New benzimidazole pyridine derivatives

Abstract

The present invention relates to a compound of formula (I): TIFF2025503005000848.tif66165 (In the formula, A1, A2, A3, R 1 , R 2 , R 2 ', R 3 , R 4 and R 5 are as described herein and in the claims. The compounds of formula (I) can be used as medicines.

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 particularly relates to a compound of formula (I): [ka] (In the formula, R 1 is hydrogen or halogen; R 2 and R 2 ' is independently selected from hydrogen, alkyl, cyclopropyl, haloalkyl, and alkoxyalkyl; A1 is -O-, -NR 6 -, -(C=O)- or a bond; R 6 is hydrogen or alkyl; R 3 is hydroxyalkyl, heterocycloalkyl, heteroaryl, phenyl, or cycloalkylalkyl, and heterocycloalkyl, heteroaryl, phenyl, and cycloalkylalkyl are optionally R 7 and when A1 is -(C=O)-, R 3 may be haloalkylamino; Each R 7 is independently selected from alkoxy, alkylamino, alkyl, aminocarbonyl, amino, cyano, cycloalkylamino, haloalkyl, halocycloalkyl, halogen, heteroaryl, hydroxycarbonylamino, alkoxyalkyl, alkylaminocarbonyl, alkylsulfonyl, alkoxycarbonimidoyl, aminocarbonyl, hydroxy, cycloalkylalkyl, haloalkoxy, heterocycloalkyl, and cycloalkyl; A2 is -O-, -NH- or a bond; R 4is hydrogen, alkyl, haloalkyl, alkoxyalkyl, dialkylaminoalkyl, cycloalkyl, cycloalkylcarbonyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, or heterocycloalkylalkyl; aryl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl are optionally selected from R 8 and when A2 is a bond, R 4 may be halogen or cyano; Each R 8 is independently selected from alkyl, halogen, cyano, alkylsulfonyl, alkylaminocarbonyl, heterocycloalkyl, and alkoxyheterocycloalkylalkyl; A3 is -O-, -NR 10 -or a bond; R 5 is hydrogen, alkyl, alkylsulfonyl, cycloalkylcarbonyl, heterocycloalkylalkyl, heterocycloalkylalkylcarbonyl, aryl, heteroaryl, or heterocycloalkyl, and cycloalkylcarbonyl, aryl, heteroaryl, and heterocycloalkyl are optionally selected from R 9 and when A3 is a bond, R 5 may be halogen or cyano; Each R 9is alkoxy, halogen, dialkylaminocarbonyl, alkyl, alkoxyalkoxy, alkoxyheterocycloalkylalkyl, alkoxyheterocycloalkylcarbonyl, haloalkyl, haloalkoxy, heterocycloalkylalkoxy, heterocycloalkyl, heterocycloalkyloxy, hydroxy, hydroxyalkyl, alkylheterocycloalkyl, (haloalkyl)cycloalkyl, alkylheterocycloalkylalkyl, heterocycloalkylalkyl, alkylsulfonyl, (alkyl)heterocycloalkyl, alkylheterocycloalkyloxy, heterocycloalkylheterocycloalkyl, heterocycloalkylheterocycloalkyl, CH3-O-(CH2-CH2-O) n -, alkylaminocarbonyl, and cyano; n is selected from 5, 6, 7, 8, and 9; R 10 is hydrogen or alkylcarbonyl) or a pharmaceutically acceptable salt thereof.

[0003] Salt-inducible kinases (SIKs) belong to a subfamily of AMP-activated protein kinases (AMPKs), known as AMPK-related kinases. Broadly speaking, there are three members, designated SIK1, SIK2, and SIK3. 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 US 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 HDCAs 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.

[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, such as isobutyl, are further specific examples of "alkyl" in compounds of formula (I).

[0013] The term "cycloalkyl," alone or in combination, refers to a cycloalkyl ring having 3 to 8 carbon atoms, particularly a cycloalkyl ring having 3 to 6 carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Particular examples of "cycloalkyl" are cyclopropyl and cyclobutyl.

[0014] 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" may 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, (7,8-dihydro-5H-pyrano[4,3-c]pyridazin-3-yl), [rac-(4aS,7aR)-4-methyl- 2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-6-yl], 6,7-dihydro-5H-cyclopenta[c]pyridazin-3-yl, 5,6-dihydropyrrolo[2,3-c]pyridazin-7-yl, 7-oxo-5H-pyrrolo[3,4-b]pyridin-2-yl, 5,6-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl, 6-azaspiro[3.4]octan-6-yl, and [rac-(3aS,6aS)-6-oxo-2,3,3a,4,5,6a-hexahydropyrrolo[2,3-c]pyrrol-1-yl]. Particular examples of "heterocycloalkyl" are pyrrolidin-1-yl and pyrrolidin-3-yl. In one particular embodiment, heterocycloalkyl is "N-heterocycloalkyl".

[0015] 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, oxazolyl, 2-oxazol-5-yl, 2-oxo-3-imidazol-1-yl, pyrimidinyl, pyrimidin-5-yl, benzotriazolyl, 1H-benzotriazol-4-yl, furanyl, furyl, and 2-furyl. , 3-furyl, [6-oxo-1H-pyridazin-5-yl], triazolyl, triazol-1-yl, triazol-2-yl, triazol-3-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 pyrazol-1-yl, pyrazol-4-yl, pyridazin-3-yl, and pyrimidin-5-yl. In one particular embodiment, heteroaryl is "N-heteroaryl."

[0016] The term "aryl" means a monovalent aromatic carbocyclic mono- or bicyclic ring system containing 6 to 10 carbon ring atoms. Examples of aryl moieties include phenyl and naphthyl. A particular example of aryl is phenyl.

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

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

[0019] The term "oxo", alone or in combination, means the group =0.

[0020] 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.

[0021] 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.

[0022] The term "haloalkoxy," alone or in combination, refers to an alkoxy group substituted with at least one halogen, particularly substituted with 1 to 5 halogens, and especially substituted with 1 to 3 halogens. Particular "haloalkoxy" groups are fluoromethoxy, fluoroethoxy, and fluoropropyloxy.

[0023] The terms "hydroxyl" and "hydroxy," alone or in combination, refer to an --OH group.

[0024] The term "carbonyl", alone or in combination, signifies the -C(O)- group.

[0025] The term "amino," alone or in combination, means a primary amino group (-NH2), a secondary amino group (-NH-), or a tertiary amino group (-N-).

[0026] The term "alkylamino" is an alkyl group bonded to an -NH- group. The term "dialkylamino" means two alkyl groups bonded to the -N- atom.

[0027] The term "sulfonyl", alone or in combination, signifies the -SO2- group.

[0028] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the free base or free acid, without being biologically or otherwise undesirable. Salts are formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, especially hydrochloric acid, and organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and N-acetylcysteine. In addition, these salts can be prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, and polyamine resins. Compounds of formula (I) can also exist in zwitterionic form. Specific pharmaceutically acceptable salts of compounds of formula (I) are salts of trifluoroacetic acid, formic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and methanesulfonic acid.

[0029] Tautomers, ie structural isomers that interconvert with compounds of formula (I), exist, particularly in solution.

[0030] For example, a compound of formula (I) in which A3 is -NH- and R5 is pyridazin-3-yl is in tautomeric equilibrium with its tautomeric form (I'). [ka]

[0031] Other tautomeric forms of compounds of formula (I) may also exist.

[0032] The compounds of formula (I) can be represented in different mesomeric structures, for example: [ka]

[0033] 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., those described in "Protective Groups in Organic Chemistry" by T.W. Greene and P.G.M.Wuts, 3 rd Protecting groups (such as those described in [End Page 109] Ed., 1999, Wiley, New York) can be introduced before a critical step applying 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).

[0034] 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.

[0035] 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.

[0036] Furthermore, the present invention includes, where applicable, all optical isomers of the compounds of formula (I), i.e., diastereomers, diastereomeric mixtures, racemic mixtures, all corresponding enantiomers and / or tautomers thereof, and solvates thereof.

[0037] If desired, racemic mixtures of the compounds of the present invention can be separated to isolate the individual enantiomers. Separation can be accomplished 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.

[0038] 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.

[0039] Furthermore, the present invention includes all substituents of the compounds of formula (I) in their corresponding deuterated forms, where applicable.

[0040] Furthermore, the present invention includes all applicable substituents of compounds of formula (I) in their corresponding tritiated form.

[0041] Certain embodiments of the present invention relate to compounds of formula (I) as described herein, or pharmaceutically acceptable salts thereof, wherein at least one substituent comprises at least one radioisotope. Particular examples of radioisotopes are H, H, C, C, and F.

[0042] 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 1-11. In some cases, 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 and reaction conditions provided below can in some cases be further modified according to the procedures described herein and in accordance with common knowledge.

[0043] Scheme 1 Scheme 1 describes the synthesis of compounds of formula (Ia). Compounds of formula (Ia) are compounds of formula (I) where each A is a bond; A is -O-; A is -O-; and R 1 is hydrogen; R 2 and R 2 ' are both hydrogen; R 3 is optionally R 7 phenyl substituted with 1, 2 or 3 substituents independently selected from 4 is alkyl; R 5 is alkyl; each R 7 is a compound independently selected from alkoxy and halogen. [ka]

[0044] Step A: Methyl 2,6-dichloronicotinate 1 can be reacted with 5,6-disubstituted benzimidazole 2 in the presence of a strong base such as NaH in a polar solvent such as DMF or DMSO at about 0° C. to give intermediate 3.

[0045] Step B: Intermediate 3 can undergo a palladium catalyzed cross-coupling reaction (Suzuki-Miyaura) with a suitable reactant such as the corresponding aryl boronic acid or aryl pinacol borane, catalytic Pd(PPh) or other suitable Pd catalyst in the presence of a suitable base such as NaCO, in a suitable solvent such as DME, and with heating (e.g., MW microwave at 120° C.) to give intermediate 4.

[0046] Step C: The ester of 4 can be reduced to the corresponding alcohol using a suitable reducing agent, such as, for example, LiAlH 4 , in a suitable solvent, such as, for example, THF, at 0° C. to give the compound of formula (Ia).

[0047] Scheme 2 Scheme 2 describes the synthesis of the racemic compound of formula (Ib) and the corresponding enantiomers (compounds I-b' and I-b''). Compounds of formula (Ib) are compounds of formula (I) where each A is a bond; A is -O-; A is -O-; and R 1 is hydrogen; R 2 is alkyl; R 2 ' is hydrogen; R 3 is optionally R 7 phenyl substituted with 1, 2 or 3 substituents independently selected from 4 is alkyl; R 5 is alkyl; each R 7 is a compound independently selected from alkoxy and halogen. [ka]

[0048] Step A: The alcohol group of compound (Ia) in Scheme 1 can be oxidized to the corresponding aldehyde 5 in the presence of a suitable oxidizing reagent, such as DMP (Dess-Martin periodinane), in a suitable solvent, such as DCM, at ambient temperature.

[0049] Step B: Aldehyde 5 can be reacted with an appropriate alkyl magnesium halide (such as MeMgBr or EtMgBr or cyclopropylMgBr) in a suitable solvent such as a mixture of THF / 2-MeTHF at −30° C. to 0° C. to provide the corresponding secondary alcohol Ib.

[0050] Step C: The racemic mixture of secondary alcohol Ib can be separated into enantiomers I-b' and I-b'' by chiral SFC.

[0051] Scheme 3 Scheme 3 describes the synthesis of compounds of formula (Ic). Compounds of formula (Ic) are compounds of formula (I) where each A is a bond; A is -O-; A is -O-; and R 1 is hydrogen; R 2 is hydrogen; R 2 ' is hydrogen; R 3 is N-heterocycloalkyl; R 4 is alkyl; R 5 is an alkyl group. [ka]

[0052] Step A: Intermediate 3 from Scheme 1 can be substituted with saturated N-heterocycle 6 in the presence of a strong base (such as NaH or CsCO or other carbonates) in a polar solvent (such as DMF, DMA, NMP or DMSO) to give intermediate 7.

[0053] Step B: The ester of intermediate 7 can be reduced to a compound of formula (Ic) in the presence of a reducing agent such as LiAlH 4 in a manner similar to that shown in Scheme 1, Step C.

[0054] Scheme 4 Scheme 4 describes the synthesis of compounds of formula (Id) and compounds of formula (Ie). Compounds of formula (Id) are compounds of formula (I) where A1 is a bond; A2 is -O-; A3 is -O-; and R 1 is hydrogen; R 2 is hydrogen; R 2 ' is hydrogen; R 3 is N-heterocycloalkyl; R is alkyl; and R is alkyl. Compounds of formula (Ie) are compounds of formula (I) where A is -NH-; A is -O-; A is -O-; and R 1 is hydrogen; R 2 is hydrogen; R 2 ' is hydrogen; R 3 is hydroxyalkyl; R 4 is alkyl; R 5 is an alkyl group. [ka]

[0055] Step A: Methyl 2,6-dichloronicotinate 1 can be reacted with cyclic amide 8 in a suitable solvent such as DMF in the presence of a suitable base such as NaH at -10°C to 0°C to give intermediate 9.

[0056] Step B: Intermediate 9 can be further substituted with a 5,6-disubstituted benzimidazole in the presence of a strong base such as NaH in a polar solvent such as DMF, DMA, NMP or DMSO at 0° C. to give intermediate 11.

[0057] Step C: In a manner similar to Step C of Scheme 1, the ester of intermediate 11 can be reduced in the presence of a suitable reducing agent, such as LiAlH, to give a compound of formula (Id). The open-chain compound (Ie) can also be obtained via a reduction step.

[0058] Scheme 5 Scheme 5 describes the synthesis of the racemic compound of formula (If) and the corresponding enantiomers (compounds If' and If''). Compounds of formula (If) are compounds of formula (I) where each A1 is a bond; A2 is -O-; A3 is -O-; and R 1 is hydrogen; R 2 is alkyl; R 2 ' is hydrogen; R 3 is phenyl or heteroaryl, and the phenyl and heteroaryl are optionally 7 and R is substituted with 1, 2, or 3 substituents independently selected from 4 is alkyl; R 5 is alkyl; each R 7 is a compound independently selected from aminocarbonyl, methyl, and cyano. [ka]

[0059] Step A: Intermediate 12 can be obtained from intermediate 3 from Scheme 1 by the following sequence: (1) reduction with a suitable reducing agent, such as LiAlH4, in a suitable solvent, such as THF, at 0°C; (2) oxidation with a suitable reagent, such as DMP, at room temperature to generate an aldehyde; (3) reaction with a suitable alkyl magnesium halide (such as MeMgBr or EtMgBr or cyclopropylMgBr) in THF at -20°C to 0°C; and finally protection of the corresponding secondary alcohol with TBDMSCl in DCM in the presence of imidazole.

[0060] Step B: Palladium catalyzed cross-coupling reaction (Suzuki-Miyaura) with the corresponding arylboronic acid or arylpinacolborane, catalytic Pd(PPh3)4 or other suitable Pd catalyst and a suitable base (K3PO4, Cs2CO3, K2CO3, Na2CO3) in a suitable solvent (DME) with heating (e.g., MW 80°C-120°C) provides compounds of formula (If).

[0061] Step C: The racemic mixture of secondary alcohol If can be further separated into enantiomers If' and If'' by chiral SFC.

[0062] Scheme 6 Scheme 6 describes the synthesis of the racemate of formula (Ig) and the corresponding enantiomers (compounds I-g' and I-g''). Scheme 6 also describes the synthesis of the racemate of formula (Ih) and the corresponding enantiomers (compounds I-h' and I-h''). Compounds of formula (Ig) are compounds of formula (I) where A1 is a bond; A2 is a bond; A3 is -NH- and: R 1 is hydrogen; R 2 is alkyl; R 2 ' is hydrogen; R 3 is optionally R 7 pyrazol-1-yl substituted by 1, 2 or 3 substituents independently selected from 4 is hydrogen; R 5 is optionally R 9 pyridazin-3-yl substituted with 7 is independently selected from alkyl, cyano, haloalkyl, alkoxy, alkylaminocarbonyl, and alkylsulfonyl; R 9 A compound of formula (Ih) is a compound of formula (I) wherein A1 is a bond; A2 is NH-; A3 is a bond; and R 1 is hydrogen; R 2 is alkyl; R 2 ' is hydrogen; R 3 is optionally R 7 pyrazol-1-yl substituted by 1, 2 or 3 substituents independently selected from 4 is optionally R 8 pyridazin-3-yl substituted with R 5 is hydrogen; each R 7 is independently selected from alkyl, cyano, haloalkyl, alkoxy, alkylaminocarbonyl, and alkylsulfonyl; R 8 is an alkyl group. [ka]

[0063] Step A: 1-(6-chloro-2-fluoro-3-pyridyl)alkanone 13 can be reacted with substituted pyrazole 14 in the presence of a suitable organic or inorganic base such as DIPEA, DBU, K2CO3, Cs2CO3 or NaH in a suitable polar solvent (e.g., DMF, DMA, NMP, DMSO or THF, MeTHF) to give intermediate 15.

[0064] Step B: Intermediate 18 can be obtained by reacting 5-aminobenzimidazole 16 with (6-alkylpyridazin-3-yl)amine 17 in iPrOH under reflux.

[0065] Step C: Intermediates 15 and 18 can be combined in a suitable polar solvent (such as DMF, DMA, NMP, DMSO or THF, MeTHF, etc.) in the presence of a suitable organic or inorganic base (such as DIPEA, DBU, K2CO3, Cs2CO3, or NaH, etc.) to give regioisomeric intermediates 19 and 20, which can be separated by flash column chromatography.

[0066] Step D: The corresponding secondary alcohols (Ig and Ih) can be obtained after reduction of the carbonyl group with a suitable reducing agent, such as NaBH or NaCNBH (1-5 equivalents), in a suitable solvent, such as MeOH (and in some cases a second co-solvent, such as DCM, THF, DMF), at temperatures between −40° C. and room temperature.

[0067] Step E: The racemic mixture of secondary alcohol Ig can be further separated into enantiomers I-g' and I-g" by chiral SFC. Similarly, the racemic mixture of secondary alcohol Ih can be further separated into enantiomers I-h' and I-h" by chiral SFC.

[0068] Scheme 7 Scheme 7 describes the synthesis of compounds of formula (Ii) and compounds of formula (Ij). Compounds of formula (Ii) are compounds of formula (I) where A1 is a bond; A2 is a bond; A3 is -NH-; and R 1 is hydrogen; R 2 is alkyl; R 2 ' is hydrogen; R 3 is optionally R 7 pyrazol-1-yl substituted by 1, 2 or 3 substituents independently selected from 4 is hydrogen; R 5 is alkyl, heterocycloalkyl, or heteroaryl, and heterocycloalkyl and heteroaryl are optionally R 9 and each R is substituted with 1, 2, or 3 substituents independently selected from 7 is independently selected from alkyl, cyano, haloalkyl, alkoxy, alkylaminocarbonyl, and alkylsulfonyl; R 9 is alkyl, cyano, or alkoxy. Compounds of formula (Ij) are compounds of formula (I) wherein A1 is a bond; A2 is NH-; A3 is a bond; and R 1 is hydrogen; R 2 is alkyl; R 2 ' is hydrogen; R 3 is optionally R 7 pyrazol-1-yl substituted by 1, 2 or 3 substituents independently selected from 4 is alkyl, heterocycloalkyl, or heteroaryl, and heterocycloalkyl and heteroaryl are optionally R 8 and R is substituted with 1, 2, or 3 substituents independently selected from 5 is hydrogen; each R 7 is independently selected from alkyl, cyano, haloalkyl, alkoxy, alkylaminocarbonyl, and alkylsulfonyl; R 8 is alkyl, cyano, or alkoxy. [ka]

[0069] Step A: Regioisomeric intermediates 22 and 23 can be obtained using intermediate 15 and 5-bromobenzimidazole 21 as the second reagent, similarly as described in Scheme 6, Step C.

[0070] Step B: Introduction of the R7 substituted amine can be achieved by Buchwald-Hartwig coupling using a suitable base such as CsCOKCO or KPO and a suitable palladium catalyst such as t-Buxphos-Pd-G3 or [tBuBrettPhos Pd(allyl)]OTf at about 80°C to about 90°C to give intermediates 24 and 25, respectively.

[0071] Step C: The corresponding secondary alcohols can be obtained after reduction of the carbonyl of intermediates 24 and 25 with a suitable reducing agent, such as NaBH (1-5 equivalents), in a suitable solvent, such as MeOH (and in some cases a second co-solvent, such as DCM, THF, or DMF), at temperatures between −40° C. and room temperature to give compounds of formula (Ii) and (Ij), respectively. The enantiomers of the secondary alcohols can be further separated by chiral SFC.

[0072] Scheme 8 Scheme 8 describes the synthesis of compounds of formula (Ik) and compounds of formula (Il). Compounds of formula (Ik) are compounds of formula (I) where A1 is a bond; A2 is a bond; A3 is -NH-; and R 1 is hydrogen; R 2 is alkyl; R 2 ' is hydrogen; R 3 is optionally R 7 pyrazol-1-yl substituted by 1, 2 or 3 substituents independently selected from 4 is hydrogen; R 5 is optionally R 9 and each R is heteroaryl substituted with 1, 2, or 3 substituents independently selected from 7is independently selected from alkyl, cyano, haloalkyl, alkoxy, alkylaminocarbonyl, and alkylsulfonyl; R 9 is alkyl, cyano, or alkoxy. Compounds of formula (Ij) are compounds of formula (I) wherein A1 is a bond; A2 is NH-; A3 is a bond; and R 1 is hydrogen; R 2 is alkyl; R 2 ' is hydrogen; R 3 is optionally R 7 pyrazol-1-yl substituted by 1, 2 or 3 substituents independently selected from 4 is optionally R 8 is heteroaryl substituted with 1, 2, or 3 substituents independently selected from 5 is hydrogen; each R 7 is independently selected from alkyl, cyano, haloalkyl, alkoxy, alkylaminocarbonyl, and alkylsulfonyl; R 8 is alkyl, cyano, or alkoxy. [ka]

[0073] Step A: The carbonyl group of the regioisomeric intermediates 22 and 23 obtained in Step A of Scheme 7 can be reduced using a suitable reducing agent, such as NaBH4 or NaCNBH3, in a suitable solvent, such as MeOH / THF (1:1), at about 0°C to give intermediates 26 and 27, respectively.

[0074] Step B: The arylamine group can be introduced by Buchwald-Hartwig coupling using, for example, Cs2CO3 as base and RuPhos-Pd-G3 as catalyst at 100°C in a suitable solvent such as 1,4-dioxane to give compounds of formula (Ik) and (Il), respectively.

[0075] Scheme 9 Scheme 9 describes the synthesis of compounds of formula (Im). Compounds of formula (Im) are compounds of formula (I) where A1 is a bond; A2 is a bond; A3 is -NH-; and R 1 is hydrogen; R 2 is methyl; R 2 ' is hydrogen; R 3 is optionally R 7 N-heteroaryl substituted with 1, 2, or 3 substituents independently selected from: 4 is hydrogen; R 5 is pyridazin-3-yl substituted with methyl; 7 is a compound independently selected from alkyl, cyano, halogen, haloalkyl, haloalkoxy, hydroxy, alkoxy, and cycloalkylamino. [ka]

[0076] Step A: 1-(2-chloro-6-fluoro-3-pyridyl)ethanone 30 can be obtained from the reaction of 3-bromo-2-chloro-6-fluoro-pyridine 28 with tributyl(1-ethoxyvinyl)tin 29 in the presence of a suitable catalyst such as Pd(PPh)Cl and a suitable base such as KCO, CsCO, or KPO at about 100 °C in a suitable solvent such as 1,4-dioxane and HO.

[0077] Step B: Intermediate 30 can then be reacted with N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine (intermediate 18 from Scheme 6) in DMSO at 60° C. to provide intermediate 31 (and its regioisomers).

[0078] Step C: Palladium-catalyzed cross-coupling reaction (Suzuki-Miyaura) with the corresponding arylboronic acid or arylpinacolborane, a suitable catalyst such as PdCl(dppf) CHCl, and a suitable base (e.g., NaCO) in a solvent such as 1,4-dioxane with heating to about 100 °C provides intermediate 32.

[0079] Step D: Compound Im can be obtained after reduction of the carbonyl group of 32 with a suitable reducing agent, such as NaBH or NaCNBH (1-5 equivalents), in a suitable solvent, such as MeOH (and in some cases, a second co-solvent, such as DCM, THF, or DMF), at a temperature between about −40° C. and room temperature.

[0080] Scheme 10 Scheme 10 describes the synthesis of compounds of formula (In). Compounds of formula (In) are compounds of formula (I) where A1 is a bond; A2 is a bond; A3 is -NH-; and R 1 is hydrogen; R 2 is methyl; R 2 ' is hydrogen; R 3 is optionally R 7 is cycloalkyl substituted with 1, 2, or 3 substituents independently selected from 4 is hydrogen; R 5 is pyridazin-3-yl substituted with methyl; 7 is a compound independently selected from alkyl, cyano, halogen, haloalkyl, haloalkoxy, hydroxy, alkoxy, and cycloalkylamino. [ka]

[0081] Step A: 1-(6-chloro-2-fluoro-3-pyridyl)ethanone 33 can be reacted with a cyclic amine (or sulfonamide or amide) in the presence of a suitable base such as KCO or CsCO in a suitable solvent such as DMSO to give intermediate 34.

[0082] Step B: Intermediate 34 can be reacted with N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine (intermediate 18 from Scheme 6) in the presence of KCO or CsCO in DMSO at 30-50°C to give intermediate 35 (and its regioisomers).

[0083] Step C: The secondary alcohol of the compound of formula (In) can be obtained after reduction of the carbonyl of intermediate 35 with a suitable reducing agent, such as NaBH4 (1-5 equivalents), in a suitable solvent, such as MeOH (and in some cases a second co-solvent, such as DCM, THF, DMF), at a temperature between about -40°C and room temperature.

[0084] Step D: The enantiomers In′ and In″ of the secondary alcohol can be separated by chiral SFC.

[0085] Scheme 11 Scheme 11 describes the synthesis of compounds of formula (Io). Compounds of formula (Io) are compounds of formula (I) where A1 is -NH-; A2 is a bond; A3 is -NH-; and R 1 is hydrogen; R 2 is methyl; R 2 ' is hydrogen; R 3 is alkyl; R 4 is hydrogen; R 5 is pyridazin-3-yl substituted with methyl; 7 is a compound independently selected from alkyl, cyano, halogen, haloalkyl, haloalkoxy, hydroxy, alkoxy, and cycloalkylamino. [ka]

[0086] Step A: 1-(6-chloro-2-fluoro-3-pyridyl)ethanone 33 can be reacted with an aliphatic amine in the presence of DIPEA in DMSO or DMF or DME or NMP to give intermediate 36.

[0087] Step B: Intermediate 36 can be reacted with N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine (intermediate 18 from Scheme 6) in DMSO in the presence of KCO at 30° C. to give intermediate 37 (and its regioisomers).

[0088] Step C: Compounds of formula (In) can be obtained after reduction of the carbonyl with a suitable reducing agent, such as NaBH4 (1-5 equivalents), in a suitable solvent, such as MeOH (and in some cases a second co-solvent, such as DCM, THF, DMF), at a temperature between about -40°C and room temperature.

[0089] The present invention therefore also relates to a process for the preparation of the compounds according to the invention, comprising one of the following steps: (a) A compound of formula (B1) [ka] and reaction with a reducing agent; (b) a compound of formula (C1) [ka] with a reducing agent; or (c) Compound (D1) [ka] and the formula R c with a compound of MgX, In the formula, A1, A2, A3, R 1 , R 2 , R 3 , R4 and R 5 is as described above, and R a is alkyl or cycloalkyl, and R b is hydrogen or alkyl, and R c is alkyl or cycloalkyl and X is halogen.

[0090] The reducing agent in step (a) can be LiAlH4, DIBAL-H.

[0091] The solvent for step (a) may advantageously be THF.

[0092] Convenient conditions for step (a) are about -60°C to about 40°C, particularly about -50°C to about 30°C, more particularly about -40°C to about 20°C, for 1 to 24 hours, advantageously 1 to 12 hours.

[0093] The reducing agent in step (b) can be, for example, NaBH4.

[0094] The solvent in step (b) can be, for example, methanol or a mixture of methanol and THF.

[0095] Convenient conditions for step (b) are about -60°C to about 40°C, particularly about -50°C to about 30°C, more particularly about -40°C to about 20°C, for 1 to 24 hours, advantageously 1 to 12 hours.

[0096] In step (c), the solvent can be, for example, THF, 2-MeTHF, or a mixture thereof.

[0097] Convenient conditions for step (c) are about -80°C to about 30°C, particularly about -78°C to about 20°C, more particularly about -40°C to about 0°C, for 1 to 24 hours, advantageously 1 to 12 hours.

[0098] Conveniently, X is chloride, bromide or iodide. Advantageously, X is bromide.

[0099] The present invention also relates to compounds according to the invention when prepared according to the processes of the invention.

[0100] 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 acetate buffer at pH 5. In another embodiment, the compound of formula (I) is sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0101] 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 delivery of the agent, the method of administration, the administration schedule, and other factors known to medical practitioners.

[0102] 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 administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0103] The compounds of the present invention may be administered in any convenient dosage form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain ingredients conventional in pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, fillers and additional active agents.

[0104] 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, opaquing agents, glidants, processing aids, colorants, sweeteners, fragrances, flavorings, diluents, and other known additives to provide proper presentation of the drug (i.e., a compound of the present invention or a pharmaceutical composition thereof) or to aid in the manufacture of a pharmaceutical product (i.e., a medicament).

[0105] Example A Film-coated tablets containing the following ingredients can be manufactured in a conventional manner. [Table 1]

[0106] 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.

[0107] Example B Capsules containing the following ingredients may be manufactured in a conventional manner. [Table 2]

[0108] The ingredients are sieved, mixed and filled into size 2 capsules.

[0109] Example C The injection solution may have the following composition: [Table 3]

[0110] Dissolve the active ingredient in a mixture of polyethylene glycol 400 and water for injection (parts). Adjust the pH to 5.0 by adding acetic acid. Add the remaining amount of water to adjust the volume to 1.0 ml. Filter the solution, fill into vials using an appropriate overage, and sterilize.

[0111] Experimental procedure 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) 2-MeTHF 2-methyltetrahydrofuran ATP adenosine triphosphate aq.Aqueous solution Boc tert-butyloxycarbonyl CDI Carbonyldiimidazole DABCO 1,8-diazabicyclo[5.4.0]undec-7-ene DAST Diethylaminosulfur trifluoride dba Dibenzylideneacetone DCM dichloromethane DIAD Diisopropyl azodicarboxylate DIBAL-H Diisobutylaluminum hydride DIPEA N,N-Diisopropylethylamine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide dppf 1,1'-ferrocenediyl-bis(diphenylphosphine) dtbbpy 4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine dtbpy 4,4'-di-tert-butyl-2,2'-dipyridyl EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide equiv. equivalent ESI electrospray ionization Et Ethyl Et2O diethyl ether EtOAc ethyl acetate EtOH ethanol FA formic acid HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium) 3-Oxidohexafluorophosphate HMDS Bis(trimethylsilyl)amine HOBt Hydroxybenzotriazole HPLC High Pressure Liquid Chromatography i PrOH isopropyl alcohol Ir[dF(CF3)ppy]2(dtbpy)(PF6)[4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-N1,N1']bis[3,5-difluoro-2- [5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate LC-MS High-Performance Liquid Chromatography LDA Lithium diisopropylamide mCPBA metachloroperoxybenzoic acid Me methyl MeOH Methanol Ms methanesulfonyl NMR nuclear magnetic resonance NPLC normal phase liquid chromatography PE Petroleum Ether ppy 2-phenylpyridine psi pounds per square inch PTSA paratoluenesulfonic acid Qphos 1,2,3,4,5 Pentaphenyl-1'-(di-tert-butylphosphino)ferrocene RT room temperature RuPhos-Pd-G3 (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)] palladium(II) methanesulfonate (CAS number 1445085-77-7) sat. saturation SFC Supercritical Fluid Chromatography sol.solution TBD Triazabicyclodecene TBDMS tert-butyldimethylsilyl t-BuXphos-Pd-G3 [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (CAS number 1447963-75-8) TEA Triethylamine Tf Trifle TFA trifluoroacetic acid TFAA Trifluoroacetic anhydride THF tetrahydrofuran TLC thin layer chromatography

[0112] Example 1 (2-(3-chlorophenyl)-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)pyridin-3-yl)methanol [ka]

[0113] Step 1: Methyl 2-chloro-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)nicotinate [ka] In a 200 mL four-neck flask, a 60% dispersion of NaH in mineral oil (637 mg, 15.9 mmol, 2 equiv.) was combined with DMF (30 mL) to give a gray suspension. The mixture was cooled to 0 °C, and 5,6-dimethoxy-1H-benzo[d]imidazole (1.42 g, 7.97 mmol, 1 equiv.) was added. The reaction mixture was stirred for 15 min. A solution of methyl 2,6-dichloronicotinate (1.64 g, 7.97 mmol, 1 equiv.) in DMF (10 mL) was added dropwise to the reaction mixture, and stirring was continued for 15 min. The reaction mixture was quenched with 30 mL of 1 M HCl, and a precipitate formed. The suspension was collected by filtration, washed with HO, and dried under high vacuum. The title compound (1.414 g, 46.9% yield) was obtained as a light brown solid. LC-MS: m / z=348.1 [M+H] + ,ESI pos.

[0114] Step 2: Methyl 2-(3-chlorophenyl)-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)nicotinate [ka] To a microwave vial was added methyl 2-chloro-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)nicotinate (1 g, 2.88 mmol, 1 equiv.), 2M Na2CO3 (5 mL, 10.1 mmol, 3.5 equiv.), 1,2-dimethoxyethane (15 mL), (3-chlorophenyl)boronic acid (674 mg, 4.31 mmol, 1.5 equiv.), and Pd(PPh3)4 (332 mg, 288 μmol, 0.1 equiv.). The vial was capped and heated in a microwave at 120 °C for 20 min. The reaction mixture was cooled to room temperature and diluted with 25 mL of HO and 25 mL of ethyl acetate. The aqueous phase was back-extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 80 g, 0% to 5% MeOH in DCM). The chromatographic product was triturated in acetone, collected by filtration, washed with acetone, and dried. The title compound (353 mg, 27.2% yield) was obtained as a light brown solid. LC-MS: m / z=424.2 [M+H] + ,ESI pos.

[0115] Step 3: (2-(3-chlorophenyl)-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)pyridin-3-yl)methanol [ka] In a 100 mL round-bottom flask, methyl 2-(3-chlorophenyl)-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)nicotinate (317 mg, 748 μmol, 1 equiv.) was suspended in anhydrous THF (5 mL). The mixture was cooled to 0 °C, and a 1 M solution of LiAlH in THF (1.0 mL, 1 mmol, 1.34 equiv.) was added. Stirring at 0 °C was continued for 10 min. The reaction mixture was quenched with 1 M sodium potassium tartrate solution (25 mL) and diluted with DCM (50 mL). The layers were separated, and the organic phase was concentrated to leave a yellow residue. The crude solid was purified by flash chromatography (silica gel, 25 g, 0–100% [DCM / MeOH / NHOH (95:5:1)] in DCM). The title compound (218 mg, 73.6% yield) was obtained as a white solid. LC-MS: m / z=396.2 [M+H] + ,ESI pos.

[0116] Example 15 (2-(3-chloro-2-fluorophenyl)-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)pyridin-3-yl)methanol [ka]

[0117] Step 1: Methyl 2-(3-chloro-2-fluorophenyl)-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)nicotinate [ka] Starting from methyl 2-chloro-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)nicotinate (obtained similarly to Step 1 of Example 1) (400 mg, 1.15 mmol, 1 eq.) and (3-chloro-2-fluorophenyl)boronic acid (301 mg, 1.73 mmol, 1.5 eq.), and following the procedure described in Step 2 of Example 2, the title compound (317 mg, 57.4% yield) was obtained as a light brown solid. LC-MS: m / z=442.2 [M+H]+ ,ESI pos.

[0118] Step 2: (2-(3-chloro-2-fluorophenyl)-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)pyridin-3-yl)methanol [ka] Following the procedure described in Step 3 of Example 1, the title compound (219 mg, 62.7% yield) was obtained as a light brown solid. LC-MS: m / z=414.2 [M+H] + ,ESI pos.

[0119] Example 16 (6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)methanol [ka]

[0120] Step 1: Methyl 6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(4-fluoro-2-methoxyphenyl)nicotinate [ka] Starting from methyl 2-chloro-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)nicotinate (obtained similarly to Step 1 of Example 1) (500 mg, 1.15 mmol, 1 eq.) and (4-fluoro-2-methoxyphenyl)boronic acid (367 mg, 2.16 mmol, 1.5 eq.), and following the procedure described in Step 2 of Example 2, the title compound (498 mg, 64.1% yield) was obtained as an off-white solid. LC-MS: m / z=438.3 [M+H] + ,ESI pos.

[0121] Step 2: (6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)methanol [ka] Following the procedure described in Step 3 of Example 1, the title compound (398 mg, quantitative yield) was obtained as an off-white solid. LC-MS: m / z=410.2 [M+H] + ,ESI pos.

[0122] Example 17 1-(6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)ethan-1-ol [ka]

[0123] Step 1: 6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(4-fluoro-2-methoxyphenyl)nicotinaldehyde [ka] In a 25 mL pear-shaped flask, (6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)methanol (398 mg, 972 μmol, 1 equiv.) (obtained similarly as in Step 2 of Example 16) was suspended in DCM (5 mL). Dess-Martin periodinane (15% solution in DCM) (3.3 g, 2.4 mL, 1.17 mmol, 1.2 equiv.) was added. The reaction mixture immediately turned to a light brown solution. After several minutes, a suspension formed. After stirring for 10 minutes, the reaction mixture was quenched with HO, diluted with DCM, and 2 M NaCO was added. The layers were separated, and the aqueous layer was back-extracted with DCM. The combined organic layers were dried over NaSO, filtered, and concentrated to leave a yellow residue. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 100% in DCM [DCM / MeOH / NH4OH (95:5:1)]). The title compound (357 mg, 72.1% yield) was obtained as a yellow solid. LC-MS: m / z=408.2 [M+H] + ,ESI pos.

[0124] Step 2: 1-(6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)ethan-1-ol [ka] In a 25 mL pear-shaped flask, 6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(4-fluoro-2-methoxyphenyl)nicotinaldehyde (120 mg, 236 μmol, 1 equiv.) was suspended in anhydrous THF (2.5 mL). After the mixture was cooled to 0°C, MeMgBr (3.2 M solution in 2-MeTHF) (81 μL, 259 μmol, 1.1 equiv.) was added, and the reaction mixture was stirred at 0°C for 30 min. Additional MeMgBr (3.2 M solution in 2-MeTHF) (81 μL, 259 μmol, 1.1 equiv.) was added, and stirring was continued for another 30 min. The reaction mixture was slowly quenched with HO (5 mL) at 0°C. Saturated aqueous NH4Cl (8 mL) was added, and the mixture was diluted with DCM / MeOH 9:1. The layers were separated and the aqueous phase was back-extracted with DCM / MeOH 9:1. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 25 g, 0% to 100% in DCM [DCM / MeOH / NH4OH (95:5:1)]). The chromatographed product was dissolved in CH3CN / H2O 1:1 and lyophilized. The title compound (90 mg, 88.4% yield) was obtained as a white lyophilized solid. LC-MS: m / z=424.3 [M+H] + ,ESI pos.

[0125] Example 18 1-(6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)propan-1-ol; [ka] Starting from 6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(4-fluoro-2-methoxyphenyl)nicotinaldehyde (obtained in a manner similar to Step 1 of Example 17) (110 mg, 216 μmol, 1 equivalent) and EtMgBr (3.0 M solution in diethyl ether) (108 μL, 324 μmol, 1.5 equivalents), and following the procedure described in Step 2 of Example 17, the title compound (66 mg, 56.6% yield) was obtained as a white lyophilized solid. LC-MS: m / z=438.3 [M+H] + ,ESI pos.

[0126] Example 19 1-(2-(3-chlorophenyl)-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)pyridin-3-yl)ethan-1-ol [ka]

[0127] Step 1: 2-(3-chlorophenyl)-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)nicotinaldehyde [ka] Starting from (2-(3-chlorophenyl)-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)pyridin-3-yl)methanol (obtained similarly to Step 3 of Example 1) (218 mg, 551 μmol, 1 equivalent), the title compound (250 mg, quantitative yield) was obtained as a yellow amorphous solid according to the procedure described in Step 1 of Example 17. LC-MS: m / z=394.1 [M+H] + ,ESI pos.

[0128] Step 2: 1-(2-(3-chlorophenyl)-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)pyridin-3-yl)ethan-1-ol [ka] Following the procedure described in Step 2 of Example 17, the title compound (120 mg, 84.3% yield) was obtained as a white lyophilized solid. LC-MS: m / z=410.2 [M+H] + ,ESI pos.

[0129] Example 20 1-(2-(3-chloro-2-fluorophenyl)-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)pyridin-3-yl)ethan-1-ol [ka]

[0130] Step 1: Methyl 2-(3-chloro-2-fluorophenyl)-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)nicotinate [ka] Starting from methyl 2-chloro-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)nicotinate (obtained in a manner similar to Step 1 of Example 1) (400 mg, 1.15 mmol, 1 equivalent) and (3-chloro-2-fluorophenyl)boronic acid (301 mg, 1.73 mmol, 1.5 equivalents), and following the procedure described in Step 2 of Example 1, the title compound (317 mg, 57.4% yield) was obtained as a light brown solid. LC-MS: m / z=442.2 [M+H] + ,ESI pos.

[0131] Step 2: (2-(3-chloro-2-fluorophenyl)-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)pyridin-3-yl)methanol [ka] Following the procedure described in Step 3 of Example 1, the title compound (219 mg, 62.7% yield) was obtained as a light brown solid. LC-MS: m / z=414.2 [M+H] + ,ESI pos.

[0132] Step 3: 2-(3-chloro-2-fluorophenyl)-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)nicotinaldehyde [ka] Following the procedure described in Step 1 of Example 17, the title compound (137 mg, 49.1% yield) was obtained as a yellow solid. LC-MS: m / z=412.2 [M+H] + ,ESI pos.

[0133] Step 4: 1-(2-(3-chloro-2-fluorophenyl)-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)pyridin-3-yl)ethan-1-ol [ka] Following the procedure described in Step 2 of Example 17, the title compound (104 mg, 66.5% yield) was obtained as a white lyophilized solid. LC-MS: m / z=428.2 [M+H] + ,ESI pos.

[0134] Example 21 (S)-1-(6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)ethan-1-ol [ka] 1-(6-(5,6-Dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)ethan-1-ol (60 mg, 142 μmol) (obtained analogously to step 2 of Example 17) was purified by chiral SFC: column Chiral IA (250 mm × 20 mm × 5 μm). 30% (MeOH / EtOH / IprOH 1:1:1) in scCO2. The title compound (22.5 mg, 36% yield) was obtained as a white lyophilized solid. LC-MS: m / z=424.2 [M+H] + ,ESI pos.

[0135] Example 22 (R)-1-(6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)ethan-1-ol [ka] 1-(6-(5,6-Dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)ethan-1-ol (60 mg, 142 μmol) (obtained analogously to step 2 of Example 17) was purified by chiral SFC: column Chiral IA (250 mm × 20 mm × 5 μm). 30% (MeOH / EtOH / IprOH 1:1:1) in scCO2. The title compound (31.9 mg, 53.2% yield) was obtained as a white lyophilized solid. LC-MS: m / z=424.2 [M+H] + ,ESI pos.

[0136] Example 23 Cyclopropyl(6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)methanol [ka] Starting from 6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(4-fluoro-2-methoxyphenyl)nicotinaldehyde (obtained in a manner similar to Step 1 of Example 17) (164 mg, 322 μmol, 1 eq.) and cyclopropylmagnesium bromide (1 M solution in 2-MeTHF) (419 μL, 419 μmol, 1.3 eq.), and following the procedure described in Step 2 of Example 17, the title compound (64.6 mg, 43.7% yield) was obtained as a white lyophilized solid. LC-MS: m / z=450.3 [M+H] + ,ESI pos.

