0046] One embodiment of the present invention is a compound of formula (IIc) [ka] In the formula, L, R 2 and R 3 is, as described herein, R 4is selected from cyano, haloalkyl and haloalkoxy, in particular cyano, difluoromethoxy, difluoromethyl and trifluoroethyl.

[0047] One embodiment of the present invention is a compound of formula (III) [ka] In the formula, L, R 1 , R 2 , R 4 and R 5 is as described herein, and R 6 is, at each instance, individually selected from methyl, oxetanyl, (oxetanyl)piperidinyloxy, (methoxy)azetidinylethyl, and dimethylaminocarbonyl. DETAILED DESCRIPTION OF THE INVENTION

[0048] 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 common knowledge. In general, the reaction conditions provided below and the reaction conditions can, in some cases, be further modified according to the procedures described herein and in accordance with common knowledge.

[0049] Scheme 1 Scheme 1 describes the synthesis of compounds of formula (Ia) or (I-a'). Compounds of formula (Ia) are those in which R 2 is hydrogen, alkoxy, halogen, dialkylaminoalkoxy, heteroarylamino, or heterocycloalkyloxy; heteroarylamino and heterocycloalkyloxy are as described herein; 5optionally substituted with 1, 2, or 3 substituents individually selected from: 1 The pyrazole of R 4 and R 4 ' and R 4 and R 4 are independently selected from cyano, alkyl, haloalkoxy, and haloalkyl; L is -NH-; R is pyridazinyl; and pyridazinyl is selected from one, two, or three R 6 optionally substituted with R 5 is a compound of formula (I) where R is independently selected from alkyl, heterocycloalkyl, (heterocycloalkyl)heterocycloalkyloxy, (alkoxy)heterocycloalkylalkyl, and dialkylaminocarbonyl. 3 is hydrogen, alkoxy, halogen, dialkylaminoalkoxy, heteroarylamino, or heterocycloalkyloxy; heteroarylamino and heterocycloalkyloxy are as defined herein; 5 optionally substituted with 1, 2, or 3 substituents individually selected from: 1 The pyrazole of R 4 and R 4 ' and R 4 and R 4 R' is independently selected from cyano, alkyl, haloalkoxy, and haloalkyl; 2 is pyridazinyl, where R 2 pyridazinyl is one, two or three R 5 optionally substituted with R 5is a compound of formula (I) in which, at each instance, R2 / R3 is hydrogen, alkoxy, halogen, dialkylaminoalkoxy, heteroarylamino, or heterocycloalkyloxy. In the schemes below, R5 / R6 are, at each instance, individually selected from alkyl, heterocycloalkyl, heterocycloalkyloxy, (alkoxy)heterocycloalkylalkyl, and dialkylaminocarbonyl. [ka]

[0050] Step A: 6-chloro-2-fluoro-pyridine-3-carbonitrile 1 is prepared by Intermediate 3 can be obtained by reaction of substituted pyrazole 2 with a suitable organic or mineral base such as, for example, DIPEA, DBU, K2CO3, Cs2CO3 or NaH in a suitable polar solvent (e.g., DMF, DMA, NMP, DMSO or THF, MeTHF) at a temperature ranging from about -10°C to about 120°C.

[0051] Step B: Intermediates 3 and 4 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 of about -10°C to about 120°C to afford regioisomeric compounds Ia and I-a', which can be separated by flash column chromatography or preparative HPLC or preparative TLC.

[0052] Alternatively, intermediates 3 and 4 can be reacted under Buchwald-Hartwig coupling conditions using a suitable base (such as CsCO, KCO, or KPO) and a suitable palladium catalyst (such as t-Buxphos-Pd-G3 or [tBuBrettPhos Pd(allyl)]OTf) in a suitable solvent (such as t-amyl alcohol) at about 80° C. to about 90° C. to give regioisomeric compounds Ia and I-a', which can be separated by flash column chromatography or preparative HPLC or preparative TLC.

[0053] Scheme 2 Scheme 2 describes the synthesis of compounds of formula (8), wherein A is selected from alkyl, dialkylaminoalkyl, heteroaryl, and heterocycloalkyl; heteroaryl and heterocycloalkyl are selected from R 5 Optionally substituted with 1, 2 or 3 substituents individually selected from: [ka]

[0054] Step A: (4-Bromo-5-fluoro-2-nitro-phenyl)amine 5 and alcohol 6 can be reacted 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 of about −10° C. to about 120° C. to provide intermediate 7.

[0055] Step B: The nitro group of intermediate 7 can be reduced in the presence of a metal reducing agent (e.g., Zn or Fe), an acid (e.g., AcOH or HCl) in a suitable polar protic solvent (e.g., MeOH or EtOH) at a temperature of about −50° C. to about 120° C. to provide diamino intermediate 8.

[0056] Alternatively, the nitro group of intermediate 7 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 8.

[0057] Step C: Diamino intermediate 8 can be cyclized to give benzimidazole intermediate 9 in the presence of an orthoformate (such as trimethyl orthoformate with triethyl orthoformate), which can be used as a reaction solvent.

[0058] Scheme 3 Scheme 3 describes the synthesis of compounds of formula (4), where R 2 is selected from hydrogen, alkoxy, halogen, dialkylaminoalkoxy, heteroarylamino, and heterocycloalkyloxy; heteroarylamino and heterocycloalkyloxy are selected from R 5 and pyridazinyl is optionally substituted by one, two, or three substituents individually selected from: 6 optionally substituted with R 6 is, at each instance, individually selected from alkyl, heterocycloalkyl, (heterocycloalkyl)heterocycloalkyloxy, (alkoxy)heterocycloalkylalkyl, and dialkylaminocarbonyl. [ka]

[0059] Step A: Intermediate 10 can be reacted with SEM-Cl in the presence of a suitable organic or mineral base (e.g., NaH, CsCO, or DBU) in a suitable polar solvent (e.g., DMF, DMA, or NMP) at a temperature of about −50° C. to about 120° C. to give regioisomeric intermediates 11-a and 11-b.

[0060] Step B: Introduction of aminopyridazine 12 can be achieved by Buchwald-Hartwig coupling using a suitable base (such as CsCO, KCO, or KPO) and a suitable palladium catalyst (such as t-Buxphos-Pd-G3 or [tBuBrettPhos Pd(allyl)]OTf) in a suitable solvent (such as 1,4-dioxane) at about 80° C. to about 90° C. to provide intermediates 13-a and 13-b.

[0061] Step C: The regioisomeric mixture of intermediates 13-a and 13-b can be combined with a strong acid (such as TFA) in a suitable solvent (such as DCM) or without solvent to give intermediate 4.

[0062] Scheme 4 Scheme 4 describes the synthesis of compounds of formula (Ib) or (I-b'). Compounds of formula (Ib) or (I-b') are compounds of formula (I), where R 1 is R 4 heteroaryl optionally substituted with 1, 2, or 3 substituents individually selected from 2 is hydrogen, alkoxy, halogen, dialkylaminoalkoxy, heteroarylamino, or heterocycloalkyloxy; heteroarylamino and heterocycloalkyloxy are 5 optionally substituted with 1, 2, or 3 substituents individually selected from: 3 is hydrogen, alkyl, dialkylaminoalkyl, heterocycloalkyl, or heteroaryl; heteroaryl and heterocycloalkyl are R 6 and L is absent, —O—, or —NH—. [ka]

[0063] Step A: 2,6-Dichloronicotinonitrile 14 and intermediate 15 can be reacted in the presence of a suitable organic or mineral base (e.g., DIPEA, DBU, K2CO3, Cs2CO3, or NaH, etc.) in a suitable polar solvent (e.g., DMF, DMA, NMP, DMSO, or THF, MeTHF, etc.) at a temperature of about -10°C to about 120°C to give regioisomeric intermediates 16-a and 16-b.

[0064] Step B: Palladium-catalyzed cross-coupling reaction (Suzuki-Miyaura) between intermediates (16-a) and / or (16-b) and the corresponding arylboronic acid R1B(OH)2 or arylpinacolborane R1Bpin using a Pd catalyst (such as P(Ph3)4 or Pd(dppf)Cl2-CH2Cl2 or other suitable Pd catalyst) and a suitable base (K3PO4, Cs2CO3, K2CO3, Na2CO3) in a suitable solvent (such as a mixture of 1,4-dioxane and water) with heating (e.g., at a temperature between about 80°C and about 110°C, or via microwave irradiation at a temperature between about 80°C and about 120°C) provides a regioisomeric mixture of compounds of formula (Ia) and (I-b'), which can be separated by flash column chromatography, preparative HPLC, or preparative TLC.

[0065] Scheme 5 Scheme 5 describes the synthesis of compounds of formula (Ic) or (I-c'). Compounds of formula (Ic) or (I-c') are compounds of formula (I), where R 1 is the R 4 heteroaryl optionally substituted with 1, 2, or 3 substituents individually selected from 2 is hydrogen, alkoxy, halogen, dialkylaminoalkoxy, heteroarylamino, or heterocycloalkyloxy; heteroarylamino and heterocycloalkyloxy are defined herein as R 5 optionally substituted with 1, 2, or 3 substituents individually selected from: 3is hydrogen, alkyl, dialkylaminoalkyl, heterocycloalkyl, or heteroaryl; heteroaryl and heterocycloalkyl are R 6 and pyridazinyl is optionally substituted by one, two, or three substituents individually selected from: 6 optionally substituted with R 6 is, at each instance, individually selected from alkyl, heterocycloalkyl, (heterocycloalkyl)heterocycloalkyloxy, (alkoxy)heterocycloalkylalkyl, and dialkylaminocarbonyl. [ka]

[0066] Step A: Introduction of aminopyridazine 12 into intermediates 17-a and 17-b (as a single compound or a regioisomeric mixture of both compounds) can be achieved via Buchwald-Hartwig coupling using a suitable base (e.g., CsCO, KCO, or KPO) and a suitable palladium catalyst (e.g., t-Buxphos-Pd-G3 or [tBuBrettPhos Pd(allyl)]OTf) in a suitable solvent (e.g., 1,4-dioxane) at about 80° C. to about 90° C. to afford compounds of formula (Ic) and (I-c′) or a regioisomeric mixture thereof, which can be separated by flash column chromatography, preparative HPLC, or preparative TLC.

[0067] Therefore, the present invention also relates to a process for the preparation of a compound according to the invention, comprising the following steps: (a) A compound of formula (A1) [ka] and a compound of formula (A2) [ka] in the presence of a suitable solvent and in the presence of a suitable base; (b) a compound of formula (B1) [ka] and a compound of formula (B2) [ka] in the presence of a suitable solvent and a suitable catalyst; or (c) a compound of formula (C1) or (C2) [ka] or [ka] and a compound of formula (C3) [ka] in the presence of a suitable solvent, a suitable base and a suitable catalyst, including one of the following; wherein X1 is halogen, OM or OT, in particular halogen; and X2 is halogen, in particular chlorine. L, R 1 , R 2 , R 3 and R 6 is as described herein; In step (a), the solvent may be, for example, a polar solvent, in particular DMF, DMA, NMP, DMSO, or THF, more particularly DMSO; In step (a), the base may be, for example, an organic or inorganic base, in particular DIPEA, DBU, K2CO3, Cs2CO3 or NaH, more particularly K2CO3; Advantageously, the reaction of step (a) is carried out at a temperature of from about 0° C. to about 120° C., in particular from about 50° C. to about 80° 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 in particular from about 2 hours to about 16 hours; Conveniently, the reaction of step (a) is carried out in the presence of DMSO and K2CO3 at a temperature of about 50°C to about 80°C for about 2 hours to about 24 hours; In step (b), the solvent may be, for example, water, 1,4-dioxane, or a mixture thereof, in particular a mixture of water and 1,4-dioxane; In step (b), the base may include, for example, K3PO4, Cs2CO3, K2CO3, Na2CO3, in particular K2CO3; In step (b), the catalyst may be, for example, a Pd catalyst, in particular Pd(PPh3)2Cl2, Pd(PPh3)4, Pd(dppf)Cl2·CH2Cl2, or Pd(Oac)2 or Pd2(dba)3 and a phosphine ligand, more particularly Pd(PPh3)4, Pd(dppf)Cl2·CH2Cl2, etc.; Advantageously, the reaction of step (b) is carried out at a temperature of from about 60°C to about 120°C, in particular from about 80°C to about 110°C; Advantageously, the reaction of step (b) 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 in particular from about 4 hours to about 16 hours; Conveniently, the reaction in step (b) is carried out in the presence of K2CO3 in a mixture of water and 1,4-dioxane at a temperature of from about 80°C to about 120°C for from about 2 hours to about 48 hours.

[0068] In step (c), the solvent may be, for example, water, 1,4-dioxane, or a mixture thereof, in particular 1,4-dioxane, or a mixture of water and 1,4-dioxane; In step (c), the base may be, for example, K2CO3, Cs2CO3 or K3PO4, in particular K2CO3; In step (c), the catalyst may be, for example, a Pd catalyst, in particular t-Buxphos-Pd-G3 or [tBuBrettPhos Pd(allyl)]OTf); Advantageously, the reaction of step (c) is carried out at a temperature of from about 60°C to about 120°C, in particular from about 80°C to about 100°C; Advantageously, the reaction of step (c) is carried out for about 1 hour to about 48 hours, in particular about 2 hours to about 24 hours, more in particular about 4 hours to about 16 hours; Conveniently, the reaction in step (c) is carried out in the presence of K2CO3 in a mixture of water and 1,4-dioxane at a temperature of from about 80°C to about 120°C for from about 2 hours to about 48 hours.

[0069] The present invention also relates to a compound according to the present invention when made by a process as described herein.

[0070] 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 described 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) as defined herein 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, 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 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) as described herein or a pharmaceutically acceptable salt thereof.

[0071] 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, as well as methods of using the compounds of the present invention to prepare such compositions and medicaments. In one example, a compound of Formula (I) 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 other embodiments, 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.

[0072] 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.

[0073] 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.

[0074] The compounds of the present invention may be administered in any convenient dosage form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain ingredients conventional in pharmaceutical preparations, such as diluents, carriers, pH modifiers, sweeteners, fillers, and additional active agents.

