Benzimidazoles as sik-activity modulators

Abstract

The application relates to a compound of formula (I) wherein L, R1, R2 R3, R4, R5 and R6 are as defined in the claims. The compounds of formula (I) are SIK-activity modulators and can be used as a medicament.

Description

[0001] BENZIMIDAZOLES AS SIK-ACTIVITY MODULATORS

[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] L is absent, -NH- or -O-;

[0005] R1is hydrogen, hydroxyalkyl or haloalkoxy;

[0006] R2is cyanoalkyl, haloalkoxy, hydrogen, alkylsulfinyl, cyanoalkoxy, haloalkyl, alkoxy, halogen, amino, haloalkoxyallylamino, azetidinyl-2-oxo-alkoxy, cycloalkyl, cycloalkyloxy, heterocycloalkyl or heterocycloalkyloxy; wherein cycloalkyl, cycloalkyloxy, heterocycloalkyl and heterocycloalkyloxy are optionally substituted with 1, 2 or 3 substituents individually selected from R7;

[0007] R3and R4are independently selected from cyano, alkyl, haloalkyl and haloalkoxy;

[0008] R5is hydrogen, alkoxy, halogen, heterocycloalkyloxy or heteroarylamino; wherein heteroarylamino is optionally substituted with 1, 2 or 3 substituents individually selected from R8; R6is alkyl, heterocycloalkyl or heteroaryl; wherein heterocycloalkyl and heteroaryl are optionally substituted with 1, 2 or 3 substituents individually selected from R9; if L is absent, then R6can also be hydrogen or halogen; each R7is individually selected from halogen, haloalkyl, hydroxy and cyano; each R8is individually selected from alkyl and alkoxyheterocycloalkylalkyl; each R9is individually selected from alkyl, halogen, dialkylaminocarbonyl, alkoxyheterocycloalkylalkyl, alkylheterocycloalkyl and alkylaminocarbonyl; or a pharmaceutically acceptable salt thereof.

[0009] 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).

[0010] 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.).

[0011] 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”. 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-

[0012] 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.

[0013] 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.

[0014] 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.

[0015] 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 HDACs in response to extracellular signals, which subsequently change the expression of several cellular factors. 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).

[0016] 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.

[0017] 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 and ethyl are further particular examples of “alkyl” in the compound of formula (I).

[0018] 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. A particular example of “cycloalkyl” is cyclopropyl.

[0019] 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-2-yl, pyrrolidin-3-yl, piperidinyl, 1 -piperidyl, 4-piperidyl, 2-oxopyrrolidin-l-yl, piperazinyl, piperazin- 1-yl, azetidinyl, azetidin-l-yl, tetrahydrofuranyl, tetrahydrofuran-2-yl, 1,3-dioxolanyl, l,3-dioxolan-2-yl, [3-oxo- piperazin-l-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. l]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] [ 1 ,4]oxazin-8-yl), pyrrolidin- 1 -yl, 2-oxo-pyrimidin-4-yl, morpholinoethyl, 2-oxa-5-azaspiro[3.4]octan-5-yl, oxetan-3-yl, (2-oxo-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), 2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][l,4]oxazin-6-yl, [rac-(4aS,7aR)-4- methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][l,4]oxazin-6-yl], 5,7-dihydropyrrolo[3,4- c]pyridazin-3-yl, 2,6-diazaspiro[3.4]octanyl, 2,6-diazaspiro[3.4]octan-6-yl and [rac-(3aS,6aS)-6- oxo-2,3,3a,4,5,6a-hexahydropyrrolo[2,3-c]pyrrol-l-yl]. Particular examples of “heterocycloalkyl” are tetrahydrofuranyl, oxetanyl, pyrrolidinyl, 1,3-dioxolanyl, 2,6- diazaspiro[3.4]octanyl, 2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][l,4]oxazinyl, and 5,7- dihydropyrrolo[3,4-c]pyridazinyl. More particularly, tetrahydrofuran-2-yl, oxetan-3-yl, pyrrolidin-2-yl, l,3-dioxolan-2-yl, 2,6-diazaspiro[3.4]octan-6-yl, 2, 3, 4a, 5, 7,7a- hexahydropyrrolo[3,4-b][l,4]oxazin-6-yl, pyrrolidin-3-yl and 5,7-dihydropyrrolo[3,4- c]pyridazin-3-yl. In a particular embodiment, heterocycloalkyl is “N-heterocycloalkyl”.

[0020] 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, pyrimidinyl, pyrimidin-5-yl, benzotriazolyl, lH-benzotriazol-4-yl, furanyl, furyl, 2-furyl, 3-furyl, [6-oxo-lH-pyridazin-5-yl], triazolyl, triazol-l-yl, triazol-2-yl, triazol-4-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 triazolyl, pyrazolyl and pyridazinyl, more particularly triazol -4-yl, pyrazol-l-yl, pyrazol-4-yl and pyridazin-3-yl. In one particular embodiment, heteroaryl is “N-heteroaryl”.

[0021] 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, i.e. wherein an “alkyl” group is linked to an “oxy” group that is further linked to the relevant compound. Examples of “alkoxy” are for instance methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, secbutoxy and tert. -butoxy. Particular examples of “alkoxy” are methoxy and ethoxy.

[0022] The term “oxy”, alone or in combination, signifies the -O- group.

[0023] The term “oxo”, alone or in combination, denotes a divalent oxygen atom =0.

[0024] The terms “halogen” or “halo”, alone or in combination, signifies fluoro, chloro, bromo or iodo and particularly fluoro, chloro or bromo, more particularly fluoro and chloro. 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.

[0025] 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. More particular “haloalkyl” are difluoromethyl and trifluoromethyl.

[0026] 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 difluoromethoxy and trifluoromethoxy.

[0027] The terms “hydroxyl” and “hydroxy”, alone or in combination, signify the -OH group.

[0028] The term “cyano”, alone or in combination, signifies a -CN group, wherein the carbon and the nitrogen atom are connected via a triple bond. The term “carbonyl”, alone or in combination, signifies the -C(O)- group.

[0029] The term “amino”, alone or in combination, signifies the primary amino group (-NH2), the secondary amino group (-NH-), or the tertiary amino group (-N-).

[0030] The term “alkylamino” alone or in combination, is an alkyl group linked to an “amino” group, wherein the “amino” group is further linked to the relevant compound. The term “dialkylamino” denotes two alkyl groups linked to a -N- atom, wherein the “amino” group is further linked to the relevant compound. An example of a” dialkylamino” group is for instance dimethylamino.

[0031] The term “haloalkoxyallylamino”, alone or in combination, signifies a “haloalkoxy” group linked to an amino group via an “allyl” group, wherein the “amino” group is further linked to the relevant compound. An example of a “haloalkoxyallylamino” group is for instance 2- (difhioromethoxy)allylamino.

[0032] The term “azetidinyl-2-oxo-alkoxy”, alone or in comination, refers to azetidinyl linked to an “alkoxy” group, wherein the “alkoxy” group is linked to an “oxo” group in -2- position and is further linked to the relevant compound via the “oxy” group of the “alkoxy” group, i.e. via the - O- moiety of the “alkoxy” group.

[0033] The term “alkoxyheterocycloalkylalkyl”, alone or in comination, refers to an “alkoxy” group that is linked to a heterocycloalkyl which is further linked to the relevant compound via an “alkyl” group. An example of “alkoxyheterocycloalkyl” is for instance (3-methoxyazetidin-l- yl)methyl.

[0034] The term “alkylaminocarbonyl”, alone or in combination, refers to an “alkylamino” group linked to a “carbonyl” group which is further linked to the relevant compound. An example of “alkylaminocarbonyl” is for instance methylaminocarbonyl (also known as methylaminocarbamoyl).

[0035] The term “dialkylaminocarbonyl”, refers to a “dialkylamino” group linked to a “carbonyl” group which is further linked to the relevant compound. An example of “dialkylaminocarbonyl” is for instance dimethylaminocarbonyl (also known as dimethylaminocarbamoyl).

[0036] The term “sulfinyl”, alone or in combination, denotes a -SO- group.

[0037] The ter “ally”, alone or in combination refers to a -CH2-HC=CH2 group. The terms “heterocyloalkyloxy” and “heterocycloalkylamino” refer to a “heterocycloalkyl” group linked to an “oxy” group or an “amino” group, as applicable, wherein said “oxy” or “amino” is further linked to the relevant compound.

[0038] The terms “heteroaryloxy” and “heteroarylamino” refer to a “heteroaryloalkyl” group linked to an “oxy” group or an “amino” group, as applicable, wherein said “oxy” or “amino” is further linked to the relevant compound.

[0039] The term “pharmaceutically acceptable salts” denotes salts which are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid and base addition salts. The term “pharmaceutically acceptable acid addition salt” denotes those pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and organic acids selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicyclic acid. The term “pharmaceutically acceptable base addition salt” denotes those pharmaceutically acceptable salts formed with an organic or inorganic base. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, and polyamine resins.

[0040] The term “compound(s) of this invention” and “compound(s) of the present invention” refers to compounds of formula (I) and stereoisomers, tautomers, solvates, and salts (e.g., pharmaceutically acceptable salts) thereof. Tautomeric forms, i.e. structural isomers which interconvert with the compound of formula (I), in particular in solution, may in some instances exist and are to be understood as being included in the invention.

[0041] 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).

[0042] 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.

[0043] 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.

[0044] 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).

[0045] 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.

[0046] 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.

[0047] Structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Particular examples of radioisotopes are2H,3H,13C,14C and18F. For example the structures wherein one or more hydrogen atoms are replaced by deuterium or tritium, or one or more carbon atoms are replaced by a13C- or14C- enriched carbon are within the scope of this invention.

[0048] The invention thus relates to:

[0049] The compound according to the invention, wherein R1is hydrogen, 1 -hydroxy ethyl or difluoromethoxy;

[0050] The compound according to the invention, wherein R1is 1 -hydroxy ethyl or difluoromethoxy;

[0051] The compound according to the invention, wherein R1is hydrogen;

[0052] The compound according to the invention, wherein R2is 1 -cyanoethyl, difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2-difluoro-l -methyl-ethoxy, hydrogen, methylsulfmyl, cyanomethoxy, 1,1 -difluoroethyl, 2,2-difluoroethyl, trifluoromethyl, methoxy, chloro, bromo, amino, 2-(difluoromethoxy)allylamino, azetidinyl-2-oxo-ethoxy, cyclopropyl, cyclopropyl oxy, tetrahydrofuran-2-yl, oxetan-3-yl, pyrrolidin-2-yl, l,3-dioxolan-2-yl or ox etan-3 -yl oxy; wherein cyclopropyl, cyclopropyl oxy, tetrahydrofuran-2-yl, oxetan-3-yl, pyrrolidin-2-yl, 1,3 -di oxolaneyl and (oxetan-3-yl)oxy are optionally substituted with a substituent selected from R7;

[0053] The compound according to the invention, wherein R2is tetrahydrofuran-2-yl or 1,3- dioxolan-2-yl; wherein tetrahydrofuran-2-yl and l,3-dioxolan-2-yl are optionally substituted with a substituent selected from R7;

[0054] The compound according to the invention, wherein R3and R4are independently selected from cyano, methyl, difluoromethyl and difluoromethoxy;

[0055] The compound according to the invention, wherein R4is methyl and R3is selected from cyano, methyl, di fluoromethyl and difluoromethoxy; The compound according to the invention, wherein R5is hydrogen, methoxy, fluoro, (ox etan-3 -yl)oxy or (pyridazin-3-yl)amino; and wherein (pyridazin-3-yl)amino is optionally substituted a substituent selected from R8;

[0056] The compound according to the invention, wherein R5is hydrogen or alkoxy, in particular hydrogen or methoxy;

[0057] The compound according to the invention, wherein R6is methyl, heterocycloalkyl or heteroaryl; wherein heterocycloalkyl and heteroaryl are at each instance optionally substituted with 1 or 2 substituents individually selected from R9; wherein heterocylcloalkyl is selected from 2,6-diazaspiro[3.4]octan-6-yl, 2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][l,4]oxazin-6-yl, pyrrolidin- 3-yl and 5,7-dihydropyrrolo[3,4-c]pyridazin-3-yl; wherein heteroaryl is selected from triazol-4-yl and pyridazin-3-yl; and wherein if L is absent, then R6can also be hydrogen or fluoro;

[0058] The compound according to the invention, wherein R6is pyridazin-3-yl substituted by alkyl, in particular methyl;

[0059] The compound according to the invention, wherein R7is at each instance individually selected from hydroxy, fluoro, cyano and difluoromethyl;

[0060] The compound according to the invention, wherein R8is at each instance individually selected from methyl and (3-methoxyazetidin-l-yl)methyl;

[0061] The compound according to the invention, wherein R9is at each instance individually selected from methyl, ethyl, fluoro, (3-methoxyazetidin-l-yl)methyl, methylaminocarbonyl, 1- m ethylazeti din-3 -yl and dimethylaminocarbonyl;

[0062] The compound according to the invention, wherein L is -NH-;

[0063] The compound according to the invention, wherein L is -O- or absent;

[0064] The compound according to the invention, wherein L is -O-; and

[0065] The compound according to the invention, wherein L is absent.