[0137] Example 24 1-(2-(3-chlorophenyl)-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)pyridin-3-yl)propan-1-ol [ka] Starting from 2-(3-chlorophenyl)-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)nicotinaldehyde (obtained similarly to Step 1 of Example 19) (125 mg, 286 μmol, 1 equivalent), and following the procedure described in Example 18, the title compound (80 mg, 66.1% yield) was obtained as a white lyophilized solid. LC-MS: m / z=424.2 [M+H] + ,ESI pos.

[0138] Example 25 (2-(3-chlorophenyl)-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)pyridin-3-yl)(cyclopropyl)methanol [ka] Starting from 2-(3-chlorophenyl)-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)nicotinaldehyde (obtained analogously to Step 1 of Example 19) (89 mg, 226 μmol, 1 equivalent), and following the procedure described in Example 23, the title compound (65 mg, 66% yield) was obtained as a white lyophilized solid. LC-MS: m / z=436.2 [M+H] + ,ESI pos.

[0139] Example 26 (6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-morpholinopyridin-3-yl)methanol [ka]

[0140] Step 1: Methyl 6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-morpholinonicotinate [ka] A mixture of methyl 2-chloro-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)nicotinate (174 mg, 0.5 mmol, 1 equiv.) (obtained similarly to Step 1 of Example 1) and morpholine (3.3 g, 3.3 mL, 37.9 mmol, 75.8 equiv.) in a sealed tube was heated to 100° C. and stirred for 1 h. The reaction mixture was then cooled to room temperature and purified by flash chromatography (silica gel, 20 g, 0-100% in DCM [DCM / MeOH (9:1)]). The title compound (128 mg, 61% yield) was obtained as a light brown solid. LC-MS: m / z=399.3 [M+H] + ,ESI pos.

[0141] Step 2: (6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-morpholinopyridin-3-yl)methanol [ka] LiAlH4 (11.4 mg, 300 μmol, 1 equiv.) was suspended in dry THF (0.3 mL). The suspension was cooled to 0 °C, and a solution of methyl 6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-morpholinonicotinate (120 mg, 0.3 mmol, 1 equiv.) in dry THF (1.6 mL) was added dropwise over 15 min while maintaining the temperature at 0 °C. Stirring at 0 °C was continued for 4 h. The cooling bath was removed, and the mixture was stirred at room temperature overnight. The mixture was cooled again to 0 °C, carefully treated with HO, and extracted with DCM. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 10 g, 20% to 100% in DCM [DCM / MeOH (9:1)]). The chromatographed product was triturated in Et2O (3 mL), collected by filtration, washed with Et2O, and dried. The title compound (51 mg, 45.9% yield) was obtained as a white solid. LC-MS: m / z=371.2 [M+H] + ,ESI pos.

[0142] Example 27 (6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(pyrrolidin-1-yl)pyridin-3-yl)methanol [ka]

[0143] Step 1: Methyl 6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(pyrrolidin-1-yl)nicotinate [ka] A mixture of methyl 2-chloro-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)nicotinate (174 mg, 0.5 mmol, 1 equiv.) (obtained analogously to Step 1 of Example 1), pyrrolidine (53 mg, 62 μL, 750 μmol, 1.5 equiv.), and KCO (131 mg, 950 μmol, 1.9 equiv.) in DMSO (1.7 mL) was heated to 95° C. and stirred at that temperature for 3 h. The mixture was cooled to room temperature and diluted with HO. A precipitate formed. The solid was collected by filtration and dissolved in DCM. The resulting solution was dried over MgSO, filtered, and concentrated to leave the title compound (150 mg, 76.1% yield) as a white solid. LC-MS: m / z=383.2 [M+H] + ,ESI pos.

[0144] Step 2: (6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(pyrrolidin-1-yl)pyridin-3-yl)methanol [ka] Following the procedure described in Step 2 of Example 26, the title compound (86 mg, 56.7% yield) was obtained as an off-white solid. LC-MS: m / z=355.2 [M+H] + ,ESI pos.

[0145] Example 28 (6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(piperidin-1-yl)pyridin-3-yl)methanol [ka]

[0146] Step 1: Methyl 6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(piperidin-1-yl)nicotinate [ka] Starting from 2-chloro-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)nicotinate (obtained similarly to Step 1 of Example 1) (164 mg, 322 μmol, 1 equivalent) and piperidine (63.9 mg, 74.1 μL, 750 μmol, 1.5 equivalents), and following the procedure described in Step 1 of Example 27, the title compound (150 mg, 71.3% yield) was obtained as a pale red solid. LC-MS: m / z=397.3 [M+H] + ,ESI pos.

[0147] Step 2: (6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(piperidin-1-yl)pyridin-3-yl)methanol [ka] Following the procedure described in Step 2 of Example 26, the title compound (93.9 mg, 61.7% yield) was obtained as an off-white solid. LC-MS: m / z=369.2 [M+H] + ,ESI pos.

[0148] Example 32 5-((6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-3-(hydroxymethyl)pyridin-2-yl)amino)pentan-1-ol [ka]

[0149] Step 1: Methyl 6-chloro-2-(2-oxopiperidin-1-yl)nicotinate [ka] To a suspension of a 60% dispersion of NaH in mineral oil (208 mg, 5.2 mmol, 1 equiv.) in dry DMF (31 mL) was added piperidin-2-one (515 mg, 5.2 mmol, 1 equiv.), and the reaction mixture was stirred at 23 °C for 30 min. The reaction mixture was cooled to 0 °C, and methyl 6-chloro-2-fluoronicotinate (986 mg, 5.2 mmol, 1 equiv.) was added. The cooling bath was removed, and the solution was allowed to warm to 23 °C. Stirring was continued for 1 h. The reaction mixture was added to ice-cold saturated aqueous NH4Cl (100 mL). Extraction with EtOAc was performed. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to leave a pale yellow liquid. The crude material was purified by flash chromatography (silica gel, 20 g, 0-80% heptane in EtOAc). The title compound (791 mg, 53.8% yield) was obtained as a pale yellow solid. LC-MS: m / z=269.1 [M+H] + ,ESI pos.

[0150] Step 2: Methyl 6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(2-oxopiperidin-1-yl)nicotinate [ka] A suspension of sodium hydride (60% dispersion in mineral oil) (20 mg, 0.5 mmol, 1.0 equiv.) in dry DMF (1.9 ml) was cooled to 0° C., 5,6-dimethoxy-1H-benzo[d]imidazole (89.1 mg, 0.5 mmol, 1.0 equiv.) was added, and the reaction mixture was stirred for 15 minutes. Methyl 6-chloro-2-(2-oxopiperidin-1-yl)nicotinate (134 mg, 0.5 mmol, 1.0 equiv.) was dissolved in dry DMF (600 μl) and the solution was added dropwise. Stirring was continued at 0° C. for 15 minutes, then allowed to warm to room temperature overnight. The reaction mixture was cooled, diluted with cold saturated aqueous NH4Cl, and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0-10% MeOH in DCM) to give the title compound (62.5 mg, 28.9% yield) as an off-white solid. LC-MS: m / z=411.2 [M+H] + ,ESI pos.

[0151] Step 3: 5-((6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-3-(hydroxymethyl)pyridin-2-yl)amino)pentan-1-ol [ka] To a stirred solution of methyl 6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(2-oxopiperidin-1-yl)nicotinate (62 mg, 0.15 mmol, 1 equiv.) in a mixture of dry THF (560 μL) and ethanol (560 μL) was added calcium chloride (58 mg, 525 μmol, 3.5 equiv.). The reaction mixture was cooled to 0° C. NaBH (25 mg, 675 μmol, 4.5 equiv.) was added in one portion, and the mixture was stirred for 10 min. The cooling bath was removed, and stirring at room temperature was continued for 2 h. The mixture was poured into ice-cold saturated aqueous NH Cl (50 mL), which was extracted with DCM. The organic layer was washed with brine, dried over MgSO, filtered, and concentrated to dryness. The crude product was purified by preparative HPLC. The title compound (19.5 mg, 30.6% yield) was obtained as an off-white solid. LC-MS: m / z=387.2 [M+H] + ,ESI pos.1H NMR(600 MHz,DMSO-d6):δ ppm 8.66(s,1 H),7.93(s,1 H),7.54(d,J=7.8 Hz,1 H),7.28(s,1 H),6.94(d,J=7.7 Hz,1 H),6.20(t,J=5.3 Hz,1 H),5.27(s,1 H),4.43(d,J=5.3 Hz,2 H),4.34(s,1 H),3.83(d,J=6.4 Hz,6 H),3.47-3.53(m,2 H),3.38(d,J=5.1 Hz,2 H),1.65(br t,J=7.3 Hz,2 H),1.42-1.48(m,2 H), 1.35-1.41(m,2 H).

[0152] Example 33 1-(6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-3-(hydroxymethyl)pyridin-2-yl)pyrrolidin-2-one [ka]

[0153] Step 1: Methyl 6-chloro-2-(2-oxopyrrolidin-1-yl)nicotinate [ka] Following the procedure described in Step 1 of Example 32, pyrrolidin-2-one (443 mg, 5.2 mmol, 1 eq.) gave the title compound (744 mg, 53.4% ​​yield) as an orange liquid. LC-MS: m / z=255.1 [M+H] + ,ESI pos.

[0154] Step 2: Methyl 6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(2-oxopyrrolidin-1-yl)nicotinate [ka] Following the procedure described in Step 2 of Example 32 (reaction time 21 hours at room temperature), the title compound (236 mg, 56.6% yield) was obtained as an off-white solid. LC-MS: m / z=397.2 [M+H] + ,ESI pos.

[0155] Step 3: 1-(6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-3-(hydroxymethyl)pyridin-2-yl)pyrrolidin-2-one [ka] Following the procedure described in Step 2 of Example 26, starting from methyl 6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(2-oxopyrrolidin-1-yl)nicotinate (119 mg, 0.3 mmol), the title compound (93.9 mg, 61.7% yield) was obtained as an off-white solid. LC-MS: m / z=369.2 [M+H] + ,ESI pos.

[0156] Example 34 4-((6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-3-(hydroxymethyl)pyridin-2-yl)amino)butan-1-ol [ka] The title compound (19.1 mg, 16.2% yield) was isolated as a by-product during the preparation of Example 33 and was obtained as an off-white solid. LC-MS: m / z=373.2 [M+H] + ,ESI pos.

[0157] Example 35 (S)-2-(6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-3-(1-hydroxyethyl)pyridin-2-yl)benzamide [ka]

[0158] Step 1: (2-chloro-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)pyridin-3-yl)methanol [ka] Starting from methyl 2-chloro-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)nicotinate (obtained similarly to Step 1 of Example 1) (1.18 g, 3.38 mmol), the title compound (702 mg, 61% yield) was obtained as a brown solid according to the procedure described in Step 3 of Example 1. LC-MS: m / z=320.1 [M+H] + ,ESI pos.

[0159] Step 2: 2-chloro-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)nicotinaldehyde [ka] Following the procedure described in Step 1 of Example 17, the title compound (752 mg, quantitative yield) was obtained as a light brown solid after a reaction time of 7 hours. LC-MS: m / z=318.1 [M+H]+ ,ESI pos.

[0160] Step 3: 1-(2-chloro-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)pyridin-3-yl)ethan-1-ol [ka] Following the procedure described in Step 2 of Example 17, using methylmagnesium bromide solution (1.4 M in THF / toluene (1:3)), the title compound (702 mg, 87.1% yield) was obtained as a yellow amorphous solid. LC-MS: m / z=334.1 [M+H] + ,ESI pos.

[0161] Step 4: 1-(5-(1-((tert-butyldimethylsilyl)oxy)ethyl)-6-chloropyridin-2-yl)-5,6-dimethoxy-1H-benzo[d]imidazole [ka] In a 150 mL round-bottom flask, 1-(2-chloro-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)pyridin-3-yl)ethan-1-ol (702 mg, 2.1 mmol, 1 equiv.) was suspended in anhydrous DCM (15 mL). After flushing the mixture with argon, imidazole (286 mg, 4.21 mmol, 2 equiv.) and tert-butylchlorodimethylsilane (485 mg, 3.15 mmol, 1.5 equiv.) were subsequently added. The reaction mixture turned into a yellow suspension, which was stirred at 20 °C for 3 h, after which only slight conversion of the starting material to the desired product was observed. DMF (6 mL) was added to the mixture, resulting in a solution. Stirring was continued at 20 °C overnight. The reaction mixture was quenched with HO and extracted with DCM. The layers were separated, and the aqueous phase was back-extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 100% EtOAc in heptane). The title compound (748 mg, 1.67 mmol, 79.4% yield) was obtained as a white solid. LC-MS: m / z=448.2 [M+H] + ,ESI pos.

[0162] Step 5: 2-(6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-3-(1-hydroxyethyl)pyridin-2-yl)benzamide [ka] Following the procedure described in Step 2 of Example 1, 1-(5-(1-((tert-butyldimethylsilyl)oxy)ethyl)-6-chloropyridin-2-yl)-5,6-dimethoxy-1H-benzo[d]imidazole (80 mg, 179 μmol, 1 equiv.) and (2-cyanophenyl)boronic acid (39.4 mg, 268 μmol, 1.5 equiv.) were reacted at 130° C. for 30 minutes to afford the title compound (20 mg, 24.9% yield) as an off-white solid. LC-MS: m / z=419.2 [M+H] + ,ESI pos.

[0163] Step 6: (S)-2-(6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-3-(1-hydroxyethyl)pyridin-2-yl)benzamide [ka] 2-(6-(5,6-Dimethoxy-1H-benzo[d]imidazol-1-yl)-3-(1-hydroxyethyl)pyridin-2-yl)benzamide (20 mg, 48 μmol) was purified by chiral SFC: column Chiral OD-H (250 mm × 20 mm × 5 μm). Flow rate: 90 mL / min. 30% MeOH in scCO2. The title compound (3.9 mg, 19.5% yield) was obtained as a white lyophilized solid. LC-MS: m / z = 419.2 [M+H] + ,ESI pos.

[0164] Example 36 (R)-2-(6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-3-(1-hydroxyethyl)pyridin-2-yl)benzamide [ka] 2-(6-(5,6-Dimethoxy-1H-benzo[d]imidazol-1-yl)-3-(1-hydroxyethyl)pyridin-2-yl)benzamide (obtained analogously to Step 5 of Example 35) (20 mg, 48 μmol) was purified by chiral SFC: column Chiral OD-H (250 mm×20 mm×5 μm). Flow rate: 90 mL / min. 30% MeOH in scCO2. The title compound (6.5 mg, 32.5% yield) was obtained as a white lyophilized solid. LC-MS: m / z=419.2 [M+H] + ,ESI pos.

[0165] Example 37 (S)-3-(6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-3-(1-hydroxyethyl)pyridin-2-yl)benzonitrile [ka]

[0166] Step 1: 3-(6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-3-(1-hydroxyethyl)pyridin-2-yl)benzonitrile [ka] Starting from 1-(5-(1-((tert-butyldimethylsilyl)oxy)ethyl)-6-chloropyridin-2-yl)-5,6-dimethoxy-1H-benzo[d]imidazole (obtained analogously to Step 4 of Example 35) (80 mg, 179 μmol, 1 equivalent) and (3-cyanophenyl)boronic acid (39 mg, 268 μmol, 1.5 equivalents), the title compound (60 mg, 83.9% yield) was obtained as a brown solid following the procedure described in Step 2 of Example 1 at 130° C. for 30 minutes. LC-MS: m / z=401.1 [M+H] + ,ESI pos.

[0167] Step 2: (S)-3-(6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-3-(1-hydroxyethyl)pyridin-2-yl)benzonitrile [ka] 3-(6-(5,6-Dimethoxy-1H-benzo[d]imidazol-1-yl)-3-(1-hydroxyethyl)pyridin-2-yl)benzonitrile (60 mg, 179 μmol) was purified by chiral SFC: column Chiral OD-H (250 mm × 20 mm × 5 μm). 30% MeOH in scCO2. The title compound (5.3 mg, 8.8% yield) was obtained as a white lyophilized solid. LC-MS: m / z = 401.2 [M+H] + ,ESI pos.

[0168] Example 38 (R)-3-(6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-3-(1-hydroxyethyl)pyridin-2-yl)benzonitrile [ka] 3-(6-(5,6-Dimethoxy-1H-benzo[d]imidazol-1-yl)-3-(1-hydroxyethyl)pyridin-2-yl)benzonitrile (obtained analogously to Step 1 of Example 37) (60 mg, 179 μmol) was purified by chiral SFC: column Chiral OD-H (250 mm×20 mm×5 μm). 30% MeOH in scCO2. The title compound (5.8 mg, 9.7% yield) was obtained as a white lyophilized solid. LC-MS: m / z=401.2 [M+H] + ,ESI pos.

[0169] Example 39 (S)-4-(6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-3-(1-hydroxyethyl)pyridin-2-yl)benzonitrile [ka]

[0170] Step 1: 4-(6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-3-(1-hydroxyethyl)pyridin-2-yl)benzonitrile [ka] Starting from 1-(5-(1-((tert-butyldimethylsilyl)oxy)ethyl)-6-chloropyridin-2-yl)-5,6-dimethoxy-1H-benzo[d]imidazole (obtained analogously to Step 4 of Example 35) (80 mg, 179 μmol, 1 eq.) and (4-cyanophenyl)boronic acid (39 mg, 268 μmol, 1.5 eq.), the title compound (26 mg, 36.4% yield) was obtained as an off-white solid following the procedure described in Step 2 of Example 1 at 130° C. for 30 minutes. LC-MS: m / z=401.2 [M+H] + ,ESI pos.

[0171] Step 2: (S)-4-(6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-3-(1-hydroxyethyl)pyridin-2-yl)benzonitrile [ka] 4-(6-(5,6-Dimethoxy-1H-benzo[d]imidazol-1-yl)-3-(1-hydroxyethyl)pyridin-2-yl)benzonitrile (26 mg, 65 μmol) was purified by chiral SFC: column Chiral OD-H (250 mm × 20 mm × 5 μm). 30% MeOH in scCO2. The title compound (7.1 mg, 27.3% yield) was obtained as a white lyophilized solid. LC-MS: m / z = 401.2 [M+H] + ,ESI pos.

[0172] Example 40 (R)-4-(6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-3-(1-hydroxyethyl)pyridin-2-yl)benzonitrile [ka] 4-(6-(5,6-Dimethoxy-1H-benzo[d]imidazol-1-yl)-3-(1-hydroxyethyl)pyridin-2-yl)benzonitrile (obtained analogously to Step 1 of Example 39) (26 mg, 65 μmol) was purified by chiral SFC: column Chiral OD-H (250 mm × 20 mm × 5 μm). 30% MeOH in scCO2. The title compound (8.5 mg, 32.7% yield) was obtained as a white lyophilized solid. LC-MS: m / z = 401.2 [M+H] + ,ESI pos.

[0173] Example 41 (S)-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-3-(1-hydroxyethyl)-1'-methyl-[2,4'-bipyridin]-2'(1'H)-one [ka]

[0174] Step 1: 6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-3-(1-hydroxyethyl)-1'-methyl-[2,4'-bipyridin]-2'(1'H)-one [ka] Starting from 1-(5-(1-((tert-butyldimethylsilyl)oxy)ethyl)-6-chloropyridin-2-yl)-5,6-dimethoxy-1H-benzo[d]imidazole (obtained analogously to Step 4 of Example 35) (80 mg, 179 μmol, 1 equivalent) and (1-methyl-2-oxo-1,2-dihydropyridin-4-yl)boronic acid (41 mg, 268 μmol, 1.5 equivalents), the title compound (35 mg, 45.8% yield) was obtained as a white lyophilized solid following the procedure described in Step 2 of Example 1 at 130° C. for 30 minutes. LC-MS: m / z=407.2 [M+H] + ,ESI pos.

[0175] Step 2: (S)-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-3-(1-hydroxyethyl)-1'-methyl-[2,4'-bipyridin]-2'(1'H)-one [ka] 6-(5,6-Dimethoxy-1H-benzo[d]imidazol-1-yl)-3-(1-hydroxyethyl)-1'-methyl-[2,4'-bipyridin]-2'(1'H)-one (35 mg, 86 μmol) was purified by chiral SFC: column Chiral OD-H (250 mm × 20 mm × 5 μm). 30% MeOH in scCO2. The title compound (3.8 mg, 10.9% yield) was obtained as a white lyophilized solid. LC-MS: m / z = 407.2 [M+H] + ,ESI pos.

[0176] Example 42 (R)-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-3-(1-hydroxyethyl)-1'-methyl-[2,4'-bipyridin]-2'(1'H)-one; [ka] 6-(5,6-Dimethoxy-1H-benzo[d]imidazol-1-yl)-3-(1-hydroxyethyl)-1'-methyl-[2,4'-bipyridin]-2'(1'H)-one (obtained in a manner similar to Step 1 of Example 41) (35 mg, 86 μmol) was purified by chiral SFC: column Chiral OD-H (250 mm × 20 mm × 5 μm). 30% MeOH in scCO2. The title compound (11.3 mg, 32.3% yield) was obtained as a white lyophilized solid. LC-MS: m / z = 407.2 [M+H] + ,ESI pos.

[0177] Example 53 1-[6-[5-(2-morpholinoethoxy)benzimidazol-1-yl]-2-phenoxy-3-pyridyl]ethanol [ka]

[0178] Intermediate 1: 1-(6-chloro-2-phenoxy-3-pyridyl)ethanone [ka] To a solution of 1-(6-chloro-2-fluoro-3-pyridyl)ethanone (CAS no. 1260663-13-5, 500 mg, 2.88 mmol, 1 equiv.) in CH3CN (8 mL) was added phenol (0.2 mL, 2.88 mmol, 1 equiv.) and K2CO3 (796 mg, 5.76 mmol, 2 equiv.). The reaction mixture was stirred at 30 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was taken up in EtOAc and H2O. The aqueous phase was back-extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0% to 30% EtOAc in petroleum ether). The title compound (1.17 g, quantitative yield) was obtained as a colorless oil. LC-MS: m / z = 248.0 [M+H] + ,ESI pos.

[0179] Intermediate 2, Step 1: 4-[2-(4-nitrophenoxy)ethyl]morpholine [ka] To a stirred solution of 4-nitrophenol (5.0 g, 35.94 mmol, 1 equiv.), 2-morpholinoethanol (5.89 g, 35.94 mmol, 1 equiv.), and triphenylphosphine (10.37 g, 39.54 mmol, 1.1 equiv.) in THF (80 mL) was added dropwise a solution of DEAD (6.89 g, 39.54 mmol, 1.1 equiv.) in THF (20 mL) at 0 °C under a nitrogen atmosphere. The mixture was then stirred at 30 °C for 16 h. The reaction mixture was poured into HO (200 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 10% MeOH in EtOAc). The title compound (3.6 g, 39.7% yield) was obtained as an off-white solid. LC-MS: m / z=253.0 [M+H] + ,ESI pos. 1 H NMR(400 MHz,CD3OD):δ=8.25-8.18(m,2H),7.14-7.08(m,2H),4.27(t,J=5.4 Hz,2H),3.75-3.68(m,4H),2.85(t,J=5.5 Hz,2H),2.64-2.56(m,4H).

[0180] Intermediate 2, Step 2: 4-(2-morpholin-4-ylethoxy)aniline [ka] To a solution of 4-[2-(4-nitrophenoxy)ethyl]morpholine (3.5 g, 13.87 mmol, 1 equiv.) in MeOH (40 mL) was added 10% Pd / C (0.67 g, 0.630 mmol, 0.050 equiv.). The mixture was stirred under H2 (15 psi) at 25 °C for 16 h. The mixture was filtered, and the filtrate was concentrated in vacuo to give the crude title compound (2.7 g, 87.5% yield) as a pale yellow solid. LC-MS: m / z = 223.1 [M+H] + ,ESI pos.

[0181] Intermediate 2, Step 3: N-[4-(2-morpholinoethoxy)phenyl]acetamide [ka] To a stirred solution of 4-(2-morpholin-4-ylethoxy)aniline (2.7 g, 12.15 mmol, 1 equiv.) and triethylamine (5.1 mL, 36.44 mmol, 3 equiv.) in DCM (30 mL) was added acetic anhydride (1.49 g, 14.58 mmol, 1.2 equiv.) at 0 °C. The mixture was then stirred at 25 °C under a nitrogen atmosphere for 16 h. The mixture was then poured into HO (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 50% to 100% EtOAc in petroleum ether). The title compound (2.2 g, 74% yield) was obtained as a white solid. LC-MS: m / z = 265.1 [M+H] + ,ESI pos. 1 H NMR (400 MHz, CDCl3): δ=7.41-7.36(m,2H),7.17(br s,1H),6.90-6.83(m,2H),4.10(t,J=5.7 Hz,2H),3.77-3.73(m,4H),2.81(t,J=5.7 Hz,2H),2.62-2.57(m,4H),2.16(s,3H).

[0182] Intermediate 2, Step 4: N-[4-(2-morpholinoethoxy)-2-nitro-phenyl]acetamide [ka] To a stirred solution of N-[4-(2-morpholinoethoxy)phenyl]acetamide (1.8 g, 6.81 mmol, 1 equiv.) in acetic anhydride (20 mL, 180.35 mmol, 26.48 equiv.) at 0 °C, nitric acid (2.6 mL, 37.88 mmol, 5.56 equiv.) was added dropwise. The cooling bath was removed, and the mixture was stirred at 20 °C for an additional 1 h. The mixture was quenched by careful addition of ice-cold HO (150 mL). The mixture was then basified by adding 1 N NaOH until a pH of 9 was reached. This was extracted with EtOAc (4 × 50 mL). The combined organic extracts were dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the crude title compound (1.8 g, 85.4% yield) as a red oil. LC-MS: m / z = 310.1 [M+H] + ,ESI pos.

[0183] Intermediate 2, Step 5: 4-(2-morpholinoethoxy)-2-nitro-aniline [ka] To a stirred solution of N-[4-(2-morpholinoethoxy)-2-nitro-phenyl]acetamide (1.8 g, 3.23 mmol, 1 equiv.) in a mixture of EtOH (15 mL) and HO (5 mL) was added potassium hydroxide (1.63 g, 29.1 mmol, 5 equiv.). The mixture was stirred at 80 °C for 4 h. The reaction mixture was cooled to room temperature and poured into HO (100 mL). It was extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the crude title compound (1.2 g, 77.1% yield) as a red oil. LC-MS: m / z = 268.2 [M+H] + ,ESI pos. 1 H NMR (400 MHz, CDCl3): δ=7.58(d,J=2.9 Hz,1H),7.12-7.07(m,1H),6.76(d,J=9.0 Hz,1H),4.09(t,J=5.6 Hz,2H),3.77-3.74(m,4H),2.80(t,J=5.6 Hz,2H),2.61-2.57(m,4H).

[0184] Step 1: 1-[6-[4-(2-morpholinoethoxy)-2-nitro-anilino]-2-phenoxy-3-pyridyl]ethanone [ka] To a stirred solution of 4-(2-morpholinoethoxy)-2-nitroaniline (Intermediate 2 of Example 53) (150 mg, 0.56 mmol, 1 equiv.) in 1,4-dioxane (3 mL) was added 1-(6-chloro-2-phenoxy-3-pyridyl)ethanone (Intermediate 1 of Example 53) (139 mg, 0.56 mmol, 1 equiv.), KCO (233 mg, 1.68 mmol, 3 equiv.), Xantphos (130 mg, 0.22 mmol, 0.4 equiv.), and Pd(dba) (103 mg, 0.110 mmol, 0.200 equiv.). The reaction mixture was stirred at 100 °C for 12 h. The reaction mixture was cooled to room temperature, poured into HO (30 mL), and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, 0% to 100% EtOAc in petroleum ether). The title compound (230 mg, 75.4% yield) was obtained as an orange solid. LC-MS: m / z = 479.2 [M+H] + ,ESI pos.

[0185] Step 2: 1-[6-[2-amino-4-(2-morpholinoethoxy)anilino]-2-phenoxy-3-pyridyl]ethanone [ka] Following the procedure described in Step 2, Intermediate 2 of Example 53, the title compound (160 mg, 94.8% yield) was obtained as a light brown solid. LC-MS: m / z=449.2 [M+H] + ,ESI pos.

[0186] Step 3: 1-[6-[5-(2-morpholinoethoxy)benzimidazol-1-yl]-2-phenoxy-3-pyridyl]ethanone [ka] A solution of 1-[6-[2-amino-4-(2-morpholinoethoxy)anilino]-2-phenoxy-3-pyridyl]ethanone (140 mg, 0.31 mmol, 1 equiv.) in trimethyl orthoformate (10 mL, 6.24 mmol, 20 equiv.) was stirred at 125° C. for 24 h. The reaction mixture was then stirred at 130° C. for an additional 24 h. The reaction mixture was cooled and concentrated to dryness. The residue was suspended in MeOH (10 mL). The solid was collected by filtration, washed with MeOH, and dried. The title compound (70 mg, 48.9% yield) was obtained as an off-white solid. LC-MS: m / z=479.2 [M+H] + ,ESI pos.

[0187] Step 4: 1-[6-[5-(2-morpholinoethoxy)benzimidazol-1-yl]-2-phenoxy-3-pyridyl]ethanol [ka] To a stirred solution of 1-[6-[5-(2-morpholinoethoxy)benzimidazol-1-yl]-2-phenoxy-3-pyridyl]ethanone (70 mg, 0.15 mmol, 1 equiv.) in MeOH (2 mL) was added NaBH (17 mg, 0.46 mmol, 3 equiv.) at 0 °C. The cooling bath was removed, and the mixture was stirred at 30 °C for 2 h. The reaction mixture was quenched by the addition of saturated aqueous NH Cl. It was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na SO, filtered, and concentrated. The crude material was purified by preparative HPLC. Column: Phenomenex Gemini-NX C18 (75 mm × 30 mm × 3 μm). Flow rate: 30 mL / min. Gradient: 24% to 54% CHCN in (10 mM NHHCO in H0) (8 min), then 100% CHCN (2 min). The title compound (47.6 mg, 67% yield) was obtained as a white solid. LC-MS: m / z = 461.2 [M+H] + ,ESI pos. 1 H NMR(400 MHz,CD3OD):δ=8.68(s,1H),8.12(d,J=8.1 Hz,1H),7.54-7.48(m,3H),7.39-7.31(m,2H),7.22(br d,J=7.6 Hz,2H),7.14(s,1H),6.64(br d,J=9.4 Hz,1H),5.34-5.25(m,1H),4.18-4.11(m,2H),3.75-3.68(m,4H),2.81(br t,J=5.1 Hz,2H),2.60(br s,4H),1.58(d,J=6.4 Hz,3H).

[0188] Example 55 1-[2-anilino-6-[5-(2-morpholinoethoxy)benzimidazol-1-yl]-3-pyridyl]ethanol [ka]

[0189] Step 1: 1-(2-anilino-6-chloro-3-pyridyl)ethanone [ka] To a stirred solution of 1-(6-chloro-2-fluoro-3-pyridyl)ethanone (CAS no. 1260663-13-5, 500 mg, 2.88 mmol, 1 equiv.) in CH3CN (8 mL) was added aniline (0.26 mL, 2.88 mmol, 1 equiv.) and DIPEA (796 mg, 5.76 mmol, 2 equiv.). The reaction mixture was then stirred at 80 °C for 20 h. The reaction mixture was cooled to room temperature and concentrated in vacuo, and the residue was purified by flash chromatography (silica gel, 0% to 100% EtOAc in petroleum ether). The title compound (400 mg, 56.3% yield) was obtained as a yellow solid. LC-MS: m / z = 247.0 [M+H] + ,ESI pos.

[0190] Step 2: 1-[2-anilino-6-[4-(2-morpholinoethoxy)-2-nitro-anilino]-3-pyridyl]ethanone [ka] Following the procedure described in Step 2 of Example 53, the title compound (200 mg, 51.7% yield) was obtained as a red solid. LC-MS: m / z=478.3 [M+H] + ,ESI pos.

[0191] Step 3: 1-[6-[2-amino-4-(2-morpholinoethoxy)anilino]-2-anilino-3-pyridyl]ethanone [ka] Following the procedure described in Step 2, Intermediate 2 of Example 53, the title compound (160 mg, 85.3% yield) was obtained as a yellow oil. LC-MS: m / z=448.4 [M+H] + ,ESI pos.

[0192] Step 4: 1-[2-anilino-6-[5-(2-morpholinoethoxy)benzimidazol-1-yl]-3-pyridyl]ethanone [ka] Following the procedure described in Step 3 of Example 53, the title compound (90 mg, 80% yield) was obtained as a yellow oil. LC-MS: m / z=458.2 [M+H] + ,ESI pos.

[0193] Step 5: 1-[2-anilino-6-[5-(2-morpholinoethoxy)benzimidazol-1-yl]-3-pyridyl]ethanol [ka] Following the procedure described in Step 4 of Example 53, the title compound (34.1 mg, 42.4% yield) was obtained as a pink lyophilized solid after purification by preparative HPLC: Column Waters Xbridge (150 mm × 25 mm × 5 μm). Flow rate 25 mL / min. Gradient: 29% to 59% CHCN in (10 mM NHHCO in HO) (9 min), then 100% CHCN (0.5 min). 1 H NMR (400 MHz, CD3OD): δ=8.69(s,1H),7.95(d,1H,J=9.0 Hz),7.70(d,1H,J=7.8 Hz),7.58(d,2H,J=7.7 Hz),7.32(t,2H,J=7.9 Hz),7.24(d,1H,J=2.1 Hz),7.11(d,1H,J=7.8 Hz),7.0-7.1(m,1H),6.92(dd,1H,J=2.1,9.1 Hz),5.05(q,1H,J=6.4 Hz),4.21(t,2H,J=5.4 Hz),3.7-3.8(m,4H),2.85(t,2H,J=5.4 Hz),2.6-2.7(m,4H),1.60(d,3H,J=6.5 Hz).LC-MS:m / z=460.4 [M+H] + ,ESI pos.

[0194] Example 62 1-[6-[5-(2-morpholinoethoxy)benzimidazol-1-yl]-2-[3-(trifluoromethyl)pyrazol-1-yl]-3-pyridyl]ethanol [ka]

[0195] Step 1: 1-[6-chloro-2-[3-(trifluoromethyl)pyrazol-1-yl]-3-pyridyl]ethanone [ka] Following the procedure described in Step 1 of Example 64, using 3-(trifluoromethyl)pyrazole (400 mg, 2.94 mmol, 1.02 equiv.), the title compound (650 mg, 74% yield) was obtained as a pale yellow solid. LC-MS: m / z=290.1 ​​[M+H] + ,ESI pos. 1 H NMR (400 MHz, CDCl3): δ=8.55-8.49(m,1H),7.80-7.73(m,1H),7.42-7.36(m,1H),6.79-6.73(m,1H),2.41-2.35(m,3H).

[0196] Step 2: 1-[6-[4-(2-morpholinoethoxy)-2-nitro-anilino]-2-[3-(trifluoromethyl)pyrazol-1-yl]-3-pyridyl]ethanone [ka] Following the procedure described in Step 1 of Example 53 (reaction time 16 h, temperature 90° C.), the title compound (210 mg, 31.3% yield) was obtained as a red gum. LC-MS: m / z=521.2 [M+H] + ,ESI pos. Purification by preparative HPLC: Column Phenomenex Gemini-NX C18 (75 mm x 30 mm x 3 μm). Flow rate 25 mL / min. Gradient: 36% to 66% CH3CN in (10 mM NH4HCO3 in H2O) (10 min), then 100% CH3CN (0.5 min).

[0197] Step 3: 1-[6-[2-amino-4-(2-morpholinoethoxy)anilino]-2-[3-(trifluoromethyl)pyrazol-1-yl]-3-pyridyl]ethanone [ka] To a mixture of 1-[6-[4-(2-morpholinoethoxy)-2-nitroanilino]-2-[3-(trifluoromethyl)pyrazol-1-yl]-3-pyridyl]ethanone (200 mg, 0.38 mmol, 1 equiv.) and NH4Cl (205 mg, 3.83 mmol, 9.97 equiv.) in EtOH (10 mL) and HO (3 mL) was added Fe (108 mg, 1.93 mmol, 5.03 equiv.) in three portions at 20 °C. Upon completion of the Fe addition, the resulting mixture was stirred at 50 °C for 16 h. The black mixture was cooled to room temperature and filtered. The filtrate was concentrated, and the residue was dissolved in 10 mL of CH3CN. The resulting suspension was filtered. The filtrate was concentrated to give the title compound (180 mg, 95.5% yield) as a yellow solid. LC-MS: m / z=491.2 [M+H] + ,ESI pos. 1 H NMR(400 MHz, CDCl3):δ=8.31-8.26(m,1H),7.76-7.70(m,1H),7.10-7.04(m,1H),6.78-6.72(m,1H),6.43-6.41 (m,1H),6.36-6.29(m,3H),4.59-4.45(m,2H),4.22-4.02(m,4H),3.49-2.92(m,6H),2.16-2.10(m,3H).

[0198] Step 4: 1-[6-[5-(2-morpholinoethoxy)benzimidazol-1-yl]-2-[3-(trifluoromethyl)pyrazol-1-yl]-3-pyridyl]ethanone [ka] To a solution of 1-[6-[2-amino-4-(2-morpholinoethoxy)anilino]-2-[3-(trifluoromethyl)pyrazol-1-yl]-3-pyridyl]ethanone (180 mg, 0.37 mmol, 1 equiv.) in EtOH (5 mL) was added trimethoxymethane (389 mg, 3.67 mmol, 10 equiv.) and p-toluenesulfonic acid (6 mg, 0.040 mmol, 0.1 equiv.). The reaction mixture was stirred at 80 °C for 1 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was taken up in DCM (20 mL) and washed with saturated aqueous NaHCO3 (20 mL). The organic layer was concentrated to dryness to give the crude title compound (120 mg, 65.3% yield) as a pale yellow solid. LC-MS: m / z = 501.2 [M+H] + ,ESI pos. 1 H NMR(400 MHz, CDCl3):δ=8.53-8.50(m,1H),8.50-8.47(m,1H),8.01-7.98(m,1H),7.95-7.91(m,1H),7.56-7.50(m,1H),7.32-7.28 (m,1H),7.05-7.01(m,1H),6.79-6.76(m,1H),4.70-4.30(m,2H),4.04-3.73(m,4H),3.37-2.77(m,6H),2.36-2.31(m,3H).

[0199] Step 5: 1-[6-[5-(2-morpholinoethoxy)benzimidazol-1-yl]-2-[3-(trifluoromethyl)pyrazol-1-yl]-3-pyridyl]ethanol [ka] 1-[6-[5-(2-morpholinoethoxy)benzimidazol-1-yl]-2-[3-(trifluoromethyl)pyrazol-1-yl]-3-pyridyl]ethanone (50 mg, 0.1 mmol, 1 equiv.) was dissolved in DCM (1 mL) with stirring at 20 °C. MeOH (0.5 mL) was added. The mixture was cooled to 0 °C. NaBH (15 mg, 0.4 mmol, 4 equiv.) was added in portions. The resulting mixture was stirred at 5 °C for 1 h. The mixture was quenched by adding 5 drops of saturated aqueous NH Cl solution, followed by the addition of formic acid until a pH of 7 was reached. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC: column Phenomenex Gemini-NX C18 (75 mm × 30 mm × 3 μm). Flow rate 30 mL / min. Gradient: 28% to 58% CH3CN in (10 mM NH4HCO3 in H2O) (8 min), then 100% CH3CN (2 min). The title compound (9.5 mg, 17.8% yield) was obtained as a colorless gum. LC-MS: m / z = 503.2 [M+H] + ,ESI pos. 1 H NMR(400 MHz,CD3OD):δ=8.96-8.85(m,1H),8.63-8.59(m,1H),8.53-8.49(m,1H),8.14-8.10(m,1H),7.99-7.95(m,1H),7.30-7.27(m,1H),7.12-7.07 (m,1H),6.96-6.92(m,1H),5.56-5.48(m,1H),4.25-4.19(m,2H),3.78 -3.70(m,4H),2.90-2.83(m,2H),2.70-2.58(m,4H),1.54-1.45(m,3H).

[0200] Example 63 1-[6-(5,6-dimethoxybenzimidazol-1-yl)-2-[3-(trifluoromethyl)pyrazol-1-yl]-3-pyridyl]ethanol [ka]

[0201] Step 1: 1-[6-(5,6-dimethoxybenzimidazol-1-yl)-2-[3-(trifluoromethyl)pyrazol-1-yl]-3-pyridyl]ethanone [ka] To a solution of 1-[6-chloro-2-[3-(trifluoromethyl)pyrazol-1-yl]-3-pyridyl]ethanone (obtained in a manner similar to Step 1 of Example 62) (100 mg, 0.35 mmol, 1 equiv.) and 5,6-dimethoxy-1H-benzimidazole (62 mg, 0.35 mmol, 1 equiv.) in CH3CN (5 mL) was added Cs2CO3 (225 mg, 0.69 mmol, 2 equiv.) and CsF (10 mg, 0.07 mmol, 0.19 equiv.). The mixture was degassed and purged with N2 (3 times). The mixture was then stirred at 70 °C under a N2 atmosphere for 16 h. The mixture was then cooled to 20 °C and filtered. The filtrate was directly purified by preparative HPLC: column Phenomenex Gemini-NX C18 (75 mm × 30 mm × 3 μm). Flow rate 30 mL / min. Gradient: 28% to 58% CH3CN in (10 mM NH4HCO3 in H2O) (8 min), then 100% CH3CN (2 min). The title compound (25 mg, 12.6% yield) was obtained as a pale yellow solid. LC-MS: m / z = 431.1 [M+H] + ,ESI pos.

[0202] Step 2: 1-[6-(5,6-dimethoxybenzimidazol-1-yl)-2-[3-(trifluoromethyl)pyrazol-1-yl]-3-pyridyl]ethanol [ka] Following the procedure described in Step 5 of Example 62, the title compound (8.5 mg, 39.7% yield) was obtained as a pale yellow solid. Purification by preparative HPLC: Column Phenomenex Gemini-NX C18 (75 mm x 30 mm x 3 μm). Flow rate 30 mL / min. Gradient: 28% to 58% CH3CN in (10 mM NH4HCO3 in H2O) (8 min), then 100% CH3CN (2 min). LC-MS: m / z = 434.1 [M+H] + ,ESI pos. 1 H NMR(400 MHz,CD3OD):δ=8.82-8.77(m,1H),8.67-8.61(m,1H),8.54-8.47(m,1H),8.04-7.97(m,1H),7.93-7.89 (m,1H),7.30-7.26(m,1H),6.99-6.93(m,1H),5.55-5.45(m,1H),3.95-3.87(m,6H),1.54-1.47(m,3H).

[0203] Example 64 1-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka]

[0204] Intermediate 1: N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine [ka] iA mixture of 5-aminobenzimidazole (8.0 g, 60.1 mmol, 1.0 equiv) and 3-chloro-6-methylpyridazine (7.34 g, 57.08 mmol, 0.950 equiv) in PrOH (120 mL) was stirred at 120° C. for 72 h. The dark brown suspension was concentrated in vacuo and the residue was triturated in MeOH (60 mL). The solid was collected by filtration and triturated in DCM (40 mL). The product was collected by filtration, washed with DCM, and dried. The title compound (10 g, 71.3% yield) was obtained as a brown solid. LC-MS: m / z=226.0 [M+H] + ,ESI pos. 1 H NMR(400 MHz,DMSO-d6):δ=9.60(br s,1H),8.72(s,1H),8.52(d,J=1.7 Hz,1H),7.63(d,J=8.8 Hz,1H),7.44(dd,J=2.0,8.8 Hz,1H),7.39(d,J=9.2 Hz,1H),7.21(d,J=9.2 Hz,1H),5.04-4.15(m,1H),2.49(s,3H).

[0205] Step 1: 1-(3-acetyl-6-chloro-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile [ka] A solution of 1-(6-chloro-2-fluoro-3-pyridyl)ethanone (CAS number 1260663-13-5, 5 g, 28.81 mmol, 1 equiv.), 5-methyl-1H-pyrazole-3-carbonitrile (2.93 g, 27.37 mmol, 0.950 equiv.), and DIPEA (14.3 mL, 86.42 mmol, 3 equiv.) in DMSO (50 mL) was stirred at 80 °C for 4 h. The reaction mixture was cooled to room temperature, poured into HO (250 mL), and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (3 × 300 mL) and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0% to 35% EtOAc in petroleum ether). The title compound (5.3 g, 70.6% yield) was obtained as a yellow oil. LC-MS: m / z=261.1 [M+H]+ ,ESI pos.

