НОВЫЕ ПИРИДИНОВЫЕ ПРОИЗВОДНЫЕ БЕНЗИМИДАЗОЛА

Abstract

The invention relates to a compound of formula (I) wherein A1, A2, A3, R1, R2, R2', R3, R4 and R5 are as defined in the description and in the claims. The compound of formula (I) can be used as a medicament.

Description

[0001] New Benzimidazole Pyridine Derivatives

[0002] The present invention relates to organic compounds useful for therapy and / or prophylaxis in a mammal, and in particular to compounds that modulate SIK activity.

[0003] The invention relates in particular to a compound of formula (I) wherein

[0004] R1is hydrogen or halogen;

[0005] R2and R2’ are independently selected from hydrogen, alkyl, cyclopropyl, haloalkyl and alkoxy alkyl;

[0006] Al is -O-, -NR6-, -(C=O)- or a bond;

[0007] R6is hydrogen or alkyl;

[0008] R3is hydroxyalkyl, heterocycloalkyl, heteroaryl, phenyl or cycloalkylalkyl, wherein heterocycloalkyl, heteroaryl, phenyl and cycloalkylalkyl are optionally substituted with 1, 2 or 3 substituents independently selected from R7; if Al is -(C=O)-, then R3can also be haloalkylamino; each R7is 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;

[0009] A2 is -O-, -NH- or a bond;

[0010] R4is hydrogen, alkyl, haloalkyl, alkoxyalkyl, dialkylaminoalkyl, cycloalkyl, cycloalkylcarbonyl, aryl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; wherein aryl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl and heterocycloalkylalkyl are optionally substituted with 1, 2 or 3 substituents independently selected from R8; if A2 is a bond, then R4can also be halogen or cyano; each R8is independently selected from alkyl, halogen, cyano, alkylsulfonyl, alkylaminocarbonyl, heterocycloalkyl and alkoxyheterocycloalkylalkyl;

[0011] A3 is -O-, -NR10- or a bond;

[0012] R5is hydrogen, alkyl, alkylsulfonyl, cycloalkylcarbonyl, heterocycloalkylalkyl, heterocycloalkylalkylcarbonyl, aryl, heteroaryl or heterocycloalkyl, wherein cycloalkylcarbonyl, aryl, heteroaryl and heterocycloalkyl are optionally substituted with 1, 2 or 3 substituents independently selected from R9; if A3 is a bond, then R5can also be halogen or cyano; each R9is independently selected from 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; wherein n is selected from 5, 6, 7, 8 and 9; and

[0013] R10is hydrogen or alkyl carbonyl; or a pharmaceutically acceptable salt thereof.

[0014] Salt-inducible kinases (SIK) belong to a subfamily of AMP-activated protein kinases (AMPK) called AMPK -related kinases. There are three members, named SIK1, SIK2 and SIK3, that are broadly expressed. Their major biological role is to modify gene expression by controlling the phosphorylation and subcellular localization of two key classes of transcriptional regulatory factors: CRTCs (cAMP-regulated transcriptional coactivators) and class Ila HDACs (Histone deacetylases). Indeed, in basal state, both CRTCs and HDACs are phosphorylated by SIK kinases, and sequestered in the cytoplasm through interactions with their cytoplasmic chaperones 14-3-3. In response to extracellular cues that usually increase intracellular levels of cAMP, the SIK kinases’ activity is inhibited, CRTCs and HDACs are no longer phosphorylated and are hence released from 14-3-3. They can therefore translocate into the nucleus and regulate gene expression (reviewed in Wein et al., Trends Endocrinol Metab. 2018 Oct;29(10):723-735).

[0015] In macrophages, the inhibition of SIK kinases leads to 1) CRTC3 shuttling to the nucleus and increasing the transcription of IL- 10,; and 2) translocation of HD AC 4 / 5 to the nucleus and subsequent deacetylation of NF-KB resulting in decreased transcription of pro-inflammatory cytokines (Clark et al., Proc Natl Acad Sci U S A. 2012 Oct 16; 109(42): 16986-91.).

[0016] Macrophages are critical to maintaining tissue homeostasis, mediating inflammation, and promoting the resolution of inflammation. To achieve this diversity of function, macrophages have the ability to “polarize” differently in response to environment cues. The two extreme phenotypes along their activation state continuum are the “Ml” or “pro-inflammatory macrophages” and the “M2” or “pro-resolution macrophages”.

[0017] Strikingly, the inhibition of intracellular SIK kinases overrides these extracellular macrophage polarization signals and pushes them toward a pro-resolution phenotype. This comes with an increase in IL- 10 (by interfering with the SIK-CRTC3 pathway) and a concomitant decrease in TNF-a, IL- 12 and IL-6 (by interfering with the SIK-HDAC4 / 5 and NF- KB pathway). The high levels of IL- 10 and low levels of pro-inflammatory cytokines upon SIK inhibition will promote resolution of inflammation. The exploration of the SIK pathway has initially been described in macrophages (Clark et al., Proc Natl Acad Sci U S A. 2012 Oct 16;109(42):16986-91) and dendritic cells (Sundberg et al., Proc Natl Acad Sci U S A. 2014 Aug 26; 111(34): 12468-73) and the therapeutic potential of pan-SIK inhibitors has been confirmed in a mouse LPS (lipopolysaccharide) challenge model (Sundberg et al., ACS Chem Biol. 2016 Aug 19; 1 l(8):2105-l 1) and in colitis models (Fu et al., Inflamm Bowel Dis. 2021 Oct 20;27(l l): 1821 -1831). SIKs have since been shown to be important players in the functions of several immune cells, including mast cells (Darling et al., J Biol Chem. 2021 Jan-

[0018] Jun;296: 100428). Importantly, SIK1 is poorly expressed in macrophages and one embodiment of the invention are SIK2 / 3 inhibitors sparing SIK1, thus limiting potential SIK 1 -related toxicities.

[0019] SIK inhibitors have a high therapeutic potential in diseases that are 1) characterized by pro- inflammatory macrophage influx in the tissues and impaired tissue homeostasis and healing, or 2) where anti-TNF therapies are beneficial (partially or fully) or with insufficient levels of the IL10. Diseases with an inflammatory macrophage signature are e.g. rheumatoid arthritis, juvenile rheumatoid arthritis, NASH, primary sclerosing cholangitis, giant cell vasculitis and inflammatory bowel diseases (“IBD”), atherosclerosis, type 2 diabetes and glomerulonephritis.

[0020] Diseases with a proven link to IL-10 and TNF-a are IBD. Genetic alterations that reduce the function of IL- 10 (such as SNPs in IL- 10 or its receptor) are associated with an increased risk for IBD in humans. In addition, anti-TNF therapies are successful but only a subset of IBD patients are responsive and much of this limited responsiveness is lost over time. The described dual effect of SIK inhibitors (increased IL- 10 and decreased TNF-a) make them particularly pertinent for the treatment of IBD.

[0021] All three SIK kinase isoforms are expressed broadly in human tissues with the highest expression observed in skin and adipose tissues for SIK1, adipose tissue for SIK2 and testis and brain for SIK3. Similarly to their role in macrophages, SIKs in these cells phosphorylate CRTCs and class II HDCAs in response to extracellular signals, which subsequently change the expression of several cellular factors.

[0022] In addition to their physiological roles, reports have linked dysregulation of SIK expression to a few diseases. For example, SIK2 has been described as a risk locus for primary sclerosing cholangitis, a fibrotic disease regularly associated with IBD. In addition, SIK2 and SIK3 expression is higher in ovarian and prostate cancers and correlated 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).

[0023] As of today many diseases caused by dysregulation of the innate immune system lack efficient therapies and there is a high unmet medical need for new therapies. The present invention relates to a novel compounds that are highly active SIK inhibitors for the treatment of inflammatory, allergic and autoimmune diseases. In addition to inflammation, allergic and autoimmune diseases, SIK inhibitors can thus also be of potential relevance in cancer, metabolic diseases, bone density dysregulation diseases, pigmentation-related diseases or cosmetology, fibrotic diseases and depressive disorders.

[0024] In the present description the term “alkyl”, alone or in combination, signifies a straightchain or branched-chain alkyl group with 1 to 8 carbon atoms, particularly a straight or branched-chain alkyl group with 1 to 6 carbon atoms and more particularly a straight or branched-chain alkyl group with 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, the isomeric pentyls, the isomeric hexyls, the isomeric heptyls and the 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, like isobutyl, are further particular examples of “alkyl” in the compound of formula (I).

[0025] The term “cycloalkyl”, alone or in combination, signifies a cycloalkyl ring with 3 to 8 carbon atoms and particularly a cycloalkyl ring with 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.

[0026] The term “heterocycloalkyl”, alone or in combination, denotes a monovalent saturated or partly unsaturated mono- or bicyclic ring system of 4 to 12 ring atoms, comprising 1, 2, or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Bicyclic means consisting of two cycles having one or two ring atoms in common. “Hetercycloylkyl” may comprise a carbonyl group, wherein the carbon is part of the ring system. The ring system can be attached to the remaining compound via an atom selected from C, N, S and O, in particular via a N atom (“N-heterocycloalkyl). Examples of “heterocycloalkyl” include, but are not limited to, morpholino, morpholin-4-yl, pyrrolidinyl, pyrrolidin-l-yl, pyrrolidin-3-yl, piperidinyl, 1- piperidyl, 4-piperidyl, 2-oxopyrrolidin-l-yl, piperazinyl, piperazin- 1-yl, azetidinyl, azetidin-l-yl, [3 -oxo-piperazin- 1-yl], (l,l-dioxo-l,2-thiazolidin-2-yl), (4,5,6,7-tetrahydropyrazolo[4,3- c]pyridin-l-yl), (3-oxo-l,5,6,8-tetrahydrooxazolo[3,4-a]pyrazin-7-yl), [rac-(3aR,6aS)- 2,3,3a,5,6,6a-hexahydro-lH-pyrrolo[3,2-b]pyrrol-4-yl], [rac-(3aS,6aR)-2,3,3a,5,6,6a-hexahydro- lH-pyrrolo[3,2-b]pyrrol-4-yl], (4-oxo-6,7-dihydro-5H-pyrazolo[l,5-a]pyrazin-3-yl), (6,7- dihydro-4H-pyrazolo[4,3-c]pyridin-l-yl), (4,7-diazaspiro[2.5]octan-7-yl), (2-oxa-5,8- diazaspiro[3.5]nonan-8-yl), 3-azabicyclo[3.2.0]heptan-3-yl), (5-azaspiro[2.4]heptan-5-yl), (2- azabicyclo[2.2.1]heptan-2-yl), 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-l-yl), 2-oxa-7-azaspiro[3.4]octan-7-yl, (2-oxo-l- piperidyl), (2,3-dihydropyridazino[4,5-b][l,4]oxazin-8-yl), pyrrolidin-l-yl, 2-oxo-pyrimidin-4- yl, morpholinoethyl, 2-oxa-5-azaspiro[3.4]octan-5-yl, oxetan-3-yl, (2-oxo-l -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][l,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]pyri din-2 -yl, 5,6-dihydro-4H-pyrazolo[4,3-c]pyridin-l-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” is pyrrolidin-l-yl and pyrrolidin-3-yl. In one particular embodiment, heterocycloalkyl is “N-heterocycloalkyl”.

[0027] The term “heteroaryl”, alone or in combination, signifies an aromatic mono- or bicyclic ring system with 5 to 12 ring atoms, comprising 1, 2, 3 or 4 heteroatoms each independently selected from N, O and S, the remaining ring atoms being carbon. The ring system can be attached to the remaining compound via an atom selected from C, N, S and O, in particular via a N atom (“N-heteroaryl). Examples of heteroaryl include, but are not limited to, pyrazolyl, pyrazol-l-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-l-yl, pyrimidinyl, pyrimidin-5-yl, benzotriazolyl, 1H- benzotriazol-4-yl, furanyl, furyl, 2-furyl, 3-furyl, [6-oxo-lH-pyridazin-5-yl], triazolyl, triazol-1- yl, triazol-2-yl, triazol-3-yl, 2-oxo-4-pyridyl. pyrimidin-2-yl, pyrimidin-5-yl, (l,3,4-oxadiazol-2- yl), (l,3,4-thiadiazol-2-yl), (l,2,4-triazin-3-yl), 2-oxo-pyrimidin-4-yl, ( 1 -m ethyl -2-oxo-3 -pyridyl) and (2,3-dihydropyridazino[4,5-b][l,4]oxazin-8-yl). Particular examples of “heteroaryl” are pyrazol-l-yl, pyrazol-4-yl, pyridazin-3-yl ane pyrimidin-5-yl. In one particular embodiment, heteroaryl is “N-heteroaryl”.

[0028] The term “aryl” denotes a monovalent aromatic carbocyclic mono- or bicyclic ring system comprising 6 to 10 carbon ring atoms. Examples of aryl moieties include phenyl and naphthyl. A particular examples of aryl is phenyl.

[0029] The term “alkoxy” or “alkyloxy”, alone or in combination, signifies a group of the formula alkyl-O- in which the term "alkyl" has the previously given significance, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert.-butoxy. Particular examples of “alkoxy” are methoxy and ethoxy.

[0030] The term “oxy”, alone or in combination, signifies the -O- group.

[0031] The term “oxo”, alone or in combination, signifies the =0 group.

[0032] The terms “halogen” or “halo”, alone or in combination, signifies fluorine, chlorine, bromine or iodine and particularly fluorine, chlorine or bromine, more particularly fluorine. The term “halo”, in combination with another group, denotes the substitution of said group with at least one halogen, particularly substituted with one to five halogens, particularly one to four halogens, i.e. one, two, three or four halogens.

[0033] The term “haloalkyl”, alone or in combination, denotes an alkyl group substituted with at least one halogen, particularly substituted with one to five halogens, particularly one to three halogens, more particularly two to three halogens. Particular “haloalkyl” are fluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl, difluoromethyl, difluoroethyl, trifluoromethyl and trifluoroethyl.

[0034] The term “haloalkoxy”, alone or in combination, denotes an alkoxy group substituted with at least one halogen, particularly substituted with one to five halogens, particularly one to three halogens. Particular “haloalkoxy” are fluoromethoxy, fluoroethoxy and fluoropropyloxy.

[0035] The terms “hydroxyl” and “hydroxy”, alone or in combination, signify the -OH group.

[0036] The term “carbonyl”, alone or in combination, signifies the -C(O)- group.

[0037] The term “amino”, alone or in combination, signifies the primary amino group (-NH2), the secondary amino group (-NH-), or the tertiary amino group (-N-).

[0038] The term “alkylamino” is alkyl group linked to a -NH- group. The term “dialkylamino” denotes two alkyl groups linked to a -N- atom.

[0039] The term “sulfonyl”, alone or in combination, signifies the -SO2- group.

[0040] The term “pharmaceutically acceptable salts” refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, particularly hydrochloric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcystein. In addition these salts may be prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts. Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyamine resins. The compound of formula (I) can also be present in the form of zwitterions. Particular pharmaceutically acceptable salts of compounds of formula (I) are the salts of trifluoroacetic acid, formic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and methanesulfonic acid.

[0041] Tautomeric forms, i.e. structural isomers which interconvert with the compound of formula (I), in particular in solution, exist.

[0042] For instance, the compound of formula (I) wherein A3 is -NH- and R5 is pyridazin-3-yl, is in tautomeric equilibrium with its tautomeric form (I’):

[0043] Other tautomeric forms of the compound of formula (I) may also exist.

[0044] The compound of formula (I) can be represented by different mesomeric structures such as for instance: If one of the starting materials or compounds of formula (I) contain one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups (as described e.g. in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wuts, 3rdEd., 1999, Wiley, New York) can be introduced before the 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-fluorenylmethyl carbamate (Fmoc), 2-trimethylsilylethyl carbamate (Teoc), carbobenzyl oxy (Cbz) and p- methoxybenzyloxycarbonyl (Moz).

[0045] The compound of formula (I) can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.

[0046] The term “asymmetric carbon atom” means a carbon atom with four different substituents. According to the Cahn-Ingold-Prelog Convention an asymmetric carbon atom can be of the “R” or “S” configuration.

[0047] Furthermore, the invention includes all optical isomers, i.e. diastereoisomers, diastereomeric mixtures, racemic mixtures, all their corresponding enantiomers and / or tautomers as well as their solvates, wherever applicable, of the compound of formula (I).

[0048] If desired, racemic mixtures of the compound of the invention may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.

[0049] In the embodiments, where an optically pure enantiomer is provided, optically pure enantiomer means that the compound contains > 90 % of the desired isomer by weight, particularly > 95 % of the desired isomer by weight, or more particularly > 99 % of the desired isomer by weight, said weight percent based upon the total weight of the isomer of the compound. A chirally pure or chirally enriched compound may be prepared by chirally selective synthesis or by separation of enantiomers. The separation of enantiomers may be carried out on the final product or alternatively on a suitable intermediate. Furthermore, the invention includes all substituents in their corresponding deuterated form, wherever applicable, of the compound of formula (I).

[0050] Furthermore, the invention includes all substituents in their corresponding tritiated form, wherever applicable, of the compound of formula (I).

[0051] A certain embodiment of the invention relates to the compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein at least one substituent comprises at least one radioisotope. Particular examples of radioisotopes are 2H, 3H, 13C, 14C and 18F.

[0052] General Synthetic Schemes

[0053] The synthesis of the compound of formula (I) can, for example, be accomplished according to the non-exhaustive procedures described below in general schemes 1-11. In some instances, the sequence of the reaction steps can be altered and the individual steps of the different schemes can be combined in different ways as disclosed herein and according to common general knowledge. In general, the reaction conditions provided below and the reaction conditions can in some instances be further modified according to the procedures described herein and according to common general knowledge.

[0054] Scheme 1

[0055] In scheme 1, the synthesis of a compound of formula (I-a) is described. The compound of formula (I-a) is a compound of formula (I), wherein each of Al is a bond; A2 is -O-; A3 is -O-; R1is hydrogen; R2and R2’ are both hydrogen; R3is phenyl optionally substituted with one, two or three substituents independently selected from R7; R4is alky; R5is alky; each R7is indepently selected from alkoxy and halogen.

[0056] Step A: Methyl 2,6-dichloronicotinate 1 can be reacted with a 5,6-disubstituted benzimidazole 2 in the presence of a strong base such as for instance NaH in a polar solvent such as DMF or DMSO at about 0 °C to yield intermediate 3. - Il ¬

[0057] Step B: Intermediate 3 can undergo a palladium-catalyzed cross-coupling reaction (Suzuki- Miyaura) with a suitable reactant such as for instance the corresponding aryl boronic acid or aryl pinacol borane, catalytic Pd(PPhs)4 or other suitable Pd catalysts in presence of a suitable base such as for instance ISfeCCh, and in a suitable solvent such as for instance DME while heating (e.g. MW microwave at 120 °C) to yield intermediate 4.

[0058] Step C: The ester of 4 can be reduced to the corresponding alcohol using a suitable reducing agent such as for instance Li AIH4 in a suitable solvent such as for instance THF at 0 °C to yield the compound of formula (I-a).

[0059] Scheme 2 in scheme 2, the synthesis of a racemic compound of formula (I-b), as well as the corresponding entantiomers (Compounds I-b’ and I-b”) is described. The compound of formula (I-b) is a compound of formula (I), wherein each of Al is a bond; A2 is -O-; A3 is -O-; R1is hydrogen; R2is alkyl; R2’ is hydrogen; R3is phenyl optionally substituted with one, two or three substituents independently selected from R7; R4is alky; R5is alky; each R7is indepently selected from alkoxy and halogen.

[0060] Step A: In the presence of a suitable oxidation reagent such as for instance DMP (Dess- Martin periodinane) in a suitable solvent such as for instance DCM, the alcohol group of Compound (I-a) in Scheme 1 can be oxidized to the corresponding aldehyde 5 at ambient temperature.

[0061] Step B: The aldehyde 5 can be reacted with a suitable alkyl magnesium halide (such as for instance MeMgBr or EtMgBr or cyclopropylMgBr) at -30 °C to 0 °C in a suitable solvent such as for instance a mixture of THF / 2-MeTHF to yield the corresponding secondary alcohol I-b.

[0062] Step C: The racemic mixture of the secondary alcohol I-b can be separated by chiral SFC into the enantiomers I-b’ and I-b”. Scheme 3

[0063] In scheme 3, the synthesis of a compound of formula (I-c) is described. The compound of formula (I-c) is a compound of formula (I), wherein each of Al is a bond; A2 is -O-; A3 is -O-; R1is hydrogen; R2is hydrogen; R2’ is hydrogen; R3is N-heterocycloalkyl; R4is alky; R5is alky.

[0064] Step A: Intermediate 3 from Scheme 1 can be substituted with a saturated N-heterocycle 6 in the presence of a strong base (such as for instance NaH, or CS2CO3 or other carbonates) in a polar solvent (such as for instance DMF, DMA, NMP or DMSO) to yield intermediate 7.

[0065] Step B: The ester of the intermediate 7 can be reduced in the presence of a reducing agent, such as for instance Li AIH4, to the a compound of formula (I-c), in a similar manner than shown step C in scheme 1.

[0066] Scheme 4

[0067] In scheme 4, the synthesis of a compound of formula (I-d) and a compound of formula (I- e) is described. The compound of formula (I-d) is a compound of formula (I), wherein Al is a bond; A2 is -O-; A3 is -O-; R1is hydrogen; R2is hydrogen; R2’ is hydrogen; R3is N- heterocycloalkyl; R4 is alkyl; R5 is alkyl. The compound of formula (I-e) is a compound of formula (I), wherein Al is -NH-; A2 is -O-; A3 is -O-; R1is hydrogen; R2is hydrogen; R2’ is hydrogen; R3is hydroxyalkyl; R4is alkyl; R5is alkyl.

[0068] Step A: Methyl 2,6-dichloronicotinate 1 can be reacted with a cyclic amide 8 in the presence of a suitable base such as for instance NaH in a suitable solvent such as DMF at -10 °C - 0 °C to yield intermediate 9. Step B: Further substitution of intermediate 9 with a 5,6-disubstituted benzimidazole in the presence of a strong base such for instance NaH in a polar solvent (such as for instance DMF, DMA, NMP or DMSO) at 0 °C yields intermediate 11.

[0069] Step C: The ester of intermediate 11 can be reduced in the presence of a suitable reducing agent such as for instance LiAIF to yield the compound of formula (I-d), in a similar manner than in step C in scheme 1. The open chain compound (I-e) can also be obtained via the reduction step.

[0070] Scheme 5

[0071] In scheme 5, the synthesis of a racemic compound of formula (I-f), as well as the corresponding entantiomers (Compounds I-f and I-f ’) is described. The compound of formula (I-f) is a compound of formula (I), wherein each of Al is a bond; A2 is -O-; A3 is -O-; R1is hydrogen; R2is alkyl; R2’ is hydrogen; R3is phenyl or heteroaryl, wherein phenyl and heteroaryl are optionally substituted with one, two or three substituents independently selected from R7; R4 is alky; R5is alky; each R7is indepently selected from aminocarbonyl, methyl and cyano.

[0072] Step A: Intermediate 12 can be obtained from Intermediate 3 from Scheme 1 through a sequence of (1) reduction with a suitable reducing agent such as for instance LiAlH4 in a suitable solvent such as for instance THF at 0 °C, (2) oxidation with suitable reagent such as for instance DMP at room temperature to yield an aldehyde, (3) reaction with a suitable alkyl magnesium halide (such as for instance MeMgBr or EtMgBr or cyclopropylMgBr) in THF at -20 °C - 0 °C, and finally protection of the corresponding secondary alcohol with TBDMSC1 in DCM in the presence of imidazole.

[0073] Step B: A Palladium-catalyzed cross-coupling reaction ( Suzuki -Miy aura) with the corresponding aryl boronic acid or aryl pinacol borane, catalytic Pd(PPhs)4 or othe suitable Pd catalysts and a suitable base (K3PO4, CS2CO3, K2CO3, ISfeCCh) in a suitable solvent (DME) while heating (e.g. MW at 80 °C - 120 °C) yields a compound of formula (I-f).

[0074] Step C: The racemic mixture of the secondary alcohol I-f can be further separated by chiral

[0075] SFC into the enantiomers I-f and I-f ’.

[0076] Scheme 6

[0077] In scheme 6, the synthesis of a racemic compound of formula (I-g), as well as the corresponding entantiomers (Compounds I-g’ and I-g”) is described. In scheme 6, the synthesis of a racemic compound of formula (I-h), as well as the corresponding entantiomers (Compounds I-h’ and I-h”) is also described. The compound of formula (I-g) is a compound of formula (I), wherein Al is a bond; A2 is a bond; A3 is -NH-: R1is hydrogen; R2is alkyl; R2’ is hydrogen; R3is pyrazol-l-yl optionally substituted with one, two or three substituents independently selected from R7; R4is hydrogen; R5is pyridazin-3-yl optionally substituted with R9; each R7is independently selected from alkyl, cyano, haloalkyl, alkoxy, alkylaminocarbonyl and alkyl sulfonyl; R9is alkyl. The compound of formula (I-h) is a compound of formula (I), wherein Al is a bond; A2 is a -NH-; A3 is a bond: R1is hydrogen; R2is alkyl; R2’ is hydrogen; R3is pyrazol-l-yl optionally substituted with one, two or three substituents independently selected from R7; R4is pyridazin-3-yl optionally substituted with R8; R5is hydrogen; each R7is independently selected from alkyl, cyano, haloalkyl, alkoxy, alkylaminocarbonyl and alkylsulfonyl; R8is alkyl.

[0078] Step A: l-(6-chloro-2-fluoro-3-pyridyl)alkanone 13 can be reacted with a substituted pyrazole 14 in the presence of a suitable organic or mineral base, such as for instance DIPEA, DBU, K2CO3, CS2CO3 or NaH, in a suitable polar solvent (for instance DMF, DMA, NMP, DMSO or THF, MeTHF) to yield intermediate 15.

[0079] Step B: Intermediate 18 can be obtained from the reaction of 5-aminobenzimidazole 16 and (6-alkylpyridazin-3-yl)amine 17 in iPrOH while heating to reflux. Step C: The intermediates 15 and 18 can be combined in the presence of a suitable organic or mineral base (such as for instance DIPEA, DBU, K2CO3, CS2CO3 or NaH) in a suitable polar solvent (such as for instance DMF, DMA, NMP, DMSO or THF, MeTHF) to yield the regioisomeric intermediates 19 and 20 which can be separated by flash column chromatography.

[0080] Step D: The corresponding secondary alcohols (I-g and I-h) can be obtained after reduction of the carbonyl group with a suitable reducing agent such as for instance NaBEU or NaCNBEE (1-5 equiv.) in a suitable solvent such as for instance MeOH (and in some cases a second co-solvent, e.g. DCM, THF, DMF) at temperatures between -40 °C and rt.

[0081] Step E: The racemic mixture of the secondary alcohol I-g can be further separated by chiral SFC into the enantiomers I-g’ and I-g”. Similarly, the racemic mixture of the secondary alcohol I-h can be further separated by chiral SFC into the enantiomers I-h’ and I-h”.

[0082] Scheme 7

[0083] In scheme 7, the synthesis of a compound of formula (I-i) and a compound of formula (I-j) is described. The compound of formula (I-i) is a compound of formula (I), wherein Al is a bond; A2 is a bond; A3 is -NH-: R1is hydrogen; R2is alkyl; R2’ is hydrogen; R3is pyrazol-l-yl optionally substituted with one, two or three substituents independently selected from R7; R4is hydrogen; R5is alkyl, heterocycloalkyl or heteroaryl, wherein heterocycloalkyl and heteroaryl are optionally substituted with one, two or three substituents independently selected from R9; each R7is independently selected from alkyl, cyano, haloalkyl, alkoxy, alkylaminocarbonyl and alkyl sulfonyl; R9is alkyl, cyano or alkoxy. The compound of formula (I-j) is a compound of formula (I), wherein Al is a bond; A2 is -NH-; A3 is a bond: R1is hydrogen; R2is alkyl; R2’ is hydrogen; R3is pyrazol-l-yl optionally substituted with one, two or three substituents independently selected from R7; R4is alkyl, heterocycloalkyl or heteroaryl, wherein heterocycloalkyl and heteroaryl are optionally substituted with one, two or three substituents independently selected from R8; R5is hydrogen; each R7is independently selected from alkyl, cyano, haloalkyl, alkoxy, alkylaminocarbonyl and alkylsulfonyl; R8is alkyl, cyano or alkoxy.

[0084] Step A: The regioi someric intermediates 22 and 23 can be obtained - similarly to the description of step C in scheme 6 - using intermediate 15 and 5-bromobenzimidazole 21 as the second reagent.

[0085] Step B: Introduction of the R7- substituted amine can be performed via a Buchwald- Hartwig coupling using a suitable base such as for instance CS2CO3 K2CO3 or K3PO4, and as suitable palladium catalyst such as for instance t-Buxphos-Pd-G3 or [tBuBrettPhos Pd(allyl)]OTf at between around 80°C to around 90 °C to yield intermediates 24 and 25, respectively .

[0086] 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 for instance NaBFU (1-5 equiv.) in a suitable solvent such as for instance MeOH (and in some cases a second cosolvent, e.g. DCM, THF or DMF) at temperatures between -40 °C and rt to yield a compound of formula (I-i) and a compound of formula (I-j), respectively. The enantiomers of the secondary alcohol can be further separated by chiral SFC.

[0087] Scheme 8

[0088] In scheme 8, the synthesis of a compound of formula (I-k) and a compound of formula (1-1) is described. The compound of formula (I-k) is a compound of formula (I), wherein Al is a bond; A2 is a bond; A3 is -NH-: R1is hydrogen; R2is alkyl; R2’ is hydrogen; R3is pyrazol-l-yl optionally substituted with one, two or three substituents independently selected from R7; R4is hydrogen; R5heteroaryl optionally substituted with one, two or three substituents independently selected from R9; each R7is independently selected from alkyl, cyano, haloalkyl, alkoxy, alkylaminocarbonyl and alkylsulfonyl; R9is alkyl, cyano or alkoxy. The compound of formula (I-j) is a compound of formula (I), wherein Al is a bond; A2 is -NH-; A3 is a bond: R1is hydrogen; R2is alkyl; R2’ is hydrogen; R3is pyrazol-l-yl optionally substituted with one, two or three substituents independently selected from R7; R4is heteroaryl optionally substituted with one, two or three substituents independently selected from R8; R5is hydrogen; each R7is independently selected from alkyl, cyano, haloalkyl, alkoxy, alkylaminocarbonyl and alkyl sulfonyl; R8is alkyl, cyano or alkoxy.

[0089] Step A: The carbonyl group of the regioisomer intermediates 22 and 23 obtained in step A of scheme 7 can be reduced with a suitable reducing agent such as for instance NaBT or NaCNBHs in a suitable solvent such as for instance MeOH / THF (1 :1) at around 0 °C, to yield intermediates 26 and 27 respectively.

[0090] Step B: An arylamine group can be introduced via a Buchwald-Hartwig coupling using for instance CS2CO3 as a base and RuPhos-Pd-G3 as catalyst in a suitable solvent such as for instance 1,4-di oxane at 100 °C, to yield a compound of formula (I-k) and a compound of formula (1-1) respectively.

[0091] Scheme 9

[0092] In scheme 9, the synthesis of a compound of formula (I-m) is described. The compound of formula (I-m) is a compound of formula (I), wherein Al is a bond; A2 is a bond; A3 is -NH-: R1is hydrogen; R2is methyl; R2’ is hydrogen; R3is N-heteroaryl optionally substituted with one, two or three substituents independently selected from R7; R4is hydrogen; R5is pyridazin-3-yl substituted with methyl; each R7is independently selected from alkyl, cyano, halogen, haloalkyl, haloalkoxy, hydroxy, alkoxy, and cycloalkylamino.

[0093] Step A: l-(2-chloro-6-fluoro-3-pyridyl)ethanone 30 can be obtained from the reaction of 3- bromo-2-chloro-6-fluoro-pyridine 28 and tributyl(l-ethoxyvinyl)tin 29 in the presence of a suitable catalyst such as for instance Pd(PPh3)C12 and a suitable base such as for instance K2CO3, CS2CO3 or K3PO4 in a suitable solvent such as for instance 1,4-di oxane and H2O at around 100 °C.

[0094] Step B: The intermediate 30 can then be reacted with N-(6-methylpyridazin-3-yl)-lH- benzimidazol-5-amine (intermediate 18 from Scheme 6) in DMSO at 60 °C to obtain intermediate 31 (and its regioisomer).

[0095] Step C: A palladium-catalyzed cross-coupling reaction ( Suzuki -Miy aura) with the corresponding aryl boronic acid or aryl pinacol borane, a suitable catalyst such as for instance PdC12(dppf) CH2C12 and a suitable base (for instance ISfeCCh) in a solvent such as for instance 1,4-di oxane while heating to around 100 °C, yields intermediate 32.

[0096] Step D: The compound I-m can be obtained after reduction of the carbonyl group of 32 with a suitable reducing agent such as for instance NaBTU or NaCNBHs (1-5 equiv.) in a suitable solvent such as for instance MeOH (and in some cases a second co-solvent, e.g. DCM, THF or DMF) at temperatures between around -40 °C and rt.