[0075] Typical formulations are prepared by mixing the compound of the present invention with carrier or excipient.Suitable carrier and excipient are well known to those skilled in the art, and are described in detail in, for example, Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R. et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, 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) in an attractive manner or to aid in the manufacture of a pharmaceutical product (i.e., a medicament). [Example]

[0076] The invention will now be illustrated by the following examples, which have no limiting character. Abbreviation [tBuBrettPhos Pd(allyl)]OTf Allyl(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II) triflate (CAS number 1798782-15-6) ACN Acetonitrile ATP adenosine triphosphate aq. aqueous solution Boc tert-butyloxycarbonyl CAS Chemical Abstracts Service dba Dibenzylideneacetone 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 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 HPLC High Pressure Liquid Chromatography iPrOH isopropanol LCMS High-Performance Liquid Chromatography-Mass Spectrometry MeOH Methanol Ms Mesylate NMR nuclear magnetic resonance NPLC normal phase liquid chromatography PE Petroleum Ether psi pounds per square inch QToF quadrupole flight time Rf retention factor RT room temperature sat. saturation tBuXPhosPdG3 [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]methanesulfonate palladium(II) (CAS#1447963-75-8) Tf Trifle TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography Ts tosylate TsOH Tosylic acid UV ultraviolet light XantPhos (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane)

[0077] Example 1 2-(3-cyano-5-methyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile [ka] Step 1: 6-chloro-2-(3-cyano-5-methyl-pyrazol-1-yl)nicotinonitrile [ka] To a stirred solution of 6-chloro-2-fluoro-nicotinonitrile (250 mg, 1.60 mmol, 1.0 eq.) in N,N-dimethylformamide (4 mL) at RT under an argon atmosphere was added 5-methyl-1H-pyrazole-3-carbonitrile (205 mg, 1.92 mmol, 1.2 eq.) and K2CO3 (221 mg, 1.60 mmol, 1.0 eq.). Stirring at RT was continued for 2 h 30 min. The mixture was diluted with HO (16 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with HO (20 mL) and brine (20 mL), dried (MgSO4), filtered, and concentrated. The crude product was purified by flash chromatography (silica gel (20 g), 50% EtOAc in n-heptane) to give 6-chloro-2-(3-cyano-5-methyl-pyrazol-1-yl)nicotinonitrile (84 mg, 0.346 mmol, 22% yield) as a white solid. ESI pos[M+H] + 244.0

[0078] Step 2: 1H-benzimidazol-5-yl-(6-methylpyridazin-3-yl)amine [ka] Under an argon atmosphere, a mixture of 1H-benzimidazol-5-ylamine (2 g, 15.02 mmol, 1.0 eq.) and 3-chloro-6-methyl-pyridazine (2.32 g, 18.02 mmol, 1.2 eq.) in iPrOH (120 mL) was heated to 120 °C (oil bath temperature). Stirring at reflux was continued for 3 × 9 h (the reaction was stopped at the end of the day and not left overnight). The next day, some solvent escaped from the flask during vigorous reflux, so additional iPrOH was added. The mixture was cooled to RT, and the solid was collected by filtration, washed with iPrOH, and dried to give 1H-benzimidazol-5-yl-(6-methylpyridazin-3-yl)amine (2.516 g, 11.18 mmol, 74% yield) as a light brown solid. ESI pos[M+H] + 226.1

[0079] Step 3: 2-(3-cyano-5-methyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile [ka] To a stirred solution of 6-chloro-2-(3-cyano-5-methyl-pyrazol-1-yl)nicotinonitrile (79 mg, 0.324 mmol, 1.0 eq.) in dimethyl sulfoxide (3 mL) at RT under an argon atmosphere was added 1H-benzimidazol-5-yl-(6-methylpyridazin-3-yl)amine (81 mg, 0.324 mmol, 1.0 eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (74 mg, 73 µL, 0.486 mmol, 1.5 eq.). The mixture was heated to 85 °C and stirred at that temperature for 1 h 30 min. The mixture was cooled to RT, diluted with EtOAc (15 mL), and washed with HO (15 mL). The aqueous phase was extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with HO (30 mL) and brine (30 mL), dried (MgSO), filtered, and concentrated. The residual yellow solid was purified by flash chromatography (silica gel, 20 g, 0% to 15% MeOH in DCM) to give a pale yellow solid containing a mixture of both regioisomers. This mixture was further purified by preparative HPLC (Gemini NX, 12 nm, 5 μm, 100 × 30 mm, ACN / Water + 0.1% TEA) to give 2-(3-cyano-5-methyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile (13 mg, 0.030 mmol, 9% yield) as a pale yellow solid. ESI pos[M+H] + 433.2

[0080] Example 2 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile [ka] Step 1: 6-chloro-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile [ka]

[0081] To a solution of 6-chloro-2-fluoro-pyridine-3-carbonitrile (1.0 g, 6.39 mmol, 1.0 eq.) in DMSO (10 mL) was added 3-(difluoromethyl)-5-methyl-1H-pyrazole (844 mg, 6.39 mmol, 1.0 eq.) and K2CO3 (2.477 mg, 19.16 mmol, 3.0 eq.) and stirred at 25 °C for 1 h. The reaction mixture was diluted with HO (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, 20 g, 30% EtOAc in petroleum ether) to give 6-chloro-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (800 mg, 2.98 mmol, 42% yield) as a white solid. ESI pos[M+H] + 268.9 1 H NMR(400MHz,CDCl3)δ=8.13(d,J=8.2Hz,1H),7.45(d,J=8.2Hz,1H),6.75(t,J=54.6Hz,1H),6.52(s,1H),2.65(s,3H).

[0082] Step 2: 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; formic acid [ka] A mixture of 6-chloro-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (180 mg, 0.67 mmol, 1.0 eq.), N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine (151 mg, 0.67 mmol, 1.0 eq.), and K2CO3 (278 mg, 2.01 mmol, 3.0 eq.) in DMSO (1 mL) was stirred at 50 °C for 2 h. The reaction mixture was diluted with HO (10 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic layers were dried (Na2SO4) and concentrated. The crude product was purified by preparative NPLC (ACSWH-PREP-NPLC-A, hexane-EtOH) to give two batches of crude product 1 and crude product 2.

[0083] The crude product 1 was further purified by preparative HPLC (ACS-WH-GX-F), ACN / water + 0.1% FA) to give 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; formate (27 mg, 0.06 mmol, 9% yield) as a yellow solid. ESI pos[M+H] + 457.9 1 H NMR(400MHz,CD3OD)δ=8.94(brs,1H),8.56(d,J=8.6Hz,1H),8.26(s,1H),8.13(d,J=8.9Hz,1H),8.08(d,J=8.6Hz,1H),7.63(dd ,J=2.0,9.0Hz,1H),7.36(d,J=9.2Hz,1H),7.12(d,J=9.2Hz,1H),6.83(t,J=54.5Hz,1H),6.64(s,1H),2.62(s,3H),2.53(s,3H).

[0084] Example 3 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile [ka] The crude product 2 from Step 2 of Example 2 was further purified by preparative HPLC (ACS-WH-GX-F, water / FA-ACN) to give 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; formic acid (25 mg, 0.06 mmol, 8% yield) as a yellow solid. ESI pos[M+H] + 457.9 1 H NMR(400MHz,CD3OD)δ=8.93(d,J=1.7Hz,1H),8.86(s,1H),8.63(d,J=8.4Hz,1H),8.10(d,J=8.6Hz,1H),7.71(d,J=8.7Hz,1H),7.49 (dd,J=2.1,8.8Hz,1H),7.37(d,J=9.2Hz,1H),7.15(d,J=9.2Hz,1H),6.83(t,J=54.5Hz,1H),6.60(s,1H),2.62(s,3H),2.55(s,3H).

[0085] Example 4 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[2-(dimethylamino)ethoxy]-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile [ka] Step 1: 2-(5-amino-2-bromo-4-nitro-phenoxy)ethyl-dimethyl-amine [ka] To a solution of 2-(dimethylamino)ethanol (2.21 g, 2.5 mL, 24.82 mmol, 1.8 eq.) in dry THF (50 mL) was added NaH (993 mg, 24.82 mmol, 1.8 eq.) at 0 °C. The ice bath was removed and the mixture was stirred at RT for 30 min. The reaction mixture was cooled to 0 °C, (4-bromo-5-fluoro-2-nitro-phenyl)amine (3.24 g, 13.79 mmol, 1.0 eq.) was added, and the mixture was warmed to RT and stirred for 12 h. The reaction was cooled to 0 °C, quenched with NH4Cl sat. solution (50 mL), and extracted with DCM (3 × 50 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The crude product was purified by flash chromatography (SiNH2, 50 g, 0% to 10% MeOH in DCM) to give 2-(5-amino-2-bromo-4-nitro-phenoxy)ethyl-dimethyl-amine (4.068 g, 13.38 mmol, 97% yield). ESI pos[M+H] + 306.1

[0086] Step 2: 2-(4,5-diamino-2-bromo-phenoxy)ethyl-dimethyl-amine [ka] 2-(5-Amino-2-bromo-4-nitrophenoxy)ethyl-dimethylamine (4.52 g, 13.38 mmol, 1.000 eq.) was dissolved in ethanol (189.4 mL) under Ar. Activated zinc (zinc was suspended in 1 M HCl, stirred for 30 min, filtered, washed with EtOH, and dried in vacuo) (8.74 g, 133.75 mmol, 10.0 eq.) was added, and the reaction mixture was cooled to 0 °C. A solution of acetic acid (5.62 g, 5.36 mL, 93.63 mmol, 7.0 eq.) in ethanol (50 mL) was added dropwise, maintaining the temperature below 5 °C. The reaction mixture was allowed to warm to RT and stirred for 2 h. The reaction mixture was filtered, the filter cake was washed with EtOH, and the solution was evaporated to dryness. The crude product was dissolved in 2 N Na2CO3 solution (50 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine, dried (MgSO), filtered, and concentrated. The crude product was purified by flash chromatography (SiNH, 50 g, 0% to 10% MeOH in DCM) to give 2-(4,5-diamino-2-bromo-phenoxy)ethyl-dimethyl-amine (3.24 g, 11.82 mmol, 84% yield). ESI pos[M+H] + 274.2

[0087] Step 3: 2-[(6-bromo-3H-benzimidazol-5-yl)oxy]ethyl-dimethyl-amine [ka] A solution of 2-(4,5-diamino-2-bromo-phenoxy)ethyl-dimethylamine (3.24 g, 11.82 mmol, 1.0 eq.) in trimethyl orthoformate (93.56 g, 96.45 mL, 881.62 mmol, 74.6 eq.) was stirred at 120 °C for 3 h. The reaction mixture was evaporated to dryness. The residue was dissolved in DCM (50 mL) and HO (30 mL) was added. The organic layer was washed with brine (20 mL), dried (MgSO), filtered, and concentrated. The crude product was purified by flash chromatography (SiNH, 50 g, 0% to 30% MeOH in DCM) to give 2-[(6-bromo-3H-benzimidazol-5-yl)oxy]ethyl-dimethylamine (984 mg, 3.464 mmol, 29% yield). ESI pos[M+H] + 284.2

[0088] Step 4: 2-[6-Bromo-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxyethyl-dimethyl-amine [ka] To a solution of 2-[(6-bromo-3H-benzimidazol-5-yl)oxy]ethyl-dimethyl-amine (805 mg, 2.69 mmol, 1.0 eq.) in DMF (6 mL) was added NaH (96.89 mg, 4.04 mmol, 1.500 eq.) in portions at 0 °C. The reaction mixture was stirred at 0 °C for 15 min. 2-(Trimethylsilyl)ethoxymethyl chloride (747 mg, 796 μL, 4.04 mmol, 1.5 eq.) was added dropwise, keeping the temperature below 5 °C. The reaction mixture was allowed to warm to RT and stirred for 2 h. The reaction mixture was cooled to 0 °C, quenched with saturated NaHCO3 solution (10 mL), and extracted with DCM (30 mL). The organic layer was washed with water (10 mL), brine (10 mL), dried (MgSO), filtered, and concentrated to give a mixture of 2-[6-bromo-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxyethyl-dimethyl-amine and 2-[6-bromo-1-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-N,N-dimethyl-ethanamine (455 mg, 1.10 mmol, 41% yield), which was used without further purification. ESI pos[M+H] + 416.3

[0089] Step 5: 6-[2-(dimethylamino)ethoxy]-N-(6-methylpyridazin-3-yl)-1-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine [ka] Ar was bubbled through a suspension of a mixture of 2-[6-bromo-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxyethyl-dimethyl-amine and 2-[6-bromo-1-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-N,N-dimethyl-ethanamine (401 mg, 0.968 mmol, 1.0 eq.), (6-methylpyridazin-3-yl)amine (211 mg, 1.94 mmol, 2.0 eq.) and CsCO (946 mg, 2.9 mmol, 3.0 eq.) in dry 1,4-dioxane (14 mL) at RT for 5 min. Next, [tBuBrettPhos Pd(allyl)]OTf (151 mg, 0.194 mmol, 0.2 eq.) was added, the vial was capped, and the mixture was stirred at 80 °C for 2 h. The reaction mixture was cooled, concentrated, and purified by flash chromatography (silica gel, 12 g, 0% to 10% MeOH in DCM). This afforded a mixture of 6-[2-(dimethylamino)ethoxy]-N-(6-methylpyridazin-3-yl)-1-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine and 6-[2-(dimethylamino)ethoxy]-N-(6-methylpyridazin-3-yl)-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine (330 mg, 0.746 mmol, 77% yield). ESI pos[M+H] + 443.5

[0090] Step 6: Dimethyl-[2-[[6-[(6-methylpyridazin-3-yl)amino]-3H-benzimidazol-5-yl]oxy]ethyl]amine [ka] A solution of a mixture of 6-[2-(dimethylamino)ethoxy]-N-(6-methylpyridazin-3-yl)-1-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine and 6-[2-(dimethylamino)ethoxy]-N-(6-methylpyridazin-3-yl)-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine (330 mg, 0.746 mmol, 1.0 eq.) in TFA (4.88 g, 3.3 mL, 42.83 mmol, 57 eq.) was stirred at RT for 1 h. The reaction mixture was concentrated to dryness, dissolved in DCM (30 mL), and washed with 2N Na2CO3 solution (10 mL). The organic layer was washed with brine (10 mL), dried (MgSO4), filtered, and concentrated. The crude product was purified by flash chromatography (SiNH2, 20 g, 0% to 10% MeOH in DCM) to give dimethyl-[2-[[6-[(6-methylpyridazin-3-yl)amino]-3H-benzimidazol-5-yl]oxy]ethyl]amine (160 mg, 0.513 mmol, 69% yield). ESI pos[M+H] + 313.3

[0091] Step 7: 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[2-(dimethylamino)ethoxy]-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile [ka] To a solution of 6-chloro-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]nicotinonitrile (50 mg, 0.186 mmol, 1.0 eq.) and dimethyl-[2-[[6-[(6-methylpyridazin-3-yl)amino]-3H-benzimidazol-5-yl]oxy]ethyl]amine (61 mg, 0.195 mmol, 1.05 eq.) in DMSO (1.5 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (31 mg, 31 μL, 0.205 mmol, 1.1 eq.) and stirred at 80 °C for 3 h. The reaction was cooled to RT and diluted with DCM (10 mL) and HO (10 mL). The organic layer was washed with brine (5 mL), dried over MgSO, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, 4 g, 0% to 10% MeOH in DCM) to give a mixture of 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[2-(dimethylamino)ethoxy]-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile and 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[2-(dimethylamino)ethoxy]-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile. The isomers were separated by preparative HPLC (YMC-Triart C18, 12 nm, 5 μm, 100 × 30 mm, ACN / water + 0.1% FA) to give 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[2-(dimethylamino)ethoxy]-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; formate (18 mg, 0.033 mmol, 18% yield) as a yellow solid. ESI pos[M+H] + 545.2. 1H NMR(600MHz,DMSO-d6)δ=9.04(s,1H),8.79(s,1H),8.80(d,J=7.9Hz,1H),8.56(brs,1H),8.29(d,J=8.7Hz,1H),7.92(s,1H),7.36(d,J=9.1H) z,1H),7.19-7.30(m,1H),7.01-7.22(m,2H),6.76(s,1H),4.19(brs,2 H),2.64-2.94(m,2H),2.60(s,3H),2.49-2.49(m,3H),2.29(brs,3H).