[0206] Step 2: 1-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile and 1-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] A mixture of 1-(3-acetyl-6-chloro-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile (5.3 g, 20.33 mmol, 1 equiv.), N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine (Intermediate 1) (4.58 g, 20.33 mmol, 1 equiv.), and K2CO3 (5.62 g, 40.66 mmol, 2 equiv.) in DMSO (50 mL) was stirred at 50 °C for 12 h. The mixture was cooled to room temperature and poured into H2O (500 mL). A solid precipitated. It was extracted with EtOAc (3 × 400 mL). The combined organic layers were concentrated. The residue was purified by preparative HPLC: column Phenomenex Luna C18 (250 mm × 70 mm × 15 μm). Flow rate 140 mL / min. Gradient: 20% to 50% CH3CN in (0.225% formic acid v / v H2O) (35 min), then 100% CH3CN (1 min). A mixture of the two title compounds was obtained. This mixture was separated by preparative NPLC: column Welch Ultimate XB-SiOH (250 mm x 70 mm x 10 μm). Flow rate: 140 mL / min. Purification by gradient: 20% to 60% EtOH in hexanes (20 min), then 100% EtOH (3 min) afforded 1-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (1.1 g, 12% yield) as a light brown solid and 1-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (600 mg, 6.6% yield) as a light brown solid. Regioisomer 1: LC-MS: m / z = 450.1 [M+H] + ,ESI pos. 1H NMR(400 MHz,DMSO-d6)δ=9.31(s,1H),9.01(s,1H),8.98(d,J=2.0 Hz,1H),8.55(d,J=8.4 Hz,1H),8.27(d,J=8.4 Hz,1H),7.70(d,J=8.7 Hz,1H),7.46(dd,J=2.0,8.7 Hz,1H),7.30(d,J=9.0 Hz,1H),7.09-7.04(m,2H),2.55(s,3H),2.50(br s,3H),2.19(s,3H).Positional isomer 2:LC-MS:m / z=450.1 [M+H] + ,ESI pos. 1 H NMR(400 MHz,DMSO-d6)δ=9.30(s,1H),9.11(s,1H),8.54(d,J=8.4 Hz,1H),8.47(d,J=1.7 Hz,1H),8.30(d,J=8.6 Hz,1H),8.14(d,J=8.9 Hz,1H),7.53(dd,J=1.9,8.9 Hz,1H),7.34(d,J=9.0 Hz,1H),7.14(s,1H),7.10(d,J=9.0 Hz,1H),2.54(s,3H),2.48(br s,3H),2.20(s,3H).

[0207] Step 3: 1-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] To a solution of 1-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (600 mg, 1.33 mmol, 1 equiv.) in a mixture of MeOH (10 mL) and THF (10 mL) was added NaBH (151 mg, 3.99 mmol, 2.99 equiv.) at 0 °C. Stirring at 0 °C was continued for 1 h. DMF (5 mL) was added to the mixture, which was stirred at 20 °C for 2 h. The mixture was again cooled to 0 °C, and NaBH (76 mg, 2 mmol, 1.5 equiv.) was added. The cooling bath was removed, and stirring at room temperature was continued for 2 h. The reaction mixture was quenched by the slow addition of HO (50 mL) and then extracted with DCM (2 × 50 mL). The combined organic extracts were concentrated under vacuum. The residue was purified by preparative HPLC: column Waters Xbridge (150 mm x 25 mm x 5 μm). Flow rate 60 mL / min. Gradient: 19% to 49% CH3CN in (10 mM NH4HCO3 in H2O) (11 min) then 100% CH3CN (2 min). The title compound (400 mg, 65% yield) was obtained as a white lyophilized solid. LC-MS: m / z = 452.2 [M+H] + ,ESI pos.

[0208] Example 65 1-[3-(1-hydroxyethyl)-6-[5-(4-methylpiperazin-1-yl)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka]

[0209] Step 1: 1-[3-acetyl-6-(5-bromobenzimidazol-1-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile and 1-[3-acetyl-6-(6-bromobenzimidazol-1-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] To a solution of 5-bromo-1H-benzimidazole (1.51 g, 7.67 mmol, 1 equiv.) in DMSO (15 mL) was added 1-(3-acetyl-6-chloro-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile (obtained similarly as in Step 1 of Example 64) (2.0 g, 7.67 mmol, 1 equiv.) and K2CO3 (1.51 g, 15.34 mmol, 2 equiv.). The mixture was stirred at 60 °C for 2 h. The reaction mixture was cooled to room temperature, poured into HO (100 mL), and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL) and concentrated in vacuo. The residue was purified by flash chromatography (20% to 100% EtOAc in petroleum ether) to give a mixture of both title compounds. This mixture was purified by preparative HPLC: Column Phenomenex Luna C18 (150 mm × 40 mm × 15 μm). Flow rate: 60 mL / min. Gradient: 53% to 63% CH3CN in (HO containing 0.225% formic acid v / v) (10 min), then 100% CH3CN (2 min) to give 1-[3-acetyl-6-(5-bromobenzimidazol-1-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (750 mg, 23.2% yield) as a pale yellow lyophilized solid and the compound 1-[3-acetyl-6-(6-bromobenzimidazol-1-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (400 mg, 12.4% yield) as a pale yellow lyophilized solid. Positional isomer 1: LC-MS: m / z=421.0 [M+H] + ,ESI pos. 1 H NMR(400 MHz,CDCl3)δ=8.60(s,1H),8.32(d,J=8.3 Hz,1H),8.25(s,1H),7.81-7.73(m,2H),7.56(dd,J=1.6,8.4 Hz,1H),6.74(s,1H),2.67(s,3H),2.25(s,3H).Positional isomer 2:LC-MS:m / z=421.0 [M+H] + ,ESI pos. 1H NMR(400 MHz,CDCl3)δ=8.67-8.52(m,1H),8.22(d,J=8.3 Hz,1H),8.00(br s,1H),7.90(br d,J=5.0 Hz,1H),7.66(d,J=8.3 Hz,1H),7.46(d,J=8.8 Hz,1H),6.64(s,1H),2.53(s,3H),2.15(s,3H).

[0210] Step 2: 1-[3-acetyl-6-[5-(4-methylpiperazin-1-yl)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] To a solution of 1-methylpiperazine (71 mg, 0.710 mmol, 2 equiv.) in 1,4-dioxane (5 mL) was added 1-[3-acetyl-6-(5-bromobenzimidazol-1-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (150 mg, 0.36 mmol, 1 equiv.), CsCO (348 mg, 1.07 mmol, 3 equiv.), and t-Buxphos-Pd-G (CAS number 1447963-75-8) (28 mg, 0.04 mmol, 0.1 equiv.). The gray suspension was stirred at 90 °C under a N atmosphere for 4 h. The reaction mixture was cooled to room temperature, poured into HO (20 mL), and extracted with EtOAc (2 × 30 mL). The combined extracts were concentrated in vacuo. The residue was purified by preparative TLC (silica gel, 20% MeOH in DCM, UV detection). The title compound (30 mg, 19.1% yield) was obtained as a yellow solid. LC-MS: m / z=441.3 [M+H] + ,ESI pos.

[0211] Step 3: 1-[3-(1-hydroxyethyl)-6-[5-(4-methylpiperazin-1-yl)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] To a stirred solution of 1-[3-acetyl-6-[5-(4-methylpiperazin-1-yl)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (30 mg, 0.07 mmol, 1 equiv.) in a mixture of MeOH (0.5 mL) and THF (0.5 mL) was added NaBH4 (8 mg, 0.2 mmol, 3 equiv.) at 0 °C. Stirring at 0 °C was continued for 1 h. The reaction mixture was quenched by the addition of HO (10 mL). DCM (10 mL) was added to the reaction mixture. The aqueous phase was back-extracted with DCM (2 × 10 mL). The combined organic extracts were concentrated under vacuum. The residue was purified by preparative HPLC: column Waters Xbridge (150 mm × 25 mm × 5 μm). Flow rate: 25 mL / min. Gradient: 25% to 55% CHCN in (10 mM NHHCO in H0) (10 min), then 100% CHCN (2 min). The title compound (4 mg, 13.2% yield) was obtained as a white lyophilized solid. LC-MS: m / z = 443.2 [M+H] + ,ESI pos. 1 H NMR(400 MHz,CD3OD):δ=8.85(s,1H),8.48(d,J=8.4 Hz,1H),8.11(d,J=8.6 Hz,1H),8.05(d,J=9.2 Hz,1H),7.28(d,J=2.1 Hz,1H),7.17(dd,J=2.1,9.1 Hz,1H),6.86(s,1H),4.76(q,J=6.6 Hz,1H),3.27-3.22(m,4H),2.69-2.63(m,4H),2.38(d,J=10.0 Hz,6H),1.40(d,J=6.4 Hz,3H).

[0212] Example 67 1-[3-(1-hydroxyethyl)-6-[5-[4-(oxetan-3-yl)piperazin-1-yl]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka]

[0213] Step 1: 1-[3-acetyl-6-[5-[4-(oxetan-3-yl)piperazin-1-yl]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Starting with 1-(oxetan-3-yl)piperazine (101 mg, 0.71 mmol, 2 equiv.), and following the procedure described in Step 2 of Example 65, using HO (0.06 mL, 3.56 mmol, 10 equiv.) as an additional reagent, the title compound (40 mg, 23.3% yield) was obtained as a yellow oil. LC-MS: m / z=473.2 [M+H] + ,ESI pos.

[0214] Step 2: 1-[3-(1-hydroxyethyl)-6-[5-[4-(oxetan-3-yl)piperazin-1-yl]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Following the procedure described in Step 3 of Example 65, at a temperature of -40°C and a reaction time of 30 minutes, the title compound (15.6 mg, 38.1% yield) was obtained as a white lyophilized solid. LC-MS: m / z = 485.2 [M+H] + ,ESI pos. Purification by preparative HPLC: Column Pheomenex Gemini-NX C18 (75 mm x 30 mm x 3 μm). Flow rate: 30 mL / min. Gradient: 15% to 45% CH3CN in (10 mM NH4HCO3 in H2O) (8 min), then 100% CH3CN (2 min). 1H NMR(400 MHz,CD3OD):δ=8.83(s,1H),8.47(d,J=8.6 Hz,1H),8.11-8.00(m,2H),7.26(d,J=2.1 Hz,1H),7.14(dd,J=2.1,9.1 Hz,1H),6.85(s,1H),4.79-4.70(m,3H),4.67-4.62(m,2H),3.57(quin,J=6.4 Hz,1H),3.24(br s,4H),2.55(br s,4H),2.38(s,3H),1.40(d,J=6.5 Hz,3H).

[0215] Example 68 1-[3-(1-hydroxyethyl)-6-[5-(2-morpholinoethoxy)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka]

[0216] Step 1: 1-[3-acetyl-6-[5-(2-morpholinoethoxy)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Starting with 2-morpholinoethanol (124 mg, 0.95 mmol, 2 eq.), the procedure described in Step 2 of Example 65 was followed to give the title compound (30 mg, 13.4% yield) as a yellow oil. LC-MS: m / z=472.3 [M+H] + ,ESI pos.

[0217] Step 2: 1-[3-(1-hydroxyethyl)-6-[5-(2-morpholinoethoxy)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Following the procedure described in Step 3 of Example 65, at -40°C for 2 hours, then at -10°C for 10 minutes, the title compound (6.8 mg, 22.6% yield) was obtained as a white lyophilized solid. LC-MS: m / z = 474.3 [M+H] + ,ESI pos. Purification by preparative HPLC: Column Waters Xbridge (150 mm x 25 mm x 5 μm). Flow rate: 25 mL / min. Gradient: 28% to 58% CH3CN in (10 mM NH4HCO3 in H2O) (10 min), then 100% CH3CN (2 min). 1 H NMR(400 MHz,CD3OD):δ=8.88(s,1H),8.49(d,J=8.5 Hz,1H),8.12(d,J=8.5 Hz,1H),8.07(d,J=9.0 Hz,1H),7.29(d,J=2.1 Hz,1H),7.07(dd,J=1.8,8.9 Hz,1H),6.86(s,1H),4.76(q,J=6.4 Hz,1H),4.22(t,J=5.4 Hz,2H),3.75-3.70(m,4H),2.85(t,J=5.4 Hz,2H),2.66-2.59(m,4H),2.39(s,3H),1.40(d,J=6.4 Hz,3H).

[0218] Example 71 1-[3-(1-hydroxyethyl)-6-[5-[[1-(oxetan-3-yl)pyrazol-4-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka]

[0219] Step 1: 1-[6-(5-bromobenzimidazol-1-yl)-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Starting from 1-[3-acetyl-6-(5-bromobenzimidazol-1-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (obtained similarly to Step 1 of Example 65) (750 mg, 1.78 mmol, 1 eq.), and following the procedure described in Step 3 of Example 65, the crude (after extractive workup) title compound (750 mg, 99.5% yield) was obtained as an off-white solid. LC-MS: m / z=425.0 [M+H] + ,ESI pos. 1 H NMR (400 MHz, CDCl3): δ=8.50(s,1H),8.32(d,J=8.4 Hz,1H),7.96(d,J=1.8 Hz,1H),7.82(d,J=8.8 Hz,1H),7.69(d,J=8.4 Hz,1H),7.44(dd,J=1.8,8.8 Hz,1H),6.64(s,1H),4.81(q,J=6.5 Hz,1H),2.42-2.39(m,3H),1.45(d,J=6.5 Hz,3H).

[0220] Step 2: 1-[3-(1-hydroxyethyl)-6-[5-[[1-(oxetan-3-yl)pyrazol-4-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] To a solution of 1-[6-(5-bromobenzimidazol-1-yl)-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (100 mg, 0.24 mmol, 1 equiv.) in 1,4-dioxane (5 mL), 1-(3-oxetanyl)-1H-pyrazol-4-amine (39 mg, 0.280 mmol, 1.2 equiv.), CsCO (154 mg, 0.47 mmol, 2 equiv.), and RuPhos-Pd-G (20 mg, 0.02 mmol, 0.1 equiv.) were added. The reaction mixture was stirred at 100 °C for 4 h under a N atmosphere. The mixture was cooled to room temperature, diluted with MeOH (20 mL), treated with thiourea resin, and stirred at room temperature for 16 h. The mixture was filtered, and the filtrate was concentrated to dryness. The residue was purified by preparative HPLC: Column Phenomenex Luna C18 (150 mm x 25 mm x 10 μm). Flow rate: 25 mL / min. Gradient: 16% to 46% CH3CN in (0.225% formic acid in H2O v / v) (10 min), then 100% CH3CN (2 min). The title compound (57.1 mg, 45.2% yield) was obtained as an off-white lyophilized solid. LC-MS: m / z = 482.2 [M+H] + ,ESI pos. 1 H NMR(400 MHz,CD3OD):δ=8.79(s,1H),8.46(d,J=8.5 Hz,1H),8.09(d,J=8.5 Hz,1H),7.96(d,J=8.9 Hz,1H),7.78(s,1H),7.54(s,1H),7.14(d,J=2.1 Hz,1H),6.96(dd,J=2.3,8.9 Hz,1H),6.85(d,J=0.6 Hz,1H),5.52(quin,J=6.9 Hz,1H),5.05(d,J=6.9 Hz,4H),4.75(q,J=6.4 Hz,1H),2.39(s,3H),1.40(d,J=6.5 Hz,3H).

[0221] Example 72 1-[6-[5-[[1-(azetidin-3-yl)pyrazol-4-yl]amino]benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka]

[0222] Step 1: tert-butyl 3-[4-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(1-hydroxyethyl)-2-pyridyl]benzimidazol-5-yl]amino]pyrazol-1-yl]azetidine-1-carboxylate [ka] To a solution of 1-[6-(5-bromobenzimidazol-1-yl)-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (140 mg, 0.33 mmol, 1 equiv.) in 1,4-dioxane (5 mL) was added tert-butyl 3-(4-aminopyrazol-1-yl)azetidine-1-carboxylate (95 mg, 0.4 mmol, 1.2 equiv.), CsCO (216 mg, 0.66 mmol, 2 equiv.), and RuPhos-Pd-G (28 mg, 0.03 mmol, 0.1 equiv.). The reaction mixture was heated to 100 °C and stirred under a N atmosphere for 4 h. The reaction mixture was poured into HO (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organics were washed with brine (2 × 50 mL) and concentrated in vacuo. The residue was purified by preparative TLC (silica gel, 10% MeOH in DCM, UV detection). The title compound (150 mg, 78.1% yield) was obtained as a brown oil. LC-MS: m / z=581.4 [M+H] + ,ESI pos.

[0223] Step 2: 1-[6-[5-[[1-(azetidin-3-yl)pyrazol-4-yl]amino]benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] To a solution of tert-butyl 3-[4-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(1-hydroxyethyl)-2-pyridyl]benzimidazol-5-yl]amino]pyrazol-1-yl]azetidine-1-carboxylate (140 mg, 0.24 mmol, 1 equiv.) in DCM (2 mL) was added HCl in 1,4-dioxane (2.0 mL, 8 mmol, 33.18 equiv.). The reaction mixture was stirred at 30° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC: column Phenomenex Luna C18 (150 mm×25 mm×10 μm). Flow rate: 25 mL / min. Gradient: 6% to 36% CHCN in (0.225% formic acid in H2O v / v) (10 min), then 100% CH3CN (2 min). The title compound (27.9 mg, 22.9% yield) was obtained as a white lyophilized solid. LC-MS: m / z = 481.2 [M+H] + ,ESI pos. 1 H NMR(400 MHz,DMSO-d6):δ=8.93(s,1H),8.42(d,J=8.6 Hz,1H),8.32(s,1H),8.23(d,J=8.4 Hz,1H),7.94-7.88(m,2H),7.68(s,1H),7.46(s,1H),7.10(s,2H),6.91(dd,J=1.9,8.8 Hz,1H),5.26-5.16(m,1H),4.55(q,J=6.4 Hz,1H),4.10-4.04(m,2H),3.92(br t,J=8.3 Hz,2H),2.34(s,3H),1.26(br d,J=6.4 Hz,3H).

[0224] Example 74 1-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxybenzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka]

[0225] Step 1: 1-(2-trimethylsilylethoxymethyl)benzimidazol-5-ol [ka] A mixture of 1H-benzimidazol-5-ol (1.0 g, 7.45 mmol, 1 equiv.), 2-(trimethylsilyl)ethoxymethyl chloride (1.98 mL, 11.18 mmol, 1.5 equiv.), and DIPEA (1.93 g, 14.91 mmol, 2 equiv.) in DCM (30 mL) was stirred at 0 °C for 10 min and then at 40 °C for 16 h. Additional 2-(trimethylsilyl)ethoxymethyl chloride (0.66 mL, 3.73 mmol, 0.5 equiv.) was added, and stirring at 40 °C was continued for 12 h. The reaction mixture was cooled to room temperature, quenched with HO (150 mL), and extracted with DCM (3 × 50 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 10% MeOH in DCM). The title compound (600 mg, 30.4% yield) was obtained as a yellow oil. LC-MS: m / z=265.1 [M+H] + ,ESI pos.

[0226] Step 2: Trimethyl-[2-[[5-(6-methylpyridazin-3-yl)oxybenzimidazol-1-yl]methoxy]ethyl]silane [ka] A mixture of 1-(2-trimethylsilylethoxymethyl)benzimidazol-5-ol (0.6 g, 2.27 mmol, 1 equiv.), 3-chloro-6-methylpyridazine (292 mg, 2.27 mmol, 1 equiv.), and K2CO3 (0.63 g, 4.54 mmol, 2 equiv.) in DMF (10 mL) was stirred at 140 °C for 12 h. The mixture was cooled to room temperature, quenched with HO (100 mL), and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 10% MeOH in DCM). The title compound (800 mg, 79.1% yield) was obtained as a brown oil. LC-MS: m / z = 357.1 [M+H] + ,ESI pos.

[0227] Step 3: 5-(6-methylpyridazin-3-yl)oxy-1H-benzimidazole [ka] A solution of trimethyl-[2-[[5-(6-methylpyridazin-3-yl)oxybenzimidazol-1-yl]methoxy]ethyl]silane (1.1 g, 3.09 mmol, 1 equiv.) in TFA (5 mL, 61.62 mmol, 19.97 equiv.) was stirred at 20 °C for 2 h. The reaction mixture was quenched with HO (10 mL) and extracted with EtOAc (3 × 10 mL). The aqueous layer was lyophilized to give the title compound (900 mg, TFA salt) as a yellow gum. The product was taken up in DCM (100 mL) and treated with KCO. Stirring at 30 °C was continued for 2 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by preparative HPLC: column Waters Xbridge (150 mm × 25 mm × 5 μm). Flow rate: 25 mL / min. Gradient: 1% to 33% CHCN in (10 mM NHHCO in H0) (9 min), then 100% CHCN (2 min). The title compound (520 mg, 74.5% yield) was obtained as a yellow lyophilized solid. LC-MS: m / z = 226.9 [M+H] + ,ESI pos.

[0228] Step 4: 1-[3-acetyl-6-[5-(6-methylpyridazin-3-yl)oxybenzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile and 1-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxybenzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] The procedure described in Step 2 of Example 64 was followed, with a reaction time of 3 hours. Purification by preparative HPLC: Column Phenomenex Synergi C18 (150 mm x 25 mm x 10 μm). Flow rate: 25 mL / min. Gradient: 30% to 60% CH3CN in (0.225% formic acid in HO v / v) (8.5 min), then 100% CH3CN (2 min). Further purification by chiral SFC separated the two regioisomers (Daicel Chiralpak AD (250 mm × 30 mm × 10 μm), flow rate: 80 mL / min. 70% (0.1% NH4OH in MeOH) to give 1-[3-acetyl-6-[5-(6-methylpyridazin-3-yl)oxybenzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (38 mg, 11% yield) as a white lyophilized solid and 1-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxybenzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (44 mg, 12.7% yield) as a white lyophilized solid. Regioisomer 1: LC-MS: m / z = 451.1 [M+H] + ,ESI pos. 1H NMR(400 MHz,CD3OD):δ=9.00(s,1H),8.44(d,J=8.4 Hz,1H),8.17-8.06(m,2H),7.82(d,J=8.7 Hz,1H),7.64(d,J=9.0 Hz,1H),7.35(d,J=9.0 Hz,1H),7.26(dd,J=2.3,8.7 Hz,1H),6.81(s,1H),2.63(s,3H),2.47(s,3H),2.19(s,3H).Positional isomer 2:LC-MS:m / z=451.1 [M+H] + ,ESI pos. 1 H NMR(400 MHz,CD3OD):δ=9.01(s,1H),8.46(d,J=8.4 Hz,1H),8.25(d,J=8.9 Hz,1H),8.13(d,J=8.3 Hz,1H),7.64(d,J=9.2 Hz,1H),7.58(d,J=2.0 Hz,1H),7.35(d,J=9.0 Hz,1H),7.26(dd,J=1.7,8.9 Hz,1H),6.88(s,1H),2.61(s,3H),2.57(s,3H),2.22(s,3H).

[0229] Step 5: 1-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxybenzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] To a solution of 1-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxybenzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (10 mg, 0.02 mmol, 1 equiv.) in methanol (3 mL) was added NaBH (2 mg, 0.05 mmol, 2.38 equiv.) at 0 °C. The mixture was stirred at 0 °C for 0.5 h and directly purified by preparative HPLC: column Phenomenex Synergi C18 (150 mm × 25 mm × 10 μm). Flow rate: 25 mL / min. Gradient: 28% to 58% CHCN in (0.225% formic acid in HO v / v) (8.5 min), then 100% CHCN (2 min). The title compound (7.6 mg, 75.2% yield) was obtained as a white lyophilized solid. LC-MS: m / z=453.1 [M+H] + ,ESI pos. 1 H NMR(400 MHz,CD3OD):δ=9.00(s,1H),8.51(d,J=8.4 Hz,1H),8.16(d,J=8.5 Hz,1H),8.04(d,J=2.3 Hz,1H),7.84(d,J=8.8 Hz,1H),7.66(d,J=9.0 Hz,1H),7.37(d,J=9.0 Hz,1H),7.27(dd,J=2.3,8.8 Hz,1H),6.80(s,1H),4.81-4.73(m,2H),2.66(s,3H),2.32(s,3H),1.40(d,J=6.5 Hz,3H).

[0230] Example 75 1-[3-(1-hydroxyethyl)-6-[5-(6-methylpyridazin-3-yl)oxybenzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Starting with 1-[3-acetyl-6-[5-(6-methylpyridazin-3-yl)oxybenzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (obtained similarly to Step 4 of Example 74) (38 mg, 0.08 mmol, 1 eq.) and following the procedure described in Step 5 of Example 74, the title compound (25.3 mg, 66.3% yield) was obtained as a white lyophilized solid. Purification by preparative HPLC: Column Phenomenex Synergi C18 (150 mm x 25 mm x 10 μm). Flow rate: 25 mL / min. Gradient: 28% to 58% CH3CN in (0.225% formic acid in HO v / v) (8.5 min), then 100% CH3CN (2 min). LC-MS: m / z = 453.1 [M+H] + ,ESI pos. 1 H NMR(400 MHz,CD3OD):δ=9.00(s,1H),8.53(d,J=8.4 Hz,1H),8.28-8.21(m,1H),8.18(d,J=8.6 Hz,1H),7.64(d,J=9.0 Hz,1H),7.59(d,J=2.1 Hz,1H),7.35(d,J=9.2 Hz,1H),7.27(br d,J=8.3 Hz,1H),6.86(s,1H),4.82-4.74(m,1H),2.61(s,3H),2.41(s,3H),1.42(d,J=6.5 Hz,3H).

[0231] Example 76 5-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-1-methyl-pyrazole-4-carbonitrile [ka]

[0232] Step 1: 1-(2-chloro-6-fluoro-3-pyridyl)ethanone [ka] A mixture of 3-bromo-2-chloro-6-fluoro-pyridine (5.0 g, 23.76 mmol, 1 equiv.), tributyl(1-ethoxyvinyl)tin (10.3 g, 28.51 mmol, 1.2 equiv.), KCO (9.85 g, 71.28 mmol, 3 equiv.), and dichloropalladium triphenylphosphine (3.34 g, 4.75 mmol, 0.2 equiv.) in a mixture of 1,4-dioxane (80 mL) and HO (5 mL) was stirred at 100 °C for 12 h under a N atmosphere. The reaction mixture was cooled to room temperature, poured into saturated aqueous KF solution (50 mL), and stirred for 2 h. The mixture was then extracted with EtOAc (3 × 20 mL). The combined organic layers were treated with 2 N HCl (20 mL), and the mixture was stirred for 2 h. The mixture was then basified by adding aqueous NaCO until a pH of 8 was reached. The layers were separated. The aqueous phase was extracted with EtOAc (2×20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, 10% EtOAc in petroleum ether). The title compound (1.9 g, 46.1% yield) was obtained as a yellow oil. 1 H NMR (400 MHz, CDCl3): δ=8.13(dd,J=7.6,8.3 Hz,1H),6.98(dd,J=3.3,8.4 Hz,1H),2.72(s,3H).

[0233] Step 2: 1-[2-chloro-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone [ka] A solution of 1-(2-chloro-6-fluoro-3-pyridyl)ethanone (1.9 g, 10.95 mmol, 1 equiv.), N,N-diisopropylethylamine (3.8 mL, 21.89 mmol, 2 equiv.), and N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine (obtained similarly as Intermediate 1 in Example 64) (2.47 g, 10.95 mmol, 1 equiv.) in DMSO (30 mL) was stirred at 60° C. for 12 h. The reaction mixture was cooled to room temperature, poured into HO (100 mL), and extracted with EtOAc (3×200 mL). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative NPLC: column Welch Ultimate XB-SiOH (250 mm×70 mm×10 μm). Flow rate: 140 mL / min. Gradient: 10% to 50% EtOH in hexanes (25 min), then 100% EtOH (4 min). The title compound (500 mg, 1.32 mmol, 12.1% yield) was obtained as a brown solid. LC-MS: m / z=379.0 [M+H] + ,ESI pos. 1 H NMR(400 MHz,DMSO-d6):δ=9.30(br s,1H),9.08(s,1H),8.49-8.44(m,2H),8.30(d,J=8.9 Hz,1H),8.11(s,1H),7.53(dd,J=2.1,8.9 Hz,1H),7.35(d,J=9.1 Hz,1H),7.11(d,J=9.1 Hz,1H),2.68(s,3H),2.49(br s,3H).

[0234] Step 3: 5-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-1-methyl-pyrazole-4-carbonitrile [ka] To a solution of 1-[2-chloro-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (100 mg, 0.26 mmol, 1 equiv.) in 1,4-dioxane (6 mL) and HO (0.3 mL) was added 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-4-carbonitrile (92 mg, 0.4 mmol, 1.5 equiv.), NaCO (84 mg, 0.79 mmol, 3 equiv.), and PdCl(dppf) CHCl (43 mg, 0.05 mmol, 0.200 equiv.). The brown reaction mixture was stirred at 100 °C under a N atmosphere for 8 h. The reaction mixture was cooled to room temperature, poured into H2O (10 mL), and extracted with EtOAc (3 x 40 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 10% MeOH in DCM). The title compound (20 mg, 16% yield) was obtained as a brown solid. LC-MS: m / z = 450.3 [M+H] + ,ESI pos.

[0235] Step 4: 5-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-1-methyl-pyrazole-4-carbonitrile [ka] Following the procedure described in Example 75, the title compound (2.2 mg, 9.9% yield) was obtained as a pale yellow lyophilized solid after a reaction time of 1 hour. Purification by preparative HPLC: Column Phenomenex Luna C18 (150 mm x 25 mm x 10 μm). Flow rate: 25 mL / min. Gradient: 2% to 32% CH3CN in (0.225% formic acid in H2O v / v) (10 min), then 100% CH3CN (2 min). LC-MS: m / z = 452.2 [M+H] + ,ESI pos. 1H NMR(400 MHz,CD3OD):δ=8.90(s,1H),8.43(d,J=8.6 Hz,1H),8.34(br s,2H),8.23(s,1H),8.14(br d,J=8.4 Hz,2H),8.09-8.02(m,1H),7.58(dd,J=1.9,8.9 Hz,1H),7.36(d,J=9.1 Hz,1H),7.14(d,J=9.1 Hz,1H),3.86(s,3H),2.53(s,3H),1.59-1.41(m,3H).

[0236] Example 77 1-[3-(1-hydroxyethyl)-6-[5-[(3R)-3-hydroxypyrrolidin-1-yl]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; Formic acid [ka]

[0237] Step 1: 1-[6-(5-bromobenzimidazol-1-yl)-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] To a suspension of 1-[3-acetyl-6-(5-bromobenzimidazol-1-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (obtained in a manner similar to Step 1 of Example 65) (750 mg, 1.78 mmol, 1 equiv.) in MeOH (10 mL) and THF (10 mL) was added NaBH (202 mg, 5.34 mmol, 3 equiv.) at 0° C. The mixture was stirred at 0° C. for 1 h. The reaction mixture was then diluted with HO (100 mL) and extracted with EtOAc (5×100 mL). The combined organic layers were washed with brine (2×100 mL), dried (NaSO), filtered, and concentrated to give the crude title compound (750 mg, 99.5% yield) as an off-white solid. LC-MS: m / z=425.0 [M+H] + ,ESI pos.1 H NMR (400 MHz, CDCl3): δ=8.50(s,1H),8.32(d,J=8.4 Hz,1H),7.96(d,J=1.8 Hz,1H),7.82(d,J=8.8 Hz,1H),7.69(d,J=8.4 Hz,1H),7.44(dd,J=1.8,8.8 Hz,1H),6.64(s,1H),4.81(q,J=6.5 Hz,1H),2.42-2.39(m,3H),1.45(d,J=6.5 Hz,3H).

[0238] Step 2: 1-[3-(1-hydroxyethyl)-6-[5-[(3R)-3-hydroxypyrrolidin-1-yl]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; formic acid [ka] Using (R)-3-hydroxypyrrolidine (0.02 mL, 0.26 mmol, 1.1 equiv.), the title compound (17.3 mg, 16.2% yield) was obtained as a yellow lyophilized solid according to the procedure described in Step 2 of Example 71. Purification by preparative HPLC: Column Phenomenex Luna C18 (150 mm x 25 mm x 10 μm). Flow rate: 25 mL / min. Gradient: 15% to 45% CH3CN in (0.225% formic acid in HO v / v) (10 min), then 100% CH3CN (2 min). LC-MS: m / z = 430.1 [M+H] + ,ESI pos. 1H NMR(400 MHz,CD3OD):δ=8.80(s,1H),8.48(d,J=8.5 Hz,1H),8.11(d,J=8.6 Hz,1H),8.02(d,J=9.0 Hz,1H),6.89-6.85(m,2H),6.80(dd,J=2.0,9.1 Hz,1H),4.77(q,J=6.5 Hz,1H),4.61-4.54(m,1H),3.62-3.49(m,2H),3.41(dt,J=3.8,8.7 Hz,1H),3.28(br d,J=10.4 Hz,1H),2.42(s,3H),2.28-2.18(m,1H),2.12-2.02(m,1H),1.43(d,J=6.5 Hz,3H).

[0239] Example 78 1-[3-(1-hydroxyethyl)-6-[5-[(3S)-3-hydroxypyrrolidin-1-yl]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; Formic acid [ka] The title compound (21.6 mg, 18.1% yield) was obtained as a yellow lyophilized solid using (S)-3-hydroxypyrrolidine (0.02 mL, 0.260 mmol, 1.1 equiv.) according to the procedure described in Step 2 of Example 71. Purification by preparative HPLC: Column Phenomenex Luna C18 (150 mm x 25 mm x 10 μm). Flow rate: 25 mL / min. Gradient: 15% to 45% CH3CN in (0.225% formic acid in HO v / v) (10 min), then 100% CH3CN (2 min). LC-MS: m / z = 430.1 [M+H] + ,ESI pos. 1H NMR(400 MHz,CD3OD):δ=8.78(s,1H),8.46(d,J=8.4 Hz,1H),8.31(s,1H),8.09(d,J=8.6 Hz,1H),8.00(d,J=9.0 Hz,1H),6.87-6.83(m,2H),6.78(dd,J=2.3,9.1 Hz,1H),4.77-4.72(m,1H),4.59-4.53(m,1H),3.58-3.48(m,2H),3.39(dt,J=3.4,8.6 Hz,1H),3.25(br s,1H),2.40(s,3H),2.27-2.14(m,1H),2.11-1.99(m,1H),1.41(d,J=6.5 Hz,3H).

[0240] Example 81 1-[3-(1-hydroxyethyl)-6-[5-[(6-methyl-3-pyridyl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka]

[0241] Step 1: 1-[3-acetyl-6-[5-[(6-methyl-3-pyridyl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Argon was bubbled through a suspension of 1-[3-acetyl-6-(5-bromobenzimidazol-1-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (obtained in a manner similar to Step 1 of Example 65) (37 mg, 0.087 mmol, 1 equiv.), (6-methyl-3-pyridyl)amine (19 mg, 0.175 mmol, 2 equiv.), and CsCO (85 mg, 0.262 mmol, 3 equiv.) in 1,4-dioxane (1.2 mL) at room temperature for 5 min. tBuXphos-Pd-G (7 mg, 0.009 mmol, 0.1 equiv.) was then added, the vial was sealed, and the mixture was heated to 90 °C and stirring was continued for 4 h. Additional tBuXphos-Pd-G3 (7 mg, 0.009 mmol, 0.1 equiv.) was added, and the mixture was stirred at 90 °C for an additional 4 h. The reaction mixture was cooled to room temperature, adsorbed onto silica gel, and directly purified by flash chromatography (12 g silica gel, 0% to 100% in DCM [DCM / MeOH 9:1]). The isolated product was purified again by flash chromatography (10 g Si-NH2, 20% to 100% EtOAc in heptane). The title compound (21.7 mg, 46.9% yield) was obtained as a yellow solid. LC-MS: m / z = 449.2 [M+H] + ,ESI pos.

[0242] Step 2: 1-[3-(1-hydroxyethyl)-6-[5-[(6-methyl-3-pyridyl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] To a solution of 1-[3-acetyl-6-[5-[(6-methyl-3-pyridyl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (22 mg, 0.041 mmol, 1 equiv.) in MeOH (1 mL) at 0 °C was added NaBH (5 mg, 0.123 mmol, 3 equiv.). The mixture was stirred at 0 °C for 30 min. The reaction mixture was quenched with saturated aqueous NH Cl at 0 °C and extracted with DCM. The organic layer was dried over MgSO, filtered, and concentrated in vacuo. The residue was adsorbed onto silica gel and purified by flash chromatography (4 g silica gel, 0% to 100% in DCM [DCM / MeOH 9:1]). The title compound (11 mg, 58.8% yield) was obtained as a pale yellow solid. LC-MS: m / z = 451.3 [M+H] + ,ESI pos.

[0243] Example 82 1-[3-(1-hydroxyethyl)-6-[5-[(5-methylpyrazin-2-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka]

[0244] Step 1: 1-[3-acetyl-6-[5-[(5-methylpyrazin-2-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Following the procedure described in Step 1 of Example 81, (5-methylpyrazin-2-yl)amine (19 mg, 0.175 mmol, 2 eq) afforded the title compound (12 mg, 29% yield) as a yellow solid. LC-MS: m / z=450.2 [M+H] + ,ESI pos.

[0245] Step 2: 1-[3-(1-hydroxyethyl)-6-[5-[(5-methylpyrazin-2-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Following the procedure described in Step 2 of Example 81, the title compound (4.5 mg, 37.3% yield) was obtained as an off-white solid. LC-MS: m / z=452.3 [M+H] + ,ESI pos.

[0246] Example 83 1-[3-(1-hydroxyethyl)-6-[5-[(5-methylpyrimidin-2-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka]

[0247] Step 1: 1-[3-acetyl-6-[5-[(5-methylpyrimidin-2-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Following the procedure described in Step 1 of Example 81, (5-methylpyrimidin-2-yl)amine (27 mg, 0.237 mmol, 2 eq) afforded the title compound (14.1 mg, 25.6% yield) as a pale yellow solid. LC-MS: m / z=450.2 [M+H] + ,ESI pos.

[0248] Step 2: 1-[3-(1-hydroxyethyl)-6-[5-[(5-methylpyrimidin-2-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] To a mixture of 1-[3-acetyl-6-[5-[(5-methylpyrimidin-2-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (14 mg, 0.031 mmol, 1 equiv.) in MeOH (0.4 mL) was added NaBH (3 mg, 0.076 mmol, 3 equiv.) at 0 °C. The mixture was stirred at 0 °C for 15 min. THF (0.4 mL) was then added to the mixture, which turned into a clear solution. Stirring at 0 °C was continued for another 15 min. The reaction mixture was quenched with saturated aqueous NH Cl at 0 °C and extracted with DCM. The organic layer was dried over MgSO, filtered, and concentrated in vacuo. The residue was adsorbed onto silica gel and purified by flash chromatography (4 g silica gel, 0% to 100% in DCM [DCM / MeOH 9:1]). The title compound (9.2 mg, 63.7% yield) was obtained as a white solid. LC-MS: m / z=452.3 [M+H] + ,ESI pos.

[0249] Example 84 1-[3-(1-hydroxyethyl)-6-[5-[(5-methyl-2-pyridyl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka]

[0250] Step 1: 1-[3-acetyl-6-[5-[(5-methyl-2-pyridyl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Following the procedure described in Step 1 of Example 81, (5-methyl-2-pyridyl)amine (26 mg, 0.237 mmol, 2 eq) afforded the title compound (27.5 mg, 46.5% yield) as a yellow solid. LC-MS: m / z=449.2 [M+H] + ,ESI pos.

[0251] Step 2: 1-[3-(1-hydroxyethyl)-6-[5-[(5-methyl-2-pyridyl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] To a mixture of 1-[3-acetyl-6-[5-[(5-methyl-2-pyridyl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (27 mg, 0.061 mmol, 1 equiv.) in MeOH (0.8 mL) and a dry excess of THF (0.8 mL) was added NaBH (3 mg, 0.076 mmol, 3 equiv.) at 0 °C. The mixture was stirred at 0 °C for 15 min. The reaction mixture was quenched with saturated aqueous NH Cl at 0 °C and extracted with DCM. The organic layer was dried over MgSO, filtered, and concentrated in vacuo. The residue was adsorbed onto silica gel and purified by flash chromatography (4 g silica gel, 0% to 100% in DCM [DCM / MeOH 9:1]). The title compound (21 mg, 72.2% yield) was obtained as a pale yellow solid. LC-MS: m / z=451.4 [M+H] + ,ESI pos.

[0252] Example 85 1-[2-(1,1-dioxo-1,2-thiazolidin-2-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol [ka]

[0253] Step 1: 1-[6-chloro-2-(1,1-dioxo-1,2-thiazolidin-2-yl)-3-pyridyl]ethanone [ka] To a solution of 1-(6-chloro-2-fluoro-3-pyridyl)ethanone (CAS number 1260663-13-5, 500 mg, 2.88 mmol, 1 equiv.) in DMSO (10 mL) was added isothiazolidine 1,1-dioxide (349 mg, 2.88 mmol, 1 equiv.) and K2CO3 (1.19 g, 8.64 mmol, 3 equiv.). The mixture was stirred at 30 °C for 2 h. The mixture was poured into HO (30 mL) and extracted with EtOAc (3 × 15 mL). The combined organic extracts were washed with brine (3 × 15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0% to 100% EtOAc in petroleum ether). The title compound (480 mg, 60.6% yield) was obtained as a pale red solid. LC-MS: m / z=274.8 [M+H] + ,ESI pos.

[0254] Step 2: 1-[2-(1,1-dioxo-1,2-thiazolidin-2-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone and 1-[2-(1,1-dioxo-1,2-thiazolidin-2-yl)-5-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone [ka] To a solution of 1-[6-chloro-2-(1,1-dioxo-1,2-thiazolidin-2-yl)-3-pyridyl]ethanone (460 mg, 1.67 mmol, 1 equiv.) in DMSO (10 mL) was added N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine (obtained analogously to Intermediate 1 in Example 64) (453 mg, 2.01 mmol, 1.2 equiv.) and K2CO3 (694 mg, 5.02 mmol, 3 equiv.). The brown suspension was stirred at 80 °C for 2 h. The mixture was directly purified by preparative HPLC: column Waters Xbridge C18 (150 mm × 50 mm × 10 μm). Flow rate: 60 mL / min. Gradient: 16% to 46% CH3CN in (10 mM NH4HCO3 in H2O) (11 min), then 100% CH3CN (2 min). A 1:1 mixture of the two title compounds (150 mg) was isolated. Further purification by chiral SFC (Daicel Chiralpak AD (250 mm x 30 mm x 10 μm). Flow rate: 70 mL / min. 50% (1% NHOH in isopropanol) gave 1-[2-(1,1-dioxo-1,2-thiazolidin-2-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (55 mg, 7.1% yield) as a brown solid and 1-[2-(1,1-dioxo-1,2-thiazolidin-2-yl)-5-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (35 mg, 4.5% yield) as a grey solid. Regioisomer 1: LC-MS: m / z=464.0 [M+H] + ,ESI pos. 1H NMR(400 MHz,CDCl3):δ ppm 2.50(s,3 H)2.52-2.59(m,3 H)2.63(s,3 H)3.26(t,J=7.50 Hz,2 H)4.25(t,J=6.82 Hz,2 H)6.96(d,J=9.13 Hz,1 H)7.03-7.07(m,1 H)7.07-7.10(m,1 H)7.35(d,J=8.38 Hz,1 H)7.62(d,J=8.63 Hz,1 H)8.08(d,J=8.25 Hz,1 H)8.35(s,1 H)8.74(d,J=1.75 Hz,1 H).Regioisomer 2: LC-MS: m / z=464.0 [M+H] + ,ESI pos.