[0097] Scheme 10

[0098] In scheme 10, the synthesis of a compound of formula (I-n) is described. The compound of formula (I-n) is a compound of formula (I), wherein Al is a bond; A2 is a bond; A3 is -NH-; R1is hydrogen; R2is methyl; R2’ is hydrogen; R3is cycloalkyl optionally substituted with one, two or three substituents independently selected from R7; R4is hydrogen; R5is pyridazin-3-yl substituted with methyl; each R7is independently selected from alkyl, cyano, halogen, haloalkyl, haloalkoxy, hydroxy, alkoxy, and cycloalkylamino.

[0099] Step A . l-(6-chloro-2-fluoro-3-pyridyl)ethanone 33 can be eacted with a cyclic amine (or sulfonamide or amide) in the presence of a suitable base such as for instance K2CO3 or CS2CO3 in a suitable solvent such as e.g. DMSO to yield intermediate 34.

[0100] Step B: Intermediate 34 can be reacted in DMSO with N-(6-methylpyridazin-3-yl)-lH- benzimidazol-5-amine (intermediate 18 from Scheme 6) in the presence of K2CO3 or CS2CO3 at 30 °C - 50 °C to obtain intermediate 35 (and its regioisomer).

[0101] Step C: The secondary alcohols of compound of formula (I-n) can be obtained after reduction of the carbonyl of intermediate 35 with a suitable reducing agent such as for instance NaBH4 (1-5 equiv.) in a suitable solvent such as for instance MeOH (and in some cases a second co-solvent, e.g. DCM, THF, DMF) at temperatures between around -40 °C and rt. Step D: The enantiomers I-n’ and I-n” of the secondary alcohol can be separated by chiral

[0102] SFC.

[0103] Scheme 11

[0104] In scheme 11, the synthesis of a compound of formula (I-o) is described. The compound of formula (I-o) is a compound of formula (I), wherein Al is -NH-; A2 is a bond; A3 is -NH-: R1is hydrogen; R2is methyl; R2’ is hydrogen; R3is alkyl; R4is hydrogen; R5is pyridazin-3-yl substituted with methyl; each R7is independently selected from alkyl, cyano, halogen, haloalkyl, haloalkoxy, hydroxy, alkoxy, and cycloalkylamino.

[0105] Step A : l-(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 yield intermediate 36.

[0106] Step B Intermediate 36 can be reacted in DMSO with N-(6-methylpyridazin-3-yl)-lH- benzimidazol-5-amine (intermediate 18 from Scheme 6) in the presence of K2CO3 at 30 °C to obtain intermediate 37 (and its regioisomer).

[0107] Step C: The compound of formula (I-o) can be obtained after reduction of the carbonyl with a suitable reducing agent such as for instance NaBEU (1-5 equiv.) in a suitable solvent such as for instance MeOH (and in some cases a second co-solvent, e.g. DCM, THF, DMF) at temperatures between around -40 °C and rt.

[0108] The invention thus also relates to a process for the preparation of a compound according to the invention, comprising one of the following steps:

[0109] (a) the reaction of a compound of formula (Bl) with a reducing agent;

[0110] (b) the reaction of a compound of formula (Cl) with a reducing agent; or

[0111] (c) the reaction of a compound (DI) with a compound of formula RcMgX, wherein Al, A2, A3, R1, R2, R3, R4and R5are as defined above, Rais alkyl or cycloalkyl, Rbis hydrogen or alkyl, Rcis alkyl or cycloalkyl, and X is halogen.

[0112] The reducing agent of step (a) can be LiAlTU, DIBAL-H,

[0113] The solvent of step (a) can advantageously be THF.

[0114] Convenient conditions for step (a) are between around -60 °C to around 40 °C, in particular between around -50 °C to around 30 °C, more particular between around -40°C to around 20 °C during 1-24 hrs, advantageously during 1-12 hrs.

[0115] The reducing agent of step (b) can be for instance NaBTU.

[0116] The solvent of step (b) can be for instance methanol or a mixture of methanol and THF.

[0117] Convenient conditions for step (b) are between around -60 °C to around 40 °C, in particular between around -50 °C to around 30 °C, more particular between around -40°C to around 20 °C during 1-24 hrs, advantageously during 1-12 hrs.

[0118] In step (c) the solvent can be for instance THF, 2-MeTHF or a mixture thereof.

[0119] Convenient conditions for step (c) are between around -80 °C to around 30 °C, in particular between around -78 °C to around 20 °C, more particular between around -40 °C to around 0 °C during 1-24 hrs, advantageously during 1-12 hrs.

[0120] Conveniently, X is chloride, bromide or iodide. Advantageously, X is bromide.

[0121] The invention also relates to a compound according to the invention when manufactured according to a process of the invention.

[0122] Pharmaceutical Compositions

[0123] Another embodiment of the invention provides a pharmaceutical composition or medicament containing a compound of the invention and a therapeutically inert carrier, diluent or excipient, as well as a method of using the compounds of the invention to prepare such composition and medicament. In one example, the compound of formula (I) may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form. The pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8. In one example, a compound of formula (I) is formulated in an acetate buffer, at pH 5. In another embodiment, the compound of formula (I) is sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.

[0124] Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.

[0125] The compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, epidural and intranasal, and if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0126] The compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.

[0127] A typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., 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 formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).

[0128] Example A Film coated tablets containing the following ingredients can be manufactured in a conventional manner: The active ingredient is sieved and mixed with microcrystalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidone in water. The granulate is then mixed with sodium starch glycolate and magnesium stearate and compressed to yield kernels of 120 or 350 mg respectively. The kernels are lacquered with an aq. solution / suspension of the above mentioned film coat.

[0129] Example B

[0130] Capsules containing the following ingredients can be manufactured in a conventional manner:

[0131] The components are sieved and mixed and filled into capsules of size 2.

[0132] Example C

[0133] Injection solutions can have the following composition: The active ingredient is dissolved in a mixture of Polyethylene glycol 400 and water for injection (part). The pH is adjusted to 5.0 by addition of acetic acid. The volume is adjusted to 1.0 ml by addition of the residual amount of water. The solution is filtered, filled into vials using an appropriate overage and sterilized.

[0134] Experimental Procedures

[0135] Abbreviations

[0136] [tBuBrettPhos Pd(allyl)]OTf allyl (2 -di -tert-butylphosphino-3,6-dimethoxy-2’, 4 ’,6’ -triisopropyl - l,l’-biphenyl)palladium(II) triflate (CAS # 1798782-15-6)

[0137] 2-MeTHF 2-methyl tetrahydrofuran

[0138] ATP adenosine triphosphate aq. aqueous

[0139] Boe tert-butyloxycarbonyl

[0140] CDI carbonyldiimidazole

[0141] D ABCO 1 , 8 -diazabicyclo [5.4.0] undec-7 -ene

[0142] DAST diethylaminosulfur trifluoride dba dibenzylideneacetone

[0143] DCM dichloromethane

[0144] DIAD diisopropyl azodicarboxylate

[0145] DIBAL-H diisobutylaluminium hydride

[0146] DIPEA A'.A'-diisopropylcthylaminc

[0147] DMF NJ -dimethylformamide

[0148] DMSO dimethyl sulfoxide dppf 1 , 1’ -ferrocenediyl -bis(diphenylphosphine) dtbbpy 4,4’-Bis(l, l-dimethylethyl)-2,2’-bipyridine dtbpy 4,4 ’ -Di-tert-butyl-2,2 ’ -dipyridyl

[0149] EDCI l-ethyl-3-(3-dimethylaminopropyl)carbodiimide equiv. equivalents

[0150] ESI electrospray ionization

[0151] Et ethyl

[0152] Et2O diethyl ether

[0153] EtOAc ethyl acetate

[0154] EtOH ethanol

[0155] FA formic acid

[0156] HATU ( l-|bis(dimcthylamino)mcthylcnc|-l / / -l.2.3-triazolo|4.5- / )|pyridinium

[0157] 3 -oxide hexafluorophosphate

[0158] HMDS bis(trimethylsilyl)amine

[0159] HOBt hydoxybenzotriazole

[0160] HPLC high pressure liquid chromatography

[0161] PrOH isopropyl alcohol

[0162] Ir[dF(CF3)ppy]2(dtbpy)(PFe) [4,4 ’ -bis( 1 , l-dimethylethyl)-2,2’-bipyridine-Nl,N l’]bis[3,5-difluoro-2-

[0163] [5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate

[0164] LC-MS high-performance liquid chromatography

[0165] LDA lithium diisopropylamide mCPBA meta-chloroperoxybenzoic acid

[0166] Me methyl

[0167] Me OH methanol

[0168] Ms methanesulfonyl

[0169] NMR nuclear magnetic resonance

[0170] NPLC normal phase liquid chromatography

[0171] PE petroleum ether ppy 2-phenylpyridine psi pounds per square inch PTSA para toluene sulfonic acid

[0172] Qphos l,2,3,4,5-Pentaphenyl-r-(di-tert-butylphosphino)ferrocene

[0173] RT room temperature

[0174] RuPhos-Pd-G3 (2-dicyclohexylphosphino-2 ’ ,6 ’ -diisopropoxy- 1,1’ -biphenyl) [2-(2 ’ - amino- l,l’-biphenyl)]palladium(II) methanesulfonate (CAS # 1445085- 77-7) sat. saturated

[0175] SFC supercritical fluid chromatography sol. solution

[0176] TBD triazabicyclodecene

[0177] TBDMS tert-butyldimethylsilyl t-BuXphos-Pd-G3 [(2-Di-tert-butylphosphino-2’,4’,6’-triisopropyl-l,l’-biphenyl)-2-(2’- amino-1,1’ -biphenyl)] palladium(II) methanesulfonate (CAS # 1447963- 75-8)

[0178] TEA triethylamine

[0179] Tf triflyl

[0180] TFA trifluoroacetic acid

[0181] TFAA trifluoroacetic acid anhydride

[0182] THF tetrahydrofuran

[0183] TLC thin layer chromatography

[0184] Example 1

[0185] (2-(3-chlorophenyl)-6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)pyridin-3-yl)methanol

[0186] Step 1: methyl 2-chloro-6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)nicotinate

[0187] In a 200 mL four-necked flask, NaH 60% dispersion in mineral oil (637 mg, 15.9 mmol, 2 equiv.) was combined with DMF (30 mL) to give a grey suspension. The mixture was cooled to 0 °C and 5,6-dimethoxy-lH-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 HC1 and a precipitate formed. The suspension was collected by filtration, washed with H2O 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. Step 2: methyl 2-(3-chlorophenyl)-6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)nicotinate

[0188] In a microwave vial were added methyl 2-chloro-6-(5,6-dimethoxy-lH-benzo[d]imidazol-l- yl)nicotinate (1 g, 2.88 mmol, 1 equiv.), 2 M Na2COs (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(PPhs)4 (332 mg, 288 pmol, 0.1 equiv.). The vial was capped and heated in the microwave at 120 °C for 20 min. The reaction mixture was cooled to RT, diluted with 25 mL of H2O and 25 mL of ethylacetate. 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 chromatographied 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.

[0189] Step 3: (2-(3-chlorophenyl)-6-(5, 6-dimethoxy-lH-benzo[d]imidazol-l-yl)pyridin-3-yl)methanol

[0190] In a 100 mL round-bottomed flask, methyl 2-(3-chlorophenyl)-6-(5,6-dimethoxy-lH- benzo[d]imidazol-l-yl)nicotinate (317 mg, 748 pmol, 1 equiv.) was suspended in anhydrous THF (5 mL). The mixture was cooled to 0 °C and LiAlEL 1 M solution 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 potassium sodium 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. This crude solid was purified by flash chromatography (silica gel, 25 g, 0-100% [DCM / Me0H / NH40H (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.

[0191] Example 15 (2-(3-Chloro-2-fluorophenyl)-6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)pyridin-3- yl)methanol Step 1: methyl 2-(3-chloro-2-fluorophenyl)-6-(5,6-dimethoxy-lH-benzo[d]imidazol-l- yl)nicotinate

[0192] Starting from methyl 2-chloro-6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)nicotinate (obtained as in step 1 of example 1) (400 mg, 1.15 mmol, 1 equiv.) with (3-chloro-2-fluorophenyl)boronic acid (301 mg, 1.73 mmol, 1.5 equiv.), 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.

[0193] Step 2: (2-(3-chloro-2-fluorophenyl)-6-(5, 6-dimethoxy-lH-benzo[d]imidazol-l-yl)pyridin-3- yl)methanol

[0194] 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.

[0195] Example 16 (6-(5,6-Dimethoxy-lH-benzo [d] imidazol-l-yl)-2-(4-fluoro-2-methoxyphenyl)pyridin-3- yl)methanol Step 1: methyl 6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)-2-(4-fluoro-2- methoxyphenyl)nicotinate

[0196] Starting from methyl 2-chloro-6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)nicotinate (obtained as in step 1 of example 1) (500 mg, 1.15 mmol, 1 equiv.) with (4-fluoro-2- methoxyphenyl)boronic acid (367 mg, 2.16 mmol, 1.5 equiv.), 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.

[0197] Step 2: (6-(5, 6-dimethoxy-lH-benzo[d]imidazol-l-yl)-2-(4-fluoro-2-methoxyphenyl)pyridin-3- yl)methanol

[0198] 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.

[0199] Example 17 l-(6-(5,6-Dimethoxy-lH-benzo[d]imidazol-l-yl)-2-(4-fluoro-2-methoxyphenyl)pyridin-3- yl)ethan-l-ol Step 1: 6-(5, 6-dimethoxy-lH-benzo[d]imidazol-l-yl)-2-(4-fluoro-2- methoxyphenyl)nicotinaldehyde

[0200] In a 25 mL pear shape flask, (6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)-2-(4-fluoro-2- m ethoxyphenyl)pyri din-3 -yl)methanol (398 mg, 972 pmol, 1 equiv.) (obtained 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 soon turned to a light brown solution. A suspension formed a few moments later. After stirring for 10 min, the reaction mixture was quenched with H2O, diluted with DCM and 2 M Na2COs was added. The layers were separated and the aqueous layer was back extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated to leave a yellow residue. This crude material was purified by flash chromatography (silica gel, 40 g, 0% to 100% [DCM / MeOH / NH4OH (95:5: 1)] in DCM). The title compound (357 mg, 72.1% yield) was obtained as a yellow solid. LC-MS: m / z = 408.2 [M+H]+, ESI pos.

[0201] Step 2: l-(6-(5, 6-dimethoxy-lH-benzo[d]imidazol-l-yl)-2-(4-fluoro-2-methoxyphenyl)pyridin-3- yl)ethan-l-ol

[0202] In a 25 mL pear shape flask, 6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)-2-(4-fluoro-2- methoxyphenyl)nicotinaldehyde (120 mg, 236 pmol, 1 equiv.) was suspended in anhydrous THF (2.5 mL). The mixture was cooled to 0 °C before MeMgBr (3.2 M solution in 2-MeTHF) (81 pL, 259 pmol, 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 pL, 259 pmol, 1.1 equiv.) was added and stirring was continued for another 30 min. The reaction mixture was slowly quenched with H2O (5 mL) at 0 °C. Sat. aq. NH4CI solution (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% [DCM / Me0H / NH40H (95:5: 1)] in DCM). The chromatographied product was dissolved in CH3CN / H2O 1 : 1 and freeze-dried. 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. Example 18 l-(6-(5,6-Dimethoxy-lH-benzo[d]imidazol-l-yl)-2-(4-fluoro-2-methoxyphenyl)pyridin-3- yl)propan-l-ol

[0203] Starting from 6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)-2-(4-fluoro-2- methoxyphenyl)nicotinaldehyde (obtained as in step 1 of example 17) (110 mg, 216 pmol, 1 equiv.) with EtMgBr (3.0 M solution in diethyl ether) (108 pL, 324 pmol, 1.5 equiv.) 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.

[0204] Example 19 l-(2-(3-Chlorophenyl)-6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)pyridin-3-yl)ethan-l-ol

[0205] Step 1: 2-(3-chlorophenyl)-6-(5, 6-dimethoxy-lH-benzo[d]imidazol-l-yl)nicotinaldehyde Starting from (2-(3-chlorophenyl)-6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)pyridin-3- yl)methanol (obtained as in step 3 of example 1) (218 mg, 551 pmol, 1 equiv.) and following the procedure described in step 1 of example 17, the title compound (250 mg, quantitative yield) was obtained as a yellow amorphous solid. LC-MS: m / z = 394.1 [M+H]+, ESI pos.

[0206] Step 2: l-(2-(3-chlorophenyl)-6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)pyridin-3-yl)ethan-l- ol

[0207] 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.

[0208] Example 20 l-(2-(3-Chloro-2-fluorophenyl)-6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)pyridin-3- yl)ethan-l-ol

[0209] Step 1: methyl 2-(3-chloro-2-fluorophenyl)-6-(5,6-dimethoxy-lH-benzo[d]imidazol-l- yl)nicotinate

[0210] Starting from methyl 2-chloro-6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)nicotinate (obtained as in step 1 of example 1) (400 mg, 1.15 mmol, 1 equiv.) with (3-chloro-2-fluorophenyl)boronic acid (301 mg, 1.73 mmol, 1.5 equiv.), 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. Step 2: (2-(3-chloro-2-fluorophenyl)-6-(5, 6-dimethoxy-lH-benzo[d]imidazol-l-yl)pyridin-3- yl)methanol

[0211] 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.

[0212] Step 3: 2-(3-chloro-2-fluorophenyl)-6-(5, 6-dimethoxy-lH-benzo[d]imidazol-l- yl)nicotinaldehyde

[0213] 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.

[0214] Step 4: l-(2-(3-chloro-2-fluorophenyl)-6-(5, 6-dimethoxy-lH-benzo[d]imidazol-l-yl)pyridin-3- yl)ethan-l-ol

[0215] 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. Example 21

[0216] (3)-l-(6-(5,6-Dimethoxy-lH-benzo[d]imidazol-l-yl)-2-(4-fluoro-2-methoxyphenyl)pyridin-

[0217] 3-yl)ethan-l-ol l-(6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)-2-(4-fluoro-2-methoxyphenyl)pyri din-3- yl)ethan-l-ol (60 mg, 142 pmol) (obtained as in step 2 of example 17) was purified by chiral SFC: column Chiral IA (250mm x 20mm x 5pm). 30 % (MeOH / EtOH / IprOH 1 : 1 : 1) in scCCE. 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. Example 22

[0218] (l?)-l-(6-(5,6-Dimethoxy-lH-benzo[d]imidazol-l-yl)-2-(4-fluoro-2-methoxyphenyl)pyridin-

[0219] 3-yl)ethan-l-ol l-(6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)-2-(4-fluoro-2-methoxyphenyl)pyri din-3- yl)ethan-l-ol (60 mg, 142 pmol) (obtained as in step 2 of example 17) was purified by chiral SFC: column Chiral IA (250mm x 20mm x 5pm). 30 % (MeOH / EtOH / IprOH 1 : 1 : 1) in scCCE. 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. Example 23 Cyclopropyl(6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)-2-(4-fluoro-2- methoxyphenyl)pyridin-3-yl)methanol Starting from 6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)-2-(4-fluoro-2- methoxyphenyl)nicotinaldehyde (obtained as in step 1 of example 17) (164 mg, 322 pmol, 1 equiv.) with cyclopropyl magnesium bromide (1 M solution in 2-MeTHF) (419 pL, 419 pmol, 1.3 equiv.) 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.

[0220] Example 24 l-(2-(3-Chlorophenyl)-6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)pyridin-3-yl)propan-l- Starting from 2-(3-chlorophenyl)-6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)nicotinaldehyde (obtained as in step 1 of example 19) (125 mg, 286 pmol, 1 equiv.) 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. Example 25 (2-(3-Chlorophenyl)-6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)pyridin-3- yl)(cyclopropyl)methanol Starting from 2-(3-chlorophenyl)-6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)nicotinaldehyde (obtained as in step 1 of example 19) (89 mg, 226 pmol, 1 equiv.) 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.

[0221] Example 26 (6-(5,6-Dimethoxy-lH-benzo [d] imidazol-l-yl)-2-morpholinopyridin-3-yl)methanol

[0222] Step 1: methyl 6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)-2-morpholinonicotinate

[0223] A mixture of methyl 2-chloro-6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)nicotinate (174 mg, 0.5 mmol, 1 equiv.) (obtained as in 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 hours. The reaction mixture was then cooled down to RT and purified by flash chromatography (silica gel, 20 g, 0- 100% [DCM / MeOH (9: 1)] in DCM). The title compound (128 mg, 61% yield) was obtained as a light brown solid. LC-MS: m / z = 399.3 [M+H]+, ESI pos. Step 2: (6-(5, 6-dimethoxy-lH-benzo[d]imidazol-l-yl)-2-morpholinopyridin-3-yl)methanol

[0224] LiAlH4 (11.4 mg, 300 pmol, 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-lH-benzo[d]imidazol-l-yl)-2- morpholinonicotinate (120 mg, 0.3 mmol, 1 equiv.) in dry THF (1.6 mL) was added dropwise for 15 min while keeping the temperature at 0 °C. Stirring at 0 °C was continued for 4 hours. The cooling bath was removed and the mixture was stirred at RT overnight. The mixture was cooled again to 0 °C, carefully treated with H2O and extracted with DCM. The organic layer was washed with brine, dried over MgSCh, filtered and concentrated to dryness. The residue was purified by flash chromatography (silicagel, 10 g, 20-100% [DCM / MeOH (9: 1)] in DCM). The chromatographied product was triturated in Et2O (3 mL), collected by filtration, washed with Et2O and dried. The tilte compound (51 mg, 45.9% yield) was obtained as a white solid. LC-MS: m / z = 371.2 [M+H]+, ESI pos.

[0225] Example 27 (6-(5,6-Dimethoxy-lH-benzo[d]imidazol-l-yl)-2-(pyrrolidin-l-yl)pyridin-3-yl)methanol

[0226] Step 1: methyl 6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)-2-(pyrrolidin-l-yl)nicotinate

[0227] A mixture of methyl 2-chloro-6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)nicotinate (174 mg, 0.5 mmol, 1 equiv.) (obtained as in step 1 of example 1), pyrrolidine (53 mg, 62 pL, 750 pmol, 1.5 equiv.) and K2CO3 (131 mg, 950 pmol, 1.9 equiv.) in DMSO (1.7 mL) was heated to 95 °C and stirred at that temperature for 3 hours. The mixture was cooled to RT and diluted with H2O. A precipitate formed. The solid was collected by filtration and dissolved in DCM. The resulting solution was dried over MgSCh, 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. Step 2: (6-(5, 6-dimethoxy-lH-benzo[d]imidazol-l-yl)-2-(pyrrolidin-l-yl)pyridin-3-yl)methanol

[0228] 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.

[0229] Example 28 (6-(5,6-Dimethoxy-lH-benzo [d] imidazol-l-yl)-2-(piperidin-l-yl)pyridin-3-yl)methanol

[0230] Step 1: methyl 6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)-2-(piperidin-l-yl)nicotinate

[0231] Starting from 2-chloro-6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)nicotinate (obtained as in step 1 of example 1) (164 mg, 322 pmol, 1 equiv.) with piperidine (63.9 mg, 74.1 pL, 750 pmol, 1.5 equiv.) and following the procedure described in step 1 of example 27, the title compound (150 mg, 71.3% yield) was obtained as a light red solid. LC-MS: m / z = 397.3 [M+H]+, ESI pos.

[0232] Step 2: (6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)-2-(piperidin-l-yl)pyridin-3-yl)methanol

[0233] 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.

[0234] Example 32 5-((6-(5,6-Dimethoxy-lH-benzo[d]imidazol-l-yl)-3-(hydroxymethyl)pyridin-2- yl)amino)pentan-l-ol

[0235] Step 1: methyl 6-chloro-2-(2-oxopiperidin-l-yl)nicotinate To a suspension of NaH 60% dispersion 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 minutes. 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 up to 23 °C. Stirring was continued for 1 hours. The reaction mixture was added to ice-cold saturated aqueous NH4CI solution (100 mL). and extracted with EtOAc. The combined organics were washed with brine, dried over MgSCh, filtered and concentrated to leave a light yellow liquid. This crude material was purified by flash chromatography (silicagel, 20 g, 0-80% heptane in EtOAc). The title compound (791 mg, 53.8% yield) was obtained as a light yellow solid. LC-MS: m / z = 269.1 [M+H]+, ESI pos. Step 2: methyl 6-(5, 6-dimethoxy-lH-benzo[d]imidazol-l-yl)-2-(2-oxopiperidin-l-yl)nicotinate

[0236] 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 and 5,6-dimethoxy-lH-benzo[d]imidazole (89.1 mg, 0.5 mmol, 1.0 equiv.) was added and the reaction mixture was stirred for 15 min . Methyl 6-chloro- 2-(2-oxopiperidin-l-yl)nicotinate.(134 mg, 0.5 mmol, 1.0 equiv.) was dissolved in dry DMF (600 pl) ) and the solution was added dropwise. Stirring was continued for 15 min at 0 °C then let to warm overnight to RT. The reaction mixture was cooled, and diluted with cold sat. aq. NH4CI sol. and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSC and concentrated unde rreduced pressure. The crude productwas purified by flash column chromatography (silica gel, 0 - 10% MeOH in DCM) to yield the title compound (62.5 mg, 28.9% yield) was obtained as an off-white solid. LC-MS: m / z = 411.2 [M+H]+, ESI pos.

[0237] Step 3: 5-((6-(5, 6-Dimethoxy-lH-benzo[d]imidazol-l-yl)-3-(hydroxymethyl)pyridin-2- yl)amino)pentan-l-ol

[0238] To a stirred solution of methyl 6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)-2-(2-oxopiperidin- l-yl)nicotinate (62 mg, 0.15 mmol, 1 equiv.) in a mixture of dry THF (560 pL) and ethanol (560 pL) was added calcium chloride (58 mg, 525 pmol, 3.5 equiv.). The reaction mixture was cooled to 0 °C. NaBT (25 mg, 675 pmol, 4.5 equiv.) was added in one portion and the mixture was stirred for 10 min. The cooling bath was removed and stirring at RT was continued for 2 hours. The mixture was poured into ice-cold sat. aq. NH4CI sol. (50 mL) and this was extracted with DCM. The organic layer was washed with brine, dried over MgSCU, filtered and concentrated to dryness. The crude product was purified by prep. 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-t / 6): 5 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).

[0239] Example 33 l-(6-(5,6-Dimethoxy-lH-benzo[d]imidazol-l-yl)-3-(hydroxymethyl)pyridin-2-yl)pyrrolidin- 2-one

[0240] Step 1: methyl 6-chloro-2-(2-oxopyrrolidin-l-yl)nicotinate

[0241] Following the procedure described in step 1 of example 32 with pyrrolidin-2-one (443 mg, 5.2 mmol, 1 equiv.), the title compound (744 mg, 53.4% yield) was obtained as an orange liquid. LC-MS: m / z = 255.1 [M+H]+, ESI pos.

[0242] Step 2: methyl 6-(5, 6-dimethoxy-lH-benzo[d]imidazol-l-yl)-2-(2-oxopyrrolidin-l-yl)nicotinate

[0243] Following the procedure described in step 2 of example 32 (with reaction time of 21 hours at RT), 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.

[0244] Step 3: l-(6-(5, 6-Dimethoxy-lH-benzo[d]imidazol-l-yl)-3-(hydroxymethyl)pyridin-2- yl)pyrrolidin-2-one

[0245] Following the procedure described in step 2 of example 26 and starting from methyl 6-(5,6- dimethoxy-lH-benzo[d]imidazol-l-yl)-2-(2-oxopyrrolidin-l-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.

[0246] Example 34 4-((6-(5,6-Dimethoxy-lH-benzo[d]imidazol-l-yl)-3-(hydroxymethyl)pyridin-2- yl)amino)butan-l-ol The title compound (19.1 mg, 16.2% yield) was isolated as a side-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.

[0247] Example 35 (5)-2-(6-(5,6-Dimethoxy-lH-benzo[d]imidazol-l-yl)-3-(l-hydroxyethyl)pyridin-2- yl)benzamide

[0248] Step 1: (2-chloro-6-(5, 6-dimethoxy-lH-benzo[d]imidazol-l-yl)pyridin-3-yl)methanol

[0249] Starting from methyl 2-chloro-6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)nicotinate (obtained as in step 1 of example 1) (1.18 g, 3.38 mmol) and following the procedure described in step 3 of example 1, the title compound (702 mg, 61% yield) was obtained as a brown solid. LC-MS: m / z = 320.1 [M+H]+, ESI pos.

[0250] Step 2: 2-chloro-6-(5, 6-dimethoxy-lH-benzo[d]imidazol-l-yl)nicotinaldehyde

[0251] Following the procedure described in step 1 of example 17, with a reaction time of 7 h, the title compound (752 mg, quantitative yield) was obtained as a light brown solid. LC-MS: m / z = 318.1 [M+H]+, ESI pos.

[0252] Step 3: l-(2-chloro-6-(5, 6-dimethoxy-lH-benzo[d]imidazol-l-yl)pyridin-3-yl)ethan-l-ol

[0253] Following the procedure described in step 2 of example 17, using methylmagnesium bromide solution (1.4M 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.

[0254] Step 4: l-(5-(l-((tert-butyldimethylsilyl)oxy)ethyl)-6-chloropyridin-2-yl)-5,6-dimethoxy-lH- benzo[d] imidazole

[0255] In a 150 mL round-bottomed flask, l-(2-chloro-6-(5,6-dimethoxy-lH-benzo[d]imidazol-l- yl)pyridin-3-yl)ethan-l-ol (702 mg, 2.1 mmol, 1 equiv.) was suspended in anhydrous DCM (15 mL). The mixture was sparged with argon before imidazole (286 mg, 4.21 mmol, 2 equiv.) and tert-butylchlorodimethylsilane (485 mg, 3.15 mmol, 1.5 equiv.) were added subsequently. The reaction mixture turned to a yellow suspension and it was stirred at 20 °C for 3 h, after which only a small conversion of the starting material to the desired product was observed. DMF (6 mL) was added to the mixture which turned to a solution. Stirring was continued at 20 °C overnight. The reaction mixture was quenched with H2O and extracted with DCM. The layers were separated and the aqueous phase was back-extracted using 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.

[0256] Step 5: 2-(6-(5, 6-dimethoxy-lH-benzo[d]imidazol-l-yl)-3-(l-hydroxyethyl)pyridin-2- yl)benzamide

[0257] Following the procedure described in step 2 of example 1, using 1 -(5 -(1 -((tertbutyl dimethylsilyl)oxy)ethyl)-6-chloropyridin-2-yl)-5,6-dimethoxy-lH-benzo[d]imidazole (80 mg, 179 pmol, 1 equiv.) and (2-cyanophenyl)boronic acid (39.4 mg, 268 pmol, 1.5 equiv.) with a reaction time of 30 min at 130 °C, the title compound (20 mg, 24.9% yield) was obtained as an off-white solid. LC-MS: m / z = 419.2 [M+H]+, ESI pos. Step 6: (S)-2-(6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)-3-(l-hydroxyethyl)pyridin-2- yl)benzamide

[0258] 2-(6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)-3-(l-hydroxyethyl)pyridin-2-yl)benzamide (20 mg, 48 pmol) was purified by chiral SFC: column Chiral OD-H (250mm x 20mm x 5pm). Flow rate: 90 mL / min. 30 % MeOH in scCCh. 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.

[0259] Example 36

[0260] (l?)-2-(6-(5,6-Dimethoxy-lH-benzo[d]imidazol-l-yl)-3-(l-hydroxyethyl)pyridin-2- yl)benzamide

[0261] 2-(6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)-3-(l-hydroxyethyl)pyridin-2-yl)benzamide

[0262] (obtained as in step 5 of example 35) (20 mg, 48 pmol) was purified by chiral SFC: column Chiral OD-H (250mm x 20mm x 5pm). Flow rate: 90 mL / min. 30 % MeOH in scCO?. 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.

[0263] Example 37 (5)-3-(6-(5,6-Dimethoxy-lH-benzo[d]imidazol-l-yl)-3-(l-hydroxyethyl)pyridin-2- yl)benzonitrile

[0264] Step 1: 3-(6-(5, 6-dimethoxy-lH-benzo[d]imidazol-l-yl)-3-(l-hydroxyethyl)pyridin-2- yl)benzonitrile

[0265] Starting from l-(5-(l -((tert-butyl dimethylsilyl)oxy)ethyl)-6-chloropyridin-2-yl)-5,6-dimethoxy- lH-benzo[d]imidazole (obtained as in step 4 of example 35) (80 mg, 179 pmol, 1 equiv.) with (3-cyanophenyl)boronic acid (39 mg, 268 pmol, 1.5 equiv.) and following the procedure described in step 2 of example 1 with a reaction time of 30 min at 130 °C, the title compound (60 mg, 83.9% yield) was obtained as a brown solid. LC-MS: m / z = 401.1 [M+H]+, ESI pos.

[0266] Step 2: (S)-3-(6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)-3-(l-hydroxyethyl)pyridin-2- yl)benzonitrile

[0267] 3-(6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)-3-(l-hydroxyethyl)pyri din-2 -yl)benzonitrile (60 mg, 179 pmol) was purified by chiral SFC: column Chiral OD-H (250mm x 20mm x 5pm). 30 % MeOH in scCCh. 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.