[0092] Example 5 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[2-(dimethylamino)ethoxy]-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile [ka] Separation of the isomers in Step 7 of Example 5 gave 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[2-(dimethylamino)ethoxy]-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; formic acid (13 mg, 0.024 mmol, 13% yield) as a yellow solid. ESI pos[M+H] + 545.2 1 H NMR(600MHz,DMSO-d6)δ=9.20(s,1H),9.06(s,1H),8.81(d,J=8.7Hz,1H),8.60(s,1H),8.25(d,J=8.7Hz,1H),7.55(s,1H),7.32(d,J=9.1Hz,1 H),7.17(d,J=9.1Hz,1H),7.01-7.22(m,1H),6.68(s,1H),4.27(t,J=5.6Hz,2H),2.67-2.81(m,2H),2.58(s,3H),2.50(s,3H),2.31(brs,5H).

[0093] Example 6 6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile [ka] Step 1: 4-Bromo-3-methyl-1-(2,2,2-trifluoroethyl)pyrazole [ka] A mixture of 4-bromo-3-methylpyrazole (15.0 g, 93.17 mmol, 1.0 eq.), 2,2,2-trifluoroethyltrifluoromethanesulfonate (22.71 g, 97.83 mmol, 1.05 eq.), and CsCO (25.33 g, 186.34 mmol, 2.0 eq.) was 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 (250 mL) and extracted with EtOAc (3 × 250 mL). The combined organic layers were washed with brine (3 × 250 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 0% to 20% EtOAc in petroleum ether). This gave a mixture of 4-bromo-3-methyl-1-(2,2,2-trifluoroethyl)pyrazole and 4-bromo-5-methyl-1-(2,2,2-trifluoroethyl)pyrazole (2:1 ratio) as a colorless oil (19.5 g, 80.24 mmol, 86% yield). ESI pos[M+H] + 242.9 1 H NMR(400MHz,DMSO-d6)δ=8.00(s,1H),5.09-4.99(m,2H),2.14(s,3H).

[0094] Step 2: 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)pyrazole [ka]

[0095] A 2:1 mixture of 4-bromo-3-methyl-1-(2,2,2-trifluoroethyl)pyrazole and 4-bromo-5-methyl-1-(2,2,2-trifluoroethyl)pyrazole (11.0 g, 45.26 mmol, 1.0 eq.) was dissolved in 1,4-dioxane (200 mL). Potassium acetate (5.66 mL, 90.53 mmol, 2.0 eq.) and bis(pinacolato)diboron (13.79 g, 54.32 mmol, 1.2 eq., CAS: 73183-34-3) were added, followed by Pd(dppf)Cl₂·CHCl₂ (3.7 g, 4.53 mmol, 0.1 eq.). The mixture was stirred at 100 °C under a N₂ atmosphere for 16 h. The mixture was cooled to RT and concentrated. The residue was purified by flash chromatography (silica gel, 0% to 20% EtOAc in petroleum ether), which gave a 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. This mixture was further purified by preparative HPLC (Welch Ultimate XB-SiOH 10 μm, 250 × 70 mm, hexane-EtOH) to give a 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 (3:1 ratio) (6.0 g, 20.68 mmol, 46% yield). ESI pos[M+H] + 291.1

[0096] Step 3: 2-chloro-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile [ka] To a solution of 2,6-dichloronicotinonitrile (100 mg, 0.58 mmol, 1.0 eq.) and N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine (130 mg, 0.58 mmol, 1.0 eq.) in DMSO (2 mL) was added diisopropylethylamine (0.2 mL, 1.16 mmol, 2.0 eq.). The mixture was stirred at 130 °C for 12 h. The mixture was cooled to RT, and HO (20 mL) was added. The mixture was extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0%–10% MeOH in DCM) and further purified by preparative HPLC (Welch Ultimate XB-SiOH 10 μm, 250 × 70 mm, hexane-EtOH) to give 2-chloro-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile (90 mg, 0.25 mmol, 34% yield) as a yellow solid. ESI pos[M+H] + 362.1 1 H NMR(400MHz,DMSO-d6)δ=9.43(s,1H),9.12(s,1H),8.66(d,J=8.5Hz,1H),8.52(d,J=1.9Hz,1H),8.28(d, J=8.9Hz,1H),8.21(d,J=8.6Hz,1H),7.58(dd,J=2.2,8.9Hz,1H),7.34(s,1H),7.13(s,1H),2.54(s,3H).

[0097] Step 4: 6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile; formic acid [ka] 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 (3:1 ratio) (221 mg, 0.76 mmol, 1.1 mL) in a mixture of 1,4-dioxane (5 mL) and water (0.5 mL). To a solution of 2-chloro-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile (250 mg, 0.69 mmol, 1.0 eq.), potassium carbonate (191 mg, 1.38 mmol, 2.0 eq.), and Pd(dppf)Cl⋅CHCl (56 mg, 0.07 mmol, 0.1 eq.) was added and the mixture was stirred at 100°C for 12 hours under a N atmosphere. The mixture was concentrated, and the residue was purified by reverse-phase flash chromatography (0% to 30% ACN + 0.1% FA in water) to give 6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile and 6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile as off-white solids (147 mg, 0.30 mmol, 43% yield). The isomers were separated by preparative SFC (column: Phenomenex Luna C18, 10 μm, 150 × 25 mm) to give 6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile (25 mg, 0.050 mmol, 7% yield) as a yellow solid. ESI pos[M+H] + 489.9. 1H NMR(400MHz,DMSO-d6)δ=9.25(s,1H),9.06(s,1H),8.60-8.54(m,2H),8.46(d,J=1.6Hz,1H),8.21(d,J=8.8Hz,1H),8.04(d,J =8.7Hz,1H),7.59-7.49(m,1H),7.34(d,J=9.0Hz,1H),7.09(d,J=9.0Hz,1H),5.30-5.20(m,2H),2.48(brs,3H),2.46(s,3H).

[0098] Example 7 6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile [ka] Separation of the isomers in Step 4 of Example 6 afforded 6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile; formic acid (4 mg, 0.001 mmol, 1% yield) as a yellow solid. ESI pos[M+H] + 490.0. 1 H NMR(400MHz,DMSO-d6)δ=9.25(s,1H),9.09(s,1H),8.58(d,J=8.6Hz,1H),8.42(d,J=2.0Hz,1H),8.23(d,J=9.0Hz,1H),8.18(s,1H),8 .06(d,J=8.8Hz,1H),7.59-7.53(m,1H),7.34(d,J=9.0Hz,1H),7.08(d,J=9.1Hz,1H),5.33-5.23(m,2H),2.59(s,3H),2.48(brs,3H).

[0099] Example 8 3-[[3-[5-cyano-6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-2-pyridyl]benzimidazol-5-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide [ka] Step 1: tert-Butyl 3-hydroxy-5-methyl-pyrazole-1-carboxylate [ka] To a solution of 5-methyl-1H-pyrazol-3-ol (5.0 g, 50.97 mmol, 1.0 eq.) in DCM (50 mL) was added di-t-butyldicarbonate (11.72 mL, 50.97 mmol, 1.0 eq.) and triethylamine (7.81 mL, 56.07 mmol, 1.1 eq.), and the reaction was stirred at RT for 18 h. The reaction was poured into water (150 mL) and extracted with DCM (2 × 100 mL). The combined organic layers were washed with brine (3 × 150 mL), dried over NaSO, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0% to 10% MeOH in DCM) to give tert-butyl 3-hydroxy-5-methyl-pyrazole-1-carboxylate as a yellow solid (9.8 g, 49.44 mmol, 90% yield). ESI pos[M-C4H8+H] + 143.0. 1 H NMR(400MHz,DMSO-d6)δ=10.68(d,J=3.5Hz,1H),5.70(d,J=0.9Hz,1H),2.37(d,J=0.6Hz,3H),1.52(s,9H).

[0100] Step 2: tert-butyl 3-(difluoromethoxy)-5-methyl-pyrazole-1-carboxylate [ka] To a solution of tert-butyl 3-hydroxy-5-methyl-pyrazole-1-carboxylate (17.0 g, 85.76 mmol, 1.0 eq.) in acetonitrile (250 mL) was added (2-chloro-2,2-difluoroacetyl)oxysodium (14.38 g, 94.34 mmol, 1.1 eq.) and CsCO (55.89 g, 171.53 mmol, 2.0 eq.). The reaction was stirred at 80 °C for 12 h. The mixture was filtered, and the filter cake was washed with acetonitrile (4 × 50 mL). The filtrate was concentrated, and the residue was purified by flash chromatography (silica gel, 10% EtOAc in petroleum ether) to give tert-butyl 3-(difluoromethoxy)-5-methyl-pyrazole-1-carboxylate as a colorless oil (14.0 g, 56.4 mmol, 66% yield). ESI pos[M-C4H8+H] + 193.0. 1 H NMR(400MHz,CD3OD)δ=7.38-6.84(m,1H),5.97(s,1H),2.46(d,J=0.7Hz,3H),1.59(s,9H).

[0101] Step 3: 3-(Difluoromethoxy)-5-methyl-1H-pyrazole [ka] To a solution of tert-butyl 3-(difluoromethoxy)-5-methyl-pyrazole-1-carboxylate (12.5 g, 50.36 mmol, 1.0 eq.) in DCM (30 mL) was added 4 M HCl in dioxane (31.25 mL, 125.0 mmol, 2.48 eq.) and stirred at RT for 24 h. The reaction mixture was concentrated to give 3-(difluoromethoxy)-5-methyl-1H-pyrazole as a colorless oil (7.4 g, 49.96 mmol, 95% yield). ESI pos[M-CH+H] + 149.1. 1 H NMR(400MHz, CDCl3)δ=13.40(s,1H),6.68(t,J=72.1Hz,1H),5.85(s,1H),2.41(s,3H).

[0102] Step 4: 6-chloro-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile [ka] A mixture of 6-chloro-2-fluoro-pyridine-3-carbonitrile (280 mg, 1.79 mmol, 1.0 eq.), 3-(difluoromethoxy)-5-methyl-1H-pyrazole (265 mg, 1.79 mmol, 1.0 eq.), and potassium carbonate (742 mg, 5.37 mmol, 3.0 eq.) was dissolved in DMSO (6 mL) and stirred at 25 °C for 2.5 h. LCMS showed 67% of the desired mass, with some starting material remaining. The mixture was poured into water (40 mL) and extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine (3 × 80 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by column chromatography (silica gel, 0% to 50% EtAOc in petroleum ether) to give 6-chloro-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile as a white solid (270 mg, 0.95 mmol, 53% yield). ESI pos[M+H] + 285.0. 1 H NMR(400MHz, CDCl3)δ=8.05(d,J=8.2Hz,1H),7.31(d,J=8.2Hz,1H),7.34-6.98(t,1H),5.95(s,1H),2.65(s,3H).

[0103] Step 5: 6-(6-bromobenzimidazol-1-yl)-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile [ka] A mixture of 6-chloro-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (310 mg, 1.09 mmol, 1.0 eq.), 5-bromo-1H-benzimidazole (215 mg, 1.09 mmol, 1.0 eq.), and potassium carbonate (452 ​​mg, 3.27 mmol, 3.0 eq.) was dissolved in DMSO (6 mL) and stirred at 25 °C for 1 h. The mixture was poured into water (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (3 × 80 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 10% to 40% EtOAc in petroleum ether) to give 6-(5-bromobenzimidazol-1-yl)-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile as a white solid (135.0 mg, 0.3 mmol, 27.84% yield): ESI pos[M+H] + 445.1. 1 H NMR (400 MHz, DMSO-d6) δ = 9.18 (s, 1H), 8.77 (d, J = 8.6 Hz, 1H), 8.18 (dd, J = 3.4, 8.6 Hz, 2H), 8.04 (d, J = 1.7 Hz, 1H), 7.61 (dd, J = 1.8, 8.7 Hz, 1H), 7.36 (t, J = 72.8 Hz, 1H), 6.35 (s, 1H), 2.53 (s, 3H). 6-(6-Bromobenzimidazol-1-yl)-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (125.0 mg, 0.28 mmol, 25.78% yield) was obtained as a white solid. ESI pos [M+H] + 445.1. 1 H NMR(400MHz,DMSO-d6)δ=9.17(s,1H),8.77(d,J=8.4Hz,1H),8.46(d,J=1.7Hz,1H),8.20(d,J=8. 6Hz,1H),7.78(d,J=8.6Hz,1H),7.58-7.54(m,1H),7.54-7.16(m,1H),6.38(s,1H),2.57(s,3H).

[0104] Step 6: Ethyl 3-(benzhydrylideneamino)-6-methyl-pyridazine-4-carboxylate [ka] To a solution of ethyl 3-chloro-6-methyl-pyridazine-4-carboxylate (50 mg, 0.25 mmol, 1.0 eq.) and diphenylmethanimine (0.06 mL, 0.37 mmol, 1.5 eq.) in 1,4-dioxane (1 mL) was added CsCO (244 mg, 0.75 mmol, 3.0 eq.) and Xantphos Pd G (21 mg, 0.02 mmol, 0.1 eq.). The mixture was bubbled with N and stirred at 100 °C under a N atmosphere for 16 h. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over NaSO, filtered, and concentrated. The crude product was purified by preparative TLC (EtOAc) to give ethyl 3-(benzhydrylideneamino)-6-methyl-pyridazine-4-carboxylate (60 mg, 0.17 mmol, 70% yield) as a yellow oil. ESI pos[M+H] + 346.1. 1 H NMR(400MHz, CDCl3)δ=7.93-7.10(m,8H),4.30(q,J=7.2Hz,2H),2.68(s,3H),1.30-1.27(m,3H).