[0255] Step 3: 1-[2-(1,1-dioxo-1,2-thiazolidin-2-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol [ka] To a solution of 1-[2-(1,1-dioxo-1,2-thiazolidin-2-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (45 mg, 0.1 mmol, 1 equiv.) in MeOH (3 mL) was added NaBH (112 mg, 0.29 mmol, 3 equiv.) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. The mixture was quenched with saturated NH Cl (5 mL) at 0 °C and extracted with DCM (2 × 10 mL). The combined organics were dried over Na SO , filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC: column Phenomenex Gemini-NX (75 mm × 30 mm × 30 μm). Flow rate: 30 mL / min. Gradient: 10% to 40% CHCN in (10 mM NHHCO in H0) (8 min), then 100% CHCN (2 min). The title compound (17.5 mg, 38.7% yield) was obtained as a white lyophilized solid. LC-MS: m / z = 466.1 [M+H] + ,ESI pos. 1H NMR(400 MHz,CD3OD):δ ppm 1.56(d,J=6.36 Hz,3 H)2.54-2.63(m,5 H)3.35-3.39(m,2 H)4.10-4.19(m,1 H)4.33(dt,J=10.70,7.06 Hz,1 H)5.48-5.56(m,1 H)7.15(d,J=9.17 Hz,1 H)7.27-7.32(m,1 H)7.37(d,J=9.05 Hz,1 H)7.69(d,J=8.68 Hz,1 H)7.85(d,J=8.31 ​​Hz,1 H)8.33(d,J=8.44 Hz,1 H)8.76(s,1 H) 9.08 (d, J = 1.83 Hz, 1 H).

[0256] Example 86 1-[3-(1-hydroxyethyl)-6-[5-[(2-methylpyrimidin-5-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka]

[0257] Step 1: 1-[3-acetyl-6-[5-[(2-methylpyrimidin-5-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Following the procedure described in Step 1 of Example 81, (2-methylpyrimidin-5-yl)amine (26 mg, 0.237 mmol, 2 eq) afforded the title compound (41.5 mg, 70% yield) as a yellow solid. LC-MS: m / z=450.3 [M+H] + ,ESI pos.

[0258] Step 2: 1-[3-(1-hydroxyethyl)-6-[5-[(2-methylpyrimidin-5-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Following the procedure described in Step 2 of Example 84, the title compound (24.7 mg, 62.5% yield) was obtained as an off-white solid. LC-MS: m / z=452.3 [M+H] + ,ESI pos.

[0259] Example 87 1-[3-(1-hydroxyethyl)-6-[5-(pyridazin-4-ylamino)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka]

[0260] Step 1: 1-[3-acetyl-6-[5-(pyridazin-4-ylamino)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Following the procedure described in Step 1 of Example 81, pyridazin-4-ylamine (23 mg, 0.237 mmol, 2 eq) afforded the title compound (8.9 mg, 16.4% yield) as a yellow solid. LC-MS: m / z=436.3 [M+H] + ,ESI pos.

[0261] Step 2: 1-[3-(1-hydroxyethyl)-6-[5-(pyridazin-4-ylamino)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Following the procedure described in Step 2 of Example 84, the title compound (4.1 mg, 43% yield) was obtained as a pale yellow solid. LC-MS: m / z=438.2 [M+H] +,ESI pos.

[0262] Example 88 1-[3-(1-hydroxyethyl)-6-[5-[(6-methoxypyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka]

[0263] Step 1: 1-[3-acetyl-6-[5-[(6-methoxypyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Following the procedure described in Step 1 of Example 81, (6-methoxypyridazin-3-yl)amine (30 mg, 0.237 mmol, 2 eq) afforded the title compound (59.7 mg, 97.3% yield) as a yellow solid. LC-MS: m / z=466.3 [M+H] + ,ESI pos.

[0264] Step 2: 1-[3-(1-hydroxyethyl)-6-[5-[(6-methoxypyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Following the procedure described in Step 2 of Example 84, the title compound (38.3 mg, 67.4% yield) was obtained as a pale yellow solid. LC-MS: m / z=468.3 [M+H] + ,ESI pos.

[0265] Example 89 1-[3-(1-hydroxyethyl)-6-[5-(pyridazin-3-ylamino)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka]

[0266] Step 1: 1-[3-acetyl-6-[5-(pyridazin-3-ylamino)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Following the procedure described in Step 1 of Example 81, pyridazin-3-ylamine (23 mg, 0.237 mmol, 2 eq) afforded the title compound (15.3 mg, 26.6% yield) as a yellow solid. LC-MS: m / z=436.3 [M+H] + ,ESI pos.

[0267] Step 2: 1-[3-(1-hydroxyethyl)-6-[5-(pyridazin-3-ylamino)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Following the procedure described in Step 2 of Example 84, the title compound (9.1 mg, 65% yield) was obtained as a pale yellow solid. LC-MS: m / z=438.3 [M+H] + ,ESI pos.

[0268] Example 90 1-[6-[5-[[6-(difluoromethyl)pyridazin-3-yl]amino]benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka]

[0269] Step 1: 1-[3-acetyl-6-[5-[[6-(difluoromethyl)pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Following the procedure described in Step 1 of Example 81, [6-(difluoromethyl)pyridazin-3-yl]amine (35 mg, 0.237 mmol, 2 eq) afforded the title compound (35.2 mg, 55% yield) as a pale yellow solid. LC-MS: m / z=486.3 [M+H] + ,ESI pos.

[0270] Step 2: 1-[6-[5-[[6-(difluoromethyl)pyridazin-3-yl]amino]benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Following the procedure described in Step 2 of Example 84, the title compound (15.4 mg, 47% yield) was obtained as a pale yellow solid. LC-MS: m / z=488.2 [M+H] + ,ESI pos.

[0271] Example 93 1-[6-[6-fluoro-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka]

[0272] Step 1: N-(2-fluoro-4,5-dinitrophenyl)-6-methyl-pyridazin-3-amine [ka] To a solution of 1,2-difluoro-4,5-dinitro-benzene (1.0 g, 4.9 mmol, 1 equiv.) in DMSO (12 mL) was added 3-amino-6-methylpyridazine (535 mg, 4.9 mmol, 1 equiv.) and potassium tert-butoxide (1.1 g, 9.8 mmol, 2 equiv.). The brown suspension was stirred at 30° C. for 3 h. The reaction mixture was poured into HO (100 mL). A solid precipitated. The solid was collected by filtration and dried to give the crude title compound (600 mg, 41.8% yield) as a brown solid. LC-MS: m / z=294.0 [M+H] + ,ESI pos.

[0273] Step 2: 6-Fluoro-N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine [ka] To a solution of N-(2-fluoro-4,5-dinitrophenyl)-6-methyl-pyridazin-3-amine (2.5 g, 8.53 mmol, 1 equiv.) in formic acid (30 mL, 795 mmol, 93.27 equiv.) was added nickel (333 mg, 5.68 mmol, 0.670 equiv.). The mixture was stirred under H2 (45 psi) at 30 °C for 16 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was poured into MeOH (30 mL). A solid precipitated. The solid was collected by filtration, washed with MeOH, and dried to give the title compound (480 mg) for the first time. The filtrate was concentrated, and the residue was purified by preparative HPLC: column Phenomenex Luna C18 (250 mm × 70 mm × 10 μm). Flow rate: 80 mL / min. Gradient: 1% to 30% CHCN in (0.225% formic acid in H2O v / v) (20 min), then 100% CH3CN (5 min). The second title compound (860 mg) was obtained. The title compound (1.34 g, 64.6% yield) was obtained as an off-white solid. LC-MS: m / z = 244.1 [M+H] +,ESI pos. 1 H NMR(400 MHz,DMSO-d6):δ=12.70-12.32(m,1H),8.73(br s,1H),8.51-8.37(m,1H),8.20-8.09(m,2H),7.49(br d,J=11.4 Hz,1H),7.33(d,J=9.2 Hz,1H),7.24-7.14(m,1H),2.47(s,3H).

[0274] Step 3: 1-[3-acetyl-6-[6-fluoro-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile and 1-[3-acetyl-6-[5-fluoro-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] To a solution of 6-fluoro-N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine (930 mg, 3.82 mmol, 1 equiv.) in DMSO (20 mL) was added 1-(3-acetyl-6-chloro-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile (obtained in a manner similar to Step 1 of Example 64) (1.2 g, 4.59 mmol, 1.2 equiv.) and K2CO3 (1.59 g, 11.47 mmol, 3 equiv.). The reaction mixture was stirred at 30 °C for 2 h. The mixture was then poured into HO (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic extracts were washed with brine (3 × 15 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative NPLC: column Welch Ultimate-XB-SiOH (250 mm × 70 mm × 10 μm). Flow rate: 140 mL / min. Gradient: 20% to 60% EtOH in hexanes (20 min), then 100% EtOH (4 min) to give 1-[3-acetyl-6-[6-fluoro-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (200 mg, 11.2% yield) as a yellow solid and 1-[3-acetyl-6-[5-fluoro-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (500 mg, 28% yield) as a yellow solid. Positional isomer 1: LC-MS: m / z=468.1 [M+H] + ,ESI pos. 1 H NMR(400 MHz,DMSO-d6):δ=9.17(s,1H),8.90(s,1H),8.72(d,J=7.7 Hz,1H),8.57(d,J=8.4 Hz,1H),8.34(d,J=8.6 Hz,1H),8.08(d,J=11.6 Hz,1H),7.41-7.35(m,1H),7.29-7.23(m,1H),7.16(s,1H),2.54(s,3H),2.49(br s,3H),2.23(s,3H).Positional isomer 2:LC-MS:m / z=468.1 [M+H] + ,ESI pos. 1H NMR(400 MHz,CD3OD):δ=9.17(d,J=7.4 Hz,1H),8.88(s,1H),8.48(d,J=8.4 Hz,1H),8.09(d,J=8.4 Hz,1H),7.52(d,J=11.0 Hz,1H),7.39(d,J=9.1 Hz,1H),7.25(d,J=9.1 Hz,1H),6.83(s,1H),2.58(s,3H),2.56(s,3H),2.23(s,3H).

[0275] Step 6: 1-[6-[6-fluoro-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] To a solution of 1-[3-acetyl-6-[6-fluoro-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (200 mg, 0.430 mmol, 1 equiv.) in MeOH (7 mL) and DCM (3 mL) was added NaBH (49 mg, 1.28 mmol, 3 equiv.) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. The mixture was quenched with saturated NH Cl (5 mL) at 0 °C and extracted with DCM (2 × 10 mL). The combined organic layers were dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC: column Phenomenex Synergi C18 (150 mm × 25 mm × 10 μm). Flow rate: 25 mL / min. Gradient: 8% to 38% CHCN in (0.225% formic acid in H2O v / v) (20 min), then 100% CH3CN (3 min). The title compound (120 mg, 59.7% yield) was obtained as a white lyophilized solid. LC-MS: m / z = 470.2 [M+H] + ,ESI pos. 1H NMR(400 MHz,CD3OD):δ=9.00-8.89(m,1H),8.61-8.46(m,2H),8.24-8.12(m,1H),8.07-7.95(m,1H),7.41(d,J=9.1 Hz,1H),7.24(d,J=9.3 Hz,1H),6.90(s,1H),4.78(q,J=6.5 Hz,1H),4.61(br s,1H),2.56(s,3H),2.43(s,3H),1.43(d,J=6.5 Hz,3H).

[0276] Example 94 1-[6-[5-fluoro-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Following the procedure described in Step 6 of Example 93, using MeOH (3 mL) as the solvent, the title compound (11.6 mg, 23.1% yield) was obtained as a white lyophilized solid. Purification by preparative HPLC (Phenomenex Gemini NX C18 (75 mm x 30 mm x 3 μm). Flow rate: 30 mL / min. Gradient: 18% to 48% CH3CN in (10 mM NH4HCO3 in HO) (8 min), then 100% CH3CN (2 min). LC-MS: m / z = 470.2 [M+H] + ,ESI pos. 1 H NMR(400 MHz,CD3OD):δ ppm 1.43(d,J=6.48 Hz,3 H)2.35-2.40(m,3 H)2.55-2.61(m,3 H)4.72-4.84(m,1 H)6.78-6.84(m,1 H)7.20-7.27(m,1 H)7.34-7.42(m,1 H)7.52-7.62(m,1 H)8.12-8.23(m,1 H)8.51-8.63(m,1 H)8.88(s,1 H)9.00-9.09(m,1 H).

[0277] Example 97 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[3-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-3-pyridyl]ethanol [ka]

[0278] Step 1: tert-butyl 1-(3-acetyl-6-chloro-2-pyridyl)-3-(trifluoromethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate [ka] To a solution of 1-(6-chloro-2-fluoro-3-pyridyl)ethanone (CAS No. 1260663-13-5, 500 mg, 2.88 mmol, 1 equiv.) in DMSO (8 mL) was added DIPEA (745 mg, 5.76 mmol, 2 equiv.) and tert-butyl 3-(trifluoromethyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (839 mg, 2.88 mmol, 1 equiv.). The reaction mixture was stirred at 80 °C for 7 h. The mixture was cooled to room temperature, poured into HO (50 mL), and extracted with EtOAc (3 × 50 mL). The combined organic layers were concentrated, and the residue was purified by flash chromatography (silica gel, 20% EtOAc in petroleum ether). The title compound (1.11 g, 86.6% yield) was obtained as a pale yellow oil. LC-MS: m / z=389.0 [M+H] + ,ESI pos. 1 H NMR (400 MHz, CDCl3): δ=7.83(d,J=8.0 Hz,1H),7.38(d,J=8.0 Hz,1H),4.57(br s,2H),3.77(br t,J=5.3 Hz,2H),3.23(br t,J=5.5 Hz,2H),2.31(s,3H),1.51(s,9H).

[0279] Step 2: tert-butyl 1-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-3-(trifluoromethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate and tert-butyl 1-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-3-(trifluoromethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate [ka] The crude material was purified by preparative NPLC following the procedure described in Step 3 of Example 76, with a reaction time of 72 hours at 50°C: Column Welch Ultimate XB-CN (250 mm x 70 mm x 10 µm). Flow rate: 140 mL / min. Gradient: 35% to 75% (0.1% NH4OH in EtOH v / v) in heptane (15 min), then 0.1% NH4OH in EtOH. Purification with NH4OH (3 min) gave tert-butyl 1-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-3-(trifluoromethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (1.5 g, 40.1% yield) as a brown solid and tert-butyl 1-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-3-(trifluoromethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (1.4 g, 38.2% yield) as a brown solid. Regioisomer 1: LC-MS: m / z = 634.3 [M+H] + ,ESI pos. 1H NMR(400 MHz,CD3OD):δ=8.90(s,1H),8.34(d,J=8.3 Hz,1H),8.30(d,J=1.4 Hz,1H),8.09(d,J=8.9 Hz,1H),8.01(d,J=8.3 Hz,1H),7.63(br d,J=8.4 Hz,1H),7.38(d,J=9.1 Hz,1H),7.15(d,J=9.1 Hz,1H),4.63(s,2H),3.79(br t,J=5.7 Hz,2H),3.21(br t,J=5.4 Hz,2H),2.55(s,3H),2.27(s,3H),1.52(s,9H).Positional isomer 2:LC-MS:m / z=634.3 [M+H] + ,ESI pos. 1 H NMR(400 MHz,CD3OD):δ=8.94(s,1H),8.59(s,1H),8.16(d,J=8.2 Hz,1H),7.78(d,J=8.2 Hz,1H),7.50(d,J=8.8 Hz,1H),7.24-7.18(m,2H),6.97(d,J=9.0 Hz,1H),4.42(s,2H),3.19(d,J=1.1 Hz,2H),3.14-3.06(m,2H),2.40(s,3H),2.14(s,3H),1.31(br s,9H).

[0280] Step 3: 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[3-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-3-pyridyl]ethanone; Hydrochloride [ka] Following the procedure described in Step 2 of Example 72, the crude title compound (1.2 g, 95% yield) was obtained as a light brown solid. LC-MS: m / z=534.2 [M+H] + ,ESI pos.

[0281] Step 4: 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[3-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-3-pyridyl]ethanol [ka] Following the procedure described in Step 6 of Example 93, using MeOH (4 mL) as solvent, the title compound (33.2 mg, 36.3% yield) was obtained as a white lyophilized solid. Purification by preparative HPLC: Column Waters Xbridge (150 mm x 25 mm x 5 μm). Flow rate: 25 mL / min. Gradient: 21% to 51% CHCN in (10 mM NHHCO in H0) (10 min), then 100% CHCN (2 min). LC-MS: m / z=536.2 [M+H] + ,ESI pos. 1 H NMR(400 MHz,CD3OD):δ=8.87(s,1H),8.52(d,J=8.4 Hz,1H),8.19(d,J=1.7 Hz,1H),8.09(dd,J=8.6,14.5 Hz,2H),7.70-7.62(m,1H),7.36(d,J=9.0 Hz,1H),7.13(d,J=9.2 Hz,1H),5.07(q,J=6.3 Hz,1H),4.14(br s,2H),3.28-3.15(m,2H),3.14-3.04(m,1H),3.02-2.93(m,1H),2.53(s,3H),1.47(d,J=6.5 Hz,3H).

[0282] Example 98 1-[6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[3-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-3-pyridyl]ethanol [ka]

[0283] Step 1: 1-[6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[3-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-3-pyridyl]ethanone; Hydrochloride [ka] Following the procedure described in Step 2 of Example 72, tert-butyl 1-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-3-(trifluoromethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (obtained similarly to Step 2 of Example 97) (1.4 g, 2.20 mmol, 1 equivalent) gave the crude title compound (1.12 g, 95% yield) as a light brown solid. LC-MS: m / z=534.2 [M+H] + ,ESI pos.

[0284] Step 2: 1-[6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[3-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-3-pyridyl]ethanol [ka] Following the procedure described in Step 6 of Example 93, using MeOH (4 mL) as solvent, the title compound (10.2 mg, 10.6% yield) was obtained as a yellow lyophilized solid. Purification by preparative HPLC: Column Phenomenex Synergi C18 (150 mm x 25 mm x 10 μm). Flow rate: 25 mL / min. Gradient: 2% to 32% CH3CN in (0.225% formic acid in HO v / v) (8.5 min), then 100% CH3CN (2 min). LC-MS: m / z = 536.2 [M+H] + ,ESI pos. 1H NMR(400 MHz,CD3OD):δ=8.92-8.83(m,2H),8.54(d,J=8.6 Hz,1H),8.50-8.44(m,1H),8.06(d,J=8.4 Hz,1H),7.74-7.66(m,1H),7.40(d,J=9.0 Hz,1H),7.23(dd,J=1.9,8.5 Hz,1H),7.18-7.11(m,1H),5.26(q,J=6.1 Hz,1H),4.43(br s,2H),3.85-3.68(m,1H),3.55-3.46(m,1H),3.45-3.36(m,2H),2.56(s,3H),1.51(d,J=6.5 Hz,3H).

[0285] Example 103 1-[3-(1-hydroxyethyl)-6-[5-[(5-methyl-1,3,4-oxadiazol-2-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka]

[0286] Step 1: 1-[3-acetyl-6-[5-[(5-methyl-1,3,4-oxadiazol-2-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Following the procedure described in Step 1 of Example 81, (5-methyl-1,3,4-oxadiazol-2-yl)amine (25 mg, 0.237 mmol, 2 equivalents) afforded the title compound (15.4 mg, 28.6% yield) as a pale yellow solid. LC-MS: m / z=440.3 [M+H] + ,ESI pos.

[0287] Step 2: 1-[3-(1-hydroxyethyl)-6-[5-[(5-methyl-1,3,4-oxadiazol-2-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Following the procedure described in Step 2 of Example 84, the title compound (8.3 mg, 52.5% yield) was obtained as a white solid. LC-MS: m / z=442.2 [M+H] + ,ESI pos.

[0288] Example 104 2-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka]

[0289] Step 1: 2-(3-acetyl-6-chloro-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile [ka] 1-(3-Acetyl-6-chloro-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile (obtained in Step 1 of Example 64) (6.03 g, 23.12 mmol) was purified by chiral SFC (chiral IG (250 mm x 30 mm x 5 μm). 13% MeOH). The title compound (747 mg, 11.1% yield) was obtained as a white solid. LC-MS: m / z=261.1 [M+H] + ,ESI pos.; 1 H NMR (600 MHz, CDCl3): δ=7.83(d,J=8.0 Hz,1H),7.42(d,J=8.0 Hz,1H),6.89(s,1H),2.35(s,3H),2.28(s,3H).

[0290] Step 2: 2-[3-acetyl-6-(5-bromobenzimidazol-1-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile and 2-[3-acetyl-6-(6-bromobenzimidazol-1-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] To a solution of 2-(3-acetyl-6-chloro-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile (459 mg, 1.76 mmol, 1 equiv.) and 5-bromo-1H-benzimidazole (354 mg, 1.76 mmol, 1.0 equiv.) in DMSO (9 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (402 mg, 398 μL, 2.64 mmol, 1.5 equiv.). The reaction mixture was stirred at 23 °C for 24 h. The mixture was poured into HO and extracted with EtOAc. The organic layer was dried over MgSO, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (25 g silica gel, 0% to 100% in DCM [DCM:MeOH 9:1]). Separation of the regioisomers required further purification by chiral SFC (Chiral OZ-H (250 mm x 20 mm x 5 μm). 50% in MeOH (0.2% diethylamine) gave 2-[3-acetyl-6-(5-bromobenzimidazol-1-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (183.5 mg, 24.4% yield) as an off-white solid and 2-[3-acetyl-6-(6-bromobenzimidazol-1-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (129 mg, 17.1% yield) as an off-white solid. Regioisomer 1: LC-MS: m / z=421.0 [M+H] + ,ESI pos. 1H NMR(600 MHz,DMSO-d6):δ=9.20-9.09(m,1H),8.40(d,J=8.4 Hz,1H),8.31(d,J=8.8 Hz,1H),8.19(d,J=8.4 Hz,1H),8.04(d,J=2.0 Hz,1H),7.58(dd,J=2.0,8.7 Hz,1H),7.48(s,1H),2.33(s,3H),2.30(s,3H) Positional isomer 2:LC-MS:m / z=421.0 [M+H] + ,ESI pos. 1 H NMR(600 MHz,DMSO-d6):δ=9.15(s,1H),8.60(d,J=1.9 Hz,1H),8.48-8.46(m,1H),8.40(d,J=8.3 Hz,1H),8.36-8.32(m,1H),8.23(d,J=8.4 Hz,1H),7.93-7.84(m,1H),7.77(d,J=8.6 Hz,1H),7.55(dd,J=1.9,8.6 Hz,1H),7.50(s,1H),2.44-2.44(m,1H),2.33-2.32(m,1H),2.33(s,2H),2.31(s,3H).

[0291] Step 3: 2-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Argon was bubbled through a suspension of 2-[3-acetyl-6-(5-bromobenzimidazol-1-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (50 mg, 0.119 mmol, 1.0 equiv.), (6-methylpyridazin-3-yl)amine (26 mg, 0.237 mmol, 2 equiv.), and CsCO (116 mg, 0.356 mmol, 3.0 equiv.) in 1,4-dioxane (1.2 mL) at room temperature for 5 min. [tBuBrettPhos Pd(allyl)]OTf (17 mg, 0.024 mmol, 0.2 equiv.) was then added, the vial was sealed, and the mixture was heated to 80 °C and stirring was continued for 2 h. The reaction mixture was cooled to room temperature, adsorbed onto silica gel, and directly purified by flash chromatography (12 g silica gel, 0% to 100% in DCM [DCM / MeOH 9:1]). The title compound (36.8 mg, 65.5% yield) was obtained as a yellow solid. LC-MS: m / z=450.3 [M+H] + ,ESI pos.

[0292] Step 4: 2-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Following the procedure described in Step 2 of Example 84, the title compound was obtained as an off-white solid, 11.3 mg, 30.2% yield. LC-MS: m / z=452.3 [M+H] + ,ESI pos.

[0293] Example 105 (3R)-1-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]pyrrolidine-3-carbonitrile [ka]

[0294] Step 1: (3R)-1-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]pyrrolidine-3-carbonitrile [ka] To a solution of 1-(6-chloro-2-fluoro-3-pyridyl)ethanone (CAS number 1260663-13-5, 400 mg, 2.3 mmol, 1 equiv.) and (R)-pyrrolidine-3-carbonitrile hydrochloride (336 mg, 2.54 mmol, 1.1 equiv.) in DMSO (6 mL) was added DIPEA (1.14 mL, 6.91 mmol, 3 equiv.). The reaction mixture was stirred at 30 °C for 3 h. The mixture was poured into HO (50 mL) and extracted with EtOAc (3 × 50 mL × 3). The combined organic layers were washed with brine (100 mL) and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 20% to 50% EtOAc in petroleum ether). The title compound (680 mg, quantitative yield) was obtained as a pale green oil. LC-MS: m / z = 250.1 [M+H] + ,ESI pos.

[0295] Step 2: (3R)-1-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]pyrrolidine-3-carbonitrile and (3R)-1-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]pyrrolidine-3-carbonitrile [ka] To a solution of (3R)-1-(3-acetyl-6-chloro-2-pyridyl)pyrrolidine-3-carbonitrile (460 mg, 1.84 mmol, 1 equiv.) in DMSO (9 mL) was added N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine (obtained similarly as Intermediate 1 in Example 64) (498 mg, 2.21 mmol, 1.2 equiv.) and KCO (764 mg, 5.53 mmol, 3 equiv.). The brown suspension was then stirred at 80° C. for 16 h. The mixture was cooled to room temperature, poured into HO (80 mL), and extracted with EtOAc (3×80 mL). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative NPLC (Welch Ultimate XB-CN (250 mm x 70 mm x 10 μm), flow rate 140 mL / min, gradient: 55% to 95% EtOH in hexanes (12 min), then 100% EtOH (5 min)) to give (3R)-1-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]pyrrolidine-3-carbonitrile (250 mg, 30.9% yield) as a yellow solid. Positional isomer 1: LC-MS: m / z=439.1 [M+H] + ,ESI pos. 1 H NMR(400 MHz,DMSO-d6):δ=9.20(s,1H),9.01(s,1H),8.36-8.24(m,3H),7.61(dd,J=2.0,8.9 Hz,1H),7.37-7.26(m,2H),7.09(d,J=9.0 Hz,1H),3.72-3.39(m,7H),2.62(s,3H),2.48(br s,3H).Positional isomer 2:LC-MS:m / z=439.1 [M+H] + ,ESI pos. 1H NMR(400 MHz,DMSO-d6):δ=9.54(d,J=1.7 Hz,1H),9.31(s,1H),8.90(s,1H),8.31(d,J=8.3 Hz,1H),7.65(d,J=8.7 Hz,1H),7.35(d,J=9.0 Hz,1H),7.25(d,J=8.3 Hz,1H),7.19(dd,J=2.0,8.7 Hz,1H),7.11(d,J=9.0 Hz,1H),3.97(br dd,J=6.9,11.6 Hz,1H),3.70(br dd,J=5.6,11.6 Hz,1H),3.60-3.42(m,4H),2.62(s,3H),2.52(s,3H),1.05(t,J=7.0 Hz,1H).

[0296] Step 3: (3R)-1-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]pyrrolidine-3-carbonitrile [ka] Following the procedure described in Step 2 of Example 98, the title compound (125 mg, 47.3% yield) was obtained as a yellow solid. Purification by preparative HPLC (Waters Xbridge (150 mm x 25 mm x 5 μm). Flow rate: 25 mL / min. Gradient: 25% to 55% CHCN in (10 mM NHHCO in H0) (8 min), then 100% CHCN (2 min)). LC-MS: m / z=441.1 [M+H] + ,ESI pos. 1H NMR(400 MHz,DMSO-d6):δ=9.15(s,1H),8.84(s,1H),8.31-8.27(m,1H),8.18-8.13(m,1H),7.98(dd,J=3.5,8.1 Hz,1H),7.57(br d,J=9.0 Hz,1H),7.35-7.28(m,2H),7.08(d,J=9.0 Hz,1H),5.05(d,J=6.5 Hz,1H),3.98-3.88(m,1H),3.88-3.79(m,1H),3.79-3.71(m,1H),3.70-3.61(m,1H),3. 61-3.47(m,2H),2.48(s,3H),2.41-2.31(m,1H),2.30-2.19(m,1H),1.39(dd,J=4.6,5.9 Hz,3H).

[0297] Example 106 (3R)-1-[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]pyrrolidine-3-carbonitrile [ka] Following the procedure described in Step 2 of Example 98, starting with (3R)-1-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]pyrrolidine-3-carbonitrile (obtained in Step 2 of Example 105-A) (250 mg, 0.6 mmol, 1 equivalent), the title compound (115 mg, 44.2% yield) was obtained as a yellow solid. Purification by preparative HPLC (Waters Xbridge (150 mm × 25 mm × 5 μm). Flow rate: 25 mL / min. Gradient: 23% to 53% CHCN in (10 mM NHHCO in H2O) (10 min), then 100% CH3CN (2 min)). LC-MS: m / z = 441.1 [M+H] + ,ESI pos. 1H NMR(400 MHz,DMSO-d6):δ=9.41(dd,J=1.7,6.2 Hz,1H),9.26(s,1H),8.70(d,J=4.8 Hz,1H),7.98(dd,J=3.6,8.1 Hz,1H),7.63(d,J=8.6 Hz,1H),7.33(d,J=9.2 Hz,1H),7.25(dd,J=2.2,7.9 Hz,1H),7.17(br d,J=8.7 Hz,1H),7.09(d,J=9.0 Hz,1H),5.07(q,J=6.1 Hz,1H),4.19-4.09(m,1H),3.91-3.81(m,1H),3.77-3.70(m,2H),3.57-3.44( m,2H),2.49-2.48(m,3H),2.40-2.31(m,1H),2.30-2.19(m,1H),1.41(t,J=5.7 Hz,3H).

[0298] Example 107 1-[2-(3,5-dimethylpyrazol-1-yl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol;Formic acid [ka]

[0299] Step 1: 1-[6-chloro-2-(3,5-dimethylpyrazol-1-yl)-3-pyridyl]ethanone [ka] A solution of 3,5-dimethylpyrazole (200 mg, 2.08 mmol, 1 equiv.), 1-(6-chloro-2-fluoro-3-pyridyl)ethanone (CAS no. 1260663-13-5, 361 mg, 2.08 mmol, 1 equiv.), and DIPEA (810 mg, 6.27 mmol, 3.01 equiv.) in DMSO (3 mL) was stirred at 30 °C for 4 h, then at 50 °C for an additional 4 h, then at 80 °C for an additional 4 h, and then at 100 °C for an additional 14 h. The reaction mixture was cooled to room temperature, quenched with HO (30 mL), and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0% to 20% EtOAc in petroleum ether). The title compound (290 mg, 44.7% yield) was obtained as a light brown solid. LC-MS: m / z=250.1 [M+H] + ,ESI pos. 1 H NMR (400 MHz, CDCl3): δ=7.86(d,J=7.9 Hz,1H),7.31(d,J=7.9 Hz,1H),6.07(s,1H),2.58(s,3H),2.24(s,3H),2.06-2.05(m,3H).

[0300] Step 2: 1-[2-(3,5-dimethylpyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone and 1-[2-(3,5-dimethylpyrazol-1-yl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone [ka] A solution of 1-[6-chloro-2-(3,5-dimethylpyrazol-1-yl)-3-pyridyl]ethanone (280 mg, 1.12 mmol, 1 equiv.), N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine (308 mg, 1.37 mmol, 1.22 equiv.), and KCO (476 mg, 3.44 mmol, 3.07 equiv.) in DMSO (3 mL) was stirred at 50° C. for 16 h and then at 80° C. for 4 h. The reaction mixture was cooled to room temperature, quenched with HO (50 mL), and extracted with EtOAc (3×30 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative NPLC (Welch Ultimate XB-CN (250 mm x 50 mm x 10 μm); flow rate: 100 mL / min; gradient: 30% to 70% EtOH in hexanes (15 min), then 100% EtOH (5 min)) to give 1-[2-(3,5-dimethylpyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (90 mg, 18.3% yield) as a brown solid. Positional isomer 1: LC-MS: m / z=439.0 [M+H] + ,ESI pos. 1 H NMR (400 MHz, CDCl3): δ=8.64(s,1H),8.19(d,J=8.3 Hz,1H),8.07(br d,J=8.4 Hz,1H),7.80(d,J=1.8 Hz,1H),7.57(d,J=8.2 Hz,1H),7.40(dd,J=1.7,8.7 Hz,1H),7.24(br d,J=5.0 Hz,2H),6.16(s,1H),2.61(d,J=7.6 Hz,6H),2.30(s,3H),2.09(s,3H).Positional isomer 2:LC-MS:m / z=439.0 [M+H] + ,ESI pos. 1H NMR(400 MHz,CD3OD):δ=8.85(d,J=1.8 Hz,1H),8.81(s,1H),8.34(d,J=8.3 Hz,1H),7.96(d,J=8.2 Hz,1H),7.69(d,J=8.8 Hz,1H),7.47(dd,J=2.0,8.7 Hz,1H),7.35(d,J=9.0 Hz,1H),7.13(d,J=9.2 Hz,1H),6.20(s,1H),2.55(d,J=6.4 Hz,6H),2.25(s,3H),2.04(s,3H).

[0301] Step 3: 1-[2-(3,5-dimethylpyrazol-1-yl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol [ka] To a solution of 1-[2-(3,5-dimethylpyrazol-1-yl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (80 mg, 0.18 mmol, 1 equiv) in MeOH (1 mL) and DCM (9 mL) was added NaBH (21 mg, 0.56 mmol, 3.04 equiv) at 0 °C. The reaction mixture was stirred at 0 °C for 15 min. The mixture was quenched with HO (30 mL) and extracted with DCM (3 × 15 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex Luna C18 (150 mm x 25 mm x 10 μm). Flow rate: 25 mL / min. Gradient: 7% to 37% CH3CN in (0.225% formic acid in HO v / v) (10 min), then 100% CH3CN (2 min)). The title compound (30.4 mg, 37.8% yield) was obtained as a pale yellow lyophilized solid. LC-MS: m / z = 441.3 [M+H] + ,ESI pos. 1H NMR(400 MHz,CD3OD):δ=8.76(s,1H),8.72(s,1H),8.49(d,J=8.4 Hz,1H),8.05(d,J=8.3 Hz,1H),7.69(d,J=8.7 Hz,1H),7.46(d,J=8.8 Hz,1H),7.34(d,J=9.3 Hz,1H),7.15(d,J=9.2 Hz,1H),6.13(s,1H),4.84(m,1H),2.55(s,3H),2.30(d,J=6.6 Hz,6H),1.36(d,J=6.5 Hz,3H).

[0302] Example 108 1-[2-(3,5-dimethylpyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol;Formic acid [ka] Following the procedure described in Step 3 of Example 107, starting with 1-[2-(3,5-dimethylpyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (80 mg, 0.18 mmol, 1 equiv.), the title compound (42.1 mg, 52.4% yield) was obtained as a pale yellow solid. Purification by preparative HPLC (Phenomenex Luna C18 (150 mm x 25 mm x 10 μm). Flow rate: 25 mL / min. Gradient: 7% to 37% CH3CN in (0.225% formic acid in HO v / v) (10 min), then 100% CH3CN (2 min)). LC-MS: m / z = 441.3 [M+H] + ,ESI pos. 1H NMR(400 MHz,CD3OD):δ=8.88(s,1H),8.43(d,J=8.3 Hz,1H),8.21(d,J=1.6 Hz,1H),8.15(d,J=8.9 Hz,1H),8.04(d,J=8.4 Hz,1H),7.61-7.55(m,1H),7.38(d,J=9.3 Hz,1H),7.15(d,J=9.0 Hz,1H),6.18(s,1H),4.84(m,1H),2.54(s,3H),2.32(d,J=6.1 Hz,6H),1.36(d,J=6.5 Hz,3H).

[0303] Example 109 5-Methyl-1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-[(1S)-1-hydroxyethyl]-2-pyridyl]pyrazole-3-carbonitrile [ka] 1-[3-(1-Hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (obtained in a manner similar to Step 3 of Example 64) (400 mg, 0.89 mmol, 1 eq.) was purified by chiral SFC (Daicel Chiralpak AY-H (250 mm x 30 mm x 10 μm). Flow rate: 70 mL / min. 60% (0.1% NHOH in isopropanol). The title compound (157.5 mg, 39.4% yield) was obtained as a white solid. LC-MS: m / z=452.2 [M+H] + ,ESI pos. 1H NMR(400 MHz,CD3OD):δ=8.89(s,1H),8.50(d,J=8.5 Hz,1H),8.22(d,J=1.9 Hz,1H),8.13(dd,J=8.7,15.2 Hz,2H),7.60(dd,J=2.1,8.9 Hz,1H),7.35(d,J=9.1 Hz,1H),7.12(d,J=9.1 Hz,1H),6.87(d,J=0.6 Hz,1H),4.78-4.74(m,1H),2.53(s,3H),2.41(s,3H),1.41(d,J=6.5 Hz,3H).

[0304] The absolute configuration of the asymmetric carbon was assigned by Mosher ester analysis: 3.6 mg (8.0 μmol) of the alcohol was dissolved in CDCl3, and 2.9 μl of pyridine (36.3 μmol, 7 equiv.) was added, followed by (R)-Mosher chloride ((R)-α-methoxy-α-trifluoromethylphenylacetyl chloride, 7.6 μl, 40.2 μmol, 5.0 equiv.) to form the corresponding (S)-Mosher ester. 1 Comparison with the H-NMR spectrum (COSY) shows an upfield shift of the C2-methyl group, thus indicating the (S) configuration of the alcohol.

[0305] Example 110 5-Methyl-1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-[(1R)-1-hydroxyethyl]-2-pyridyl]pyrazole-3-carbonitrile [ka] 1-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (obtained in a manner similar to Step 3 of Example 64) (400 mg, 0.89 mmol, 1 eq.) was purified by chiral SFC (Daicel Chiralpak AY-H (250 mm x 30 mm x 10 μm). Flow rate: 70 mL / min. 60% (0.1% NH4OH in isopropanol)). The title compound (174.5 mg, 43.6% yield) was obtained as a white solid. LC-MS: m / z=452.2 [M+H] + ,ESI pos. 1 H NMR(400 MHz,CD3OD):δ=8.89(s,1H),8.50(d,J=8.4 Hz,1H),8.22(d,J=2.0 Hz,1H),8.16-8.08(m,2H),7.59(dd,J=2.1,8.9 Hz,1H),7.35(d,J=9.3 Hz,1H),7.12(d,J=9.1 Hz,1H),6.87(s,1H),4.79-4.74(m,1H),2.53(s,3H),2.41(s,3H),1.41(d,J=6.5 Hz,3H).

[0306] The absolute configuration of the asymmetric carbon was assigned by Mosher ester analysis: 1.5 mg (3.3 μmol) of the alcohol was dissolved in CDCl3, and 1.9 μl of pyridine (23.8 μmol, 7 equiv.) was added, followed by (R)-Mosher chloride ((R)-α-methoxy-α-trifluoromethylphenylacetyl chloride, 3.1 μl, 16.5 μmol, 5.0 equiv.) to form the corresponding (S)-Mosher ester. 1 Comparison with the H-NMR spectrum (COSY) shows a downfield shift of the C2-methyl group, thus indicating the (R) configuration of the alcohol.

[0307] Example 111 1-[3-(1-hydroxyethyl)-6-[5-[(5-methyl-1,3,4-thiadiazol-2-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka]

[0308] Step 1: 1-[3-acetyl-6-[5-[(5-methyl-1,3,4-thiadiazol-2-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Following the procedure described in Step 3 of Example 104, (5-methyl-1,3,4-thiadiazol-2-yl)amine (27 mg, 0.237 mmol, 2 eq) afforded the title compound (41.3 mg, 73.8% yield) as an off-white solid. LC-MS: m / z=456.3 [M+H] + ,ESI pos.

[0309] Step 2: 1-[3-(1-hydroxyethyl)-6-[5-[(5-methyl-1,3,4-thiadiazol-2-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Following the procedure described in Step 2 of Example 84, the title compound (9 mg, 21% yield) was obtained as a pale yellow solid. LC-MS: m / z=458.3 [M+H] + ,ESI pos.

[0310] Example 113 1-[3-(1-hydroxyethyl)-6-[5-[[1-(oxetan-3-yl)-4-piperidyl]oxy]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka]

[0311] Step 1: 4-(3,4-dinitrophenoxy)-1-(oxetan-3-yl)piperidine [ka] 1-(Oxetan-3-yl)piperidin-4-ol (5.0 g, 31.8 mmol, 1 equiv.) and 3,4-dinitrofluorobenzene (6.51 g, 34.99 mmol, 1.1 equiv.) were dissolved in DMSO (8 mL), potassium tert-butoxide (4.28 g, 38.17 mmol, 1.2 equiv.) was added, and the mixture was stirred at 30 °C for 12 h. The reaction mixture was then poured into HO (50 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was initially purified by flash chromatography (silica gel, 10% MeOH in DCM). The isolated material was then purified by preparative HPLC (Kromasil Eternity XT (250 mm x 80 mm x 10 μm). Flow rate: 100 mL / min. Gradient: 35% to 65% CHCN in (10 mM NHHCO in H0) (18 min), then 100% CHCN (8 min)). The title compound (1.2 g, 11.7% yield) was obtained as a light brown solid. LC-MS: m / z=324.0 [M+H] + ,ESI pos.

[0312] Step 2: 4-[[1-(oxetan-3-yl)-4-piperidyl]oxy]benzene-1,2-diamine [ka] To a solution of 4-(3,4-dinitrophenoxy)-1-(oxetan-3-yl)piperidine (1.2 g, 3.71 mmol, 1 equiv.) in a mixture of MeOH (16 mL) and THF (8 mL) was added 10% Pd / C (197 mg, 0.190 mmol, 0.050 equiv.). The mixture was stirred under H2 (50 psi) at 40 °C for 16 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0% to 20% MeOH in EtOAc). The title compound (800 mg, 81.8% yield) was obtained as a light brown solid. LC-MS: m / z = 264.1 [M+H] + ,ESI pos.

[0313] Step 3: 5-[[1-(oxetan-3-yl)-4-piperidyl]oxy]-1H-benzimidazole [ka] A suspension of 4-[[1-(oxetan-3-yl)-4-piperidyl]oxy]benzene-1,2-diamine (800 mg, 3.04 mmol, 1 equiv.) in trimethyl orthoformate (6.45 g, 60.76 mmol, 20 equiv.) was stirred at 120° C. for 20 h. The reaction mixture was cooled to room temperature and quenched with 1N HCl (1.5 mL) and THF (1.5 mL). The mixture was then stirred at 30° C. for 12 h. The pH of the reaction mixture was adjusted to 7 by adding 1N HCl. The mixture was extracted with EtOAc (2×15 mL). The combined organic layers were concentrated under reduced pressure. The crude title compound (800 mg, 96.3% yield) was obtained as a light brown solid. LC-MS: m / z=274.1 [M+H] + ,ESI pos.

[0314] Step 4: 1-[3-acetyl-6-[5-[[1-(oxetan-3-yl)-4-piperidyl]oxy]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile and 1-[3-acetyl-6-[6-[[1-(oxetan-3-yl)-4-piperidyl]oxy]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] To a solution of 5-[[1-(oxetan-3-yl)-4-piperidyl]oxy]-1H-benzimidazole (400 mg, 1.46 mmol, 1 equiv.) in DMSO (8 mL) was added 1-(3-acetyl-6-chloro-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile (obtained in a manner similar to Step 1 of Example 64) (458 mg, 1.76 mmol, 1.2 equiv.) and K2CO3 (607 mg, 4.39 mmol, 3 equiv.). The reaction mixture was stirred at 30 °C for 12 h. The mixture was then poured into HO (20 mL) and extracted with EtOAc (3 × 25 mL). The combined organic extracts were washed with brine (3 × 15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 10% MeOH in DCM) to give 1-[3-acetyl-6-[5-[[1-(oxetan-3-yl)-4-piperidyl]oxy]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (Rf 0.55, UV detection) (50 mg, 6.9% yield) as a pale yellow oil and 1-[3-acetyl-6-[6-[[1-(oxetan-3-yl)-4-piperidyl]oxy]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (Rf 0.6, UV detection) (50 mg, 6.9% yield) as a pale yellow solid. Regioisomer 1: LC-MS: m / z=498.2 [M+H] + ,ESI pos. 1H NMR (400 MHz, CDCl3): δ=8.60(s,1H),8.30(d,J=8.3 Hz,1H),7.93(d,J=9.0 Hz,1H),7.75(d,J=8.3 Hz,1H),7.39(d,J=2.0 Hz,1H),7.28(s,1H),7.07(dd,J=1.9,8.9 Hz,1H),6.73(s,1H),4.70(br d,J=6.5 Hz,4H),4.52-4.42(m,1H),3.58(br s,1H),2.70-2.60(m,5H),2.32-2.21(m,5H),2.12(br d,J=3.4 Hz,2H),1.96(br s,2H).Positional isomer 2:LC-MS:m / z=498.2 [M+H] + ,ESI pos. 1 H NMR (400 MHz, CDCl3): δ=8.51(s,1H),8.33-8.28(m,1H),7.75(d,J=8.6 Hz,2H),7.57(d,J=2.1 Hz,1H),7.03(dd,J=2.2,8.8 Hz,1H),6.71(s,1H),4.70-4.62(m,4H),4.40-4.32(m,1H),3.57-3.50(m,1H),2.63-2.56(m,5H),2.23-2.15(m,5H),2.02(br d,J=4.2 Hz,2H),1.94-1.84(m,2H).