[0268] Example 38 (l?)-3-(6-(5,6-Dimethoxy-lH-benzo[d]imidazol-l-yl)-3-(l-hydroxyethyl)pyridin-2- yl)benzonitrile

[0269] 3-(6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)-3-(l-hydroxyethyl)pyri din-2 -yl)benzonitrile (obtained as in step 1 of example 37) (60 mg, 179 pmol) was purified by chiral SFC: column

[0270] Chiral OD-H (250mm x 20mm x 5pm). 30 % MeOH in scCCh. 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.

[0271] Example 39 (5)-4-(6-(5,6-Dimethoxy-lH-benzo[d]imidazol-l-yl)-3-(l-hydroxyethyl)pyridin-2- yl)benzonitrile Step 1: 4-(6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)-3-(l-hydroxyethyl)pyridin-2- yl)benzonitrile

[0272] Starting from l-(5-(l -((tert-butyl dimethylsilyl)oxy)ethyl)-6-chloropyridin-2-yl)-5,6-dimethoxy- lH-benzo[d]imidazole (obtained as in step 4 of example 35) (80 mg, 179 pmol, 1 equiv.) with (4-cyanophenyl)boronic acid (39 mg, 268 pmol, 1.5 equiv.) and following the procedure described in step 2 of example 1 with a reaction time of 30 min at 130 °C, the title compound (26 mg, 36.4% yield) was obtained as an off-white solid. LC-MS: m / z = 401.2 [M+H]+, ESI pos. Step 2: (S)-4-(6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)-3-(l-hydroxyethyl)pyridin-2- yl)benzonitrile

[0273] 4-(6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)-3-(l-hydroxyethyl)pyridin-2-yl)benzonitrile (26 mg, 65 pmol) was purified by chiral SFC: column Chiral OD-H (250mm x 20mm x 5pm). 30 % MeOH in scCO?. 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.

[0274] Example 40 (l?)-4-(6-(5,6-Dimethoxy-lH-benzo[d]imidazol-l-yl)-3-(l-hydroxyethyl)pyridin-2- yl)benzonitrile

[0275] 4-(6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)-3-(l-hydroxyethyl)pyridin-2-yl)benzonitrile

[0276] (obtained as in step 1 of example 39) (26 mg, 65 pmol) was purified by chiral SFC: column Chiral OD-H (250mm x 20mm x 5pm). 30 % MeOH in scCCh. 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.

[0277] Example 41 (5)-6-(5,6-Dimethoxy-lH-benzo[d]imidazol-l-yl)-3-(l-hydroxyethyl)-l'-methyl-[2,4'- bipyridin]-2'(l'H)-one

[0278] Step 1 : 6-(5, 6-dimethoxy-lH-benzo[ d]imidazol-l-yl)-3-( 1 -hydroxyethyl)-! ' -methyl- [ 2, 4 '- bipyridin ]-2 '( I 'H)-one

[0279] Starting from l-(5-(l -((tert-butyl dimethylsilyl)oxy)ethyl)-6-chloropyridin-2-yl)-5,6-dimethoxy- lH-benzo[d]imidazole (obtained as in step 4 of example 35) (80 mg, 179 pmol, 1 equiv.) with (l-methyl-2-oxo-l,2-dihydropyridin-4-yl)boronic acid (41 mg, 268 pmol, 1.5 equiv.) and following the procedure described in step 2 of example 1 with a reaction time of 30 min at 130 °C, the title compound (35 mg, 45.8% yield) was obtained as a white lyophilized solid. LC-MS: m / z = 407.2 [M+H]+, ESI pos.

[0280] Step 2: (S)-6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)-3-(l-hydroxyethyl)-l'-methyl-[2,4'- bipyridin ]-2 '( 1 'H)-one

[0281] 6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)-3-(l-hydroxyethyl)-r-methyl-[2,4'-bipyridin]- 2'(l'H)-one (35 mg, 86 pmol) was purified by chiral SFC: column Chiral OD-H (250mm x 20mm x 5um). 30 % MeOH in scCCh. 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. Example 42 (l?)-6-(5,6-Dimethoxy-lH-benzo[d]imidazol-l-yl)-3-(l-hydroxyethyl)-l'-methyl-[2,4'- bipyridin]-2'(l'H)-one

[0282] 6-(5,6-dimethoxy-lH-benzo[d]imidazol-l-yl)-3-(l-hydroxyethyl)-r-methyl-[2,4'-bipyridin]- 2'(l'H)-one (obtained as in step 1 of example 41) (35 mg, 86 pmol) was purified by chiral SFC: column Chiral OD-H (250mm x 20mm x 5pm). 30 % MeOH in scCCh. 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.

[0283] Example 53

[0284] 1- [6- [5-(2-Morpholinoethoxy)benzimidazol-l-yl]-2-phenoxy-3-pyridyl] ethanol

[0285] Intermediate 1: l-(6-chloro-2-phenoxy-3-pyridyl)ethanone

[0286] To a solution of l-(6-chloro-2-fhioro-3-pyridyl)ethanone (CAS# 1260663-13-5, 500 mg, 2.88 mmol, 1 equiv.) in CH3CN (8 mL) were 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 hours. The reaction mixture was concentrated under reduced pressure. The residue was taken in EtOAc and H2O. The aqueous phase was back-extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silicagel, 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.

[0287] Intermediate 2, step 1: 4- [2-(4-nitrophenoxy)ethyl] morpholine

[0288] 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 hours. The reaction mixture was poured into H2O (200 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were dried over anhydrous ISfeSCU, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silicagel, 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. 'H NMR (400 MHz, CD3OD): 5 = 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).

[0289] Intermediate 2, step 2: 4-(2-morpholin-4-ylethoxy)aniline

[0290] 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 at 25 °C for 16 h under H2 (15 psi). The mixture was filtered and the filtrate was concentrated in vacuo to afford the crude title compound (2.7 g, 87.5% yield) as light yellow solid. LC-MS: m / z = 223.1 [M+H]+, ESI pos.

[0291] Intermediate 2, step 3: N-[4-(2-morpholinoethoxy)phenyl] acetamide

[0292] 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. Then the mixture was stirred at 25 °C for 16 h under a nitrogen atmosphere. Then the mixture was poured into H2O (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4, 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. 'H NMR (400 MHz, CDCI3): 8 = 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).

[0293] Intermediate 2, step 4: N-[4-(2-morpholinoethoxy)-2-nitro-phenyl] acetamide

[0294] 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.) was added dropwise nitric acid (2.6 mL, 37.88 mmol, 5.56 equiv.) at 0 °C. The cooling bath was removed and the mixture was stirred at 20 °C for another 1 hours. The mixture was quenched by the careful addition of ice- cold H2O (150 mL). The mixture was then basified by the addition of 1 N NaOH until to pH 9 was reached. This was extracted with EtOAc (4 x 50 mL). The combined organic extracts were dried over anhydrous ISfeSCU, filtered and concentrated in vacuo to afford the crude title compound (1.8 g, 85.4% yield) as a red oil. LC-MS: m / z = 310.1 [M+H]+, ESI pos.

[0295] Intermediate 2, step 5: 4-(2-morpholinoethoxy)-2-nitro-aniline

[0296] To a stirred solution of 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 H2O (5 mL) was added potassium hydroxide (1.63 g, 29.1 mmol, 5 equiv.). The mixture was stirred at 80 °C for 4 hours. The reaction mixture was coold to RT and poured into H2O (100 mL). This was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the crude title compound (1.2 g, 77.1% yield) as red oil. LC-MS: m / z = 268.2 [M+H]+, ESI pos. 'H NMR (400 MHz, CDCI3): 6 = 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).

[0297] Step 1: 1- [6- [4-(2-morpholinoethoxy)-2-nitro-anilino]-2-phenoxy-3-pyridyl] ethanone

[0298] To a stirred solution of 4-(2-morpholinoethoxy)-2-nitro-aniline (intermediate 2 of example 53) (150 mg, 0.56 mmol, 1 equiv.) in 1,4-dioxane (3 mL) were added l-(6-chloro-2-phenoxy-3- pyridyl)ethanone (intermediate 1 of example 53) (139 mg, 0.56 mmol, 1 equiv.), K2CO3 (233 mg, 1.68 mmol, 3 equiv.), Xantphos (130 mg, 0.22 mmol, 0.4 equiv.) and Pd2(dba)3 (103 mg, 0.110 mmol, 0.200 equiv.). The reaction mixture was stirred at 100 °C for 12 hours. The reaction mixture cooled to RT, poured into H2O (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over ISfeSCU, 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.

[0299] Step 2: l-[6-[2-amino-4-(2-morpholinoethoxy)anilino]-2-phenoxy-3-pyridyl] ethanone

[0300] Following the procedure described in step 2, intermediate 2 of example 53, the title compound (160 mg, 94.8% yield) was obtained as light brown solid. LC-MS: m / z = 449.2 [M+H]+, ESI pos.

[0301] Step 3: l-[6-[5-(2-morpholinoethoxy)benzimidazol-l-yl]-2-phenoxy-3-pyridyl] ethanone A solution of l-[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 hours. Then the reaction mixture was stirred at 130 °C for another 24 hours. The reaction mixture was cooled and concentrated to dryness. The residue was suspended in MeOH (10 mL). The solid was collected 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.

[0302] Step 4: l-[6-[5-(2-morpholinoethoxy)benzimidazol-l-yl]-2-phenoxy-3-pyridyl] ethanol

[0303] To a stirred solution of l-[6-[5-(2-morpholinoethoxy)benzimidazol-l-yl]-2-phenoxy-3- pyridyl] ethanone (70 mg, 0.15 mmol, 1 equiv.) in MeOH (2 mL) was added NaBE (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 hours. The reaction mixture was quenched by the addition of saturated aq. NH4CI solution. This was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous ISfeSCU, filtered and concentrated. The crude material was purified by preparative HPLC. Column Phenomenex Gemini -NX C18 (75mm x 30mm x 3 pm). Flow rate 30 mL / min. Gradient: 24% to 54% CH3CN in (10 mM NH4HCO3 in H2O) (8 min) then 100% CH3CN (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. 'H NMR (400 MHz, CD3OD): 5 = 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).

[0304] Example 55 l-[2-Anilino-6-[5-(2-morpholinoethoxy)benzimidazol-l-yl]-3-pyridyl] ethanol

[0305] Step 1: l-(2-anilino-6-chloro-3-pyridyl)ethanone

[0306] To a stirred solution of l-(6-chloro-2-fluoro-3-pyridyl)ethanone (CAS# 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

[0307] DIPEA (796 mg, 5.76 mmol, 2 equiv.). The reaction mixture was then stirred at 80 °C for 20 hours. The reaction mixture was cooled to RT, 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.

[0308] Step 2: l-[2-anilino-6-[4-(2-morpholinoethoxy)-2-nitro-anilino]-3-pyridyl] ethanone

[0309] 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. Step 3: l-[6-[2-amino-4-(2-morpholinoethoxy)anilino]-2-anilino-3-pyridyl] ethanone 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.

[0310] Step 4: l-[2-anilino-6-[5-(2-morpholinoethoxy)benzimidazol-l-yl]-3-pyridyl] ethanone 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.

[0311] Step 5: l-[2-anilino-6-[5-(2-morpholinoethoxy)benzimidazol-l-yl]-3-pyridyl] ethanol

[0312] 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

[0313] Waters Xbridge (150mm x 25mm x 5pm). Flow rate 25 mL / min. Gradient: 29% to 59% CH3CN in (10 mM NH4HCO3 in H2O) (9 min) then 100% CH3CN (0.5 min). 'H NMR (400 MHz, CD3OD): 5 = 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

[0314] (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. Example 62 l-[6-[5-(2-Morpholinoethoxy)benzimidazol-l-yl]-2-[3-(trifluoromethyl)pyrazol-l-yl]-3- pyridyl] ethanol

[0315] Step 1 : l-[ 6-chloro-2-[ 3-( trifluoromethyl)pyrazol-l-yl ]-3-pyridyl ] ethanone

[0316] Following the procedure described in step 1 of example 64, with 3-(trifluoromethyl)pyrazole (400 mg, 2.94 mmol, 1.02 equiv.), the title compound (650 mg, 74% yield) was obtained as a light yellow solid. LC-MS: m / z = 290.1 [M+H]+, ESI pos. 'H NMR (400 MHz, CDCI3): 8 = 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).

[0317] Step 2: l-[ 6-[ 4-(2-morpholinoethoxy)-2-nitro-anilino ]-2-[ 3-(trifluoromethyl)pyrazol-l-yl J-3- pyridyl ethanone

[0318] 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.

[0319] Purification by preparative HPLC: column Phenom enex Gemini -NX C18 (75mm x 30mm x 3pm). Flow rate 25 mL / min. Gradient: 36% to 66% CH3CN in (10 mM NH4HCO3 in H2O) (10 min) then 100% CH3CN (0.5 min). Step 3: l-[ 6-[ 2-amino-4-(2-morpholinoethoxy)anilino ]-2-[ 3-(trifluoromethyl)pyrazol-l-yl ]-3- pyridyl ethanone

[0320] To a mixture of l-[6-[4-(2-morpholinoethoxy)-2-nitro-anilino]-2-[3-(trifluoromethyl)pyrazol-l- yl]-3-pyridyl]ethanone (200 mg, 0.38 mmol, 1 equiv.) and NH4CI (205 mg, 3.83 mmol, 9.97 equiv.) in EtOH (10 mL) and H2O (3 mL) was added Fe (108 mg, 1.93 mmol, 5.03 equiv.) in three portions at 20 °C. When the addition of Fe was complete, the resulting mixture was stirred at 50 °C for 16 hours. The black mixture was cooled to RT 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. 'H NMR (400 MHz, CDCI3): 5 = 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).

[0321] Step 4: l-[6-[5-(2-morpholinoethoxy)benzimidazol-l-yl]-2-[3-(trifluoromethyl)pyrazol-l-yl]-3- pyridyl ethanone

[0322] To a solution of l-[6-[2-amino-4-(2-morpholinoethoxy)anilino]-2-[3-(trifluoromethyl)pyrazol-l- yl]-3-pyridyl]ethanone (180 mg, 0.37 mmol, 1 equiv.) in EtOH (5 mL) were 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 hour. The mixture was then cooled to RT and concentrated in vacuo. The residue was taken in DCM (20 mL) and washed with sat. aq. NaHCOs. Sol. (20 mL). The organic layer was concentrated to dryness to afford the crude title compound (120 mg, 65.3% yield) as a light yellow solid. LC-MS: m / z = 501.2 [M+H]+, ESI pos. 'H NMR (400 MHz, CDCI3): 8 = 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).

[0323] Step 5: l-[6-[5-(2-morpholinoethoxy)benzimidazol-l-yl]-2-[3-(trifluoromethyl)pyrazol-l-yl]-3- pyridyl ethanol l-[6-[5-(2-morpholinoethoxy)benzimidazol-l-yl]-2-[3-(trifluoromethyl)pyrazol-l-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. NaBLL (15 mg, 0.4 mmol, 4 equiv.) was added protion-wise. The resulting mixture was stirred at 5 °C for 1 hour. The mixture was quenched by the addition of 5 drops of sat. aq. NH4CI sol., then formic acid was added until pH 7 was reached. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC: column Phenom enex Gemini -NX Cl 8 (75mm x 30mm x 3pm). 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. 'H NMR (400 MHz, CD3OD): 5 = 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). Example 63 l-[6-(5,6-Dimethoxybenzimidazol-l-yl)-2-[3-(trifluoromethyl)pyrazol-l-yl]-3- pyridyl] ethanol Step 1: l-[6-(5,6-dimethoxybenzimidazol-l-yl)-2-[3-(trifluoromethyl)pyrazol-l-yl]-3- pyridyl ] ethanone

[0324] To a solution of l-[6-chloro-2-[3-(trifluoromethyl)pyrazol-l-yl]-3-pyridyl]ethanone (obtained as in step 1 of example 62) (100 mg, 0.35 mmol, 1 equiv.) and 5,6-dimethoxy-lH-benzimidazole (62 mg, 0.35 mmol, 1 equiv. )in CH3CN (5 mL) were 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 (three times). The mixture was then stirred at 70 °C for 16 h under N2 atomosphere. The mixture then was cooled to 20 °C and filtered. The filtrate was purified directly purified by preparative HPLC: column Phenomenex Gemini-NX C18 (75mm x 30mm x 3pm). 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 light yellow solid. LC-MS: m / z = 431.1 [M+H]+, ESI pos. Step 2: l-[6-(5,6-dimethoxybenzimidazol-l-yl)-2-[3-(trifluoromethyl)pyrazol-l-yl]-3- pyridyl ethanol

[0325] Following the procedure described in step 5 of example 62, the title compound (8.5 mg, 39.7% yield) was obtained as a light yellow solid. Purification by preparative HPLC: column Phenomenex Gemini-NX C18 (75mm x 30mm x 3pm). 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. 'H NMR (400 MHz, CD3OD): 5 = 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).

[0326] Example 64

[0327] 1- [3-(l-Hydroxyethyl)-6- [5- [(6-methylpyridazin-3-yl)amino] benzimidazol-l-yl]-2-pyridyl]- 5-methyl-pyrazole-3-carbonitrile

[0328] Intermediate 1 : N-( 6-methylpyridazin-3-yl)-lH-benzimidazol-5-amine

[0329] A 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 hours. The dark brown suspension was concentrated in vacuo and the residue was triturated in MeOH (60 mL). The solid was collected by filtration and it was 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 brown solid. LC-MS: m / z = 226.0 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-t / 6): 5 = 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).

[0330] Step 1 : l-(3-acetyl-6-chloro-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile

[0331] A solution of l-(6-chloro-2-fluoro-3-pyridyl)ethanone (CAS# 1260663-13-5, 5 g, 28.81 mmol, 1 equiv.), 5-methyl-lH-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 hours. The reaction mixture was cooled to RT, poured into H2O (250 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (3 x 300mL) 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 yellow oil. LC-MS: m / z = 261.1 [M+H]+, ESI pos.

[0332] Step 2: l-[ 3-acetyl-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2-pyridyl -5- methyl-pyrazole-3-carbonitrile and l-[ 3-acetyl-6-[ 6-[ ( 6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl / -2 -pyridyl ]-5-methyl-pyrazole-3-carbonitrile

[0333] A mixture of l-(3-acetyl-6-chloro-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile (5.3 g, 20.33 mmol, 1 equiv.), N-(6-methylpyridazin-3-yl)-lH-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 hours. The mixture was cooled to RT and poured into H2O (500 mL). A solid precipitated out. This was extracted with EtOAc (3 x 400 mL). The combined organic layers were concentrated. The residue was purified by preparative HPLC: column Phenom enex Luna C18 (250mm x 70 mm x 15pm. Flow rate 140 mL / min. Gradient: 20% to 50% CH3CN in (H2O with 0.225% formic acid v / v) (35 min) then 100% CH3CN (1 min). A mixture of the 2 title compounds was obtained. This mixture was purified by preparative NPLC: column Welch Ultimate XB-SiOH (250mm x 70mm x lOum). Flow rate 140 mL / min. Gradient: 20% to 60% EtOH in hexane (20 min) then 100% EtOH (3 min) to yield l-[3-acetyl-6-[6-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (1.1 g, 12% yield) as a light brown solid and l-[3-acetyl-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (600 mg, 6.6% yield) as light brown solid. Regioisomer 1 : LC-MS: m / z = 450.1 [M+H]+, ESI pos.JH NMR (400 MHz, DMSO-t / e) 5 = 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). Regioisomer 2: LC-MS: m / z = 450.1 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-t / 6) 6 = 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).

[0334] Step 3: l-[ 3-( 1 -hydroxyethyl)-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl -2- pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0335] To a solution of l-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-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 NaBLL (151 mg, 3.99 mmol, 2.99 equiv.) at 0 °C. Stirring at 0 °C was continued for 1 hour. DMF (5 mL) was added to the mixture which was stirred at 20 °C for 2 hours. The mixture was cooled again to 0 °C and NaBJLj (76 mg, 2 mmol, 1.5 equiv.) was added. The cooling bath was removed and stirring at RT was continued for 2 hours. The reaction mixture was quenched by the slow addition of H2O (50 mL) and then extracted with DCM (2 x 50 mL). The combined organic extracts were concentrated under vacuum. The residue was purified by preparative HPLC: column Waters Xbridge (150mm x 25mm x 5pm). 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 liophilized solid. LC-MS: m / z = 452.2 [M+H]+, ESI pos.

[0336] Example 65 l-[3-(l-Hydroxyethyl)-6-[5-(4-methylpiperazin-l-yl)benzimidazol-l-yl]-2-pyridyl]-5- methyl-pyrazole-3-carbonitrile

[0337] Step 1: l-[3-acetyl-6-(5-bromobenzimidazol-l-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile and l-[ 3-acetyl-6-( 6-bromobenzimidazol-l-yl)-2 -pyridyl ]-5-methyl-pyrazole-3-carbonitrile

[0338] To a solution of 5-bromo-lH-benzimidazole (1.51 g, 7.67 mmol, 1 equiv.) in DMSO (15 mL) were added l-(3-acetyl-6-chloro-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile (obtained as in step 1 of example 64) (2.0 g, 7.67 mmol, 1 equiv.) and K^CCh (1.51 g, 15.34 mmol, 2 equiv.) . The mixture was stirred at 60 °C for 2 hours. The reaction mixture was cooled to RT, poured into H2O (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL) and concentrated under vacuum. 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 (150mm x 40mm x 15pm). Flow rate: 60 mL / min. Gradient: 53% to 63% CH3CN in (H2O with 0.225% formic acid v / v) (10 min) then 100% CH3CN (2 min) to yield l-[3-acetyl-6-(5- bromobenzimidazol-l-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (750 mg, 23.2% yield) as a light yelow liophilized solid and compound l-[3-acetyl-6-(6-bromobenzimidazol-l-yl)-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile (400 mg, 12.4% yield) as a light yellow lyophilized solid. Regioisomer 1 : LC-MS: m / z = 421.0 [M+H]+, ESI pos. 'H NMR (400 MHz, CDC13) 8 = 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). Regioisomer 2: LC-MS: m / z = 421.0 [M+H]+, ESI pos. 'H NMR (400 MHz, CDCI3) 6 = 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).

[0339] Step 2: l-[3-acetyl-6-[5-(4-methylpiperazin-l-yl)benzimidazol-l-yl]-2-pyridyl]-5-methyl- pyrazole-3-carbonitrile

[0340] To a solution of 1 -methylpiperazine (71 mg, 0.710 mmol, 2 equiv.) in 1,4-dioxane (5 mL) were added l-[3-acetyl-6-(5-bromobenzimidazol-l-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (150 mg, 0.36 mmol, 1 equiv.), CS2CO3 (348 mg, 1.07 mmol, 3 equiv.) and t-Buxphos-Pd-G3 (CAS # 1447963-75-8) (28 mg, 0.04 mmol, 0.1 equiv.). The grey suspension was stirred at 90 °C for 4 h under N2 atmosphere. The reaction mixture was cooled to RT, poured into H2O (20 mL) and extracted with EtOAc (2 x 30 mL). The combined extracts were concentrated under vacuum. 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. Step 3: l-[3-(l-hydroxyethyl)-6-[5-(4-methylpiperazin-l-yl)benzimidazol-l-yl]-2-pyridyl]-5- methyl-pyrazole-3-carbonitrile

[0341] To a stirred solution of l-[3-acetyl-6-[5-(4-methylpiperazin-l-yl)benzimidazol-l-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 NaBTLj (8 mg, 0.2 mmol, 3 equiv.) at 0 °C. Stirring at 0 °C was continued for 1 hour. The reaction mixture was quenched by the addition of H2O (10 mL). DCM (10 mL) was added to the reaction mixture. The aqueous phase was back-extracted with DCM (2 x 10 mL). The combined organic extracts were concentrated under vacuum. The residue was purified by prep-HPLC: column Waters Xbridge (150mm x 25mm x 5pm). Flow rate: 25 mL / min. Gradient: 25% to 55% CH3CN in (lOmM NH4HCO3 in H2O) (10 min) then 100% CH3CN (2 mmin). 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. 'H NMR (400 MHz, CD3OD): 5 = 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).

[0342] Example 67 l-[3-(l-Hydroxyethyl)-6-[5-[4-(oxetan-3-yl)piperazin-l-yl]benzimidazol-l-yl]-2-pyridyl]-5- methyl-pyrazole-3-carbonitrile Step 1 : l-[ 3-acetyl-6-[5-[ 4-(oxetan-3-yl)piperazin-l-yl ]benzimidazol-l-yl / -2 -pyridyl ]-5-methyl- pyrazole-3-carbonitrile

[0343] Following the procedure described in step 2 of example 65, starting with l-(oxetan-3- yl)piperazine (101 mg, 0.71 mmol, 2 equiv.) and using H2O (0.06 mL, 3.56 mmol, 10 equiv.) as 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.

[0344] Step 2: l-[ 3-( I -hydroxyethyl)-6-[5-[ 4-(oxetan-3-yl)piperazin-l-yl ]benzimidazol-l-yl -2- pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0345] Following the procedure described in step 3 of example 65, at a temperature of -40 °C and a reaction time of 30 min, 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.

[0346] Purification by preparative HPLC: column Pheomenex Gemini-NX C18 (75mm x 30mm x 3pm). Flow rate: 30 mL / min. Gradient: 15% to 45% CH3CN in (lOmM NH4HCO3 in H2O) (8 min) then 100% CH3CN (2 min). 'H NMR (400 MHz, CD3OD): 5 = 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). Example 68 l-[3-(l-Hydroxyethyl)-6-[5-(2-morpholinoethoxy)benzimidazol-l-yl]-2-pyridyl]-5-methyl- pyrazole-3-carbonitrile Step 1: l-[3-acetyl-6-[5-(2-morpholinoethoxy)benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole- 3-carbonitrile

[0347] Starting with of 2-morpholinoethanol (124 mg, 0.95 mmol, 2 equiv.) and following the procedure described in step 2 of example 65, the title compound (30 mg, 13.4% yield) was obtained as yellow oil. LC-MS: m / z = 472.3 [M+H]+, ESI pos.

[0348] Step 2: l-[ 3-( 1 -hydroxyethyl)-6-[5-(2-morpholinoethoxy)benzimidazol-l-yl ]-2-pyridyl -5- methyl-pyrazole-3-carbonitrile

[0349] Following the procedure described in step 3 of example 65, at -40 °C for 2 h, then at -10 °C for 10 min, the title compound (6.8 mg, 22.6% yield) was obtained as a white lyophilized solid. LC-

[0350] MS: m / z = 474.3 [M+H]+, ESI pos. Purification by preparative HPLC: column Waters Xbridge (150mm x 25mm x 5pm). Flow rate: 25 mL / min. Gradient: 28% to 58% CH3CN in (lOmM NH4HCO3 in H2O) (10 min) then 100% CH3CN (2 min). 'H NMR (400 MHz, CD3OD): 5 = 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).

[0351] Example 71 l-[3-(l-Hydroxyethyl)-6-[5-[[l-(oxetan-3-yl)pyrazol-4-yl]amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0352] Step 1: l-[6-(5-bromobenzimidazol-l-yl)-3-(l-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile

[0353] Starting from l-[3-acetyl-6-(5-bromobenzimidazol-l-yl)-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile (obtained as in step 1 of example 65) (750 mg, 1.78 mmol, 1 equiv.) and following the procedure described in step 3 of example 65, the crude (after extraction work-up) title compound (750 mg, 99.5% yield) was obtained as an off-white solid. LC-MS: m / z = 425.0 [M+H]+, ESI pos. 'H NMR (400 MHz, CDC13): 8 = 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). Step 2: l-[ 3-( 1 -hydroxyethyl)-6-[5-[[ l-(oxetan-3-yl)pyrazol-4-yl ] amino ]benzimidazol-l-yl ]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0354] To a solution of l-[6-(5-bromobenzimidazol-l-yl)-3-(l-hydroxyethyl)-2-pyridyl]-5-methyl- pyrazole-3 -carbonitrile (100 mg, 0.24 mmol, 1 equiv.) in 1,4-dioxane (5 mL) were added l-(3- oxetanyl)-lH-pyrazol-4-amine (39 mg, 0.280 mmol, 1.2 equiv.), CS2CO3 (154 mg, 0.47 mmol, 2 equiv.) and RuPhos-Pd-G3 (20 mg, 0.02 mmol, 0.1 equiv.). The reaction mixture was stirred for 4 hours at 100 °C under N2 atmosphere. The mixture was cooled to RT, diluted with MeOH (20 mL), treated with thiourea resin and stirred at RT for 16 hours. The mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by preparative HPLC: column Phenomenex Luna C18 (150mm x 25mm x 10pm). 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. 'H NMR (400 MHz, CD3OD): 5 = 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).

[0355] Example 72

[0356] 1- [6- [5- [ [l-(Azetidin-3-yl)pyrazol-4-yl] amino] benzimidazol- 1-yl] -3-(l-hydroxyethyl)-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile Step 1: tert-butyl 3-[4-[[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(l-hydroxyethyl)-2- pyridyl ]benzimidazol-5-yl amino ]pyrazol-l-yl azetidine- 1 -carboxylate

[0357] To a solution of l-[6-(5-bromobenzimidazol-l-yl)-3-(l-hydroxyethyl)-2-pyridyl]-5-methyl- pyrazole-3 -carbonitrile (140 mg, 0.33 mmol, 1 equiv.) in 1,4-dioxane (5 mL) were added tertbutyl 3 -(4-aminopyrazol-l-yl)azetidine-l -carboxylate (95 mg, 0.4 mmol, 1.2 equiv.), CS2CO3 (216 mg, 0.66 mmol, 2 equiv.) and RuPhos-Pd-G3 (28 mg, 0.03 mmol, 0.1 equiv.). The reaction mixture was heated to 100 °C and stirred for 4 hours under N2 atmosphere. The reaction mixture was poured into H2O (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organics were washed with brine (2 x 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.

[0358] Step 2: l-[ 6-[5-[[l -(azetidin-3-yl)pyrazol-4-yl amino ]benzimidazol-l-yl ]-3-( I -hydroxyethyl)-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0359] To a solution of tert-butyl 3-[4-[[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(l-hydroxyethyl)-2- pyridyl]benzimidazol-5-yl]amino]pyrazol-l-yl]azetidine-l-carboxylate (140 mg, 0.24 mmol, 1 equiv.) in DCM (2 mL) was added HC1 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 Phenom enex Luna C18 (150mm x 25mm x 10pm). Flow rate: 25 mL / min. Gradient: 6% to 36% CH3CN 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. 'H NMR (400 MHz, DMSO-t / 6): 8 = 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).

[0360] Example 74 l-[3-(l-Hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxybenzimidazol-l-yl]-2-pyridyl]-5- methyl-pyrazole-3-carbonitrile

[0361] Step 1: l-(2-trimethylsilylethoxymethyl)benzimidazol-5-ol

[0362] A mixture of lH-benzimidazol-5-ol (1.0 g, 7.45 mmol, 1 equiv.), 2-(trimethylsilyl)ethoxym ethyl 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 minutes, and then at 40 °C for 16 hours. More 2- (trimethylsilyl)ethoxymethyl chloride (0.66 mL, 3.73 mmol, 0.5 equiv.) was added and stirring at 40 °C was continued for 12 hours. The reaction mixture was cooled to RT, quenched with H2O (150 mL) and extracted with DCM (3 x 50 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 (600 mg, 30.4% yield) was obtained as a yellow oil. LC-MS: m / z = 265.1 [M+H]+, ESI pos.

[0363] Step 2: trimethyl- [ 2-[ [5-( 6-methylpyridazin-3-yl)oxybenzimidazol-l-yl / methoxy ] ethyl ] silane A mixture of l-(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 sirred at 140 °C for 12 hours. The mixture was cooled to RT, quenched with H2O (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue which 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.

[0364] Step 3: 5-(6-methylpyridazin-3-yl)oxy-lH-benzimidazole

[0365] A solution of trimethyl-[2-[[5-(6-methylpyridazin-3-yl)oxybenzimidazol-l- 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 hours. The reaction mixture was quenched with H2O (10 mL) and extracted with EtOAc (3 x 10 mL). The aqueous layer was freeze-dried to give the title compound (900 mg, TFA salt) as a yellow gum. This product was taken in DCM (100 mL) and treated with K2CO3. Stirring at at 30 °C was continued for 2 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified by preparative HPLC: column Waters Xbridge (150mm x 25mm x 5pm). Flow rate: 25 mL / min. Gradient: 1% to 33% CH3CN in (10 mM NH4HCO3 in H2O) (9 min) then 100% CH3CN (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.

[0366] Step 4: l-[ 3-acetyl-6-[5-( 6-methylpyridazin-3-yl)oxybenzimidazol-l-yl ]-2-pyridyl ]-5-methyl- pyrazole-3-carbonitrile and l-[ 3-acetyl-6-[ 6-( 6-methylpyridazin-3-yl)oxybenzimidazol-l-yl -2- pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0367] Following the procedure described in step 2 of example 64 and with a reaction time of 3 hours.