[0066] The invention also relates in particular to the compound according to the invention selected from

[0067] 5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-tetrahydrofuran-2- yl-2-pyridyl]pyrazole-3-carbonitrile; 5-methyl-l-[6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-tetrahydrofuran-2- yl-2-pyridyl]pyrazole-3-carbonitrile;

[0068] 1-[3-(3-hydroxyoxetan-3-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile;

[0069] 5-methyl-l-[6-[5-[(l -methyltri azol -4-yl)amino]benzimidazol-l-yl]-3-tetrahydrofuran-2-yl-

[0070] 2-pyridyl]pyrazole-3-carbonitrile; l-[6-[5-(2,6-diazaspiro[3.4]octan-6-yl)benzimidazol-l-yl]-3-tetrahydrofuran-2-yl-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile;

[0071] 5-methyl-l-[6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-[rac-(2R,4R)-4- hydroxyoxolan-2-yl]pyridin-2-yl]pyrazole-3-carbonitrile;

[0072] 5-methyl-l-[6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-[rac-(2R,4S)-4- hydroxyoxolan-2-yl]pyridin-2-yl]pyrazole-3-carbonitrile;

[0073] 5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-[rac-(2R,4R)-4- hydroxyoxolan-2-yl]pyridin-2-yl]pyrazole-3-carbonitrile;

[0074] 5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-[rac-(2R,4S)-4- hydroxyoxolan-2-yl]pyridin-2-yl]pyrazole-3-carbonitrile; l-[6-[5-[[(3R,4S)-4-fluoropyrrolidin-3-yl]amino]benzimidazol-l-yl]-3-tetrahydrofuran-2- yl-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile;

[0075] 5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-[rac-(2R,4R)-4- fluorooxolan-2-yl]pyridin-2-yl]pyrazole-3-carbonitrile;

[0076] 5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-[rac-(2R,4S)-4- fluorooxolan-2-yl]pyridin-2-yl]pyrazole-3-carbonitrile; l-[6-[5-[[6-[(3-methoxyazetidin-l-yl)methyl]pyridazin-3-yl]amino]benzimidazol-l-yl]-3- tetrahydrofuran-2-yl-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[6-[6-[[6-[(3-methoxyazetidin-l-yl)methyl]pyridazin-3-yl]amino]benzimidazol-l-yl]-3- tetrahydrofuran-2-yl-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(l-cyanoethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5- m ethyl -pyrazole-3 -carbonitrile;

[0077] 2-[3-(l-cyanocyclopropyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[3-(difluoromethoxy)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[3-(difluoromethoxy)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[4-(l-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]- 5 -methyl -pyrazol e-3 -carb onitril e; l-[4-(l-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]- 5 -methyl -pyrazol e-3 -carb onitril e; l-[3-(2,2-difluoroethoxy)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[3-(2,2-difluoroethoxy)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyri dyl ] -5 -methyl -pyrazol e-3 -carb onitril e;

[0078] 5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-[rac-(2R,4R)-4- fluoropyrroli din-2 -yl]pyridin-2-yl]pyrazole-3-carbonitrile;

[0079] 5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-[rac-(2R,4S)-4- fluoropyrroli din-2 -yl]pyridin-2-yl]pyrazole-3-carbonitrile;

[0080] 1-[3-chloro-4-(l-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-

[0081] 2-pyridyl]-5-methyl-pyrazole-3-carbonitrile;

[0082] 1-[3-chloro-4-(l-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-

[0083] 2-pyridyl]-5-methyl-pyrazole-3-carbonitrile;

[0084] 5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-methylsulfinyl-2- pyridyl]pyrazole-3-carbonitrile; 5-methyl-l-[6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-methylsulfinyl-2- pyridyl]pyrazole-3-carbonitrile; formic acid;5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3- (oxetan-3-yloxy)-2-pyridyl]pyrazole-3-carbonitrile; l-[3-(2,2-difluoro-l-methyl-ethoxy)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[3-methoxy-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5- m ethyl -pyrazole-3 -carbonitrile; l-[3-(cyanomethoxy)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-

[0085] 5 -methyl -pyrazol e-3 -carb onitril e; l-[3-(cyanomethoxy)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-

[0086] 5 -methyl -pyrazol e-3 -carb onitril e;

[0087] 5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-[rac-(2R,4S)-4- cyanooxolan-2-yl]pyridin-2-yl]pyrazole-3-carbonitrile;

[0088] 5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-[rac-(2R,4R)-4- cyanooxolan-2-yl]pyridin-2-yl]pyrazole-3-carbonitrile;

[0089] 5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-[rac-(2R,4R)-4- (difluoromethyl)oxolan-2-yl]pyridin-2-yl]pyrazole-3-carbonitrile;

[0090] 5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-[rac-(2R,4S)-4- (difluoromethyl)oxolan-2-yl]pyridin-2-yl]pyrazole-3-carbonitrile;

[0091] 3-[[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethoxy)-2-pyridyl]benzimidazol-5- yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide; l-[3-(2,2-difluoroethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[3-(l,3-dioxolan-2-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile; [l-[6-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-5-(l,3-dioxolan-2-yl)-2- pyridyl]benzimidazol-5-yl]-(6-methylpyridazin-3-yl)amine; l-[5-bromo-6-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-2-pyridyl]benzimidazol-5-yl]-(6- methylpyridazin-3-yl)amine;

[0092] 5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3- (trifluoromethoxy)-2-pyridyl]pyrazole-3-carbonitrile;

[0093] [l-[5-amino-6-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-2-pyridyl]benzimidazol-5-yl]- (6-methylpyridazin-3-yl)amine; l-[3-(l-cyanocyclopropoxy)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[6-[5-methoxy-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-[rac-(2R,4R)-4- fluoroox olan-2-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-[rac-(2R,4R)-4- fluoroox olan-2-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile;

[0094] 3-[[l-[6-(3-cyano-5-methylpyrazol-l-yl)-5-[rac-(2R,4R)-4-fluorooxolan-2-yl]pyri din-2- yl]benzimidazol-5-yl]amino]-N,N,6-trimethylpyridazine-4-carboxamide; l-[6-[5-[(4aS,7aR)-4-methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][l,4]oxazin-6- yl]benzimidazol-l-yl]-3-(l,3-dioxolan-2-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[3-(l,l-difluoroethyl)-6-[5-[[6-[(3-methoxyazetidin-l-yl)methyl]pyridazin-3- yl]amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[3-[2-(difluoromethoxy)prop-2-enylamino]-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol- 1 -yl]pyri din-2 -yl]-5-methylpyrazole-3-carbonitrile;

[0095] 1-[6-[5-fluoro-6-(pyridazin-3-ylamino)benzimidazol-l-yl]-3-[rac-(2R,4R)-4-fluorooxolan-

[0096] 2-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile;

[0097] 1-[6-[6-fluoro-5-(pyridazin-3-ylamino)benzimidazol-l-yl]-3-[rac-(2R,4R)-4-fluorooxolan-

[0098] 2-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; 5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-l-yl]- 3 -(trifluoromethyl)-2-pyridyl]pyrazole-3 -carbonitrile; l-[3-cyclopropyl-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[3-amino-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl- pyrazole-3 -carbonitrile; l-[5-cyclopropyl-6-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-2-pyridyl]-6-methoxy-N- (6-methylpyridazin-3-yl)benzimidazol-5-amine; l-[3-cyclopropyl-6-[5-[[6-methyl-5-(l-methylazetidin-3-yl)pyridazin-3- yl]amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[3-cyclopropyl-6-[5-[(6-ethyl-5,7-dihydropyrrolo[3,4-c]pyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile;

[0099] 3-[[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethoxy)-2-pyridyl]benzimidazol-5- yl]amino]-N,6-dimethyl-pyridazine-4-carboxamide; l-[4-(difluoromethoxy)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile; and l-[3-[2-(azetidin-l-yl)-2-oxo-ethoxy]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol- l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; or a pharmaceutically acceptable salt thereof.

[0100] The invention further relates in particular to a compound according to the invention selected from

[0101] 5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-tetrahydrofuran-2- yl-2-pyridyl]pyrazole-3-carbonitrile;

[0102] 5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-[rac-(2R,4S)-4- hydroxyoxolan-2-yl]pyridin-2-yl]pyrazole-3-carbonitrile; 5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-[rac-(2R,4R)-4- fluorooxolan-2-yl]pyridin-2-yl]pyrazole-3-carbonitrile; l-[6-[5-[[6-[(3-methoxyazetidin-l-yl)methyl]pyridazin-3-yl]amino]benzimidazol-l-yl]-3- tetrahydrofuran-2-yl-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[3-(difluoromethoxy)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile;

[0103] 5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-[rac-(2R,4R)-4- fluoropyrroli din-2 -yl]pyridin-2-yl]pyrazole-3-carbonitrile; l-[3-(cyanomethoxy)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-

[0104] 5 -methyl -pyrazol e-3 -carb onitril e;

[0105] 5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-[rac-(2R,4R)-4- (difluoromethyl)oxolan-2-yl]pyridin-2-yl]pyrazole-3-carbonitrile;

[0106] 5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-[rac-(2R,4S)-4- (difluoromethyl)oxolan-2-yl]pyridin-2-yl]pyrazole-3-carbonitrile; l-[3-(l,3-dioxolan-2-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile;

[0107] [l-[6-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-5-(l,3-dioxolan-2-yl)-2- pyridyl]benzimidazol-5-yl]-(6-methylpyridazin-3-yl)amine; and l-[3-cyclopropyl-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile; or a pharmaceutically acceptable salt thereof.

[0108] One embodiment of the invention relates to a compound according to the invention, wherein the compound is a compound of formula (II)

[0109] wherein R2is tetrahydrofuran-2-yl optionally substituted with R7selected from halogen, hydroxyl and haloalkyl; L, R1, R3, R4, R5and R6are as described herein.

[0110] One embodiment of the invention relates to a compound according to the invention, wherein the compound is a compound of formula (III) wherein R2is l,3-dioxolan-2-yl optionally substituted with R7selected from halogen, hydroxyl and haloalkyl; L, R1, R3, R4, R5and R6are as described herein.

[0111] One embodiment of the invention relates to a compound according to the invention, wherein the compound is a compound of formula (IV) wherein L is -NH-, R6is pyridazin-3-yl optionally substituted with R9selected from alkyl and alkoxyheterocycloalkylalkyl; R1, R2, R3, R4and R5are as described herein.

[0112] 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-X or according to methods known to those skilled in the art. In some instances, the sequence of the reaction steps can be modified and the individual steps of the different schemes can be combined in different ways as disclosed herein.

[0113] General synthetic schemes

[0114] The synthesis of the compound of formula (I) can, for example, be accomplished according to the non-exhaustive procedures described below in general schemes 1-4. 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.

[0115] Scheme 1

[0116] In scheme 1, the synthesis of a compound of formula (I-a) or (I-a’) is described. The compound of formula (I-a) or (I-a’) is a compound of formula (I), wherein R1is hydrogen, R2is tetrahydrofuran-2-yl, R3and R4are independently selected from alkyl, cyano, halogen, alkoxyalkyl, cycloalkyl, haloalkoxy and haloalkyl, R5is selected from hydrogen, alkoxy, alkyl, halogen, dialkylaminocarbonylalkoxy, heterocycloalkyl oxy, heterocycloalkylalkoxy and alkylheteroarylamino; L is -NH- and R6is 6-methylpyridazin-3-yl.

[0117]

[0118] Step A: 2-chloro-6-fluoro-pyridine 1 can be reacted in the presence of a suitable base (such as for instance LDA) in the presence of a suitable solvent (such as for instance THF, MeTHF or dioxane) at temperatures from about -78 °C to about 25 °C and the deprotonated intermediate can be reacted with gamma-butyrolactone at temperatures from about -78 °C to about 25°C to yield intermediate 2.

[0119] Step B: The secondary alcohol of l-(6-chloro-2-fluoro-3-pyridyl)-4-hydroxy-butan-l-one 2 can be protected with TBDMSC1 in DCM in the presence of imidazole at temperatures from about -78 °C to about 25°C to yield intermediate 3. Step C: Intermediate 3 can be reacted with a substituted pyrazole 4 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) at temperatures ranging from about -10 °C and about 120 °C to yield intermediate 5. Step D: The carbonyl group of intermediate 5 can be reduced to the corresponding secondary alcohol with a suitable reducing agent such as for instance NaBT in a suitable solvent such as for instance MeOH at temperatures between -40 °C and rt to yield intermediate 6.

[0120] Step E: The TBS protecting group on intermediate 6 can be removed using a suitable fluoride source (such as for instance ammonium fluoride or tetrabutylammonium fluoride) in a suitable solvent (such as for instance MeOH or DCM) at temperatures ranging from 0°C to 80°C to yield intermediate 7.

[0121] Step F: The diol 7 can be cyclized to the corresponding THF group using p- toluenesulfonic acid in a suitable solvent (such as for instance toluene) to yield intermediate 8.

[0122] Step G: Intermediates 8 and 9 can be reacted 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), at a temperature ranging from about -10 °C to about 120 °C to yield the regioisomeric compounds I-a and I-a’ which can be separated by flash column chromatography or preparative HPLC or preparative TLC or reacted in the next step as a regioisomeric mixture.

[0123] Scheme 2

[0124] In scheme 2, the synthesis of a compound of formula (I-b) or (I-b’) is described. The compound of formula (I-b) or (I-b’) is a compound of formula (I), wherein R1is hydrogen, R2is tetrahydrofuran-2-yl, R3and R4are independently selected from alkyl, cyano, halogen, alkoxyalkyl, cycloalkylalkyl, haloalkoxy and haloalkyl, R5is selected from hydrogen, alkoxy, alkyl, halogen, dialkylaminocarbonylalkoxy, heterocycloalkyloxy, heterocycloalkylalkoxy and alkylheteroarylamino; L is -NH- and R6alkyl, heterocycloalkyl or heteroaryl; wherein heterocycloalkyl and heteroaryl are optionally substituted with 1, 2 or 3 substituents individually selected from R9.

[0125]

[0126] Step A: Intermediates 8 and 10 can be reacted 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), at a temperature ranging from about 80 °C to about 110 °C to yield the regioisomeric compounds 11 and 11’ which can be separated by flash column chromatography or preparative HPLC or preparative TLC or reacted in the next step as a regioisomeric mixture.

[0127] Step B: Introduction of the R6-NH2 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 tBuXPhosPdG3, RuPhos-Pd-G3 or [tBuBrettPhos Pd(allyl)]OTf), in a suitable solvent (such as for instance 1,4-di oxane or t-amyl alcohol), at a temperature ranging from around 80 °C to around 100 °C to yield compounds I-b and I-b’ which can be separated by flash column chromatography or preparative HPLC or preparative TLC.

[0128] Scheme 3

[0129] In scheme 3, the synthesis of a compound of formula (I-c) or (I-c’) is described. The compound of formula (I-c) or (I-c’) is a compound of formula (I), wherein R1is hydrogen, R2is difluoromethoxy, R3and R4are independently selected from alkyl, cyano, halogen, alkoxyalkyl, cycloalkyl, haloalkoxy and haloalkyl, R5is selected from hydrogen, alkoxy, alkyl, halogen, dialkylaminocarbonylalkoxy, heterocycloalkyl oxy, heterocycloalkylalkoxy and alkylheteroarylamino; L is -NH- and R6is 6-methylpyridazin-3-yl. Step A: 6-chl oro-2-fluoro-pyri din-3 -ol can be alkylated with sodium chlorodifluoroacetate in the presence of a suitable inorganic base (such as for instance CS2CO3 or K2CO3), in a suitable polar solvent (such as for instance DMF, DMA or NMP) at temperatures ranging from about 25 °C to about 120 °C to yield intermediate 13.

[0130] Step B: Intermediate 13 can be reacted with a substituted pyrazole 4 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) at temperatures ranging from about -10 °C to about 120 °C to yield intermediate 5.