[0105] Step 7: 3-(Benzhydrylideneamino)-6-methyl-pyridazine-4-carboxylic acid [ka] To a mixture of ethyl 3-(benzhydrylideneamino)-6-methyl-pyridazine-4-carboxylate (1.4 g, 4.05 mmol, 1.0 eq.) in a mixture of THF (5 mL) / methanol (5 mL) / HO (2.5 mL) was added LiOH (243 mg, 10.14 mmol, 2.5 eq.). The mixture was stirred at RT for 1 h. The mixture was concentrated to give 3-(benzhydrylideneamino)-6-methyl-pyridazine-4-carboxylic acid as a yellow solid (1.2 g, 3.78 mmol, 93% yield). The crude product was used directly in the next step without further purification. ESI pos[M+H] + 318.0.

[0106] Step 8: 3-(Benzhydrylideneamino)-N,N,6-trimethyl-pyridazine-4-carboxamide [ka] To a solution of 3-(benzhydrylideneamino)-6-methyl-pyridazine-4-carboxylic acid (1.00 g, 3.15 mmol, 1.0 eq.) in DMF (15 mL) was added DIPEA (1.65 mL, 9.45 mmol, 3.0 eq.), HATU (2.22 g, 9.45 mmol, 3.0 eq.) and dimethylamine hydrochloride (514 mg, 6.3 mmol, 2.0 eq.). The reaction mixture was stirred at 30° C. for 16 h. The reaction mixture was poured into water (60 mL) and extracted with EtOAc (3×40 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to give (3-(benzhydrylideneamino)-N,N,6-trimethyl-pyridazine-4-carboxamide (1.09 mg, 3.15 mmol, quantitative yield), which was used in the next step without further purification. ESI pos[M+H] + 345.1.

[0107] Step 9: 3-amino-N,N,6-trimethyl-pyridazine-4-carboxamide [ka] To a solution of 3-(benzhydrylideneamino)-N,N,6-trimethyl-pyridazine-4-carboxamide (400 mg, 1.16 mmol, 1.0 eq.) in methanol (20 mL) was added hydroxylamine hydrochloride (161 mg, 2.32 mmol, 2.0 eq.) and sodium acetate (0.22 mL, 2.9 mmol, 2.5 eq.) and stirred at RT for 2 h. The reaction mixture was concentrated. The residue was dissolved in EtOAc (30 mL) and washed with HO (20 mL). The aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with brine (3 × 10 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by preparative TLC (EtOAc) to give 3-amino-N,N,6-trimethyl-pyridazine-4-carboxamide (199 mg, 1.10 mmol, 95% yield) as a brown solid. ESI pos[M+H] + 181.1. 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).

[0108] Step 10: 3-[[3-[5-cyano-6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-2-pyridyl]benzimidazol-5-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide; formic acid [ka] N2 was bubbled through a solution of 3-amino-N,N,6-trimethyl-pyridazine-4-carboxamide (41 mg, 0.22 mmol, 2.0 eq.), 6-(6-bromobenzimidazol-1-yl)-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (50 mg, 0.11 mmol, 1.0 eq.), and cesium carbonate (110 mg, 0.34 mmol, 3.0 eq.) in 1,4-dioxane (2 mL) for 3 min. [tBuBrettPhos Pd(allyl)]OTf (18 mg, 0.02 mmol, 0.2 eq.) was added, and the mixture was stirred at 80 °C for 2 h. The solution was filtered, the filtrate was concentrated, and the residue was purified by preparative HPLC (Phenomenex Luna C18 10 μm, 150 mm x 25 mm, water + 0.1% FA-ACN) to give 3-[[3-[5-cyano-6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-2-pyridyl]benzimidazol-5-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide; formate as a yellow solid (23 mg, 0.04 mmol, 37% yield). ESI pos[M+H] + 545.2. 1 H NMR(400MHz,DMSO-d6)δ=9.02(s,1H),8.75(d,J=8.6Hz,1H),8.64(d,J=1.8Hz,1H),8.56(s,1H),8.13(d,J=8.7Hz,1H),7.71(d,J=8.7 Hz,1H),7.59(dd,J=2.0,8.8Hz,1H),7.33(s,1H),7.53-7.17(t,1H),6.27(s,1H),2.97(s,3H),2.87(s,3H),2.54(s,3H),2.52(s,3H).

[0109] Example 9 3-[[1-[5-cyano-6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-2-pyridyl]benzimidazol-5-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide [ka] N2 was bubbled through a solution of 3-amino-N,N,6-trimethyl-pyridazine-4-carboxamide (40 mg, 0.22 mmol, 2.0 eq.), 6-(5-bromobenzimidazol-1-yl)-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (50 mg, 0.11 mmol, 1.0 eq.), and cesium carbonate (110 mg, 0.34 mmol, 3.0 eq.) in 1,4-dioxane (2 mL) for 10 min. [tBuBrettPhos Pd(allyl)]OTf (18 mg, 0.02 mmol, 0.2 eq.) was added, and the mixture was stirred at 80 °C for 2 h. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by preparative HPLC (Phenomenex Luna C18 10 μm, 150 mm × 25 mm, water + 0.1% FA-ACN) to give 3-[[1-[5-cyano-6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-2-pyridyl]benzimidazol-5-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide; formate as a yellow solid (33 mg, 0.06 mmol, 53% yield). ESI pos[M+H] + 545.2. 1 H NMR(400MHz,DMSO-d6)δ=9.10(s,1H),8.74(d,J=8.6Hz,1H),8.44(s,1H),8.24(d,J=1.8Hz,1H),8.16(dd,J=8.8,12.6Hz,2H), 7.58(dd,J=2.0,8.9Hz,1H),7.34(s,1H),7.55-7.19(t,1H),6.35(s,1H),2.99(s,3H),2.90(s,3H),2.58(s,3H),2.52(s,3H).

[0110] Example 10 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile [ka] Step 1: 6-[5-bromo-6-(oxetan-3-yloxy)benzimidazol-1-yl]-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile [ka] To a solution of 6-chloro-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (200 mg, 0.74 mmol, 1.0 eq., prepared in Step 1 of Example 2) in DMSO (3 mL), 5-bromo-6-(oxetan-3-yloxy)-1H-benzimidazole (200 mg, 0.74 mmol, 1.0 eq.; prepared in Step 3 of Example 14), K2CO3 (308.68 mg, 2.23 mmol, 3.0 eq.) were added and stirred at RT for 1 h. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic phase was washed with brine (3 × 5 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (DCM / MeOH 10:1) to give the following: 6-[5-bromo-6-(oxetan-3-yloxy)benzimidazol-1-yl]-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (70 mg, 0.14 mmol, 18% yield) as a white solid; ESI pos[M+H] + 502.7; 1 H NMR(400MHz,CDCl3)δ=8.47(s,1H),8.40(d,J=8.4Hz,1H),8.12(s,1H),7.65(d,J=8.4Hz,1H),7.33(s,1H),6.8 3(t,J=54.6Hz,1H),6.64(s,1H),5.22(quin,J=5.7Hz,1H),4.94-4.90(m,2H),4.89-4.84(m,2H),2.60(s,3H); and 6-[6-Bromo-5-(oxetan-3-yloxy)benzimidazol-1-yl]-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (80 mg, 0.16 mmol, 20% yield); ESI pos[M+H] + I got 502.7. 1 H NMR(400MHz,CDCl3)δ=8.59(s,1H),8.41(d,J=8.4Hz,1H),8.35(s,1H),7.66(d,J=8.4Hz,1H),6.96(s,1H),6.8 0(brt,J=54.6Hz,1H),6.62(s,1H),5.38-5.31(m,1H),5.09(brt,J=6.7Hz,2H),4.93-4.89(m,2H),2.69(s,3H).

[0111] Step 2: 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile [ka] To a solution of 6-[5-bromo-6-(oxetan-3-yloxy)benzimidazol-1-yl]-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (70 mg, 0.14 mmol, 1.0 eq.) in 1,4-dioxane (3 mL), 3-amino-6-methylpyridazine (18 mg, 0.17 mmol, 1.2 eq.) and CsCO (136.49 mg, 0.42 mmol, 3.0 eq.) were added, and the mixture was bubbled with N for 10 min. [tBuBrettPhos Pd(allyl)]OTf (22 mg, 0.03 mmol, 0.2 eq.) was added, and the mixture was stirred at 80 °C for 2 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (10 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (ACS-WH-GX-F, water + 0.1% FA-ACN). 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile; formic acid was obtained as a white solid (15 mg, 0.03 mmol, 20% yield). ESI pos[M+H] + 529.9. 1 H NMR(400MHz,DMSO-d6)δ=9.05(s,1H),8.87(s,1H),8.81(d,J=8.6Hz,1H),8.38(s,1H),8.29(d,J=8.7Hz,1H),7.42(s,1H),7. 37(s,2H),7.15(t,J=54.2Hz,1H),6.82(s,1H),5.28(quin,J=5.4Hz,1H),4.79-4.75(m,2H),4.75-4.71(m,2H),2.55(s,6H).

[0112] Example 11 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]-5-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile [ka] The title compound was prepared in accordance with Step 2 of Example 10 using 6-[6-bromo-5-(oxetan-3-yloxy)benzimidazol-1-yl]-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (Step 1 of Example 10) (80 mg, 0.16 mmol, 1.0 eq.), 1,4-dioxane (3 mL), 3-amino-6-methylpyridazine (21 mg, 0.19 mmol, 1.2 eq.), CsCO (155.99 mg, 0.48 mmol, 3.0 eq.) and [tBuBrettPhos Pd(allyl)]OTf (25 mg, 0.03 mmol, 0.2 eq.) was reacted to give 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]-5-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile (19.5 mg, 0.04 mmol, 21.92% yield) as a white solid. ESI pos[M+H] + 529.9. 1 H NMR(400MHz,DMSO-d6)δ=9.28(s,1H),9.03(s,1H),8.79(d,J=8.6Hz,1H),8.41(s,1H),8.22(d,J=8.7Hz,1H),7.32(s,2H),7.24-6 .95(m,2H),6.66(s,1H),5.45(quin,J=5.3Hz,1H),5.02(t,J=6.7Hz,2H),4.72(dd,J=5.1,7.2Hz,2H),2.55(s,3H),2.48(brs,3H).

[0113] Example 12 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-fluoro-5-[[6-[[1-(oxetan-3-yl)-4-piperidyl]oxy]pyridazin-3-yl]amino]benzimidazol-1-yl]pyridine-3-carbonitrile [ka] Step 1: tert-butyl 4-(6-chloropyridazin-3-yl)oxypiperidine-1-carboxylate [ka] To a solution of 1-Boc-4-hydroxypiperidine (1621 mg, 8.05 mmol, 1.2 eq.) in THF (15 mL) at 0 °C under a N atmosphere was added NaH (60% in oil) (537 mg, 13.43 mmol, 2.0 eq.) in portions. The reaction mixture was stirred at 0 °C for 30 min. 3,6-Dichloropyridazine (1.0 g, 6.71 mmol, 1.0 eq.) was added at 0 °C, and the reaction mixture was allowed to warm to RT and stirred for 2 h. The reaction mixture was poured into saturated aqueous NH Cl (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic phases were dried over Na SO , filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 15% EtAOc in petroleum ether) to give tert-butyl 4-(6-chloropyridazin-3-yl)oxypiperidine-1-carboxylate as a white solid (1.8 mg, 5.74 mmol, 85% yield). ESI pos[M+H] + 314.2. 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).

[0114] Step 2: 3-chloro-6-(4-piperidyloxy)pyridazine; hydrochloride [ka] To a solution of tert-butyl 4-(6-chloropyridazin-3-yl)oxypiperidine-1-carboxylate (300 mg, 0.96 mmol, 1.0 eq.) in DCM (3 mL) was added 4 M HCl (1.0 mL, 4.0 mmol, 4.18 eq.) dissolved in dioxane. The reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated to give 3-chloro-6-(4-piperidyloxy)pyridazine hydrochloride (200 mg, 0.8 mmol, 98% yield) as a white solid. ESI pos[M+H] + 214.2. 1 H NMR(400MHz,DMSO-d6)δ=8.92(brs,2H),7.83(d,J=9.3Hz,1H),7.36(d,J=9.3Hz,1H),5.40(tt,J=3.7 ,7.8Hz,1H),3.24(brs,2H),3.17-3.07(m,2H),2.20(ddd,J=3.3,6.9,10.2Hz,2H),2.01-1.90(m,2H).

[0115] Step 3: 3-chloro-6-[[1-(oxetan-3-yl)-4-piperidyl]oxy]pyridazine [ka] A solution of 3-chloro-6-(4-piperidyloxy)pyridazine (150 mg, 0.7 mmol, 1.0 eq.) and 3-oxetanone (152 mg, 2.11 mmol, 3.0 eq.) in MeOH (3 mL) was stirred at RT for 10 min. NaBHCN (88 mg, 1.4 mmol, 2.0 eq.) was added, and the mixture was stirred at RT for 1 h. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over NaSO, filtered, and concentrated. The residue was purified by preparative TLC (DCM / MeOH = 10:1) to give 3-chloro-6-[[1-(oxetan-3-yl)-4-piperidyl]oxy]pyridazine as a white solid (160 mg, 0.59 mmol, 84% yield). ESI pos[M+H] + 270.1. 1H NMR(400MHz,DMSO-d6)δ=7.78(d,J=9.3Hz,1H),7.31(d,J=9.3Hz,1H),5.16(td,J=4.3,8.3Hz,1H),4.53(t,J= 6.4Hz,2H),4.46-4.39(m,2H),3.42(t,J=6.4Hz,1H),2.61-2.54(m,2H),2.15-2.00(m,4H),1.78-1.67(m,2H).

[0116] Step 4: N-[6-[[1-(oxetan-3-yl)-4-piperidyl]oxy]pyridazin-3-yl]-1,1-diphenyl-methanimine [ka] To a solution of diphenylmethanimine (0.12 mL, 0.72 mmol, 1.5 eq.) and 3-chloro-6-[[1-(oxetan-3-yl)-4-piperidyl]oxy]pyridazine (130 mg, 0.48 mmol, 1.0 eq.) in 1,4-dioxane (4 mL) was added Cs2CO3 (314 mg, 0.96 mmol, 2.0 eq.) and Xantphos Pd G4 (23 mg, 0.02 mmol, 0.05 eq.). The mixture was bubbled with N2 for 10 min and stirred at 100 °C under a N2 atmosphere for 16 h. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (DCM / MeOH=10:1) to give N-[6-[[1-(oxetan-3-yl)-4-piperidyl]oxy]pyridazin-3-yl]-1,1-diphenyl-methanimine as a white solid (120 mg, 0.29 mmol, 60% yield). ESI pos[M+H] + 415.3. 1H NMR(400MHz,DMSO-d6)δ=7.73-7.68(m,2H),7.59(d,J=7.4Hz,1H),7.54- 7.47(m,2H),7.36-7.32(m,3H),7.17-7.13(m,2H),7.10(s,1H),7.11-7.0 7(m,1H),7.03-6.98(m,1H),5.07-4.97(m,1H),4.52(t,J=6.5Hz,2H),4. 44-4.38(m,2H),3.43-3.35(m,2H),2.08-1.96(m,4H),1.68-1.57(m,2H).