[0368] Purification by preparative HPLC: column Phenomenex Synergi C18 (150mm x 25mm x 10pm). Flow rate: 25 mL / min. Gradient: 30% to 60% CH3CN in (0.225% formic acid in H2O v / v) (8.5 min) then 100% CH3CN (2 min). Further purification by chiral SFC performed to separate the 2 regioisomers (Daicel Chiralpak AD (250mm x 30mm x 10pm), flow rate: 80 mL / min. 70% (0.1% NH4OH in MeOH) to yield l-[3-acetyl-6-[5-(6-methylpyridazin-3-yl)oxybenzimidazol-l- yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (38 mg, 11% yield) as a white lyophilized solid and l-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxybenzimidazol-l-yl]-2-pyridyl]-5-methyl- pyrazole-3 -carbonitrile (44 mg, 12.7% yield) as white lyophilized solid. Regioisomer 1 : LC-MS: m / z = 451.1 [M+H]+, ESI pos. 'H NMR (400 MHz, CD3OD): 5 = 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). Regioisomer 2: LC-MS: m / z = 451.1 [M+H]+, ESI pos. 'H NMR (400 MHz, CD3OD): 5 = 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).

[0369] Step 5: l-[ 3-( 1 -hydroxyethyl)-6-[ 6-( 6-methylpyridazin-3-yl)oxybenzimidazol-l-yl ]-2-pyridyl ]-5- methyl-pyrazole-3-carbonitrile

[0370] To a solution of l-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxybenzimidazol-l-yl]-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile (10 mg, 0.02 mmol, 1 equiv.) in Methanol (3 mL) was added NaBH4 (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 (150mm x 25mm x 10pm). Flow rate: 25 mL / min. Gradient: 28% to 58% CH3CN in (0.225% formic acid in H2O v / v) (8.5 min) then 100% CH3CN (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. 'H NMR (400 MHz, CD3OD): 5 = 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). Example 75 l-[3-(l-Hydroxyethyl)-6-[5-(6-methylpyridazin-3-yl)oxybenzimidazol-l-yl]-2-pyridyl]-5- methyl-pyrazole-3-carbonitrile

[0371] Starting from l-[3-acetyl-6-[5-(6-methylpyridazin-3-yl)oxybenzimidazol-l-yl]-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile (obtained as in step 4 of example 74) (38 mg, 0.08 mmol, 1 equiv.) 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 (150mm x 25mm x 10pm). Flow rate: 25 mL / min. Gradient: 28% to 58% CH3CN in (0.225% formic acid in H2O v / v) (8.5 min) then 100% CH3CN (2 min). LC-MS: m / z = 453.1 [M+H]+, ESI pos. 'H NMR (400 MHz, CD3OD): 5 = 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= 92 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).

[0372] Example 76

[0373] 5- [3-(l-Hydroxyethyl)-6- [5- [(6-methylpyridazin-3-yl)amino] benzimidazol-l-yl]-2-pyridyl]- l-methyl-pyrazole-4-carbonitrile

[0374] Step 1: l-(2-chloro-6-fluoro-3-pyridyl)ethanone

[0375] A mixture of 3-bromo-2-chloro-6-fluoro-pyridine (5.0 g, 23.76 mmol, 1 equiv.), tributyl(l- ethoxyvinyl)tin (10.3 g, 28.51 mmol, 1.2 equiv.), K2CO3 (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- di oxane (80 mL) and H2O (5 mL) was stirred at 100 °C for 12 hours under N2 atmosphere. The reaction mixture was cooled to RT, poured into sat. aq. KF sol. (50 mL) and stirred for 2 hours. The mixture was then extracted with EtOAc (3 x 20 mL). The combined organic layers were treated with 2N HC1 (20 mL) and the mixture was stirred for 2 hours. Then the mixture was basified by the addition of aqueous ISfeCCL until pH 8 was reached. The layers were separated. The aqueous phase was extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. 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. 'H NMR (400 MHz, CDCI3): 5 = 8.13 (dd, J= 7.6, 8.3 Hz, 1H), 6.98 (dd, J= 3.3, 8.4 Hz, 1H), 2.72 (s, 3H).

[0376] Step 2: l-[2-chloro-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3- pyridyl ethanone

[0377] A solution of l-(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)-lH- benzimidazol-5-amine (obtained as in intermediate 1 of example 64) (2.47 g, 10.95 mmol, 1 equiv.) in DMSO (30 mL) was stirred at 60 °C for 12 hours. The reaction mixture was cooled to rt, poured into H2O (100 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative NPLC: column Welch Ultimate XB-SiOH (250mm x 70mm x 10pm). Flow rate: 140 mL / min. Gradient: 10% to 50% EtOH in hexane (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. 'H NMR (400 MHz, DMSO-t / 6): 8 = 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).

[0378] Step 3: 5-[ 3-acetyl-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2-pyridyl ]-l- methyl-pyrazole-4-carbonitrile

[0379] To a solution of l-[2-chloro-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3- pyridyl] ethanone (100 mg, 0.26 mmol, 1 equiv.) in 1,4-dioxane (6 mL) and H2O (0.3 mL) were added l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole-4-carbonitrile (92 mg, 0.4 mmol, 1.5 equiv.), ISfeCCL (84 mg, 0.79 mmol, 3 equiv.) and PdC^dppff CJbCh (43 mg, 0.05 mmol, 0.200 equiv.). The brown reaction mixture was stirred at 100 °C for 8 h under N2 atmosphere. The reaction mixture was cooled to rt, poured into H2O (10 mL) and extracted with EtOAc (3 x 40 mL). The combined organic layers were dried over ISfeSCU, 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.

[0380] Step 4: 5-[ 3-(l -hydroxyethyl)-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2- pyridyl]-l-methyl-pyrazole-4-carbonitrile

[0381] Following the procedure described in example 75, with a reaction time of 1 h, the title compound (2.2 mg, 9.9% yield) was obtained as light yellow lyophilized solid. Purification by preparative HPLC: column Phenomenex Luna C18 (150mm x 25mm x 10pm). 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. 'HNMR (400 MHz, CD3OD): 5 = 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).

[0382] Example 77 l-[3-(l-Hydroxyethyl)-6-[5-[(3R)-3-hydroxypyrrolidin-l-yl]benzimidazol-l-yl]-2-pyridyl]- 5-methyl-pyrazole-3-carbonitrile; formic acid

[0383] Step 1: l-[6-(5-bromobenzimidazol-l-yl)-3-(l-hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile

[0384] To a suspension of l-[3-acetyl-6-(5-bromobenzimidazol-l-yl)-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile (obtained as in step 1 of example 65) (750 mg, 1.78 mmol, 1 equiv.) in MeOH (10 mL) and THF (10 mL) was added NaBT (202 mg, 5.34 mmol, 3 equiv.) at 0 °C. The mixture was stirred at 0 °C for 1 hour. The reaction mixture was then diluted with H2O (100 mL) and extracted with EtOAc (5 x 100 mL. The combined organics were washed with brine (2 x 100 mL), dried (ISfeSCL), 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.JH NMR (400 MHz, CDCI3): 8 = 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). Step 2: l-[3-(l-hydroxyethyl)-6-[5-[(3R)-3-hydroxypyrrolidin-l-yl]benzimidazol-l-yl]-2- pyridyl ]-5-methyl-pyrazole-3-carbonitrile; formic acid

[0385] Following the procedure described in step 2 of example 71, with (R)-3 -hydroxypyrrolidine (0.02 mL, 0.26 mmol, 1.1 equiv.), the title compound (17.3 mg, 16.2% yield) was obtained as yellow lyophilized solid. Purification by prep-HPLC: column Phenomenex Luna C18 (150mm x 25mm x 10pm). Flow rate: 25 mL / min. Gradient: 15% to 45% CH3CN in (0.225% formic acid in H2O v / v) (10 min) then 100% CH3CN (2 min). LC-MS: m / z = 430.1 [M+H]+, ESI pos. 'H NMR (400 MHz, CD3OD): 5 = 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, = 6.5 Hz, 3H).

[0386] Example 78 l-[3-(l-hydroxyethyl)-6-[5-[(3S)-3-hydroxypyrrolidin-l-yl]benzimidazol-l-yl]-2-pyridyl]-5- methyl-pyrazole-3-carbonitrile; formic acid

[0387] Following the procedure described in step 2 of example 71, with (S)-3 -hydroxypyrrolidine (0.02 mL, 0.260 mmol, 1.1 equiv.), the title compound (21.6 mg, 18.1% yield) was obtained as yellow lyophilized solid. Purification by prep-HPLC: column Phenomenex Luna C18 (150mm x 25mm x 10pm). Flow rate: 25 mL / min. Gradient: 15% to 45% CH3CN in (0.225% formic acid in H2O v / v) (10 min) then 100% CH3CN (2 min). LC-MS: m / z = 430.1 [M+H]+, ESI pos. 'H NMR (400 MHz, CD3OD): 5 = 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, = 6.5 Hz, 3H).

[0388] Example 81

[0389] 1- [3-(l-Hydroxyethyl)-6- [5- [(6-methyl-3-pyridyl)amino] benzimidazol-l-yl]-2-pyridyl]-5- methyl-pyrazole-3-carbonitrile

[0390] Step 1 : l-[ 3-acetyl-6-[5-[ ( 6-methyl-3-pyridyl)amino ]benzimidazol-l-yl ]-2-pyridyl ]-5-methyl- pyrazole-3-carbonitrile

[0391] Argon was bubbled for 5 min through a suspension of l-[3-acetyl-6-(5-bromobenzimidazol-l- yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (obtained as in 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 CS2CO3 (85 mg, 0.262 mmol, 3 equiv.) at RT in 1,4-dioxane (1.2 mL). Then tBuXphos-Pd-G3 (7 mg, 0.009 mmol, 0.1 equiv.) was added, the vial was sealed, the mixture was then heated to 90 °C and stirring was continued for 4 hours. More tBuXphos-Pd-G3 (7 mg, 0.009 mmol, 0.1 equiv.) was added and the mixture was stirred for another 4 h at 90 °C. The reaction mixture was cooled to RT, adsorbed on silica gel and directly purified by flash chromatography (12 g silica gel, 0% to 100% [DCM / MeOH 9: 1] in DCM). The isolated product was purified again by flash chromatography (10g 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. Step 2: l-[ 3-( 1 -hydroxyethyl)-6-[5-[ ( 6-methyl-3-pyridyl)amino ]benzimidazol-l-yl ]-2-pyridyl ]-5- methyl-pyrazole-3-carbonitrile To a solution of l-[3-acetyl-6-[5-[(6-methyl-3-pyridyl)amino]benzimidazol-l-yl]-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile (22 mg, 0.041 mmol, 1 equiv.) in MeOH (1 mL) was added NaBE (5 mg, 0.123 mmol, 3 equiv.) at 0 °C. The mixture was stirred at 0 °C for 30 min. The reaction mixture was quenched at 0 °C with NH4CI aq. sat. sol. and extracted with DCM. The organic layer was dried over MgSC , filtered and concentrated in vacuo. The residue was adsorbed on silica gel and purified by flash chromatography (4 g silica gel, 0% to 100% [DCM / MeOH 9: 1] in DCM). The title compound (11 mg, 58.8% yield) was obtained as a light yellow solid. LC-MS: m / z = 451.3 [M+H]+, ESI pos.

[0392] Example 82 l-[3-(l-Hydroxyethyl)-6-[5-[(5-methylpyrazin-2-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5- methyl-pyrazole-3-carbonitrile

[0393] Step 1: l-[ 3-acetyl-6-[5-[ (5-methylpyrazin-2-yl)amino ]benzimidazol-l-yl ]-2-pyridyl ]-5-methyl- pyrazole-3-carbonitrile

[0394] Following the procedure described in step 1 of example 81, with (5-methylpyrazin-2-yl)amine (19 mg, 0.175 mmol, 2 equiv.), the title compound (12 mg, 29% yield) was obtained as a yellow solid. LC-MS: m / z = 450.2 [M+H]+, ESI pos. Step 2: l-[ 3-( 1 -hydroxyethyl)-6-[5-[ (5-methylpyrazin-2-yl)amino ]benzimidazol-l-yl ]-2-pyridyl / - 5-methyl-pyrazole-3-carbonitrile

[0395] 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. Example 83

[0396] 1- [3-(l-Hydroxyethyl)-6- [5- [(5-methylpyrimidin-2-yl)amino] benzimidazol-l-yl]-2-pyridyl]- 5-methyl-pyrazole-3-carbonitrile Step 1: l-[3-acetyl-6-[5-[(5-methylpyrimidin-2-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5- methyl-pyrazole-3-carbonitrile

[0397] Following the procedure described in step 1 of example 81, with (5-methylpyrimidin-2-yl)amine (27 mg, 0.237 mmol, 2 eq), the title compound (14.1 mg, 25.6% yield) was obtained as a light yellow solid. LC-MS: m / z = 450.2 [M+H]+, ESI pos.

[0398] Step 2: l-[ 3-( 1 -hydroxyethyl)-6-[5-[ (5-methylpyrimidin-2-yl)amino ]benzimidazol-l-yl ]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0399] To a mixture of l-[3-acetyl-6-[5-[(5-methylpyrimidin-2-yl)amino]benzimidazol-l-yl]-2-pyridyl]- 5-methyl-pyrazole-3-carbonitrile (14 mg, 0.031 mmol, 1 eq) in MeOH (0.4 mL) was added NaBE (3 mg, 0.076 mmol, 3 eq) at 0 °C. The mixture was stirred at 0 °C for 15 min. Then THF (0.4 mL) was added to the mixture which turned to a clear solution. Stirring at 0 °C was continued for another 15 min. The reaction mixture was quenched at 0 °C with NH4CI aq. sat. sol. and extracted with DCM. The organic layer was dried over MgSCh, filtered and concentrated in vacuo. The residue was adsorbed on silica gel and purified by flash chromatography (4 g silica gel, 0% to 100% [DCM / MeOH 9: 1] in DCM). 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.

[0400] Example 84 l-[3-(l-hydroxyethyl)-6-[5-[(5-methyl-2-pyridyl)amino]benzimidazol-l-yl]-2-pyridyl]-5- methyl-pyrazole-3-carbonitrile

[0401]

[0402] Step 1: l-[3-acetyl-6-[5-[(5-methyl-2-pyridyl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl- pyrazole-3-carbonitrile Following the procedure described in step 1 of example 81, with (5-methyl-2-pyridyl)amine (26 mg, 0.237 mmol, 2 equiv.), the title compound (27.5 mg, 46.5% yield) was obtained as a yellow solid. LC-MS: m / z = 449.2 [M+H]+, ESI pos.

[0403] Step 2: l-[ 3-( 1 -hydroxyethyl)-6-[5-[ (5 -me thy 1-2 -pyridyl) amino ]benzimidazol-l-yl ]-2-pyridyl ]-5- methyl-pyrazole-3-carbonitrile

[0404] To a mixture of l-[3-acetyl-6-[5-[(5-methyl-2-pyridyl)amino]benzimidazol-l-yl]-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile (27 mg, 0.061 mmol, 1 equiv.) in MeOH (0.8 mL) and THF, extra dry (0.8 mL) was added NaBEL (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 at 0 °C with NH4CI aq. sat. sol. and extracted with DCM. The organic layer was dried over MgSCh, filtered and concentrated in vacuo. The residue was adsorbed on silica gel and purified by flash chromatography (4 g silica gel, 0% to 100% [DCM / MeOH 9: 1] in DCM). The title compound (21 mg, 72.2% yield) was obtained as a light yellow solid. LC-MS: m / z = 451.4 [M+H]+, ESI pos. Example 85 l-[2-(l,l-dioxo-l,2-thiazolidin-2-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl] -3-pyridyl] ethanol

[0405] Step 1: l-[6-chloro-2-(l, 1 -dioxo- l,2-thiazolidin-2-yl)-3-pyridyl] ethanone

[0406] To a solution of l-(6-chloro-2-fluoro-3-pyridyl)ethanone (CAS# 1260663-13-5, 500 mg, 2.88 mmol, 1 equiv.) in DMSO (10 mL) were added isothiazolidine 1,1-dioxide (349 mg, 2.88 mmol, 1 equiv.) and added K2CO3 (1.19 g, 8.64 mmol, 3 equiv.). The mixture was stirred at 30 °C for 2 hours. The mixture poured into H2O (30 mL) and extracted with EtOAc (3 x 15 mL). The combined organic extracts were washed with brine (3 x 15 mL), dried over anhydrous ISfeSCU, 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 light red solid. LC-MS: m / z = 274.8 [M+H]+, ESI pos.

[0407] Step 2: l-[2-(l,l-dioxo-l,2-thiazolidin-2-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol- 1-yl / -3-pyridyl ethanone and l-[ 2-( 1, 1 -dioxo- 1, 2-thiazolidin-2-yl)-5-[ 6-[ ( 6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl / -3-pyridyl ethanone To a solution of l-[6-chloro-2-(l,l-dioxo-l,2-thiazolidin-2-yl)-3-pyridyl]ethanone (460 mg, 1.67 mmol, 1 equiv.) in DMSO (10 mL) were added N-(6-methylpyridazin-3-yl)-lH-benzimidazol-5- amine (obtained as in intermediate 1 of 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 hours. The mixture was directly purified by preparative HPLC: column Waters Xbridge C18 (150mm x 50mm x 10pm). 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 2 title compounds (150 mg) was isolated. Further purification by chiral SFC (Daicel Chiralpak AD (250mm x 30mm x 10pm). Flow rate: 70 mL / min. 50% (1% NH4OH in isopropanol) to yield l-[2-(l,l-dioxo-l,2- thiazolidin-2-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-pyridyl]ethanone (55 mg, 7.1% yield) as a brown solid and l-[2-(l,l-dioxo-l,2-thiazolidin-2-yl)-5-[6-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-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. 'H NMR (400 MHz, CDCI3): 5 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.

[0408] Step 3: l-[2-(l,l-dioxo-l,2-thiazolidin-2-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol- 1-yl ]-3-pyridyl ethanol

[0409] To a solution of l-[2-(l,l-dioxo-l,2-thiazolidin-2-yl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-pyridyl]ethanone (45 mg, 0.1 mmol, 1 equiv.) in MeOH (3 mL) was added NaBT (112 mg, 0.29 mmol, 3 equiv.) at 0°C. The reaction mixture was stirred at 0 °C for 30 minutes. The mixture was quenched with saturated NH4CI (5 mL) at 0 °C and extracted with DCM (2 x 10 mL). The combined organics were dried over ISfeSCL, filtered and concentracted under reduce pressure. The crude product was purified by preparative HPLC: column Phenomenex Gemini-NX (75mm x 30mm x 30pm). Flow rate: 30 mL / min. Gradient: 10% to 40% CH3CN in (10 mM NH4HCO3 in H2O) (8 min) then 100% CH3CN (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. 'H NMR (400 MHz, CD3OD): 5 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).

[0410] Example 86

[0411] 1- [3-(l-Hydroxyethyl)-6- [5- [(2-methylpyrimidin-5-yl)amino] benzimidazol-l-yl]-2-pyridyl]- 5-methyl-pyrazole-3-carbonitrile Step 1: l-[3-acetyl-6-[5-[(2-methylpyrimidin-5-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5- methyl-pyrazole-3-carbonitrile

[0412] Following the procedure described in step 1 of example 81, with (2-methylpyrimidin-5-yl)amine (26 mg, 0.237 mmol, 2 equiv.), the title compound (41.5 mg, 70% yield) was obtained as a yellow solid. LC-MS: m / z = 450.3 [M+H]+, ESI pos.

[0413] Step 2: l-[ 3-( 1 -hydroxyethyl)-6-[5-[ (2-methylpyrimidin-5-yl)amino ]benzimidazol-l-yl -2- pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0414] 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.

[0415] Example 87 l-[3-(l-Hydroxyethyl)-6-[5-(pyridazin-4-ylamino)benzimidazol-l-yl]-2-pyridyl]-5-methyl- pyrazole-3-carbonitrile

[0416] Step 1: l-[3-acetyl-6-[5-(pyridazin-4-ylamino)benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole- 3-carbonitrile

[0417] Following the procedure described in step 1 of example 81, with pyridazin-4-ylamine (23 mg, 0.237 mmol, 2 equiv.), the title compound (8.9 mg, 16.4% yield) was obtained as a yellow solid. LC-MS: m / z = 436.3 [M+H]+, ESI pos.

[0418] Step 2: l-[ 3-( 1 -hydroxyethyl)-6-[5-(pyridazin-4-ylamino)benzimidazol-l-yl ]-2-pyridyl -5- methyl-pyrazole-3-carbonitrile

[0419] Following the procedure described in step 2 of example 84, the title compound (4.1 mg, 43% yield) was obtained as a light yellow solid. LC-MS: m / z = 438.2 [M+H]+, ESI pos.

[0420] Example 88 1- [3-(l-Hydroxyethyl)-6- [5- [(6-methoxypyridazin-3-yl)amino] benzimidazol- 1-yl] -2- pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0421] Step 1 : l-[ 3-acetyl-6-[5-[ ( 6-methoxypyridazin-3-yl)amino ] benzimidazol- 1-yl / -2 -pyridyl ]-5- methyl-pyrazole-3-carbonitrile

[0422] Following the procedure described in step 1 of example 81, with (6-methoxypyridazin-3- yl)amine (30 mg, 0.237 mmol, 2 equiv.), the title compound (59.7 mg, 97.3% yield) was obtained as a yellow solid. LC-MS: m / z = 466.3 [M+H]+, ESI pos.

[0423] Step 2: l-[ 3-( I -hydroxyethyl)-6-[5-[ ( 6-methoxypyridazin-3-yl)amino ] benzimidazol- 1-yl ]-2- pyridyl ]-5-methyl-pyrazole-3-carbonitrile

[0424] Following the procedure described in step 2 of example 84, the title compound (38.3 mg, 67.4% yield) was obtained as a light yellow solid. LC-MS: m / z = 468.3 [M+H]+, ESI pos.

[0425] Example 89 l-[3-(l-Hydroxyethyl)-6-[5-(pyridazin-3-ylamino)benzimidazol-l-yl]-2-pyridyl]-5-methyl- pyrazole-3-carbonitrile

[0426] Step 1: l-[3-acetyl-6-[5-(pyridazin-3-ylamino)benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole- 3-carbonitrile

[0427] Following the procedure described in step 1 of example 81, with pyridazin-3-ylamine (23 mg, 0.237 mmol, 2 equiv.), the title compound (15.3 mg, 26.6% yield) was obtained as a yellow solid. LC-MS: m / z = 436.3 [M+H]+, ESI pos.

[0428] Step 2: l-[ 3-( 1 -hydroxyethyl)-6-[5-(pyridazin-3-ylamino)benzimidazol-l-yl ]-2-pyridyl -5- methyl-pyrazole-3-carbonitrile

[0429] Following the procedure described in step 2 of example 84, the title compound (9.1 mg, 65% yield) was obtained as a light yellow solid. LC-MS: m / z = 438.3 [M+H]+, ESI pos.

[0430] Example 90 1- [6- [5- [[6-(Difluoromethyl)pyridazin-3-yl]amino] benzimidazol-l-yl]-3-(l-hydroxyethyl)-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0431] Step 1: l-[3-acetyl-6-[5-[[ 6-(difluoromethyl)pyridazin-3-yl] amino] benzimidazol-l-yl] -2- pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0432] Following the procedure described in step 1 of example 81, with [6-(difluoromethyl)pyridazin-3- yl]amine (35 mg, 0.237 mmol, 2 equiv.), the title compound (35.2 mg, 55% yield) was obtained as a light yellow solid. LC-MS: m / z = 486.3 [M+H]+, ESI pos.

[0433] Step 2: l-[ 6-[5-[[ 6-(difluoromethyl)pyridazin-3-yl amino ] benzimidazol-l-yl ]-3-( I - hydroxyethyl)-2-pyridyl ]-5-methyl-pyrazole-3-carbonitrile

[0434] Following the procedure described in step 2 of example 84, the title compound (15.4 mg, 47% yield) was obtained as a light yellow solid. LC-MS: m / z = 488.2 [M+H]+, ESI pos.

[0435] Example 93

[0436] 1- [6- [6-Fluoro-5- [(6-methylpyridazin-3-yl)amino] benzimidazol-l-yl]-3-(l-hydroxyethyl)-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0437] Step 1: N-(2-fluoro-4,5-dinitro-phenyl)-6-methyl-pyridazin-3-amine

[0438] To a solution of l,2-difluoro-4,5-dinitro-benzene (1.0 g, 4.9 mmol, 1 equiv.) in DMSO (12 mL) were 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 hours. The reaction mixture was poured into H2O (100 mL). A solid precipitated out. 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.

[0439] Step 2: 6-fluoro-N-( 6-methylpyridazin-3-yl)-lH-benzimidazol-5-amine To a solution of N-(2-fluoro-4,5-dinitro-phenyl)-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 at 30 °C for 16 h under H2 (45 psi). The mixture was filtered and the filtrate was concentrated in vacuo. The residue was poured into MeOH (30 mL). A solid precipitated out. The solid was collected by filtration, washed with MeOH and dried to give a first crop of the title compound (480 mg). The filtrate was concentrated and the residue was purified by preparative HPLC: column Phenomenex Luna C18 (250mm x 70mm x 10pm). Flow rate: 80 mL / min. Gradient: 1% to 30% CH3CN in (0.225% formic acid in H2O v / v) (20 min) then 100% CH3CN (5 min). A second crop of the 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. 'H NMR (400 MHz, DMSO-t / 6): 8 = 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).

[0440] Step 3: l-[ 3-acetyl-6-[ 6-fluoro-5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2- pyridyl ]-5-methyl-pyrazole-3-carbonitrile and l-[ 3-acetyl-6-[5-fluoro-6-[ ( 6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl / -2 -pyridyl ]-5-methyl-pyrazole-3-carbonitrile

[0441] To a solution of 6-fluoro-N-(6-methylpyridazin-3-yl)-lH-benzimidazol-5-amine (930 mg, 3.82 mmol, 1 equiv.) in DMSO (20 mL) were added l-(3-acetyl-6-chloro-2-pyridyl)-5-methyl- pyrazole-3 -carbonitrile (obtained as in 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 hours. The mixture was then poured into H2O (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (3 x 15 mL), dried over anhydrous ISfeSCU, filtered and concentrated. The residue was purified by preparative NPLC: column Welch Ultimate-XB-SiOH (250mm x 70mm x 10pm). Flow rate: 140 mL / min. Gradient: 20% to 60% EtOH in hexane (20 min) then 100% EtOH (4 min) to yield l-[3-acetyl-6-[6-fluoro-5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (200 mg, 11.2% yield) as a yellow solid and l-[3-acetyl-6-[5-fluoro-6-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (500 mg, 28% yield) as a yellow solid. Regioisomer 1 : LC-MS: m / z = 468.1 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-t / e): 8 = 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). Regioisomer 2: LC-MS: m / z = 468.1 [M+H]+, ESI pos. 'H NMR (400 MHz, CD3OD): 5 = 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).

[0442] Step 6: l-[ 6-[ 6-fluoro-5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-3-( 1 -hydroxyethyl)- 2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0443] To a solution of l-[3-acetyl-6-[6-fluoro-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-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 NaBJL (49 mg, 1.28 mmol, 3 equiv.) at 0°C. The reaction mixture was stirred at 0 °C for 30 minutes. The mixture was quenched with saturated NH4CI (5 mL) at 0 °C and extracted with DCM (2 x 10 mL). The combined organic layers were dried over ISfeSCU, filtered and concentracted under reduce pressure. The residue was purified by preparative HPLC: column Phenomenex Synergi C18 (150mm x 25mm x 10pm). Flow rate: 25 mL / min. Gradient: 8% to 38% CH3CN 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. 'H NMR (400 MHz, CD3OD): 5 = 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). Example 94

[0444] 1- [6- [5-Fluoro-6- [(6-methylpyridazin-3-yl)amino] benzimidazol-l-yl]-3-(l-hydroxyethyl)-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0445] Following the procedure described in step 6 of example 93, using MeOH (3 mL) as 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 (75mm x 30mm x 3pm). Flow rate: 30 mL / min. Gradient: 18% to 48% CH3CN in (10 mM NH4HCO3 in H2O) (8 min) then 100% CH3CN (2 min). LC-MS: m / z = 470.2 [M+H]+, ESI pos. 'HNMR (400 MHz, CD3OD): 5 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).

[0446] Example 97

[0447] 1- [6- [5- [(6-Methylpyridazin-3-yl)amino] benzimidazol- 1-yl] -2- [3-(trifluoromethyl)-4, 5,6,7- tetrahydropyrazolo [4, 3-c] pyridin-l-yl]-3-pyridyl] ethanol

[0448] Step 1: tert-butyl l-(3-acetyl-6-chloro-2-pyridyl)-3-(trifluoromethyl)-6, 7-dihydro-4H- pyrazolo[ 4, 3-c ]pyridine-5-carboxylate

[0449] To a solution of l-(6-chloro-2-fhioro-3-pyridyl)ethanone (CAS# 1260663-13-5, 500 mg, 2.88 mmol, 1 equiv.) in DMSO (8 mL) were added DIPEA (745 mg, 5.76 mmol, 2 equiv.) and tertbutyl 3-(trifluoromethyl)-l,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 hours. The mixture was cooled to rt, poured into H2O (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were concentracted and the residue was purified by flash chromatography (silica gel, 20% EtOAc in petroleum ether). The title (1.11 g, 86.6% yield) was obtained as a light yellow oil. LC-MS: m / z = 389.0 [M+H]+, ESI pos. 'H NMR (400 MHz, CDCI3): 8 = 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).

[0450] Step 2: tert-butyl l-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl] -3 -(trifluoromethyl) -6, 7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate and tertbutyl l-[ 3-acetyl-6-[ 6-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl / -2 -pyridyl J-3-

[0451] (trijluoromethyl)-6, 7-dihydro-4H-pyrazolo [4, 3-c] pyridine-5-carboxylate

[0452] Following the procedure described in step 3 of example 76, with a reaction time of 72 h at 50 °C, the crude material was purified by preparative NPLC: column Welch Ultimate XB-CN (250mm x 70mm x 10pm). 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 (3 min) to yield tert-butyl l-[3-acetyl-6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-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 l-[3- acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-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. ‘H NMR (400 MHz, CD3OD): 5 = 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). Regioisomer 2: LC-MS: m / z = 634.3 [M+H]+, ESI pos. 'H NMR (400 MHz, CD3OD): 5 = 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).

[0453] Step 3: l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-[3-(trifluoromethyl)- 4, 5, 6, 7-tetrahydropyrazolo[ 4, 3-c ]pyridin-l-yl (-3-pyridyl (ethanone; hydrochloride

[0454] 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. Step 4: l-[ 6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl (-2-[ 3 -(trifluor ome thy I) - 4, 5, 6, 7-tetrahydropyrazolo[ 4, 3-c ]pyridin-l-yl (-3-pyridyl (ethanol

[0455] 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 (150mm x 25mm x 5pm). Flow rate: 25 mL / min. Gradient: 21% to 51% CH3CN in (10 mM NH4HCO3 in H2O) (10 min) then 100% CH3CN (2 min). LC-MS: m / z = 536.2 [M+H]+, ESI pos. 'H NMR (400 MHz, CD3OD): 5 = 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= 92 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).

[0456] Example 98

[0457] 1- [6- [6- [(6-Methylpyridazin-3-yl)amino] benzimidazol- 1-yl] -2- [3-(trifluoromethyl)-4, 5,6,7- tetrahydropyrazolo [4,3-c] pyridin-l-yl]-3-pyridyl] ethanol

[0458] Step 1 : l-[ 6-[ 6-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2-[ 3 -(trifluor ome thy I) - 4,5, 6, 7-tetrahydropyrazolo[4,3-c]pyridin-l-yl] -3-pyridyl] ethanone; hydrochloride Following the procedure described in step 2 of example 72, using tert-butyl l-[3-acetyl-6-[6-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-3-(trifluoromethyl)-6,7-dihydro-4H- pyrazolo[4,3-c]pyridine-5-carboxylate (obtained as in step 2 of example 97) (1.4 g, 2.20 mmol, 1 equiv.), the crude title compound (1.12 g, 95% yield) was obtained as a light brown solid. LC- MS: m / z = 534.2 [M+H]+, ESI pos. Step 2: l-[6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-[3-(trifluoromethyl)- 4, 5, 6, 7-tetrahydropyrazolo[ 4, 3-c ]pyridin-l-yl / -3-pyridyl (ethanol 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 (150mm x 25mm x 10pm). Flow rate: 25 mL / min. Gradient: 2% to 32% CH3CN in (0.225% formic acid in H2O v / v) (8.5 min) then 100% CH3CN (2 min). LC-MS: m / z = 536.2 [M+H]+, ESI pos. 'H NMR (400 MHz, CD3OD): 5

[0459] = 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). Example 103

[0460] 1- [3-(l-Hydroxyethyl)-6- [5- [(5-methyl- 1 ,3,4-oxadiazol-2-yl)amino] benzimidazol- 1-yl] -2- pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0461] Step 1: l-[3-acetyl-6-[5-[(5-methyl-l ,3,4-oxadiazol-2-yl)amino]benzimidazol-l-yl] -2-pyridyl] - 5-methyl-pyrazole-3-carbonitrile

[0462] According to the procedure described in step 1 of example 81, with (5-methyl-l,3,4-oxadiazol-2- yl)amine (25 mg, 0.237 mmol, 2 equiv.), the title compound (15.4 mg, 28.6% yield) was obtained as a light yellow solid. LC-MS: m / z = 440.3 [M+H]+, ESI pos. Step 2: l-[ 3-( 1 -hydroxyethyl)-6-[5-[ (5-methyl-l, 3, 4-oxadiazol-2-yl)amino ]benzimidazol-l-yl ]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0463] 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.