[0131] Step C: Intermediates 14 and 9 can be reacted 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), at a temperature ranging from about -100to about 120 °C to yield the regioisomeric compounds I-c and I-c’ which can be separated by flash column chromatography or preparative HPLC or preparative TLC or reacted in the next step as a regioisomeric mixture. Scheme 4

[0132] In scheme 4, the synthesis of a compound of formula (I-d) or (I-d’) is described. The compound of formula (I-d) or (I-d’) is a compound of formula (I), wherein R1is hydrogen, R2is cyclopropyl, R3and R4are independently selected from alkyl, cyano, halogen, alkoxyalkyl, cycloalkyl, haloalkoxy and haloalkyl, R5is selected from hydrogen, alkoxy, alkyl, halogen, dialkylaminocarbonylalkoxy, heterocycloalkyl oxy, heterocycloalkylalkoxy and alkylheteroarylamino; L is -NH- and R6is 6-methylpyridazin-3-yl. Step A: 3-bromo-6-chloro-2-fluoropyridine and cyclopropylboronic acid can be reacted via Suzuki coupling using a suitable base (such as for instance CS2CO3, K2CO3 or K3PO4) and a suitable palladium catalyst (such as for instance tetrakis(triphenylphosphine)palladium(0)), in a suitable solvent (such as for instance 1,4. dioxane), at a temperature ranging from around 80 °C to around 100 °C to yield intermediate 16. Compounds I-d and I-d’ can be obtained from intermediate 16 in analogy to following steps B and C described in Scheme 3. The invention thus also relates to a process for the preparation of a compound according to the invention, comprising at least one of the following steps:

[0133] (a) the reaction of a compound of formula (Al) with a compound of formula (A2) in presence of a suitable solvent and a suitable base;

[0134] (b) the reaction of a compound of formula (Bl) with a compound of formula (B2)

[0135] H2N - R6

[0136] (B2) in presence of a suitable catalyst, a suitable solvent and a suitable solvent; in the above process, L and I -R6are as described herein;

[0137] In step (a) the base can be a suitable organic or mineral base such as for instance DIPEA, DBU, K2CO3, CS2CO3 or NaH;

[0138] In step (a) the solvent can be a suitable polar solvent such as for instance DMF, DMA, NMP, DMSO, THF, MeTHF or a mixture thereof;

[0139] The reaction of step (a) is preferentially run at a temperature ranging from about -10 °C to about 120 °C;

[0140] In step (b) the catalyst can be for instance a suitable palladium catalyst such as for instance tBuXPhosPdG3, RuPhos-Pd-G3 or [tBuBrettPhos Pd(allyl)]OTf;

[0141] In step (b) the base can be for instance a suitable base such as for instance CS2CO3, K2CO3 or K3PO4;

[0142] In step (b) the solvent can be a suitable solvent such as for instance 1,4-di oxane or t-amyl alcohol;

[0143] The reaction of step (b) is preferentially run at a temperature ranging from about 80 °C to about 100 °C.

[0144] The present invention also relates to a compound according to the invention when manufactured according to a process as described above.

[0145] The invention also relates in particular to:

[0146] A compound of formula (I) as describe herein or a pharmaceutically acceptable salt thereof, for use as therapeutically active substance;

[0147] A pharmaceutical composition comprising a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier;

[0148] The use of a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, for the treatment or prophylaxis of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel diseases (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis, in particular inflammatory bowel diseases (IBD); The use of a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prophylaxis rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel diseases (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis, in particular inflammatory bowel diseases (IBD);

[0149] A compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel diseases (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis, in particular inflammatory bowel diseases (IBD); and

[0150] A method for the treatment or prophylaxis of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel diseases (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis, which method comprises administering an effective amount of a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

[0151] Pharmaceutical Compositions

[0152] 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.

[0153] 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.

[0154] 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.

[0155] 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.

[0156] 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).

[0157] The invention will now be illustrated by the following examples which have no limiting character. Examples

[0158] Abbreviations

[0159] [tBuBrettPhos Pd(allyl)]OTf allyl(2-di-tert-butylphosphino-3,6-dimethoxy-2’,4’,6’-triisopropyl-

[0160] 1,1’ -biphenyl )palladium(II) triflate (CAS # 1798782-15-6)

[0161] ACN acetonitrile

[0162] AIBN azobi si sobutyronitrile

[0163] ATP adenosine triphosphate

[0164] BAST Bi s(2-m ethoxy ethyl)aminosulfur trifluoride

[0165] Boc tert-butyl oxycarbonyl

[0166] CAS chemical abstracts service

[0167] DAST diethylaminosulfur trifluoride

[0168] DCM dichloromethane

[0169] DIPEA 7V,7V-diisopropylethylamine

[0170] DMF N,N -dimethylformamide

[0171] DMSO dimethyl sulfoxide

[0172] EDCI l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide eq. equivalents

[0173] ESI electrospray ionization

[0174] EtOAc ethyl acetate

[0175] EtOH ethanol

[0176] FA formic acid

[0177] HATU (l-[bis(dimethylamino)methylene]-U / -l,2,3-triazolo[4,5-

[0178] Z>]pyridinium 3 -oxide hexafluorophosphate

[0179] HPLC high-performance liquid chromatography iPrOH iso-propanol LC-MS liquid chromatography - mass spectrometry

[0180] LDA lithium diisopropylamide mCPBA meto-chloroperoxybenzoic acid

[0181] MeOH methanol

[0182] MsCl mesyl chloride

[0183] NBS N-bromosuccinimide

[0184] NMR nuclear magnetic resonance

[0185] NPLC normal phase liquid chromatography

[0186] PE petroleum ether psi pounds per square inch

[0187] QToF quadrupole time of flight

[0188] Rf retention factor

[0189] RT or rt room temperature

[0190] RuPhos-Pd-G3 (2-Dicyclohexylphosphino-2 6 '-dii sopropoxy- 1 , 1 '-biphenyl) [2-(2 amino- l,r-biphenyl)]palladium(II) methanesulfonate (CAS # 1445085-77-7)

[0191] SEM-C1 2-(trimethylsilyl)ethoxym ethyl chloride

[0192] TBDMS-C1 tert-butyldimethylsilyl chloride tBuXPhosPdG3 [(2-Di-tert-butylphosphino-2’ ,4’ ,6’ -triisopropyl- 1,1’ -biphenyl)-2- (2’ -amino- 1,1’ -biphenyl)] palladium(II) methanesulfonate (CAS # 1447963-75-8)

[0193] TEA triethylamine

[0194] Tf triflyl

[0195] TFA trifluoroacetic acid

[0196] THF tetrahydrofuran

[0197] TLC thin layer chromatography TsOH tosylic acid

[0198] UV ultraviolet

[0199] Example 1 5-Methyl- 1- [6- [5- [(6-methylpyridazin-3-yl)amino] benzimidazol- 1-yl] -3-tetrahydrofuran-2- yl-2-pyridyl]pyrazole-3-carbonitrile

[0200] Step 1: l-(4-chloro-2-fluoro-phenyl)-4-hydroxy-butan-l-one To a solution of 2-chloro-6-fluoro-pyridine (10 g, 76.02 mmol, 1 eq.) in THF (100 mL) was added LDA (49.4 mL, 98.83 mmol, 1.3 eq.) dropwise while keeping the inner temperature between -70 and -60 °C under N2 atmosphere. Then a solution of gamma-butyrolactone (7.2 g, 83.62 mmol, 1.1 eq.) in THF (20 mL) was added dropwise while keeping the inner temperature between -70 and -60 °C under N2 atmosphere. When the addition was complete, the mixture was stirred at -60 °C for 3 hours. The mixture was poured into saturated aqueous solution of NH4CI (300 mL) and extracted with EtOAc (2 x 200 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% EtOAc in petroleum ether). The title compound (7.4 g, 34% yield) was obtained as an off-white gum. LC-MS: m / z = 200.0 [M -H2O+H]+, ESI pos. Step 2: 4-[tert-butyl(dimethyl)silyl]oxy-l-(6-chloro-2-fluoro-3-pyridyl)butan-l-one

[0201] To a solution of l-(6-chloro-2-fluoro-3-pyridyl)-4-hydroxy-butan-l-one (7.4 g, 23.8 mmol, 1 eq.) in DCM (50 mL) were added tert-butyldimethylchlorosilane (4.31 g, 28.56 mmol, 1.2 eq.) and imidazole (2.43 g, 35.7 mmol, 1.5 eq.). The reaction mixture was stirred at 20 °C for 16 hours. The mixture was washed wth H2O (2 x 50 mL) and the organic layer was concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 10% EtOAc in petroleum ether, UV detetction, Rf = 0.4). The title compound (6.2 g, 79% yield) was obtained as a colourless oil. 'H NMR (400 MHz, CDCI3): 5 = 8.31 (dd, J= 8.1, 9.0 Hz, 1H), 7.35 (dd, J= 1.3, 7.9 Hz, 1H), 3.70 (t, J = 6.1 Hz, 2H), 3.08 (dt, J = 2.9, 7.2 Hz, 2H), 1.94 (quin, J= 6.6 Hz, 2H), 0.88 (s, 9H), 0.04 (s, 6H).

[0202] Step 3: l-[3-[4-[tert-butyl(dimethyl)silyl] oxybutanoyl] -6-chloro-2-pyridyl] -5-methyl-pyrazole- 3-carbonitrile

[0203] A mixture of of 5-methyl-lH-pyrazole-3-carbonitrile (1.96 g, 18.31 mmol, 0.980 eq.), 4-[tert- butyl(dimethyl)silyl]oxy-l-(6-chloro-2-fluoro-3-pyridyl)butan-l-one (6.2 g, 18.68 mmol, 1 eq.) and DIPEA (9.3 mL, 56.04 mmol, 3 eq.) in DMSO (50 mL) was stirred at 30 °C for 16 hours. The reaction mixture was poured into H2O (500 mL) and extracted with EtOAc (3 x 200 mL). The combined organics were washed with brine (3 x 200 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 5% to 50% EtOAc in petroleum ether). The first title compound (1.2 g, 15% yield) was obtained as colourless oil. LC-MS: m / z = 419.1 [M+H]+, ESI pos. ‘HNMR (400 MHz, CDCI3): 8 = 7.92 (d, J= 8.0 Hz, 1H), 7.52 - 7.45 (m, 1H), 6.62 - 6.58 (m, 1H), 3.63 (t, J= 5.9 Hz, 2H), 2.62 (s, 3H), 2.55 (t, J= 7.3 Hz, 2H), 1.89 (br d, J= 7.1 Hz, 2H), 0.86 (s, 10H), 0.06 - 0.00 (m, 6H).

[0204] Step 4: l-[3-[ 4-[ ter t-butyl(dimethyl) silyl ] oxy-1 -hydroxy-butyl / -6-chloro-2-pyridyl ]-5-methyl- pyrazole-3-carbonitrile

[0205] To a solution of l-[3-[4-[tert-butyl(dimethyl)silyl]oxybutanoyl]-6-chloro-2-pyridyl]-5-methyl- pyrazole-3 -carbonitrile (1.2 g, 2.86 mmol, 1 eq.) in MeOH (15 mL) was added portiowise NaBT (130 mg, 3.44 mmol, 1.2 eq.) at 0 °C. The reaction mixture was stirred at 0 °C for 20 minutes. The mixture was quenched with saturated aqueous NH4CI solution (50 mL) and extrated with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous ISfeSCU, filtered and concentrated to give the crude title product (1 g, 83% yield) as a colourless oil. LC-MS: m / z = 421.3 [M+H]+, ESI pos.

[0206] Step 5: l-[ 6-chloro-3-( 1, 4-dihydroxybutyl)-2 -pyridyl ]-5-methyl-pyrazole-3-carbonitrile

[0207] To a solution of l-[3-[4-[tert-butyl(dimethyl)silyl]oxy-l-hydroxy-butyl]-6-chloro-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile (1.2 g, 2.85 mmol, 1 eq.) in MeOH (10 mL) was added ammonium fluoride (1.06 g, 28.5 mmol, 10 eq.). The mixture was stirred at 80 °C for 2 hours. The mixture was cooled to RT, poured into H2O (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the crude title product l-[6-chloro-3-(l,4-dihydroxybutyl)-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile (900 mg, 2.93 mmol, quantitative yield) as a colorless oil. LC-MS: m / z = 289.1 [M+H-H20]+, ESI pos. Step 6: l-( 6-chloro-3-tetrahydrofuran-2-yl-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile

[0208] To a colourless solution of l-[6-chloro-3-(l,4-dihydroxybutyl)-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile (0.9 g, 2.93 mmol, 1 eq.) in toluene (10 mL) was added p-toluenesulfonic acid (50 mg, 0.29 mmol, 0.1 eq.). The reaction mixture was then stirred at 130 °C for 16 hours. The mixture was cooled to rt and H2O (50 mL) was added. This was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (80 mL), dried over ISfeSCU, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 10% EtOAc in petroleum ether). The title compound (800 mg, 94% yield) was obtained as a light brown oil. LC-MS: m / z = 289.0 [M+H]+, ESI pos.

[0209] Step 7: lH-benzimidazol-5-yl-(6-methylpyridazin-3-yl)amine

[0210] 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 iPrOH (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. 1H NMR (400 MHz, DMSO-d6): 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= 92 Hz, 1H), 7.21 (d, J= 92 Hz, 1H), 5.04 - 4.15 (m, 1H), 2.49 (s, 3H). Step 8: 5-methyl-l-[ 6-[5-[ ( 6-methylpyridazin-3-yl)amino ] benzimidazol- 1-yl / -3-tetrahydrofuran- 2-yl-2-pyridyl]pyrazole-3-carbonitrile

[0211] To a solution of l-(6-chloro-3-tetrahydrofuran-2-yl-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile (70 mg, 0.24 mmol, 1 eq.) in DMSO (1 mL) were added N-(6-methylpyridazin-3-yl)-lH- benzimidazol-5-amine (obtained as in step 1 of example 59) (55 mg, 0.24 mmol, 1 eq.) and K2CO3 (100 mg, 0.73 mmol, 3 eq.). Then the brown suspension was stirred at 90 °C for 16 hours. The reaction mixture was cooled to , poured into H2O (30 mL) and a solid precipitate out. The solid was collected by filtration and directly purified by preparative The filter cake was purified by preparative HPLC (column Phenomenex Synergi C18 (150mm x 25mm x 10pm). Flow rate: 25 mL / minutes., CH3CN in (0.225% formic acid in H2O v / v) (10 min) then 100% CH3CN (2 min)) to give 5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]- 3-tetrahydrofuran-2-yl-2-pyridyl]pyrazole-3-carbonitrile (6.3 mg, 5% yield) was obtained as an off-white solid. LC-MS: m / z = 478.1 [M+H]+, ESI pos. 'H NMR (400 MHz, CDCI3): 8 = 8.60 - 8.56 (m, 1H), 8.40 - 8.34 (m, 1H), 8.02 - 7.97 (m, 1H), 7.81 - 7.77 (m, 1H), 7.77 - 7.73 (m, 1H), 7.42 - 7.36 (m, 1H), 7.23 - 7.13 (m, 2H), 6.68 (s, 1H), 4.89 (t, J= 7.5 Hz, 1H), 4.13 (br d, J= 8.2 Hz, 1H), 3.94 (d, J= 8.3 Hz, 1H), 2.60 (s, 3H), 2.44 (s, 3H), 2.34 - 2.27 (m, 1H), 2.09 - 2.00 (m, 3H).