[0117] Step 5: 6-[[1-(oxetan-3-yl)-4-piperidyl]oxy]pyridazin-3-amine [ka] To a solution of N-[6-[[1-(oxetan-3-yl)-4-piperidyl]oxy]pyridazin-3-yl]-1,1-diphenylmethanimine (400 mg, 0.97 mmol, 1.0 eq.) in MeOH (8 mL), sodium acetate (0.18 mL, 2.41 mmol, 2.5 eq.) and hydroxylamine hydrochloride (134 mg, 1.93 mmol, 2.0 eq.) were added, and the reaction mixture was stirred at RT for 30 min. The reaction mixture was concentrated, and the residue was purified by preparative TLC (DCM / MeOH = 10:1) to give 6-[[1-(oxetan-3-yl)-4-piperidyl]oxy]pyridazin-3-amine as a white solid (180 mg, 0.72 mmol, 75% yield). ESI pos[M+H] + 251.1. 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)

[0118] Step 6: 5-Bromo-6-fluoro-1H-benzimidazole [ka] A mixture of 4-bromo-5-fluoro-benzene-1,2-diamine (4.0 g, 19.51 mmol, 1.0 eq.) dissolved in formic acid (33 mL, 883.5 mmol, 45 eq.) was stirred at 100 °C for 16 h. The reaction mixture was concentrated, and the resulting oil was partitioned between EtOAc (200 mL) and saturated aqueous NaHCO (500 mL). The aqueous layer was extracted with EtOAc (2 × 100 mL), and the combined organic layers were dried over NaSO, filtered, and concentrated to give 5-bromo-6-fluoro-1H-benzimidazole (4.0 g, 18.6 mmol, 95% yield) as a brown solid, which was used without further purification. ESI pos[M+H] + 217.0.

[0119] Step 7: 6-(5-Bromo-6-fluoro-benzimidazol-1-yl)-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile and 6-(6-bromo-5-fluoro-benzimidazol-1-yl)-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile [ka] To a solution of 6-chloro-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (Example 2, Step 1) (400 mg, 1.49 mmol, 1.0 eq.) in DMSO (5 mL), 5-bromo-6-fluoro-1H-benzimidazole (320 mg, 1.49 mmol, 1.0 eq.) and K2CO3 (617 mg, 4.47 mmol, 3.0 eq.) were added and stirred at RT for 1 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 20% ethoxyacetate in petroleum ether). This gave a mixture of 6-(5-bromo-6-fluoro-benzimidazol-1-yl)-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile and 6-(6-bromo-5-fluoro-benzimidazol-1-yl)-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile as a yellow solid (400 mg, 0.89 mmol, 42% yield). ESI pos[M+H] + 448.8.

[0120] Step 8: 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-fluoro-5-[[6-[[1-(oxetan-3-yl)-4-piperidyl]oxy]pyridazin-3-yl]amino]benzimidazol-1-yl]pyridine-3-carbonitrile; formic acid [ka] A suspension of 6-[[1-(oxetan-3-yl)-4-piperidyl]oxy]pyridazin-3-amine (34 mg, 0.13 mmol, 1.2 eq.) in 1,4-dioxane (2 mL) was treated with a mixture of 6-(5-bromo-6-fluoro-benzimidazol-1-yl)-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile and 6-(6-bromo-5-fluoro-benzimidazol-1-yl)-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (50 mg, 0.11 mmol, 1.0 eq.), Cs2CO3 (109 mg, 0.34 mmol, 3.0 eq.) and [tBuBrettPhos Pd(allyl)]OTf (17 mg, 0.02 mmol, 0.2 eq.) was added. The mixture was stirred at 80 °C for 2 h while N was bubbled through for 10 min. The reaction mixture was poured into HO (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic phases were dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by preparative HPLC (ACS-WH-GX-F, water + 0.1% FA-ACN) to give 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-fluoro-5-[[6-[[1-(oxetan-3-yl)-4-piperidyl]oxy]pyridazin-3-yl]amino]benzimidazol-1-yl]pyridine-3-carbonitrile; formic acid (28 mg, 0.05 mmol, 41% yield) as a white solid. ESI pos[M+H] + 617.3. 1 H NMR(400MHz,DMSO-d6)δ=9.16(s,1H),8.88-8.79(m,3H),8.30(d,J=8.6Hz,1H),8.09(d,J=11.7Hz,1H),7.45(brd,J=9.4Hz,1H),7.28-6.98(m,2 H),6.79(s,1H),5.17-5.00(m,1H),4.86-4.64(m,1H),4.62-4.36(m,4H ),3.51-3.34(m,2H),2.58(s,3H),2.16-1.98(m,4H),1.79-1.62(m,2H).

[0121] Example 13 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-fluoro-5-[[6-[2-(3-methoxyazetidin-1-yl)ethyl]pyridazin-3-yl]amino]benzimidazol-1-yl]pyridine-3-carbonitrile [ka] Step 1: 3-Methoxyazetidine; hydrochloride [ka] To a solution of tert-butyl 3-methoxyazetidine-1-carboxylate (1.5 mg, 8.01 mmol, 1.0 eq.) in 1,4-dioxane (10 mL) was added 4 M HCl (10 mL, 40.0 mmol, 5.0 eq.) dissolved in dioxane. The reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated to give 3-methoxyazetidine (600 mg, 6.89 mmol, 86% yield) as a pale yellow oil, which was used in the next step without further purification.

[0122] Step 2: 3-chloro-6-vinyl-pyridazine [ka]

[0123] 3,6-Dichloropyridazine (2.0 g, 13.42 mmol, 1.0 eq.) and vinylboronic acid pinacol ester (2.1 g, 13.42 mmol, 1.0 eq.) were dissolved in a mixture of 1,4-dioxane (20 mL) and HO (8 mL), and N was bubbled through for 10 min. Pd(dppf)Cl·DCM (1.1 g, 1.34 mmol, 0.1 eq.) and KCO (5.6 g, 40.27 mmol, 3.0 eq.) were added and stirred at 100 °C under N for 4 h. The mixture was cooled to RT, poured into HO (20 mL), and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over NaSO, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 30% EtOAc in petroleum ether) to give 3-chloro-6-vinyl-pyridazine as a white solid (1.0 g, 7.11 mmol, 53% yield). ESI pos[M+H] + 141.0

[0124] Step 3: tert-butyl N-(6-vinylpyridazin-3-yl)carbamate [ka] N was bubbled through a suspension of 3-chloro-6-vinyl-pyridazine (700 mg, 4.98 mmol, 1.0 eq.), tert-butyl carbamate (875 mg, 7.47 mmol, 1.5 eq.), and CsCO (3.2 g, 9.96 mmol, 2.0 eq.) in 1,4-dioxane (10 mL) for 10 min. Pd(dba) (456 mg, 0.5 mmol, 0.1 eq.) and Xantphos (577 mg, 1.0 mmol, 0.2 eq.) were added, and the reaction mixture was stirred at 90 °C under a N atmosphere for 3 h. The reaction mixture was cooled to RT, poured into saturated NHCl (200 mL), and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 0% to 60% EtOAc in petroleum ether) to give tert-butyl N-(6-vinylpyridazin-3-yl)carbamate as a pale yellow gum (1.10 g, 4.97 mmol, 99% yield). ESI pos[M+H] + 166.0. 1 H NMR(400MHz,CDCl3)δ=8.20(d,J=9.4Hz,1H),7.95(brs,1H),7.59(d,J=9.3Hz,1H),6.9 9(dd,J=11.1,17.8Hz,1H),6.10(d,J=17.9Hz,1H),5.58(d,J=11.1Hz,1H),1.55(s,9H).

[0125] Step 4: tert-butyl N-[6-[2-(3-methoxyazetidin-1-yl)ethyl]pyridazin-3-yl]carbamate [ka] To a solution of tert-butyl N-(6-vinylpyridazin-3-yl)carbamate (1.10 g, 4.97 mmol, 1.0 eq.) and 3-methoxyazetidine hydrochloride (1.23 g, 9.94 mmol, 2.0 eq.) in MeOH (10 mL) was added acetic acid (940 μL, 14.91 mmol, 3.0 eq.). The mixture was stirred at 65 °C under N for 16 h. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (Phenomenex Luna C18 15 μm, 150 mm × 40 mm, water + 0.1% FA-ACN) to give tert-butyl N-[6-[2-(3-methoxyazetidin-1-yl)ethyl]pyridazin-3-yl]carbamate as a colorless gum (840 mg, 2.72 mmol, 55% yield). ESI pos[M+H] + 309.1. 1 H NMR(400MHz,CDCl3)δ=8.43(s,1H),8.17(d,J=9.3Hz,1H),7.88(brd,J=1.4Hz,1H),7.37(d,J=9.3Hz,1H ),4.23-4.16(m,1H),4.14-4.08(m,2H),3.38-3.31(m,4H),3.27(s,3H),3.16-3.10(m,2H),1.54(s,9H).

[0126] Step 5: 6-[2-(3-methoxyazetidin-1-yl)ethyl]pyridazin-3-amine [ka] To a solution of tert-butyl N-[6-[2-(3-methoxyazetidin-1-yl)ethyl]pyridazin-3-yl]carbamate (200 mg, 0.65 mmol, 1.0 eq.) in DCM (2 mL) was added TFA (2.0 mL, 25.92 mmol, 40 eq.) and stirred at RT for 2 h. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (Phenomenex Luna C18 10 μm, 150 mm × 25 mm, water + 0.1% FA-ACN). This afforded 6-[2-(3-methoxyazetidin-1-yl)ethyl]pyridazin-3-amine as a white solid (120.0 mg, 0.58 mmol, 89% yield). ESI pos[M+H] + 209.0. 1 H NMR(400MHz,CD3OD)δ=7.74(d,J=9.4Hz,1H),7.48(d,J=9.5Hz,1H),4.59-4.38(m,2H),4.31(qu in,J=5.3Hz,1H),4.21-3.90(m,2H),3.68(brt,J=7.0Hz,2H),3.35(s,3H),3.13(t,J=7.0Hz,2H)

[0127] Step 6: 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-fluoro-5-[[6-[2-(3-methoxyazetidin-1-yl)ethyl]pyridazin-3-yl]amino]benzimidazol-1-yl]pyridine-3-carbonitrile [ka] To a solution of a mixture of 6-(5-bromo-6-fluoro-benzimidazol-1-yl)-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile and 6-(6-bromo-5-fluoro-benzimidazol-1-yl)-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (50 mg, 0.110 mmol, 1.0 eq., prepared in step 7 of Example 12) in 1,4-dioxane (2 mL), 6-[2-(3-methoxyazetidin-1-yl)ethyl]pyridazin-3-amine; 2,2,2-trifluoroacetic acid (72 mg, 0.220 mmol, 2.0 eq.) and CsCO (109 mg, 0.340 mmol, 3 eq.) were added. After bubbling N2 through the mixture for 10 min, [tBuBrettPhos Pd(allyl)]OTf (9 mg, 0.010 mmol, 0.10 eq.) was added. The mixture was stirred at 80 °C for 2 h. The mixture was cooled to RT, poured into saturated NH4Cl solution (50 mL), and extracted with EtOAc (3 × 30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (Phenomenex luna C18 10 μm, 150 mm × 25 mm, water + 0.1% FA-ACN). This gave a mixture of 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-fluoro-5-[[6-[2-(3-methoxyazetidin-1-yl)ethyl]pyridazin-3-yl]amino]benzimidazol-1-yl]pyridine-3-carbonitrile and 2-[5-(difluoromethyl)-3-methyl-pyrazol-1-yl]-6-[5-fluoro-6-[[6-[2-(3-methoxyazetidin-1-yl)ethyl]pyridazin-3-yl]amino]benzimidazol-1-yl]pyridine-3-carbonitrile as a yellow solid.The mixture was purified by SFC (Daicel Chiral OD 10 μm 250 mm × 30 mm, 0.1% NHOH in EtOH) followed by preparative HPLC (Waters Xbridge 5 μm 150 × 25 mm, water + 0.1% NHHCO-ACN) to give 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-fluoro-5-[[6-[2-(3-methoxyazetidin-1-yl)ethyl]pyridazin-3-yl]amino]benzimidazol-1-yl]pyridine-3-carbonitrile (7 mg, 0.01 mmol, 8% yield) as a yellow solid. ESI pos [M+H]. + 217.0. 1 H NMR(400MHz,CDCl3)δ=8.63(d,J=7.5Hz,1H),8.61(s,1H),8.39(d,J=8.4Hz,1H),7 .90(d,J=10.9Hz,1H),7.67(d,J=8.4Hz,1H),7.36(d,J=9.0Hz,1H),7.05(d,J=9.0H z,1H),6.93(s,1H),6.79(s,1H),6.66(s,1H),6.60(s,1H),4.56-4.43(m,2H),4.3 9-4.32(m,1H),3.83-3.68(m,4H),3.36(t,J=7.4Hz,2H),3.32(s,3H),2.65(s,3H).

[0128] Example 14 2-[3-(Difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]-5-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile [ka] Step 1: 4-Bromo-2-nitro-5-(oxetan-3-yloxy)aniline [ka] To a solution of oxetan-3-ol (4.26 g, 57.46 mmol, 1.5 eq.) in THF (90 mL) under N2 cooled to 0 °C, 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-nitroaniline (9.0 g, 38.3 mmol, 1.0 eq.) was added, and the reaction mixture was warmed to RT and stirred at RT for 12 h. The reaction was quenched with HO (100 mL), which caused 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 in a mixture of petroleum ether / EtOAc (10:1, 30 mL) at RT 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).

[0129] Step 2: 4-Bromo-5-(oxetan-3-yloxy)benzene-1,2-diamine [ka] 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 N was added Fe (10.14 g, 181.61 mmol, 5.0 eq.), NH Cl (19.43 g, 363.22 mmol, 10.0 eq.), and HO (40 mL). The reaction mixture was stirred at 50 °C under N for 12 h. The reaction mixture was cooled to RT 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.

[0130] Step 3: 5-Bromo-6-(oxetan-3-yloxy)-1H-benzimidazole; formic acid [ka] 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 RT and concentrated. The residue was purified by preparative HPLC (Phenomenex Luna C18 10 μm, 150 mm x 40 mm, water + 0.1% FA-ACN) to give 5-bromo-6-(oxetan-3-yloxy)-1H-benzimidazole as a white solid (8.6 g, 31.96 mmol, 91% yield). 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).