[0315] Step 5: 1-[3-(1-hydroxyethyl)-6-[5-[[1-(oxetan-3-yl)-4-piperidyl]oxy]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] To a clear, light brown solution of 1-[3-acetyl-6-[5-[[1-(oxetan-3-yl)-4-piperidyl]oxy]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (50 mg, 0.1 mmol, 1 equiv.) in a mixture of MeOH (2.5 mL) and DCM (0.5 mL) was added NaBH (11 mg, 0.3 mmol, 3 equiv.) at 0 °C. Stirring at 0 °C was continued for 1 h. The mixture was quenched with saturated NH Cl (5 mL) at 0 °C and extracted with EtOAc (2 × 10 mL). The combined organic layers were dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC: column Waters Xbridge (150 mm × 25 mm × 5 μm). Flow rate: 25 mL / min. Gradient: 25% to 55% CHCN in (10 mM NHHCO in H0) (9 min), then 100% CHCN (0.5 min). The title compound (20.5 mg, 40.8% yield) was obtained as an off-white solid. LC-MS: m / z = 500.2 [M+H] + ,ESI pos. 1 H NMR(400 MHz,CD3OD):δ=8.91(s,1H),8.51(d,J=8.4 Hz,1H),8.14(d,J=8.4 Hz,1H),8.09(d,J=9.0 Hz,1H),7.32(d,J=2.1 Hz,1H),7.08(dd,J=2.3,9.0 Hz,1H),6.88(s,1H),4.80-4.71(m,3H),4.64(d,J=6.4 Hz,2H),4.58-4.51(m,1H),3.67-3.59(m,1H),2.76-2.66(m,2H),2.41(s,3H),2.37(br dd,J=4.3,5.6 Hz,2H),2.13-2.07(m,2H),1.94-1.86(m,2H),1.43(d,J=6.5 Hz,3H).

[0316] Example 114 1-[3-(1-hydroxyethyl)-6-[6-[[1-(oxetan-3-yl)-4-piperidyl]oxy]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Following the procedure described in Step 5 of Example 113, starting with 1-[3-acetyl-6-[6-[[1-(oxetan-3-yl)-4-piperidyl]oxy]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (obtained in Step 4 of Example 113) (50 mg, 0.1 mmol, 1 equiv.), MeOH (2.5 mL) was used as solvent to give the title compound (17 mg, 33.9% yield) as an off-white lyophilized solid. Purification by preparative HPLC (Waters Xbridge (150 mm × 25 mm × 5 μm). Flow rate: 25 mL / min. Gradient: 22% to 52% CHCN in (10 mM NHHCO in HO) (9 min), then 100% CHCN (2 min)). LC-MS: m / z=508.2 [M+H] + ,ESI pos. 1 H NMR(400 MHz,CD3OD):δ=8.83(s,1H),8.50(d,J=8.4 Hz,1H),8.13(d,J=8.6 Hz,1H),7.78(d,J=2.1 Hz,1H),7.62(d,J=8.8 Hz,1H),7.00(dd,J=2.2,8.8 Hz,1H),6.92(s,1H),4.79-4.72(m,3H),4.63(t,J=6.2 Hz,2H),4.28(br s,1H),3.58(quin,J=6.4 Hz,1H),2.67(br s,2H),2.39(s,3H),2.12(br s,2H),2.07-1.99(m,2H),1.85-1.76(m,2H),1.43(d,J=6.5 Hz,3H).

[0317] Example 115 1-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]pyrazole-3-carbonitrile [ka]

[0318] Step 1: 1-(3-acetyl-6-chloro-2-pyridyl)pyrazole-3-carbonitrile [ka] A solution of 1H-pyrazole-3-carbonitrile (200 mg, 2.15 mmol, 1 equiv.), 1-(6-chloro-2-fluoro-3-pyridyl)ethanone (CAS number 1260663-13-5, 375 mg, 2.16 mmol, 1 equiv.) and DIPEA (840 mg, 6.5 mmol, 3 equiv.) in DMSO (4 mL) was stirred at 30° C. for 16 h. The reaction mixture was quenched with HO (30 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, 20% EtOAc in petroleum ether, UV detection). The title compound (300 mg, 56.6% yield) was obtained as a white solid. LC-MS: m / z=247.2 [M+H] + ,ESI pos. 1 H NMR (400 MHz, CDCl3): δ=8.56(d,J=2.7 Hz,1H),7.78(d,J=7.9 Hz,1H),7.43(d,J=7.9 Hz,1H),6.89(d,J=2.7 Hz,1H),2.44(s,3H).

[0319] Step 2: 1-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]pyrazole-3-carbonitrile [ka] Following the procedure described in Step 4 of Example 113, N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine (obtained similarly as Intermediate 1 in Example 64) (319 mg, 1.42 mmol, 1.2 equiv) was used to obtain the crude material, which was then first purified by preparative HPLC (Phenomenex Luna C18 (150 mm × 25 mm × 10 μm). Flow rate: 25 mL / min. Gradient: 11% to 41% CHCN in (0.225% formic acid in HO v / v) (10 min), then 100% CHCN (2 min)). Further purification by preparative NPLC (Welch Ultimate XB-CN (250 mm × 50 mm × 10 μm). Flow rate: 100 mL / min. Gradient: 40% to 80% EtOH in hexanes (0.1% NH4OH v / v in 15 min, then 100% EtOH in 5 min) gave 1-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]pyrazole-3-carbonitrile (80 mg, 15.6% yield) as a brown solid and 1-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]pyrazole-3-carbonitrile (50 mg, 9.8% yield) as a brown solid. Regioisomer 1: LC-MS: m / z = 436.3 [M+H] + ,ESI pos. 1 H NMR(400 MHz,CD3OD):δ=8.99(s,1H),8.83(d,J=2.7 Hz,1H),8.29-8.21(m,4H),8.03(d,J=8.3 Hz,1H),7.69(dd,J=1.7,8.8 Hz,1H),7.37(d,J=9.3 Hz,1H),7.18-7.12(m,2H),2.54(s,3H),2.41(s,3H).Positional isomer 2:LC-MS:m / z=436.3 [M+H] + ,ESI pos. 1H NMR(400 MHz,CD3OD):δ=9.44(d,J=2.1 Hz,1H),9.18(d,J=2.7 Hz,1H),8.92(s,1H),8.26-8.23(m,2H),8.04(d,J=8.2 Hz,1H),7.68(d,J=8.7 Hz,1H),7.39(d,J=9.2 Hz,1H),7.30(dd,J=2.0,8.7 Hz,1H),7.15(d,J=9.3 Hz,1H),7.08(d,J=2.8 Hz,1H),2.59(s,3H),2.42(s,3H).

[0320] Step 3: 1-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]pyrazole-3-carbonitrile [ka] Following the procedure described in Step 3 of Example 107, the title compound (6.9 mg, 8.2% yield) was obtained as a pale yellow lyophilized solid. Purification by preparative HPLC (Phenomenex Luna C18 (150 mm x 25 mm x 10 μm). Flow rate: 25 mL / min. Gradient: 9% to 39% CH3CN in (0.225% formic acid in HO v / v) (10 min), then 100% CH3CN (2 min)). LC-MS: m / z = 438.1 [M+H] + ,ESI pos. 1 H NMR(400 MHz,CD3OD):δ=8.93(s,1H),8.68(d,J=2.7 Hz,1H),8.54(d,J=8.2 Hz,1H),8.23(d,J=1.8 Hz,1H),8.17(d,J=8.9 Hz,1H),8.04(d,J=8.6 Hz,1H),7.64(dd,J=1.9,8.9 Hz,1H),7.37(d,J=9.3 Hz,1H),7.16-7.11(m,2H),5.50(q,J=6.2 Hz,1H),2.54(s,3H),1.51(d,J=6.4 Hz,3H).

[0321] Example 116 1-[[[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]amino]methyl]cyclopropanecarbonitrile;Formic acid [ka]

[0322] Step 1: 1-[[(3-acetyl-6-chloro-2-pyridyl)amino]methyl]cyclopropanecarbonitrile [ka] To a solution of 1-(6-chloro-2-fluoro-3-pyridyl)ethanone (CAS number 1260663-13-5, 1.05 g, 6.05 mmol, 1 equiv.), 1-(aminomethyl)cyclopropanecarbonitrile hydrochloride (963 mg, 7.26 mmol, 1.2 equiv.) in DMSO (20 mL), DIPEA (3 mL, 18.15 mmol, 3 equiv.) was added and stirring was continued at 30 °C for 12 h. The mixture was poured into HO (200 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude title compound (1.5 g, 99.3% yield) was obtained as a yellow solid. LC-MS: m / z = 250.0 [M+H] + ,ESI pos.

[0323] Step 2: 1-[[[3-acetyl-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]amino]methyl]cyclopropanecarbonitrile and 1-[[[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]amino]methyl]cyclopropanecarbonitrile [ka] Following the procedure described in Step 2 of Example 115, crude material was obtained and purified by preparative NPLC (Welch Ultimate XB-SiOH (250 mm × 70 mm × 10 μm). Flow rate: 140 mL / min. Gradient: 20% to 60% (EtOH) in heptane (20 min), then 100% EtOH (3 min)) to give 1-[[[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]amino]methyl]cyclopropanecarbonitrile (200 mg, 28.5% yield) as a brown solid and 1-[[[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]amino]methyl]cyclopropanecarbonitrile (170 mg, 24.2% yield) as a yellow solid. Positional isomer 1: LC-MS: m / z=439.1 [M+H] + ,ESI pos. 1 H NMR(400 MHz,DMSO-d6):δ=9.56(t,J=5.6 Hz,1H),9.40(d,J=1.9 Hz,1H),9.32(s,1H),8.93(s,1H),8.47(d,J=8.5 Hz,1H),7.67(d,J=8.8 Hz,1H),7.36(d,J=9.1 Hz,1H),7.24(dd,J=2.0,8.6 Hz,1H),7.19(d,J=8.4 Hz,1H),7.12(d,J=9.1 Hz,1H),4.03-3.94(m,2H),2.62(s,3H),2.49-2.48(m,3H),1.16-1.12(m,2H),1.03-0.98(m,2H).Positional isomer 2:LC-MS:m / z=439.1 [M+H] + ,ESI pos. 1H NMR(400 MHz,DMSO-d6):δ=9.50(br t,J=6.1 Hz,1H),9.35(s,1H),9.06(s,1H),8.45(d,J=8.5 Hz,1H),8.38(d,J=2.0 Hz,1H),8.26(d,J=8.9 Hz,1H),7.62(dd,J=2.0,8.9 Hz,1H),7.37(d,J=9.0 Hz,1H),7.23(d,J=8.5 Hz,1H),7.15(d,J=9.1 Hz,1H),3.88(d,J=6.0 Hz,2H),2.61(s,3H),2.49-2.49(m,3H),1.26(t,J=3.0 Hz,2H),1.21-1.16(m,2H),1.05(t,J=7.0 Hz,1H).

[0324] Step 3: 1-[[[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]amino]methyl]cyclopropanecarbonitrile; formic acid [ka] Following the procedure described in Step 3 of Example 107, using a mixture of MeOH (5 mL) and DMF (3 mL) as the solvent, the title compound (39.5 mg, 21.8% yield) was obtained as a white lyophilized solid. Purification by preparative HPLC (Phenomenex Luna C18 (150 mm x 25 mm x 10 μm). Flow rate: 25 mL / min. Gradient: 6% to 36% CH3CN in (0.225% formic acid in HO v / v) (10 min), then 100% CH3CN (2 min)). LC-MS: m / z = 441.3 [M+H] + ,ESI pos. 1H NMR(400 MHz,DMSO-d6):δ=9.18(br s,1H),8.82(s,1H),8.36(d,J=1.8 Hz,1H),8.15(s,1H),8.09(d,J=8.8 Hz,1H),7.65(d,J=7.8 Hz,1H),7.52(dd,J=1.8,8.9 Hz,1H),7.32(d,J=9.0 Hz,1H),7.08(d,J=9.0 Hz,1H),7.03(d,J=7.8 Hz,1H),6.84(t,J=6.0 Hz,1H),4.86(q,J=6.2 Hz,1H),3.74(br dd,J=2.4,5.7 Hz,2H),2.47(s,3H),1.40(d,J=6.4 Hz,3H),1.22-1.17(m,2H),1.16-1.10(m,2H).

[0325] Example 117 1-[[[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]amino]methyl]cyclopropanecarbonitrile;Formic acid [ka] Following the procedure described in Step 3 of Example 115, 1-[[[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]amino]methyl]cyclopropanecarbonitrile (obtained in Step 2 of Example 116) (180 mg, 0.41 mmol, 1 equivalent) gave the title compound (69 mg, 37% yield) as a white lyophilized solid. Purification by preparative HPLC (Phenomenex Luna C18 (150 mm x 25 mm x 10 μm). Flow rate: 25 mL / min. Gradient: 6% to 36% CH3CN in (0.225% formic acid in HO v / v) (10 min), then 100% CH3CN (2 min)). LC-MS: m / z = 441.2 [M+H] + ,ESI pos. 1H NMR(400 MHz,DMSO-d6):δ=9.26(br s,1H),9.18(d,J=1.8 Hz,1H),8.69(s,1H),8.19(s,1H),7.65(dd,J=3.4,8.3 Hz,2H),7.33(d,J=9.0 Hz,1H),7.23(dd,J=2.0,8.7 Hz,1H),7.10(d,J=9.0 Hz,1H),6.98(d,J=7.8 Hz,1H),6.88(t,J=5.7 Hz,1H),4.90(q,J=6.4 Hz,1H),3.86-3.74(m,2H),2.48(s,3H),1.43(d,J=6.4 Hz,3H),1.11-1.06(m,2H),1.05-0.99(m,2H).

[0326] Example 118 5-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]pyridine-3-carbonitrile; Formic acid [ka]

[0327] Step 1: 5-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]pyridine-3-carbonitrile [ka] Following the procedure described in Step 3 of Example 76, 5-cyanopyridine-3-boronic acid (52 mg, 0.35 mmol, 1.2 equivalents) was used, and the crude material obtained was purified by preparative TLC (silica gel, 10% MeOH in DCM, UV detection) with a reaction time of 3 hours. The title compound (110 mg, 84.8% yield) was obtained as a yellow solid. LC-MS: m / z=447.3 [M+H] + ,ESI pos.

[0328] Step 2: 5-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]pyridine-3-carbonitrile [ka] Following the procedure described in Step 5 of Example 113, the title compound (20 mg, 16.3% yield) was obtained as a brown lyophilized solid. Purification by preparative HPLC (Phenomenex Luna C18 (150 mm x 25 mm x 10 μm). Flow rate: 25 mL / min. Gradient: 5% to 35% CH3CN in (0.225% formic acid in HO v / v) (10 min), then 100% CH3CN (2 min)). LC-MS: m / z = 449.1 [M+H] + ,ESI pos. 1 H NMR(400 MHz,DMSO-d6):δ=9.21(s,1H),9.17(br s,2H),9.01(s,1H),8.67(s,1H),8.42(s,1H),8.32(br d,J=8.6 Hz,1H),8.11(br dd,J=8.7,15.5 Hz,2H),7.48(br d,J=8.4 Hz,1H),7.32(br d,J=8.9 Hz,1H),7.08(br d,J=9.0 Hz,1H),4.85-4.76(m,1H),3.17(s,1H),2.47(br s,3H),1.39(br d,J=6.2Hz,3H).

[0329] Example 119 1-[3-(1-hydroxyethyl)-6-[5-(1,2,4-triazin-3-ylamino)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka]

[0330] Step 1: 1-[3-acetyl-6-[5-(1,2,4-triazin-3-ylamino)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Following the procedure described in Step 3 of Example 104, 1,2,4-triazin-3-ylamine (23 mg, 0.237 mmol, 2 eq.) afforded the title compound (56.7 mg, quantitative yield) as a yellow solid. LC-MS: m / z=437.3 [M+H] + ,ESI pos.

[0331] Step 2: 1-[3-(1-hydroxyethyl)-6-[5-(1,2,4-triazin-3-ylamino)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Following the procedure described in Step 2 of Example 84, the title compound (8.4 mg, 14.5% yield) was obtained as a yellow solid. LC-MS: m / z=439.2 [M+H] + ,ESI pos.

[0332] Example 120 1-[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-3-methyl-pyrrolidine-3-carbonitrile [ka]

[0333] Step 1: 1-(3-acetyl-6-chloro-2-pyridyl)-3-methyl-pyrrolidine-3-carbonitrile [ka] A solution of 1-(6-chloro-2-fluoro-3-pyridyl)ethanone (CAS number 1260663-13-5, 400 mg, 2.3 mmol, 1 equiv.), 3-methylpyrrolidine-3-carbonitrile hydrochloride (338 mg, 2.3 mmol, 1 equiv.), and DIPEA (1.14 mL, 6.91 mmol, 3 equiv.) in DMSO (4 mL) was stirred at 100 °C for 3 h. The reaction mixture was cooled to room temperature, poured into HO (10 mL), and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL) and concentrated to dryness. The crude title compound (300 mg, 98.7% yield) was obtained as a yellow oil. LC-MS: m / z = 264.2 [M+H] + ,ESI pos.

[0334] Step 2: 1-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-3-methyl-pyrrolidine-3-carbonitrile; formic acid and 1-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-3-methyl-pyrrolidine-3-carbonitrile; formic acid [ka] Following the procedure described in Step 4 of Example 113, with a reaction time of 16 hours at 100°C, the reaction mixture was cooled to room temperature, filtered, and purified directly by preparative HPLC (Phenomenex Luna C18 (150 mm x 40 mm x 15 μm). Flow rate: 60 mL / min. Gradient: 10% to 40% CH3CN in (0.225% formic acid in HO v / v) (13 min), then 100% CH3CN (2 min)). A mixture of both title compounds (454 mg) was obtained. This mixture was further purified by preparative NPLC (Welch Ultimate XB-SiOH (250 mm × 70 mm × 10 μm). Flow rate: 140 mL / min. Gradient: 45% to 85% EtOH in hexanes (12 min), then 100% EtOH (5 min)) to give 1-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-3-methyl-pyrrolidine-3-carbonitrile; formic acid (200 mg, 29.1% yield) as a yellow solid and 1-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-3-methyl-pyrrolidine-3-carbonitrile; formic acid (190 mg, 27.7% yield) as a pale yellow oil. Positional isomer 1: LC-MS: m / z=453.3 [M+H] + ,ESI pos. 1 H NMR (400 MHz, CDCl3):δ=8.61-8.57(m,1H),8.16-8.08(m,2H),7.76-7.72(m,1H),7.43- 7.39(m,1H),7.14(s,1H),6.97-6.93(m,1H),5.31(s,1H),4.00-3.88(m,1H),3 .84-3.75(m,1H),3.50-3.41(m,2H),2.67-2.64(m,3H),2.62-2.59(m,3H),2.5 7-2.49(m,1H),2.17-2.11(m,1H),1.63-1.59(m,3H).Positional isomer 2:LC-MS:m / z=453.3 [M+H] + ,ESI pos.

[0335] Step 3: 1-[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-3-methyl-pyrrolidine-3-carbonitrile [ka] Following the procedure described in Step 5 of Example 113, the title compound (88.9 mg, 22.1% yield) was obtained as a white lyophilized solid. Purification by preparative HPLC (Waters Xbridge (150 mm x 25 mm x 5 μm). Flow rate: 25 mL / min. Gradient: 27% to 57% CHCN in (10 mM NHHCO in H0) (8 min), then 100% CHCN (2 min)). LC-MS: m / z=455.2 [M+H] + ,ESI pos. 1 H NMR(400 MHz, CDCl3):δ=8.54-8.47(m,1H),8.42-8.35(m,1H),7.96-7.89(m,1H),7.75-7.68( m,1H),7.66-7.38(m,1H),7.22-7.17(m,1H),7.16-7.12(m,1H),7.10-7.05(m,1H),6 .98-6.92(m,1H),5.23-5.14(m,1H),4.13-3.86(m,1H),3.78-3.56(m,2H),2.64-2.5 7(m,3H),2.49-2.41(m,1H),2.05-1.99(m,1H),1.61-1.53(m,3H),1.52-1.47(m,3H).

[0336] Example 121 1-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-3-methyl-pyrrolidine-3-carbonitrile [ka] Following the procedure described in Step 5 of Example 113, 1-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-3-methyl-pyrrolidine-3-carbonitrile (obtained in Step 2 of Example 120) (150 mg, 0.33 mmol, 1 equivalent) gave the title compound (52.5 mg, 34.3% yield) as a white lyophilized solid. Purification by preparative HPLC (Waters Xbridge (150 mm × 25 mm × 5 μm). Flow rate: 25 mL / min. Gradient: 27% to 57% CHCN in (10 mM NHHCO in H2O) (8 min), then 100% CH3CN (2 min)). LC-MS: m / z = 455.3 [M+H] + ,ESI pos. 1 H NMR(400 MHz,DMSO-d6):δ=9.20-9.12(m,1H),8.88-8.80(m,1H),8.33-8.28(m,1H),8.17-8. 10(m,1H),8.03-7.93(m,1H),7.62-7.54(m,1H),7.35-7.27(m,2H),7.12-7.04(m,1H ),5.34-5.21(m,1H),5.09-5.00(m,1H),4.08-3.97(m,1H),3.91-3.62(m,3H),2.48 (s,3H),2.45-2.39(m,1H),2.18-2.05(m,1H),1.59-1.49(m,3H),1.47-1.33(m,3H).

[0337] Example 122 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]-3-pyridyl]ethanol [ka]

[0338] Step 1: 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]-3-pyridyl]ethanone [ka] Following the procedure described in Step 3 of Example 76, 1-methyl-3-(trifluoromethyl)pyrazole-5-boronic acid pinacol ester (41 mg, 0.150 mmol, 1.4 equiv.) was used. The reaction mixture was cooled to room temperature and filtered. The filter cake was placed in MeOH (30 mL) and the suspension was stirred at 30° C. for 1 h. The mixture was filtered and the filtrate was concentrated to leave the title compound (35 mg, 67.3% yield) as a yellow solid. LC-MS: m / z=493.2 [M+H] + ,ESI pos.

[0339] Step 2: 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]-3-pyridyl]ethanol [ka] Following the procedure described in Step 5 of Example 113, the title compound (2.4 mg, 6.4% yield) was obtained as a white lyophilized solid. LC-MS: m / z=495.2 [M+H] + ,ESI pos. 1 H NMR(400 MHz,CD3OD):δ=8.90(s,1H),8.39(d,J=8.8 Hz,1H),8.24(d,J=2.0 Hz,1H),8.14(d,J=8.8 Hz,1H),8.05(d,J=8.8 Hz,1H),7.64-7.55(m,1H),7.35(d,J=9.2 Hz,1H),7.13(d,J=9.2 Hz,1H),6.92(s,1H),4.98-4.95(m,1H),3.95(s,3H),2.53(s,3H),1.47(d,J=6.4 Hz,3H).

[0340] Example 123 1-[3-(1-hydroxyethyl)-6-[5-(isoxazol-3-ylamino)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka]

[0341] Step 1: 1-[3-acetyl-6-[5-(isoxazol-3-ylamino)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Following the procedure described in Step 3 of Example 104, using 3-aminoisoxazole (21 mg, 19 μL, 0.237 mmol, 2 eq.), the title compound (9.3 mg, 17.2% yield) was obtained as a pale yellow solid. LC-MS: m / z=425.3 [M+H] + ,ESI pos.

[0342] Step 2: 1-[3-(1-hydroxyethyl)-6-[5-(isoxazol-3-ylamino)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Following the procedure described in Step 2 of Example 84, the title compound (6.1 mg, 65.7% yield) was obtained as a pale yellow solid. LC-MS: m / z=427.2 [M+H] + ,ESI pos.

[0343] Example 124 3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)pyridine-2-carboxamide; Formic acid [ka]

[0344] Step 1: 3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)pyridine-2-carboxamide [ka] To a suspension of 2,2,2-trifluoroethylamine (3.0 mL, 142.43 mmol, 270 equiv.) and 1-[2-chloro-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (obtained as in Step 2 of Example 76) (200 mg, 0.53 mmol, 1 equiv.) in DMF (3 mL), dppf (117 mg, 0.21 mmol, 0.4 equiv.), Pd(OAc) (24 mg, 0.11 mmol, 0.2 equiv.), and NEt (0.22 mL, 1.58 mmol, 3 equiv.) were added. The reaction mixture was then stirred at 70 °C under CO (50 psi) for 16 h. The reaction mixture was cooled to room temperature, poured into HO (50 mL), and extracted with DCM (4 × 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative TLC (silica gel, 10% MeOH in DCM, UV detection). The title compound (50 mg, 20.2% yield) was obtained as a light brown solid. LC-MS: m / z=470.3 [M+H] + ,ESI pos.

[0345] Step 2: 3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)pyridine-2-carboxamide; formic acid [ka] To a solution of 3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)pyridine-2-carboxamide (58 mg, 0.12 mmol, 1 equiv.) in a mixture of MeOH (2 mL) and DMF (2 mL), NaBH (14 mg, 0.37 mmol, 3 equiv.) was added at 0 °C. The mixture was then stirred at 20 °C for 1 h. The reaction mixture was directly purified by preparative HPLC: column Phenomenex Luna C18 (150 mm × 25 mm × 10 μm). Flow rate: 25 mL / min. Gradient: 10% to 40% CHCN in (0.225% formic acid in HO v / v) (10 min), then 100% CHCN (2 min). The title compound (9.1 mg, 14.8% yield) was obtained as a yellow lyophilized solid. LC-MS: m / z=472.1 [M+H] + ,ESI pos. 1 H NMR(400 MHz,CD3OD):δ=9.05(s,1H),8.49(d,J=8.6 Hz,1H),8.24(d,J=2.0 Hz,1H),8.22(d,J=8.9 Hz,1H),8.11(s,1H),8.09(s,1H),7.62(dd,J=2.1,8.8 Hz,1H),7.59(d,J=9.2 Hz,1H),7.38(d,J=9.3 Hz,1H),5.75(q,J=6.3 Hz,1H),4.25-4.11(m,2H),2.61(s,3H),1.54(d,J=6.4 Hz,3H).

[0346] Example 125 1-[6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[(3aR,6aS)-2,3,3a,5,6,6a-hexahydro-1H-pyrrolo[3,2-b]pyrrol-4-yl]-3-pyridyl]ethanol; Formic acid [ka]

[0347] Step 1: rac-trans-1-(3-acetyl-6-chloro-2-pyridyl)-2,3,3a,5,6,6a-hexahydropyrrolo[3,2-b]pyrrole-4-carboxylate [ka] Following the procedure described in Step 4 of Example 113, using rac-trans-hexahydro-pyrrolo[3,2-b]pyrrole-1-carboxylic acid tert-butyl ester (856 mg, 4.03 mmol, 1 equiv.), the title compound (1.28 g, 86.1% yield) was obtained as a colorless oil. LC-MS: m / z=366.1 [M+H] + ,ESI pos.

[0348] Step 2: tert-butyl rac-trans-1-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-2,3,3a,5,6,6a-hexahydropyrrolo[3,2-b]pyrrole-4-carboxylate and tert-butyl rac-trans-1-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-2,3,3a,5,6,6a-hexahydropyrrolo[3,2-b]pyrrole-4-carboxylate [ka] Following the procedure described in Step 2 of Example 120, with an additional reaction time of 6 hours at 110°C, the reaction mixture was cooled to room temperature, poured into HO (100 mL), and extracted with DCM (3 x 100 mL). The combined organic extracts were washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Phenomenex Luna C18 (250 mm x 70 mm x 10 μm). Flow rate: 140 mL / min. Gradient: 23% to 50% CHCN in (0.225% formic acid in HO v / v) (20 min), then 100% CHCN (5 min)). A mixture of both title compounds (800 mg) was isolated and further purified by preparative NPLC (Welch Ultimate XB-CN (250 mm × 70 mm × 10 μm). Flow rate: 140 mL / min. Gradient: 30% to 70% (EtOH with 0.1% NHOH v / v) in hexanes (12 min), then 100% EtOH (5 min)). tert-Butyl rac-trans-1-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-2,3,3a,5,6,6a-hexahydropyrrolo[3,2-b]pyrrole-4-carboxylate (350 mg, 18% yield) was obtained as a yellow solid, and tert-butyl rac-trans-1-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-2,3,3a,5,6,6a-hexahydropyrrolo[3,2-b]pyrrole-4-carboxylate (420 mg, 21.6% yield) was obtained as a yellow solid. Regioisomer 1: LC-MS: m / z = 555.3 [M+H] + ,ESI pos. 1H NMR (400 MHz, CDCl3): δ=8.47(s,1H),8.02(d,J=8.1 Hz,1H),7.92(d,J=8.8 Hz,1H),7.70(d,J=2.0 Hz,1H),7.34-7.28(m,1H),7.12-7.05(m,2H),6.91(d,J=8.1 Hz,1H),4.12(dt,J=6.8,10.8 Hz,1H),3.82-3.71(m,3H),3.06(br dd,J=8.5,10.8 Hz, 1H), 2.55 (s, 3H), 2.52 (s, 3H), 2.51-2.40 (m, 3H), 2.03-1.89 (m, 1H), 1.79 (quin, J = 10.5 Hz, 1H), 1.42 (s, 9H). Positional isomer 2: LC-MS: m / z = 555.3 [M+H] + ,ESI pos. 1 H NMR (400 MHz, CDCl3): δ=8.74-8.59(m,1H),8.36(s,1H),8.00(d,J=8.1 Hz,1H),7.69(d,J=8.6 Hz,1H),7.32-7.23(m,1H),7.10-7.03(m,2H),6.90(dd,J=8.7,10.4 Hz,2H),4.08(dt,J=6.6,10.8 Hz,1H),3.84(dt,J=4.8,11.0 Hz,1H),3.69-3.61(m,2H),3.02(br dd,J=8.5,10.8 Hz,1H),2.53(s,3H),2.51(s,3H),2.48-2.39(m,2H),2.05-1.95(m,2H),1.74-1.65(m,1H),1.40(s,9H).

[0349] Engineering 3:1-[6-[6-[(6-メチルピリダジン-3-イル)アミノ]ベンズイミダゾール-1-イル]-2-[rac-トランス-2,3,3a,5,6,6a-ヘキサヒドロ-1H-ピロロ[3,2-b]ピロール-4-イル]-3-ピリジル]エタノン

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[0350] Step 4: 1-[6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[(3aR,6aS)-2,3,3a,5,6,6a-hexahydro-1H-pyrrolo[3,2-b]pyrrol-4-yl]-3-pyridyl]ethanol; formic acid [ka] To a solution of 1-[6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[rac-trans-2,3,3a,5,6,6a-hexahydro-1H-pyrrolo[3,2-b]pyrrol-4-yl]-3-pyridyl]ethanone (250 mg, 0.55 mmol, 1 equiv.) in MeOH (3 mL) was added NaBH (62 mg, 1.65 mmol, 3 equiv.) at 0 °C. The mixture was then stirred at 20 °C for 1 h. NaBH (62.43 mg, 1.65 mmol, 3 equiv.) was added to the solution. The reaction mixture was stirred at 20 °C for an additional 1 h. The mixture was diluted with HO (30 mL) and extracted with (DCM / MeOH 9:1) (6 × 30 mL). The combined organic layers were dried over NaSO, filtered, and concentrated. The residue was purified by preparative HPLC (Unisil 3-100 C18 Ultra (150 mm × 50 mm × 10 μm). Flow rate: 25 mL / min. Gradient: 1% to 30% CH3CN in (0.225% formic acid in H2O v / v) (10 min), then 100% Purification by CH3CN (2 min) gave 1-[6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[(3aR,6aS)-2,3,3a,5,6,6a-hexahydro-1H-pyrrolo[3,2-b]pyrrol-4-yl]-3-pyridyl]ethanol; formic acid (32 mg, 12.7% yield) as an off-white lyophilized solid and 1-[6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[(3aS,6aR)-2,3,3a,5,6,6a-hexahydro-1H-pyrrolo[3,2-b]pyrrol-4-yl]-3-pyridyl]ethanol (71.9 mg, 28.1% yield) as a yellow lyophilized solid. Positional isomer 1: LC-MS: m / z=457.2 [M+H] + ,ESI pos. 1H NMR (400 MHz, DMSO-d6): δ=9.50(s,1H),9.01(s,1H),8.64(s,1H),8.40(s,1H),8.03(d,J=8.1 Hz,1H),7.67(d,J=8.6 Hz,1H),7.42(d,J=9.1 Hz,1H),7.34(dd,J=1.8,8.6 Hz,1H),7.27(d,J=8.1 Hz,1H),7.19(d,J=9.1 Hz,1H),5.01(q,J=6.0 Hz, 1H), 4.40-4.25 (m, 2H), 3.81-3.76 (m, 1H), 3.56-3.48 (m, 3H), 2.49 (s, 3H), 2.30-2.22 (m, 1H), 2.20-2.05 (m, 2H), 1.51-1.39 (m, 1H), 1.32 (d, J=6.3 Hz, 3H). Positional isomer 2: LC-MS: m / z=457.2 [M+H] + ,ESI pos. 1 H NMR (400 MHz, DMSO-d6): δ=9.55(s,1H),8.96(d,J=1.4 Hz,1H),8.66(s,1H),8.40(s,1H),7.98(d,J=8.0 Hz,1H),7.67(d,J=8.8 Hz,1H),7.42(d,J=9.1 Hz,1H),7.38(dd,J=1.7,8.7 Hz,1H),7.33(d,J=8.0 Hz,1H),7.20(d,J=9.1 Hz,1H),4.97(q,J=6.1 Hz,1H),4.43-4.30(m,2H),3.84-3.79(m,1H),3.62-3.51(m,3H),2.49(s,3H),2.30-2.22(m,1H),2.19-2.10(m,2H),1.56-1.46(m,4H).

[0351] Example 126 1-[6-[6-[(6-メチルピリダジン-3-イル)アミノ]ベンズイミダゾール-1-イル]-2-[(3aS,6aR)- 2,3,3a,5,6,6a-ヘキサヒドロ-1H-ピロロ[3,2-b]ピロール-4-イル]-3-ピリジル]エタノール;ギ acid

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[0352] Example 127 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[rac-trans-2,3,3a,5,6,6a-hexahydro-1H-pyrrolo[3,2-b]pyrrol-4-yl]-3-pyridyl]ethanol [ka]

[0353] Step 1: 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[rac-trans-2,3,3a,5,6,6a-hexahydro-1H-pyrrolo[3,2-b]pyrrol-4-yl]-3-pyridyl]ethanone [ka] Following the procedure described in Step 3 of Example 125, using tert-butyl rac-trans-1-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-2,3,3a,5,6,6a-hexahydropyrrolo[3,2-b]pyrrole-4-carboxylate (330 mg, 0.59 mmol, 1 equivalent), the title compound (250 mg, 92.4% yield) was obtained as a yellow solid. LC-MS: m / z=455.3 [M+H] + ,ESI pos.

[0354] Step 2: 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[rac-trans-2,3,3a,5,6,6a-hexahydro-1H-pyrrolo[3,2-b]pyrrol-4-yl]-3-pyridyl]ethanol [ka] To a solution of 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[rac-trans-2,3,3a,5,6,6a-hexahydro-1H-pyrrolo[3,2-b]pyrrol-4-yl]-3-pyridyl]ethanone (230 mg, 0.51 mmol, 1 equiv.) in MeOH (3 mL) was added NaBH (57 mg, 1.52 mmol, 3 equiv.) at 0 °C. The reaction mixture was stirred at 20 °C for 1 h. DMF (3 mL) and NaBH (57 mg, 1.52 mmol, 3 equiv.) were added to the mixture, which was stirred at room temperature for an additional 1 h. The mixture was diluted with HO (30 mL) and extracted with (DCM / MeOH 9:1) (6 × 30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (Unisil 3-100 C18 Ultra (150 mm x 50 mm x 10 μm). Flow rate: 25 mL / min. Gradient: 1% to 28% CH3CN in (0.225% formic acid in H2O v / v) (10 min), then 100% CH3CN (2 min)). The title compound (137.4 mg, 59.5% yield) was obtained as a yellow lyophilized solid. LC-MS: m / z = 457.2 [M+H] + ,ESI pos. 1 H NMR(400 MHz,DMSO-d6):δ=9.23(s,1H),8.85-8.79(m,1H),8.40-8.32(m,2H),8.21-8.13(m,1H),8.07-7.98(m,1H),7.59(td,J=2.4,8.7 Hz,1H),7.48-7.37(m,1H),7.34(d,J=9.0 Hz,1H),7.10(d,J=9.0 Hz,1H),5.05-4.89(m,1H),4.32-4.24(m,1H),4.06(dt,J=5.9,10.7 Hz,1H),3.76-3.70(m,2H),3.65-3.49(m,2H),2.49(s,3H),2.31-2.22(m,1H),2.14-2.02(m,2H),1.61-1.25(m,4H).

[0355] Example 128 1-[2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol [ka]

[0356] Step 1: 1-[6-chloro-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-3-pyridyl]ethanone and 1-[6-chloro-2-[5-(difluoromethyl)-3-methyl-pyrazol-1-yl]-3-pyridyl]ethanone [ka] To a solution of 1-(6-chloro-2-fluoro-3-pyridyl)ethanone (CAS number 1260663-13-5, 1.0 g, 5.76 mmol, 1 equiv.) and 3-(difluoromethyl)-5-methyl-1H-pyrazole (837.3 mg, 6.34 mmol, 1.1 equiv.) in DMSO (38 mL) was added KCO (1.19 g, 8.64 mmol, 1.5 equiv.). The reaction mixture was stirred at 65 °C for 2 h. The mixture was poured into HO (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 10% EtOAc in PE) to give 1-[6-chloro-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-3-pyridyl]ethanone (885 mg, 3.09 mmol, 53.7% yield) as a white solid and 1-[6-chloro-2-[5-(difluoromethyl)-3-methyl-pyrazol-1-yl]-3-pyridyl]ethanone (200 mg, 0.662 mmol, 11.5% yield) as a white solid. Regioisomer 1: LC-MS: m / z=286.1 [M+H] + ,ESI pos. 1H NMR(400 MHz, CDCl3):δ=7.96-7.91(m,1H),7.46-7.40(m,1H),6.77-6.47(m,2H),2.65-2.61(m,3H),2.07-2.01(m,3H).Positional isomer 2:LC-MS:m / z=286.1[M+H] + ,ESI pos. 1 H NMR(600 MHz,DMSO-d6)δ ppm 8.00-8.06(m,1 H),7.90-7.96(m,1 H),7.37-7.58(m,2 H),6.66(br s,1 H),2.25(s,3 H),2.13(s,3 H).

[0357] Step 2: 1-[2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone and 1-[2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone [ka] The residue obtained after extractive workup was purified by preparative NPLC (Welch Ultimate XB-CN (250 mm × 50 mm × 10 μm). Flow rate: 140 mL / min. Gradient: 40% to 80% in hexanes (EtOH with 0.1% NHOH v / v (12 min) then 100% EtOH (5 min)) according to the procedure described in step 4 of Example 113 at 50 °C for 16 h reaction time to give 1-[2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (300 mg, 22.6% yield) as a pale yellow solid (trace of 1-[2-[5-(difluoromethyl)-3-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone. Regioisomer 1 (containing 1-[2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone) and 1-[2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (300 mg, 22.6% yield) were obtained as pale yellow solids. LC-MS: m / z = 475.1 [M+H] + ,ESI pos. 1 H NMR(400 MHz,DMSO-d6):δ=9.29(s,1H),9.09(s,1H),8.46(d,J=1.8 Hz,1H),8.39(d,J=8.4 Hz,1H),8.21(d,J=8.4 Hz,1H),8.17(d,J=8.8 Hz,1H),7.54(dd,J=2.0,8.9 Hz,1H),7.35(d,J=9.0 Hz,1H),7.11(d,J=9.2 Hz,1H),7.05(s,1H),6.75(s,1H),2.61(s,3H),2.49(br s,3H),2.01(s,3H).Positional isomer 2:LC-MS:m / z=475.1 [M+H] + ,ESI pos. 1H NMR(400 MHz,DMSO-d6):δ=9.31(s,1H),8.97(s,1H),8.86(d,J=1.8 Hz,1H),8.40(d,J=8.3 Hz,1H),8.16(d,J=8.3 Hz,1H),7.71(d,J=8.7 Hz,1H),7.53(dd,J=2.0,8.7 Hz,1H),7.30(d,J=9.2 Hz,1H),7.08(d,J=9.0 Hz,1H),7.03(s,1H),6.69(s,1H),2.60(s,3H),2.47(s,3H),2.00(s,3H).

[0358] Step 3: 1-[2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol [ka] Following the procedure described in Step 3 of Example 107, the title compound (179.2 mg, 61.5% yield) was obtained as a pale yellow lyophilized solid. Purification by preparative HPLC (Phenomenex Synergi C18 (150 mm x 25 mm x 10 μm). Flow rate: 25 mL / min. Gradient: 8% to 38% CH3CN in (0.225% formic acid in HO v / v) (10 min), then 100% CH3CN (2 min)). 477.2 [M+H] + ,ESI pos. 1 H NMR(400 MHz,CD3OD):δ=8.79(s,1H),8.71(d,J=1.7 Hz,1H),8.53(d,J=8.4 Hz,1H),8.10(d,J=8.4 Hz,1H),7.69(d,J=8.7 Hz,1H),7.45(dd,J=2.0,8.7 Hz,1H),7.35(d,J=9.2 Hz,1H),7.16(d,J=9.2 Hz,1H),6.93-6.63(m,1H),6.53(s,1H),4.83(br s,1H),2.55(s,3H),2.38(s,3H),1.39(d,J=6.5 Hz,3H).

[0359] Example 129 1-[2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol;Formic acid [ka] Following the procedure described in Step 3 of Example 107, starting with 1-[2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (obtained in Step 2 of Example 128) (290 mg, 0.61 mmol, 1 equivalent), the title compound (127 mg, 43.9% yield) was obtained as a pale yellow lyophilized solid. Purification by preparative HPLC (column Phenomenex Synergi C18 (150 mm × 25 mm × 10 μm). Flow rate: 25 mL / min. Gradient: 9% to 39% CH3CN in (0.225% formic acid in HO v / v) (10 min), then 100% CH3CN (2 min)). 477.4 [M+H] + ,ESI pos. 1 H NMR(400 MHz,CD3OD):δ=8.90(s,1H),8.47(d,J=8.4 Hz,1H),8.21(d,J=1.6 Hz,1H),8.15-8.12(m,1H),8.09(d,J=8.4 Hz,1H),7.57(br d,J=8.8 Hz,1H),7.40(d,J=9.2 Hz,1H),7.18(d,J=9.2 Hz,1H),6.95-6.65(m,1H),6.58(s,1H),4.83(q,J=6.5 Hz,1H),2.54(s,3H),2.40(s,3H),1.39(d,J=6.5 Hz,3H).

[0360] Example 130 1-[6-[6-bromo-5-[4-(oxetan-3-yl)piperazin-1-yl]benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka]

[0361] Step 1: 4-Bromo-2-nitro-5-[4-(oxetan-3-yl)piperazin-1-yl]aniline [ka] To a solution of 4-bromo-5-fluoro-2-nitro-aniline (0.95 g, 4.04 mmol, 1.0 equiv.) and 1-(oxetan-3-yl)piperazine (0.86 g, 6.06 mmol, 1.5 equiv.) in DMSO (10 mL) was added TEA (1.69 mL, 12.13 mmol, 3.0 equiv.). The reaction mixture was stirred at 50° C. for 16 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to give 4-bromo-2-nitro-5-[4-(oxetan-3-yl)piperazin-1-yl]aniline (1.3 g, 3.64 mmol, 90.0% yield) as a yellow solid. LC-MS: m / z=357.1 [M+H] + ,ESI pos.