[0212] Example 2

[0213] 5-Methyl- 1- [6- [6- [(6-methylpyridazin-3-yl)amino] benzimidazol- 1-yl] -3-tetrahydrofuran-2- yl-2-pyridyl]pyrazole-3-carbonitrile

[0214]

[0215] The title compound 5-methyl-l-[6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3- tetrahydrofuran-2-yl-2-pyridyl]pyrazole-3-carbonitrile (9.9 mg, 8% yield) was obtained in step 7 of Example 1 after the purification by preparative TLC, as an off-white solid. LC-MS: m / z = 478.1 [M+H]+, ESI pos.XH NMR (400 MHz, CDC13): 5 = 8.51 (s, 1H), 8.41 - 8.33 (m, 1H), 8.29 - 8.21 (m, 1H), 7.82 - 7.74 (m, 2H), 7.24 - 7.19 (m, 1H), 7.17 - 7.12 (m, 1H), 7.11 - 7.06 (m, 1H), 6.64 - 6.62 (m, 1H), 4.86 (t, J = 7.4 Hz, 1H), 4.11 (d, J = 8.2 Hz, 1H), 3.93 (d, J = 7.9 Hz, 1H), 2.62 (s, 3H), 2.40 (s, 3H), 2.26 (dd, J= 5.9, 12.7 Hz, 2H), 2.02 (t, J= 7.2 Hz, 2H). Example s

[0216] 1- [3-(3-hydroxyoxetan-3-yl)-6- [5- [(6-methylpyridazin-3-yl)amino] benzimidazol- 1-yl] -2- pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0217] Step 1: 3-(6-chloro-2-fluoro-3-pyridyl)oxetan-3-ol

[0218] To the solution of 2-chloro-6-fhioropyridine (1.0 g, 7.6 mmol, 1.0 eq.) in THF (10 mL) was added LDA (3.65 mL, 9.12 mmol, 1.2 eq.) dropwise at -70 °C over a period of 15 minutes under N2. The reaction mixture was stirred at -70 °C under N2 for 30 minutes after which 3-oxetanone (0.6 g, 8.36 mmol, 1.1 eq.) was added dropwise at -70 °C, and the reaction mixture was further stirred at -70 °C for 2.5 hours. The reaction mixture was quenched with 50 mL of water under stirring. The aqueous layer was extracted with ethyl acetate, and the combined extracts were concentrated under vacuum. The residue was purified by flash column chromatography (40% EtOAc in PE) to yield 3-(6-chloro-2-fluoro-3-pyridyl)oxetan-3-ol (1.1 g, 5.4 mmol, 71% yield) as off-white solid. LC-MS: m / z = 203.9 [M+H]+, ESI pos. 'H NMR (400 MHz, CDCI3) 8 = 7.84 (dd, J= 7.8, 9.8 Hz, 1H), 7.30 (dd, J= 1.0, 7.9 Hz, 1H), 5.11 (d, J= 7.3 Hz, 2H), 4.86 (d, = 7.5 Hz, 2H), 2.84 (s, 1H).

[0219] Step 2: l-[6-chloro-3-(3-hydroxyoxetan-3-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0220] A solution of 3 -(6-chloro-2-fluoro-3 -pyri dyl)ox etan-3 -ol (400 mg, 1.96 mmol, 1.0 eq.), 5- methyl-lH-pyrazole-3-carbonitrile (210 mg, 1.96 mmol, 1.0 eq.) and DIPEA (0.97 mL, 5.89 mmol, 3.0 eq.) in DMSO (5 mL) was stirred at 120 °C for 12 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were concentrated under vacuum. The residue was purified by preparative HPLC (column Phenomenex Synergi C18 (150mm x 25mm x 10pm). Flow rate: 25 mL / minutes., CH3CN in (0.225% formic acid in H2O v / v) (10 min) then 100% CH3CN (2 min)) to afford l-[6-chl oro-3 -(3 -hydroxyox etan-3 -yl)- 2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (150 mg, 0.52 mmol, 26% yield) as purple solid. LC-MS: m / z = 291.0 [M+H]+, ESI pos. 'H NMR (400 MHz, CDCI3) 6 = 8.25 (d, J = 8.3 Hz, 1H), 7.85 (d, J= 8.3 Hz, 1H), 6.97 (d, J= 0.8 Hz, 1H), 6.27 (s, 1H), 4.78 (d, J= 7.6 Hz, 2H), 4.37 (d, J= 7.8 Hz, 2H), 2.25 (s, 3H). Step 3: l-[3-(3-hydroxyoxetan-3-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl] -5-methyl-pyrazole-3-carbonitrile

[0221] To a solution of l-[6-chloro-3-(3-hydroxyoxetan-3-yl)-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile (150 mg, 0.52 mmol, 1.0 eq.) in DMSO (3 mL) was added N-(6-methylpyridazin-3- yl)-lH-benzimidazol-5-amine (Example 1, step 7) (116 mg, 0.52 mmol, 1.0 eq.) and K^CCL (143 mg, 1.03 mmol, 2.0 eq.). The reaction mixture was stirred at 100 °C for 15hours. 30 mL of water was added and the mixture was stirred at 30 °C for 10 minutes. The reaction mixture was filtered and the filter cake was dried under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH 10: 1) followed by preparative HPLC (column Phenom enex Synergi C18 (150mm x 25mm x 10pm). Flow rate: 25 mL / minutes., CH3CN in (0.225% formic acid in H2O v / v) (10 min) then 100% CH3CN (2 min)) to afford l-[3-(3-hydroxyoxetan-3-yl)-6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (15.5 mg, 0.03 mmol, 6% yield) as yellow solid. LC-MS: m / z = 480.3 [M+H]+, ESI pos.JH NMR (400 MHz, CDCI3) 8 = 9.58 - 9.40 (m, 1H), 9.09 (s, 1H), 8.45 - 8.37 (m, 2H), 8.26 (d, J= 8.4 Hz, 1H), 8.13 (s, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.53 - 7.43 (m, 2H), 7.24 (br d, J= 9.9 Hz, 1H), 7.04 (s, 1H), 6.23 (s, 1H), 4.85 (d, J= 7.2 Hz, 2H), 4.43 (d, J= 7.2 Hz, 2H), 2.49 - 2.48 (m, 3H), 2.36 (s, 3H).

[0222] Example 4 5-Methyl-l-[6-[5-[(l-methyltriazol-4-yl)amino]benzimidazol-l-yl]-3-tetrahydrofuran-2-yl- 2-pyridyl]pyrazole-3-carbonitrile

[0223] Step 1: l-[6-(5-bromobenzimidazol-l-yl)-3-tetrahydrofuran-2-yl-2-pyridyl]-5-methyl-pyrazole- 3-carbonitrile and l-[6-( 6-bromobenzimidazol-l-yl)-3-tetrahydrofuran-2-yl-2-pyridyl -5- methyl-pyrazole-3-carbonitrile

[0224] To a solution of l-(6-chloro-3-tetrahydrofuran-2-yl-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile (obtained in step 6 of example 1) (540 mg, 1.87 mmol, 1.0 eq.) in DMSO (10 mL) were added K2CO3 (378 mg, 3.74 mmol, 2.0 eq.) and 5-bromo-lH-benzimidazole (368 mg, 1.87 mmol, 1.0 eq.). The mixture was stirred at 90 °C for 16 hours. The reaction mixture was cooled to rt, poured into H2O (100 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 20% to 100% EtOAc in petroleum ether). A mixture of both title compounds (300 mg) was obtained, which was further purified by preparative TLC (silica gel, 80% EtOAc in petroleum ether, UV detection).

[0225] The first title compound l-[6-(5-bromobenzimidazol-l-yl)-3-tetrahydrofuran-2-yl-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile (150 mg, 18% yield) was obtained as a white solid. LC-MS: m / z = 449.1 [M+H]+, ESI pos. 'H NMR (400 MHz, CDCI3): 8 = 9.03 (s, 1H), 8.43 - 8.28 (m, 1H),

[0226] 8.12 - 7.98 (m, 1H), 7.93 - 7.79 (m, 2H), 7.56 - 7.43 (m, 1H), 6.60 (s, 1H), 4.94 - 4.77 (m, 1H),

[0227] 4.11 - 3.97 (m, 1H), 3.92 - 3.82 (m, 1H), 2.34 (s, 3H), 2.29 - 2.18 (m, 2H), 1.99 - 1.91 (m, 3H),

[0228] 1.65 - 1.52 (m, 1H). The second title compound l-[6-(6-bromobenzimidazol-l-yl)-3-tetrahydrofuran-2-yl-2-pyridyl]- 5-methyl-pyrazole-3-carbonitrile (140 mg, 12% yield) was obtained as an off-white solid. LC- MS: m / z = 449.1 [M+H]+, ESI pos. 'HNMR (400 MHz, CDCI3): 8 = 9.25 - 8.93 (m, 1H), 8.50 - 8.41 (m, 1H), 8.29 - 8.19 (m, 1H), 7.99 - 7.77 (m, 2H), 7.65 - 7.51 (m, 1H), 6.73 - 6.64 (m, 1H), 4.99 - 4.86 (m, 1H), 4.20 - 4.07 (m, 1H), 4.01 - 3.89 (m, 1H), 2.46 (s, 3H), 2.36 - 2.26 (m, 2H), 2.11 - 1.98 (m, 3H), 1.67 (dd, J= 8.0, 12.6 Hz, 1H).

[0229] Step 2: 5-methyl-l-[ 6-[5-[ ( 1 -methyltriazol-4-yl)amino ]benzimidazol-l-yl / -3-tetrahydrofuran-2- yl-2-pyridyl]pyrazole-3-carbonitrile

[0230] To a light brown solution of l-[6-(5-bromobenzimidazol-l-yl)-3-tetrahydrofuran-2-yl-2-pyridyl]- 5-methyl-pyrazole-3-carbonitrile (30 mg, 0.07 mmol, 1.0 eq.) in 1,4-dioxane (2 mL) were added 1 -methyltriazol -4-amine (8 mg, 0.08 mmol, 1.2 eq.), CS2CO3 (43 mg, 0.13 mmol, 2.0 eq.) and RuPhos-Pd-G3 (6 mg, 0.01 mmol, 0.1 eq.). The reaction mixture was heated to 100 °C and stirred for 16 hours under N2 atmosphere. The reaction mixture was cooled to rt and filtered through a celite pad. The filter cake was washed with EtOAc. The filtrate was concentrated under vacuum. The residue was purified by preparative HPLC (column Phenomenex Synergi C18 (150mm x 25mm x 10pm). Flow rate: 25 mL / minutes., CH3CN in (0.225% formic acid in H2O v / v) (10 min) then 100% CH3CN (2 min)) to give 5-methyl-l-[6-[5-[(l-methyltriazol-4- yl)amino]benzimidazol-l-yl]-3-tetrahydrofuran-2-yl-2-pyridyl]pyrazole-3-carbonitrile (15 mg, 43% yield) as a white solid. LC-MS: m / z = 467.2 [M+H]+, ESI pos. 'H NMR (400 MHz, METHANOL-d4) 5 = 8.84 (s, 1H), 8.44 - 8.38 (m, 1H), 8.12 - 8.05 (m, 1H), 8.04 - 8.00 (m, 1H), 7.71 (s, 1H), 7.46 - 7.42 (m, 1H), 7.18 - 7.11 (m, 1H), 6.87 (s, 1H), 4.83 (t, J= 7.4 Hz, 1H), 4.14 (br s, 4H), 3.94 - 3.86 (m, 1H), 2.42 (s, 3H), 2.23 - 2.13 (m, 1H), 2.09 - 1.95 (m, 2H), 1.77 - 1.67 (m, 1H). Example 5 l-[6-[5-(2,6-Diazaspiro[3.4]octan-6-yl)benzimidazol-l-yl]-3-tetrahydrofuran-2-yl-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile Step 1: tert-butyl 7-[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-tetrahydrofuran-2-yl-2- pyridyl ]benzimidazol-5-yl ]-2, 7 -diazaspiro [ 3.4 ] octane-2-carboxylate

[0231] Following the procedure decribed in Example 4, step 2, with tert-butyl 2,6- diazaspiro[3.4]octane-2-carboxylate (34 mg, 0.16 mmol, 1.2 eq.), and after purification by preparative TLC (silica gel, EtOAc, UV detection), the title compound (30 mg, 39% yield) was obtained as a light brown solid. LC-MS: m / z = 581.4 [M+H]+, ESI pos.

[0232] Step 2: l-[ 6-[5-(2, 6-diazaspiro[ 3.4 ] octan-6-yl)benzimidazol-l-yl / -3-tetrahydrofuran-2-yl-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0233] To a solution of tert-butyl 7-[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-tetrahydrofuran-2-yl-2- pyridyl]benzimidazol-5-yl]-2,7-diazaspiro[3.4]octane-2-carboxylate (30 mg, 0.05 mmol, 1.0 eq.) in DCM (2 mL) was added TFA (0.4 mL, 5.19 mmol, 100 eq.). The reaction mixture was stirred at 20 °C for 0.5 hours. The reaction mixture was concentrated and the residue was purified by preparative HPLC (column Phenomenex Gemini-NX C18 (75mm x 30mm x 3pm). Flow rate: 25 mL / minutes., CH3CN in (0.225% formic acid in H2O v / v) (7 min) then 100% CH3CN (2 min)) to give the title compound (11 mg, 43% yield) as a white solid. LC-MS: m / z = 481.2 [M+H]+, ESI pos. 'H NMR (400 MHz, METHANOL-d4) 5 = 8.78 (s, 1H), 8.54 (s, 1H), 8.40 - 8.34 (m, 1H), 8.05 - 7.96 (m, 2H), 6.88 - 6.82 (m, 2H), 6.81 - 6.70 (m, 1H), 4.82 - 4.77 (m, 1H), 4.17 - 4.03 (m, 5H), 3.94 - 3.84 (m, 1H), 3.59 (s, 2H), 3.47 - 3.37 (m, 2H), 2.41 - 2.32 (m, 5H), 2.21 - 2.09 (m, 1H), 2.05 - 1.92 (m, 2H), 1.75 - 1.62 (m, 1H).