[0131] Step 4: 6-[6-Bromo-5-(oxetan-3-yloxy)benzimidazol-1-yl]-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile and 6-[5-Bromo-6-(oxetan-3-yloxy)benzimidazol-1-yl]-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile [ka] To a colorless solution of 6-chloro-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (350 mg, 1.23 mmol, 1.0 eq.) in DMSO (10 mL) was added 5-bromo-6-(oxetan-3-yloxy)-1H-benzimidazole (331 mg, 1.23 mmol, 1.0 eq.), N,N-diisopropylethylamine (0.64 mL, 3.69 mmol, 3.0 eq.), and the mixture was stirred at 100 °C for 12 h. The reaction mixture was cooled to RT, poured into HO (30 mL), and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over NaSO, filtered, and concentrated. The residue was purified by preparative TLC (DCM / MeOH=9:1, Rf=0.60 / 0.65) to give 6-[5-bromo-6-(oxetan-3-yloxy)benzimidazol-1-yl]-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (70 mg, 0.14 mmol, 11% yield) as a pale yellow solid; ESI pos[M+H] + 519.0. 1H NMR(400MHz,DMSO-d6)δ=9.07(s,1H),8.79(d,J=8.4Hz,1H),8.18(d,J=8.6Hz,1H),8.11(s,1H),7.57-7.20(t,1H), 7.48(s,1H),6.39(s,1H),5.32(quin,J=5.4Hz,1H),4.82(t,J=6.7Hz,2H),4.64(dd,J=5.0,7.2Hz,2H),3.33(s,3H); and 6-[6-bromo-5-(oxetan-3-yloxy)benzimidazol-1-yl]-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (30 mg, 0.06 mmol, 5% yield) were obtained as pale yellow solids. ESI pos[M+H] + 519.0

[0132] Step 5: 2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]-5-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile; formic acid [ka] N was bubbled through a solution of 6-[6-bromo-5-(oxetan-3-yloxy)benzimidazol-1-yl]-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (30 mg, 0.06 mmol, 1.0 eq.) and 3-amino-6-methylpyridazine (13 mg, 0.12 mmol, 2.0 eq.) in 1,4-dioxane (10 mL) for 10 min. [tBuBrettPhos Pd(allyl)]OTf (9 mg, 0.01 mmol, 0.2 eq.) and CsCO (57 mg, 0.17 mmol, 3.0 eq.) were added, and the reaction mixture was stirred at 80 °C under N for 2 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Phenomenex Synergi C18 10 μm, 150 mm × 25 mm, 0.1% FA-ACN in water). This afforded 2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]-5-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile; formic acid (11 mg, 0.02 mmol, 35% yield) as an off-white solid. ESI pos[M+H] + 546.2. 1 H NMR(400MHz,DMSO-d6)δ=9.31-9.27(m,1H),9.00(s,1H),8.75(d,J=8.6Hz,1H),8.46-8.41(m,1H),8.11(d,J=8.6Hz,1H),7.54-7.17(t,1 H),7.37-7.33(m,2H),7.08(s,1H),6.25(s,1H),5.48-5.42(m,1H),5.02(t,J=6.5Hz,2H),4.74-4.70(m,2H),3.32(s,3H),2.55(brs,3H)

[0133] Example 15 2-[3-(Difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile [ka] 6-[5-Bromo-6-(oxetan-3-yloxy)benzimidazol-1-yl]-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (50 mg, 0.1 mmol, 1.0 eq.) and 3-amino-6-methylpyridazine (21 mg, 0.19 mmol, 2.0 eq.) were dissolved in 1,4-dioxane (10 mL) and bubbled with N for 10 min. [tBuBrettPhos Pd(allyl)]OTf (15 mg, 0.02 mmol, 0.2 eq.) and CsCO (94.48 mg, 0.29 mmol, 3.0 eq.) were added, and the reaction mixture was stirred at 80 °C under N atmosphere for 2 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC (Phenomenex Synergi C18 10 μm, 150 mm × 25 mm, 0.1% FA-ACN in water). This afforded 2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile; formic acid (22 mg, 0.04 mmol, 42% yield) as a pale yellow solid. ESI pos[M+H] + 546.2. 1H NMR(400MHz,DMSO-d6)δ=9.00(s,1H),8.89-8.86(m,1H),8.76(d,J=8.6Hz,1H),8.39(s,1H),8.20-8.17(m,1H),7.58-7.22(t,1H), 7.42-7.37(m,3H),6.39(s,1H),5.32(quin,J=5.4Hz,1H),4.86-4.81(m,2H),4.78-4.73(m,2H),3.29-3.22(m,3H),2.54(brs,3H).

[0134] Example 16 2-[3-(Difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile [ka] Step 1: 4-Bromo-5-methoxy-2-nitroaniline [ka] To a solution of 5-methoxy-2-nitroaniline (10.0 g, 59.47 mmol, 1.0 eq.) in acetonitrile (150 mL) at RT under a N2 atmosphere, NBS (11.6 g, 65.42 mmol, 1.1 eq.) was added portionwise, and the reaction mixture was stirred at RT for 3 h. The reaction mixture was poured into saturated Na2SO3 solution (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)

[0135] Step 2: 4-Bromo-5-methoxy-benzene-1,2-diamine [ka] To a solution of 4-bromo-5-methoxy-2-nitroaniline (13.0 g, 52.6 mmol, 1.0 eq.) in a mixture of DCM (260 mL) and MeOH (260 mL) was added saturated NH4Cl (520 mL, 1052 mmol, 20.0 eq.) at RT, and N2 was bubbled through the mixture for 10 min. Zn (34.4 g, 527 mmol, 10.0 eq.) was added portionwise at RT, and the reaction mixture was stirred at RT 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).

[0136] Step 3: 5-Bromo-6-methoxy-1H-benzimidazole [ka] 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.), formic acid (10.0 mL, 265 mmol, 5.2 eq.) was added, 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. 1 H 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).

[0137] Step 4: 2-[(5-bromo-6-methoxy-benzimidazol-1-yl)methoxy]ethyl-trimethylsilane and 2-[(6-bromo-6-methoxy-benzimidazol-1-yl)methoxy]ethyl-trimethylsilane [ka] 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 RT 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 reach RT 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). This gave 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 as a yellow oil (2.8 g, 7.84 mmol, 59% yield). ESI pos[M+H] + 357.0.

[0138] 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 [ka] To a solution 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). This afforded 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 as a yellow oil (3.0 g, 7.78 mmol, 94% yield). ESI pos[M+H] + 386.1.

[0139] Step 6: 6-Methoxy-N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine [ka] 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.) at RT was stirred for 3 h at RT. The mixture was concentrated, and the resulting gum was dissolved in MeOH (10 mL). Aqueous NH3 (10%) (10 mL) was carefully added until pH 7 was reached, 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-ACN in water). This gave 6-methoxy-N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine as a yellow solid (0.5 g, 1.96 mmol, 26% yield). 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).

[0140] Step 7: 2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; formic acid [ka] To a solution of 6-chloro-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (100 mg, 0.35 mmol, 1.0 eq.), 6-methoxy-N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine (90 mg, 0.35 mmol, 1.0 eq.) in DMSO (2 mL) was added KCO (136 mg, 1.05 mmol, 3.0 eq.). The reaction mixture was then stirred at 50 °C for 16 h. The reaction mixture was cooled to RT and diluted with HO (20 mL) and EtOAc (10 mL). The resulting mixture of regioisomers was filtered. The filter cake was dissolved in DMSO (2 mL) and purified by preparative HPLC (ACS-WH-GX-F, 0.1% FA-ACN in water). This gave 2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; formic acid (18 mg, 0.04 mmol, 10% yield) as a white solid. ESI pos[M+H] + 504.2. 1 H NMR(400MHz,DMSO-d6)δ=8.97(s,1H),8.87-8.83(m,1H),8.74(d,J=8.6Hz,1H),8.40(s,1H),8.19(d,J=8.7Hz,1H),7.83 (s,1H),7.55(s,1H),7.37(s,1H),7.36-7.32(m,2H),7.19(s,1H),6.35(s,1H),3.92(s,3H),2.62(s,3H),2.48(brs,3H).

[0141] Example 17 2-[3-(Difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[5-methoxy-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile [ka] The aqueous layer from Step 7 of Example 16 was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over NaSO, filtered, and concentrated. The residue was purified by preparative TLC (dichloromethane:methanol = 10:1) to give 2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[5-methoxy-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile as a yellow solid (9 mg, 0.02 mmol, 5% yield). ESI pos[M+H] + 504.2. 1 H NMR(400MHz,DMSO-d6)δ=9.26(d,J=8.1Hz,1H),8.97(s,1H),8.73(d,J=8.6Hz,1H),8.42(s,1H),8.10(d,J=8.6Hz,1H),7. 53(s,1H),7.44(s,1H),7.34(s,1H),7.31-7.28(m,2H),7.16(s,1H),6.24(s,1H),3.96(s,3H),2.55(s,3H),2.46(s,3H).

[0142] Example 18 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-(3-methyloxetan-3-yl)oxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile [ka] Step 1: 4-Bromo-5-(3-methyloxetan-3-yl)oxy-2-nitroaniline [ka] To a solution of 3-methyloxetan-3-ol (742 mg, 8.43 mmol, 1.1 eq.) in THF (80 mL) was added sodium hydride (60% in oil) (460 mg, 11.49 mmol, 1.5 eq.) portionwise at RT under a N2 atmosphere. The mixture was stirred at 70 °C under N2 for 1 h. The reaction mixture was cooled to RT, and 4-bromo-5-fluoro-2-nitroaniline (1.80 g, 7.66 mmol, 1.0 eq.) dissolved in THF (10 mL) was added dropwise to the reaction mixture. The mixture was stirred at 50 °C under N2 for 16 h. The mixture was poured into water (100 mL) and extracted with EtOAc (3 × 80 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, 0% to 75% EtOAc in petroleum ether) to give 4-bromo-5-(3-methyloxetan-3-yl)oxy-2-nitroaniline (700 mg, 2.31 mmol, 30% yield) as a yellow solid. ESI pos[M+H] + 303.0. 1 H NMR(400MHz,CDCl3)δ=8.41(s,1H),6.33-6.03(m,2H),5.61(s,1H),4.99(d,J=6.8Hz,2H),4.65(d,J=7.5Hz,3H),1.85(s,3H).

[0143] Step 2: 4-Bromo-5-(3-methyloxetan-3-yl)oxy-benzene-1,2-diamine [ka] To a solution of 4-bromo-5-(3-methyloxetan-3-yl)oxy-2-nitroaniline (700 mg, 2.31 mmol, 1.0 eq.) in EtOH (40 mL) was added iron (645 mg, 11.55 mmol, 5.0 eq.), NH4Cl (1.24 g, 23.09 mmol, 10 eq.), and HO (20 mL). The suspension was stirred at 50 °C for 2 h under N2. MeOH (100 mL) was added, and the mixture was stirred at 50 °C for 30 min. The mixture was filtered while hot, and the filtrate was concentrated and diluted with HO (50 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with saturated NaHCO3 solution (3 × 50 mL), brine (50 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography (SiO, 20 g, EtOAc) to give 4-bromo-5-(3-methyloxetan-3-yl)oxy-benzene-1,2-diamine (370 mg, 1.35 mmol, 59% yield) as a dark green solid. ESI pos[M+H] + 272.9. 1 H NMR(400MHz,CDCl3)δ=6.94(s,1H),6.08(s,1H),4.97(d,J=6.5Hz,2H),4.50(d,J=7.1Hz,2H),3.92-2.91(m,4H),1.72(s,3H).

[0144] Step 3: 5-bromo-6-(3-methyloxetan-3-yl)oxy-1H-benzimidazole [ka] To a solution of 4-bromo-5-(3-methyloxetan-3-yl)oxy-benzene-1,2-diamine (370 mg, 1.35 mmol, 1.0 eq.) in EtOH (10 mL) was added trimethyl orthoformate (1.44 g, 13.55 mmol, 10 eq.) and TsOH (23 mg, 0.14 mmol, 0.1 eq.). The mixture was stirred at 80 °C for 2 h. The reaction mixture was cooled to RT, quenched with saturated NaHCO (10 mL), and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were dried over NaSO, filtered, and concentrated. The crude product was purified by flash chromatography (SiO2, 20 g, 10% MeOH in EtOAc) to give 5-bromo-6-(3-methyloxetan-3-yl)oxy-1H-benzimidazole (300 mg, 1.06 mmol, 78% yield) as a brown solid. ESI pos[M+H] + 282.9

[0145] Step 4: 6-[5-bromo-6-(3-methyloxetan-3-yl)oxy-benzimidazol-1-yl]-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile [ka] To a solution of 6-chloro-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (Example 2, Step 1) (237 mg, 0.88 mmol, 1.0 eq.) in DMSO (10 mL) was added 5-bromo-6-(3-methyloxetan-3-yl)oxy-1H-benzimidazole (250 mg, 0.88 mmol, 1.0 eq.) and KCO (366 mg, 2.65 mmol, 3.0 eq.) and stirred at RT for 2 h. The reaction mixture was poured into HO (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over NaSO, filtered, and concentrated. The crude product was purified by preparative NPLC (Welch Ultimate XB-SiOH 10 μm, 250 mm × 70 mm, hexane-EtOH). This gave 6-[6-bromo-5-(3-methyloxetan-3-yl)oxy-benzimidazol-1-yl]-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (100 mg, 0.19 mmol, 22% yield) as an off-white solid: ESI pos[M+H] + 515.1; 1 H NMR(400MHz,CDCl3)δ=8.60(brs,1H),8.41(d,J=8.4Hz,1H),8.35(s,1H),7.66(d,J=8.4Hz,1H),6.9 7-6.65(m,2H),6.62(s,1H),5.06(d,J=6.7Hz,2H),4.69(d,J=7.1Hz,2H),2.70(s,3H),1.86(s,3H); and 6-[5-bromo-6-(3-methyloxetan-3-yl)oxy-benzimidazol-1-yl]-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (100 mg, 0.19 mmol, 22% yield) was obtained as a yellow oil. ESI pos[M+H] + 515.1; 1H NMR(400MHz,CDCl3)δ=8.50(s,1H),8.40(d,J=8.4Hz,1H),8.12(s,1H),7.65(d,J=8.4Hz,1H),7.35(s,1H), 6.80(t,J=54.6Hz,1H),6.62(s,1H),4.97(d,J=6.6Hz,2H),4.47(d,J=7.1Hz,2H),2.58(s,3H),1.75(s,3H).