[0362] Step 2: 4-Bromo-5-[4-(oxetan-3-yl)piperazin-1-yl]benzene-1,2-diamine [ka] To a solution of 4-bromo-2-nitro-5-[4-(oxetan-3-yl)piperazin-1-yl]aniline (1.0 g, 2.8 mmol, 1.0 equiv) in EtOH (18 mL) was added Fe 0(781.6 mg, 14 mmol, 5.0 equiv), NH4Cl (1.5 g, 28 mmol, 10 equiv), and water (6 mL) were added. The reaction mixture was stirred under nitrogen at 50 °C for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (50% CH3CN in H2O) to give 4-bromo-5-[4-(oxetan-3-yl)piperazin-1-yl]benzene-1,2-diamine (500 mg, 1.53 mmol, 54.6% yield) as a yellow solid. LC-MS: m / z = 329.0 [M+H] + ,ESI pos.

[0363] Step 3: 5-Bromo-6-[4-(oxetan-3-yl)piperazin-1-yl]-1H-benzimidazole [ka] To a solution of 4-bromo-5-[4-(oxetan-3-yl)piperazin-1-yl]benzene-1,2-diamine (400.0 mg, 1.22 mmol, 1.0 equiv) in EtOH (8 mL), trimethoxymethane (1.30 g, 12.22 mmol, 10 equiv) and TsOH (21.1 mg, 0.120 mmol, 0.10 equiv) were added and stirred at 80 °C for 1 h. Saturated aqueous NaHCO was added to the reaction to adjust the pH to 7-8, and the product was extracted with EtOAc. The combined organic layers were concentrated in vacuo to give 5-bromo-6-[4-(oxetan-3-yl)piperazin-1-yl]-1H-benzimidazole (400 mg, 1.19 mmol, 97.0% yield) as an orange solid. LC-MS: m / z=339.0 [M+H] + ,ESI pos.

[0364] Step 4: 1-[3-acetyl-6-[6-bromo-5-[4-(oxetan-3-yl)piperazin-1-yl]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile and 1-[3-acetyl-6-[5-bromo-6-[4-(oxetan-3-yl)piperazin-1-yl]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Prepared as in Example 64, step 2 using 5-bromo-6-[4-(oxetan-3-yl)piperazin-1-yl]-1H-benzimidazole (400.0 mg, 1.19 mmol, 1.0 equiv) and 1-(3-acetyl-6-chloro-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile (309.22 mg, 1.19 mmol, 1.0 equiv, prepared in Example 64, step 1). The regioisomers were purified by preparative TLC (10% MeOH in DCM) to give 1-[3-acetyl-6-[6-bromo-5-[4-(oxetan-3-yl)piperazin-1-yl]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (230 mg, 0.410 mmol, 32.81% yield) as a yellow solid and 1-[3-acetyl-6-[5-bromo-6-[4-(oxetan-3-yl)piperazin-1-yl]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (240.9 mg, 0.430 mmol, 34% yield) as an orange solid. Regioisomer 1: LC-MS: m / z=563.1 [M+H] + ,ESI pos. 1H NMR(400 MHz,DMSO-d6)δ=9.13(s,1H),8.60(d,J=8.4 Hz,1H),8.32(d,J=8.4 Hz,1H),8.06(d,J=11.2 Hz,2H),7.16(s,1H),4.60-4.54(m,2H),4.49(t,J=6.1 Hz,2H),3.50(t,J=6.4 Hz,1H),2.98(br s,4H),2.49-2.49(m,3H),2.47(br s,4H),2.28(s,3H).Positional isomer 2:LC-MS:m / z=563.1[M+H] + ,ESI pos. 1 H NMR(400 MHz,DMSO-d6)δ=9.19(s,1H),8.55(d,J=8.6 Hz,1H),8.51(s,1H),8.32(d,J=8.6 Hz,1H),7.62(s,1H),7.16(d,J=0.6 Hz,1H),4.59-4.55(m,2H),4.51-4.46(m,2H),3.50(quin,J=6.4 Hz,1H),3.03(br s,4H),2.56(s,3H),2.49-2.45(m,4H),2.21(s,3H).

[0365] Step 5: 1-[6-[6-bromo-5-[4-(oxetan-3-yl)piperazin-1-yl]benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Prepared as in Example 53, step 4 using 1-[3-acetyl-6-[6-bromo-5-[4-(oxetan-3-yl)piperazin-1-yl]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (200.0 mg, 0.360 mmol, 1.0 equiv) and NaBH4 (40.0 mg, 1.06 mmol, 3.0 equiv) in MeOH / THF to give 1-[6-[6-bromo-5-[4-(oxetan-3-yl)piperazin-1-yl]benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (143.8 mg, 0.260 mmol, 65.6% yield) as an orange solid. LC-MS: m / z=565.1 [M+H] + ,ESI pos.

[0366] Example 133 1-[2-(3-ethoxy-5-methyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol;Formic acid [ka]

[0367] Step 1: 1-[6-chloro-2-(3-ethoxy-5-methyl-pyrazol-1-yl)-3-pyridyl]ethanone [ka] Prepared in analogy to Example 64, step 1, using 3-ethoxy-5-methyl-1H-pyrazole (420.0 mg, 3.33 mmol, 1.0 equiv.) and 1-(6-chloro-2-fluoro-3-pyridyl)ethanone (CAS number 1260663-13-5, 866.8 mg, 4.99 mmol, 1.5 equiv.) to give 1-[6-chloro-2-(3-ethoxy-5-methyl-pyrazol-1-yl)-3-pyridyl]ethanone (110 mg, 0.390 mmol, 11.8% yield) as an orange solid. LC-MS: m / z=280.1 [M+H]+ ,ESI pos.

[0368] Step 2: 1-[2-(3-ethoxy-5-methyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone and 1-[2-(3-ethoxy-5-methyl-pyrazol-1-yl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone [ka] Prepared as in Example 64, step 2 using 1-[6-chloro-2-(3-ethoxy-5-methyl-pyrazol-1-yl)-3-pyridyl]ethanone (110.0 mg, 0.390 mmol, 1.0 equiv.) and N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine (106.3 mg, 0.470 mmol, 1.2 equiv.) to give 1-[2-(3-ethoxy-5-methyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (90 mg, 0.190 mmol, 48.85% yield) as a yellow gum. Regioisomer 1: LC-MS: 469.2 [M+H] + ,ESI pos. 1 H NMR(400 MHz,CD3OD)δ=8.82(s,1H),8.21(d,J=1.8 Hz,1H),8.14(d,J=8.3 Hz,1H),8.09(d,J=8.9 Hz,1H),7.79(d,J=8.2 Hz,1H),7.60(dd,J=2.1,8.8 Hz,1H),7.35(d,J=9.2 Hz,1H),7.12(d,J=9.2 Hz,1H),5.87(d,J=0.6 Hz,1H),4.16(q,J=7.0 Hz,2H),2.60(s,3H),2.53(s,3H),2.17(s,3H),1.37(t,J=7.0 Hz,3H).Positional isomer 2:LC-MS:469.2[M+H] + ,ESI pos.

[0369] Step 3: 1-[2-(3-ethoxy-5-methyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; formic acid [ka] Prepared in analogy to Example 53, step 4, using 1-[2-(3-ethoxy-5-methyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (90.0 mg, 0.190 mmol, 1.0 equiv.) and NaBH4 (21.8 mg, 0.580 mmol, 3.0 equiv.) to give 1-[2-(3-ethoxy-5-methyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; formic acid (42.3 mg, 0.080 mmol, 46.8% yield) as a yellow solid. LC-MS: m / z=471.2 [M+H] + ,ESI pos. 1 H NMR(400 MHz,DMSO-d6)δ=9.21(s,1H),8.96(s,1H),8.42(d,J=1.9 Hz,1H),8.35(d,J=8.5 Hz,1H),8.18(s,1H),8.08(dd,J=6.4,8.6 Hz,2H),7.50(dd,J=2.1,8.9 Hz,1H),7.33(d,J=9.1 Hz,1H),7.08(d,J=9.1 Hz,1H),5.86(s,1H),5.66-5.17(m,1H),4.96(br d,J=6.4 Hz,1H),4.16(q,J=7.0 Hz,2H),2.48(s,3H),2.31(s,3H),1.33(t,J=7.0 Hz,3H),1.29(d,J=6.4 Hz,3H).

[0370] Example 134 1-[2-(3-ethoxy-5-methyl-pyrazol-1-yl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol [ka] Prepared in a manner analogous to Example 53, step 4, using 1-[2-(3-ethoxy-5-methyl-pyrazol-1-yl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (90.0 mg, 0.190 mmol, 1.0 equiv., prepared in Example 133, step 2) and NaBH4 (21.8 mg, 0.580 mmol, 3 equiv.) to give 1-[2-(3-ethoxy-5-methyl-pyrazol-1-yl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol (52.2 mg, 0.110 mmol, 57.8% yield) as a yellow solid. LC-MS: m / z=471.2 [M+H] + ,ESI pos. 1 H NMR(400 MHz,DMSO-d6)δ=9.28(s,1H),8.78(s,1H),8.65(d,J=1.9 Hz,1H),8.39(d,J=8.4 Hz,1H),7.99(d,J=8.3 Hz,1H),7.69(d,J=8.6 Hz,1H),7.47(dd,J=2.1,8.7 Hz,1H),7.30(d,J=9.1 Hz,1H),7.08(d,J=9.0 Hz,1H),5.80(d,J=0.6 Hz,1H),5.43(br s,1H),4.95(br d,J=6.4 Hz,1H),4.14(q,J=7.0 Hz,2H),2.47(s,3H),2.30(s,3H),1.34-1.28(m,6H).

[0371] Example 135 1-[2-(6-methylpyridazin-4-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol [ka]

[0372] Step 1: 1-[2-(6-methylpyridazin-4-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone [ka] 1-[2-Chloro-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (160.0 mg, 0.420 mmol, 1.0 equiv), 3-methylpyridazine-5-boronic acid, pinacol ester (111.54 mg, 0.510 mmol, 1.2 equiv), PdCl(dppf) CHCl (34.3 mg, 0.042 mmol, 0.1 equiv), and NaCO (89 mg, 0.84 mmol, 2 equiv) were suspended in 1,4-dioxane (1.33 mL) and HO (0.33 mL). The reaction mixture was heated to 80 °C and stirred for 12 h. The mixture was cooled to room temperature, diluted with HO (7 mL) and EtOAc (7 mL), and stirred for 30 min. The insoluble material was filtered off and the filter cake was washed with 7 mL of EtOAc. The organic layer from the filtrate was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to leave the crude title compound, 1-[2-(6-methylpyridazin-4-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (140 mg, 0.320 mmol, 75.9% yield) as a yellow solid. LC-MS: m / z=437.1 [M+H] + ,ESI pos.

[0373] Step 2: 1-[2-(6-methylpyridazin-4-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol [ka] Prepared analogously to Example 53, step 4, using 1-[2-(6-methylpyridazin-4-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (140.0 mg, 0.320 mmol, 1.0 equiv) and NaBH in MeOH / DMF (1:1) (36.4 mg, 0.960 mmol, 3.0 equiv) at −40 °C to give 1-[2-(6-methylpyridazin-4-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol (22 mg, 0.050 mmol, 15.6% yield) as a yellow solid. LC-MS: m / z=439.1 [M+H] + ,ESI pos. 1 H NMR(400 MHz,CD3OD)δ=9.35(d,J=1.7 Hz,1H),8.90(s,1H),8.38(d,J=8.6 Hz,1H),8.20-8.15(m,2H),8.01(d,J=8.6 Hz,1H),7.92(d,J=2.0 Hz,1H),7.53(dd,J=2.0,8.9 Hz,1H),7.45(d,J=9.2 Hz,1H),7.23(d,J=9.2 Hz,1H),4.98(q,J=6.4 Hz,1H),2.82(s,3H),2.55(s,3H),1.51(d,J=6.4 Hz,3H).

[0374] Example 136 4-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-1-(2,2,2-trifluoroethyl)piperazin-2-one [ka]

[0375] Step 1: Benzyl 3-oxo-4-(2,2,2-trifluoroethyl)piperazine-1-carboxylate [ka] To a mixture of 2,2,2-trifluoroethyl trifluoromethanesulfonate (3.3 g, 14.09 mmol, 1.1 equiv) in anhydrous DMF (60 mL) was added NaH (618.0 mg, 15.45 mmol, 1.2 equiv) under nitrogen at 0 °C and stirred at 0 °C for 30 min. Benzyl 3-oxopiperazine-1-carboxylate (3.0 g, 12.81 mmol, 1.0 equiv) was added dropwise and the reaction was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure and purified by preparative HPLC (Phenomenex Luna C18 250 x 80 mm x 10 μm, gradient 35-65% CH3CN (with 0.225% formic acid) in HO over 20 min, then 100% CH3CN (4 min), flow rate 140 mL / min, single injection) to give benzyl 3-oxo-4-(2,2,2-trifluoroethyl)piperazine-1-carboxylate (1700 mg, 5.37 mmol, 41.97% yield) as a colorless oil. LC-MS: m / z = 317.2 [M+H] + ,ESI pos.

[0376] Step 2: 1-(2,2,2-trifluoroethyl)piperazin-2-one [ka] A mixture of benzyl 3-oxo-4-(2,2,2-trifluoroethyl)piperazine-1-carboxylate (1.7 g, 5.37 mmol, 1.0 equiv.) and Pd / C (578.0 mg, 0.540 mmol, 0.10 equiv.) in MeOH (30 mL) was hydrogenated under 45 psi H pressure at 30 °C for 16 h. The suspension was filtered through a Celite pad, and the filter cake was washed with MeOH. The combined filtrate was concentrated to give 1-(2,2,2-trifluoroethyl)piperazin-2-one (100 mg, 0.550 mmol, 86.8% yield) as a dark green oil. LC-MS: m / z = 183.0 [M+H] + ,ESI pos.

[0377] Step 3: 4-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-1-(2,2,2-trifluoroethyl)piperazin-2-one and 4-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-1-(2,2,2-trifluoroethyl)piperazin-2-one [ka] A solution of a mixture of 1-[2-chloro-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone and 1-[2-chloro-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (200.0 mg, 0.530 mmol, 1 equiv.), 1-(2,2,2-trifluoroethyl)piperazin-2-one (164.0 mg, 0.9 mmol, 1.7 equiv.), and DIPEA (205.0 mg, 1.59 mmol, 3.0 equiv.) in DMF (3 mL) was stirred for 16 hours at 30° C. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure and purified by preparative NPLC (Welch Ultimate XB-SiOH 250 mm x 50 mm x 10 μm, gradient 20-60% EtOH in hexanes over 15 min, then 100% Purification with EtOH (3 min, flow rate 100 mL / min) gave 4-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-1-(2,2,2-trifluoroethyl)piperazin-2-one (150 mg, 0.290 mmol, 54.2% yield) as a pale yellow solid and 4-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-1-(2,2,2-trifluoroethyl)piperazin-2-one (50 mg, 0.100 mmol, 18.1% yield) as a pale yellow solid. Regioisomer 1: LC-MS: m / z = 525.4 [M+H] + ,ESI pos. 1H NMR(400 MHz,CDCl3)δ=8.60(s,1H),8.21(d,J=8.3 Hz,1H),8.03(d,J=8.9 Hz,1H),7.78(d,J=1.8 Hz,1H),7.44(dd,J=1.9,8.8 Hz,1H),7.21(s,2H),7.10(d,J=8.3 Hz,1H),4.18-4.08(m,5H),3.90-3.84(m,2H),3.78-3.74(m,2H),2.66(s,3H),2.61(s,3H).Positional isomer 2:LC-MS:m / z=525.4[M+H] + ,ESI pos.

[0378] Step 4: 4-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-1-(2,2,2-trifluoroethyl)piperazin-2-one [ka] Prepared in a similar manner to Example 53, step 4, using 4-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-1-(2,2,2-trifluoroethyl)piperazin-2-one (50 mg, 0.100 mmol, 1.0 equiv) and NaBH (8.7 mg, 0.231 mmol, 3.0 equiv) in DCM / MeOH (9:1) to give 4-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-1-(2,2,2-trifluoroethyl)piperazin-2-one (3.3 mg, 0.006 mmol, 8.22% yield) as a pale yellow solid. LC-MS: m / z=527.4[M+H] + ,ESI pos. 1H NMR(400 MHz,CD3OD)δ=8.78(s,1H),8.19(d,J=1.8 Hz,1H),8.17(d,J=8.2 Hz,1H),8.12(d,J=8.8 Hz,1H),7.60(d,J=4.5 Hz,1H),7.60-7.57(m,1H),7.38(d,J=9.2 Hz,1H),7.17(d,J=9.2 Hz,1H),5.21(q,J=6.4 Hz,1H),4.22(d,J=9.3 Hz,2H),4.17(d,J=17.0 Hz,1H),4.07-4.02(m,1H),3.78-3.71(m,1H),3.68-3.59(m,3H),2.54(s,3H),1.55(d,J=6.5 Hz,3H).

[0379] Example 137 4-[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-1-(2,2,2-trifluoroethyl)piperazin-2-one [ka] 4-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-1-(2,2,2-trifluoroethyl)piperazin-2-one (40.0 mg, 0.080 mmol, 1.0 equiv., prepared in Example 136, Step 3) and NaBH4 (9.0 mg, 0.240 mmol, 3.12 equiv.) were dissolved in DCM / MeOH ( Prepared as in Example 53, step 4 using 4-[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-1-(2,2,2-trifluoroethyl)piperazin-2-one (2.5 mg, 0.005 mmol, 6.23% yield) as a pale yellow solid. LC-MS: m / z=527.4 [M+H] + ,ESI pos. 1H NMR(400 MHz,CD3OD)δ=9.04(d,J=2.0 Hz,1H),8.71(s,1H),8.20(d,J=8.2 Hz,1H),7.64(dd,J=8.5,16.4 Hz,2H),7.43-7.32(m,2H),7.15(d,J=9.2 Hz,1H),5.21(q,J=6.6 Hz,1H),4.24-4.11(m,3H),4.07-4.00(m,1H),3.82-3.75(m,1H),3.72-3.59(m,3H),2.53(s,3H),1.56(d,J=6.5 Hz,3H).

[0380] Example 140 1-[3-(1-hydroxyethyl)-6-[5-methoxy-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka]

[0381] Step 1: N-(2-Methoxy-4,5-dinitrophenyl)-6-methyl-pyridazin-3-amine [ka] To a solution of potassium tert-butoxide (488.06 mg, 4.35 mmol, 2.0 equiv.) in DMSO (5 mL), 3-amino-6-methylpyridazine (237.33 mg, 2.17 mmol, 1.0 equiv.) and 1-fluoro-2-methoxy-4,5-dinitro-benzene (470.0 mg, 2.17 mmol, 1.0 equiv.) were added. The brown suspension was then stirred at 0 °C for 3 h. The mixture was purified on a silica column (water (0.05% ammonium hydroxide v / v) -CH3CN) (100 / 0 to 7 / 94) to give N-(2-methoxy-4,5-dinitrophenyl)-6-methyl-pyridazin-3-amine (560 mg, 1.83 mmol, 84.36% yield) as a light brown solid. LC-MS: m / z = 306.0 [M+H] + ,ESI pos.

[0382] Step 2: 6-Methoxy-N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine [ka] To a solution of N-(2-methoxy-4,5-dinitrophenyl)-6-methyl-pyridazin-3-amine (800.0 mg, 2.62 mmol, 1.0 equiv.) in formic acid (120.62 mg, 2.62 mmol, 1.0 equiv.) was added nickel (101.77 mg, 1.73 mmol, 0.66 equiv.). The mixture was stirred under H2 (45 psi) at 30 °C for 16 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The resulting residue was treated with MeOH (5 mL), and the liquid was collected and concentrated in vacuo. The brown solid was purified by preparative HPLC (Waters Xbridge C18 150 mm x 50 mm x 10 μm, gradient 3-33% CH3CN (containing 10 mM NH4CO3) in HO over 11 min, then 100% CH3CN (2 min), flow rate 60 mL / min) to give 6-methoxy-N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine (200 mg, 0.780 mmol, 29.9% yield) as a white solid. LC-MS: m / z = 256.1 [M+H] + ,ESI pos.

[0383] Step 3: 1-[3-acetyl-6-[5-methoxy-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Prepared as in Example 64, Step 2, using 6-methoxy-N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine (200.0 mg, 0.780 mmol, 1.0 equiv.) and 1-(3-acetyl-6-chloro-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile (245.08 mg, 0.940 mmol, 1.2 equiv., prepared in Example 64, Step 1). Preparative HPLC (Welch Ultimate XB-SiOH 250 mm x 50 mm x 10 μm, gradient 10-50% EtOH (with 0.1% ammonium hydroxide) in heptane over 15 min, then 100% Separation of the isomers with EtOH (containing 0.1% ammonium hydroxide) for 3 min afforded 1-[3-acetyl-6-[5-methoxy-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (120 mg, 0.250 mmol, 31.9% yield) as a yellow solid and 1-[3-acetyl-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (20 mg, 0.040 mmol, 5.3% yield) as a yellow solid. Regioisomer 1: LC-MS: m / z = 480.1 [M+H] + ,ESI pos.Positional isomer 2:LC-MS:m / z=480.1[M+H] + ,ESI pos. 1 H NMR(400 MHz,CD3OD)δ=2.25(s,3 H)2.58(d,J=1.38 Hz,6 H)4.01-4.06(m,3 H)6.85(d,J=0.63 Hz,1 H)7.29-7.32(m,1 H)7.35-7.39(m,2 H)8.11-8.17(m,1 H)8.52(d,J=8.38 Hz,1 H)8.83(s,1 H)9.28(s,1 H).

[0384] Step 4: 1-[3-(1-hydroxyethyl)-6-[5-methoxy-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Prepared as in Example 53, step 4 using 1-[3-acetyl-6-[5-methoxy-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (100.0 mg, 0.210 mmol, 1.0 equiv) and NaBH (23.67 mg, 0.630 mmol, 3.0 equiv) in THF / MeOH (4:1) to give 1-[3-(1-hydroxyethyl)-6-[5-methoxy-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (46.8 mg, 0.100 mmol, 46.6% yield) as a white solid by lyophilization. LC-MS: m / z=482.2 [M+H] + ,ESI pos. 1 H NMR(400 MHz,CD3OD)δ ppm 1.44(d,J=6.36 Hz,3 H)2.40(s,3 H)2.59(s,3 H)4.02(s,3 H)4.74-4.83(m,1 H)6.82(d,J=0.61 Hz,1 H)7.27-7.32(m,1 H)7.34-7.39(m,2 H)8.16(d,J=8.44 Hz,1 H)8.55-8.60(m,1 H)8.75-8.78(m,1 H)9.10(s,1 H).

[0385] Example 143 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanol [ka]

[0386] Step 1: 4-bromo-3-methyl-1-(2,2,2-trifluoroethyl)pyrazole and 4-bromo-5-methyl-1-(2,2,2-trifluoroethyl)pyrazole [ka] A mixture of 4-bromo-3-methylpyrazole (15.0 g, 93.17 mmol, 1.0 equiv), 2,2,2-trifluoroethyl trifluoromethanesulfonate (22.71 g, 97.83 mmol, 1.05 equiv), and CsCO (25.33 g, 186.34 mmol, 2 equiv) in DMF (150 mL) was stirred at 100 °C for 12 h. The reaction mixture was filtered, and the filtrate was diluted with HO and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, and the volatiles were removed under reduced pressure. The residue was purified by flash column chromatography (silica gel, 10-16% EtOAc in DCM) to give a mixture of 4-bromo-5-methyl-1-(2,2,2-trifluoroethyl)pyrazole (6.5 g, 26.75 mmol, 28.7% yield) and 4-bromo-3-methyl-1-(2,2,2-trifluoroethyl)pyrazole (13 g, 53.49 mmol, 57.4% yield) as an off-white oil. LC-MS: m / z = 242.9 [M+H] + ,ESI pos.

[0387] Step 2: 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)pyrazole [ka] To a mixture of bis(pinacolato)diboron (17.24 g, 67.9 mmol, 1.5 equiv.) and 4-bromo-3-methyl-1-(2,2,2-trifluoroethyl)pyrazole (11.0 g, 45.26 mmol, 1.0 equiv.) in 1,4-dioxane (200 mL) was added Pd(dppf)Cl.CH.Cl. (3.7 g, 4.53 mmol, 0.10 equiv.) and KOAc (8.9 g, 90.53 mmol, 2.0 equiv.), and the mixture was stirred at 100 °C under an inert atmosphere for 16 h. The mixture was concentrated under reduced pressure and purified by flash chromatography (silica gel, 10-20% EtOAc in PE) to give 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)pyrazole (15.1 g, 52.1 mmol, 84.0% yield) as a yellow gum. LC-MS: m / z = 291.1 [M+H] + ,ESI pos.

[0388] Step 4: 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanone and 1-[6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanone [ka] Prepared in the same manner as in Example 135, Step 2, using 1-[2-chloro-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (0.5 g, 1.32 mmol, 1 equivalent, prepared in Example 76, Step 2) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)pyrazole (574.33 mg, 1.98 mmol, 1.5 equivalents). SFC (Chiralpak AD-3 50 mm x 4.6 mm, 3 μm, 40% with 0.05% EtNH) i Purification with PrOH+CH3CN (flow rate 3 mL / min, back pressure 100 bar) gave 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanone (319 mg, 0.63 mmol, 47.7% yield) as a yellow solid and 1-[6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanone (190 mg, 0.376 mmol, 28.5% yield) as a yellow solid. LC-MS: m / z = 507.2 [M+H] + ,ESI pos. 1 H NMR(400 MHz,CD3OD)δ=8.92(s,1H),8.39-8.17(m,3H),7.97(s,1H),7.87(d,J=8.4 Hz,1H),7.68-7.57(m,1H),7.35(d,J=9.2 Hz,1H),7.13(d,J=9.2 Hz,1H),5.01-4.94(m,2H),2.53(s,3H),2.39(s,3H),2.36(s,3H).

[0389] Step 5: 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanol [ka] Prepared as in Example 53, step 4 using 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanone (750.0 mg, 1.48 mmol, 1.0 equiv) and NaBH4 (281.58 mg, 7.4 mmol, 5 equiv) at −70 °C to give 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanol (450 mg, 0.880 mmol, 69.0% yield) as a yellow solid. LC-MS: m / z=509.1 [M+H] + ,ESI pos.

[0390] Example 144 1-[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-N,5-dimethyl-pyrazole-3-carboxamide [ka]

[0391] Step 1: N,5-dimethyl-1H-pyrazole-3-carboxamide [ka] To a stirred solution of 3-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (280 mg, 1.82 mmol, 1.0 equiv.) in MeOH (2 mL) at room temperature under an argon atmosphere was added methylamine, 41% aqueous solution (2.75 g, 3.08 mL, 36.32 mmol, 20 equiv.). The mixture was heated to 60° C. and stirring at that temperature was continued overnight. The mixture was cooled to room temperature and concentrated to dryness to give N,3-dimethyl-1H-pyrazole-5-carboxamide as a white solid, which was used in the next step without further purification. LC-MS: m / z=140.1 [M+H] + ,ESI pos.

[0392] Step 2: 1-(3-acetyl-6-chloro-2-pyridyl)-N,5-dimethyl-pyrazole-3-carboxamide [ka] Prepared analogously to Example 62, Step 1, using N,5-dimethyl-1H-pyrazole-3-carboxamide (used crude from the previous step) and 1-(6-chloro-2-fluoro-3-pyridyl)ethanone (296.2 mg, 1.71 mmol, 1.0 equiv) to give 1-(3-acetyl-6-chloro-2-pyridyl)-N,5-dimethyl-pyrazole-3-carboxamide (142 mg, 24.7% yield) as a brown solid. LC-MS: m / z=293.1 [M+H] + ,ESI pos.

[0393] Step 3: 1-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-N,5-dimethyl-pyrazole-3-carboxamide and 1-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-N,5-dimethyl-pyrazole-3-carboxamide [ka] Prepared analogously to Step 1, Example 65, Step 1 using 1-(3-acetyl-6-chloro-2-pyridyl)-N,5-dimethyl-pyrazole-3-carboxamide (137 mg, 0.407 mmol, 1 equiv) and 1H-benzimidazol-5-yl-(6-methylpyridazin-3-yl)amine (101.91 mg, 0.407 mmol, 1 equiv) over 8 hours to give 1-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amine] 1-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-N,5-dimethyl-pyrazole-3-carboxamide (40 mg, 19.6% yield) and 1-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-N,5-dimethyl-pyrazole-3-carboxamide (33 mg, 15.5% yield) were obtained as orange solids after separation of the isomers by flash column chromatography. Regioisomer 1: LC-MS: m / z = 482.2 [M+H] + ,ESI pos.1H NMR(600 MHz,DMSO-d6)d ppm 9.28(s,1 H),9.11(s,1 H),8.46(d,J=2.2 Hz,1 H),8.44(d,J=8.4 Hz,1 H),8.24(d,J=8.5 Hz,1 H),8.17(d,J=9.1 Hz,1 H),7.53(dd,J=8.9,2.2 Hz,1 H),7.35(d,J=9.1 Hz,1 H),7.11(d,J=9.1 Hz,1 H),6.79(d,J=0.8 Hz,1 H),2.74(d,J=4.7 Hz,3 H),2.55(d,J=0.8 Hz,3 H),2.48(s,3 H),2.04(s,3 H) positional isomer 2:LC-MS:m / z=482.2[M+H] + ,ESI pos. 1H NMR(600 MHz,DMSO-d6)δ=9.32(s,1 H),8.98(s,1 H),8.81(d,J=2.0 Hz,1 H),8.43-8.49(m,1 H),8.18(d,J=8.5 Hz,1 H),8.04(q,J=4.7 Hz,1 H),7.71(d,J=8.7 Hz,1 H),7.53(dd,J=8.7,2.1 Hz,1 H),7.30(d,J=9.1 Hz,1 H),7.09(d,J=9.1 Hz,1 H),6.73(d,J=0.9 Hz,1 H),2.74(d,J=4.7 Hz,3 H),2.55(d,J=0.7 Hz,3 H),2.48(s,3 H), 2.04(s,3 H).

[0394] Step 4: 1-[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-N,5-dimethyl-pyrazole-3-carboxamide [ka] Prepared analogously to Example 53, step 4 using 1-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-N,5-dimethyl-pyrazole-3-carboxamide (37 mg, 0.077 mmol, 1.0 equiv) in MeOH / THF (1:1) to give 1-[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-N,5-dimethyl-pyrazole-3-carboxamide (23 mg, 60.7% yield) as a light brown solid. LC-MS: m / z=484.3 [M+H] + ,ESI pos.

[0395] Example 145 1-[2-(5-methyl-3-methylsulfonyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol [ka]

[0396] Step 1: 1-[2-(3-bromo-5-methyl-pyrazol-1-yl)-6-chloro-3-pyridyl]ethanone [ka] Prepared as in Example 64, step 1, using 1-(6-chloro-2-fluoro-3-pyridyl)ethanone (CAS number 1260663-13-5, 2.0 g, 11.52 mmol, 1.0 equiv.) and 3-bromo-5-methyl-1H-pyrazole (1.86 g, 11.52 mmol, 1.0 equiv.) to give 1-[2-(3-bromo-5-methyl-pyrazol-1-yl)-6-chloro-3-pyridyl]ethanone (1.8 g, 5.72 mmol, 47.2% yield) as a pale yellow solid. LC-MS: m / z=313.9 [M+H] + and 315.9 [M+H] + ,(Bromoisotope)ESI pos. 1 H NMR(400 MHz,CDCl3)δ=7.91(d,J=8.1 Hz,1H),7.39(d,J=8.1 Hz,1H),6.29(d,J=0.8 Hz,1H),2.60(d,J=0.8 Hz,3H),2.14(s,3H).

[0397] Step 2: 1-[2-(3-bromo-5-methyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone [ka] Prepared in analogy to Example 64, step 2 using 1-[2-(3-bromo-5-methyl-pyrazol-1-yl)-6-chloro-3-pyridyl]ethanone (1000.0 mg, 3.18 mmol, 1.0 equiv) and N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine (716.06 mg, 3.18 mmol, 1.0 equiv, prepared in Example 64, intermediate 1) to give 1-[2-(3-bromo-5-methyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (373 mg, 0.740 mmol, 23.31% yield) as a yellow solid. LC-MS: m / z=503.1 [M+H] + and 505.1[M+H] + ,ESI pos.

[0398] Step 3: 1-[2-(5-methyl-3-methylsulfonyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone [ka] A mixture of 1-[2-(3-bromo-5-methyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (378.0 mg, 0.750 mmol, 1.0 equiv), copper(I) triflate (23.95 mg, 0.11 mmol, 0.150 equiv), (1R,2R)-N,N-dimethyl-1,2-cyclohexanediamine (32.05 mg, 0.230 mmol, 0.30 equiv) and sodium methanesulfinate (115.0 mg, 1.13 mmol, 1.5 equiv) in DMSO (12 mL) was stirred at 95° C. under an inert atmosphere for 16 hours. The mixture was filtered and purified by preparative HPLC (formic acid buffer?) to give 1-[2-(5-methyl-3-methylsulfonyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (168 mg, 0.330 mmol, 43.6% yield) as a yellow solid. LC-MS: m / z=503.1 [M+H] + ,ESI pos.

[0399] Step 4: 1-[2-(5-methyl-3-methylsulfonyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol [ka] Prepared in a similar manner as in Example 53, step 4 using 1-[2-(5-methyl-3-methylsulfonyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (168.0 mg, 0.330 mmol, 1.0 equiv) and NaBH (50.0 mg, 1.32 mmol, 3.95 equiv) in DMF / MeOH (3:1) to give 1-[2-(5-methyl-3-methylsulfonyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol (66.3 mg, 0.130 mmol, 39.3% yield) as a yellow solid. LC-MS: m / z=505.1 [M+H] + ,ESI pos. 1 H NMR(400 MHz,CD3OD)δ=8.94(s,1H),8.53(d,J=8.4 Hz,1H),8.27(s,1H),8.23(br s,1H),8.19-8.13(t,J=8.4 Hz,2H),7.63-7.57(m,1H),7.40(d,J=9.2 Hz,1H),7.17(d,J=8.8 Hz,1H),6.91(s,1H),4.81(q,J=7.6 Hz,1H),3.30(s,3H),2.56(s,3H),2.47(s,3H),1.45(d,J=6.4 Hz,3H).

[0400] Example 146 1-[3-(1-hydroxyethyl)-6-[5-[(2-keto-1-methyl-pyrimidin-4-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka]

[0401] Step 1: 1-[3-acetyl-6-[5-[(2-keto-1-methyl-pyrimidin-4-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Prepared analogously to Example 104, step 3 using 1-[3-acetyl-6-(5-bromobenzimidazol-1-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (50 mg, 0.119 mmol, 1.0 equiv., prepared in Example 65, step 1) and 4-amino-1-methyl-pyrimidin-2-one (29.7 mg, 0.237 mmol, 2.0 equiv.) to give the title compound (39.8 mg, 68.4% yield) as a yellow solid. LC-MS: m / z=466.3 [M+H] + ,ESI pos.

[0402] Step 2: 1-[3-(1-hydroxyethyl)-6-[5-[(2-keto-1-methyl-pyrimidin-4-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Prepared analogously to Example 53, step 4 using 1-[3-acetyl-6-[5-[(2-keto-1-methyl-pyrimidin-4-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (39.8 mg, 0.081 mmol, 1 equiv.) in MeOH / THF to give the title compound (19.9 mg, 49.8% yield) as a pale yellow solid. LC-MS: m / z=468.3 [M+H] + ,ESI pos.

[0403] Example 148 5-Methyl-1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-(2,2,2-trifluoro-1-hydroxy-ethyl)-2-pyridyl]pyrazole-3-carbonitrile [ka]

[0404] Step 1: 1-(6-chloro-2-fluoro-3-pyridyl)-2,2,2-trifluoro-ethanone [ka] LDA (4.56 mL, 9.12 mmol, 1.2 equiv) was added dropwise to a solution of 2-chloro-6-fluoropyridine (1.0 g, 7.6 mmol, 1 equiv) in THF (20 mL) at −70° C. A yellow suspension was formed. The mixture was stirred at −70° C. for 1 h, and then N-methoxy-N-methyltrifluoroacetamide (1.26 g, 7.99 mmol, 1.05 equiv) was added dropwise. After the addition, the clear yellow solution was stirred at −70° C. for 1 h. The mixture was quenched with 100 mL of saturated aqueous NH4Cl, extracted with EtOAc, and the organic layer was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 25% EtOAc in PE) to give 1-(6-chloro-2-fluoro-3-pyridyl)-2,2,2-trifluoro-ethanone (600 mg, 2.64 mmol, 34.7% yield) as a light brown oil. LC-MS: m / z=246.1 [M+HO+H] + ,ESI pos.

[0405] Step 2: 1-[6-chloro-3-(2,2,2-trifluoroacetyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] To a mixture of 1-(6-chloro-2-fluoro-3-pyridyl)-2,2,2-trifluoro-ethanone (6.2 g, 27.25 mmol, 1.0 equiv) and 5-methyl-1H-pyrazole-3-carbonitrile (2.91 g, 27.21 mmol, 1.0 equiv) in DMSO (50 mL) was added DIPEA (7.9 mL, 54.5 mmol, 2.0 equiv) dropwise at 0° C. After the addition, the mixture was stirred at 20° C. for 3 h. The mixture was quenched with 100 mL of water, extracted with 100 mL of EtOAc, and the organic layer was concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC (Waters Xbridge BEH C18 150 mm x 50 mm x 10 μm, gradient 30-50% CH3CN (containing 10 mM NH4HCO3) in HO over 22 min, then 100% CH3CN (5 min), flow rate 140 mL / min) to give 1-[6-chloro-3-(2,2,2-trifluoroacetyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (3.2 g, 10.17 mmol, 37.3% yield) as a pink solid. LC-MS: m / z = 315.1 [M+H] + ,333.1[M+H2O+H] + ESI pos.

[0406] Step 3: 5-methyl-1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-(2,2,2-trifluoroacetyl)-2-pyridyl]pyrazole-3-carbonitrile; formic acid and 5-methyl-1-[6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-(2,2,2-trifluoroacetyl)-2-pyridyl]pyrazole-3-carbonitrile; formic acid [ka] A mixture of 1-[6-chloro-3-(2,2,2-trifluoroacetyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (0.4 g, 1.27 mmol, 1.0 equiv), N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine (301.0 mg, 1.34 mmol, 1.05 equiv) and DIPEA (0.45 mL, 2.54 mmol, 2.0 equiv) in DMF (10 mL) was stirred at 100° C. for 16 h. The mixture was purified by preparative HPLC (Shim-pack C18 150 mm × 25 mm × 10 μm, gradient 1–30% CH3CN (containing 0.225% formic acid) in HO over 10 min, then 100% CH3CN (2 min), flow rate 25 mL / min, single injection) to give 5-methyl-1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-(2,2,2-trifluoroacetyl)-2-pyridyl]pyrazole-3-carbonitrile; formic acid (170 mg, 26.6% yield) as a dark brown solid. LC-MS: m / z = 504.1 [M+H] + ,ESI pos. and 5-methyl-1-[6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-(2,2,2-trifluoroacetyl)-2-pyridyl]pyrazole-3-carbonitrile; formic acid (120 mg, 18.8% yield) was obtained as a dark brown solid. LC-MS: m / z=504.1 [M+H] + ,ESI pos.

[0407] Step 4: 5-methyl-1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-(2,2,2-trifluoro-1-hydroxy-ethyl)-2-pyridyl]pyrazole-3-carbonitrile and 5-methyl-1-[6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-(2,2,2-trifluoro-1-hydroxy-ethyl)-2-pyridyl]pyrazole-3-carbonitrile [ka] Prepared as in Step 3 of Example 53 using 5-methyl-1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-(2,2,2-trifluoroacetyl)-2-pyridyl]pyrazole-3-carbonitrile (40.0 mg, 0.080 mmol, 1 equiv.) and NaBH (8.0 mg, 0.210 mmol, 2.7 equiv.), purified by preparative HPLC (Waters Xbridge BEH C18 150 mm × 50 mm × 5 μm, gradient 29–59% CHCN in HO (containing 10 mM NHHCO) over 8 min, then 100% CHCN (2 min), flow rate 25 mL / min) and preparative NPLC (Welch Ultimate XB-SiOH 250 mm x 50 mm x 10 μm, gradient 10–50% EtOH (containing 0.1% ammonium hydroxide) in heptane over 15 min, then 100% After separation of the two isomers with EtOH (containing 0.1% ammonium hydroxide) for 3 min at a flow rate of 100 mL / min, 5-methyl-1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-(2,2,2-trifluoro-1-hydroxy-ethyl)-2-pyridyl]pyrazole-3-carbonitrile (5.3 mg, 0.010 mmol, 11.9% yield) and 5-methyl-1-[6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-(2,2,2-trifluoro-1-hydroxy-ethyl)-2-pyridyl]pyrazole-3-carbonitrile (1.0 mg, 0.002 mmol, 2.5% yield) were obtained as white solids. Positional isomer 1: LC-MS: m / z=506.2[M+H] + ,ESI pos. 1H NMR(400 MHz, CDCl3)δ=8.54-8.47(m,1H),8.42-8.35(m,1H),7.96-7.89(m,1H),7.75-7.68(m,1H),7 .66-7.38(m,1H),7.22-7.17(m,1H),7.16-7.12(m,1H),7.10-7.05(m,1H),6.98-6.92(m,1H) ,5.23-5.14(m,1H),4.13-3.86(m,1H),3.78-3.56(m,2H),2.64-2.57(m,3H),2.49-2.41(m,1 H),2.05-1.99(m,1H),1.61-1.53(m,3H),1.52-1.47(m,3H).Positional isomer 2:LC-MS:m / z=506.2[M+H] + ,ESI pos. 1 H NMR(400 MHz,CD3OD)δ=8.97-8.95(m,1H),8.64-8.61(m,1H),8.27-8.25(m,1H),8.25-8.22(m,1H),8.18-8.14(m,1H),7.66-7.62(m,1H) ,7.39-7.36(m,1H),7.16-7.13(m,1H),6.91(s,1H),5.55-5.49(m,1H),2.56-2.54(m,3H),2.45-2.43(m,3H),2.06-2.05(m,1H).

[0408] Example 149 1-[2-[1-(difluoromethyl)-3-methyl-pyrazol-4-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol [ka]

[0409] Step 1: 4-Bromo-1-(difluoromethyl)-3-methyl-pyrazole [ka] To a solution of 4-bromo-3-methylpyrazole (200.0 mg, 1.24 mmol, 1.0 equiv.) in DMF (5 mL) was added sodium chlorodifluoroacetate (378.8 mg, 2.48 mmol, 2.0 equiv.) and potassium carbonate (515.1 mg, 3.73 mmol, 3.0 equiv.). The mixture was heated to 100 °C for 12 h. The reaction mixture was then diluted with 20 mL of water and extracted with EtOAc. The combined extracts were washed with brine and concentrated under reduced pressure. The residue was purified by flash column chromatography (0-20% EtOAc in PE) to give 4-bromo-1-(difluoromethyl)-3-methyl-pyrazole (200 mg, 0.950 mmol, 66.4% yield) as a colorless oil. LC-MS: m / z = 213.0 [M+H] + ,ESI pos.

[0410] Step 2: 1-(difluoromethyl)-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole [ka] Prepared analogously to Example 143, step 2, using bis(pinacolato)diboron (240.7 mg, 0.950 mmol, 2.0 equiv.) and 4-bromo-1-(difluoromethyl)-3-methyl-pyrazole (100 mg, 0.474 mmol, 1.0 equiv.) to give 1-(difluoromethyl)-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (113 mg, 0.436 mmol, 98.4% yield) as a white crystalline solid. LC-MS: m / z=259.2 [M+H] + ,ESI pos.

[0411] Step 3: 1-[2-[1-(difluoromethyl)-3-methyl-pyrazol-4-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone [ka] 1-[2-chloro-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (5.0 mg, 0.010 mmol, 1.0 equiv, prepared in Example 76, Step 2) and 1-[2-chloro-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone were added at 100° C. for 2 hours. Prepared analogously to Step 2 of Example 135 using 1-[2-[1-(difluoromethyl)-5-methyl-pyrazol-4-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (5.0 mg, 0.010 mmol, 1 equiv.) to give 1-[2-[1-(difluoromethyl)-5-methyl-pyrazol-4-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (12 mg, 0.030 mmol, 7.44% yield). LC-MS: m / z 475.2 [M+H] + ,ESI pos.