[0464] Example 104

[0465] 2- [3-(l-Hydroxyethyl)-6- [5- [(6-methylpyridazin-3-yl)amino] benzimidazol-l-yl]-2-pyridyl]- 5-methyl-pyrazole-3-carbonitrile Step 1: 2-(3-acetyl-6-chloro-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile l-(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 (250mm x 30 mm x 5pm). 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.; ‘H NMR (600 MHz, CDC13): 8 = 7.83 (d, J= 8.0 Hz, 1H), 7.42 (d, J

[0466] = 8.0 Hz, 1H), 6.89 (s, 1H), 2.35 (s, 3H), 2.28 (s, 3H). Step 2: 2-[ 3-acetyl-6-(5-bromobenzimidazol-l-yl)-2-pyridyl ]-5-methyl-pyrazole-3-carbonitrile and 2-[ 3-acetyl-6-( 6-bromobenzimidazol-l-yl)-2 -pyridyl ]-5-methyl-pyrazole-3-carbonitrile

[0467] 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-lH-benzimidazole (354 mg, 1.76 mmol, 1.0 equiv.) in DMSO (9 mL) was added l,8-diazabicyclo[5.4.0]undec-7-ene (402 mg, 398 pL, 2.64 mmol, 1.5 equiv.). The reaction mixture was stirred at 23 °C for 24 hours. The mixture was poured into H2O and extracted with EtOAc. The organic layer was dried over MgSCU, filtered and concentrated in vacuo. The crude material was purified by flash chromatogaphy (25 g silica gel, 0% to 100% [DCM:MeOH 9: 1] in DCM). Further purification by chiral SFC was required for the separation of the regioisomers (Chiral OZ-H (250mm x 20 mm x 5 pm). 50% (0.2% di ethylamine) in MeOH) to give 2-[3-acetyl-6-(5-bromobenzimidazol-l-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-l-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. 'H NMR (600 MHz, DMSO- e): 5 = 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) Regioisomer 2: LC-MS: m / z = 421.0 [M+H]+, ESI pos. 'H NMR (600 MHz, DMSO-t / e): 5 = 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).

[0468] Step 3: 2-[ 3-acetyl-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2-pyridyl ]-5- methyl-pyrazole-3-carbonitrile Argon was bubbled for 5 min through a suspension of 2-[3-acetyl-6-(5-bromobenzimidazol-l- 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 CS2CO3 (116 mg, 0.356 mmol, 3.0 equiv.) at RT in 1,4-dioxane (1.2 mL). Then [tBuBrettPhos Pd(allyl)]OTf (17 mg, 0.024 mmol, 0.2 equiv.) was added, the vial was sealed, the mixture was then heated to 80 °C and stirring was continued for 2 hours. The reaction mixture was cooled to RT, adsorbed on silica gel and directly purified by flash chromatography (12 g silica gel, 0% to 100% [DCM / MeOH 9: 1] in DCM). 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. Step 4: 2-[3-(l-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0469] Following the procedure described in step 2 of example 84, the title compound (11.3 mg, 30.2% yield) was obtained as an off-white solid. LC-MS: m / z = 452.3 [M+H]+, ESI pos. Example 105

[0470] (3R)-l-[3-(l-Hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]pyrrolidine-3-carbonitrile Step 1 : (3R)-l-[3-(l -hydroxyethyl)-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2- pyridyl]pyrrolidine-3-carbonitrile

[0471] To a solution of l-(6-chloro-2-fhioro-3-pyridyl)ethanone (CAS# 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 hours. The mixture was poured into H2O (50 mL) and extracted with EtOAc (3 x 50 mL x 3). The combined organic layers were washed with brine( 100 mL) and concentrated under vacuum. 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 light green oil. LC-MS: m / z = 250.1 [M+H]+, ESI pos.

[0472] Step 2: (3R)-l-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl ]pyrrolidine-3-carbonitrile and ( 3R)-l-[ 3-acetyl-6-[ 6-[ ( 6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl / -2 -pyridyl ]pyrrolidine-3-carbonitrile

[0473] 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) were added N-(6-methylpyridazin-3-yl)-lH-benzimidazol-5- amine (obtained as in intermediate 1 of example 64) (498 mg, 2.21 mmol, 1.2 equiv.) and K2CO3 (764 mg, 5.53 mmol, 3 equiv.). The brown suspension was then stirred at 80 °C for 16 hours. The mixture was cooled to RT, poured into H2O (80 mL) and extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine, dried over ISfeSCU, filtered and concentrated in vacuo. The residue was purified by preparative NPLC (Welch Ultimate XB-CN (250mm x 70mm x lOum). Flow rate 140 mL / min. Gradient: 55% to 95% EtOH in hexane (12 min) then 100% EtOH (5 min)) to give (3R)-l-[3-acetyl-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]pyrrolidine-3-carbonitrile (250 mg, 30.9% yield) as a yellow solid and (3R)-l-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]pyrrolidine-3-carbonitrile (250 mg, 30.9% yield) as a yellow solid. Regioisomer 1 : LC- MS: m / z = 439.1 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-t / 6): 8 = 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). Regioisomer 2: LC-MS: m / z = 439.1 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-t / 6): 6 = 9.54 (d, J = 1.7 Hz, 1H), 9.31 (s, 1H), 8.90 (s, 1H), 8.31 (d, .7= 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, 7 = 7.0 Hz, 1H).

[0474] Step 3: (3R)-l-[ 3-( 1 -hydroxyethyl)-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2- pyridyl]pyrrolidine-3-carbonitrile

[0475] 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 (150mm x 25mm x 5pm). Flow rate: 25 mL / min. Gradient: 25% to 55% CH3CN in (10 mM NH4HCO3 in H2O) (8 min) then 100% CH3CN (2 min)). LC-MS: m / z = 441.1 [M+H]+, ESI pos.JH NMR (400 MHz, DMSO-t / 6): 6 = 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).

[0476] Example 106 (3R)-l-[3-(l-Hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]pyrrolidine-3-carbonitrile

[0477] Following the procedure described in step 2 of example 98, starting with (3R)-l-[3-acetyl-6-[6- [(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]pyrrolidine-3-carbonitrile (obtained in step 2 of example 105-A) (250 mg, 0.6 mmol, 1 equiv.), the title compound (115 mg, 44.2% yield) was obtained as a yellow solid. Purification by preparative HPLC (Waters Xbridge (150mm x 25mm x 5pm). Flow rate: 25 mL / min. Gradient: 23% to 53% CH3CN in (10 mM NH4HCO3 in H2O) (10 min) then 100% CH3CN (2 min)). LC-MS: m / z = 441.1 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-t / 6): 8 = 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).

[0478] Example 107 l-[2-(3,5-Dimethylpyrazol-l-yl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3- pyridyl] ethanol; formic acid

[0479] Step 1 : l-[ 6-chloro-2-( 3, 5-dimethylpyrazol-l-yl)-3-pyridyl ] ethanone A solution of 3,5-dimethylpyrazole (200 mg, 2.08 mmol, 1 equiv.), l-(6-chloro-2-fluoro-3- pyridyl)ethanone (CAS# 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 hours, then at 50 °C for another 4 hours, then at 80 °C for another 4 hours and then at 100 °C for another 14 hours. The reaction mixture was cooled to RT, quenched with H2O (30 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over Na2SO4, 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. 'H NMR (400 MHz, CDCI3): 6 = 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).

[0480] Step 2: l-[ 2-(3, 5-dimethylpyrazol-l-yl)-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l- yl] -3-pyridyl ethanone and l-[ 2-( 3, 5-dimethylpyrazol-l-yl)-6-[ 6-[ ( 6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl / -3-pyridyl ethanone

[0481] A solution of l-[6-chloro-2-(3,5-dimethylpyrazol-l-yl)-3-pyridyl]ethanone (280 mg, 1.12 mmol, 1 equiv.), N-(6-methylpyridazin-3-yl)-lH-benzimidazol-5-amine (308 mg, 1.37 mmol, 1.22 equiv.) and K2CO3 (476 mg, 3.44 mmol, 3.07 equiv.) in DMSO (3 mL) was stirred at 50 °C for 16 hours, then at 80 °C for 4 hours. The reaction mixture was cooled to RT, quenched with H2O (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative NPLC (Welch Ultimate XB-CN (250mm x 50mm x 10pm). Flow rate: 100 mL / min. Gradient: 30% to 70% EtOH in hexane (15 min) then 100% EtOH (5 min)) to give l-[2- (3,5-dimethylpyrazol-l-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3- pyridyl] ethanone (90 mg, 18.3% yield) as a brown solid and l-[2-(3,5-dimethylpyrazol-l-yl)-6- [6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-pyridyl]ethanone (90 mg, 18.3% yield) as a brown solid. Regioisomer 1 : LC-MS: m / z = 439.0 [M+H]+, ESI pos.JH NMR (400 MHz, CDCI3): 8 = 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). Regioisomer 2: LC-MS: m / z = - Ill -

[0482] 439.0 [M+H]+, ESI pos. 'H NMR (400 MHz, CD30D): 5 = 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).

[0483] Step 3: l-[ 2-(3, 5-dimethylpyrazol-l-yl)-6-[ 6-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l- yl] -3-pyridyl ethanol

[0484] To a solution of l-[2-(3,5-dimethylpyrazol-l-yl)-6-[6-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-pyridyl]ethanone (80 mg, 0.18 mmol, 1 equiv.) in MeOH (1 mL) and DCM (9 mL) was added NaBH4 (21 mg, 0.56 mmol, 3.04 equiv.) at 0 °C. The reaction mixture was stirred at 0 °C for 15 minutes. The mixture was quenched with H2O (30 mL) and extracted with DCM (3 x 15 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was by preparative HPLC (Phenomenex Luna C18 (150mm x 25mm x 10pm). Flow rate: 25 mL / min. Gradient: 7% to 37% CH3CN in (0.225% formic acid in H2O v / v) (10 min) then 100% CH3CN (2 min)). The title compound (30.4 mg, 37.8% yield) was obtained as a light yellow liophilized solid. LC-MS: m / z = 441.3 [M+H]+, ESI pos. 'H NMR (400 MHz, CD3OD): 5 = 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).

[0485] Example 108 l-[2-(3,5-Dimethylpyrazol-l-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3- pyridyl] ethanol; formic acid

[0486] Following the procedure described in step 3 of example 107, starting with l-[2-(3,5- dimethylpyrazol-l-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3- pyridyl] ethanone (80 mg, 0.18 mmol, 1 equiv.), the title compound (42.1 mg, 52.4% yield) was obtained as a light yellow solid. Purification by preparative HPLC (Phenom enex Luna Cl 8 (150mm x 25mm x 10pm). Flow rate: 25 mL / min. Gradient: 7% to 37% CH3CN in (0.225% formic acid in H2O v / v) (10 min) then 100% CH3CN (2 min)). LC-MS: m / z = 441.3 [M+H]+, ESI pos. 'H NMR (400 MHz, CD3OD): 5 = 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).

[0487] Example 109 5-Methyl-l- [6- [5- [(6-methylpyridazin-3-yl)amino] benzimidazol-l-yl]-3-[(l S)-l- hydroxy ethyl] -2-pyridyl] pyrazole-3-carbonitrile l-[3-(l-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile (obtained as in step 3 of example 64) (400 mg, 0.89 mmol, 1 equiv.) was purified by chiral SFC (Daicel Chiralpak AY-H (250mm x 30mm x 10pm). Flow rate: 70 mL / min. 60% (0.1% NH4OH 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. 'H NMR (400 MHz, CD3OD): 5 = 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).

[0488] Assignment of the absolute configuration of the stereogenic carbon was performed by Mosher ester analysis: 3.6 mg (8.0 pmol) of alcohol were dissolved in CDCI3 and 2.9 pl of pyridine (36.3 pmol, 7 equiv.), were added followed by of (A -Mosher chloride ((A)-a-Methoxy-a- trifluoromethylphenylacetyl chloride, 7.6 pl, 40.2 umol, 5.0 equiv.) for the formation of the corresponding (S -Mosher ester. Comparison with the 'H-NMR spectrum (COSY) of example 110 by overlay shows an upfield shift of the C2-m ethyl group hence indicating an (5)- configuration of the alcohol.

[0489] Example 110 5-Methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-[(lR)-l- hydroxy ethyl] -2-pyridyl] pyrazole-3-carbonitrile l-[3-(l-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile (obtained as in step 3 of example 64) (400 mg, 0.89 mmol, 1 equiv.) was purified by chiral SFC (Daicel Chiralpak AY-H (250mm x 30mm x 10pm). 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.JH NMR (400 MHz, CD3OD): 5 = 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).

[0490] Assignment of the absolute configuration of the stereogenic carbon was performed by Mosher ester analysis: 1.5 mg (3.3 pmol) of alcohol were dissolved in CDCI3 and 1.9 pl of pyridine (23.8 pmol, 7 equiv.), were added followed by of (A -Mosher chloride ((A)-a-Methoxy-a- trifluoromethylphenylacetyl chloride, 3.1 pl, 16.5 umol, 5.0 equiv.) for the formation of the corresponding (S -Mosher ester. Comparison with the 'H-NMR spectrum (COSY) of example 109 by overlay shows a downfield shift of the C2-methyl group hence indicating an (Reconfiguration of the alcohol. Example 111 l-[3-(l-Hydroxyethyl)-6-[5-[(5-methyl-l,3,4-thiadiazol-2-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0491] Step J: l-[3-acetyl-6-[5-[(5-methyl-l ,3,4-thiadiazol-2-yl)amino]benzimidazol-l-yl] -2-pyridyl] - 5-methyl-pyrazole-3-carbonitrile

[0492] According to the procedure described in step 3 of example 104, with (5-methyl-l,3,4-thiadiazol- 2-yl)amine (27 mg, 0.237 mmol, 2 equiv.), the title compound (41.3 mg, 73.8% yield) was obtained as an off-white solid. LC-MS: m / z = 456.3 [M+H]+, ESI pos. Step 2: l-[ 3-( 1 -hydroxyethyl)-6-[5-[ (5-methyl-l, 3, 4-thiadiazol-2-yl)amino ]benzimidazol-l-yl -2- pyridyl]-5-methyl-pyrazole-3-carbonitrile Following the procedure described in step 2 of example 84, the title compound (9 mg, 21% yield) was obtained as a light yellow solid. LC-MS: m / z = 458.3 [M+H]+, ESI pos.

[0493] Example 113 l-[3-(l-Hydroxyethyl)-6-[5-[[l-(oxetan-3-yl)-4-piperidyl]oxy]benzimidazol-l-yl]-2-pyridyl]- 5-methyl-pyrazole-3-carbonitrile

[0494] Step 1: 4-(3,4-dinitrophenoxy)-l-(oxetan-3-yl)piperidine l-(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), then potassium tert-butoxide (4.28 g, 38.17 mmol, 1.2 equiv.) was added and the mixture was stirred at 30 °C for 12 hours. The reaction mixture was then poured into H2O (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over ISfeSCU, filtered and concentrated under reduced pressure. The residue was first purified by flash chromatography (silica gel, 10% MeOH in DCM). The isolated material was then purified by preparative HPLC (Kromasil Eternity XT (250mm x 80mm x 10pm). Flow rate: 100 mL / min. Gradient: 35% to 65% CH3CN in (10 mM NH4HCO3 in H2O) (18 min) then 100% CH3CN (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.

[0495] Step 2: 4-[[ l-(oxetan-3-yl)-4-piperidyl] oxy] benzene- 1,2-diamine

[0496] To a solution of 4-(3,4-dinitrophenoxy)-l-(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 at 40 °C for 16 h under H2 (50 psi). 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.

[0497] Step 3: 5-[[l-(oxetan-3-yl)-4-piperidyl]oxy]-lH-benzimidazole

[0498] A suspension of 4-[[l-(oxetan-3-yl)-4-piperidyl]oxy]benzene-l,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 hours. The reaction mixture was cooled to RT and quenched with 1 N HC1 (1.5 mL) and THF (1.5 mL). The mixture was then stirred at 30 °C for 12 hours. The pH of the reaction mixture was adjusted to 7 by the addition of 1 N HC1. The mixture was extracted with EtOAc (2 x 15 mL). The combined organic layers were concentrated under reduced pressure. The crude title (800 mg, 96.3% yield) was obtained as a light brown solid. LC-MS: m / z = 274.1 [M+H]+, ESI pos.

[0499] Step 4: l-[3-acetyl-6-[5-[[ l-(oxetan-3-yl)-4-piperidyl] oxy]benzimidazol-l-yl] -2-pyridyl] -5- methyl-pyrazole-3-carbonitrile and l-[ 3-acetyl-6-[ 6-[[ l-(oxetan-3-yl)-4- piperidyl ]oxy]benzimidazol-l-yl / -2-pyridyl ]-5-methyl-pyrazole-3-carbonitrile

[0500] To a solution of 5-[[l-(oxetan-3-yl)-4-piperidyl]oxy]-lH-benzimidazole (400 mg, 1.46 mmol, 1 equiv.) in DMSO (8 mL) were added l-(3-acetyl-6-chloro-2-pyridyl)-5-methyl-pyrazole-3- carbonitrile (obtained as in 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 hours. The mixture was then poured into H2O (20 mL) and extracted with EtOAc (3 x 25 mL). The combined organic extracts were washed with brine (3 x 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 l-[3-acetyl-6-[5-[[l-(oxetan-3-yl)-4- piperidyl]oxy]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (Rf 0.55, UV detection) (50 mg, 6.9% yield) as a light yellow oil and l-[3-acetyl-6-[6-[[l-(oxetan-3-yl)-4- piperidyl]oxy]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (Rf 0.6, UV detection) (50 mg, 6.9% yield) as a light yellow solid.. Regioisomer 1 : LC-MS: m / z = 498.2 [M+H]+, ESI pos. 'H NMR (400 MHz, CDC13): 8 = 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). Regioisomer 2: LC-MS: m / z = 498.2 [M+H]+, ESI pos. 'H NMR (400 MHz, CDCI3): 5 = 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).

[0501] Step 5: l-[ 3-( 1 -hydroxyethyl)-6-[5-[ [ 1 -(oxetan-3-yl)-4-piperidyl ]oxy]benzimidazol-l-yl -2- pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0502] To a clear light brown solution of l-[3-acetyl-6-[5-[[l-(oxetan-3-yl)-4- piperidyl]oxy]benzimidazol-l-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 NaBH4 (11 mg, 0.3 mmol, 3 equiv.) at 0 °C . Stirring at 0 °C was continued for 1 hours. The mixture was quenched with saturated NH4CI (5 mL) at 0 °C and extracted with EtOAc (2 x 10 mL). The combined organic layers were dried over Na2SO4, filtered and concentracted under reduced pressure. The residue was purified by preparative HPLC: column Waters Xbridge (150mm x 25mm x 5pm). Flow rate: 25 mL / min. Gradient: 25% to 55% CH3CN in (10 mM NH4HCO3 in H2O) (9 min) then 100% CH3CN (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. ‘H NMR (400 MHz, CD3OD): 5 = 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). Example 114 l-[3-(l-Hydroxyethyl)-6-[6-[[l-(oxetan-3-yl)-4-piperidyl]oxy]benzimidazol-l-yl]-2-pyridyl]-

[0503] 5-methyl-pyrazole-3-carbonitrile Following the procedure described in step 5 of example 113, starting with l-[3-acetyl-6-[6-[[l- (oxetan-3-yl)-4-piperidyl]oxy]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (obtained in step 4 of example 113) (50 mg, 0.1 mmol, 1 equiv.) and using MeOH (2.5 mL) as solvent, the title compound (17 mg, 33.9% yield) was obtained as an off-white lyophilized solid. Purificationby preparative HPLC (Waters Xbridge (150mm x 25mm x 5pm). Flow rate: 25 mL / min. Gradient: 22% to 52% CH3CN in (10 mM NH4HCO3 in H2O) (9 min) then 100% CH3CN (2 min)). LC-MS: m / z = 508.2 [M+H]+, ESI pos. 'H NMR (400 MHz, CD3OD): 5 = 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).

[0504] Example 115

[0505] 1- [3-(l-Hydroxyethyl)-6- [5- [(6-methylpyridazin-3-yl)amino] benzimidazol- 1-yl] -2- pyridyl] pyrazole-3-carbonitrile Step 1: l-(3-acetyl-6-chloro-2-pyridyl)pyrazole-3-carbonitrile

[0506] A solution of lH-pyrazole-3-carbonitrile (200 mg, 2.15 mmol, 1 equiv.), l-(6-chloro-2-fluoro-3- pyridyl)ethanone (CAS# 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 hours. The reaction mixture was quenched with H2O (30 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over Na2SO4, 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. 'H NMR (400 MHz, CDCI3): 8 = 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).

[0507] Step 2: l-[ 3-acetyl-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2-pyridyl Jpyrazole- 3-carbonitrile

[0508] Following the procedure described in step 4 of example 113, with N-(6-methylpyridazin-3-yl)- lH-benzimidazol-5-amine (obtained as in intermediate 1 of example 64) (319 mg, 1.42 mmol, 1.2 equiv.), the crude material was obtained and then first purified by preparative HPLC (Phenomenex Luna C18 (150mm x 25mm x 10pm). Flow rate: 25 mL / min. Gradient: 11% to 41% CH3CN in (0.225% formic acid in H2O v / v) (10 min) then 100% CH3CN (2 min)). Additional purifiaction by preparative NPLC (Welch Ultimate XB-CN (250mm x 50mm x 10pm). Flow rate: 100 mL / min. Gradient: 40% to 80% (EtOH with 0.1% NH4OH v / v) in hexane (15 min) then 100% EtOH (5 min)) to give l-[3-acetyl-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]pyrazole-3-carbonitrile (80 mg, 15.6% yield) as a brown solid and l-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-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. 'H NMR (400 MHz, CD3OD): 5 = 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). Regioisomer 2: LC-MS: m / z = 436.3 [M+H]+, ESI pos.XH NMR (400 MHz, CD3OD): 5 = 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).

[0509] Step 3: l-[ 3-( 1 -hydroxyethyl)-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2- pyridyl]pyrazole-3-carbonitrile

[0510] Following the procedure described in step 3 of example 107, the title compound (6.9 mg, 8.2% yield) was obtained as a light yellow liophilized solid. Purification by preparative HPLC (Phenomenex Luna C18 (150mm x 25mm x 10pm). Flow rate: 25 mL / min. Gradient: 9% to 39% CH3CN in (0.225% formic acid in H2O v / v) (10 min) then 100% CH3CN (2 min)). LC-MS: m / z = 438.1 [M+H]+, ESI pos. 'H NMR (400 MHz, CD3OD): 5 = 8.93 (s, 1H), 8.68 (d, J = 2.7 Hz, 1H), 8.54 (d, .7= 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).

[0511] Example 116

[0512] 1- [[[3-(l-Hydroxyethyl)-6- [5- [(6-methylpyridazin-3-yl)amino] benzimidazol-l-yl]-2- pyridyl] amino] methyl] cyclopropanecarbonitrile; formic acid Step 1: l-[[(3-acetyl-6-chloro-2-pyridyl)amino]methyl] cyclopropanecarbonitrile

[0513] To a solution of l-(6-chloro-2-fluoro-3-pyridyl)ethanone (CAS# 1260663-13-5, 1.05 g, 6.05 mmol, 1 equiv.), l-(aminomethyl)cyclopropanecarbonitrile hydrochloride (963 mg, 7.26 mmol, 1.2 equiv.) in DMSO (20 mL) was added DIPEA (3 mL, 18.15 mmol, 3 equiv.) stirring was continued at 30 °C for 12 hours. The mixture was poured into H2O (200 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers wereas washed with brine (3 x 100 mL), dried over Na2SO4, 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.

[0514] Step 2: l-[[[3-acetyl-6-56-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl amino ] methyl cyclopropanecarbonitrile and !-[[[ 3-acetyl-6-[ 6-[ ( 6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl / -2 -pyridyl amino ] methyl cyclopropanecarbonitrile

[0515] Following the procedure described in step 2 of example 115, the crude material was obtained and purified by preparative NPLC (Welch Ultimate XB-SiOH (250mm x 70mm x 10pm). Flow rate: 140 mL / min. Gradient: 20% to 60% (EtOH) in heptane (20 min) then 100% EtOH (3 min)) to give l-[[[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-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-l-yl]-2- pyridyl]amino]methyl]cyclopropanecarbonitrile (170 mg, 24.2% yield) as a yellow solid. Regioisomer 1 : LC-MS: m / z = 439.1 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-t / 6): 8 = 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). Regioisomer 2: LC-MS: m / z = 439.1 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-t / 6): 6 = 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).

[0516] Step 3: l-[[[3-( 1 -hydroxyethyl)-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl -2- pyridyl amino ] methyl cyclopropanecarbonitrile; formic acid

[0517] Following the procedure described in step 3 of example 107, using a mixture of MeOH (5 mL) and DMF (3 mL) as solvent, the title compound (39.5 mg, 21.8% yield) was obtained as a white liophilized solid. Purification by preparative HPLC (Phenomenex Luna C18 (150mm x 25mm x 10pm). Flow rate: 25 mL / min. Gradient: 6% to 36% CH3CN in (0.225% formic acid in H2O v / v) (10 min) then 100% CH3CN (2 min)). LC-MS: m / z = 441.3 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-t / e): 5 = 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).

[0518] Example 117

[0519] 1- [[[3-(l-Hydroxyethyl)-6- [6- [(6-methylpyridazin-3-yl)amino] benzimidazol-l-yl]-2- pyridyl] amino] methyl] cyclopropanecarbonitrile; formic acid

[0520] Following the procedure described in step 3 of example 115, with l-[[[3-acetyl-6-[6-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]amino]methyl]cyclopropanecarbonitrile (obtained in step 2 of example 116) (180 mg, 0.41 mmol, 1 equiv.), the title compound (69 mg, 37% yield) was obtained as a white liophilized solid. Purification by preparative HPLC (Phenomenex Luna C18 (150mm x 25mm x 10pm). Flow rate: 25 mL / min. Gradient: 6% to 36% CH3CN in (0.225% formic acid in H2O v / v) (10 min) then 100% CH3CN (2 min)). LC-MS: m / z = 441.2 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-t / e): 8 = 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).

[0521] Example 118

[0522] 5- [3-(l-Hydroxyethyl)-6- [5- [(6-methylpyridazin-3-yl)amino] benzimidazol- 1-yl] -2- pyridyl]pyridine-3-carbonitrile; formic acid

[0523] Step 1 : 5-[ 3-acetyl-6-[5-[ ( 6-methylpyridazin-3-yl)amino ] benzimidazol- 1-yl / -2 -pyridyl Jpyridine- 3-carbonitrile

[0524] Following the procedure described in step 3 of example 76, with 5-cyanopyridine-3-boronic acid (52 mg, 0.35 mmol, 1.2 equiv.), with a reaction time of 3 h, the obtained crude material was purified preparative TLC (silica gel, 10% MeOH in DCM, UV detection). The title compound (110 mg, 84.8% yield) was obtained as a yellow solid. LC-MS: m / z = 447.3 [M+H]+, ESI pos. Step 2: 5-[ 3-( 1 -hydroxyethyl)-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2- pyridyl]pyridine-3-carbonitrile

[0525] 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 (150mm x 25mm x 10pm). Flow rate: 25 mL / min. Gradient: 5% to 35% CH3CN in (0.225% formic acid in H2O v / v) (10 min) then 100% CH3CN (2 min)). LC-MS: m / z = 449.1 [M+H]+, ESI pos. 'HNMR (400 MHz, DMSO-t / 6): 8 = 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 -

[0526] 4.76 (m, 1H), 3.17 (s, 1H), 2.47 (br s, 3H), 1.39 (br d, J= 6.2 Hz, 3H).

[0527] Example 119 l-[3-(l-Hydroxyethyl)-6-[5-(l,2,4-triazin-3-ylamino)benzimidazol-l-yl]-2-pyridyl]-5- methyl-pyrazole-3-carbonitrile

[0528] Step 1 : l-[ 3-acetyl-6-[5-( 1, 2, 4-triazin-3-ylamino)benzimidazol-l-yl ]-2-pyridyl ]-5-methyl- pyrazole-3-carbonitrile Following the procedure described in step 3 of example 104, with l,2,4-triazin-3-ylamine (23 mg, 0.237 mmol, 2 equiv.), the title compound (56.7 mg, quantitative yield) was obtained as a yellow solid. LC-MS: m / z = 437.3 [M+H]+, ESI pos.

[0529] Step 2: l-[ 3-( 1 -hydroxyethyl)-6-[5-( 1, 2, 4-triazin-3-ylamino)benzimidazol-l-yl ]-2-pyridyl ]-5- methyl-pyrazole-3-carbonitrile

[0530] 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.

[0531] Example 120 1- [3-(l-Hydroxyethyl)-6- [6- [(6-methylpyridazin-3-yl)amino] benzimidazol-l-yl]-2-pyridyl]-

[0532] 3-methyl-pyrrolidine-3-carbonitrile

[0533] Step 1 : l-(3-acetyl-6-chloro-2-pyridyl)-3-methyl-pyrrolidine-3-carbonitrile A solution of l-(6-chloro-2-fluoro-3-pyridyl)ethanone (CAS# 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 hours. The reaction mixture was cooled to RT, poured into H2O (10 mL9 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (2 x 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.

[0534] Step 2: l-[ 3-acetyl-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2-pyridyl -3- methyl-pyrrolidine-3-carbonitrile; formic acid and l-[3-acetyl-6-[6-[(6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl / -2 -pyridyl ]-3-methyl-pyrrolidine-3-carbonitrile; formic acid

[0535] Following the procedure described in step 4 of example 113, with a reaction time of 16 h at 100 °C, the reaction mixture was cooled to RT, filtered and directly purified by preparative HPLC (Phenomenex Luna C18 (150mm x 40mm x 15pm). Flow rate: 60 mL / min. Gradient: 10% to 40% CH3CN in (0.225% formic acid in H2O v / v) (13 min) then 100% CH3CN (2 min)). A mixture (454 mg) of both title compounds was obtained. This mixture was further purified by preparative NPLC (Welch Ultimate XB-SiOH (250mm x 70mm x 10pm). Flow rate: 140 mL / min. Gradient: 45% to 85% EtOH in hexane (12 min) then 100% EtOH (5 min)) to give l-[3- acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-3-methyl-pyrrolidine- 3 -carbonitrile; formic acid (200 mg, 29.1% yield) as a yellow solid and l-[3-acetyl-6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-3-methyl-pyrrolidine-3-carbonitrile; formic acid (190 mg, 27.7% yield) as a light yellow oil. Regioisomer 1 : LC-MS: m / z = 453.3 [M+H]+, ESI pos. 'H NMR (400 MHz, CDCI3): 8 = 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), 2.57 - 2.49 (m, 1H), 2.17 - 2.11 (m, 1H), 1.63 - 1.59 (m, 3H). Regioisomer 2: LC-MS: m / z = 453.3 [M+H]+, ESI pos.

[0536] Step 3: l-[ 3-( 1 -hydroxyethyl)-6-[ 6-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl -2- pyridyl]-3-methyl-pyrrolidine-3-carbonitrile

[0537] 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 (150mm x 25mm x 5pm). Flow rate: 25 mL / min. Gradient: 27% to 57% CH3CN in (10 mM NH4HCO3 in H2O) (8 min) then 100% CH3CN (2 min)). LC-MS: m / z = 455.2 [M+H]+, ESI pos. 'H NMR (400 MHz, CDCI3): 6 = 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, 1H), 2.05 - 1.99 (m, 1H), 1.61 - 1.53 (m, 3H), 1.52 - 1.47 (m, 3H).

[0538] Example 121

[0539] 1- [3-(l-Hydroxyethyl)-6- [5- [(6-methylpyridazin-3-yl)amino] benzimidazol-l-yl]-2-pyridyl]- 3-methyl-pyrrolidine-3-carbonitrile

[0540] Following the procedure described in step 5 of example 113, with l-[3-acetyl-6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-3-methyl-pyrrolidine-3-carbonitrile (obtained in step 2 of example 120) (150 mg, 0.33 mmol, 1 equiv.), the title compound (52.5 mg, 34.3% yield) was obtained as a white liophilized solid. Purification by preparative HPLC (Waters Xbridge (150mm x 25mm x 5pm). Flow rate: 25 mL / min. Gradient: 27% to 57% CH3CN in (10 mM NH4HCO3 in H2O) (8 min) then 100% CH3CN (2 min)). LC-MS: m / z = 455.3 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-t / 6): 8 = 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).

[0541] Example 122

[0542] 1- [6- [5- [(6-Methylpyridazin-3-yl)amino] benzimidazol-l-yl]-2-[2-methyl-5- (trifluoromethyl)pyrazol-3-yl] -3-pyridyl] ethanol

[0543] Step 1 : l-[ 6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2-[ 2-methyl-5- ( trifluoromethyl)pyrazol-3-yl -3-pyridyl ethanone Following the procedure described in step 3 of example 76, with l-methyl-3- (trifluoromethyl)pyrazole-5-boronic acid pinacol ester (41 mg, 0.150 mmol, 1.4 equiv.), the reaction mixture was cooled to RT and filtered. The filter cake was taken in MeOH (30 mL) and the suspension was stirred at 30 °C for 1 hour. 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.