[0146] Step 5: 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-(3-methyloxetan-3-yl)oxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile [ka] To a solution of 3-amino-6-methylpyridazine (42 mg, 0.39 mmol, 2.0 equiv.) in 1,4-dioxane (5 mL) was added 6-[5-bromo-6-(3-methyloxetan-3-yl)oxy-benzimidazol-1-yl]-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (100 mg, 0.19 mmol, 1.0 equiv.) and CsCO (190 mg, 0.58 mmol, 3.0 equiv.). N was bubbled through the reaction mixture for 10 min, and [tBuBrettPhos Pd(allyl)]OTf (15 mg, 0.02 mmol, 0.1 equiv.) was added and the mixture was stirred at 80 °C under N atmosphere for 1 h. The mixture was poured into HO (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated. The residue was purified by preparative HPLC (Phenomenex C18 3 μm, 75 mm × 30 mm, 0.1% FA-ACN in water) followed by preparative TLC (DCM / MeOH 10:1, Rf = 0.4) to give 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-(3-methyloxetan-3-yl)oxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile as a yellow solid (24 mg, 0.04 mmol, 23% yield). ESI pos[M+H]+ 544.1. 1 H NMR(400MHz,CDCl3)δ=8.55(s,1H),8.48(s,1H),8.38(d,J=8.6Hz,1H),7.66(d,J=8.4Hz,1H),7.28(brs,1H),7.25-7.21(m,1H),7.1 5-7.10(m,1H),6.96-6.66(m,1H),6.62(s,1H),4.96(d,J=6.6Hz,2H),4.48(d,J=7.0Hz,2H),2.66(s,3H),2.58(s,3H),1.74(s,3H).

[0147] Example 19 2-[2-(Difluoromethoxy)-5-methyl-4-pyridyl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile [ka] Step 1: 4-Bromo-5-methyl-pyridin-2-ol [ka] A mixture of 4-bromo-2-chloro-5-methylpyridine (4.0 g, 19.37 mmol, 1.0 eq.) and t-BuONa (11.17 g, 116.24 mmol, 6.0 eq.) in tert-butanol (80 mL) was stirred at 120 °C for 24 h. The reaction mixture was diluted with HO (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by reverse-phase HPLC (Phenomenex Synergi C18 10 μm, 150 mm × 25 mm, 0.1% FA-ACN in water) to give 4-bromo-5-methyl-pyridin-2-ol as a yellow solid (3.5 g, 18.62 mmol, 96% yield). ESI pos[M+H] + 188.1.

[0148] Step 2: 4-Bromo-2-(difluoromethoxy)-5-methyl-pyridine [ka] A mixture of (2-chloro-2,2-difluoroacetyl)oxysodium (10.4 g, 31.9 mmol, 3.0 eq.), CsCO (13.9 g, 42.6 mmol, 4.0 eq.), and 4-bromo-5-methyl-pyridin-2-ol (2.0 g, 10.6 mmol, 1.0 eq.) in DMF (40 mL) was stirred at 100 °C for 12 h. The reaction mixture was filtered, and the filtrate was diluted with HO (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 20% EtOAc in petroleum ether) to give 4-bromo-2-(difluoromethoxy)-5-methyl-pyridine as a colorless oil (450 mg, 1.89 mmol, 18% yield). ESI pos[M+H] + 237.7.

[0149] Step 3: 2-(Difluoromethoxy)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine [ka] A mixture of 4-bromo-2-(difluoromethoxy)-5-methyl-pyridine (400 mg, 1.68 mmol, 1.0 eq.), bis(pinacolato)diboron (1.71 mg, 6.72 mmol, 4.0 eq.), potassium acetate (330 mg, 3.36 mmol, 2.0 eq.), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (137 mg, 0.17 mmol, 0.1 eq.) in 1,4-dioxane (20 mL) was stirred at 80 °C under a N atmosphere for 2 h. The reaction mixture was filtered over Celite, and the filtrate was concentrated. The residue was purified on a silica column (silica gel, 20% to 50% EtOAc in petroleum ether) to give 2-(difluoromethoxy)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine as a yellow solid (260 g, 0.912 mmol, 54% yield). ESI pos[M+H] + 286.1.

[0150] Step 4: 6-chloro-2-[2-(difluoromethoxy)-5-methyl-4-pyridyl]pyridine-3-carbonitrile [ka] To a solution of 2-bromo-6-chloro-pyridine-3-carbonitrile (100 mg, 0.460 mmol, 1.0 eq.) in a mixture of 1,4-dioxane (2 mL) and water (0.2 mL) was added a mixture of 2-(difluoromethoxy)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.31 g, 4.60 mmol, 10 eq.), NaCO (146.22 mg, 1.38 mmol, 3 eq.), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (38 mg, 0.050 mmol, 0.10 eq.). The mixture was bubbled with nitrogen for 10 min and heated at 60 °C for 2 h. N2The mixture was stirred under atmospheric pressure. The mixture was poured into saturated NH4Cl solution (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (Phenomenex luna C18 10 μm, 150 mm x 25 mm, 0.225% FA-ACN in water) to give 6-chloro-2-[2-(difluoromethoxy)-5-methyl-4-pyridyl]pyridine-3-carbonitrile as a white solid (50 mg, 0.17 mmol, 37% yield). ESI pos[M+H] + 296.2. 1 H NMR(400MHz,CD3OD)δ=8.33(d,J=8.4Hz,1H),8.26(s,1H),7.76(s,1H),7.74-7.39(m,1H),7.08(s,1H),2.21(s,3H).

[0151] Step 5 2-[[5-bromo-6-(oxetan-3-yloxy)benzimidazol-1-yl]methoxy]ethyl-trimethylsilane and 2-[[6-bromo-5-(oxetan-3-yloxy)benzimidazol-1-yl]methoxy]ethyl-trimethylsilane [ka] To a solution of 5-bromo-6-(oxetan-3-yloxy)-1H-benzimidazole (4.5 g, 16.7 mmol, 1.0 eq.) in DMF (80 mL) was added sodium hydride (60% in oil) (0.80 g, 20.1 mmol, 1.2 eq.) slowly at 0 °C. The mixture was allowed to reach RT and stirred at RT for 1 h. The mixture was cooled to 0 °C, and 2-(trimethylsilyl)ethoxymethyl chloride (4.44 mL, 25.1 mmol, 1.5 eq.) was added dropwise. The mixture was stirred at RT for 16 h. The mixture was poured into saturated aqueous NH4Cl (400 mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0% to 10% MeOH in EtOAc) to give a mixture of 2-[[5-bromo-6-(oxetan-3-yloxy)benzimidazol-1-yl]methoxy]ethyl-trimethylsilane and 2-[[6-bromo-5-(oxetan-3-yloxy)benzimidazol-1-yl]methoxy]ethyl-trimethylsilane as a yellow oil (2.0 g, 5.01 mmol, 30% yield). ESI pos[M+H] + 401.0.

[0152] Step 6: N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)-1-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine and N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine [ka] To a yellow solution of 2-[[5-bromo-6-(oxetan-3-yloxy)benzimidazol-1-yl]methoxy]ethyl-trimethylsilane and 2-[[6-bromo-5-(oxetan-3-yloxy)benzimidazol-1-yl]methoxy]ethyl-trimethylsilane (2.0 mg, 5.01 mmol, 1.0 eq.) in 1,4-dioxane (40 mL) was added 3-amino-6-methylpyridazine (1.1 g, 10.02 mmol, 2.0 eq.) and CsCO (4.9 g, 15.02 mmol, 3.0 eq.). N was bubbled through the reaction mixture for 10 min. [tBuBrettPhos Pd(allyl)]OTf (783 mg, 1.0 mmol, 0.20 eq.) was added, and the mixture was stirred at 80 °C for 4 h. The mixture was poured into saturated aqueous NH4Cl (200 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0% to 15% MeOH in EtOAc) to give a mixture of N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)-1-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine and N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine as a pale yellow oil (1.5 g, 3.51 mmol, 70% yield). ESI pos[M+H] + 428.1

[0153] Step 7: N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)-1H-benzimidazol-5-amine [ka] A solution of a mixture of N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)-1-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine and N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine (1.5 g, 3.51 mmol, 1.0 eq.) in trifluoroacetic acid (10 mL, 129.8 mmol, 37 eq.) was stirred at RT for 3 h. The mixture was concentrated, and the residue was dissolved in HO (30 mL) and acetonitrile (10 mL) at RT. The solution was lyophilized to give a yellow solid. This solid was purified by flash chromatography (silica gel, MeOH in EtOAc 0% to 105%) to give a yellow solid: N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)-1H-benzimidazol-5-amine (1.0 g, 3.36 mmol, 96% yield). ESI pos[M+H] + 298.1. 1 H NMR(400MHz,CD3OD)δ=8.97(brs,1H),8.64(brs,1H),7.79-7.69(m,2H),7.01(s,1 H),5.49(brs,1H),5.13-5.05(m,2H),4.79(brd,J=3.5Hz,2H),2.66-2.61(m,3H).

[0154] Step 8: 2-[2-(difluoromethoxy)-5-methyl-4-pyridyl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile; formic acid [ka] To a solution of N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)-1H-benzimidazol-5-amine (60 mg, 0.2 mmol, 1.2 eq.) in t-amyl alcohol (1.0 mL) was added 6-chloro-2-[2-(difluoromethoxy)-5-methyl-4-pyridyl]pyridine-3-carbonitrile (50 mg, 0.17 mmol, 1.0 eq.) and KPO (108 mg, 0.51 mmol, 3.0 eq.). N was bubbled through the mixture for 10 min. tBuXPhosPdG (13 mg, 0.02 mmol, 0.1 eq.) was added, and the reaction mixture was stirred at 80 °C under a N atmosphere for 2 h. The reaction mixture was cooled to RT, poured into saturated NHCl solution (30 mL), and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over NaSO, filtered, and concentrated. The residue was purified by preparative TLC (DCM / MeOH 10:1) to give a mixture of 2-[2-(difluoromethoxy)-5-methyl-4-pyridyl]-6-[6-[(6-methylpyridazin-3-yl)amino]-5-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile and 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile (20 mg, 0.04 mmol, 21% yield).

[0155] The mixture of regioisomers was purified by preparative HPLC (Phenomenex Luna C18 10 μm 150 mm × 25 mm, 0.225% FA-ACN in water) to give 2-[2-(difluoromethoxy)-5-methyl-4-pyridyl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile; formate (2.29 mg, 0.0 mmol, 2.25% yield) (LCMS: WUX002952-507-P1F2; HNMR: WUX002952-507-P1B) as a pale yellow solid. ESI pos [M+H] + 557.3. 1 H NMR(400MHz,DMSO-d6)δ=9.11(s,1H),8.87-8.84(m,1H),8.74(d,J=8.8Hz,1H),8.44(s,1H),8.36-8.30(m,2H),7.82(t,J=72.8Hz,1 H),7.51(s,1H),7.47(s,1H),7.37-7.34(m,2H),5.18-5.11(m,1H),4.67-4.62(m,2H),4.60-4.56(m,2H),2.54(s,3H),2.27(s,3H).

[0156] Example 20 2-[3-(Difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[5-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile [ka] To a solution of 6-chloro-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (Example 8, Step 4) (100 mg, 0.35 mmol, 1.0 eq.) and 5-(oxetan-3-yloxy)-1H-benzimidazole (87 mg, 0.46 mmol, 1.3 eq.) in DMSO (3 mL) was added KCO (145.35 mg, 1.05 mmol, 3.0 eq.). The reaction was stirred at 80 °C for 16 h. The mixture was cooled to RT, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Phenomenex Luna C18 10 μm 150 mm x 25 mm, 0.225% FA-ACN in water) followed by SFC (Daicel ChiralPak IG 10 μm 250 mm x 30 mm, 0.1% NH4OH-EtOH) to give 2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[5-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile as a yellow solid (5 mg, 0.01 mmol, 3% yield). ESI pos[M+H] + 439.1. 1 H NMR(400MHz,METHANOL-d4)δ=8.90(s,1H),8.51(d,J=8.4Hz,1H),8.20-8.05(m,1H),7.94(d,J=8.4Hz,1H),7.4 5-6.97(m,3H),6.14(s,1H),5.43-5.31(m,1H),5.06(t,J=6.7Hz,2H),4.73(dd,J=5.1,7.2Hz,3H),2.61(s,3H).

[0157] Example 21 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[[1-(oxetan-3-yl)-4-piperidyl]amino]benzimidazol-1-yl]pyridine-3-carbonitrile [ka] Step 1: tert-butyl N-[1-(oxetan-3-yl)-4-piperidyl]carbamate [ka] To a solution of tert-butyl N-(4-piperidyl)carbamate (5.0 g, 24.97 mmol, 1.0 eq.) in DCM (250 mL), 3-oxetanone (5.4 g, 74.94 mmol, 3.0 eq.) and acetic acid (1.05 g, 17.48 mmol, 0.7 eq.) were added and stirred at RT for 10 min. Sodium triacetoxyboride (15.9 g, 75.02 mmol, 3.0 eq.) was added, and the mixture was stirred at RT for 16 h. The reaction mixture was diluted with saturated aqueous NaHCO3 (200 mL) and extracted with DCM (3 × 100 mL). The combined organic layers were washed with HO (100 mL) and brine (3 × 50 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash (silica gel, 0% to 10% MeOH in EtOAc) to give tert-butyl N-[1-(oxetan-3-yl)-4-piperidyl]carbamate (5.4 g, 21.07 mmol, 84% yield) as a white solid. ESI pos[M+H]+ 257.1. 1 H NMR(400MHz,CDCl3)δ=4.67-4.61(m,2H),4.60-4.55(m,2H),4.47(brs,1H),3 .52-3.37(m,2H),2.66(brd,J=11.4Hz,2H),2.01-1.86(m,4H),1.44(s,11H).

[0158] Step 2: 1-(Oxetan-3-yl)piperidin-4-amine; dihydrochloride salt [ka]

[0159] To a solution of tert-butyl N-[1-(oxetan-3-yl)-4-piperidyl]carbamate (5.4 g, 21.1 mmol, 1.0 eq.) in DCM (40 mL) and MeOH (20 mL) was added HCl 4M in dioxane (32 mL, 128 mmol, 6.1 eq.). The reaction mixture was stirred at RT for 4 h to give a white suspension. The reaction mixture was concentrated to give 1-(oxetan-3-yl)piperidin-4-amine; dihydrochloride salt (4.8 g, 21.0 mmol, 99% yield) as a white solid, which was used without further purification. ESI pos[M+H] + 157.1.