[0412] Step 4: 1-[2-[1-(difluoromethyl)-3-methyl-pyrazol-4-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol [ka] Prepared analogously to Example 53, step 3, using 1-[2-[1-(difluoromethyl)-3-methyl-pyrazol-4-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (20.0 mg, 0.040 mmol, 1.0 equiv.) and NaBH4 (4.78 mg, 0.130 mmol, 3 equiv.) to give 1-[2-[1-(difluoromethyl)-3-methyl-pyrazol-4-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol (5.9 mg, 0.010 mmol, 29.4% yield) as a white solid. LC-MS: m / z=477.1 [M+H] + ,ESI pos.

[0413] Example 150 1-[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-4-carbonitrile [ka]

[0414] Step 1: 1-(3-acetyl-6-chloro-2-pyridyl)-3-methyl-pyrazole-4-carbonitrile [ka] Prepared as in Example 62, Step 1, using 5-methyl-1H-pyrazole-4-carbonitrile (616.9 mg, 5.76 mmol, 1.0 equiv.) and 1-(6-chloro-2-fluoro-3-pyridyl)ethanone (CAS number 1260663-13-5, 1.0 g, 5.76 mmol, 1.0 equiv.) to give 1-(3-acetyl-6-chloro-2-pyridyl)-3-methyl-pyrazole-4-carbonitrile (900 mg, 3.45 mmol, 59.9% yield) as a white solid. LC-MS: m / z=260.9 [M+H] + ,ESI pos.

[0415] Step 2: 1-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-4-carbonitrile and 1-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-4-carbonitrile [ka] Prepared as in Example 53, step 3 using 1-(3-acetyl-6-chloro-2-pyridyl)-5-methyl-pyrazole-4-carbonitrile (182.0 mg, 0.700 mmol, 1.0 equiv), N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine (188.72 mg, 0.840 mmol, 1.2 equiv, prepared in Example 64, Intermediate 1), and DIPEA (0.24 mL, 1.4 mmol, 2 equiv), purified by preparative NPLC (Welch Ultimate XB-SiOH 250 mm x 70 mm x 10 μm, gradient 20-60% EtOH in hexanes over 20 min, then 100% After separation with EtOH (3 min, flow rate 140 mL / min), 1-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-4-carbonitrile (100 mg, 0.220 mmol, 31.87% yield) was obtained as a light brown solid, and 1-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-4-carbonitrile (60 mg, 0.130 mmol, 19.12% yield) was obtained as a light brown solid. Regioisomer 1: LC-MS: m / z = 450.2 [M+H] + ,ESI pos. 1 H NMR(400 MHz, CDCl3)δ=8.62(s,1H),8.32-8.25(m,1H),8.03-7.97(m,1H),7.94-7.91(m,1H),7.87-7.82(m,1H),7.78-7.72(m,1H),7. 50-7.44(m,1H),7.21-7.16(m,1H),7.15-7.09(m,1H),2.79(s,3H),2.62(s,3H),2.24(s,3H).Positional isomer 2:LC-MS:m / z=450.2[M+H] + ,ESI pos. 1H NMR(400 MHz, CDCl3)δ=8.71-8.64(m,1H),8.58-8.53(m,1H),8.35-8.23(m,1H),7.93-7.89(m,1H),7.86- 7.77(m,2H),7.25-7.15(m,2H),7.05-6.94(m,2H),2.80(s,3H),2.64(s,3H),2.28-2.22(m,3H).

[0416] Step 3: 1-[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-4-carbonitrile [ka] Prepared as in Example 53, Step 3, using 1-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-4-carbonitrile (60.0 mg, 0.130 mmol, 1.0 equiv.), the product was purified by preparative HPLC (Phenomenex Synergi C18 150 x 25 mm x 10 μm, gradient 2-32% CHCN (with 0.225% formic acid) over 10 min, followed by 100% After CH3CN (2 min, flow rate 25 mL / min, single injection), 1-[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-4-carbonitrile (34.5 mg, 0.080 mmol, 57.24% yield) was obtained as an off-white solid. LC-MS: m / z = 451.9 [M+H] + ,ESI pos. 1H NMR(400 MHz,CD3OD)δ=8.87-8.74(m,2H),8.56-8.47(m,1H),8.16-8.02(m,2H),7.70-7.61(m,1H),7.41-7.29 (m,2H),7.15-7.06(m,1H),4.83-4.80(m,1H),2.58-2.54(m,3H),2.53-2.48(m,3H),1.45-1.36(m,3H)

[0417] Example 151 1-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-4-carbonitrile [ka] Prepared as in Example 53, Step 3, using 1-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-4-carbonitrile (100.0 mg, 0.220 mmol, 1.0 equiv., prepared in Example 150, Step 2) in CHCl3 / MeOH (1:1) gave 1-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-4-carbonitrile (58.5 mg, 0.130 mmol, 58.24% yield) by preparative HPLC (Phenomenex Synergi C18 150 × 25 mm × 10 μm, 3-36% gradient in HO in 1:1). Obtained after 11 min in CH3CN (with 0.225% formic acid) followed by 100% CH3CN (2 min, flow rate 25 mL / min) as a yellow solid. LC-MS: m / z = 452.0 [M+H] + ,ESI pos. 1H NMR(400 MHz,CD3OD)δ=8.87(s,1H),8.51-8.44(m,1H),8.24-8.18(m,1H),8.13-8.04(m,3H),7.59-7.5 4(m,1H),7.40-7.34(m,1H),7.17-7.10(m,1H),4.82-4.80(m,1H),2.53(s,6H),1.41(d,J=6.5 Hz,3H).

[0418] Example 152 1-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-N,5-dimethyl-pyrazole-3-carboxamide [ka] Prepared analogously to Example 55, step 4 using 1-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-N,5-dimethyl-pyrazole-3-carboxamide (30 mg, 0.062 mmol, 1.0 equiv., prepared in Example 144, step 3) in MeOH / THF (1:1) with stirring overnight to give the title compound (14 mg, 46% yield) as a light brown solid. LC-MS: m / z=484.3 [M+H] + ,ESI pos.

[0419] Example 155 1-[3-(1-hydroxyethyl)-6-[5-[(2-keto-1-methyl-4-piperidyl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka]

[0420] Step 1: 1-[3-acetyl-6-[5-[(2-keto-1-methyl-4-piperidyl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Prepared as in Example 104, Step 2, using 4-amino-1-methyl-2-piperidone; dihydrochloride (23.87 mg, 0.119 mmol, 2.0 equiv.) for 6 h to afford the title compound (10.7 mg, 36.6% yield) as a yellow solid. LC-MS: m / z=469.3 [M+H] + ,ESI pos.

[0421] Step 2: 1-[3-(1-hydroxyethyl)-6-[5-[(2-keto-1-methyl-4-piperidyl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Prepared in MeOH / THF (1:1) as in Example 53, step 4 to give the title compound (6.5 mg, 58.7% yield) as a yellow solid. LC-MS: m / z=471.3 [M+H] + ,ESI pos.

[0422] Example 158 [2-(3-Methoxy-5-methyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]methanol [ka]

[0423] Intermediate 1: N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine [ka] iA mixture of 5-aminobenzimidazole (8.0 g, 60.1 mmol, 1.0 equiv) and 3-chloro-6-methylpyridazine (7.34 g, 57.08 mmol, 0.950 equiv) in PrOH (120 mL) was stirred at 120° C. for 72 h. The dark brown suspension was concentrated in vacuo and the residue was triturated in MeOH (60 mL). The solid was collected by filtration and triturated in DCM (40 mL). The product was collected by filtration, washed with DCM, and dried. The title compound (10 g, 71.3% yield) was obtained as a brown solid. LC-MS: m / z=226.0 [M+H] + ,ESI pos. 1 H NMR(400 MHz,DMSO-d6):δ=9.60(br s,1H),8.72(s,1H),8.52(d,J=1.7 Hz,1H),7.63(d,J=8.8 Hz,1H),7.44(dd,J=2.0,8.8 Hz,1H),7.39(d,J=9.2 Hz,1H),7.21(d,J=9.2 Hz,1H),5.04-4.15(m,1H),2.49(s,3H).

[0424] Step 1: Methyl 6-chloro-2-(3-methoxy-5-methyl-pyrazol-1-yl)pyridine-3-carboxylate [ka] Prepared analogously to Example 133, step 1 using methyl 6-chloro-2-fluoro-pyridine-3-carboxylate (1.0 g, 5.28 mmol, 1.0 equiv) and 3-methoxy-5-methyl-1H-pyrazole (600.0 mg, 5.35 mmol, 1.0 equiv) to give methyl 6-chloro-2-(3-methoxy-5-methyl-pyrazol-1-yl)pyridine-3-carboxylate (1.4 g, 4.97 mmol, 94.2% yield) as a white solid. LC-MS: m / z=282.2 [M+H] + ,ESI pos.

[0425] Step 2: Methyl 2-(3-methoxy-5-methyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carboxylate [ka] A mixture of N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine (0.92 g, 4.07 mmol, 1.04 equiv., Intermediate 1), methyl 6-chloro-2-(3-methoxy-5-methyl-pyrazol-1-yl)pyridine-3-carboxylate (1.1 g, 3.91 mmol, 1.0 equiv.) and K2CO3 (1.65 g, 11.94 mmol, 3.1 equiv.) in DMSO (50 mL) was stirred at 50 °C for 12 h. The mixture was cooled to room temperature and poured into H2O (500 mL). A solid precipitated out, which was extracted with EtOAc (3 × 400 mL). The combined organic layers were concentrated. The residue was purified by preparative HPLC: column Phenomenex Luna C18 (250 mm x 70 mm x 15 μm. Flow rate 140 mL / min. Gradient: 20% to 50% CH3CN in (HO containing 0.225% formic acid v / v) (35 min), then 100% CH3CN (1 min). Methyl 2-(3-methoxy-5-methyl-pyrazol-1-yl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carboxylate A mixture of methyl 2-(3-methoxy-5-methyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carboxylate (370 mg, 0.79 mmol, 20.1% yield) and methyl 2-(3-methoxy-5-methyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carboxylate (350 mg, 0.74 mmol, 18.1% yield) was obtained as a pale yellow solid. LC-MS: m / z=471.1 [M+H] + This mixture was purified by preparative NPLC: column Welch Ultimate XB-SiOH (250 mm × 70 mm × 10 μm). Flow rate 140 mL / min. Gradient: 20% to 60% EtOH in hexane (20 min), then 100% EtOH (3 min).

[0426] Step 3: [2-(3-methoxy-5-methyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]methanol [ka] To a solution of methyl 2-(3-methoxy-5-methyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carboxylate (30.0 mg, 0.060 mmol, 1.0 equiv) in DCM (4 mL) was added DIBAL-H (0.14 mL, 0.140 mmol, 2.2 equiv) over 5 min at −76° C. The mixture was stirred at −76° C. for 1 h. Another portion of DIBAL-H (0.14 mL, 0.140 mmol, 2.2 equiv) was added after 2 and 4 h at −76° C., and the reaction mixture was stirred at this temperature for an additional 1 h. The reaction mixture was then diluted with 5 mL of THF and warmed to 0 °C. The reaction mixture was quenched by the addition of 0.16 mL of HO, followed by 0.16 mL of 15% aqueous NaOH, and 0.4 mL of HO, in that order. After stirring at room temperature for 15 minutes, MgSO was added to the reaction mixture, which was stirred at room temperature for 15 minutes. After filtration, the volatiles were removed under reduced pressure. The residue was purified by preparative TLC (silica gel, 9% MeOH in DCM) to give [2-(3-methoxy-5-methyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]methanol (20 mg, 0.050 mmol, 68.8% yield) as a pale yellow solid. LC-MS: m / z = 443.1 [M+H] + ,ESI pos. 1H NMR(400 MHz,CD3OD):δ=8.84(s,1H),8.34(d,J=8.3 Hz,1H),8.21(d,J=2.0 Hz,1H),8.13(d,J=8.9 Hz,1H),7.92(d,J=8.3 Hz,1H),7.61(dd,J=2.1,8.9 Hz,1H),7.35(d,J=9.1 Hz,1H),7.13(d,J=9.1 Hz,1H),5.85(s,1H),4.69(s,2H),3.90(s,3H),2.53(s,3H),2.41(s,3H).

[0427] Example 159 1-[2-(3,5-dimethylisoxazol-4-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol [ka]

[0428] Step 1: 1-[2-(3,5-dimethylisoxazol-4-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone [ka] Prepared in a manner analogous to Example 143, Step 2, using (3,5-dimethylisoxazol-4-yl)boronic acid (26.0 mg, 0.180 mmol, 1.4 equiv.) and 1-[2-chloro-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (50.0 mg, 0.130 mmol, 1.0 equiv., prepared in Example 76, Step 2) to give 1-[2-(3,5-dimethylisoxazol-4-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (25 mg, 0.060 mmol, 43.1% yield) as a yellow solid. LC-MS: 440.2 [M+H] + ,ESI pos.

[0429] Step 2: 1-[2-(3,5-dimethylisoxazol-4-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol [ka] Prepared as in Example 53, step 4, to give 1-[2-(3,5-dimethylisoxazol-4-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol (9.8 mg, 0.020 mmol, 39.0% yield) as a white solid. LC-MS: m / z=442.2 [M+H] + ,ESI pos.

[0430] Example 160 1-[3-(1-hydroxyethyl)-6-[5-[(4-methoxypyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka]

[0431] Step 1: 1-[3-acetyl-6-[5-[(4-methoxypyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Prepared in a similar manner to Step 2 of Example 104 using (4-methoxypyridazin-3-yl)amine (23.76 mg, 0.190 mmol, 2.0 equiv.) to give the title compound (29.6 mg, 63.6% yield) as a yellow solid. LC-MS: 466.3 [M+H] + ,ESI pos.

[0432] Step 2: 1-[3-(1-hydroxyethyl)-6-[5-[(4-methoxypyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] The title compound (18.9 mg, 63.6% yield) was obtained in MeOH / THF (1:1) in the same manner as in Example 53, Step 4, as a pale yellow solid. LC-MS: 468.3 [M+H] + ,ESI pos.

[0433] Example 161 1-[3-(1-hydroxyethyl)-6-[5-[(5-keto-1-methyl-pyrrolidin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka]

[0434] Step 1: 1-[3-acetyl-6-[5-[(5-keto-1-methyl-pyrrolidin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Prepared analogously to Example 104, step 2 using 4-amino-1-methyl-2-pyrrolidone (27.1 mg, 0.237 mmol, 2 equiv) to give the title compound (43.1 mg, 75.9% yield). LC-MS: 455.3 [M+H] + ,ESI pos.

[0435] Step 2: 1-[3-(1-hydroxyethyl)-6-[5-[(5-keto-1-methyl-pyrrolidin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] The title compound (36.7 mg, 81.4% yield) was obtained in MeOH / THF (1:1) as a yellow solid in analogy to Example 53, Step 4. LC-MS: 457.3 [M+H] + ,ESI pos.

[0436] Example 162 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-(3-methyl-4-pyridyl)-3-pyridyl]ethanol [ka]

[0437] Step 1: 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-(3-methyl-4-pyridyl)-3-pyridyl]ethanone [ka] Prepared analogously to Example 143, step 2 using 3-methylpyridine-4-boronic acid (36.15 mg, 0.260 mmol, 2 equiv.) and 1-[2-chloro-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (50.0 mg, 0.130 mmol, 1.0 equiv., prepared in Example 76, step 2) to give 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-(3-methyl-4-pyridyl)-3-pyridyl]ethanone (22 mg, 0.050 mmol, 38.28% yield) as a yellow solid. LC-MS: m / z=436.2, [M+H] + ,ESI pos.

[0438] Step 2: 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-(3-methyl-4-pyridyl)-3-pyridyl]ethanol [ka] As in Example 53, Step 4, using 5.0 equivalents of NaBH4, 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-(3-methyl-4-pyridyl)-3-pyridyl]ethanol (8.9 mg, 0.020 mmol, 44.3% yield) was obtained as a white solid. LC-MS: m / z = 438.2, [M+H] + ,ESI pos.

[0439] Example 163 1-[2-[4-(cyclopropylamino)pyrimidin-5-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol [ka]

[0440] Step 1: [4-(cyclopropylamino)pyrimidin-5-yl]boronic acid [ka] Prepared analogously to Example 143, Step 2, using 5-bromo-N-cyclopropyl-pyrimidin-4-amine (1.0 g, 4.67 mmol, 1.0 equiv) and bis(pinacolato)diboron (1779.45 mg, 7.01 mmol, 1.5 equiv) to give [4-(cyclopropylamino)pyrimidin-5-yl]boronic acid (368 mg, 2.06 mmol, 44.0% yield) as a white solid. LC-MS: m / z=180.1, [M+H] + ,ESI pos.

[0441] Step 2: 1-[2-chloro-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol [ka] As in Example 53, Step 4, using 1-[2-chloro-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (200.0 mg, 0.530 mmol, 1.0 equiv., prepared in Example 76, Step 2) and 5.0 equiv. of NaBH4, 1-[2-chloro-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol (130 mg, 0.340 mmol, 51.7% yield) was obtained as a gray solid. LC-MS: m / z = 381.1, [M+H] + ,ESI pos.

[0442] Step 3: 1-[2-[4-(cyclopropylamino)pyrimidin-5-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol [ka] Using 1-[2-chloro-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol (30.0 mg, 0.080 mmol, 1.0 equiv., from Example 163, Step 2) and [4-(cyclopropylamino)pyrimidin-5-yl]boronic acid (42.3 mg, 0.240 mmol, 3.0 equiv., from Example 163, Step 1) in a similar manner as in Example 143, Step 2, 1-[2-[4-(cyclopropylamino)pyrimidin-5-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol (4 mg, 0.010 mmol, 10.5% yield) was obtained as a white solid. LC-MS: m / z=480.1, [M+H] + ,ESI pos.

[0443] Example 164 5-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-4-(trifluoromethyl)pyridin-2-ol [ka]

[0444] Step 1: 5-Bromo-2-methoxy-4-(trifluoromethyl)pyridine [ka] A solution of 5-bromo-2-chloro-4-(trifluoromethyl)pyridine (1.0 g, 3.84 mmol, 1.0 equiv.) and sodium methoxide (0.41 g, 7.68 mmol, 2 equiv.) in methanol (7 mL) was stirred at 70° C. for 2 h. The reaction mixture was dissolved in DCM (10 mL), filtered, and the filtrate was concentrated in vacuo to give the desired product as a white solid, which was used without further purification. LC-MS: m / z=257.9, [M+H] + ,ESI pos.

[0445] Step 2: 2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyridine [ka] Prepared similarly to Example 143, Step 2, to give 3-bromo-6-methoxy-2-(trifluoromethyl)pyridine (used crude from the previous step) to give the desired compound as an off-white solid (400 mg, 62.7% yield). LC-MS: m / z=304.1, [M+H] + ,ESI pos.

[0446] Step 3: 1-[2-[6-methoxy-4-(trifluoromethyl)-3-pyridyl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone [ka] 2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyridine (240.03 mg, 0.790 mmol, 3 equiv.) and 1-[2-chloro-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (100.0 mg, 0.260 mmol, Prepared similarly to Example 143, step 2 using 1.0 equiv. (prepared in Example 76, step 2) to give 1-[2-[6-methoxy-4-(trifluoromethyl)-3-pyridyl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (45 mg, 0.090 mmol, 32.82% yield) as a yellow solid. LC-MS: m / z=520.2, [M+H] + ,ESI pos.

[0447] Step 4: 1-[2-[6-hydroxy-4-(trifluoromethyl)-3-pyridyl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone; formic acid [ka] To a solution of 1-[2-[6-methoxy-4-(trifluoromethyl)-3-pyridyl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (40.0 mg, 0.080 mmol, 1.0 equiv) in HCl (2008.86 mg, 3 mmol, 39.0 equiv) was added and the resulting mixture was stirred at 100° C. for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex Luna C18 (150 mm × 40 mm × 15 μm). Flow rate: 60 mL / min. Gradient: 10% to 40% CH3CN (13 min) in (0.225% formic acid in HO v / v), then 100% CH3CN (2 min)) and lyophilized to give 1-[2-[6-hydroxy-4-(trifluoromethyl)-3-pyridyl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone; formate (30 mg, 0.060 mmol, 77.1% yield) as a yellow solid. LC-MS: m / z = 506.1, [M+H] + ,ESI pos.

[0448] Step 5: 5-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-4-(trifluoromethyl)pyridin-2-ol [ka] Prepared similarly to Example 53, step 4 to give 5-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-4-(trifluoromethyl)pyridin-2-ol (10.1 mg, 0.020 mmol, 32.7% yield) as a gray solid. LC-MS: m / z=508.1, [M+H] + ,ESI pos.

[0449] Example 165 3-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one [ka]

[0450] Step 1: 6,7-Dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one [ka] To a solution of tert-butyl N-(2-bromoethyl)carbamate (10.66 g, 47.58 mmol, 1.2 equiv.) in DMF (100 mL) was added tert-butyl N-(2-bromoethyl)carbamate (10.66 g, 47.58 mmol, 1.2 equiv.) and CsCO (25.84 g, 79.3 mmol, 2 equiv.). The mixture was stirred at 30 °C for 12 h. The mixture was filtered, and the filter cake was rinsed with EtOAc. The filtrate was concentrated under reduced pressure to remove EtOAc, diluted with water, and extracted with EtOAc. The combined extracts were washed with brine and concentrated under reduced pressure. The residue was purified by flash column chromatography (0–25% EtOAc in PE) and concentrated under reduced pressure to give a colorless oil. This oil was dissolved in 4 M HCl in 1,4-dioxane (20 mL), and 1,4-dioxane (20.0 mL, 80 mmol, 2.02 equiv.) was added at 0 °C. The mixture was stirred at 20 °C for 2 h. The volatiles were removed, and the residue was dissolved in 1,4-dioxane (50 mL), and sodium carbonate (16.81 g, 158.59 mmol, 4 equiv.) was added as a solid. The mixture was stirred at 30 °C for 12 h. The reaction mixture was filtered, and the filter cake was rinsed with EtOAc. The filtrate was concentrated under reduced pressure to remove the volatiles. The residue was purified by flash column chromatography (0–100% EtOAc in PE) to afford 6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (1.5 g, 10.94 mmol, 27.6% yield) as an orange powder. LC-MS: m / z=138.2, [M+H] + ,ESI pos.

[0451] Step 2: 3-Bromo-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one [ka] To a solution of 6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (1.5 g, 10.94 mmol, 1.0 equiv) in DMF (15 mL) was added 1-bromopyrrolidine-2,5-dione (2.14 g, 12.03 mmol, 1.1 equiv). The mixture was stirred at 30 °C for 12 h. The reaction mixture was poured into saturated aqueous NH Cl and stirred for 10 min. The mixture was then filtered and rinsed with water (10 mL * 2) and saturated Na SO (10 mL). The filter cake was concentrated under reduced pressure to give 3-bromo-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (2.2 g, 10.18 mmol, 93.1% yield) as an off-white solid. LC-MS: m / z=216.0, [M+H] + ,ESI pos.

[0452] Step 3: (4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-3-yl)boronic acid [ka] Prepared as in Example 143, Step 2, using 3-bromo-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (500.0 mg, 2.31 mmol, 1.0 equiv.) to give (4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-3-yl)boronic acid (800 mg, 4.42 mmol, 48.61% yield) as a yellow solid. LC-MS: m / z=182.1, [M+H] + ,ESI pos.

[0453] Step 4: 3-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one [ka] Prepared as in Example 143, Step 2 from (4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-3-yl)boronic acid (600.0 mg, 1.23 mmol, 7.75 equiv) and 1-[2-chloro-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (60.0 mg, 0.160 mmol, 1.0 equiv, prepared in Example 76, Step 2) to give 3-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (35 mg, 0.070 mmol, 45.6% yield) as a brown solid. LC-MS: m / z=480.2, [M+H] + ,ESI pos.

[0454] Step 5: 3-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one [ka] Prepared similarly to Example 53, step 4, to give 3-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (6.8 mg, 0.010 mmol, 22.6% yield) as a white solid. LC-MS: m / z=482.2, [M+H] + ,ESI pos.

[0455] Example 166 1-[6-[6-fluoro-5-[[(3S,4R)-4-fluoropyrrolidin-3-yl]amino]benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; Formic acid [ka]

[0456] Step 1: tert-butyl (3R,4S)-3-fluoro-4-(2-fluoro-4,5-dinitroanilino)pyrrolidine-1-carboxylate [ka] To a solution of 1,2-difluoro-4,5-dinitro-benzene (450.0 mg, 2.2 mmol, 1.0 equiv.) in DMF (10 mL) were added tert-butyl (3S,4R)-3-amino-4-fluoropyrrolidine-1-carboxylate (450.0 mg, 2.2 mmol, 1.0 equiv.) and N,N-diisopropylethylamine (1.09 mL, 6.61 mmol, 3.0 equiv.). The reaction mixture was stirred at 30° C. for 12 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine and concentrated in vacuo to give tert-butyl (3R,4S)-3-fluoro-4-(2-fluoro-4,5-dinitroanilino)pyrrolidine-1-carboxylate (800 mg, 2.06 mmol, 93.4% yield) as a yellow solid. LC-MS: m / z=289.1 [M-Boc+H] + ,ESI pos.

[0457] Step 2: 6-fluoro-N-[(3S,4R)-4-fluoropyrrolidin-3-yl]-1H-benzimidazol-5-amine [ka] To a solution of tert-butyl (3R,4S)-3-fluoro-4-(2-fluoro-4,5-dinitroanilino)pyrrolidine-1-carboxylate (550.0 mg, 1.42 mmol, 1.0 equiv.) in formic acid (65.19 mg, 1.42 mmol, 1.0 equiv.) was added nickel (83.13 mg, 1.42 mmol, 1.0 equiv.). The mixture was stirred at 30° C. under an H atmosphere (50 psi) for 12 hours. The mixture was filtered through a Celite pad, and the filtrate was concentrated in vacuo to give crude 6-fluoro-N-[(3S,4R)-4-fluoropyrrolidin-3-yl]-1H-benzimidazol-5-amine (500 mg, 2.1 mmol, 74.1% yield) as a dark brown gum. LC-MS: m / z=239.1 [M+H] + ,ESI pos.

[0458] Step 3: tert-butyl (3R,4S)-3-fluoro-4-[(6-fluoro-1H-benzimidazol-5-yl)amino]pyrrolidine-1-carboxylate [ka] To a solution of 6-fluoro-N-[(3S,4R)-4-fluoropyrrolidin-3-yl]-1H-benzimidazol-5-amine (600.0 mg, 1.26 mmol, 1.0 equiv.) in DCM (10 mL) was added TEA (382.27 mg, 3.78 mmol, 3 equiv.) and tert-butyl (2-methylpropan-2-yl)oxycarbonyl carbonate (412.24 mg, 1.89 mmol, 1.5 equiv.). The mixture was stirred at 25° C. for 12 hours. The mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in MeOH, and saturated aqueous K2CO3 solution was added to the solution. The mixture was stirred at 25° C. for 12 hours. The mixture was extracted with EtOAc, the combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (Waters Xbridge C18 150 mm × 50 mm × 10 μm, gradient 3–33% CH3CN (containing 10 mM NH4CO3) in HO over 11 min, then 100% CH3CN (2 min), flow rate 60 mL / min), and the eluent was lyophilized to afford tert-butyl (3R,4S)-3-fluoro-4-[(6-fluoro-1H-benzimidazol-5-yl)amino]pyrrolidine-1-carboxylate (180 mg, 0.530 mmol, 42.3% yield) as an off-white solid. LC-MS: m / z = 339.2 [M+H] + ,ESI pos.

[0459] Step 4: tert-Butyl (3S,4R)-3-[[1-[5-acetyl-6-(3-cyano-5-methyl-pyrazol-1-yl)-2-pyridyl]-6-fluoro-benzimidazol-5-yl]amino]-4-fluoro-pyrrolidine-1-carboxylate [ka] Prepared in a similar manner to Example 64, Step 2 using tert-butyl (3S,4R)-3-fluoro-4-[(6-fluoro-1H-benzimidazol-5-yl)amino]pyrrolidine-1-carboxylate (170.0 mg, 0.500 mmol, 1.0 equiv) and 1-(3-acetyl-6-chloro-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile (196.46 mg, 0.750 mmol, 1.5 equiv, prepared in Example 64, Step 1) to give tert-butyl (3S,4R)-3-[[3-[5-acetyl-6-(3-cyano-5- Methyl-pyrazol-1-yl)-2-pyridyl]-6-fluoro-benzimidazol-5-yl]amino]-4-fluoro-pyrrolidine-1-carboxylate (40 mg, 0.070 mmol, 14.2% yield) and tert-butyl (3S,4R)-3-[[1-[5-acetyl-6-(3-cyano-5-methyl-pyrazol-1-yl)-2-pyridyl]-6-fluoro-benzimidazol-5-yl]amino]-4-fluoro-pyrrolidine-1-carboxylate (50 mg, 0.090 mmol, 17.7% yield) were obtained as a pale yellow gum. The regioisomers were separated by preparative NPLC (Welch Ultimate XB-SiOH 250 x 50 x 10 μm, 10-50% EtOH (0.1% ammonium hydroxide) in hexanes over 15 min, followed by 100% EtOH (0.1% ammonium hydroxide) (5 min), flow rate 100 mL / min). LC-MS: m / z = 563.2 [M+H] + ,ESI pos. positional isomer 1: 1 H NMR(400 MHz,CDCl3)δ=8.52(s,1H),8.28(d,J=8.4 Hz,1H),7.78(d,J=11.1 Hz,1H),7.68(d,J=8.4 Hz,1H),7.18(d,J=7.8 Hz,1H),6.73(s,1H),5.36-5.13(m,1H),4.41(br d,J=7.8 Hz,1H),4.27-4.02(m,2H),3.73(q,J=6.9 Hz,1H),3.21(q,J=9.7 Hz,1H),2.61(s,3H),2.20(s,3H),1.49(s,9H).Positional isomer 2: 1H NMR(400 MHz,CDCl3)δ=8.45-8.37(m,1H),8.32(d,J=8.3 Hz,1H),7.70(br d,J=8.3 Hz,1H),7.51(br d,J=11.1 Hz,1H),7.40(d,J=7.5 Hz,1H),6.76-6.67(m,1H),5.28-5.04(m,1H),4.64-4.40(m,1H),4.04-3.53( m,4H),3.27-3.11(m,1H),2.58(s,3H),2.26-2.17(s,3H),1.54-1.46(s,9H).

[0460] Step 5: 1-[3-acetyl-6-[6-fluoro-5-[[(3S,4R)-4-fluoropyrrolidin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] A solution of tert-butyl (3S,4R)-3-[[1-[5-acetyl-6-(3-cyano-5-methyl-pyrazol-1-yl)-2-pyridyl]-6-fluoro-benzimidazol-5-yl]amino]-4-fluoro-pyrrolidine-1-carboxylate (50.0 mg, 0.090 mmol, 1.0 equiv.) and trifluoroacetic acid (0.63 mL, 8.11 mmol, 91.3 equiv.) in DCM (2.5 mL) was stirred at 25 ° C. for 1 hour. The mixture was concentrated in vacuo to give 60 mg of crude 1-[3-acetyl-6-[6-fluoro-5-[[(3S,4R)-4-fluoropyrrolidin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile. The crude product was used in the next step without further purification. LC-MS: m / z=463.1 [M+H] + ,ESI pos.

[0461] Step 6: 1-[6-[6-fluoro-5-[[(3S,4R)-4-fluoropyrrolidin-3-yl]amino]benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; formic acid [ka] To a solution of 1-[3-acetyl-6-[6-fluoro-5-[[(3S,4R)-4-fluoropyrrolidin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 2,2,2-trifluoroacetic acid (used crude from the previous step) in methanol (3 mL) was added NaBH (11.81 mg, 0.310 mmol, 3.0 equiv.) at 0 °C and stirred for 30 minutes. The mixture was quenched with saturated aqueous NH Cl and extracted with EtOAc. The combined organic layers were dried over Na SO and concentrated in vacuo. The residue was purified by preparative HPLC (Waters Xbridge 150*25mm*5um, HO (10 mM NH4HCO3)-CH3CN, 23-53% B, gradient time 8 min, 100% B hold time 2 min, flow rate 25 mL / min) and the eluent was lyophilized to give 1-[6-[6-fluoro-5-[[(3S,4R)-4-fluoropyrrolidin-3-yl]amino]benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; formate (13.6 mg, 0.030 mmol, 26.73% yield) as a white solid. LC-MS: m / z = 465.3 [M+H] + ,ESI pos.

[0462] Example 167 1-[2-[2-(difluoromethoxy)-5-methyl-4-pyridyl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol [ka]

[0463] Step 1: 4-Bromo-2-(difluoromethoxy)-5-methyl-pyridine [ka] A mixture of 4-bromo-5-methyl-pyridin-2-ol (290.0 mg, 1.54 mmol, 1.0 equiv.), CsCO (1.01 g, 3.08 mmol, 2.0 equiv.), and sodium chlorodifluoroacetate (705.46 mg, 4.63 mmol, 3.0 equiv.) in DMF (5 mL) was stirred at 100 °C for 12 h. The reaction mixture was filtered, the filtrate was dissolved in brine, extracted with ethyl acetate, and the combined extracts were concentrated under reduced pressure. The residue was purified by flash column chromatography (9% EtOAc in PE) to give 4-bromo-2-(difluoromethoxy)-5-methyl-pyridine (200 mg, 0.840 mmol, 54.48% yield) as a colorless oil. LC-MS: m / z = 238.0, [M+H] + ,ESI pos.

[0464] Step 2: 2-(Difluoromethoxy)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine [ka] Prepared as in Example 143, step 2 using 4-bromo-2-(difluoromethoxy)-5-methyl-pyridine (150.0 mg, 0.630 mmol, 1.0 equiv) to give 2-(difluoromethoxy)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (250 mg, 0.880 mmol, 139.2% yield) as a yellow oil. LC-MS: m / z=286.2, [M+H] + ,ESI pos.

[0465] Step 3: 1-[2-[2-(difluoromethoxy)-5-methyl-4-pyridyl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone [ka] Prepared as in Example 143, step 2 using 1-[2-chloro-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (50.0 mg, 0.130 mmol, 1.0 equiv, prepared in Example 76, step 2) and 2-(difluoromethoxy)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (718.5 mg, 2.5 mmol, 20 equiv) to give 1-[2-[2-(difluoromethoxy)-5-methyl-4-pyridyl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (30 mg, 0.060 mmol, 45.3% yield) as a yellow solid. LC-MS: m / z=502.3, [M+H] + ,ESI pos.

[0466] Step 4: 1-[2-[2-(difluoromethoxy)-5-methyl-4-pyridyl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol [ka] Prepared as in Example 53, step 4 using 5.0 equivalents of NaBH (11.37 mg, 0.300 mmol) to give 1-[2-[2-(difluoromethoxy)-5-methyl-4-pyridyl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol (19.4 mg, 0.040 mmol, 64.4% yield) as a yellow solid. LC-MS: m / z=502.4, [M+H] + ,ESI pos.

[0467] Example 168 1-[2-(2-fluoro-5-methyl-4-pyridyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol [ka]

[0468] Step 1: 2-Fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine [ka] Prepared as in Example 143, step 2, using 4-bromo-2-fluoro-5-methyl-pyridine (950.0 mg, 5 mmol, 1.0 equiv.) to give 2-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1000 mg, 4.22 mmol, 84.4% yield) as a pale yellow solid. LC-MS: m / z=238.1 [M+H] + ,ESI pos. 1 H NMR(400MHz, CDCl3)δ=8.00(s,1H),7.22(s,1H),2.44(s,3H),1.35(s,13H).

[0469] Step 2: 1-[2-(2-fluoro-5-methyl-4-pyridyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone [ka] Prepared as in Example 143, step 2 using 1-[2-chloro-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (50.0 mg, 0.130 mmol, 1.0 equiv, prepared in Example 76, step 2) and 2-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (125.17 mg, 0.530 mmol, 4.0 equiv) to give 1-[2-(2-fluoro-5-methyl-4-pyridyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (30 mg, 0.070 mmol, 50.1% yield) as a gray solid. LC-MS: m / z=454.1 [M+H] + ,ESI pos.

[0470] Step 3: 1-[2-(2-fluoro-5-methyl-4-pyridyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol [ka] Prepared similarly to Example 53, step 4, using 5.0 eq. of NaBH (11.26 mg, 0.300 mmol, 5 eq.). LC-MS: m / z=456.2 [M+H] + ,ESI pos.

[0471] Example 169 1-[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-4-methyl-pyrazole-3-carbonitrile; Formic acid [ka]

[0472] Step 1: 1-(3-acetyl-6-chloro-2-pyridyl)-4-bromo-pyrazole-3-carbonitrile [ka] Prepared as in Example 62, step 1 using 4-bromopyrazole-3-carbonitrile (1.0 g, 5.81 mmol, 1.0 equiv) to give 1-(3-acetyl-6-chloro-2-pyridyl)-4-bromo-pyrazole-3-carbonitrile (1.5 g, 4.61 mmol, 79.2% yield) as an off-white solid. LC-MS: m / z=326.8 [M+H] + ,ESI pos.

[0473] Step 2: 1-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-4-bromo-pyrazole-3-carbonitrile and 1-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-4-bromo-pyrazole-3-carbonitrile [ka] Prepared analogously to Example 76, Step 1 using 1-(3-acetyl-6-chloro-2-pyridyl)-4-bromo-pyrazole-3-carbonitrile (1.0 g, 3.07 mmol, 1.0 equiv) and N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine (0.83 g, 3.69 mmol, 1.2 equiv, prepared in Example 64, Step 1) to give 1-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl) 1-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-4-bromo-pyrazole-3-carbonitrile (350 mg, 0.680 mmol, 22.2% yield) and 1-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-4-bromo-pyrazole-3-carbonitrile (160 mg, 0.310 mmol, 10.1% yield) were obtained as light brown solids. Regioisomer 1: LC-MS: m / z = 514.0 [M+H] + ,ESI pos.1 H NMR(400 MHz,DMSO-d6)δ=9.32(s,1H),9.29(s,1H),9.17(s,1H),8.44(d,J=1.7 Hz,1H),8.40(d,J=8.4 Hz,1H),8.21(dd,J=8.7,10.7 Hz,2H),7.61(dd,J=1.8,8.8 Hz,1H),7.35(d,J=9.2 Hz,1H),7.10(d,J=9.0 Hz,1H),2.49(s,3H),2.41(s,3H).Positional isomer 2:LC-MS:m / z=514.0[M+H] + ,ESI pos. 1 H NMR(400 MHz,DMSO-d6)δ=9.64(d,J=1.7 Hz,1H),9.45(s,1H),9.39(s,1H),8.99(s,1H),8.40(d,J=8.4 Hz,1H),8.20-8.13(m,1H),7.68(d,J=8.7 Hz,1H),7.37(d,J=9.0 Hz,1H),7.25(dd,J=1.9,8.7 Hz,1H),7.15(d,J=9.0 Hz,1H),2.51(br d,J=1.5 Hz,3H),2.43(s,2H).

[0474] Step 3: 1-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-4-methyl-pyrazole-3-carbonitrile [ka] Prepared in analogy to Example 169 / 170, step 3, using 1-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-4-bromo-pyrazole-3-carbonitrile (50.0 mg, 0.100 mmol, 1.0 equiv) to afford the title compound as an off-white solid (25.1 mg, 0.056 mmol, 56.2% yield). LC-MS: m / z=450.1, [M+H] + ,ESI pos.

[0475] Step 4: 1-[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-4-methyl-pyrazole-3-carbonitrile; formic acid [ka] Prepared as in Example 53, step 4, using 1-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-4-methyl-pyrazole-3-carbonitrile (20.0 mg, 0.040 mmol, 1.0 equiv) in MeOH / DCM (5:1) to give 1-[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-4-methyl-pyrazole-3-carbonitrile; formic acid (3.8 mg, 0.010 mmol, 14.9% yield) as a yellow solid after lyophilization. LC-MS: m / z=452.2, [M+H] + ,ESI pos. 1 H NMR(400 MHz,CD3OD)δ=9.31(d,J=1.7 Hz,1H),8.86-8.81(m,1H),8.71(s,1H),8.57(d,J=8.4 Hz,1H),8.44(br s,2H),8.03-7.98(m,1H),7.69(d,J=8.8 Hz,1H),7.40(d,J=9.2 Hz,1H),7.30(dd,J=1.8,8.6 Hz,1H),7.20-7.15(m,1H),5.61(q,J=6.3 Hz,1H),2.58(s,3H),2.21(s,3H),1.54(d,J=6.4 Hz,3H).

[0476] Example 170 1-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-4-methyl-pyrazole-3-carbonitrile; Formic acid [ka]

[0477] Step 1: 1-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-4-methyl-pyrazole-3-carbonitrile [ka] To a solution of 1-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-4-bromo-pyrazole-3-carbonitrile (200.0 mg, 0.390 mmol, 1.0 equiv., provided in Example 169, Step 2) and trimethylboroxine (195.25 mg, 0.780 mmol, 2.0 equiv.) in DMF (15 mL) was added KPO (0.13 mL, 1.56 mmol, 4.0 equiv.) and PdCl(dppf) CHCl (31.73 mg, 0.040 mmol, 0.10 equiv.). The mixture was purged with nitrogen for several minutes, and then the reaction was stirred under a nitrogen atmosphere at 100 °C for 12 hours. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by preparative TLC (10% MeOH in DCM) to give 1-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-4-methyl-pyrazole-3-carbonitrile (40 mg, 0.090 mmol, 22.9% yield) as an off-white solid. LC-MS: m / z=450.2, [M+H] + ,ESI pos.

[0478] Step 2: 1-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-4-methyl-pyrazole-3-carbonitrile; formic acid [ka] Prepared as in Example 53, step 4 using 1-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-4-methyl-pyrazole-3-carbonitrile (40.0 mg, 0.090 mmol, 1.0 equiv) in MeOH / DCM (5:1) to give 1-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-4-methyl-pyrazole-3-carbonitrile; formic acid (10.3 mg, 0.020 mmol, 23.3% yield) as a yellow solid. LC-MS: m / z=452.2, [M+H] + ,ESI pos. 1 H NMR(400 MHz,CD3OD)δ=8.93(s,1H),8.53(d,J=8.4 Hz,1H),8.49(s,1H),8.41(br s,1H),8.24(d,J=1.8 Hz,1H),8.17(d,J=8.8 Hz,1H),8.02(d,J=8.3 Hz,1H),7.67(dd,J=1.9,9.0 Hz,1H),7.38(d,J=9.0 Hz,1H),7.15(d,J=9.2 Hz,1H),5.53(q,J=6.0 Hz,1H),2.56(s,3H),2.36(s,3H),1.52(d,J=6.4 Hz,3H).

[0479] Example 171 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[5-methyl-3-(trifluoromethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]-3-pyridyl]ethanol;Formic acid [ka]

[0480] Step 1: 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[5-methyl-3-(trifluoromethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]-3-pyridyl]ethanone [ka] A solution of 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[3-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-3-pyridyl]ethanone; hydrochloride (300.0 mg, 0.530 mmol, 1.0 equiv., prepared in Example 97, Step 3) and formaldehyde (50.0 mg, 1.67 mmol, 3.2 equiv.) in MeOH (10 mL) was stirred at 30° C. for 30 minutes. NaBHCN (100.0 mg, 1.59 mmol, 3.0 equiv.) was then added to the mixture, which was further stirred at 30° C. for 1.5 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[5-methyl-3-(trifluoromethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]-3-pyridyl]ethanone (183 mg, 0.334 mmol, 63.1% yield) as a yellow solid. The crude product was used without further purification. LC-MS: m / z=548.3 [M+H] + ,ESI pos.

[0481] Step 2: 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[5-methyl-3-(trifluoromethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]-3-pyridyl]ethanol; formic acid [ka] Prepared as in Example 53, step 4 using 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[5-methyl-3-(trifluoromethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]-3-pyridyl]ethanone (183 mg, 0.334 mmol, 1.0 equiv) in DCM / MeOH (9:1) to give 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[5-methyl-3-(trifluoromethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]-3-pyridyl]ethanol; formic acid (58 mg, 0.106 mmol, 31.8% yield) as a pale yellow solid. LC-MS: m / z=550.2 [M+H] + ,ESI pos.