[0544] Step 2: l-[ 6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2-[ 2-methyl-5-

[0545] ( trifhioromethyl)pyrazol-3-yl / -3-pyridyl ethanol

[0546] Following the procedure described in step 5 of example 113, the title compound (2.4 mg, 6.4% yield) was obtained as a white liophilized solid. LC-MS: m / z = 495.2 [M+H]+, ESI pos.JH NMR (400 MHz, CD3OD): 5 = 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= 92 Hz, 1H), 7.13 (d, J

[0547] = 92 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).

[0548] Example 123 l-[3-(l-Hydroxyethyl)-6-[5-(isoxazol-3-ylamino)benzimidazol-l-yl]-2-pyridyl]-5-methyl- pyrazole-3-carbonitrile

[0549] Step 1: l-[3-acetyl-6-[5-(isoxazol-3-ylamino)benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole- 3-carbonitrile Following the procedure described in step 3 of example 104, with 3-aminoisoxazole (21 mg, 19 pL, 0.237 mmol, 2 equiv.), the title compound (9.3 mg, 17.2% yield) was obtained as a light yellow solid. LC-MS: m / z = 425.3 [M+H]+, ESI pos. Step 2: l-[ 3-( 1 -hydroxyethyl)-6-[5-(isoxazol-3-ylamino)benzimidazol-l-yl ]-2-pyridyl ]-5-methyl- pyrazole-3-carbonitrile

[0550] Following the procedure described in step 2 of example 84, the title compound (6.1 mg, 65.7% yield) was obtained as a light yellow solid. LC-MS: m / z = 427.2 [M+H]+, ESI pos.

[0551] Example 124 3-(l-Hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-N-(2,2,2- trifluoroethyl)pyridine-2-carboxamide; formic acid

[0552] Step 1: 3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-N-(2,2,2- trifluoroethyl)pyridine-2-carboxamide

[0553] To a suspension of l-[2-chloro-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3- pyridyl] ethanone (obtained as in step 2 of example 76) (200 mg, 0.53 mmol, 1 equiv.) in 2,2,2- trifluoroethylamine (3.0 mL, 142.43 mmol, 270 equiv.) and DMF (3 mL) were added dppf (117 mg, 0.21 mmol, 0.4 equiv.), Pd(OAc)2 (24 mg, 0.11 mmol, 0.2 equiv.) and NEt (0.22 mL, 1.58 mmol, 3 equiv.). The reaction mixture was then stirred under CO (50 psi) at 70 °C for 16 hours. The reaction mixture was cooled to RT, poured into H2O (50 mL) and extracted with DCM (4 x 50 mL). The combined organics 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 light brown solid. LC-MS: m / z = 470.3 [M+H]+, ESI pos.

[0554] Step 2: 3-( 1 -hydroxyethyl)-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-N-(2, 2, 2- trijluoroethyl)pyridine-2-carboxamide; formic acid

[0555] To a solution of 3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-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) was added NaBELj (14 mg, 0.37 mmol, 3 equiv.) at 0 °C. The mixture was then stirred at 20 °C for 1 hour. The reaction mixture was directly purified by preparative HPLC: column Phenomenex Luna C18 (150mm x 25mm x 10pm). Flow rate: 25 mL / min. Gradient: 10% to 40% CH3CN in (0.225% formic acid in H2O v / v) (10 min) then 100% CH3CN (2 min). The title compound (9.1 mg, 14.8% yield) was obtained as yellow liophilized solid. LC-MS: m / z = 472.1 [M+H]+, ESI pos. 'H NMR (400 MHz, CD3OD): 5 = 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= 92 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, = 6.4 Hz, 3H).

[0556] Example 125

[0557] 1- [6- [6- [(6-Methylpyridazin-3-yl)amino] benzimidazol- 1-yl] -2- [(3aR,6aS)-2,3,3a,5,6,6a- hexahydro-lH-pyrrolo[3,2-b]pyrrol-4-yl]-3-pyridyl]ethanol; formic acid Step 1 : rac-trans-l-(3-acetyl-6-chloro-2-pyridyl)-2, 3, 3a, 5, 6, 6a-hexahydropyrrolo[ 3, 2-b ]pyrrole- 4-carboxylate

[0558] Following the procedure described in step 4 of example 113, with rac-trans-hexahydro- pyrrolo[3,2-b]pyrrole-l -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.

[0559] Step 2: tert-butyl rac-trans-l-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl]-2-pyridyl]-2,3,3a,5,6,6a-hexahydropyrrolo[3,2-b]pyrrole-4-carboxylate and tert-butyl rac- trans-l-[ 3-acetyl-6-[ 6-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl / -2 -pyridyl / - 2, 3, 3a, 5, 6, 6a-hexahydropyrrolo[ 3, 2-b ]pyrrole-4-carboxylate

[0560] Following the procedure described in step 2 of example 120, with additional reaction time of 6 h at 110 °C, the reaction mixture was cooled to RT, poured into H2O (100 mL) and extracted with DCM (3 x 100 mL). The combined organic extracts were washed with brine, dried over lSfeSCU, filtered and concentrated under vacuum. The residue was purified by preparative HPLC (Phenomenex Luna C18 (250mm x 70mm x 10pm). Flow rate: 140 mL / min. Gradient: 23% to 50% CH3CN in (0.225% formic acid in H2O v / v) (20 min) then 100% CH3CN (5 min)). A mixture of both title compounds (800 mg) was isolated and further purified by preparative NPLC (Welch Ultimate XB-CN (250mm x 70mm x 10pm). Flow rate: 140 mL / min. Gradient: 30% to 70% (EtOH with 0.1% NH4OH v / v) in hexane (12 min) then 100% EtOH (5 min)). To give tertbutyl rac-trans-l-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]- 2,3,3a,5,6,6a-hexahydropyrrolo[3,2-b]pyrrole-4-carboxylate (350 mg, 18% yield) as a yellow solid and tert-butyl rac-trans-l-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl]-2-pyridyl]-2,3,3a,5,6,6a-hexahydropyrrolo[3,2-b]pyrrole-4-carboxylate (420 mg, 21.6% yield) as a yellow solid.. Regioisomer 1 : LC-MS: m / z = 555.3 [M+H]+, ESI pos.JH NMR (400 MHz, CDC13): 6 = 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). Regioisomer 2: LC-MS: m / z = 555.3 [M+H]+, ESI pos. 'H NMR (400 MHz, CDCI3): 8 = 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).

[0561] Step 3: l-[ 6-[ 6-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2-[rac-trans-2, 3, 3a, 5, 6, 6a- hexahydro-lH-pyrrolo[ 3, 2-b ]pyrrol-4-yl ]-3-pyridyl ethanone

[0562] To a solution of tert-butyl rac-trans-l-[3-acetyl-6-[6-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-2,3,3a,5,6,6a-hexahydropyrrolo[3,2-b]pyrrole-4- carboxylate (400 mg, 0.72 mmol, 1 equiv.) in DCM (3 mL) was added TFA (3 mL, 12 mmol, 16.64 equiv.). The reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated and the residue was dissolved in DCM (20 mL). The pH of the solution was adjusted to 8 with sat. NaHCCh aq.sol. and the mixture was extracted with DCM / MeOH 9: 1 (9 x). The combined organic layers were dried over Na2SO4, filtered and concentrated to afford the title compound (270 mg, 82.4% yield) as a yellow solid. LC-MS: m / z = 455.3 [M+H]+, ESI pos.

[0563] Step 4: l-[ 6-[ 6-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2-[ ( 3aR, 6aS)-2, 3, 3a, 5, 6, 6a- hexahydro-lH-pyrrolo[ 3, 2-b ]pyrrol-4-yl ]-3-pyridyl ethanol; formic acid To a solution of l-[6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-[rac-trans- 2,3,3a,5,6,6a-hexahydro-lH-pyrrolo[3,2-b]pyrrol-4-yl]-3-pyridyl]ethanone (250 mg, 0.55 mmol, 1 equiv.) in MeOH (3 mL) was added NaBIH (62 mg, 1.65 mmol, 3 equiv.) at 0 °C. The mixture was then stirred at 20 °C for 1 hour. NaBT (62.43 mg, 1.65 mmol, 3 equiv.) was added to the solution. The reaction mixture was stirred at 20 °C for another 1 hour. The mixture was diluted with H2O (30 mL) and extracted with (DCM / MeOH 9: 1) (6 x 30 mL) . The combined organics were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (Unisil 3-100 C18 Ultra (150mm x 50mm x 10pm). Flow rate: 25 mL / min. Gradient: 1% to 30% CH3CN in (0.225% formic acid in H2O v / v) (10 min) then 100% CH3CN (2 min)) to give l-[6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-[(3aR,6aS)- 2,3,3a,5,6,6a-hexahydro-lH-pyrrolo[3,2-b]pyrrol-4-yl]-3-pyridyl]ethanol; formic acid (32 mg, 12.7% yield) as an off-white liophilized solid and l-[6-[6-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-[(3aS,6aR)-2,3,3a,5,6,6a-hexahydro-lH-pyrrolo[3,2-b]pyrrol-4- yl]-3-pyridyl]ethanol (71.9 mg, 28.1% yield) as a yellow liophilized solid. Regioisomer 1 : LC- MS: m / z = 457.2 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-t / 6): 8 = 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). Regiosimer 2: LC-MS: m / z = 457.2 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-t / 6): 6 = 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).

[0564] Example 126 l-[6-[6-[(6-Methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-[(3aS,6aR)-2,3,3a,5,6,6a- hexahydro-lH-pyrrolo[3,2-b]pyrrol-4-yl]-3-pyridyl]ethanol; formic acid The title compound l-[6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-[(3aS,6aR)- 2,3,3a,5,6,6a-hexahydro-lH-pyrrolo[3,2-b]pyrrol-4-yl]-3-pyridyl]ethanol (71.9 mg, 28.1% yield) was obtained in step 4 of example 125 (after the purification by preparative HPLC) as a yellow lyophilized solid. LC-MS: m / z = 457.2 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-t / 6): 8 = 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).

[0565] Example 127

[0566] 1- [6- [5- [(6-Methylpyridazin-3-yl)amino] benzimidazol-l-yl]-2-[rac-trans-2,3,3a,5,6,6a- hexahydro- IH-pyrrolo [3, 2-b] pyrrol-4-yl] -3-pyridyl] ethanol

[0567] Step 1 : l-[ 6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2-[rac-trans-2, 3, 3a, 5, 6, 6a- hexahydro- lH-pyrrolo[ 3, 2-b ]pyrrol-4-yl ]-3-pyridyl ] ethanone

[0568] Following the procedure described in step 3 of example 125, with tert-butyl rac-trans-l-[3- acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-2,3,3a,5,6,6a- hexahydropyrrolo[3,2-b]pyrrole-4-carboxylate (330 mg, 0.59 mmol, 1 equiv.), the title compound (250 mg, 92.4% yield) was obtained as a yellow solid. LC-MS: m / z = 455.3 [M+H]+, ESI pos. Step 2: l-[ 6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2-[rac-trans-2, 3, 3a, 5, 6, 6a- hexahydro-lH-pyrrolo[ 3, 2-b ]pyrrol-4-yl ]-3-pyridyl ethanol

[0569] To a solution of l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-[rac-trans- 2,3,3a,5,6,6a-hexahydro-lH-pyrrolo[3,2-b]pyrrol-4-yl]-3-pyridyl]ethanone (230 mg, 0.51 mmol, 1 equiv.) in MeOH (3 mL) was added NaBT (57 mg, 1.52 mmol, 3 equiv.) at 0 °C. The reaction mixture was stirred at 20 °C for 1 hour. DMF (3 mL) and NaBFL (57 mg, 1.52 mmol, 3 equiv.) were added to the mixture which was stirred at RT for another 1 hour. The mixture was diluted with H2O (30 mL) and extracted with (DCM / MeOH 9: 1) (6 x 30 mL) . The combined organics were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (Unisil 3-100 C18 Ultra (150mm x 50mm x 10pm). 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) as yellow liophilized solid. LC-MS: m / z = 457.2 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-t / 6): 8 = 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).

[0570] Example 128

[0571] 1- [2- [3-(Difluoromethyl)-5-methyl-pyrazol- 1-yl] -6- [6- [(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-pyridyl]ethanol Step 1: l-[6-chloro-2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-3-pyridyl]ethanone and l-[6- chloro-2-[5-(difluoromethyl)-3-methyl-pyrazol-l-yl ]-3-pyridyl ethanone

[0572] To a solution of l-(6-chloro-2-fluoro-3-pyridyl)ethanone (CAS# 1260663-13-5, 1.0 g, 5.76 mmol, 1 equiv.) and 3-(difluoromethyl)-5-methyl-lH-pyrazole (837.3 mg, 6.34 mmol, 1.1 equiv.) in DMSO (38 mL) was added K2CO3 (1.19 g, 8.64 mmol, 1.5 equiv.). The reaction mixture was stirred at 65 °C for 2 hours. The mixture was poured into H2O (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL) dried over anhydrous ISfeSCU, filtered and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 10% EtOAc in PE) to give l-[6-chloro-2-[3- (difhioromethyl)-5-methyl-pyrazol-l-yl]-3-pyridyl]ethanone (885 mg, 3.09 mmol, 53.7% yield) as a white solid and l-[6-chloro-2-[5-(difluoromethyl)-3-methyl-pyrazol-l-yl]-3- pyridyl] ethanone (200 mg, 0.662 mmol, 11.5% yield) as a white solid. Regiosimore 1 : LC-MS: m / z = 286.1 [M+H]+, ESI pos. 'H NMR (400 MHz, CDCI3): 8 = 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). Regioisomer 2: LC-MS: m / z = 286.1 [M+H]+, ESI pos. 'H NMR (600 MHz, DMSO-d6) 5 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).

[0573] Step 2: l-[2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[5-[(6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl ]-3-pyridyl ethanone and l-[ 2-[ 3-(difluoromethyl)-5-methyl- pyrazol-l-yl] -6- [ 6-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-3-pyridyl ethanone

[0574] Following the procedure described in step 4 of example 113, with a reaction time of 16 h at 50 °C, the residue obtained after extraction work-up was purified by preparative NPLC (Welch Ultimate XB-CN (250mm x 50mm x 10pm). Flow rate: 140 mL / min. Gradient: 40% to 80% (EtOH with 0.1% NH4OH v / v) in hexane (12 min) then 100% EtOH (5 min)) to give l-[2-[3- (difhioromethyl)-5-methyl-pyrazol-l-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl]-3-pyridyl]ethanone (300 mg, 22.6% yield) as a light yellow solid (containing traces of l-[2- [5-(difluoromethyl)-3-methyl-pyrazol-l-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol- 1-yl] -3 -pyridyl] ethanone) and l-[2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[6-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-pyridyl]ethanone (300 mg, 22.6% yield) as a light yellow solid. Regioisomer 1 : LC-MS: m / z = 475.1 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-t / e): 8 = 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). Regioisomer 2: LC-MS: m / z = 475.1 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-t / 6): 6 = 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 = 92 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).

[0575] Step 3: l-[ 2-[ 3-(difluoromethyl)-5-methyl-pyrazol-l-yl -6-[ 6-[ ( 6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl ]-3-pyridyl ethanol

[0576] Following the procedure described in step 3 of example 107, the title compound (179.2 mg, 61.5% yield) was obtained as a light yellow liophilized solid. Purification by preparative HPLC (Phenomenex Synergi C18 (150mm x 25mm x 10pm). Flow rate: 25 mL / min. Gradient: 8% to 38% CH3CN in (0.225% formic acid in H2O v / v) (10 min) then 100% CH3CN (2 min)). 477.2 [M+H]+, ESI pos. 'HNMR (400 MHz, CD3OD): 5 = 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= 92 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). Example 129

[0577] 1- [2- [3-(Difluoromethyl)-5-methyl-pyrazol- 1-yl] -6- [5- [(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-pyridyl]ethanol; formic acid Following the procedure described in step 3 of example 107, starting with l-[2-[3- (difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl]-3-pyridyl]ethanone (obtained in step 2 of example 128) (290 mg, 0.61 mmol, 1 equiv.) the title compound (127 mg, 43.9% yield) was obtained as a light yellow liophilized solid. Purification by preparative HPLC (column Phenomenex Synergi C18 (150mm x 25mm x 10pm). Flow rate: 25 mL / min. Gradient: 9% to 39% CH3CN in (0.225% formic acid in H2O v / v) (10 min) then 100% CH3CN (2 min)). 477.4 [M+H]+, ESI pos. 'H NMR (400 MHz, CD3OD): 5 = 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= 92 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).

[0578] Example 130 l-[6-[6-Bromo-5-[4-(oxetan-3-yl)piperazin-l-yl]benzimidazol-l-yl]-3-(l-hydroxyethyl)-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile Step 1: 4-bromo-2-nitro-5-[4-(oxetan-3-yl)piperazin-l-yl] aniline

[0579] To a solution of 4-bromo-5-fluoro-2-nitro-aniline (0.95 g, 4.04 mmol, 1.0 equiv.) and l-(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 layers were washed with brine, dried over Na2SO4 and concentrated under vacuum to give 4-bromo-2-nitro-5-[4-(oxetan- 3 -yl)piperazin-l-yl] aniline (1.3 g, 3.64 mmol, 90.0% yield) as yellow solid. LC-MS: m / z = 357.1 [M+H]+, ESI pos.

[0580] Step 2: 4-bromo-5-[ 4-(oxetan-3-yl)piperazin-l-yl Jbenzene-1, 2-diamine

[0581] To a solution of 4-bromo-2-nitro-5-[4-(oxetan-3-yl)piperazin-l-yl]aniline (1.0 g, 2.8 mmol, 1.0 equiv.) in EtOH (18 mL) was added Fe° (781.6 mg, 14 mmol, 5.0 equiv.), NH4CI (1.5 g, 28 mmol, 10 equiv.) and water (6 mL). The reaction mixture was stirred under notrogen at 50 °C for 12 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure. The residue was purified by reversed phase chromatography (50% CH3CN in H2O) to yield 4-bromo-5-[4-(oxetan-3-yl)piperazin-l-yl]benzene-l, 2-diamine (500 mg, 1.53 mmol, 54.6% yield) as yellow solid. LC-MS: m / z = 329.0 [M+H]+, ESI pos.

[0582] Step 3: 5-bromo-6-[ 4-(oxetan-3-yl)piperazin-l-yl J-lH-benzimidazole

[0583] To a solution of 4-bromo-5-[4-(oxetan-3-yl)piperazin-l-yl]benzene-l, 2-diamine (400.0 mg, 1.22 mmol, 1.0 equiv.) in EtOH (8 mL) was added trimethoxymethane (1.30 g, 12.22 mmol, 10 equiv.) and TsOH (21.1 mg, 0.120 mmol, 0.10 equiv.), and the mixture was stirred at 80 °C for 1 hour. Sat. aq. NaHCCE was added to the reaction to adjust pH to 7 - 8, and the product was extractedwith EtOAc. The combined organic layers were concentrated under vacuum to yield 5- bromo-6-[4-(oxetan-3-yl)piperazin-l-yl]-lH-benzimidazole (400 mg, 1.19 mmol, 97.0% yield) as orange solid. LC-MS: m / z = 339.0 [M+H]+, ESI pos.

[0584] Step 4: l-[ 3-acetyl-6-[ 6-bromo-5-[ 4-(oxetan-3-yl)piperazin-l-yl ] benzimidazol-l-yl ] -2-pyridyl ]- 5-methyl-pyrazole-3-carbonitrile and l-[ 3-acetyl-6-[5-bromo-6-[ 4-(oxetan-3-yl)piperazin-l- yl] benzimidazol-l-yl] -2-pyridyl] -5-methyl-pyrazole-3-carbonitrile

[0585] Prepared in analogy to example 64, step 2 using 5-bromo-6-[4-(oxetan-3-yl)piperazin-l-yl]-lH- benzimidazole (400.0 mg, 1.19 mmol, 1.0 equiv.) and l-(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 l-[3-acetyl-6-[6- bromo-5-[4-(oxetan-3-yl)piperazin-l-yl]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile (230 mg, 0.410 mmol, 32.81% yield) as yellow solid and l-[3-acetyl-6-[5-bromo-6- [4-(oxetan-3-yl)piperazin-l-yl]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (240.9 mg, 0.430 mmol, 34% yield) as orange solid. Regioisomer 1 : LC-MS: m / z = 563.1 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-t / 6) 5 = 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). Regioisomer 2: LC-MS: m / z = 563.1 [M+H]+, ESI pos. 'HNMR (400 MHz, DMSO-t / 6) 5 = 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).

[0586] Step 5: l-[ 6-[ 6-bromo-5-[ 4-(oxetan-3-yl)piperazin-l-yl / benzimidazol-l-yl ]-3-( I -hydr oxy ethyl) - 2-pyridyl] -5-methyl-pyrazole-3-carbonitrile

[0587] Prepared in analogy to example 53, step 4 using l-[3-acetyl-6-[6-bromo-5-[4-(oxetan-3- yl)piperazin-l-yl]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (200.0 mg, 0.360 mmol, 1.0 equiv.) and NaBEL (40.0 mg, 1.06 mmol, 3.0 equiv.) in MeOH / THF to yield 1- [6-[6-bromo-5-[4-(oxetan-3-yl)piperazin-l-yl]benzimidazol-l-yl]-3-(l-hydroxyethyl)-2-pyridyl]-

[0588] 5-methyl-pyrazole-3-carbonitrile (143.8 mg, 0.260 mmol, 65.6% yield) as orange solid. LC-MS: m / z = 565.1 [M+H]+, ESI pos.

[0589] Example 133 l-[2-(3-Ethoxy-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol- l-yl]-3-pyridyl]ethanol; formic acid

[0590] Step 1 : l-[ 6-chlor o-2-(3-ethoxy-5-methyl-pyr azol- l-yl)-3-pyr idyl ] ethanone

[0591] Prepared in analogy to example 64, step 1 using 3-ethoxy-5-methyl-lH-pyrazole (420.0 mg, 3.33 mmol, 1.0 equiv.) and l-(6-chloro-2-fluoro-3-pyridyl)ethanone (CAS# 1260663-13-5, 866.8 mg, 4.99 mmol, 1.5 equiv.) to yield l-[6-chloro-2-(3-ethoxy-5-methyl-pyrazol-l-yl)-3- pyridyl] ethanone (110 mg, 0.390 mmol, 11.8% yield) as orange solid. LC-MS: m / z = 280.1 [M+H]+, ESI pos. Step 2: l-[2-(3-ethoxy-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl ]-3-pyridyl ethanone and l-[ 2-(3-ethoxy-5-methyl-pyrazol-l-yl)-6- [ 6-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-3-pyridyl ethanone

[0592] Prepared in analogy to example 64, step 2 using l-[6-chloro-2-(3-ethoxy-5-methyl-pyrazol-l-yl)- 3 -pyridyl] ethanone (110.0 mg, 0.390 mmol, 1.0 equiv.) and N-(6-methylpyridazin-3-yl)-lH- benzimidazol-5-amine (106.3 mg, 0.470 mmol, 1.2 equiv.) to yield l-[2-(3-ethoxy-5-methyl- pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-pyridyl]ethanone (90 mg, 0.190 mmol, 48.85% yield) as yellow gum. Regioisomer 1 : LC-MS:469.2 [M+H]+, ESI pos.JH NMR (400 MHz, CD3OD) 5 = 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 = 92 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). Regioisomer 2: LC-MS:469.2 [M+H]+, ESI pos.

[0593] Step 3: l-[2-(3-ethoxy-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl ]-3-pyridyl ethanol; formic acid

[0594] Prepared in analogy to example 53, step 4 using l-[2-(3-ethoxy-5-methyl-pyrazol-l-yl)-6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-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 yield l-[2-(3-ethoxy-5-methyl-pyrazol- l-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-pyridyl]ethanol; formic acid (42.3 mg, 0.080 mmol, 46.8% yield) as yellow solid. LC-MS: m / z = 471.2 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-t / 6) 8 = 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, .7= 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). Example 134 l-[2-(3-Ethoxy-5-methyl-pyrazol-l-yl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol- l-yl]-3-pyridyl] ethanol

[0595] Prepared in analogy to example 53, step 4 using l-[2-(3-ethoxy-5-methyl-pyrazol-l-yl)-6-[6-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-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 equivalents to yield l-[2-(3-ethoxy-5-methyl-pyrazol-l-yl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol- 1-yl] -3 -pyridyl] ethanol (52.2 mg, 0.110 mmol, 57.8% yield) as yellow solid. LC-MS: m / z = 471.2 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-t / 6) 8 = 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

[0596] (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).

[0597] Example 135

[0598] 1- [2-(6-Methylpyridazin-4-yl)-6- [5- [(6-methylpyridazin-3-yl)amino] benzimidazol-l-yl]-3- pyridyl] ethanol

[0599] Step 1 : l-[2-( 6-methylpyridazin-4-yl)-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]- 3-pyridyl ethanone l-[2-chloro-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-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.), PdCh(dppf) CH2C12 (34.3 mg, 0.042 mmol, 0.1 equiv.) and Na2COs (89 mg, 0.84 mmol, 2 equiv.) were suspended in 1,4-dioxane (1.33 mL) and H2O (0.33 mL). The reaction mixture was heated to 80 °C and stirred for 12 hours. The mixture was cooled to RT, diluted with H2O (7 mL) and EtOAc (7 mL) and stirred for 30 minutes. The insoluble materials were 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 to yield l-[2-(6-methylpyridazin-4-yl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-pyridyl]ethanone (140 mg, 0.320 mmol, 75.9% yield) as yellow solid. LC-MS: m / z = 437.1 [M+H]+, ESI pos.

[0600] Step 2: l-[ 2-( 6-methylpyridazin-4-yl)-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]- 3-pyridyl ethanol

[0601] Prepared in analogy to example 53, step 4 using l-[2-(6-methylpyridazin-4-yl)-6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-pyridyl]ethanone (140.0 mg, 0.320 mmol, 1.0 equiv.) and NaBELj in MeOH / DMF (1 : 1) (36.4 mg, 0.960 mmol, 3.0 equiv.) at -40 °C to yield 1- [2-(6-methylpyridazin-4-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3- pyridyl] ethanol (22 mg, 0.050 mmol, 15.6% yield) as yellow solid. LC-MS: m / z = 439.1 [M+H]+, ESI pos. 'H NMR (400 MHz, CD3OD) 5 = 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 = 92 Hz, 1H), 7.23 (d, J = 92 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).

[0602] Example 136

[0603] 4- [3-(l-Hydroxyethyl)-6- [5- [(6-methylpyridazin-3-yl)amino] benzimidazol-l-yl]-2-pyridyl]- l-(2,2,2-trifluoroethyl)piperazin-2-one Step 1: benzyl 3-oxo-4-(2, 2, 2-trifluoroethyl)piper azine- 1 -carboxylate

[0604] 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 RT for 16 hours. The reaction mixture was quenched with aq. sat. NH4CI and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure and purified by preparative HPLC (Phenomenex Luna Cl 8 250 x 80 mm x 10 pm, gradient 35 - 65% CH3CN in H2O (with 0.225% formic acid) over 20 min, then 100% CH3CN (4 min), flow rate 140 mL / min, 1 injection), to yield benzyl 3 -oxo-4-(2,2,2-trifluoroethyl)piperazine-l -carboxylate (1700 mg, 5.37 mmol, 41.97% yield) as colorless oil. LC-MS: m / z = 317.2 [M+H]+, ESI pos.

[0605] Step 2: l-(2,2,2-trifluoroethyl)piperazin-2-one

[0606] A mixture of benzyl 3 -oxo-4-(2,2,2-trifluoroethyl)piperazine-l -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 of H2 pressure at 30 °C for 16 hours. The suspension was filtered through a pad of Celite and the filter cake was washed with MeOH. The combined filtrates were concentrated to give l-(2,2,2-trifluoroethyl)piperazin-2-one (100 mg, 0.550 mmol, 86.8% yield) as dark green oil. LC-MS: m / z = 183.0 [M+H]+, ESI pos.

[0607] Step 3: 4-[ 3-acetyl-6-[ 6-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2-pyridyl ]-l-(2, 2, 2- trijluoroethyl)piperazin-2-one and 4-[ 3-acetyl-6-[5-[ ( 6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl ]-2-pyridyl -l-(2, 2, 2 -trifluor oethyl)piper azin-2 -one

[0608] A solution of a mixture of l-[2-chloro-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]- 3 -pyridyl] ethanone and l-[2-chloro-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3- pyridyl] ethanone (200.0 mg, 0.530 mmol, 1 equiv.), l-(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 at 30 °C for 16 hours. 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 pm, gradient 20 - 60% EtOH in hexane over 15 min, then 100% EtOH (3 min), flow rate 100 mL / min) to give 4-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-l-(2,2,2- trifluoroethyl)piperazin-2-one (150 mg, 0.290 mmol, 54.2% yield) as light yellow solid and 4-[3- acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-l-(2,2,2- trifluoroethyl)piperazin-2-one (50 mg, 0.100 mmol, 18.1% yield) as light yellow solid. Regioisomer 1 : LC-MS: m / z = 525.4 [M+H]+, ESI pos. 'HNMR (400 MHz, CDCI3) 8 = 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). Regioisomer 2: LC-MS: m / z = 525.4 [M+H]+, ESI pos.

[0609] Step 4: 4-[ 3-(l -hydroxyethyl)-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2- pyridyl -l-(2, 2, 2-trifluoroethyl)piperazin-2-one

[0610] Prepared in analogy to example 53, step 4 using 4-[3-acetyl-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-l-(2,2,2-trifluoroethyl)piperazin-2-one (50 mg, 0.100 mmol, 1.0 equiv.) and NaBIH (8.7 mg, 0.231 mmol, 3.0 equiv.) in DCM / MeOH (9: 1) to yield 4- [3-(l-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-l- (2,2,2-trifluoroethyl)piperazin-2-one (3.3 mg, 0.006 mmol, 8.22% yield) as light yellow solid. LC-MS: m / z = 527.4 [M+H]+, ESI pos.1H NMR (400 MHz, CD3OD) 5 = 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).

[0611] Example 137

[0612] 4- [3-(l-Hydroxyethyl)-6- [6- [(6-methylpyridazin-3-yl)amino] benzimidazol-l-yl]-2-pyridyl]- l-(2,2,2-trifluoroethyl)piperazin-2-one

[0613] Prepared in analogy to example 53, step 4 using 4-[3-acetyl-6-[6-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-l-(2,2,2-trifluoroethyl)piperazin-2-one (40.0 mg, 0.080 mmol, 1.0 equiv., prepared in example 136, step 3) and NaBE (9.0 mg, 0.240 mmol, 3.12 equiv.) in DCM / MeOH (9:1) to yield 4-[3-(l-hydroxyethyl)-6-[6-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-l-(2,2,2-trifluoroethyl)piperazin-2-one (2.5 mg, 0.005 mmol, 6.23% yield) as light yellow solid. LC-MS: m / z = 527.4 [M+H]+, ESI pos. 'H NMR (400 MHz, CD3OD) 5 = 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 = 92 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).

[0614] Example 140 l-[3-(l-Hydroxyethyl)-6-[5-methoxy-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]- 2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0615] Step 1: N-(2-methoxy-4, 5-dinitro-phenyl)-6-methyl-pyridazin-3-amine

[0616] To a solution of potassium tert-butoxide (488.06 mg, 4.35 mmol, 2.0 equiv.) in DMSO (5 mL) was added 3-amino-6-methylpyridazine (237.33 mg, 2.17 mmol, 1.0 equiv.) and l-fluoro-2- methoxy-4,5-dinitro-benzene (470.0 mg, 2.17 mmol, 1.0 equiv.). Then the brown suspension was stirred at 0 °C for 3 hours. The mixture was purified by silica column (water (0.05% ammonium hydroxide v / v)-CH3CN) (100 / 0-7 / 94) to yield N-(2-methoxy-4,5-dinitro-phenyl)-6- methyl-pyridazin-3 -amine (560 mg, 1.83 mmol, 84.36% yield) as light brown solid. LC-MS: m / z = 306.0 [M+H]+, ESI pos.

[0617] Step 2: 6-methoxy-N-( 6-methylpyridazin-3-yl)-lH-benzimidazol-5-amine

[0618] To a solution of N-(2-methoxy-4,5-dinitro-phenyl)-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 at 30 °C for 16 h under H2 (45 psi). The mixture was filtered and the filtrate was concentrated in vacuo. The resulting residue was treated with MeOH (5 mL), 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 pm, gradient 3 - 33% CH3CN in H2O (with 10 mM NH4CO3) over 11 min, then 100% CH3CN (2 min), flow rate 60 mL / min) to yield 6-methoxy-N-(6-methylpyridazin-3-yl)-lH-benzimidazol-5-amine (200 mg, 0.780 mmol, 29.9% yield) as white solid. LC-MS: m / z = 256.1 [M+H]+, ESI pos.