[0234] Example 6 l-[3-[(21?,41?)-4-hydroxytetrahydrofuran-2-yl]-6-[6-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile and l-[3-[(25',45)-4-hydro ytetrahydrofuran-2-yl]-6-[6-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile Step 1: l-(6-chloro-2-fluoro-3-pyridyl)but-3-en-l-ol

[0235] 6-chloro-2-fluoro-nicotinaldehyde (15 g, 94.01 mmol, 1.00 eq.) was dissolved in THF (350 mL) and allylmagnesium bromide IM in Et20 (99 mL, 99 mmol, 1.05 eq.) was added slowly at -10 °C. The reaction mixture was stirred at -10 °C for 3 hours. The mixture was then quenched with saturated aqueous NH4CI sol. and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgSCU, filtered and concentrated. The crude material was purified by flash chromatography (SiCh, 0% to 50% EtOAc in heptane) to give the title compound (13.64 g, 68% yield) as a red liquid.JH NMR (300 MHz, CDCI3): 8 = 7.92 (t, J= 8.5 Hz, 1H), 7.28 - 7.24 (m, 2H), 5.80 (dddd, J = 6.5, 7.9, 10.4, 16.9 Hz, 1H), 5.30 - 4.96 (m, 3H), 2.68 - 2.54 (m, 1H), 2.47 - 2.32 (m, 1H), 2.17 (d, J= 3.8 Hz, 1H).

[0236] Step 2: l-(6-chloro-2-fluoro-3-pyridyl)-2-(oxiran-2-yl)ethanol l-(6-chloro-2-fhioro-3-pyridyl)but-3-en-l-ol (13.6 g, 67.45 mmol, 1.0 eq.) was dissolved in DCM (330 mL). 3 -chloroperoxybenzoic acid (19.95 g, 80.94 mmol, 1.2 eq.) was added at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour and then at RT overnight. The mixture was poured into saturated aqueous Na2COs sol. and extracted with DCM twice. The combined organic layers were washed with saturated aqueous Na2COs sol., dried over MgSCU, filtered and concentrated in vacuo to get the crude title compound (13.68 g, 89% yield) as light yellow liquid which was used without further purification. LC-MS: m / z = 218.1 [M+H]+, ESI pos. Step 3: 5-(6-chloro-2-fluoro-3-pyridyl)tetrahydrofuran-3-ol l-(6-chloro-2-fluoro-3-pyridyl)-2-(oxiran-2-yl)ethanol (4.8 g, 22.06 mmol, 1.0 eq.) was dissolved in 1,4-dioxane (120 mL) and H2SO4 (2.08 g, 1.13 mL, 21.17 mmol, 0.96 eq.) was added at RT. The reaction mixture was then stirred for 5 hours at 50 °C. The mixture was cooled to rt, quenched with saturated aqueous NaHCCh sol. and extracted twice with EtOAc. The combined organic layers were washed twice with saturated aqueous NaHCCh sol., dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography (SiCh, 0% to 100% EtOAc in heptane) to give the title compound (2.4 g, 50% yield) as a light yellow oil. LC-MS: m / z = 218.0 [M+H]+, ESI pos.

[0237] Step 4: l-[ 6-chloro-3-( 4-hydroxytetrahydrofuran-2-yl)-2-pyridyl / -5-methyl-pyrazole-3- carbonitrile

[0238] 5-(6-chloro-2-fluoro-3-pyridyl)tetrahydrofuran-3-ol (1.92 g, 8.82 mmol, 1 eq.) was dissolved in DMF and 5-methyl-lH-pyrazole-3-carbonitrile (1.13 g, 10.59 mmol, 1.2 eq.) and K2CO3 (1.83 g, 13.23 mmol, 1.5 eq.) were added at RT. The reaction mixture was then stirred at 70 °C overnight. The mixture was cooled to rt, diluted with H2O and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by flash chromatography (SiO2, 0% to 80% EtOAc in heptane) to give title compound (1.67 g, 59% yield) as a colorless viscous oil. LC-MS: m / z = 305.1 [M+H]+, ESI pos. Step 5: l-[ 3-[ (2R, 4R)-4-hydroxytetrahydrofuran-2-yl ]-6-[ 6-[ ( 6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl ]-2-pyridyl ]-5-methyl-pyrazole-3-carbonitrile and l-[ 3-[ (2S, 4S)-4- hydroxytetrahydrofuran-2-yl -6-[ 6-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl -2- pyridyl]-5-methyl-pyrazole-3-carbonitrile l-[6-chloro-3-(4-hydroxytetrahydrofuran-2-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (100 mg, 0.328 mmol, 1.0 eq.) was dissolved in DMF and lH-benzimidazol-5-yl-(6-methylpyridazin- 3-yl)amine (Example 1, step 7) (81 mg, 0.361 mmol, 1.1 eq.) and CS2CO3 (214 mg, 0.656 mmol, 2 eq.) were added at RT. The reaction mixture was stirred for 4 hours at 120 °C. The mixture was cooled to rt, diluted with H2O and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgSCU, filtered and concentrated. The crude material was purified by flash chromatography (SiCh, 0% to 10% MeOH in DCM). Two fractions were obtianed. They were both further purified by preparative SFC (column achiral 100 PEI (250mm x 20 mm x 5pm). 30% (0.2% diethylamine in MeOH) in SCCO2). The title compound (14 mg, 8% yield; also known as 5-methyl-l-[6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]- 3 -[rac-(2A, 4 / ?)-4-hydroxyoxolan-2-yl]pyri din-2 -yl]pyrazole-3 -carbonitrile) was obtained as a light yellow solid. LC-MS: m / z = 494.2 [M+H]+, ESI pos. 'H NMR (600 MHz, CDCI3): 8 = 11.64 - 11.21 (m, 1H), 8.62 - 8.55 (m, 1H), 8.49 (s, 1H), 8.26 (d, J= 1.7 Hz, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.72 (d, J= 8.4 Hz, 1H), 7.22 (dd, J= 2.1, 8.6 Hz, 1H), 7.10 (d, J= 9.1 Hz, 1H), 7.08 (br d, J= 7.3 Hz, 1H), 7.00 (d, J = 9.1 Hz, 1H), 6.62 (d, J= 0.8 Hz, 1H), 4.92 (dd, J= 5.9, 8.8 Hz, 1H), 4.61 (br d, J= 1.4 Hz, 1H), 4.13 (td, J= 1.4, 10.0 Hz, 1H), 3.86 (dd, J= 3.9, 10.0 Hz, 1H), 2.61 (s, 3H), 2.61 (s, 1H), 2.42 (d, J= 0.8 Hz, 2H), 1.92 - 1.83 (m, 1H). Cis-isomery confirmed by ROESY (correlation visible between H-4’ and H-5 and between H-4’ and H-3). Example 7

[0239] 1- [3- [(21?,45)-4-Hydroxytetrahydrofuran-2-yl]-6- [6- [(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile and 1- [3- [(25,41?)-4-Hydroxytetrahydrofuran-2-yl]-6- [6- [(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0240] The title compounds (19 mg, 11% yield; also known as 5-methyl-l-[6-[6-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-[rac-(27?,45)-4-hydroxyoxolan-2-yl]pyridin-2-yl]pyrazole-3- carbonitrile) were obtained in step 5 of Example 6 as a light yellow solid. LC-MS: m / z = 494.2 [M+H]+, ESI pos. 'H NMR (600 MHz, CDC13): 5 = 8.51 (s, 1H), 8.36 (d, J = 8.5 Hz, 1H), 8.32 (d, J = 2.0 Hz, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.20 (dd, J= 2.1, 8.6 Hz, 1H), 7.11 (d, J = 9.1 Hz, 1H), 6.99 (d, J= 9.1 Hz, 1H), 6.94 (br s, 1H), 6.63 (d, J= 0.8 Hz, 1H), 5.19 - 5.19 (m, 1H), 5.13 (dd, J = 5.8, 10.1 Hz, 1H), 4.64 (t, J = 4.6 Hz, 1H), 4.22 (dd, J= 4.3, 9.8 Hz, 1H), 3.92 (td, J= 1.3, 9.8 Hz, 1H), 2.62 (s, 3H), 2.40 (d, J= 0.7 Hz, 3 H), 2.36 - 2.31 (m, 1H), 1.86(ddd, J= 5.1, 10.1, 13.5 Hz, 1H).

[0241] Example 8 l-[3-[(21?,41?)-4-Hydroxytetrahydrofuran-2-yl]-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile and l-[3-[(25',45)-4-Hydroxytetrahydrofuran-2-yl]-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0242] The title compounds (13 mg, 8% yield; 5-methyl-l-[6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l -yl]-3-[rac-(2 / , 4 / ?)-4-hydroxyoxolan-2-yl]pyri din-2 -yl]pyrazole-3- carbonitrile) were obtained in step 5 of example 6 as a light yellow solid. LC-MS: m / z = 494.2 [M+H]+, ESI pos. ‘H NMR (600 MHz, CDC13): 8 = 11.58 - 11.18 (m, 1H), 8.61 (d, J = 8.4 Hz, 1H), 8.54 (s, 1H), 7.93 (d, J = 8.7 Hz, 1H), 7.74 (d, J = 1.9 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 2.2, 8.7 Hz, 1H), 7.15 - 7.11 (m, 1H), 7.06 (d, J= 9.2 Hz, 1H), 6.99 (br s, 1H), 6.66 (d, J= 0.8 Hz, 1H), 4.96 (dd, J= 5.8, 8.9 Hz, 1H), 4.64 (ddd, J= 1.6, 3.8, 5.5 Hz, 1H), 4.17 (d, J = 10.0 Hz, 1H), 3.87 (dd, J= 3.8, 10.0 Hz, 1H), 2.66 - 2.62 (m, 1H), 2.60 (s, 3H), 2.46 (d, J = 0.8 Hz, 3H), 1.93 - 1.82 (m, 1H).

[0243] Example 9

[0244] 1- [3- [(21?,45)-4-Hydroxytetrahydrofuran-2-yl]-6- [5- [(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile and

[0245] 1- [3- [(25,41?)-4-Hydroxytetrahydrofuran-2-yl]-6- [5- [(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0246] The title compounds (15.4 mg, 9.2% yield; also known as 5-methyl-l-[6-[5-[(6-methylpyridazin- 3-yl)amino]benzimidazol-l-yl]-3-[rac-(27?,45)-4-hydroxyoxolan-2-yl]pyridin-2-yl]pyrazole-3-) were obtained in step 5 of example 6 as a light yellow solid. LC-MS: m / z = 494.2 [M+H]+, ESI pos. 'H NMR (600 MHz, CDC13): 8 = 8.79 - 8.64 (m, 1H), 8.61 - 8.49 (m, 1H), 8.35 (dd, J= 0.6, 8.5 Hz, 1H), 7.97 - 7.96 (m, 1H), 7.97 (d, J= 8.7 Hz, 1H), 7.77 (d, J= 1.7 Hz, 1H), 7.74 (s, 1H), 7.39 (dd, J= 2.1, 8.7 Hz, 1H), 7.16 - 7.11 (m, 1H), 7.09 - 7.04 (m, 1H), 6.98 - 6.93 (m, 1H), 6.67 (d, J = 0.8 Hz, 1H), 5.14 (dd, J= 5.7, 10.1 Hz, 1H), 4.71 - 4.62 (m, 1H), 4.24 (dd, J= 4.3, 9.8 Hz, 1H), 3.92 (td, J= 1.2, 10.0 Hz, 1H), 2.60 (s, 2H), 2.58 - 2.55 (m, 1H), 2.44 (d, J = 0.8 Hz, 3H), 2.42 - 2.36 (m, 1H), 1.88 (ddd, J= 5.0, 10.1, 13.5 Hz, 1H), 1.44 - 1.35 (m, 1H).

[0247] Example 10 l-[6-[5-[[(3R,4S)-4-Fluoropyrrolidin-3-yl]amino]benzimidazol-l-yl]-3-tetrahydrofuran-2- yl-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile Step 1: 1 tert-butyl (3R,4S)-3-[[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-tetrahydrofuran-2-yl-2- pyridyl ]benzimidazol-5-yl amino ] -4-fluoro-pyrrolidine-l -carboxylate

[0248] Following the procedure decribed in Example 4, step 2, with tert-butyl (3R,4S)-3-amino-4- fluoropyrrolidine-1 -carboxylate (45 mg, 0.22 mmol, 2 eq.), and after purification by preparative TLC (silica gel, EtOAc, UV detection), the title compound (50 mg, 78.5% yield) was obtained as a light brown solid. LC-MS: m / z = 573.1 [M+H]+, ESI pos.

[0249] Step 2: l-[ 6-[5-[[ ( 3R, 4S)-4-fluoropyrrolidin-3-yl amino ]benzimidazol-l-yl / -3-tetrahydrofuran- 2-yl-2-pyridyl ]-5-methyl-pyrazole-3-carbonitrile; formic acid

[0250] The title compound was obtained following the procedure described in step 2 of example 4 and purification by preparative HPLC (column Phenomenex Gemini-NX C18 (75mm x 30mm x 3pm). Flow rate: 25 mL / minutes., CH3CN in (0.225% formic acid in H2O v / v) (7 min) then 100% CH3CN (2 min)), (8 mg, 18% yield) as an off-white solid. LC-MS: m / z = 473.1 [M+H]+, ESI pos. 'H NMR (400 MHz, METHANOL-d4): 5 = 8.81 (s, 1H), 8.43 - 8.36 (m, 1H), 8.10 - 8.03 (m, 1H), 7.99 - 7.94 (m, 1H), 7.09 - 7.04 (m, 1H), 6.95 - 6.89 (m, 1H), 6.86 (s, 1H), 5.42 -

[0251] 5.21 (m, 1H), 4.83 - 4.79 (m, 1H), 4.41 - 4.26 (m, 1H), 4.14 - 4.06 (m, 1H), 3.93 - 3.85 (m, 1H),

[0252] 3.69 - 3.57 (m, 2H), 3.56 - 3.48 (m, 1H), 3.12 - 3.02 (m, 1H), 2.40 (s, 3H), 2.21 - 2.11 (m, 1H),