[0160] Step 3: 4-nitro-N1-[1-(oxetan-3-yl)-4-piperidyl]benzene-1,3-diamine [ka]

[0161] To a suspension of 1-(oxetan-3-yl)piperidin-4-amine dihydrochloride (3.24 g, 14.1 mmol, 1.1 eq.) in DMSO (20 mL) was added K2CO3 (5.33 g, 38.6 mmol, 3.0 eq.) and stirred at RT for 5 min. 5-Fluoro-2-nitroaniline (2.0 g, 12.8 mmol, 1.0 eq.) was added and the mixture was stirred at 100 °C for 16 h. The reaction mixture was cooled to RT and poured into saturated aqueous NH4Cl solution (300 mL) with stirring and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, 0% to 10% MeOH in EtOAc) to give 4-nitro-N1-[1-(oxetan-3-yl)-4-piperidyl]benzene-1,3-diamine (1.4 g, 4.79 mmol, 37% yield) as a yellow solid. ESI pos[M+H] + 293.0. 1 H NMR(400MHz,DMSO-d6)δ=7.71(d,J=9.5Hz,1H),7.28(brs,2H),6.84(brd,J=7.5Hz,1H),6.02(dd,J=2.0,9.5Hz,1H),5.88(d,J=1.8Hz,1H),4.57 -4.47(m,2H),4.41(t,J=6.0Hz,2H),3.38(brt,J=6.4Hz,1H),3.25-3.15 (m,1H),2.67(brd,J=11.1Hz,2H),1.94-1.83(m,4H),1.51-1.37(m,2H).

[0162] Step 4: N4-[1-(oxetan-3-yl)-4-piperidyl]benzene-1,2,4-triamine [ka] To a solution of 4-nitro-N1-[1-(oxetan-3-yl)-4-piperidyl]benzene-1,3-diamine (100 mg, 0.34 mmol, 1.0 eq.) in MeOH (15 mL) was added Fe (191 mg, 3.42 mmol, 10 eq.), NH4Cl (366 mg, 6.84 mmol, 20 eq.), and HO (5 mL), and the reaction mixture was stirred at 50 °C for 2 h under a N2 atmosphere. The reaction was cooled to RT and diluted with MeOH (10 mL). Aqueous NH3 (10%) (0.5 mL) was added and stirred at 30 °C for 10 min. The mixture was filtered through a Celite pad, and the filter cake was washed with MeOH (3 × 5 mL). The filtrate was dried over NaSO, filtered, and concentrated to give N-[1-(oxetan-3-yl)-4-piperidyl]benzene-1,2,4-triamine (100 mg, 0.38 mmol, quantitative yield) as a dark brown solid, which was used without further purification. TLC: DCM / MeOH=10:1, Rf=0.20.

[0163] Step 5: N-[1-(oxetan-3-yl)-4-piperidyl]-1H-benzimidazol-5-amine [ka] To a solution of N-[1-(oxetan-3-yl)-4-piperidyl]benzene-1,2,4-triamine (100 mg, 0.38 mmol, 1.0 eq.) in EtOH (2 mL), TsOH (7 mg, 0.04 mmol, 0.1 eq.) and trimethoxymethane (417 μL, 3.81 mmol, 10 eq.) were added, and the reaction mixture was stirred at 80 °C under a N atmosphere for 2 h. The reaction mixture was cooled to RT and concentrated. The residue was purified by preparative HPLC (Phenomenex Luna C18 15 μm 150 mm × 40 mm, 0.1% NHOH-ACN in water) to give N-[1-(oxetan-3-yl)-4-piperidyl]-1H-benzimidazol-5-amine as a brown solid (35 mg, 0.13 mmol, 34% yield). ESI pos[M+H] + 273.1.

[0164] Step 6: 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[[1-(oxetan-3-yl)-4-piperidyl]amino]benzimidazol-1-yl]pyridine-3-carbonitrile [ka] To a solution of 6-chloro-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (Example 2, Step 1) (48 mg, 0.18 mmol, 1.2 eq.) in t-amyl alcohol (2.0 mL) was added N-[1-(oxetan-3-yl)-4-piperidyl]-1H-benzimidazol-5-amine (40 mg, 0.15 mmol, 1.0 eq.) and KPO (94 mg, 0.44 mmol, 3.0 eq.). N was bubbled through the reaction mixture for 10 min, tBuXPhosPdG (23 mg, 0.03 mmol, 0.2 eq.) was added, and the mixture was stirred at 80 °C under a N atmosphere for 16 h. The reaction mixture was cooled to RT, poured into saturated aqueous NHCl (30 mL), and extracted with EtOAc (3 × 10 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (DCM / MeOH=10:1) to give a mixture of 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[[1-(oxetan-3-yl)-4-piperidyl]amino]benzimidazol-1-yl]pyridine-3-carbonitrile and 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[[1-(oxetan-3-yl)-4-piperidyl]amino]benzimidazol-1-yl]pyridine-3-carbonitrile as a yellow oil (20 mg, 0.04 mmol, 27% yield). The mixture of isomers was purified by SFC (DAICEL CHIRALCEL OD 10 μm, 250 mm × 30 mm, 0.1% NHOH-ACN in MeOH). This gave 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[[1-(oxetan-3-yl)-4-piperidyl]amino]benzimidazol-1-yl]pyridine-3-carbonitrile (6 mg, 0.01 mmol, 29% yield) as a yellow solid. ESI pos[M+H]+ 505.1. 1H NMR(400MHz,DMSO-d6)δ=8.98(s,1H),8.72(d,J=8.6Hz,1H),8.19(d,J=8.6Hz,1H),7.93(brd,J=8.9Hz,1H),7.11(brt,J=54.0Hz,1H),6.87(s,1H),6. 76(brs,2H),5.54(brd,J=8.0Hz,1H),4.53(brt,J=6.3Hz,2H),4.42(brt,J =6.0Hz,2H),3.39(brs,1H),2.67(brs,5H),2.55(s,3H),1.98-1.89(m,4H).

[0165] Example 22 - リン acidified アッセイSIK1-3: In the presence of SIK2 (SIK1 or SIK3, respectively) and ATP, the CHK peptide (KKKVSRSGLYRSPSMPENLNRPR, with a C-terminal arginine amide modification) was phosphorylated at one of four viable serines. Only one phosphorylation was observed under these assay conditions. A 60 nL dilution series of each compound (12 points; dilution factor 3, generally 30 μM to 170 pM) in DMSO was transferred to the assay plate by acoustic dispensing. Following the addition of 5 μL of SIK1 (5 nM), 5 μL of SIK2 (0.5 nM), or 7 μL of SIK3 (1.5 nM) in assay buffer (12.5 mM HEPES (pH 7.0), 10 mM magnesium acetate, 0.005% BSA), the mixture was preincubated for 30 min at ambient temperature. Five μl of a 10 μM CHK peptide solution and 100 μM ATP solution were added to SIK1 and SIK2, respectively, and 3 μl of a 10 μM CHK peptide solution and 100 μM ATP solution were added to SIK3 in assay buffer and incubated at ambient temperature for 45 minutes. The reaction was quenched by adding 40 μl of 0.125% formic acid in water. RapidFire (RF) mass spectrometry was used for data generation as described below. Phosphorylated and non-phosphorylated multiple charged species (3–5 charges) measured by MRM (Multiple Reaction Monitoring; API 5000 or 6500+) or EIC (Extracted Ion Current; QToF) were summed, and a ratio was calculated for data evaluation (sum of phosphorylated species / sum of all species). Normalization was performed using Genedata software based on the non-inhibited control DMSO and the commercially available SIK inhibitor ® 1 μM YKL-05-099 (CAS number 1936529-65-5). The results of the assay are expressed as half-maximal inhibitory concentrations (IC50) and are summarized in Table 1 below.

[0166] RapidFire Setup: The sample was vacuumed for up to 600 ms and loaded onto a C4 cartridge (Agilent; #G9203A) at 3000 ms @ 1.5 ml / min using 0.1% formic acid in water. The sample was then transferred to an API 5000 (API 6500+) or QToF mass spectrometer at 4000 ms @ 1.25 ml / min using 90% acetonitrile; 10% water; 0.007% TFA; 0.093% formic acid. The cartridge was reconditioned for an additional 500 ms with 0.1% formic acid in water.

[0167] MS settings for Sciex API5000 / API6500+: All MS analyses used the following MS settings in MRM mode: electrospray positive; ion spray voltage: 4000 V; temperature: 550 °C; collision gas: 5; curtain gas: 15; gas 1:40; gas 2:42; EP: 10. DP = declustering potential; CE = collision energy; CXP = cell exit potential. [Table 1]

[0168] MS settings Agilent QToF 6545 For all MS analyses, the following MS settings were used in mode MS: Dual AJS electrospray positive; VCap: 3000V; Drying and sheath gas: 340°C @ 8 l / min; Nebulizer: 60 psig; Nozzle voltage: 2000V; Fragmenter: 130V; Skimmer: 35V; Oct1 RF Vpp: 700V; Ref mass @ 5 spectra / sec [Table 2] [Table 3]

[0169] Example A Film-coated tablets containing the following ingredients may be manufactured in a conventional manner. [Table 4]

[0170] The active ingredient is sieved and mixed with microcrystalline cellulose, and the mixture is granulated with an aqueous solution of polyvinylpyrrolidone.The granules are then mixed with sodium starch glycolate and magnesium stearate and compressed to obtain cores of 120 mg or 350 mg, respectively.The cores are then lacquered with an aqueous solution / suspension of the above film coat.

[0171] Example B Capsules containing the following ingredients may be prepared in a conventional manner. [Table 5]

[0172] The ingredients are sieved, mixed and filled into size 2 capsules.

[0173] Example C The injection solution may have the following composition: [Table 6]

[0174] The active ingredient is dissolved in a mixture of polyethylene glycol 400 and water for injection (partially). The pH is adjusted to 5.0 by adding acetic acid. The remaining amount of water is added to adjust the volume to 1.0 ml. The solution is filtered, filled into vials using an appropriate overage, and sterilized.

Claims

1. Formula (I) 【Chemistry 1】 (In the formula, R １ is R ４ heteroaryl optionally substituted with 1, 2, or 3 substituents individually selected from: R ２ is hydrogen, alkoxy, halogen, dialkylaminoalkoxy, heteroarylamino, or heterocycloalkyloxy, where heteroarylamino and heterocycloalkyloxy are R ５ optionally substituted with 1, 2, or 3 substituents individually selected from: R ３ is hydrogen, alkyl, dialkylaminoalkyl, heterocycloalkyl, or heteroaryl, where heteroaryl and heterocycloalkyl are ６ optionally substituted with 1, 2, or 3 substituents individually selected from: R ４ are independently selected from cyano, alkyl, alkoxy, halogen, haloalkoxy, and haloalkyl; R ５ each occurrence of is individually selected from alkyl and dialkylaminocarbonyl; R ６ is independently selected from alkyl, heterocycloalkyl, (heterocycloalkyl)heterocycloalkyloxy, (alkoxy)heterocycloalkylalkyl, and dialkylaminocarbonyl; L is absent, —O— or —NH—. or a pharmaceutically acceptable salt thereof.

2. R １ is selected from pyrazolyl and pyridinyl, and pyrazolyl and pyridinyl are selected from R ４ 2. 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, halogen, dialkylaminoalkoxy, pyridazinylamino or oxetanyloxy, and pyridazinylamino and oxetanyloxy are R ５ 4. The compound of any one of claims 1 to 3, optionally substituted with 1, 2 or 3 substituents individually selected from:

5. R ２ is hydrogen, methoxy, fluoro, dimethylaminoethoxy, pyridazinylamino or oxetanyloxy, and pyridazinylamino and oxetanyloxy are R ５ 5. The compound of any one of claims 1 to 4, optionally substituted with 1, 2 or 3 substituents individually selected from:

6. R ３ is hydrogen, alkyl, dialkylaminoalkyl, piperidyl, oxetanyl, or pyridazinyl, and piperidyl, oxetanyl, and pyridazinyl are R ６ 6. The compound of any one of claims 1 to 5, optionally substituted with 1, 2 or 3 substituents individually selected from:

7. R ３ is hydrogen, methyl, dimethylaminoethyl, piperidyl, oxetanyl or pyridazinyl; piperidyl, oxetanyl and pyridazinyl are R ６ 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 The compound of any one of claims 1 to 7, wherein each occurrence of is individually selected from cyano, alkyl, haloalkoxy, and haloalkyl.

9. R ４ The compound of any one of claims 1 to 8, wherein each occurrence is independently selected from cyano, methyl, difluoromethoxy, difluoromethyl, and trifluoroethyl.

10. R ５ is, at each occurrence, independently selected from methyl and dimethylaminocarbonyl.

11. R ６ is, at each occurrence, individually selected from alkyl, oxetanyl, (oxetanyl)piperidinyloxy, (methoxy)azetidinylethyl, and dialkylaminocarbonyl.

12. R ６ is individually selected from methyl, oxetanyl, (oxetanyl)piperidinyloxy, (methoxy)azetidinylethyl, and dimethylaminocarbonyl.

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

14. 2-(3-cyano-5-methyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[2-(dimethylamino)ethoxy]-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[2-(dimethylamino)ethoxy]-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; 6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile; 6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile; 3-[[3-[5-cyano-6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-2-pyridyl]benzimidazol-5-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide; 3-[[1-[5-cyano-6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-2-pyridyl]benzimidazol-5-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide; 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]-5-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-fluoro-5-[[6-[[1-(oxetan-3-yl)-4-piperidyl]oxy]pyridazin-3-yl]amino]benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-fluoro-5-[[6-[2-(3-methoxyazetidin-1-yl)ethyl]pyridazin-3-yl]amino]benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]-5-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[5-methoxy-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-(3-methyloxetan-3-yl)oxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[2-(difluoromethoxy)-5-methyl-4-pyridyl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[5-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile; and 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[[1-(oxetan-3-yl)-4-piperidyl]amino]benzimidazol-1-yl]pyridine-3-carbonitrile The compound (I) according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, selected from:

15. 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; 6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile; 6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile; 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; and 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-(3-methyloxetan-3-yl)oxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile The compound (I) according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, selected from:

16. A process for preparing a compound according to any one of claims 1 to 15, comprising the steps of: (a) Formula (A1) 【Chemistry 2】 and a compound of formula (A2) 【Transformation 3】 in the presence of a suitable solvent or in the presence of a suitable base; (b) Formula (B1) 【Chemistry 4】 and a compound of formula (B2) 【Transformation 5】 in the presence of a suitable solvent and a suitable catalyst; or (c) Formula (C1) or (C2) 【Transformation 6】 and a compound of formula (C3) 【Transformation 7】 in the presence of a suitable solvent, a suitable base and a suitable catalyst. (In the formula, X １ is halogen, OM or OT, especially halogen, and X ２ is halogen, especially chloro; L, R １ , R ２ , R ３ and R ６ is as defined in any one of claims 1 to 13) The method includes one of the following:

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

18. A compound of formula (I) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

19. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier.

20. 16. Use of a compound of formula (I) according to any one of claims 1 to 15 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.

21. 16. Use of a compound of formula (I) according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof for the preparation of a medicament 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.

22. 16. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15 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.

23. 19. 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 15 or a pharmaceutically acceptable salt thereof.

24. The invention as hereinbefore described.

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