[0619] Step 3: l-[ 3-acetyl-6-[5-methoxy-6-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0620] Prepared in analogy to example 64, step 2 using 6-methoxy-N-(6-methylpyridazin-3-yl)-lH- benzimidazol-5-amine (200.0 mg, 0.780 mmol, 1.0 equiv.) and l-(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). Separation of the isomers by preparative HPLC (Welch Ultimate XB-SiOH 250 mm x 50 mm x 10 pm, gradient 10 - 50% EtOH (with 0.1% ammonium hydroxide) in heptane over 15 min, then 100% EtOH (with 0.1% ammonium hydroxide) for 3 min) yielded l-[3-acetyl-6-[5- methoxy-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile (120 mg, 0.250 mmol, 31.9% yield) as yellow solid and l-[3-acetyl-6-[6-methoxy-5- [(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (20 mg, 0.040 mmol, 5.3% yield) as yellow solid. Regioisomer 1 : LC-MS: m / z = 480.1 [M+H]+, ESI pos. Regioisomer 2: LC-MS: m / z = 480.1 [M+H]+, ESI pos. 'H NMR (400 MHz, CD3OD) 5 = 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).

[0621] Step 4: l-[3-(l -hydroxyethyl)-6-[5-methoxy-6-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l- y I] -2 -pyridyl ]-5-methyl-pyrazole-3-carbonitrile

[0622] Prepared in analogy to example 53, step 4 using l-[3-acetyl-6-[5-methoxy-6-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (100.0 mg, 0.210 mmol, 1.0 equiv.) and NaBE (23.67 mg, 0.630 mmol, 3.0 equiv.) in THF / MeOH (4: 1) to yield l-[3-(l-hydroxyethyl)-6-[5-methoxy-6-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (46.8 mg, 0.100 mmol, 46.6% yield) as white solid by lyophilization. LC-MS: m / z = 482.2 [M+H]+, ESI pos. 'H NMR (400 MHz, CD3OD) 5 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).

[0623] Example 143

[0624] 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 Step 1: 4-bromo-3-methyl-l-(2,2,2-trifluoroethyl)pyrazole and 4-bromo-5-methyl-l-(2,2,2- trifluoroethyl)pyrazole

[0625] A mixture of 4-bromo-3 -methyl pyrazole (15.0 g, 93.17 mmol, 1.0 equiv.), 2,2,2-trifluoroethyl trifluoromethanesulfonate (22.71 g, 97.83 mmol, 1.05 equiv.) and CS2CO3 (25.33 g, 186.34 mmol, 2 equiv.) in DMF (150 mL) was stirred at 100 °C for 12 hours. The reaction mixture was filtered and the filtrate was diluted with H2O and extractedwith EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and the volatiles removed under reduced pressure. The residue was purified by fish column chromatography (silica gel, 10-16% EtOAc in DCM) to yield a mixture of 4-bromo-5-methyl-l-(2,2,2-trifluoroethyl)pyrazole (6.5 g, 26.75 mmol, 28.7% yield) and 4-bromo-3-methyl-l-(2,2,2-trifluoroethyl)pyrazole (13 g, 53.49 mmol, 57.4% yield) as off-white oil. LC-MS: m / z = 242.9 [M+H]+, ESI pos.

[0626] Step 2: 3-methyl-4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-l-(2, 2, 2-trifluoroethyl)pyr azole

[0627] To a mixture of bis(pinacolato)diboron (17.24 g, 67.9 mmol, 1.5 equiv.) and 4-bromo-3 -methyl- l-(2,2,2-trifhioroethyl)pyrazole (11.0 g, 45.26 mmol, 1.0 equiv.) in 1,4-dioxane (200 mL) was added Pd(dppf)C12-CH2C12 (3.7 g, 4.53 mmol, 0.10 equiv.) and KO Ac (8.9 g, 90.53 mmol, 2.0 equiv.), the mixture was stirred at 100 °C for 16 h under an inert atmosphere. The mixture was concentrated under reduced pressure and purified by flash chromatography (silica gel, 10 - 20% EtOAc in PE) to yield 3-methyl-4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-l-(2, 2,2- trifhioroethyl)pyrazole (15.1 g, 52.1 mmol, 84.0% yield) as yellow gum. LC-MS: m / z = 291.1 [M+H]+, ESI pos.

[0628] Step 4: l-[ 6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl -2-[ 3-methyl-l-(2, 2, 2- trijluoroethyl)pyrazol-4-yl]-3-pyridyl ethanone and l-[ 6-[ 6-[ ( 6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl ]-2-[5-methyl-l-(2, 2, 2-trifhioroethyl)pyrazol-4-yl -3- pyridyl ethanone

[0629] Prepared in analogy to example 135, step 2 using l-[2-chloro-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-pyridyl]ethanone (0.5 g, 1.32 mmol, 1 equiv., prepared in example 76, step 2) and 3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-(2,2,2- trifluoroethyl)pyrazole (574.33 mg, 1.98 mmol, 1.5 equiv. ). Purification by SFC (Chiralpak AD- 3 50 mm x 4.6 mm, 3 pm, 40% 'PrOH+CHsCN with 0.05% Et2NH, flow rate 3 mL / min, back pressure 100 bar)) yielded l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-[3- methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanone (319 mg, 0.63 mmol, 47.7% yield) as yellow solid and l-[6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-[5- methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanone (190 mg, 0.376 mmol, 28.5% yield) as yellow solid. LC-MS: m / z = 507.2 [M+H]+, ESI pos. 'H NMR (400 MHz, CD3OD) 5 = 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).

[0630] Step 5: l-[ 6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2-[ 3-methyl-l-(2, 2, 2- trijluoroethyl)pyrazol-4-yl]-3-pyridyl ethanol

[0631] Prepared in analogy to example 53, step 4 using l-[6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-[3-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3- pyridyl] ethanone (750.0 mg, 1.48 mmol, 1.0 equiv.) and NaBIH (281.58 mg, 7.4 mmol, 5 equiv.) at -70 °C to yield l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-[3-methyl-l- (2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanol (450 mg, 0.880 mmol, 69.0% yield) as yellow solid. LC-MS: m / z = 509.1 [M+H]+, ESI pos.

[0632] Example 144

[0633] 1- [3-(l-Hydroxyethyl)-6- [6- [(6-methylpyridazin-3-yl)amino] benzimidazol-l-yl]-2-pyridyl]- N,5-dimethyl-pyrazole-3-carboxamide

[0634] Step 1: N,5-dimethyl-lH-pyrazole-3-carboxamide

[0635] To a stirred solution of 3-methyl-lH-pyrazole-5-carboxylic acid ethyl ester (280 mg, 1.82 mmol, 1.0 equiv.) at RT in MeOH (2 mL) under an argon atmosphere was added methylamine, 41% in water (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 RT and concentrated to dryness to yield N,3-dimethyl-lH-pyrazole-5-carboxamide as white solid, which was used in the next step without further purification. LC-MS: m / z = 140.1 [M+H]+, ESI pos.

[0636] Step 2: l-(3-acetyl-6-chloro-2-pyridyl)-N, 5-dimethyl-pyrazole-3-carboxamide

[0637] Prepared in analogy to example 62, step 1 using N,5-dimethyl-lH-pyrazole-3-carboxamide (used as crude from the previous step) and l-(6-chloro-2-fluoro-3-pyridyl)ethanone (296.2 mg, 1.71 mmol, 1.0 equiv.) to yield l-(3-acetyl-6-chloro-2-pyridyl)-N,5-dimethyl-pyrazole-3-carboxamide (142 mg, 24.7% yield) as bowrn solid. LC-MS: m / z = 293.1 [M+H]+, ESI pos. Step 3: l-[ 3-acetyl-6-[ 6-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2-pyridyl ]-N, 5- dimethyl-pyrazole-3-carboxamide and l-[ 3-acetyl-6-[5-[ ( 6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl / -2 -pyridyl -N, 5-dimethyl-pyrazole-3-carboxamide

[0638] Prepared in analogy to example 65, step 1 using l-(3-acetyl-6-chloro-2-pyridyl)-N,5-dimethyl- pyrazole-3 -carboxamide (137 mg, 0.407 mmol, 1 equiv.) and lH-benzimidazol-5-yl-(6- methylpyridazin-3-yl)amine (101.91 mg, 0.407 mmol, 1 equiv.) over 8 h to yield l-[3-acetyl-6- [6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-N,5-dimethyl-pyrazole-3- carboxamide (40 mg, 19.6% yield) and l-[3-acetyl-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-N,5-dimethyl-pyrazole-3-carboxamide (33 mg, 15.5% yield) as orange solid after separation of the isomers by flash column chromatography. Regiosisomer 1 : LC-MS: m / z = 482.2 [M+H]+, ESI pos. 1H NMR (600 MHz, DMSO-t / 6) 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, = 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) Regioisomer 2: LC-MS: m / z = 482.2 [M+H]+, ESI pos. 'H NMR (600 MHz, DMSO-t / e) 8 = 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).

[0639] Step 4: l-[3-(l -hydroxyethyl)-6-[ 6-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2- pyridyl -N, 5-dimethyl-pyrazole-3-carboxamide Prepared in analogy to example 53, step 4 using l-[3-acetyl-6-[6-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-N,5-dimethyl-pyrazole-3-carboxamide (37 mg, 0.077 mmol, 1.0 equiv.) in MeOH / THF (1 : 1) to yield l-[3-(l-hydroxyethyl)-6-[6-[(6-methylpyridazin- 3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-N,5-dimethyl-pyrazole-3-carboxamide (23 mg, 60.7% yield) as light brown solid. LC-MS: m / z = 484.3 [M+H]+, ESI pos.

[0640] Example 145 l-[2-(5-Methyl-3-methylsulfonyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-pyridyl]ethanol Step 1: l-[2-(3-bromo-5-methyl-pyrazol-l-yl)-6-chloro-3-pyridyl] ethanone

[0641] Prepared in analogy to example 64, step 1 using l-(6-chloro-2-fluoro-3-pyridyl)ethanone (CAS# 1260663-13-5, 2.0 g, 11.52 mmol, 1.0 equiv.) and 3-bromo-5-methyl-lH-pyrazole (1.86 g, 11.52 mmol, 1.0 equiv.) to yield l-[2-(3-bromo-5-methyl-pyrazol-l-yl)-6-chloro-3-pyridyl]ethanone (1.8 g, 5.72 mmol, 47.2% yield) as light yellow solid. LC-MS: m / z = 313.9 [M+H]+and 315.9 [M+H]+, (bromo isotopes) ESI pos. 'H NMR (400 MHz, CDC13) 8 = 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).

[0642] Step 2: l-[2-(3-bromo-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl ]-3-pyridyl ethanone

[0643] Prepared in analogy to example 64, step 2 using l-[2-(3-bromo-5-methyl-pyrazol-l-yl)-6-chloro- 3 -pyridyl] ethanone (1000.0 mg, 3.18 mmol, 1.0 equiv.) and N-(6-methylpyridazin-3-yl)-lH- benzimidazol-5-amine (716.06 mg, 3.18 mmol, 1.0 equiv., prepared in example 64, intermediate 1) to yield l-[2-(3-bromo-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-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.

[0644] Step 3: l-[2-(5-methyl-3-methylsulfonyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl ]-3-pyridyl ethanone

[0645] A mixture of l-[2-(3-bromo-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-pyridyl]ethanone (378.0 mg, 0.750 mmol, 1.0 equiv.), copper (I) tritiate (23.95 mg, 0.11 mmol, 0.150 equiv.), (lR,2R)-N,N-dimethyl-l,2-cyclohexanediamine (32.05 mg, 0.230 mmol, 0.30 equiv.) and sodium methanesulphinate (115.0 mg, 1.13 mmol, 1.5 equiv.) in DMSO (12 mL) was stirred at 95 °C for 16 h under inert atmosphere. The mixture was filtered and purified by preparative HPLC (formic acid buffer?) to yield l-[2-(5-methyl-3- methylsulfonyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-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. Step 4: l-[2-(5-methyl-3-methylsulfonyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl ]-3-pyridyl ethanol

[0646] Prepared in analogy to example 53, step 4 using l-[2-(5-methyl-3-methylsulfonyl-pyrazol-l-yl)- 6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-pyridyl]ethanone (168.0 mg, 0.330 mmol, 1.0 equiv.) and NaBELj (50.0 mg, 1.32 mmol, 3.95 equiv.) in DMF / MeOH (3: 1) to yield l-[2-(5-methyl-3-methylsulfonyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-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. 'H NMR (400 MHz, CD3OD) 5 = 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

[0647] (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).

[0648] Example 146 l-[3-(l-Hydroxyethyl)-6-[5-[(2-keto-l-methyl-pyrimidin-4-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile Step 1: l-[3-acetyl-6-[5-[(2-keto-l-methyl-pyrimidin-4-yl)amino]benzimidazol-l-yl]-2-pyridyl]- 5-methyl-pyrazole-3-carbonitrile

[0649] Prepared in analogy to example 104, step 3 using l-[3-acetyl-6-(5-bromobenzimidazol-l-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-l-methyl-pyrimidin-2-one (29.7 mg, 0.237 mmol, 2.0 equiv.) to yield the title compound (39.8 mg, 68.4% yield ) as yellow solid. LC-MS: m / z = 466.3 [M+H]+, ESI pos.

[0650] Step 2: l-[ 3-( 1 -hydroxyethyl)-6-[5-[ (2-keto-l-methyl-pyrimidin-4-yl)amino ]benzimidazol-l-yl / - 2 -pyridyl ]-5-methyl-pyrazole-3-carbonitrile

[0651] Prepared in analogy to example 53, step 4 using l-[3-acetyl-6-[5-[(2-keto-l-methyl-pyrimidin-4- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (39.8 mg, 0.081 mmol, 1 equiv.) in MeOH / THF to yield the title compound (19.9 mg, 49.8% yield) as light yellow solid. LC-MS: m / z = 468.3 [M+H]+, ESI pos. Example 148

[0652] 5-Methyl-l- [6- [5- [(6-methylpyridazin-3-yl)amino] benzimidazol-l-yl]-3-(2,2,2-trifluoro-l- hydroxy-ethyl)-2-pyridyl]pyrazole-3-carbonitrile

[0653] Step 1: l-(6-chloro-2-fluoro-3-pyridyl)-2,2,2-trifluoro-ethanone

[0654] 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 hour, then N-methoxy-N- methyltrifluoroacetamide (1.26 g, 7.99 mmol, 1.05 equiv.) was added dropwise. After addition, the clear yellow solution was stirred at -70 °C for 1 hour. The mixture was quenched with 100 mL sat. aq. NH4CI, extracted with EtOAc and the organic layers were concentrated under reduced pressure. The residue was purified by flash column choromatography (silica gel, 25% EtOAc in PE) to yield l-(6-chloro-2-fluoro-3-pyridyl)-2,2,2-trifluoro-ethanone (600 mg, 2.64 mmol, 34.7% yield) as light brown oil. LC-MS: m / z = 246.1 [M+H2O+H] , ESI pos.

[0655] Step 2: l-[ 6-chloro-3-(2, 2, 2 -trifluoroacetyl) -2 -pyridyl ]-5-methyl-pyrazole-3-carbonitrile

[0656] To mixture of l-(6-chloro-2-fluoro-3-pyridyl)-2,2,2-trifluoro-ethanone (6.2 g, 27.25 mmol, 1.0 equiv.) and 5-methyl-lH-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 addition, the mixture was stirred at 20 °C for 3 hours. The mixture was quenched with 100 mL water, extracted with 100 mL EtOAc, and the organic layer concentrated under reduced pressure. The residue was purified by reversed phase preparative HPLC (Waters Xbridge BEH C18 150 mm x 50 mm x 10 pm, gradient 30 - 50% CH3CN in H2O (with lOmM NH4HCO3) over 22 min, then 100% CH3CN (5 min), flow rate 140 mL / min) to give l-[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+H20+H]+ESI pos.

[0657] Step 3: 5-methyl-l-[ 6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-3-(2, 2, 2- trijluoroacetyl)-2-pyridyl] pyrazole-3-carbonitrile ; formic acid and 5-methyl-l-[6-[6-[(6- methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-3-(2, 2, 2-trijluoroacetyl)-2-pyridyl ]pyrazole-3- carbonitrile ; formic acid

[0658] A mixture of l-[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)-lH-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 hours. The mixture was purified by preparative HPLC (Shim-pack Cl 8 150 mm x 25mm x 10 pm, gradient 1 - 30% CH3CN in H2O (with 0.225% formic acid) over 10 min, then 100% CH3CN (2 min), flow rate 25 mL / min, 1 injection) to yield 5-methyl-l-[6-[5- [(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-(2,2,2-trifluoroacetyl)-2-pyridyl]pyrazole- 3 -carbonitrile; formic acid (170 mg, 26.6% yield) as dark brown solid. LC-MS: m / z = 504.1 [M+H]+, ESI pos. and 5-methyl-l-[6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3- (2, 2, 2-trifluoroacetyl)-2-pyridyl]pyrazole-3 -carbonitrile; formic acid (120 mg, 18.8% yield) as dark brown solid. LC-MS: m / z = 504.1 [M+H]+, ESI pos. Step 4: 5-methyl-l-[ 6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-3-(2, 2, 2-trifluoro- l-hydroxy-ethyl)-2-pyridyl]pyrazole-3-carbonitrile and 5-methyl-l-[ 6-[ 6-[(6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl ]-3-(2, 2, 2-trifluoro-l-hydroxy-ethyl)-2-pyridyl ]pyrazole-3- carbonitrile

[0659] Prepared in analogy to example 53, step 3, using 5-methyl-l-[6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-(2,2,2-trifluoroacetyl)-2-pyridyl]pyrazole-3-carbonitrile (40.0 mg, 0.080 mmol, 1 equiv.) and NaBIH (8.0 mg, 0.210 mmol, 2.7 equiv.) to yield 5-methyl-l-[6- [5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-(2,2,2-trifluoro-l-hydroxy-ethyl)-2- pyridyl]pyrazole-3 -carbonitrile (5.3 mg, 0.010 mmol, 11.9% yield) and 5-methyl-l-[6-[6-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-(2,2,2-trifluoro-l-hydroxy-ethyl)-2- pyridyl]pyrazole-3 -carbonitrile (1.0 mg, 0.002 mmol, 2.5% yield) as a white solids after purification by preparative HPLC (Waters Xbridge BEH C18 150 mm x 50 mm x 5 pm, gradient 29 - 59% CH3CN in H2O (with lOmM NH4HCO3) over 8 min, then 100% CH3CN (2 min), flow rate 25 mL / min) and separation of the two isomers by preparative NPLC (Welch Ultimate XB- SiOH 250 mm x 50 mm x 10 pm, gradient 10 - 50% EtOH (with 0.1% ammonium hydroxide) in heptane over 15 min, then 100% EtOH (with 0.1% ammonium hydroxide) for 3 min), flow rate 100 mL / min). Regioisomer 1 : LC-MS: m / z = 506.2 [M+H]+, ESI pos. 'H NMR (400 MHz, CDCI3) 8 = 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, 1H), 2.05 - 1.99 (m, 1H), 1.61 - 1.53 (m, 3H), 1.52 - 1.47 (m, 3H). Regioisomer 2: LC-MS: m / z = 506.2 [M+H]+, ESI pos. 'H NMR (400 MHz, CD3OD) 5 = 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). Example 149

[0660] 1- [2- [l-(Difluoromethyl)-3-methyl-pyrazol-4-yl]-6- [5- [(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-pyridyl]ethanol

[0661] Step 1: 4-bromo-l-(difluoromethyl)-3-methyl-pyrazole

[0662] To a solution of 4-bromo-3 -methyl pyrazole (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 hours. The reaction mixture was then diluted with 20 mL 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 yield 4-bromo-l- (difhioromethyl)-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.

[0663] Step 2: l-(difluoromethyl)-3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole

[0664] Prepared in analogy to example 143, step 2 using bis(pinacolato)diboron (240.7 mg, 0.950 mmol, 2.0 equiv.) and 4-bromo-l-(difluoromethyl)-3 -methyl -pyrazole (100 mg, 0.474 mmol, 1.0 equiv.) to yield l-(difhioromethyl)-3-methyl-4-(4,4,5,5-tetramethyl-l,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. Step 3: l-[ 2-[ 1 -(difluor omethyl)-3-methyl-pyrazol-4-yl (-6-[5-[ ( 6-methylpyridazin-3- yl) amino ]benzimidazol-l-yl (-3-pyridyl (ethanone

[0665] Prepared in analogy to example 135 Step 2, using of l-[2-chloro-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-pyridyl]ethanone (5.0 mg, 0.010 mmol, 1.0 equiv., prepared in example 76, step 2) and l-[2-chloro-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3- pyridyl] ethanone (5.0 mg, 0.010 mmol, 1 equiv.) while running the reaction for 2h at 100 °C to yield l-[2-[l-(difluoromethyl)-5-methyl-pyrazol-4-yl]-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-pyridyl]ethanone (12 mg, 0.030 mmol, 7.44% yield). LC-MS: m / z 475.2 [M+H]+, ESI pos.

[0666] Step 4: l-[ 2-[ I -(difluor omethyl)-3-methyl-pyrazol-4-yl ]-6-[5-[ ( 6-methylpyridazin-3- yl) amino ]benzimidazol-l-yl (-3-pyridyl (ethanol

[0667] Prepared in analogy to example 53, Step 3, using l-[2-[l-(difluoromethyl)-3-methyl-pyrazol-4- yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-pyridyl]ethanone (20.0 mg, 0.040 mmol, 1.0 equiv.) and NaBEL (4.78 mg, 0.130 mmol, 3 equiv.) to yield l-[2-[l-(difhroromethyl)- 3-methyl-pyrazol-4-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-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. Example 150

[0668] 1- [3-(l-Hydroxyethyl)-6- [6- [(6-methylpyridazin-3-yl)amino] benzimidazol-l-yl]-2-pyridyl]- 5-methyl-pyrazole-4-carbonitrile

[0669] Step 1 : l-(3-acetyl-6-chloro-2-pyridyl)-3-methyl-pyrazole-4-carbonitrile

[0670] Prepared in analogy to example 62, step 1 using 5-methyl-lH-pyrazole-4-carbonitrile (616.9 mg, 5.76 mmol, 1.0 equiv.) and l-(6-chloro-2-fluoro-3-pyridyl)ethanone (CAS# 1260663-13-5, 1.0 g, 5.76 mmol, 1.0 equiv.) to yield l-(3-acetyl-6-chloro-2-pyridyl)-3-methyl-pyrazole-4-carbonitrile (900 mg, 3.45 mmol, 59.9% yield) as white solid. LC-MS: m / z = 260.9 [M+H]+, ESI pos.

[0671] Step 2: l-[ 3-acetyl-6-[ 6-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2-pyridyl ]-5- methyl-pyrazole-4-carbonitrile and l-[3-acetyl-6-[5-[(6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl / -2 -pyridyl ]-5-methyl-pyrazole-4-carbonitrile

[0672] Prepared in analogy to example 53, step 3 using l-(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)-lH- 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.) to yield l-[3-acetyl-6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-4-carbonitrile (100 mg, 0.220 mmol, 31.87% yield) as light brown solid and l-[3-acetyl-6-[6-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-4-carbonitrile (60 mg, 0.130 mmol, 19.12% yield) as light brown solid after separation by preparative NPLC (preparative NPLC (Welch Ultimate XB-SiOH 250 mm x 70 mm x 10 pm, gradient 20 - 60% EtOH in hexane over 20 min, then 100% EtOH (3 min), flow rate 140 mL / min). Regiosisomer 1 : LC-MS: m / z = 450.2 [M+H]+, ESI pos. 'HNMR (400 MHz, CDC13) 8 = 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). Regiosisomer 2: LC-MS: m / z = 450.2 [M+H]+, ESI pos. 'H NMR (400 MHz, CDCI3) 6 = 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).

[0673] Step 3: l-[ 3-( 1 -hydroxyethyl)-6-[ 6-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2- pyridyl]-5-methyl-pyrazole-4-carbonitrile

[0674] Prepared in analogy to example 53, Step 3, using of l-[3-acetyl-6-[6-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-4-carbonitrile (60.0 mg, 0.130 mmol, 1.0 equiv.) to yield l-[3-(l-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl]-2-pyridyl]-5-methyl-pyrazole-4-carbonitrile (34.5 mg, 0.080 mmol, 57.24% yield) as an off- white solid after preparative HPLC (Phenomenex Synergi Cl 8 150 x 25mm x 10 pm, gradient 2 - 32% CH3CN in H2O (with 0.225% formic acid) over 10 min, then 100% CH3CN (2 min), flow rate 25 mL / min, 1 injection). LC-MS: m / z = 451.9 [M+H]+, ESI pos. 'H NMR (400 MHz, CD3OD) 5 = 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)

[0675] Example 151

[0676] 1- [3-(l-Hydroxyethyl)-6- [5- [(6-methylpyridazin-3-yl)amino] benzimidazol-l-yl]-2-pyridyl]- 5-methyl-pyrazole-4-carbonitrile

[0677] Prepared in analogy to example 53, Step 3 using l-[3-acetyl-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-4-carbonitrile (100.0 mg, 0.220 mmol, 1.0 equiv., prepared in example 150, step 2) in CHCh / MeOH (1 : 1) to yield l-[3-(l- hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl- pyrazole-4-carbonitrile (58.5 mg, 0.130 mmol, 58.24% yield) as yellow solid after preparative HPLC (Phenomenex Synergi C18 150 x 25mm x 10 pm, gradient 3 - 36% CH3CN in H2O (with 0.225% formic acid) over 11 min, then 100% CH3CN (2 min), flow rate 25 mL / min). LC-MS: m / z = 452.0 [M+H]+, ESI pos. 'H NMR (400 MHz, CD3OD) 5 = 8.87 (s, 1H), 8.51 - 8.44 (m, 1H), 8.24 - 8.18 (m, 1H), 8.13 - 8.04 (m, 3H), 7.59 - 7.54 (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).

[0678] Example 152

[0679] 1- [3-(l-Hydroxyethyl)-6- [5- [(6-methylpyridazin-3-yl)amino] benzimidazol-l-yl]-2-pyridyl]- N,5-dimethyl-pyrazole-3-carboxamide

[0680] Prepared in analogy to example 55, Step 4, using of l-[3-acetyl-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-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) while stirring overnight to yield to yield the title compound (14 mg, 46% yield) as a light brown solid. LC-MS: m / z = 484.3 [M+H]+, ESI pos. Example 155 l-[3-(l-Hydroxyethyl)-6-[5-[(2-keto-l-methyl-4-piperidyl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile Step 1: l-[3-acetyl-6-[5-[(2-keto-l-methyl-4-piperidyl)amino]benzimidazol-l-yl]-2-pyridyl]-5- methyl-pyrazole-3-carbonitrile

[0681] Prepared in analogy to example 104, Step 2 with 4-amino-l-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 yellow solid. LC-MS: m / z = 469.3 [M+H]+, ESI pos.

[0682] Step 2: l-[ 3-( 1 -hydroxyethyl)-6-[5-[ (2-keto-l-methyl-4-piperidyl)amino ]benzimidazol-l-yl ]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0683] Prepared in analogy to example 53, step 4 in MeOH / THF (1 :1) to afford the title compound (6.5 mg, 58.7% yield) as yellow solid. LC-MS: m / z = 471.3 [M+H]+, ESI pos. Example 158 [2-(3-methoxy-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl]-3-pyridyl] methanol

[0684] Intermediate 1 : N-( 6-methylpyridazin-3-yl)-lH-benzimidazol-5-amine

[0685] A 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 hours. The dark brown suspension was concentrated in vacuo and the residue was triturated in MeOH (60 mL). The solid was collected by filtration and it was 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 brown solid. LC-MS: m / z = 226.0 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-t / 6): 5 = 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).

[0686] Step 1: methyl 6-chloro-2-(3-methoxy-5-methyl-pyrazol-l-yl)pyridine-3-carboxylate

[0687] Prepared in analogy to example 133, Step 1 using methyl 6-chloro-2-fluoro-pyridine-3- carboxylate (1.0 g, 5.28 mmol, 1.0 equiv.) and and 3-methoxy-5-methyl-lH-pyrazole (600.0 mg, 5.35 mmol, 1.0 equiv.) to give methyl 6-chloro-2-(3-methoxy-5-methyl-pyrazol-l-yl)pyridine-3- carboxylate (1.4 g, 4.97 mmol, 94.2% yield) as white solid. LC-MS: m / z = 282.2 [M+H]+, ESI pos. Step 2: methyl 2-(3-methoxy-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl ]pyridine-3-carboxylate

[0688] A mixture of N-(6-methylpyridazin-3-yl)-lH-benzimidazol-5-amine (0.92 g, 4.07 mmol, 1.04 equiv., intermediate 1), methyl 6-chloro-2-(3-methoxy-5-methyl-pyrazol-l-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 hours. The mixture was cooled to RT and poured into H2O (500 mL). A solid precipitated out. This was extracted with EtOAc (3 x 400 mL). The combined organic layers were concentrated. The residue was purified by preparative HPLC: column Phenomenex Luna C18 (250mm x 70 mm x 15pm. Flow rate 140 mL / min. Gradient: 20% to 50% CH3CN in (H2O with 0.225% formic acid v / v) (35 min) then 100% CH3CN (1 min). A mixture of methyl 2-(3-methoxy-5-methyl-pyrazol-l-yl)-6-[6-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]pyridine-3-carboxylate (370 mg, 0.79 mmol, 20.1% yield) and methyl 2-(3-methoxy-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]pyridine-3-carboxylate (350 mg, 0.74 mmol, 18.1% yield) as light yellow solids was obtained. LC-MS: m / z = 471.1 [M+H]+, ESI pos. This mixture was purified by preparative NPLC: column Welch Ultimate XB-SiOH (250mm x 70mm x lOum). Flow rate 140 mL / min. Gradient: 20% to 60% EtOH in hexane (20 min) then 100% EtOH (3 min).

[0689] Step 3: [2-(3-methoxy-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl ]-3-pyridyl methanol

[0690] A solution of methyl 2-(3-methoxy-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-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.) at -76 °C over 5 min. The mixture was stirred at -76 °C for 1 hour. Another portion of DIBAL-H (0.14 mL, 0.140 mmol, 2.2 equiv.) was added after 2 hours and 4 hours at - 76 °C, and the reaction mixture stirred for another hour at this temperature. Then the reaction mixture was diluted with 5 mL THF and warmed to 0 °C, the reaction mixture was quenched by addition of 0.16 mL of H2O, followed by 0.16 mL of 15% aq. NaOH and 0.4 mL H2O in this order. After being stirred at RT for 15 min, the MgSCU was added to the reaction mixture which was stirred at RT for 15 min. 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-l-yl)- 6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-pyridyl]methanol (20 mg, 0.050 mmol, 68.8% yield) as light yellow solid. LC-MS: m / z = 443.1 [M+H]+, ESI pos. 'HNMR (400 MHz, CD3OD): 5 = 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).

[0691] Example 159

[0692] 1- [2-(3,5-Dimethylisoxazol-4-yl)-6- [5- [(6-methylpyridazin-3-yl)amino] benzimidazol- 1-yl] -3- pyridyl] ethanol

[0693] Step 1 : l-[ 2-(3, 5-dimethylisoxazol-4-yl)-6-[5-[ ( 6-methylpyridazin-3-yl)amino ] benzimidazol- 1- yl] -3-pyridyl ethanone Prepared in analogy to example 143, step 2 using (3,5-dimethylisoxazol-4-yl)boronic acid (26.0 mg, 0.180 mmol, 1.4 equiv.) and of l-[2-chloro-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-pyridyl]ethanone (50.0 mg, 0.130 mmol, 1.0 equiv., prepared in example 76, step 2) to give l-[2-(3,5-dimethylisoxazol-4-yl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-pyridyl]ethanone (25 mg, 0.060 mmol, 43.1% yield) as yellow solid. LC-MS: 440.2 [M+H]+, ESI pos.

[0694] Step 2: l-[2-(3,5-dimethylisoxazol-4-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl] -3-pyridyl ethanol Prepared in analogy to example 53, step 4 to yield l-[2-(3,5-dimethylisoxazol-4-yl)-6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-pyridyl]ethanol (9.8 mg, 0.020 mmol, 39.0% yield) as white solid. Lc-MS: m / z = 442.2 [M+H]+, ESI pos.

[0695] Example 160

[0696] 1- [3-(l-Hydroxyethyl)-6- [5- [(4-methoxypyridazin-3-yl)amino] benzimidazol- 1-yl] -2- pyridyl]-5-methyl-pyrazole-3-carbonitrile Step 1 : l-[ 3-acetyl-6-[5-[ ( 4-methoxypyridazin-3-yl)amino ]benzimidazol-l-yl / -2 -pyridyl ]-5- methyl-pyrazole-3-carbonitrile

[0697] Was prepared in analogy to example 104, step 2 using (4-methoxypyridazin-3-yl)amine (23.76 mg, 0.190 mmol, 2.0 equiv.) to yield the title compound (29.6 mg, 63.6% yield) as yellow solid.

[0698] LC-MS: 466.3 [M+H]+, ESI pos.

[0699] Step 2: l-[3-(l-hydroxyethyl)-6-[5-[(4-methoxypyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile In analogy to example 53, step 4, in MeOH / THF (1 : 1) the title compound (18.9 mg, 63.6% yield) was obtained as light yellow solid. LC-MS: 468.3 [M+H]+, ESI pos.