[0253] 2.06 - 1.95 (m, 2H), 1.77 - 1.64 (m, 1H). Example 11 l-[3-[(2R,4R)-4-fluorotetrahydrofuran-2-yl]-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile and l-[3-[(2S,4S)-4-fluorotetrahydrofuran-2-yl]-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0254] Step 1: l-[6-chloro-3-[(2R,4R)-4-fluorotetrahydrofuran-2-yl]-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile and l-[ 6-chloro-3-[ (2S, 4S)-4-fluorotetrahydrofuran-2-yl ]-2-pyridyl ]-5-methyl- pyrazole-3-carbonitrile and l-[ 6-chloro-3-[ (2R, 4S)-4-fluorotetrahydrojuran-2-yl ]-2-pyridyl / -5-methyl-pyrazole-3- carbonitrile and l-[ 6-chloro-3-[ (2S, 4R)-4-fluorotetrahydrojuran-2-yl ]-2-pyridyl ]-5-methyl- pyrazole-3-carbonitrile l-[6-chloro-3-(4-hydroxytetrahydrofuran-2-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (200 mg, 0.656 mmol, 1.0 eq., prepared in Example 6, step 4) was dissolved in DCM (6 mL) and DAST (212 mg, 173 pL, 1.31 mmol, 2.0 eq.) was added at -78 °C. The mixture was warmed to rt and stirred overnight. The reaction mixture was quenched with saturated aqueous NaHCCf and extracted with DCM. The organic layers were dried over MgSCU, filtered and concentrated. The crude material was purified by flash column chromatography (SiCh, 0 - 40% EtOAc in heptane) to obtain a racemic mixture of l-[6-chloro-3-[(2R,4R)-4-fluorotetrahydrofuran-2-yl]-2-pyridyl]- 5-methyl-pyrazole-3-carbonitrile and l-[6-chloro-3-[(2S,4S)-4-fluorotetrahydrofuran-2-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile (63 mg, 31%) as colorless gum. LC-MS: m / z = 307.1 [M+H]+, ESI pos. 'H NMR (600 MHz, CDCI3) 6 ppm 8.22 (d, J= 8.3 Hz, 1 H), 7.48 (d, J= 8.3 Hz, 1 H), 6.60 (d, J = 0.8 Hz, 1 H), 5.20 - 5.37 (m, 1 H), 4.96 (dd, J= 9.1, 5.3 Hz, 1 H), 4.33 - 4.46 (m, 1 H), 3.69 - 3.91 (m, 1 H), 2.60 - 2.69 (m, 1 H), 2.43 (br d, J= 0.8 Hz, 1 H), 2.46 (d, J= 0.8 Hz, 2 H), 2.02 - 2.11 (m, 1 H) Cis-isomery determined by NOESY. and a racemic misture of l-[6-chloro-3-[(2R,4S)-4-fluorotetrahydrofuran-2-yl]-2-pyridyl]-5-methyl- pyrazole-3 -carbonitrile and l-[6-chloro-3-[(2S,4R)-4-fluorotetrahydrofuran-2-yl]-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile (63 mg, 31%) as white solid. LC-MS: m / z = 307.1 [M+H]+, ESI pos. 'H NMR (600 MHz, CDC13) 8 ppm 8.08 (dd, J = 8.2, 0.7 Hz, 1 H), 7.49 (d, J = 7.8 Hz, 1 H), 6.51 - 6.68 (m, 1 H), 5.23 -5.46 (m, 1 H), 5.05 (dd, J= 10.5, 5.4 Hz, 1 H), 4.01 - 4.29 (m, 2 H), 2.55 - 2.74 (m, 1 H), 2.40 (d, J = 0.8 Hz, 3 H), 1.69 - 1.85 (m, 1 H). Trans-isomery determined by NOESY.

[0255] Step 2: l-[ 3-[ (2R, 4R)-4-fluorotetrahydrofuran-2-yl ]-6-[5-[ ( 6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl / -2 -pyridyl ]-5-methyl-pyrazole-3-carbonitrile and l-[ 3-[ (2S, 4S)-4-fluorotetrahydrofuran-2-yl ]-6-[5-[ ( 6-methylpyridazin-3-yl)amino Jbenzimidazol-

[0256] 1-yl ]-2-pyridyl ]-5-methyl-pyrazole-3-carbonitrile l-[6-chloro-3-[(2R,4R)-4-fluorotetrahydrofuran-2-yl]-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile and 1 -[6-chloro-3-[(2S,4S)-4-fluorotetrahydrofuran-2-yl]-2-pyridyl]-5-methyl- pyrazole-3 -carbonitrile (28 mg, 0.091 mmol, 1 eq., prepared in example 132, step 1) was dissolved in DMF (1 mL) and lH-benzimidazol-5-yl-(6-methylpyridazin-3-yl)amine (Example 1, step 7) (22.6 mg, 0.10 mmol, 1.1 eq.) and and CS2CO3 (59.5 mg, 0.183 mmol, 2.0 eq.) were added at rt. The mixture was stirred overnight at 80 °C The reaction mixture was diluted with water and extracted with EtOAc. The organic layers were washed with brine, dried over MgSO4 and concentrated to dryness. The crude material was purified by flash column chromatography (silica gel, 0 -% MeOH in DCM) to obtain a racemic mixture of the title compounds (10 mg, 22%; also known as 5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3- [rac-(2A,4A)-4-fluorooxolan-2-yl]pyridin-2-yl]pyrazole-3 -carbonitrile) as a white solid. LC-MS: m / z = 496.3 [M+H]+, ESI pos. 'H NMR (600 MHz, DMSO-d6) 5 ppm 9.21 (s, 1 H), 9.00 (s, 1 H), 8.43 (d, J = 2.1 Hz, 1 H), 8.36 (d, J= 8.5 Hz, 1 H), 8.26 (d, J= 8.6 Hz, 1 H), 8.05 (d, J= 8.8 Hz, 1 H), 7.50 (dd, J= 8.9, 2.1 Hz, 1 H), 7.33 (d, J= 9.1 Hz, 1 H), 7.12 (d, J= 0.8 Hz, 1 H), 7.08 (d, J = 9.1 Hz, 1 H), 5.32 - 5.54 (m, 1 H), 4.83 (dd, J= 8.9, 5.6 Hz, 1 H), 4.23 - 4.33 (m, 1 H), 3.71 - 3.94 (m, 1 H), 2.48 (s, 3 H), 2.42 (d, J= 0.7 Hz, 3 H), 1.86 - 1.99 (m, 1 H).

[0257] Example 12 l-[3-[(2S,4R)-4-fluorotetrahydrofuran-2-yl]-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile and l-[3-[(2R,4S)-4-fluorotetrahydrofuran-2-yl]-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0258] A mixture of l-[6-chloro-3-[(2R,4S)-4-fluorotetrahydrofuran-2-yl]-2-pyridyl]-5-methyl- pyrazole-3 -carbonitrile and l-[6-chloro-3-[(2S,4R)-4-fluorotetrahydrofuran-2-yl]-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile (obtained in step 1, Example 11) (60 mg, 0.196 mmol, 1.0 eq.) was dissolved in DMF (2 mL) and lH-benzimidazol-5-yl-(6-methylpyridazin-3-yl)amine (Example 1, step 7) (49 mg, 0.215 mmol, 1.1 eq.) and CS2CO3 (128 mg, 0.391 mmol, 2.0 eq.) were added at rt. The mixture was stirred overnight at 80 °C. The reaction mixture was diluted with water and extracted with EtOAc. The organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by flash column chromatography (SiCh, 0 - 5% MeOH in DCM) to obtain the title compounds as a racemic mixture (16 mg, 16%; also known as 5-methyl-l-[6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-[rac-(27?,45)-4-fluorooxolan-2-yl]pyridin-2-yl]pyrazole-3- carbonitrile). LC-MS: m / z = 496.3 [M+H]+, ESI pos. 'H NMR (600 MHz, DMSO-d6) d ppm 9.11 - 9.27 (m, 1 H), 9.04 (s, 1 H), 8.43 (dd, J= 5.3, 3.2 Hz, 2 H), 8.28 (d, J= 8.5 Hz, 1 H), 8.05 (s, 1 H), 7.48 - 7.50 (m, 1 H), 7.32 (s, 1 H), 7.11 - 7.12 (m, 1 H), 7.07 (s, 1 H), 5.34 - 5.54 (m, 1 H), 4.88 (dd, J= 10.5, 5.6 Hz, 1 H), 4.20 (s, 1 H), 3.95 - 4.08 (m, 1 H), 2.48 (s, 3 H), 2.40 (d, J= 0.8 Hz, 3 H), 2.22 - 2.35 (m, 1 H), 1.95 - 2.13 (m, 1 H)

[0259] Example 13 l-[6-[5-[[6-[(3-Methoxyazetidin-l-yl)methyl]pyridazin-3-yl]amino]benzimidazol-l-yl]-3- tetrahydrofuran-2-yl-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0260] Step 1: 3-chloro-6-[(3-methoxyazetidin-l-yl)methyl]pyridazine

[0261] To a solution of 3-methoxyazetidine;hydrochloride (4.55 g, 36.81 mmol, 1.2 eq.) in CH3CN (50 mL) was added K2CO3 (6.14 g, 61.35 mmol, 2.0 eq.). The mixture was stirred for 1 hours at 30 °C. 3-chloro-6-(chloromethyl)pyridazine 3-chloro-6-(chloromethyl)pyridazine (5.0 g, 30.67 mmol, 1.0 eq.) was added. The reaction was stirred at 30 °C for 12 hours. The reaction mixture was filtered and the filtrate was concentrated. The crude was purified by flash chromatography (SiCL, 0 - 10% MeOH in DCM) to give 3-chloro-6-[(3-methoxyazetidin-l-yl)methyl]pyridazine (5.00 g, 23.4 mmol, 76% yield) as brown oil. LC-MS: m / z = 214.0 [M+H]+, ESI pos.

[0262] Step 2: N-[ 6-[(3-methoxyazetidin-l-yl)methyl]pyridazin-3-yl]-lH-benzimidazol-5-amine

[0263] To a solution of 5 -aminobenzimidazole (125 mg, 0.940 mmol, 1.0 eq.) in 1,4-dioxane (5 mL) were added 3-chloro-6-[(3-methoxyazetidin-l-yl)methyl]pyridazine (200 mg, 0.94 mmol, 1.0 eq), NaOT3u (270 mg, 2.81 mmol, 3.0 eq.) and t-Buxphos-Pd-G3 (74.36 mg, 0.090 mmol, 0.10 eq.). Then the mixture was stirred at 100 °C for 16 hours under inert atmosphere. The mixture was diluted with DMF (1 mL) and MeOH (5 mL). The suspension was stirred with thiourea resin for 2 hours and filtered. The filtrate was concentrated and the crude was purified by preparative HPLC (Waters Xbridge 150*25mm* 5um, water (lOmM NH4HCO3) - CH3CN, gradient time 9 minutes, 100% B hold time 2 min, flow rate 25 mL / min) to give N-[6-[(3-methoxyazetidin-l- yl)methyl]pyridazin-3-yl]-lH-benzimidazol-5-amine (30 mg, 0.100 mmol, 10% yield) as brown gum. LC-MS: m / z = 311.1 [M+H]+, ESI pos.

[0264] Step 3: l-[6-[5-[[6-[(3-methoxyazetidin-l-yl)methyl]pyridazin-3-yl]amino]benzimidazol-l-yl]- 3-tetrahydrofuran-2-yl-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0265] Prepared in analogy to Example 1, step 8, using N-[6-[(3-methoxyazetidin-l- yl)methyl]pyridazin-3-yl]-lH-benzimidazol-5-amine (150 mg, 0.480 mmol, 1.0 eq.) and l-(6- chloro-3-tetrahydrofuran-2-yl-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile (Example 1, step 6) (167 mg, 0.580 mmol, 1.2 eq.) followed by preparative NPLC (Welch Ultimate XB-SiOH 250 mm x 70 mm x 10 pm, gradient 15 - 55% EtOH (with 0.1% ammonium hydroxide) in hexane over 15 minutes, then 100% EtOH (with 0.1% ammonium hydroxide) (3 min), flow rate 100 mL / min) to yield l-[6-[5-[[6-[(3-methoxyazetidin-l-yl)methyl]pyridazin-3- yl]amino]benzimidazol-l-yl]-3-tetrahydrofuran-2-yl-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (12 mg, 0.020 mmol, 4% yield) as yellow solid. LC-MS: m / z = 563.2 [M+H]+, ESI pos. 'H NMR (400 MHz, CD3OD) 5 = 8.88 (s, 1H), 8.41 (d, J= 8.4 Hz, 1H), 8.22 (d, J= 1.5 Hz, 1H), 8.10 (dd, J= 3.5, 8.7 Hz, 2H), 7.58 (dd, J= 1.8, 8.8 Hz, 1H), 7.44 (d, J= 92 Hz, 1H), 7.15 (d, J = 9.0 Hz, 1H), 6.86 (s, 1H), 4.85 - 4.80 (m, 1H), 4.14 - 4.04 (m, 2H), 3.93 - 3.86 (m, 1H), 3.83 (s, 2H), 3.64 (br t, 7.3 Hz, 2H), 3.26 (s, 3H), 3.20 - 3.13 (m, 2H), 2.41 (s, 3H), 2.21 - 2.11 (m, 1H), 2.03 - 1.94 (m, 2H), 1.77 - 1.63 (m, 1H).

[0266] Example 14 l-[6-[6-[[6-[(3-Methoxyazetidin-l-yl)methyl]pyridazin-3-yl]amino]benzimidazol-l-yl]-3- tetrahydrofuran-2-yl-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile l-[6-[6-[[6-[(3-methoxyazetidin-l-yl)methyl]pyridazin-3-yl]amino]benzimidazol-l-yl]-3- tetrahydrofuran-2-yl-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (10 mg, 0.020 mmol, 4% yield) was obtained as second regioisomer of example 13 as a yellow solid after purification by NPLC (Welch Ultimate XB-SiOH 250 mm x 70 mm x 10 pm, gradient 15 - 55% EtOH (with 0.1% ammonium hydroxide) in hexane over 15 minutes, then 100% EtOH (with 0.1% ammonium hydroxide) (3 min), flow rate 100 mL / min). LC-MS: m / z = 563.2 [M+H]+, ESI pos. 'H NMR (400 MHz, CD3OD) 5 = 8.82 - 8.74 (m, 2H), 8.46 (d, J= 8.4 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.68 (d, J= 8.7 Hz, 1H), 7.46 - 7.40 (m, 2H), 7.15 (d, J = 92 Hz, 1H), 6.82 (s, 1H), 4.85 - 4.81 (m, 1H), 4.15 - 4.06 (m, 2H), 3.94 - 3.87 (m, 1H), 3.85 (s, 2H), 3.65 (br t, J= 7.3 Hz, 2H), 3.27 (s, 3H), 3.22 - 3.14 (m, 2H), 2.40 (s, 3H), 2.23 - 2.11 (m, 1H), 2.06 - 1.96 (m, 2H), 1.70 (qd, J = 7.9, 12.2 Hz, 1H). Example 15 l-[3-(l-Cyanoethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5- methyl-pyrazole-3-carbonitrile Step 1: l-(3-acetyl-6-chloro-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile

[0267] 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. 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

[0268] 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 / minutes. 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 / minutes. 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. LC-MS: m / z = 450.1 [M+H]+, ESI pos.JH NMR (400 MHz, DMSO- f,) 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). 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. LC-MS: m / z = 450.1 [M+H]+, ESI pos. 'HNMR (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).