[0482] Example 172 1-[[[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-methyl-amino]methyl]cyclopropanecarbonitrile [ka]

[0483] Step 1: tert-butyl N-[(1-cyanocyclopropyl)methyl]carbamate [ka] To a solution of 1-(aminomethyl)cyclopropanecarbonitrile hydrochloride (450.0 mg, 3.39 mmol, 1.0 equiv) in DCM (15 mL) was added tert-butyl (2-methylpropan-2-yl)oxycarbonyl carbonate (962.9 mg, 4.41 mmol, 1.3 equiv) and TEA (1.03 g, 10.18 mmol, 3.0 equiv). The mixture was stirred at 30 °C for 12 h. The mixture was diluted with DCM and purified by flash column chromatography (10–90% MeOH in DCM) to give tert-butyl N-[(1-cyanocyclopropyl)methyl]carbamate (350 mg, 1.78 mmol, 52.6% yield) as an off-white solid. 1 H NMR(400 MHz, CDCl3)δ=3.25(d,J=6.4 Hz,2H),1.46(s,9H),1.29-1.22(m,2H),1.06(s,2H).

[0484] Step 2: tert-butyl N-[(1-cyanocyclopropyl)methyl]-N-methyl-carbamate [ka] To a solution of tert-butyl N-[(1-cyanocyclopropyl)methyl]carbamate (680.0 mg, 3.46 mmol, 1.0 equiv) in THF (15 mL) and an inert atmosphere was added NaH (207.9 mg, 5.2 mmol, 1.5 equiv) at 0 °C. The mixture was stirred at 0 °C for 30 min. Then, MeI (737.7 mg, 5.2 mmol, 1.5 equiv) was added. The mixture was warmed to 25 °C and stirred for 12 h. The mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were dried over Na2SO4, and the volatiles were evaporated to give crude tert-butyl N-[(1-cyanocyclopropyl)methyl]-N-methyl-carbamate as a yellow oil, which was used in the next step without further purification.

[0485] Step 3: 1-(methylaminomethyl)cyclopropanecarbonitrile; 2,2,2-trifluoroacetic acid [ka] A solution of tert-butyl N-[(1-cyanocyclopropyl)methyl]-N-methyl-carbamate (used crude from the previous step) and TFA (5.0 mL, 64.9 mmol, 20 equiv.) in DCM (5 mL) was stirred at 30° C. for 12 h. The mixture was concentrated in vacuo to give the crude product 1-(methylaminomethyl)cyclopropanecarbonitrile; 2,2,2-trifluoroacetic acid as a pale yellow gum, which was used in the next step without further purification. LC-MS: m / z=111.1 [M+H] + ,ESI pos.

[0486] Step 4: 1-[[(3-acetyl-6-chloro-2-pyridyl)-methyl-amino]methyl]cyclopropanecarbonitrile [ka] To a solution of 1-(6-chloro-2-fluoro-3-pyridyl)ethanone (CAS no. 1260663-13-5, 696.8 mg, 4.01 mmol, 1.2 equiv.), 1-(methylaminomethyl)cyclopropanecarbonitrile, and 2,2,2-trifluoroacetic acid (used crude from the previous step) in DMSO (8 mL) was added DIPEA (1.66 mL, 10.04 mmol, 3.0 equiv.) and stirred at 30 °C for 12 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and the volatiles were evaporated. The residue was purified by flash column chromatography (10–33% EtOAc in PE) to afford 1-[[(3-acetyl-6-chloro-2-pyridyl)-methyl-amino]methyl]cyclopropanecarbonitrile (650 mg, 2.46 mmol, 70.7% yield) as a colorless gum. LC-MS: m / z=254.0 [M+H] + ,ESI pos.

[0487] Step 5: 1-[[[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-methyl-amino]methyl]cyclopropanecarbonitrile and 1-[[[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-methyl-amino]methyl]cyclopropanecarbonitrile [ka] Prepared analogously to Example 64, step 2 using 1-[[(3-acetyl-6-chloro-2-pyridyl)-methyl-amino]methyl]cyclopropanecarbonitrile (550.0 mg, 2.09 mmol, 1.0 equiv) and N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine (704.65 mg, 3.13 mmol, 1.5 equiv, prepared in Example 64, Intermediate 1) to give 1-[[[3-acetyl-6-[6-[(6-methylpyridazin-3-yl) [[[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-methyl-amino]methyl]cyclopropanecarbonitrile (110 mg, 0.240 mmol, 11.7% yield) was obtained as a yellow solid, and 1-[[[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-methyl-amino]methyl]cyclopropanecarbonitrile (110 mg, 0.240 mmol, 11.7% yield) was obtained as a brown solid. Regioisomer 1: LC-MS: m / z = 453.2 [M+H] + ,ESI pos. 1H NMR(400 MHz,DMSO-d6)δ=9.33(br s,2H),8.86(s,1H),8.21(d,J=8.2 Hz,1H),7.67(d,J=8.7 Hz,1H),7.36(d,J=9.0 Hz,1H),7.29(d,J=8.2 Hz,1H),7.25(dd,J=1.7,8.9 Hz,1H),7.13(d,J=9.0 Hz,1H),4.02(s,2H),3.02(s,3H),2.62(s,3H),2.53-2.51(m,3H),1.22-1.16(m,2H),1.02-0.97(m,2H).Positional isomer 2:LC-MS:m / z=453.2[M+H] + ,ESI pos. 1 H NMR(400 MHz,DMSO-d6)δ=9.23(s,1H),8.98(s,1H),8.38(d,J=1.8 Hz,1H),8.21(d,J=3.3 Hz,1H),8.19(d,J=4.0 Hz,1H),7.59(dd,J=2.0,8.9 Hz,1H),7.33(dd,J=5.8,8.6 Hz,2H),7.09(d,J=9.0 Hz,1H),3.87(s,2H),3.01(s,3H),2.59(s,3H),2.48(s,3H),1.34-1.28(m,2H),1.18-1.16(m,2H).

[0488] Step 6: 1-[[[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-methyl-amino]methyl]cyclopropanecarbonitrile [ka] Prepared analogously to Example 53, step 4, using 1-[[[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]methyl-amino]methyl]cyclopropanecarbonitrile (110.0 mg, 0.240 mmol, 1.0 equiv) in MeOH:DMF (3:2) to give 1-[[[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]methylamino]methyl]cyclopropanecarbonitrile (45.9 mg, 0.100 mmol, 39.1% yield) as a pale yellow solid. LC-MS: m / z=455.2 [M+H] + ,ESI pos.

[0489] Example 173 1-[[[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-methyl-amino]methyl]cyclopropanecarbonitrile [ka] Prepared analogously to Example 53, step 4 using 1-[[[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]methyl-amino]methyl]cyclopropanecarbonitrile (110.0 mg, 0.240 mmol, 1.0 equiv., prepared in Example 172, step 5) in MeOH:DMF (3:2) to give 1-[[[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]methyl-amino]methyl]cyclopropanecarbonitrile (53.6 mg, 0.120 mmol, 45.4% yield) as a pale yellow solid. LC-MS: m / z=455.2 [M+H] + ,ESI pos.

[0490] Example 174 1-[2-(2-chloro-5-fluoro-3-pyridyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol;Formic acid [ka]

[0491] Step 1: 2-chloro-5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine [ka] Prepared as in Example 143, step 2, using 3-bromo-2-chloro-5-fluoro-pyridine (2.0 g, 9.5 mmol, 1.0 equiv) to give 2-chloro-5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.4 g, 9.22 mmol, 97% yield) as a white solid. LC-MS: m / z=258.2, [M+H] + ,ESI pos.

[0492] Step 2: 1-[2-(2-chloro-5-fluoro-3-pyridyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone [ka] Prepared as in Example 143, step 2 using 2-chloro-5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (84.97 mg, 0.330 mmol, 2.5 equiv) and 1-[2-chloro-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (50.0 mg, 0.130 mmol, 1.0 equiv, prepared in Example 76, step 2) to give 1-[2-(2-chloro-5-fluoro-3-pyridyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone (25 mg, 0.050 mmol, 39.97% yield) as a yellow solid. LC-MS: m / z=474.3, [M+H] + ,ESI pos.

[0493] Step 3: 1-[2-(2-chloro-5-fluoro-3-pyridyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; formic acid [ka] Prepared as in Example 53, step 4 using 1-[2-(2-chloro-5-fluoro-3-pyridyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone and NaBH (6.01 mg, 0.160 mmol, 5 equiv.) to give 1-[2-(2-chloro-5-fluoro-3-pyridyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; formic acid (3.2 mg, 0.010 mmol, 21.2% yield) as a yellow solid. LC-MS: m / z=476.3 [M+H] + ,ESI pos.

[0494] Example 175 1-[3-(1-hydroxyethyl)-6-[6-[[6-[(3-methoxyazetidin-1-yl)methyl]pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile;Formic acid [ka]

[0495] Step 1: 1-[3-acetyl-6-[5-[[6-[(3-methoxyazetidin-1-yl)methyl]pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile and 1-[3-acetyl-6-[6-[[6-[(3-methoxyazetidin-1-yl)methyl]pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Prepared in a similar manner as in Example 64, step 2 using N-[6-[(3-methoxyazetidin-1-yl)methyl]pyridazin-3-yl]-1H-benzimidazol-5-amine (200.0 mg, 0.640 mmol, 1.0 equiv., prepared in Example 141, steps 1 and 2) and 1-(3-acetyl-6-chloro-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile (251.99 mg, 0.970 mmol, 1.5 equiv., prepared in Example 64, step 1) to give 1-[3-acetyl-6-[5-[[6-[(3-methoxyazetidin-1-yl)methyl]pyridazin-3-yl]-1H-benzimidazol-5-amine 1-[3-acetyl-6-[6-[[6-[(3-methoxyazetidin-1-yl)methyl]pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (40 mg, 0.070 mmol, 11.6% yield) and 1-[3-acetyl-6-[6-[[6-[(3-methoxyazetidin-1-yl)methyl]pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (50 mg, 0.090 mmol, 14.5% yield) were obtained as yellow solids. Regioisomer 1: LC-MS: m / z = 535.1 [M+H] + ,E...

Claims

1. Formula (I): 【Chemistry 1】 (In the formula, R １ is hydrogen or halogen; R ２ and R ２ ' is independently selected from hydrogen, alkyl, cyclopropyl, haloalkyl, and alkoxyalkyl; A1 is -O-, -NR ６ -, -(C=O)- or a bond; R ６ is hydrogen or alkyl; R ３ is hydroxyalkyl, heterocycloalkyl, heteroaryl, phenyl, or cycloalkylalkyl, and heterocycloalkyl, heteroaryl, phenyl, and cycloalkylalkyl are optionally selected from R ７ and when A1 is -(C=O)-, R ３ may be haloalkylamino; Each R ７ is independently selected from alkoxy, alkylamino, alkyl, aminocarbonyl, amino, cyano, cycloalkylamino, haloalkyl, halocycloalkyl, halogen, heteroaryl, hydroxycarbonylamino, alkoxyalkyl, alkylaminocarbonyl, alkylsulfonyl, alkoxycarbonimidoyl, aminocarbonyl, hydroxy, cycloalkylalkyl, haloalkoxy, heterocycloalkyl, and cycloalkyl; A2 is -O-, -NH- or a bond; R ４ is hydrogen, alkyl, haloalkyl, alkoxyalkyl, dialkylaminoalkyl, cycloalkyl, cycloalkylcarbonyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, or heterocycloalkylalkyl; aryl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl are optionally selected from R ８ and when A2 is a bond, R ４ may be halogen or cyano; Each R ８ is independently selected from alkyl, halogen, cyano, alkylsulfonyl, alkylaminocarbonyl, heterocycloalkyl, and alkoxyheterocycloalkylalkyl; A3 is -O-, -NR １０ - or a bond; R ５ is hydrogen, alkyl, alkylsulfonyl, cycloalkylcarbonyl, heterocycloalkylalkyl, heterocycloalkylalkylcarbonyl, aryl, heteroaryl, or heterocycloalkyl, and cycloalkylcarbonyl, aryl, heteroaryl, and heterocycloalkyl are optionally selected from R ９ and when A is a bond, R ５ may be halogen or cyano; Each R ９ is alkoxy, halogen, dialkylaminocarbonyl, alkyl, alkoxyalkoxy, alkoxyheterocycloalkylalkyl, alkoxyheterocycloalkylcarbonyl, haloalkyl, haloalkoxy, heterocycloalkylalkoxy, heterocycloalkyl, heterocycloalkyloxy, hydroxy, hydroxyalkyl, alkylheterocycloalkyl, (haloalkyl)cycloalkyl, alkylheterocycloalkylalkyl, heterocycloalkylalkyl, alkylsulfonyl, (alkyl)heterocycloalkyl, alkylheterocycloalkyloxy, heterocycloalkylheterocycloalkyl, heterocycloalkylheterocycloalkyl, CH ３ -O-(CH ２ -CH ２ -O) ｎ -, alkylaminocarbonyl, and cyano; n is selected from 5, 6, 7, 8, and 9; R １０ is hydrogen or alkylcarbonyl) or a pharma- ceutically acceptable salt thereof.

2. R １ The compound of claim 1 , wherein is hydrogen or chloro.

3. R ２ and R ２ 3. The compound of claim 1 or 2, wherein: R 1 is independently selected from hydrogen, methyl, ethyl, cyclopropyl, difluoromethyl, trifluoromethyl and methoxymethyl.

4. A1 is -O-, -NR ６ - or a bond; R ６ The compound according to any one of claims 1 to 3, wherein is hydrogen or methyl.

5. R ３ is hydroxypentyl, hydroxybutyl, phenyl, cyclopropylmethyl, heterocycloalkyl or heteroaryl, and phenyl, heterocycloalkyl and heteroaryl are optionally selected from R ７ and when A1 is -(C=O)-, R ３ may be trifluoroethylamino; Each R ７ is independently selected from aminocarbonyl, amino, cyano, methoxy, ethoxy, chloro, fluoro, hydroxy, trifluoromethyl, trifluoroethyl, difluoromethyl, methylsulfonyl, methylaminocarbonyl, methoxyethyl, cyclopropylamino, difluoromethoxy, oxetan-3-yl, methylamino, 1H-pyrazol-4-yl, difluorocyclopropyl, methyl, ethyl, cyclopropylmethyl, and cyclobutylmethyl.

6. A2 is -O-, -NH- or a bond; R ４ is hydrogen, haloalkyl, alkoxyalkyl, dialkylaminoalkyl, cycloalkyl, cycloalkylcarbonyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl, or heterocycloalkylalkyl; aryl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl are optionally selected from R ８ and when A2 is a bond, R ４ may be halogen or cyano; when A2 is -O- or -NH-, R ４ may be alkyl; Each R ８ is independently selected from alkyl, halogen, cyano, alkylsulfonyl, alkylaminocarbonyl, heterocycloalkyl, and alkoxyheterocycloalkylalkyl; A3 is -O-, -NH- or a bond; R ５ is hydrogen, alkylsulfonyl, cycloalkylcarbonyl, heterocycloalkylalkyl, heterocycloalkylalkylcarbonyl, aryl, heteroaryl, or heterocycloalkyl, and aryl, cycloalkylcarbonyl, heteroaryl, and heterocycloalkyl are optionally selected from R ９ and when A is a bond, R ５ may be halogen or cyano; when A3 is -O- or -NH-, R ５ may be alkyl; Each R ９ is alkoxy, halogen, dialkylaminocarbonyl, alkyl, alkoxyalkoxy, alkoxyheterocycloalkylalkyl, alkoxyheterocycloalkylcarbonyl, haloalkyl, haloalkoxy, heterocycloalkylalkoxy, heterocycloalkyl, heterocycloalkyloxy, hydroxy, alkylheterocycloalkyl, alkylheterocycloalkylalkyl, heterocycloalkylalkyl, alkylsulfonyl, (alkyl)heterocycloalkyl, alkylheterocycloalkyloxy, heterocycloalkylheterocycloalkyl, heterocycloalkylheterocycloalkyl, CH ３ -O-(CH ２ -CH ２ -O) ｎ -, alkylaminocarbonyl, and cyano; n is selected from 5, 6, 7, 8, and 9; However, R ４ and R ５ can be hydrogen; The compound according to any one of claims 1 to 5.

7. The compound according to any one of claims 1 to 6, wherein A2 is -O- or a bond.

8. R ４ is hydrogen, trifluoromethyl, methoxyethyl, dimethylaminoethyl, cyclopropylcarbonyl, morpholinoethyl, (1,1-dioxo-1,2-thiazolidin-2-yl)methyl, (2-oxopyrrolidin-1-yl)methyl, (2-oxo-1-piperidyl)methyl, heteroaryl or heterocycloalkyl, and heteroaryl and heterocycloalkyl are optionally selected from R ８ and when A2 is a bond, R ４ may be fluoro, bromo or cyano; when A2 is -O- or -NH-, R ４ may be methyl; Each R ８ is independently selected from methyl, fluoro, cyano, methylsulfonyl, oxetan-3-yl, and (3-methoxyazetidin-1-yl)methyl; A compound according to any one of claims 1 to 7.

9. The compound according to any one of claims 1 to 8, wherein A3 is -O- or -NH-.

10. R ５ is hydrogen, methylsulfonyl, morpholinoethyl, (2-oxopyrrolidin-1-yl)methyl, (2-oxo-1-piperidyl)methyl, (oxetan-3-yl)methyl, 1-piperidylethylcarbonyl, phenyl, heteroaryl, or heterocycloalkyl; phenyl, heteroaryl, and heterocycloalkyl are optionally selected from R ９ and when A is a bond, R ５ may be fluoro or cyano; when A3 is -O- or -NH-, R ５ may be methyl; Each R ９ methyl, methoxy, oxetan-3-yl, azetidin-3-yl, azetidin-1-yl, 3,3-difluoroazetidin-1-yl, 2-oxopyrrolidin-1-yl, hydroxy, difluoromethyl, trifluoromethyl, (3-methoxyazetidin-1-yl)methyl, 3-methoxyazetidine-1-carbonyl, methoxyethoxy, difluoroethoxy, difluoromethoxy, [2-(1,1-dioxo-1,4-thiazin-4-yl)ethoxy], oxetan-3-yloxy, chloro, dimethylaminocarbonyl, cyano, methylsulfonyl, morpholinomethyl, morpholino, (4-methylpiperazin-1-yl)methyl, CH ３ -O-(CH ２ -CH ２ -O) ７ -, oxetan-3-yl, [1-(oxetan-3-yl)pyrrolidin-2-yl] and (2-methyl-1,3-dioxolan-2-yl), A compound according to any one of claims 1 to 9.

11. The following: [2-(3-chlorophenyl)-6-(5,6-dimethoxybenzimidazol-1-yl)-3-pyridyl]methanol; (2-(3-chloro-2-fluorophenyl)-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)pyridin-3-yl)methanol; (6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)methanol; 1-(6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)ethan-1-ol; 1-(6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)propan-1-ol; 1-(2-(3-chlorophenyl)-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)pyridin-3-yl)ethan-1-ol; 1-(2-(3-chloro-2-fluorophenyl)-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)pyridin-3-yl)ethan-1-ol; (S)-1-(6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)ethan-1-ol; (R)-1-(6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)ethan-1-ol; Cyclopropyl(6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)methanol; 1-(2-(3-chlorophenyl)-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)pyridin-3-yl)propan-1-ol; (2-(3-chlorophenyl)-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)pyridin-3-yl)(cyclopropyl)methanol; (6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-morpholinopyridin-3-yl)methanol; (6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(pyrrolidin-1-yl)pyridin-3-yl)methanol; (6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(piperidin-1-yl)pyridin-3-yl)methanol; 5-((6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-3-(hydroxymethyl)pyridin-2-yl)amino)pentan-1-ol; 1-(6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-3-(hydroxymethyl)pyridin-2-yl)pyrrolidin-2-one; 4-((6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-3-(hydroxymethyl)pyridin-2-yl)amino)butan-1-ol; (S)-2-(6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-3-(1-hydroxyethyl)pyridin-2-yl)benzamide; (R)-2-(6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-3-(1-hydroxyethyl)pyridin-2-yl)benzamide; (S)-3-(6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-3-(1-hydroxyethyl)pyridin-2-yl)benzonitrile; (R)-3-(6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-3-(1-hydroxyethyl)pyridin-2-yl)benzonitrile; (S)-4-(6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-3-(1-hydroxyethyl)pyridin-2-yl)benzonitrile; (R)-4-(6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-3-(1-hydroxyethyl)pyridin-2-yl)benzonitrile; (S)-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-3-(1-hydroxyethyl)-1'-methyl-[2,4'-bipyridin]-2'(1'H)-one; (R)-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-3-(1-hydroxyethyl)-1'-methyl-[2,4'-bipyridin]-2'(1'H)-one; 1-[6-[5-(2-morpholinoethoxy)benzimidazol-1-yl]-2-phenoxy-3-pyridyl]ethanol; 1-[2-anilino-6-[5-(2-morpholinoethoxy)benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[6-[5-(2-morpholinoethoxy)benzimidazol-1-yl]-2-[3-(trifluoromethyl)pyrazol-1-yl]-3-pyridyl]ethanol; 1-[6-(5,6-dimethoxybenzimidazol-1-yl)-2-[3-(trifluoromethyl)pyrazol-1-yl]-3-pyridyl]ethanol; 1-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-(4-methylpiperazin-1-yl)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-[4-(oxetan-3-yl)piperazin-1-yl]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-(2-morpholinoethoxy)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-[[1-(oxetan-3-yl)pyrazol-4-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[6-[5-[[1-(azetidin-3-yl)pyrazol-4-yl]amino]benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxybenzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-(6-methylpyridazin-3-yl)oxybenzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 5-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-1-methyl-pyrazole-4-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-[rac-(3R)-3-hydroxypyrrolidin-1-yl]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-[(3S)-3-hydroxypyrrolidin-1-yl]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-[(6-methyl-3-pyridyl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-[(5-methylpyrazin-2-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-[(5-methylpyrimidin-2-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-[(5-methyl-2-pyridyl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[2-(1,1-dioxo-1,2-thiazolidin-2-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[3-(1-hydroxyethyl)-6-[5-[(2-methylpyrimidin-5-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-(pyridazin-4-ylamino)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-[(6-methoxypyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-(pyridazin-3-ylamino)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[6-[5-[[6-(difluoromethyl)pyridazin-3-yl]amino]benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[6-[6-fluoro-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[6-[5-fluoro-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[3-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-3-pyridyl]ethanol; 1-[6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[3-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-3-pyridyl]ethanol; 1-[3-(1-hydroxyethyl)-6-[5-[(5-methyl-1,3,4-oxadiazol-2-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 2-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; (3R)-1-[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]pyrrolidine-3-carbonitrile; rac-(3R)-1-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]pyrrolidine-3-carbonitrile; 1-[2-(3,5-dimethylpyrazol-1-yl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[2-(3,5-dimethylpyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 5-methyl-1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-[rac-(1R)-1-hydroxyethyl]-2-pyridyl]pyrazole-3-carbonitrile; 5-methyl-1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-[rac-(1S)-1-hydroxyethyl]-2-pyridyl]pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-[(5-methyl-1,3,4-thiadiazol-2-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-[[1-(oxetan-3-yl)-4-piperidyl]oxy]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[6-[[1-(oxetan-3-yl)-4-piperidyl]oxy]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]pyrazole-3-carbonitrile; 1-[[[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]amino]methyl]cyclopropanecarbonitrile; 1-[[[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]amino]methyl]cyclopropanecarbonitrile; 5-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]pyridine-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-(1,2,4-triazin-3-ylamino)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-3-methyl-pyrrolidine-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-3-methyl-pyrrolidine-3-carbonitrile; 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]-3-pyridyl]ethanol; 1-[3-(1-hydroxyethyl)-6-[5-(isoxazol-3-ylamino)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-N-(2,2,2-trifluoroethyl)pyridine-2-carboxamide; 1-[6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[rac-(3aR,6aS)-2,3,3a,5,6,6a-hexahydro-1H-pyrrolo[3,2-b]pyrrol-4-yl]-3-pyridyl]ethanol; 1-[6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[rac-(3aS,6aR)-2,3,3a,5,6,6a-hexahydro-1H-pyrrolo[3,2-b]pyrrol-4-yl]-3-pyridyl]ethanol; 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[rac-(3aR,6aS)-2,3,3a,5,6,6a-hexahydro-1H-pyrrolo[3,2-b]pyrrol-4-yl]-3-pyridyl]ethanol; 1-[2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[6-[6-bromo-5-[4-(oxetan-3-yl)piperazin-1-yl]benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[2-(3-ethoxy-5-methyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[2-(3-ethoxy-5-methyl-pyrazol-1-yl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[2-(6-methylpyridazin-4-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 4-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-1-(2,2,2-trifluoroethyl)piperazin-2-one; 4-[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-1-(2,2,2-trifluoroethyl)piperazin-2-one; 1-[[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]oxymethyl]cyclopropanecarbonitrile; 1-[[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]oxymethyl]cyclopropanecarbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-methoxy-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanol; 1-[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-N,5-dimethyl-pyrazole-3-carboxamide; 1-[2-(5-methyl-3-methylsulfonyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[3-(1-hydroxyethyl)-6-[5-[(2-keto-1-methyl-pyrimidin-4-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 5-methyl-1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-(2,2,2-trifluoro-1-hydroxy-ethyl)-2-pyridyl]pyrazole-3-carbonitrile; 1-[2-[1-(difluoromethyl)-3-methyl-pyrazol-4-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-4-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-4-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-N,5-dimethyl-pyrazole-3-carboxamide; 1-[3-(1-hydroxyethyl)-6-[5-[(2-keto-1-methyl-4-piperidyl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; [2-(3-methoxy-5-methyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]methanol; 1-[2-(3,5-dimethylisoxazol-4-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[3-(1-hydroxyethyl)-6-[5-[(4-methoxypyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-[(5-keto-1-methyl-pyrrolidin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-(3-methyl-4-pyridyl)-3-pyridyl]ethanol; 1-[2-[4-(cyclopropylamino)pyrimidin-5-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 5-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-4-(trifluoromethyl)pyridin-2-ol; 3-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one; 1-[6-[6-fluoro-5-[[(3S,4R)-4-fluoropyrrolidin-3-yl]amino]benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[2-[2-(difluoromethoxy)-5-methyl-4-pyridyl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[2-(2-fluoro-5-methyl-4-pyridyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-4-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-4-methyl-pyrazole-3-carbonitrile; 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[5-methyl-3-(trifluoromethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]-3-pyridyl]ethanol; 1-[[[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-methyl-amino]methyl]cyclopropanecarbonitrile; 1-[[[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-methyl-amino]methyl]cyclopropanecarbonitrile; 1-[2-(2-chloro-5-fluoro-3-pyridyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[3-(1-hydroxyethyl)-6-[6-[[6-[(3-methoxyazetidin-1-yl)methyl]pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-[[6-[(3-methoxyazetidin-1-yl)methyl]pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[5-(oxetan-3-yl)-3-(trifluoromethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]-3-pyridyl]ethanol; 1-[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-3-methyl-pyrazole-4-carbonitrile; 1-[2-[2-(methylamino)-3-pyridyl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-3-methyl-pyrazole-4-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-3-methyl-azetidine-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-3-methyl-azetidine-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[2-(1H-pyrazol-4-yl)-3-pyridyl]-3-pyridyl]ethanol; 1-[3-(1-hydroxyethyl)-6-[6-(2-methoxyethoxy)-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[6-[5-fluoro-6-[[rac-(3R,4S)-4-fluoropyrrolidin-3-yl]amino]benzimidazol-1-yl]-3-(1-hydroxyethyl)pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; 1-[6-[6-[2-(dimethylamino)ethoxy]-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[6-[5-bromo-6-[4-(oxetan-3-yl)piperazino]benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-[[6-(3-methoxyazetidine-1-carbonyl)pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]-6-pyrrolidin-3-yloxy-benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-[[6-(2-methoxyethoxy)pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[2-(1H-benzotriazol-4-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[6-[5-[[6-(2,2-difluoroethoxy)pyridazin-3-yl]amino]benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[6-[5-[[6-(difluoromethoxy)pyridazin-3-yl]amino]benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(2,2-difluoro-1-hydroxy-ethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(2,2-difluoro-1-hydroxy-ethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[6-[6-[(1,1-dioxo-1,2-thiazolidin-2-yl)methyl]benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[6-[5-[(1,1-dioxo-1,2-thiazolidin-2-yl)methyl]benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 3-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-2-methoxy-phenol; 3-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]furan-2-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridin-2-yl]-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carbonitrile; 1-[6-[5-[[6-[2-(1,1-diketo-1,4-thiazin-4-yl)ethoxy]pyridazin-3-yl]amino]benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-[[6-(oxetan-3-yloxy)pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[(3S)-pyrrolidin-3-yl]oxy-3-pyridyl]ethanol; 1-[3-(1-hydroxyethyl)-6-[6-[(2-oxopyrrolidin-1-yl)methyl]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-[(2-oxopyrrolidin-1-yl)methyl]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[2-(3-methoxy-5-methyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[3-(1-hydroxyethyl)-6-[6-[(2-oxo-1-piperidyl)methyl]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-[(2-oxo-1-piperidyl)methyl]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 3-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(1-hydroxyethyl)-2-pyridyl]benzimidazol-5-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide; 5-hydroxy-2-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]benzonitrile; 5-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-3-(trifluoromethyl)-1H-pyridazin-6-one; 2-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]furan-3-carbonitrile; 1-[2-[2-(2,2-difluorocyclopropyl)pyrazol-3-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[3-(1-hydroxyethyl)-6-[5-[[6-(oxetan-3-yl)pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; (1S)-1-[2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; (1R)-1-[2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[2-[5-(difluoromethyl)-3-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[3-(1-hydroxy-2-methoxy-ethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxy-2-methoxy-ethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[6-[6-fluoro-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-[(1S)-1-hydroxyethyl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[6-[6-fluoro-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-[(1R)-1-hydroxyethyl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[5-chloro-3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]pyrazole-3-carbonitrile; 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanol; 1-[6-[5-[(6-chloro-4-methoxy-pyridazin-3-yl)amino]benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; rac-(3R,5S)-1-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrrolidine-3-carbonitrile; 1-[5-chloro-3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 5-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-2-methyl-pyrazole-3-carbonitrile; 1-[3-[(1R)-1-hydroxyethyl]-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[2-[3,5-bis(difluoromethyl)pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridin-3-yl]ethanol; 1-[3-(1-hydroxyethyl)-6-[5-[[6-(trifluoromethyl)pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[2-[2-ethyl-5-(trifluoromethyl)pyrazol-3-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; rac-(1S)-1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanol; rac-(1R)-1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanol; 1-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]triazole-4-carbonitrile; (3S,5R)-1-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrrolidine-3-carbonitrile; 5-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-1-methyl-pyrazole-3-carbonitrile; 2-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]triazole-4-carbonitrile; 1-[6-(3-cyano-5-methylpyrazol-1-yl)-5-(1-hydroxyethyl)pyridin-2-yl]benzimidazole-5-carbonitrile; 1-[2-(1-ethyl-3-methyl-pyrazol-4-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[2-[1-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[2-[1-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 5-methyl-1-[3-methylol-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]pyrazole-3-carbonitrile; 5-methyl-1-[3-methylol-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]pyrazole-3-carbonitrile; 1-[2-(1-ethyl-5-methyl-pyrazol-4-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[2-[1-(cyclopropylmethyl)-5-methyl-pyrazol-4-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[2-[1-(cyclobutylmethyl)-3-methyl-pyrazol-4-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[2-[1-(cyclobutylmethyl)-5-methyl-pyrazol-4-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(trifluoromethyl)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-[(1S)-1-hydroxyethyl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carboximidic acid methyl ester; 1-[2-[1-(2,2-difluorocyclopropyl)-3-methyl-pyrazol-4-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[2-[1-(2-methoxypropyl)-3-methyl-pyrazol-4-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[2-[1-(2-methoxypropyl)-5-methyl-pyrazol-4-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[3-[(1S)-1-hydroxyethyl]-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[2-[1-(2,2-difluoropropyl)-3-methyl-pyrazol-4-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[2-(2-ethyl-5-methyl-4-pyridyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[2-[1-(2,2-difluoropropyl)-5-methyl-pyrazol-4-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[2-(2-methoxy-5-methyl-4-pyridyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; (1S)-1-[2-[3,5-bis(difluoromethyl)pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; (1R)-1-[2-[3,5-bis(difluoromethyl)pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[2-(2-cyclopropyl-5-methyl-4-pyridyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-6,7-dihydro-4-{H}-pyrazolo[4,3-c]pyridine-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-[(6-methyl-4-methylsulfonyl-pyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-[[6-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[6-[(6-methyl-3-pyridyl)amino]-5-(2-morpholinoethoxy)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[6-(2-oxa-5-azaspiro[3.4]octan-5-yl)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-(2-oxa-5-azaspiro[3.4]octan-5-yl)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-[(6-methyl-3-pyridyl)amino]-6-(2-morpholinoethoxy)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[2-[3-(difluoromethyl)pyrrolidin-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[2-(2,2-difluoro-5-azaspiro[2.4]heptan-5-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; (1S)-1-[2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-fluoro-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[6-[6-fluoro-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanol; 5-(difluoromethyl)-2-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-[[6-[1-(oxetan-3-yl)pyrrolidin-2-yl]pyridazin-3-yl]amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 7,7-difluoro-1-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5,6-dihydro-4-{H}-pyrazolo[4,3-c]pyridine-3-carbonitrile; 5-(difluoromethyl)-1-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]pyrazole-3-carbonitrile; (1S)-1-[2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-fluoro-5-(pyridazin-3-ylamino)benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[5-methyl-2-(2,2,2-trifluoroethyl)triazol-4-yl]-3-pyridyl]ethanol; 1-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-4,5-dimethyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-[(4-methyl-2,3-dihydropyridazino[4,5-b][1,4]oxazin-8-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[5-methyl-1-(2,2,2-trifluoroethyl)triazol-4-yl]-3-pyridyl]ethanol; 1-[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(1-hydroxyethyl)-2-pyridyl]benzimidazol-5-yl]-N,N-dimethyl-pyrrolidine-2-carboxamide; 1-[2-[1-(2,2-difluoroethyl)-3-methyl-pyrazol-4-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[6-[5-fluoro-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-(hydroxymethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; [6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]methanol; [6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]methanol; [2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-(7,8-dihydro-5H-pyrano[4,3-c]pyridazin-3-ylamino)benzimidazol-1-yl]-3-pyridyl]methanol; [6-[5-[(4aS,7aR)-4-methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-6-yl]benzimidazol-1-yl]-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-3-pyridyl]methanol; [2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-fluoro-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]methanol; 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[2-(trifluoromethyl)morpholin-4-yl]-3-pyridyl]ethanol; 3-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-3-azabicyclo[3.1.0]hexane-1-carbonitrile; 1-[2-(5,5-difluoro-2-azabicyclo[2.2.1]heptan-2-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[2-[2-(difluoromethyl)morpholin-4-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[2-(6,6-difluoro-2-azabicyclo[2.2.1]heptan-2-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[2-[7-(difluoromethyl)-5-azaspiro[2.4]heptan-5-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[2-(6,6-difluoro-3-azabicyclo[3.2.0]heptan-3-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; N-[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(1-hydroxyethyl)-2-pyridyl]benzimidazol-5-yl]cyclopropanecarboxamide; N-[3-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(1-hydroxyethyl)-2-pyridyl]benzimidazol-5-yl]cyclopropanecarboxamide; 1-[2-(4,7-diazaspiro[2.5]octan-7-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[6-[5-[(3aS,6aS)-6-oxo-2,3,3a,4,5,6a-hexahydropyrrolo[2,3-c]pyrrol-1-yl]benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[3-(trifluoromethyl)piperazin-1-yl]-3-pyridyl]ethanol; 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[5-methyl-2-(trifluoromethyl)-4-pyridyl]-3-pyridyl]ethanol; 1-[3-(1-hydroxyethyl)-6-[5-[(2-keto-1-methyl-3-pyridyl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-(3-methoxy-1-methyl-pyrazol-4-yl)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[2-[2-(difluoromethyl)-5-methyl-4-pyridyl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[3-(1-hydroxyethyl)-6-[6-(1-methyl-2-oxo-pyrimidin-4-yl)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-fluoro-5-[[6-(2-methyl-1,3-dioxolan-2-yl)pyridazin-3-yl]amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[3-(1-hydroxyethyl)-6-[5-(1-methyl-2-oxo-pyrimidin-4-yl)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-(6-methylpyridazin-3-yl)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[6-[6-[(2S)-2-cyanopyrrolidin-1-yl]benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[6-[5-[(2S)-2-cyanopyrrolidin-1-yl]benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[6-[6-[(3aS,6aS)-6-oxo-2,3,3a,4,5,6a-hexahydropyrrolo[2,3-c]pyrrol-1-yl]benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[2-[3-(difluoromethyl)-5-methyl-1,2,4-triazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 3-[[1-[6-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-5-[(1-{S})-1-hydroxyethyl]-2-pyridyl]-6-fluoro-benzimidazol-5-yl]amino]--{N},-{N},6-trimethyl-pyridazine-4-carboxamide; 1-[2-[2-(difluoromethoxy)-5-methyl-4-pyridyl]-6-[6-fluoro-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[6-[6-fluoro-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-(hydroxymethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 3-[[1-[6-[3,5-bis(difluoromethyl)pyrazol-1-yl]-5-(hydroxymethyl)-2-pyridyl]benzimidazol-5-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide; 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[4-methyl-1-(2,2,2-trifluoroethyl)pyrazol-3-yl]-3-pyridyl]ethanol; 1-[2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-6-[5-[6-(morpholinomethyl)pyridazin-3-yl]oxybenzimidazol-1-yl]-3-pyridyl]ethanol; 1-[6-[5-(6-methylpyridazin-3-yl)oxybenzimidazol-1-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanol; 1-[6-[5-[6-[(4-methylpiperazin-1-yl)methyl]pyridazin-3-yl]oxybenzimidazol-1-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanol; 1-[2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]-5-(oxetan-3-yloxy)benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[2-(3-chloro-5-methyl-pyrazol-1-yl)-6-[5-fluoro-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[2-(3-chloro-5-methyl-pyrazol-1-yl)-6-[6-fluoro-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[2-[1-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-6-[6-fluoro-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]-3-pyridyl]ethanol; N-[1-[5-(1-hydroxyethyl)-6-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]benzimidazol-5-yl]-2-(1-piperidyl)acetamide; 6-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-6-azaspiro[3.4]octane-8-carbonitrile; 4-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]morpholine-2-carbonitrile; N-[1-[6-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-5-(1-hydroxyethyl)-2-pyridyl]-6-fluoro-benzimidazol-5-yl]cyclopropanecarboxamide; 1-[6-[6-(2,3-difluoro-4-methyl-anilino)-5-fluoro-benzimidazol-1-yl]-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-3-pyridyl]ethanol; 1-[2-[1-(difluoromethyl)-4-methyl-pyrazol-3-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-fluoro-6-(2,3,4-trifluoroanilino)benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[3-(1-hydroxyethyl)-6-[6-(6-methyl-7-oxo-5H-pyrrolo[3,4-b]pyridin-2-yl)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-(6-methyl-7-oxo-5H-pyrrolo[3,4-b]pyridin-2-yl)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[2-[3-(difluoromethoxy)-5-methylpyrazol-1-yl]-6-[5-[[6-(difluoromethyl)pyridazin-3-yl]amino]benzimidazol-1-yl]pyridin-3-yl]ethanol; 1-[2-[3-(difluoromethyl)-5-ethyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[2-[3-(difluoromethyl)-4,5-dimethyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[2-[3-(difluoromethyl)-5-ethyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[6-[6-[(6-chloropyridazin-3-yl)amino]-5-fluoro-benzimidazol-1-yl]-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-3-pyridyl]ethanol; 1-[6-[5-[(6-chloropyridazin-3-yl)amino]-6-fluoro-benzimidazol-1-yl]-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-3-pyridyl]ethanol; (1S)-1-[2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[6-fluoro-5-(pyridazin-3-ylamino)benzimidazol-1-yl]-3-pyridyl]ethanol; (1S)-1-[2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[6-fluoro-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; (1R)-1-[2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[6-fluoro-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[6-[5-fluoro-6-[(5-methyl-1,3,4-oxadiazol-2-yl)amino]benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[6-[6-fluoro-5-[(5-methyl-1,3,4-oxadiazol-2-yl)amino]benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[6-[6-fluoro-5-(2,3,4-trifluoroanilino)benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[6-[5-fluoro-6-(2,3,4-trifluoroanilino)benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; N-[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-(1-hydroxyethyl)-2-pyridyl]benzimidazol-5-yl]-1-fluoro-cyclopropanecarboxamide; 1-[6-[6-(6,7-dihydro-5-{H}-cyclopenta[c]pyridazin-3-ylamino)-5-fluoro-benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[6-[5-(6,7-dihydro-5-{H}-cyclopenta[c]pyridazin-3-ylamino)-6-fluoro-benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; (1S)-1-[2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]-3-pyridyl]ethanol; (1R)-1-[2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[6-[6-fluoro-5-[(5-methyl-1,3,4-thiadiazol-2-yl)amino]benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 3-fluoro-4-[3-(1-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-1-(2,2,2-trifluoroethyl)pyridin-2-one; 1-[2-[3,5-bis(difluoromethyl)pyrazol-1-yl]-6-[6-fluoro-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[6-[6-(difluoromethoxy)-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[6-[6-fluoro-5-[(5-fluoro-6-methyl-3-pyridyl)amino]benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[6-[5-[[5-(azetidin-1-yl)pyridazin-3-yl]amino]-6-fluoro-benzimidazol-1-yl]-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-3-pyridyl]ethanol; 1-[6-[6-fluoro-5-[(5-fluoro-6-methyl-3-pyridyl)amino]benzimidazol-1-yl]-3-[(1S)-1-hydroxyethyl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[5-[2-(2-oxopyrrolidin-1-yl)oxazol-5-yl]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[2-(4,4-difluoropyrrolidin-3-yl)oxy-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[6-[5-(7,8-dihydro-5-{H}-pyrano[4,3-c]pyridazin-3-ylamino)-6-methoxy-benzimidazol-1-yl]-3-(1-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[6-[2-(2-oxopyrrolidin-1-yl)oxazol-5-yl]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[2-[6-(difluoromethoxy)-3-methyl-pyridazin-4-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[2-[3-(difluoromethyl)-5-methoxy-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[2-[3-(difluoromethyl)-5-methoxy-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[2-[1-(2,3-difluoropropyl)-3-methyl-pyrazol-4-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; (1S)-1-[2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[6-methoxy-5-[(2-methylpyrimidin-5-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[2-methyl-5-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-yl]-3-pyridyl]ethanol; 1-[6-[6-(difluoromethoxy)-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-[(1S)-1-hydroxyethyl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[6-[6-(difluoromethoxy)-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-[(1R)-1-hydroxyethyl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[2-[3-(difluoromethoxy)-5-(difluoromethyl)pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[2-[3-(difluoromethoxy)-5-(difluoromethyl)pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanol; 1-[2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]-5-(oxetan-3-ylmethyl)benzimidazol-1-yl]-3-pyridyl]ethanol; and 1-[2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-ylmethyl)benzimidazol-1-yl]-3-pyridyl]ethanol 11. The compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt thereof, selected from:

12. A process for the preparation of a compound according to any one of claims 1 to 11, comprising the steps of: (a) Formula (B1): 【Chemistry 2】 with a reducing agent; (b) Formula (C1): 【Chemistry 3】 with a reducing agent; or (c) Compound (D1): 【Chemistry 4】 and formula R ｃ Reaction with MgX compounds (In the formula, A1, A2, A3, R １ , R ２ , R ３ , R ４ and R ５ is as defined in any one of claims 1 to 11, and R ａ is alkyl or cycloalkyl; R ｂ is hydrogen or alkyl; R ｃ is alkyl or cycloalkyl, and X is halogen. The method includes one of the following:

13. A compound according to any one of claims 1 to 11 when produced according to the method of claim 12.

14. A compound of formula (I) as defined in any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, for use as a therapeutically active substance.

15. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 11 or a pharma- ceutically acceptable salt thereof and a therapeutically inert carrier.

16. 12. Use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 11 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.

17. 12. Use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 11 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.

18. 12. A compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 11 for use in the treatment or prophylaxis 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.

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) as defined in any one of claims 1 to 11 or a pharma- ceutically acceptable salt thereof.

20. The invention as hereinbefore described.

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