[0700] Example 161 l-[3-(l-Hydroxyethyl)-6-[5-[(5-keto-l-methyl-pyrrolidin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile Step 1: l-[3-acetyl-6-[5-[(5-keto-l-methyl-pyrrolidin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]- 5-methyl-pyrazole-3-carbonitrile

[0701] Was prepared in analogy to example 104, step 2 using 4-amino-l-m ethyl -2-pyrrolidone (27.1 mg, 0.237 mmol, 2 equiv.) to yield the title compound (43.1 mg, 75.9% yield). LC-MS: 455.3 [M+H]+, ESI pos.

[0702] Step 2: l-[ 3-( 1 -hydroxyethyl)-6-[5-[ (5-keto-l-methyl-pyrrolidin-3-yl)amino ]benzimidazol-l-yl ]- 2-pyridyl]-5-methyl-pyrazole-3-carbonitrile In analogy to example 53, step 4, in MeOH / THF (1 : 1) the title compound (36.7 mg, 81.4% yield) was obtained as yellow solid. LC-MS: 457.3 [M+H]+, ESI pos.

[0703] Example 162

[0704] 1- [6- [5- [(6-Methylpyridazin-3-yl)amino] benzimidazol- 1-yl] -2-(3-methyl-4-pyridyl)-3- pyridyl] ethanol Step 1 : l-[ 6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl / -2-(3-methyl-4-pyridyl)-3- pyridyl ethanone

[0705] Prepared in analogy to example 143, step 2 using 3-methylpyridine-4-boronic acid (36.15 mg, 0.260 mmol, 2 equiv.) and of l-[2-chloro-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl]-3-pyridyl]ethanone (50.0 mg, 0.130 mmol, 1.0 equiv., prepared in example 76, step 2) to give l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-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. Step 2: l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-(3-methyl-4-pyridyl)-3- pyridyl ethanol

[0706] In analogy to example 53, step 4, using 5.0 equivalents of NaBEL, l-[6-[5-[(6-methylpyridazin- 3-yl)amino]benzimidazol-l-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. Example 163 l-[2-[4-(Cyclopropylamino)pyrimidin-5-yl]-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-pyridyl]ethanol Step 1: [4-(cyclopropylamino)pyrimidin-5-yl]boronic acid

[0707] Prepared in analogy 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 yield [4-(cyclopropylamino)pyrimidin-5-yl]boronic acid (368 mg, 2.06 mmol, 44.0% yield) as white solid. LC-MS: m / z = 180.1, [M+H]+, ESI pos.

[0708] Step 2: l-[2-chloro-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-3-pyridyl ethanol

[0709] In analogy to example 53, step 4 using l-[2-chloro-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-pyridyl]ethanone (200.0 mg, 0.530 mmol, 1.0 equiv. prepared in example 76, step 2) and 5.0 equivalents of NaBH4 l-[2-chloro-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-pyridyl]ethanol (130 mg, 0.340 mmol, 51.7% yield) was obtained as a grey solid. LC-MS: m / z = 381.1, [M+H]+, ESI pos. Step 3: l-[2-[4-(cyclopropylamino)pyrimidin-5-yl]-6-[5-[(6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl ]-3-pyridyl ethanol

[0710] In analogy to example 143, step 2 using l-[2-chloro-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-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), l-[2-[4-(cyclopropylamino)pyrimidin-5-yl]-6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-pyridyl]ethanol (4 mg, 0.010 mmol, 10.5% yield) was obtained as white solid. LC-MS: m / z = 480.1, [M+H]+, ESI pos.

[0711] Example 164

[0712] 5- [3-(l-Hydroxyethyl)-6- [5- [(6-methylpyridazin-3-yl)amino] benzimidazol-l-yl]-2-pyridyl]- 4-(trifluoromethyl)pyridin-2-ol

[0713] Step 1: 5-bromo-2-methoxy-4-(trifluoromethyl)pyridine

[0714] A solution of 5-bromo-2-chloro-4-(trifluoromethyl)pyridine (1.0 g, 3.84 mmol, 1.0 equiv.) and methoxysodium (0.41 g, 7.68 mmol, 2 equiv.) in methanol (7 mL) was stirred at 70 °C for 2 hour. The reaction mixture was dissolved in DCM (10 mL) and filtered, the filtrate was concentrated in vacuum to give the desired product as white solid, which was used without further purification. LC-MS: m / z = 257.9, [M+H]+, ESI pos. Step 2: 2-methoxy-5-(4, 4, 5,5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-4-(trijluoromethyl)pyridine

[0715] Prepared in analogy to example 143, step 2 3 -bromo-6-methoxy-2-(trifluorom ethyl )pyri dine (used as crude from the previous step) to provide the desied compound as an off-white solid (400 mg, 62.7% yield). LC-MS: m / z = 304.1, [M+H]+, ESI pos.

[0716] Step 3: l-[2-[6-methoxy-4-(trijluoromethyl)-3-pyridyl]-6-[5-[(6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl ]-3-pyridyl ethanone

[0717] Prepared in analogy to example 143, step 2 using 2-methoxy-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-4-(trifluoromethyl)pyridine (240.03 mg, 0.790 mmol, 3 equiv.) and l-[2- chloro-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-pyridyl]ethanone (100.0 mg, 0.260 mmol, 1.0 equiv., prepared in example 76, step 2) to give l-[2-[6-methoxy-4- (trifluoromethyl)-3-pyridyl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3- pyridyl] ethanone (45 mg, 0.090 mmol, 32.82% yield) as yellow solid. LC-MS: m / z = 520.2, [M+H]+, ESI pos.

[0718] Step 4: l-[ 2-[ 6-hydroxy-4-( trifhioromethyl)-3-pyridyl ]-6-[5-[ ( 6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl ]-3-pyridyl ethanone; formic acid

[0719] To a solution of l-[2-[6-methoxy-4-(trifluoromethyl)-3-pyridyl]-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-pyridyl]ethanone (40.0 mg, 0.080 mmol, 1.0 equiv.) in HC1 (2008.86 mg, 3 mmol, 39.0 equiv.) 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 (150mm x 40mm x 15pm). Flow rate: 60 mL / min. Gradient: 10% to 40% CH3CN in (0.225% formic acid in H2O v / v) (13 min) then 100% CH3CN (2 min)) and lyophilized to yield l-[2-[6-hydroxy-4-(trifluoromethyl)-3-pyridyl]-6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-pyridyl]ethanone; formic acid (30 mg, 0.060 mmol, 77.1% yield) as yellow solid. LC-MS: m / z = 506.1, [M+H]+, ESI pos.

[0720] Step 5: 5-[ 3-(l -hydroxyethyl)-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2- pyridyl ]-4-( trifluor ome thy l)pyridin-2-ol Prepared in analogy to example 53, step 4 to yield 5-[3-(l-hydroxyethyl)-6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-4-(trifluoromethyl)pyridin-2-ol (10.1 mg, 0.020 mmol, 32.7% yield) as grey solid. LC-MS: m / z = 508.1, [M+H]+, ESI pos.

[0721] Example 165

[0722] 3- [3-(l-Hydroxyethyl)-6- [5- [(6-methylpyridazin-3-yl)amino] benzimidazol-l-yl]-2-pyridyl]- 6,7-dihydro-5H-pyrazolo[l,5-a]pyrazin-4-one

[0723] Step 1: 6, 7-dihydro-5H-pyrazolo[l,5-a]pyrazin-4-one 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 CS2CO3 (25.84 g, 79.3 mmol, 2 equiv.). The mixture was stirred at 30 °C for 12 hours. The mixture was filtered and the filter cake 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 colorless oil. This oil was dissolved in 1,4-dioxane (20 mL) 4M HC1 in 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 hours. 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 hours. The reaction mixture was filtered and the filter cake 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 yield 6,7-dihydro-5H-pyrazolo[l,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.

[0724] Step 2: 3-bromo-6, 7-dihydro-5H-pyrazolo [ 1 ,5-a] pyrazin-4-one

[0725] To a solution of 6,7-dihydro-5H-pyrazolo[l,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, 1.1.0 equiv.). The mixture was stirred at 30 °C for 12 hours. The reaction mixture was poured into aq. sat. NH4CI and stirred for 10 min. Then mixture was filtered and rinsed with water (10 mL*2) and sat. Na2S2C>3 (10 mL). The filter cake was concentrated under reduced pressure yield 3-bromo-6,7- dihydro-5H-pyrazolo[l,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.

[0726] Step 3: (4-oxo-6, 7-dihydro-5H-pyrazolo[l,5-a]pyrazin-3-yl)boronic acid Prepared in analogy to example 143, step 2 using 3-bromo-6,7-dihydro-5H-pyrazolo[l,5- a]pyrazin-4-one (500.0 mg, 2.31 mmol, 1.0 equiv.) to yield (4-oxo-6,7-dihydro-5H-pyrazolo[l,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.

[0727] Step 4: 3-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-6, 7- dihydro-5H-pyrazolo[ 1, 5 -a ]pyrazin-4-one

[0728] Prepared in analogy to example 143, step 2 (4-oxo-6,7-dihydro-5H-pyrazolo[l,5-a]pyrazin-3- yl)boronic acid (600.0 mg, 1.23 mmol, 7.75 equiv.) and l-[2-chloro-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-pyridyl]ethanone ((60.0 mg, 0.160 mmol, 1.0 equiv., prepared in example 76, step 2) to yield 3-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl]-2-pyridyl]-6,7-dihydro-5H-pyrazolo[l,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.

[0729] Step 5: 3-[3-(l -hydroxyethyl)-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl -2- pyridyl -6, 7-dihydro-5H-pyrazolo[ 1, 5 -a ]pyrazin-4-one

[0730] Prepared in analogy to example 53, step 4 to give the 3-[3-(l-hydroxyethyl)-6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-6,7-dihydro-5H-pyrazolo[l,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. Example 166 l-[6-[6-Fluoro-5-[[(3S,4R)-4-fluoropyrrolidin-3-yl]amino]benzimidazol-l-yl]-3-(l- hydroxyethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; formic acid

[0731] Step 1: tert-butyl (3R,4S)-3-fluoro-4-(2-fluoro-4,5-dinitro-anilino)pyrrolidine-l-carboxylate

[0732] To a solution of l,2-difluoro-4,5-dinitro-benzene (450.0 mg, 2.2 mmol, 1.0 equiv.) in DMF (10 mL) was added tert-butyl (3 S,4R)-3-amino-4-fluoropyrrolidine-l -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 layers were washed with brine and concentrated under vacuum to yield tert-butyl (3R,4S)-3-fluoro-4-(2-fluoro-4,5-dinitro-anilino)pyrrolidine-l- carboxylate (800 mg, 2.06 mmol, 93.4% yield) as yellow solid. LC-MS: m / z = 289.1 [M- Boc+H]+, ESI pos.

[0733] Step 2: 6-fluoro-N-[ ( 3S, 4R)-4-fluoropyrrolidin-3-yl / -lH-benzimidazol-5-amine

[0734] A solution of tert-butyl (3R,4S)-3-fluoro-4-(2-fluoro-4,5-dinitro-anilino)pyrrolidine-l- 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 for 12 h under EE atmosphere (50 psi). The mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to yield crude 6-fluoro-N-[(3S,4R)-4-fluoropyrrolidin-3-yl]-lH- benzimidazol-5-amine (500 mg, 2.1 mmol, 74.1% yield) as dark brown gum. LC-MS: m / z = 239.1 [M+H]+, ESI pos.

[0735] Step 3: tert-butyl (3R,4S)-3-fluoro-4-[(6-fluoro-lH-benzimidazol-5-yl)amino]pyrrolidine-l- carboxylate

[0736] To a solution of 6-fluoro-N-[(3S,4R)-4-fluoropyrrolidin-3-yl]-lH-benzimidazol-5-amine (600.0 mg, 1.26 mmol, 1.0 equiv.) in DCM (10 mL) and 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 ISfeSCU, filtered and the filtrate was concentrated in vacuo. The residue was dissolved in MeOH, and to the solution was added sat. aq. K2CO3. The mixture was stirred at 25 °C for 12 hours. The mixture was extracted with EtOAc and the combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (Waters Xbridge C18 150 mm x 50 mm x 10 pm, gradient 3 - 33% CH3CN in H2O (with 10 mM NH4CO3) over 11 min, then 100% CH3CN (2 min), flow rate 60 mL / min)), and the eluent was lyophilized to yield tert-butyl (3R,4S)-3-fluoro-4-[(6-fluoro-lH-benzimidazol-5- yl)amino]pyrrolidine-l -carboxylate (180 mg, 0.530 mmol, 42.3% yield) as off-white solid. LC- MS: m / z = 339.2 [M+H]+, ESI pos.

[0737] Step 4: tert-butyl (3S,4R)-3-[[l-[5-acetyl-6-(3-cyano-5-methyl-pyrazol-l-yl)-2-pyridyl]-6-fluoro- benzimidazol-5-yl] amino] -4-fluoro-pyrrolidine-l-carboxylate

[0738] Prepared in analogy to example 64, step 2 using tert-butyl rac-(3R,4S)-3-fluoro-4-[(6-fluoro-lH- benzimidazol-5-yl)amino]pyrrolidine-l -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 Exaple 64, step 1) to yield tert-butyl (3S,4R)-3-[[3-[5-acetyl-6-(3-cyano-5- methyl-pyrazol-l-yl)-2-pyridyl]-6-fluoro-benzimidazol-5-yl]amino]-4-fluoro-pyrrolidine-l- carboxylate (40 mg, 0.070 mmol, 14.2% yield) and tert-butyl (3S,4R)-3-[[l-[5-acetyl-6-(3- cyano-5-methyl-pyrazol-l-yl)-2-pyridyl]-6-fluoro-benzimidazol-5-yl]amino]-4-fluoro- pyrrolidine-1 -carboxylate (50 mg, 0.090 mmol, 17.7% yield) as light yellow gums. The regioisomers were separated by preparative NPLC (Welch Ultimate XB-SiOH 250 x 50 x 10 pm, 10 - 50% EtOH (0.1% ammonium hydroxide) in hexane over 15 min, then 100% EtOH (0.1% ammonium hydroxide) (5 min), flow rate 100 mL / min). LC-MS: m / z = 563.2 [M+H]+, ESI pos. Regioisomer 1 : 'H NMR (400 MHz, CDC13) 8 = 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). Regioisomer 2 : 'H NMR (400 MHz, CDCI3) 6 = 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). Step 5: l-[ 3-acetyl-6-[ 6-fluoro-5-[ [ ( 3S, 4R)-4-jluoropyrrolidin-3-yl ] amino ]benzimidazol-l-yl ]- 2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0739] A solution of tert-butyl (3S,4R)-3-[[l-[5-acetyl-6-(3-cyano-5-methyl-pyrazol-l-yl)-2-pyridyl]-6- fluoro-benzimidazol-5-yl]amino]-4-fluoro-pyrrolidine-l-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 yield 60 mg of crude l-[3-acetyl- 6-[6-fluoro-5-[[(3S,4R)-4-fluoropyrrolidin-3-yl]amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl- pyrazole-3 -carbonitrile. The crude product was used in next step without further purification. LC-MS: m / z = 463.1 [M+H]+, ESI pos.

[0740] Step 6: l-[ 6-[ 6-fluoro-5-[ [ ( 3S, 4R)-4-fluoropyrrolidin-3-yl amino ]benzimidazol-l-yl -3-( 1 - hydroxyethyl)-2-pyridyl ]-5-methyl-pyrazole-3-carbonitrile; formic acid

[0741] To a solution of l-[3-acetyl-6-[6-fluoro-5-[[(3S,4R)-4-fluoropyrrolidin-3- yl]amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile;2, 2, 2-tri fluoroacetic acid (used as crude from the previous step) in methanol (3 mL) was added NaBEL (11.81 mg, 0.310 mmol, 3.0 equiv.) at 0 °C and stirred for 30 min. The mixture was quenched by sat. aq. NH4CI and extracted with EtOAc. The combined organic layers were dried over ISfeSCU and was concentrated in vacuo. The residue was purified by preparative HPLC (Waters Xbridge 150*25mm*5um, H2O (lOmM NH4HCO3) - CH3CN, 23 - 53% B, gradient time 8 min, 100% B hold time 2 min, flow rate 25 mL / min), the eluent was lyophilized to yield l-[6-[6-fluoro-5- [[(3S,4R)-4-fluoropyrrolidin-3-yl]amino]benzimidazol-l-yl]-3-(l-hydroxyethyl)-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile; formic acid (13.6 mg, 0.030 mmol, 26.73% yield) as white solid. LC-MS: m / z = 465.3 [M+H]+, ESI pos. Example 167 l-[2-[2-(Difluoromethoxy)-5-methyl-4-pyridyl]-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-pyridyl]ethanol

[0742] Step 1: 4-bromo-2-(difluoromethoxy)-5-methyl-pyridine

[0743] A mixture of 4-bromo-5-methyl-pyridin-2-ol (290.0 mg, 1.54 mmol, 1.0 equiv.), CS2CO3 (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 hours. 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 yield 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.

[0744] Step 2: 2-(difluoromethoxy)-5-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine

[0745] Prepared in analogy to example 143, step 2 using 4-bromo-2-(difluoromethoxy)-5-methyl- pyridine (150.0 mg, 0.630 mmol, 1.0 equiv) to yield 2-(difluoromethoxy)-5-methyl-4-(4, 4,5,5- tetramethyl-l,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. Step 3: l-[2-[2-(dijluoromethoxy)-5-methyl-4-pyridyl]-6-[5-[(6-methylpyridazin-3- yl amino ]benzimidazol-l-yl ]-3-pyridyl ethanone

[0746] Prepared in analogy to example 143, step 2 using l-[2-chloro-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-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-l,3,2- dioxaborolan-2-yl)pyridine (718.5 mg, 2.5 mmol, 20 equiv.) to afford l-[2-[2- (difluoromethoxy)-5-methyl-4-pyridyl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- 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.

[0747] Step 4: l-[ 2-[ 2-(difluoromethoxy)-5-methyl-4-pyridyl ]-6-[5-[ ( 6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl ]-3-pyridyl ethanol

[0748] Prepared in analogy to example 53, step 4 using 5.0 equivalents of NaBEL (11.37 mg, 0.300 mmol) to yield l-[2-[2-(difluoromethoxy)-5-methyl-4-pyridyl]-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-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.

[0749] Example 168

[0750] 1- [2-(2-Fluoro-5-methyl-4-pyridyl)-6- [5- [(6-methylpyridazin-3-yl)amino] benzimidazol- 1- yl] -3-pyridyl] ethanol

[0751] Step 1 : 2-fluoro-5-methyl-4-( 4, 4, 5, 5 -tetr ame thy l-l , 3, 2-dioxaborolan-2-yl)pyridine

[0752] Prepared in analogy to example 143, step 2 using 4-bromo-2-fluoro-5-methyl-pyridine (950.0 mg, 5 mmol, 1.0 equiv.) to afford 2-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)pyridine (1000 mg, 4.22 mmol, 84.4% yield) as light yellow solid. LC-MS: m / z = 238.1 [M+H]+, ESI pos. 'H NMR (400MHz, CDC13) 8 = 8.00 (s, 1H), 7.22 (s, 1H), 2.44 (s, 3H), 1.35 (s, 13H).

[0753] Step 2: l-[2-(2-fluoro-5-methyl-4-pyridyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl] -3-pyridyl ethanone

[0754] Prepared in analogy to example 143, step 2 using l-[2-chloro-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-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-l,3,2-dioxaborolan-2- yl)pyridine (125.17 mg, 0.530 mmol, 4.0 equiv.) to yield l-[2-(2-fluoro-5-methyl-4-pyridyl)-6- [5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-pyridyl]ethanone (30 mg, 0.070 mmol,

[0755] 50.1% yield) as grey solid. LC-MS: m / z = 454.1 [M+H] , ESI pos. Step 3: l-[2-(2-fluoro-5-methyl-4-pyridyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl] -3-pyridyl ethanol

[0756] Prepared in analogy to example 53, step 4 using 5.0 equivalents of NaBEL (11.26 mg, 0.300 mmol, 5 equiv.) LC-MS: m / z = 456.2 [M+H]+, ESI pos.

[0757] Example 169

[0758] 1- [3-(l-Hydroxyethyl)-6- [6- [(6-methylpyridazin-3-yl)amino] benzimidazol-l-yl]-2-pyridyl]- 4-methyl-pyrazole-3-carbonitrile; formic acid Step 1: l-(3-acetyl-6-chloro-2-pyridyl)-4-bromo-pyrazole-3-carbonitrile

[0759] Prepared in analogy to example 62, step 1 using 4-bromopyrazole-3 -carbonitrile (1.0 g, 5.81 mmol, 1.0 equiv.) to afford 1 -(3 -acetyl-6-chloro-2-pyridyl)-4-bromo-pyrazole-3 -carbonitrile (1.5 g, 4.61 mmol, 79.2% yield) as off-white solid. LC-MS: m / z = 326.8 [M+H]+, ESI pos. Step 2: l-[ 3-acetyl-6-[ 6-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2-pyridyl ]-4- bromo-pyrazole-3-carbonitrile and l-[ 3-acetyl-6-[5-[ ( 6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl / -2 -pyridyl ]-4-bromo-pyrazole-3-carbonitrile

[0760] Prepared in analogy to example 76, step 1 using l-(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)-lH- benzimidazol-5-amine (0.83 g, 3.69 mmol, 1.2 equiv., prepared in example 64, step 1) to provide l-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-4-bromo- pyrazole-3 -carbonitrile (350 mg, 0.680 mmol, 22.2% yield) and l-[3-acetyl-6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-4-bromo-pyrazole-3-carbonitrile (160 mg, 0.310 mmol, 10.1% yield) as an light brown solid. Regioisomer 1 : LC-MS: m / z = 514.0 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-t / 6) 8 = 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). Regioisomer 2: LC-MS: m / z = 514.0 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-t / 6) 6 = 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).

[0761] Step 3: l-[ 3-acetyl-6-[ 6-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2-pyridyl ]-4- methyl-pyrazole-3-carbonitrile

[0762] Prepared in analogy to example 169 / 170, step 3 using l-[3-acetyl-6-[6-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-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.

[0763] Step 4: l-[3-(l -hydroxyethyl)-6-[ 6-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2- pyridyl ]-4-methyl-pyrazole-3-carbonitrile; formic acid

[0764] Prepared in analogy to example 53, step 4 using l-[3-acetyl-6-[6-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-4-methyl-pyrazole-3-carbonitrile (20.0 mg, 0.040 mmol, 1.0 equiv.) in MeOH / DCM (5: 1) to provide l-[3-(l-hydroxyethyl)-6-[6-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-4-methyl-pyrazole-3-carbonitrile; formic acid (3.8 mg, 0.010 mmol, 14.9% yield) as yellow solid by lyophilization. LC-MS: m / z = 452.2, [M+H]+, ESI pos. 'H NMR (400 MHz, CD3OD) 5 = 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).

[0765] Example 170

[0766] 1- [3-(l-Hydroxyethyl)-6- [5- [(6-methylpyridazin-3-yl)amino] benzimidazol-l-yl]-2-pyridyl]- 4-methyl-pyrazole-3-carbonitrile; formic acid Step 1 : l-[ 3-acetyl-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl / -2 -pyridyl ]-4- methyl-pyrazole-3-carbonitrile

[0767] To a solution of l-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-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) were added K3PO4 (0.13 mL, 1.56 mmol, 4.0 equiv.) and PdCh(dppf) CH2C12 (31.73 mg, 0.040 mmol, 0.10 equiv.). The mixture was purged with nitrogen for several min, and then the reaction was stirred at 100 °C for 12 h under nitrogen atmosphere. The mixture was poured into water and extracted with EtOAc. The organic layers were separated, dried over ISfeSCU, filtered and concentracted under reduce pressure. The crude was purified by preparative TLC (10% MeOH in DCM) to provide l-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-4- methyl-pyrazole-3 -carbonitrile (40 mg, 0.090 mmol, 22.9% yield) as off white solid. LC-MS: m / z = 450.2, [M+H]+, ESI pos.

[0768] Step 2: l-[ 3-( 1 -hydroxyethyl)-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2- pyridyl ]-4-methyl-pyrazole-3-carbonitrile; formic acid

[0769] Prepared in analogy to example 53, step 4 using l-[3-acetyl-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-4-methyl-pyrazole-3-carbonitrile (40.0 mg, 0.090 mmol, 1.0 equiv.) in MeOH / DCM (5: 1) to provide l-[3-(l-hydroxyethyl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-4-methyl-pyrazole-3-carbonitrile; formic acid (10.3 mg, 0.020 mmol, 23.3% yield) as yellow solid. LC-MS: m / z = 452.2, [M+H]+, ESI pos. 'H NMR (400 MHz, CD3OD) 5 = 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).

[0770] Example 171

[0771] 1- [6- [5- [(6-Methylpyridazin-3-yl)amino] benzimidazol-l-yl]-2-[5-methyl-3- (trifluoromethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-l-yl]-3-pyridyl]ethanol; formic acid

[0772] Step 1: l-[ 6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-[5-methyl-3- ( trifluoromethyl) -6, 7-dihydro-4H-pyrazolo[ 4, 3-c ]pyridin-l-yl ]-3-pyridyl ethanone

[0773] A solution of l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-[3-(trifluoromethyl)- 4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-l-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 min. Then NaBHsCN (100.0 mg, 1.59 mmol, 3.0 equiv.) was 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 yield crude l-[6-[5- [(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-[5-methyl-3-(trifluoromethyl)-6,7- dihydro-4H-pyrazolo[4,3-c]pyridin-l-yl]-3-pyridyl]ethanone (183 mg, 0.334 mmol, 63.1% yield) as yellow solid. The crude product was used without further purification. LC-MS: m / z = 548.3 [M+H]+, ESI pos.

[0774] Step 2: l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-[5-methyl-3- (trifluoromethyl)-6, 7-dihydro-4H-pyrazolo[ 4, 3-c ]pyridin-l-yl ]-3-pyridyl ethanol; formic acid

[0775] Prepared in analogy to example 53, step 4 in DCM / MeOH (9:1) using l-[6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-[5-methyl-3-(trifluoromethyl)-6,7-dihydro- 4H-pyrazolo[4,3-c]pyridin-l-yl]-3-pyridyl]ethanone (183 mg, 0.334 mmol, 1.0 eq.) to yield l-[6- [5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-[5-methyl-3-(trifluoromethyl)-6,7- dihydro-4H-pyrazolo[4,3-c]pyridin-l-yl]-3-pyridyl]ethanol; formic acid (58 mg, 0.106 mmol, 31.8% yield) as light yellow solid. LC-MS: m / z = 550.2 [M+H]+, ESI pos.

[0776] Example 172 l-[[[3-(l-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]- methyl-amino] methyl] cyclopropanecarbonitrile

[0777] Step 1: tert-butyl N-[(l-cyanocyclopropyl)methyl] carbamate

[0778] To a solution of l-(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 hours. The mixture was diluted with DCM and purified by flash column chromatography (10 - 90% MeOH in DCM) to yield tert-butyl N-[(l- cyanocyclopropyl)methyl]carbamate (350 mg, 1.78 mmol, 52.6% yield) as an off-white solid.JH NMR (400 MHz, CDCI3) 5 = 3.25 (d, J= 6.4 Hz, 2H), 1.46 (s, 9H), 1.29 - 1.22 (m, 2H), 1.06 (s, 2H).

[0779] Step 2: tert-butyl N-[(l-cyanocyclopropyl)methyl]-N-methyl-carbamate

[0780] To a solution of tert-butyl N-[(l-cyanocyclopropyl)methyl]carbamate (680.0 mg, 3.46 mmol, 1.0 equiv.) in THF (15 mL) und 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 Mel (737.7 mg, 5.2 mmol, 1.5 equiv.) was added. The mixture was warmed to 25 °C and stirred for 12 hours. The mixture was quenched by sat. aq. NH4CI and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and the volatiles evaporated to yield crude tert-butyl N-[(l- cyanocyclopropyl)methyl]-N-methyl-carbamate as yellow oil which was used without further purification in the next step.

[0781] Step 3: l-(methylaminomethyl)cyclopropanecarbonitrile;2,2,2-trifluoroacetic acid

[0782] A solution of tert-butyl N-[(l-cyanocyclopropyl)methyl]-N-methyl-carbamate (used as 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 hours. The mixture was concentrated in vacuo to give the crude product 1- (methylaminomethyl)cyclopropanecarbonitrile;2,2,2-trifluoroacetic as light yellow gum which was used in the next step without further purification. LC-MS: m / z = 111.1 [M+H]+, ESI pos.

[0783] Step 4: l-[[ ( 3-acetyl-6-chloro-2-pyridyl)-methyl-amino ] methyl cyclopropanecarbonitrile To a solution of l-(6-chloro-2-fluoro-3-pyridyl)ethanone (CAS# 1260663-13-5, 696.8 mg, 4.01 mmol, 1.2 equiv.), l-(methylaminomethyl)cyclopropanecarbonitrile;2,2,2-trifluoroacetic acid (used as crude from the previous step) in DMSO (8 mL) was added DIPEA (1.66 mL, 10.04 mmol, 3.0 equiv.) and was stirred at 30 °C for 12 hours. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and the volatiles evaporated. The residue was purified by flash column chromatography (10 - 33% EtOAc in PE) to yield l-[[(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.

[0784] Step 5: !-[[[ 3-acetyl-6-[ 6-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl / -2 -pyridyl ]- methyl-amino ] methyl cyclopropanecarbonitrile and !-[[[ 3-acetyl-6-[5-[ ( 6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl / -2 -pyridyl / -methyl-amino ] methyl cyclopropanecarbonitrile

[0785] Prepared in analogy to example 64, step 2 using l-[[(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)-lH-benzimidazol-5-amine (704.65 mg, 3.13 mmol, 1.5 equiv., prepared in example 64, intermediate 1) to yield l-[[[3-acetyl-6-[6-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-methyl-amino]methyl]cyclopropanecarbonitrile (110 mg, 0.240 mmol, 11.7% yield) as yellow solid and l-[[[3-acetyl-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-methyl-amino]methyl]cyclopropanecarbonitrile (110 mg, 0.240 mmol, 11.7% yield) as brown solid. Regioisomer 1 : LC-MS: m / z = 453.2 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-t / 6) 8 = 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). Regioisomer 2: LC-MS: m / z = 453.2 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-t / 6) 6 = 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).

[0786] Step 6: l-[[[3-(l -hydroxyethyl)-6-[ 6-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2- pyridyl / -methyl-amino ] methyl cyclopropanecarbonitrile

[0787] Prepared in analogy to example 53, step 4 using l-[[[3-acetyl-6-[6-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-methyl-amino]methyl]cyclopropanecarbonitrile (110.0 mg, 0.240 mmol, 1.0 equiv.) in MeOH:DMF (3:2) to yield l-[[[3-(l-hydroxyethyl)-6-[6-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-methyl amino]methyl]cyclopropanecarbonitrile (45.9 mg, 0.100 mmol, 39.1% yield) as light yellow solid . LC-MS: m / z = 455.2 [M+H]+, ESI pos.

[0788] Example 173

[0789] 1- [[[3-(l-Hydroxyethyl)-6- [5- [(6-methylpyridazin-3-yl)amino] benzimidazol-l-yl]-2- pyridyl] -methyl-amino] methyl] cyclopropanecarbonitrile

[0790] Prepared in analogy to example 53, step 4 using l-[[[3-acetyl-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-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 yield 1- [[[3-(l-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]- methyl-amino]methyl]cyclopropanecarbonitrile (53.6 mg, 0.120 mmol, 45.4% yield) as light yellow solid. LC-MS: m / z = 455.2 [M+H]+, ESI pos. Example 174 l-[2-(2-Chloro-5-fluoro-3-pyridyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl]-3-pyridyl] ethanol; formic acid Step 1 : 2-chloro-5-fluoro-3-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)pyridine

[0791] Prepared in analogy to 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-l, 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.

[0792] Step 2: l-[ 2-(2-chloro-5-fluoro-3-pyridyl)-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l- yl] -3-pyridyl ethanone

[0793] Prepared in analogy to example 143, step 2 using 2-chloro-5-fhroro-3-(4, 4, 5, 5-tetramethyl-l, 3, 2- dioxaborolan-2-yl)pyridine (84.97 mg, 0.330 mmol, 2.5 equiv.) and l-[2-chloro-6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-pyridyl]ethanone (50.0 mg, 0.130 mmol, 1.0 equiv., prepared in example 76, step 2) to afford l-[2-(2-chloro-5-fluoro-3-pyridyl)-6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-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. Step 3: l-[2-(2-chloro-5-fluoro-3-pyridyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl] -3-pyridyl ethanol; formic acid

[0794] Prepared in analogy to example 53, step 4 using l-[2-(2-chloro-5-fluoro-3-pyridyl)-6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-pyridyl]ethanone and NaBEU (6.01 mg, 0.160 mmol, 5 equiv.) to afford l-[2-(2-chloro-5-fluoro-3-pyridyl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-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.

[0795] Example 175 l-[3-(l-Hydroxyethyl)-6-[6-[[6-[(3-methoxyazetidin-l-yl)methyl]pyridazin-3- yl]amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile;formic acid

[0796] Step 1: l-[3-acetyl-6-[5-[[ 6-[(3-methoxyazetidin-l-yl)methyl]pyridazin-3- yl amino ]benzimidazol-l-yl / -2 -pyridyl ]-5-methyl-pyrazole-3-ca...

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