[0269] Step 3: l-[ 3-( 1 -hydroxyethyl)-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl -2- pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0270] 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 NaBFL (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 NaBFL (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 (Waters Xbridge (150mm x 25mm x 5pm). Flow rate 60 mL / minutes. Gradient: 19% to 49% CH3CN in (10 mM NH4HCO3 in H2O) for 11 minutes then 100 % CH3CN for 2 min) to give l-[3-(l-hydroxyethyl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (400 mg, 0.887 mmol, 65% yield) was obtained as a white solid. LC-MS: m / z = 452.2 [M+H]+, ESI pos.

[0271] Step 4: l-[3-(l -chloroethyl)-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0272] A solution of l-[3-(l-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile (110 mg, 0.240 mmol, 1.0 eq.) in DCM (5 mL) was cooled to 0 °C. Thionyl chloride (1.0 mL, 13.77 mmol, 56.5 eq.) was added, followed by a drop of DMF. The mixture was warmed to 20 °C and stirred for 6 hours. The mixture was concentrated to afford l-[3-(l-chloroethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol- l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile as light brown solid which was used without further purification. LC-MS: m / z = 470.3 [M+H]+, ESI pos.

[0273] Step 5: l-[ 3-( 1 -cyanoethyl)-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2-pyridyl ]- 5-methyl-pyrazole-3-carbonitrile

[0274] To l-[3-(l-chloroethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile (used as crude from the previous step) and DIPEA (0.42 mL, 2.43 mmol, 10 eq.) in DMSO (3 mL) was added sodium iodide (36 mg, 0.240 mmol, 1.0 eq.) and sodium cyanide (71 mg, 1.46 mmol, 6.0 eq.) portionwise. The mixture was stirred at 60 °C for 16 hours. The mixture was poured into water, and the precipitate was filtered off. The mother liquor was extracted with EtOAc and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue combined with the filter cake was purified by preparative HPLC (Unisil 3-100 C18 Ultra 150 x 50mm x 3 pm), CH3CN in H2O (0.225% formic acid) over 10 minutes, then 100% CH3CN (2 min), flow rate 25 mL / min) to give l-[3-(l- cyanoethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl- pyrazole-3 -carbonitrile (3 mg, 0.010 mmol, 3% yield). LC-MS: m / z = 461.0 [M+H]+, ESI pos.

[0275] Example 16 2-[3-(l-cyanocyclopropyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0276] Step 1: 2-(6-chloro-2-fluoro-3-pyridyl)acetonitrile

[0277] To a solution of 6-chloro-3-(chloromethyl)-2-fluoro-pyridine (2.0 g, 11.11 mmol, 1.0 eq.) in DMSO (20 mL) was added NaCN (1.0 g, 20.4 mmol, 1.84 eq.). The mixture was stirred at 20 °C for 16 hours. The mixture was poured into water, and the product extracted with EtOAc. The combined organic layers were concentrated and the residue was purified by flash column chromatography (Si Ch, 25% EtOAc in PE) to give 2-(6-chloro-2-fluoro-3-pyridyl)acetonitrile (1.40 g, 8.21 mmol, 73% yield) as a yellow solid. LC-MS: m / z = 170.9 [M+H]+, ESI pos.

[0278] Step 2: l-(6-chloro-2-fluoro-3-pyridyl)cyclopropanecarbonitrile

[0279] A solution of 2-(6-chloro-2-fluoro-3-pyridyl)acetonitrile (1.2 g, 7.04 mmol, 1.0 eq.) in THF (24 mL) was cooled to 0 °C under nitrogen atmosphere. NaH (60% in mineral oil) (704 mg, 17.6 mmol, 2.5 eq.) was added and the mixture was stirred for another 10 minutes, after which 1,2- dibromoethane (1.59 g, 8.44 mmol, 1.2 eq.) in THF (0.5 mL) was added and stirred at 0 °C for 0.5 hours. The reaction mixture was allowed to reach rt and stirred for another 2 hours. The mixture was poured into saturated aqueous NH4CI and extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (SiCL, 0-25% EtOAc in PE) to give 1 -(6-chl oro-2-fluoro-3- pyridyl)cyclopropanecarbonitrile (130 mg, 0.660 mmol, 9% yield) as a brown oil. LC-MS: m / z = 196.9 [M+H]+, ESI pos.

[0280] Step 3: l-[6-chloro-3-(l-cyanocyclopropyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile and 2- [ 6-chloro-3-( I -cyanocyclopropyl)-2-pyridyl ]-5-methyl-pyrazole-3-carbonitrile

[0281] To a solution of l-(6-chloro-2-fluoro-3-pyridyl)cyclopropanecarbonitrile (130 mg, 0.660 mmol, 1.0 eq.) and 5-methyl-lH-pyrazole-3-carbonitrile (71 mg, 0.660 mmol, 1.0 eq.) in DMSO (3 mL) was added DIPEA (0.35 mL, 1.99 mmol, 3.0 eq.). The mixture was stirred at 120 °C for 32 hours. The reaction mixture was diluted with water and the product extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (SiCE, 33% EtOAc in PE) to yield 1 -[6-chl oro-3 -(1- cyanocyclopropyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (40 mg, 0.140 mmol, 21% yield) as light brown oil. LC-MS: m / z = 284.0 [M+H]+, ESI pos. 'H NMR (400 MHz, CHLOROFORM-d) 5 = 7.83 (d, J = 8.2 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), 6.66 (s, 1H), 2.44 (s, 3H), 1.70 - 1.65 (m, 2H), 1.40 - 1.35 (m, 2H) and

[0282] 2-[6-chloro-3-(l-cyanocyclopropyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (40 mg, 0.140 mmol, 22% yield) as light brown oil. LC-MS: m / z = 284.0 [M+H]+, ESI pos. 'H NMR (400 MHz, CDC13) 8 = 7.88 (d, J= 8.1 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), 6.91 (s, 1H), 2.46 (s, 3H), 1.71 - 1.66 (m, 2H), 1.21 - 1.14 (m, 2H).

[0283] Step 4: 2-[3-(l -cyanocyclopropyl) -6- [ 6-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0284] A solution of N-(6-methylpyridazin-3-yl)-lH-benzimidazol-5-amine (33 mg, 0.150 mmol, 1.04 eq.), l-[6-chloro-3-(l-cyanocyclopropyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (40 mg, 0.140 mmol, 1.0 eq.) and K2CO3 (59 mg, 0.430 mmol, 3.03 eq.) in DMSO (1 mL) was stirred at 100 °C for 16 hours. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (Phenomenex Luna Cl 8 150 x 25mm x 10 pm, CH3CN in H2O (with 0.225% formic acid) over 10 minutes, then 100% CH3CN (2 min), flow rate 25 mL / min) to give 2-[3-(l-cyanocyclopropyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile (5 mg, 0.010 mmol, 7% yield) as brown solid. LC-MS: m / z = 473.1 [M+H]+, ESI pos. 'H NMR (400 MHz, CD3OD) 5 = 8.85 (d, J = 2.0 Hz, 1H), 8.80 (s, 1H), 8.41 (d, J= 8.4 Hz, 1H), 8.13 (d, J= 8.6 Hz, 1H), 7.70 (d, J= 8.8 Hz, 1H), 7.44 (dd, J = 1.9, 8.6 Hz, 1H), 7.36 (d, J = 9.3 Hz, 1H), 7.14 (d, J = 92 Hz, 1H), 6.85 (s, 1H), 2.56 (s, 3H), 2.45 (s, 3H), 1.66 - 1.62 (m, 2H), 1.45 (br d, J= 2.3 Hz, 2H).

[0285] Example 17

[0286] 1- [3-(Difluoromethoxy)-6- [5- [(6-methylpyridazin-3-yl)amino] benzimidazol- 1-yl] -2- pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0287] Step 1: 6-chloro-3-(difluoromethoxy)-2-fluoro-pyridine

[0288] To a mixture of sodium chlorodifluoroacetate (8.27 g, 54.23 mmol, 2.0 eq.), 6-chloro-2-fluoro- pyridin-3-ol (4.0 g, 27.11 mmol, 1.0 eq.) and CS2CO3 (17.67 g, 54.23 mmol, 2. eq.) in DMF (60 mL) was stirred at 80 °C for 2 hours. The mixture was poured into water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (SiCh, 15 - 25% EtOAc in PE) to give 6-chloro-3-(difluoromethoxy)-2-fluoro-pyridine (2.30 g, 11.64 mmol, 43% yield) as colorless oil. LC-MS: m / z = 198.0 [M+H]+, ESI pos.

[0289] Step 2: l-[6-chloro-3-(difluoromethoxy)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile and 2-[6- chloro-3-(difluoromethoxy)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0290] A suspension of 6-chloro-3-(difhioromethoxy)-2-fhioro-pyridine (2.2 g, 11.14 mmol, 1.0 eq.), 5- methyl-lH-pyrazole-3-carbonitrile (1.2 g, 11.17 mmol, 1.0 eq.) and K2CO3 (4.62 g, 33.43 mmol, 3 eq.) in DMSO (108 mL) was stirred at 80 °C for 3 hours. The mixture was poured into water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and the combined organic extracts were concentrated. The crude was purified by flash chromatography (SiO2, 0-10% EtOAc in PE) to give 1 -[6-chl oro-3 -(difluoromethoxy)-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile (2.2 g, 7.73 mmol, 69.4% yield) as white solid. LC- MS: 285.1 [M+H]+, ESI pos. 'H NMR (400 MHz, CDCI3) 8 = 7.82 (d, J= 8.6 Hz, 1H), 7.54 (d, J= 8.6 Hz, 1H), 6.77 - 6.38 (m, 2H), 2.39 (s, 3H). and 2-[6-chloro-3-(difluoromethoxy)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (600 mg, 2.11 mmol, 19% yield). LC-MS: 285.1 [M+H]+, ESI pos.

[0291] Step 3: l-[ 3-(difluoromethoxy)-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl -2- pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0292] In analogy to Example 1, step 8, using l-[6-chloro-3-(difluoromethoxy)-2-pyridyl]-5-methyl- pyrazole-3 -carbonitrile (350 mg, 1.23 mmol, 1.0 eq.) and N-(6-methylpyridazin-3-yl)-lH- benzimidazol-5-amine (Example 1, step 7) (249 mg, 1.11 mmol, 0.9 eq.) followed by preparative HPLC (Waters Xbridge 150 mm x 25 mm x 5 pm, water (10 mM NH4HCO3) - CH3CN, 26% - 56% B, gradient time 9 minutes, 100% B hold time 2 min, flow rate 25 mL / min) to give l-[3- (difluoromethoxy)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile (30 mg, 0.060 mmol, 5% yield) as white solid. LC-MS: m / z = 474.1 [M+H]+, ESI pos. 'H NMR (400 MHz, CD3OD) 5 ppm 2.41 - 2.46 (m, 3 H) 2.55 (s, 3 H) 6.79 - 7.19 (t, 1 H) 6.85 - 6.91 (m, 1 H) 7.12 - 7.16 (m, 1 H) 7.35 - 7.40 (m, 1 H) 7.60 - 7.65 (m, 1 H) 8.10 - 8.16 (m, 1 H) 8.18 - 8.23 (m, 1 H) 8.24 - 8.27 (m, 1 H) 8.27 - 8.29 (m, 1 H) 8.88 - 8.93 (m, 1 H).

[0293] Example 18

[0294] 1- [3-(Difluoromethoxy)-6- [6- [(6-methylpyridazin-3-yl)amino] benzimidazol- 1-yl] -2- pyridyl]-5-methyl-pyrazole-3-carbonitrile l-[3-(difluoromethoxy)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile (26 mg, 0.050 mmol, 5% yield) was obtained as white solid in Example 17, step 2, after purification by preparative HPLC (Waters Xbridge 150*25mm* 5um, water (lOmM NH4HCO3) - CH3CN, gradient time 9 minutes, 100% hold time 2 min, flow rate 25 mL / min). LC-MS: m / z = 474.1 [M+H]+, ESI pos. 'H NMR (400 MHz, CD3OD) 5 ppm 2.35 - 2.47 (m, 3 H) 2.53 - 2.63 (m, 3 H) 6.83-7.19(t, 1 H) 6.83 - 6.86 (m, 1 H) 7.12 - 7.18 (m, 1 H)

[0295] 7.33 - 7.40 (m, 1 H) 7.44 (dd, J=8.74, 2.02 Hz, 1 H) 7.68 - 7.74 (m, 1 H) 8.19 - 8.25 (m, 1 H) 8.28 - 8.35 (m, 1 H) 8.78 - 8.82 (m, 1 H) 8.83 - 8.89 (m, 1 H). Example 19

[0296] 1- [4-(l-Hydroxyethyl)-6- [6- [(6-methylpyridazin-3-yl)amino] benzimidazol-l-yl]-2-pyridyl]- 5-methyl-pyrazole-3-carbonitrile

[0297] Step 1 : l-(4-bromo-6-fluoro-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile

[0298] A solution of 5-methyl-lH-pyrazole-3-carbonitrile (460 mg, 4.29 mmol, 1.0 eq.), 4-bromo-2,6- difluoro-pyridine (916.4 mg, 4.72 mmol, 1.1 eq.) and DIPEA (2.25 mL, 12.88 mmol, 3.0 eq.) in DMSO (20 mL) was stirred at 30 °C for 16 hours. The reaction mixture diluted with water then extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentracted. The residue was purified by flash chromatography (Si Ch, 16% EtOAc in PE) to afford l-(4-bromo-6-fluoro-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile (600 mg, 2.13 mmol, 50% yield) as white solid. LC-MS: m / z = 280.9 [M+H]+, ESI pos.

[0299] Step 2: l-[ 4-( 1 -ethoxyvinyl)-6-fluoro-2-pyridyl ]-5-methyl-pyrazole-3-carbonitrile A mixture of l-(4-bromo-6-fluoro-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile (400 mg, 1.42 mmol, 1.0 eq.), tributyl(l-ethoxyvinyl)tin (771 mg, 2.13 mmol, 1.5 eq.) and Pd(PPhs)4 (82.22 mg, 0.070 mmol, 0.05 eq.) in 1,4-dioxane (20 mL) was bubbled with N2 for 5 minutes and then stirred at 110 °C for 20 hours under N2. The reaction mixture was poured into saturated aqueous KF solution and the resulting mixture was stirred vigorously for 30 minutes and then extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentracted. The residue was purified by flash chromatography (SiCh, 0 - 16% EtOAc in PE) to afford l-[4- (l-ethoxyvinyl)-6-fluoro-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (300 mg, 1.1 mmol, 77% yield) as an off-white solid. LC-MS: m / z = 273.0 [M+H]+, ESI pos.

[0300] Step 3: l-(4-acetyl-6-fluoro-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile

[0301] To a solution of l-[4-(l-ethoxyvinyl)-6-fluoro-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (200 mg, 0.730 mmol, 1.0 eq.) in THF (5 mL)) was added IM aqueous HC1 (10.0 mL, 10 mmol, 13.61 eq.), and the mixture was stirred at 30 °C for 12 hours. The mixture reaction was poured into saturated aqueous NaHCCL and extracted with EtOAc. The organic layers were dried over Na2SO4, filtered and concentracted to give l-(4-acetyl-6-fluoro-2-pyridyl)-5-methyl-pyrazole-3- carbonitrile (150 mg, 0.610 mmol, 84% yield) as an off-white solid which was used without further purification. LC-MS: m / z = 245.0, [M+H]+, ESI pos.

[0302] Step 4: l-[ 4-acetyl-6-[ 6-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl / -2 -pyridyl -5- methyl-pyrazole-3-carbonitrile and l-[ 4-acetyl-6-[5-[ ( 6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl / -2 -pyridyl ]-5-methyl-pyrazole-3-carbonitrile Prepared in analogy to Example 1, step 8, using l-(4-acetyl-6-fluoro-2-pyridyl)-5-methyl- pyrazole-3 -carbonitrile (50 mg, 0.200 mmol, 1.0 eq.) and N-(6-methylpyridazin-3-yl)-lH- benzimidazol-5-amine (Example 1, step 7) (55 mg, 0.250 mmol, 1.2 eq.) followed by purification by preparative TLC (SiCL, DCM:MeOH 10:1 Rf=0.55 / 0.56, UV) to give l-[4-acetyl- 6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile (30 mg, 0.070 mmol, 33% yield) as an off-white solid. LC-MS: m / z = 450.1 [M+H]+, ESI pos. and l-[4-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl- pyrazole-3 -carbonitrile (20 mg, 0.040 mmol, 22% yield) as light brown solid. LC-MS: m / z = 450.1 [M+H]+, ESI pos.

[0303] Step 5: l-[ 4-( 1 -hydroxyethyl)-6-[ 6-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl -2- pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0304] Prepared in analogy to Example 15, step 3, using l-[4-acetyl-6-[6-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (20 mg, 0.040 mmol, 1.0 eq.) in MeOH / DCM (5:1) followed by preparative HPLC (Phenomenex Gemini -NX C18 75 mm x 30mm x 3 pm), water(0.225%FA)-ACN, gradient time 7 minutes, hold Time 2 min, flow rate 25 mL / min) followed by preparative SFC (DAICEL CHIRALPAK IC (250 mm x 30mm x 10 pm)), 0.1%NH4OH in MeOH, gradient time 4 minutes, flow rate 80 mL / min) to give l-[4-(l- hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl- pyrazole-3 -carbonitrile (6 mg, 0.010 mmol, 27% yield). LC-MS: m / z = 452.1, [M+H]+, ESI pos. 'H NMR (400 MHz, METHANOL-d4) 5 = 8.83 (d, J= 1.8 Hz, 1H), 8.72 (s, 1H), 8.01 (s, 1H), 7.89 (s, 1H), 7.71 (d, J= 8.7 Hz, 1H), 7.47 (dd, J = 2.0, 8.7 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H), 7.15 (d, J= 9.2 Hz, 1H), 6.79 (d, J= 0.6 Hz, 1H), 5.13 (q, J= 6.5 Hz, 1H), 2.74 (s, 3H), 2.54 (s, 3H), 1.61 (d, .7= 6.6 Hz, 3H) Example 20

[0305] 1- [4-(l-Hydroxyethyl)-6- [5- [(6-methylpyridazin-3-yl)amino] benzimidazol-l-yl]-2-pyridyl]-

[0306] 5-methyl-pyrazole-3-carbonitrile Prepared in analogy to Example 15, step 3, using l-[4-acetyl-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (20 mg, 0.040 mmol, 1.0 eq.) (Example 19, step 4) in MeOH / DMF (1 : 1) followed by purification by preparative HPLC (Phenomenex Gemini-NX C18 75 mm x 30mm x 3 pm), water(0.225%FA)- ACN, gradient time 7 minutes, hold Time 2 min, flow rate 25 mL / min) followed by preparative SFC (DAICEL CHIRALPAK IC (250 mm x 30mm x 10 pm)), 0.1%NH4OH in MeOH, gradient time 4 minutes, flow rate 80 mL / min) to give l-[4-(l-hydroxyethyl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (8 mg, 0.020 mmol, 39% yield) as an off-white solid. LC-MS: m / z = 452.1, [M+H]+, ESI pos. 'H NMR (400 MHz, METHANOL-d4) 5 = 8.85 (s, 1H), 8.29 - 8.25 (m, 1H), 8.09 - 8.06 (m, 1H), 7.96 (s, 1H), 7.91 (s, 1H), 7.67 (dd, J= 2.0, 9.0 Hz, 1H), 7.39 (d, J= 92 Hz, 1H), 7.16 (d, J= 9.3 Hz, 1H), 6.84 (s, 1H), 5.14 - 5.09 (m, 1H), 2.76 (s, 3H), 2.56 (s, 3H), 1.61 (d, J= 6.6 Hz, 3H)

[0307] Example 21

[0308] 1- [3-(2,2-Difluoroethoxy)-6- [5- [(6-methylpyridazin-3-yl)amino] benzimidazol- 1-yl] -2- pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0309] Step 1: 6-chloro-3-(2,2-difluoroethoxy)-2-fluoro-pyridine

[0310] To a suspension of 6-chl oro-2-fluoro-pyri din-3 -ol (1.5 g, 10.17 mmol, 1.0 eq.) in 2-butanone (20 mL) was added l,l-difluoro-2-iodoethane (3.9 g, 20.33 mmol, 2.0 eq.) and K2CO3 (3.51 g, 25.42 mmol, 2.5 eq.). The mixture was stirred at 80 °C for 16 hours. The reaction mixture was poured into H2O and the extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (SiCh, 15% EtOAc in PE) to give 6-chloro-3-(2,2-difluoroethoxy)-2-fluoro-pyridine (1.5 g, 7.09 mmol, 70% yield) as an off-white solid. LC-MS: m / z = 211.8 [M+H]+, ESI pos.JH NMR (400 MHz, CDCI3) 8 = 7.40 - 7.34 (m, 1H), 7.21 - 7.16 (m, 1H), 6.28 - 5.92 (m, 1H), 4.28 (dt, J= 4.0, 12.9 Hz, 2H).

[0311] Step 2: l-[ 6-chloro-3-(2, 2 -difluoroethoxy) -2 -pyridyl ]-5-methyl-pyrazole-3-carbonitrile

[0312] A suspension of 6-chloro-3-(2,2-difluoroethoxy)-2-fluoro-pyridine (1.44 g, 6.78 mmol, 1.0 eq.), 5-methyl-lH-pyrazole-3-carbonitrile (719.22 mg, 6.71 mmol, 0.990 eq.) and K2CO3 (2.81 g, 20.35 mmol, 3.0 eq.) in DMSO (15 mL) was stirred at 80 °C for 3 hours. The mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (SiO2, 10-20% EtOAc in PE) to give l-[6-chloro-3-(2,2-difluoroethoxy)-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile (1.47 g, 4.92 mmol, 73% yield) as an off-white solid. LC-MS: m / z = 299.1 [M+H]+, ESI pos. 'H NMR (400 MHz, CDC13) 8 = 7.52 (m, 2H), 6.59 (s, 1H), 5.95-6.14 (m, 1H), 4.19-4.27 (m, 2H), 2.31 (s, 3H).

[0313] Step 3: l-[ 3-(2, 2-difluoroethoxy)-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2- pyridyl ]-5-methyl-pyrazole-3-carbonitrile and l-[ 3-(2, 2 -difluoroethoxy) -6- [ 6-[ ( 6- methylpyridazin-3-yl)amino] benzimidazol-1 -yl] -2-pyridyl] -5-methyl-pyrazole-3-carbonitrile

[0314] Prepared in analogy to Example 1, step 8, using l-[6-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile (500 mg, 1.67 mmol, 1.0 eq.) and N-(6-methylpyridazin-3-yl)- lH-benzimidazol-5-amine (Example 1, step 7) (377 mg, 1.67 mmol, 1.0 eq.) while stirring at 100 °C for 44 hours. The reaction was poured into water and the resulting precipitate was filtered. The filter cake was dried and purified by flash chromatography (SiCh, 10% MeOH in DCM) followed by trituration with MeOH to give l-[3-(2,2-difluoroethoxy)-6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (47 mg, 0.100 mmol, 6% yield) as an off-white solid. LC-MS: m / z = 487.9 [M+H]+, ESI pos. 'H NMR (400 MHz, METHANOL-d4) 5 = 8.86 - 8.72 (m, 1H), 8.24 - 8.16 (m, 1H), 8.13 - 8.00 (m, 3H), 7.60 - 7.50 (m, 1H), 7.42 - 7.32 (m, 1H), 7.22 - 7.07 (m, 1H), 6.89 - 6.72 (m, 1H), 6.32 - 5.91 (m, 1H), 4.46 (dt, J = 3.5, 13.8 Hz, 2H), 2.53 (s, 3H), 2.34 (s, 3H). Example 22

[0315] 1- [3-(2,2-Difluoroethoxy)-6- [6- [(6-methylpyridazin-3-yl)amino] benzimidazol- 1-yl] -2- pyridyl]-5-methyl-pyrazole-3-carbonitrile l-[3-(2,2-difluoroethoxy)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile (31 mg, 0.060 mmol, 4% yield) was obtained in Example 21, step 3 after further purification by preparative HPLC (Phenomenex Gemini-NX C18 75*30mm*3um, (water(0.225%FA)-ACN), gradient time 7 minutes, hold time 2 min, flow rate 25 ml / min) as obtained as light yellow solid. LC-MS: m / z = 487.9 [M+H]+, ESI pos.JH NMR (400 MHz, CD3OD) 5 = 8.81 - 8.68 (m, 2H), 8.25 - 8.14 (m, 2H), 7.76 - 7.68 (m, 1H), 7.44 - 7.40 (m, 1H), 7.39 - 7.33 (m, 1H), 7.21 - 7.09 (m, 1H), 6.87 - 6.72 (m, 1H), 6.35 - 5.99 (m, 1H), 4.56 - 4.45 (m, 2H), 2.57 (s, 3H), 2.36 (s, 3H).

[0316] Example 23 l-[3-[(2R,4R)-4-fluoropyrrolidin-2-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol- l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile and l-[3-[(2S,4S)-4-fluoropyrrolidin-2-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0317] Step 1: 4-[tert-butyl(dimethyl)silyl]oxy-2-pyrrolidone 4-hydroxy-2-pyrrolidone (2.00 g, 19.78 mmol, 1.0 eq. ) was dissolved in DMF (20 mL) and imidazole (2.02 g, 29.67 mmol, 1.5 eq. ) followed by TBDMS-C1 (3.13 g, 20.77 mmol, 1.05 eq.) were added at 0 °C. The mixture was stirred for 15 minutes at 0 °C before it was warmed to rt and stirred overnight. The reaction mixture was diluted with water and the suspension was stirred for 15 minutes. Solids were filtered off and washed with water and dried in vacuo to obtain the crude title compound 4-[tert-butyl(dimethyl)silyl]oxy-2-pyrrolidone as white solid which was used in the next step without further purification. LC-MS: m / z = 216.15 [M+H]+, ESI pos.

[0318] Step 2: 4-[tert-butyl(dimethyl)silyl]oxy-2-keto-pyrrolidine-l-carboxylic acid tert-butyl ester 4-[tert-butyl(dimethyl)silyl]oxy-2-pyrrolidone (used as crude from the previous step) was dissolved in CH3CN (50 mL) and 4-dimethylaminopyridine (1.13 g, 9.26 mmol, 0.5 eq. ) and EtsN (2.25 g, 3.1 mL, 22.23 mmol, 1.2 euiv.q ) were added. The reaction mixture was cooled 0 °C and (BOC)2O (5.26 g, 5.59 mL, 24.09 mmol, 1.3 eq. ) was added in one portion. The reaction mixture was stirred for 15 minutes at 0 °C before it was warmed to rt and stirred overnight. The reaction mixture was diluted with water and stirred for 15 minutes. The solids were filtered off and washed with water and dried in vacuo. The crude material was purified by flash chromatography (SiO2, 0 - 100% EtOAc in heptane) to obtain the title compound 4-[tert- butyl(dimethyl)silyl]oxy-2-keto-pyrrolidine-l-carboxylic acid tert-butyl ester (5.45 g, 93% over 2 steps) as a white solid. LC-MS: m / z = 216.19 [M+H]+, ESI pos.

[0319] Step 3: N- 2-[ tert-butyl(dimethyl)silyl ]oxy-4-( 6-chloro-2-fluoro-3-pyridyl)-4-keto- butyl] carbamic acid tert-butyl ester

[0320] Diisopropylamine (923 mg, 1.3 mL, 9.12 mmol, 1.2 eq. ) was dissolved in THF (5 mL) and 1.6 M BuLi (5.7 mL, 9.12 mmol, 1.2 eq.) was added at -78 °C. The solution was stirred for 15 minutes at -78 °C. To a solution of 2-chloro-6-fhioro-pyridine (1.00 g, 7.60 mmol, 1.0 eq. ) in THF (30 mL) was added the freshly prepared LDA solution dropwise at -78 °C. After addition the reaction mixture was stirred for 10 minutes before 4-[tert-butyl(dimethyl)silyl]oxy-2-keto- pyrrolidine-1 -carboxylic acid tert-butyl ester (2.88 g, 9.12 mmol, 1.2 eq. ) was added dropwise. After addition, the mixture was stirred at -70 °C for 1.5 hours. The mixture was quenched with 10 mL saturated aqueous NH4CI at -78 °C and the suspension was allowed to warm to rt. The reaction mixture was diluted with water and extracted twice with EtOAc. The organic layers were dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography (SiO2, 0 - 50% EtOAc in heptane) to yield the title compound as light yellow oil (1.46 g, 3.12 mmol, 41%, yield). LC-MS: m / z = 447.18 [M+H]+, ESI pos. Step 4: N-[ 2-[ tert-butyl(dimethyl)silyl ]oxy-4-( 6-chloro-2-fluoro-3-pyridyl)-4-hydroxy- butyl] carbamic acid tert-butyl ester

[0321] N-[2-[tert-butyl(dimethyl)silyl]oxy-4-(6-chloro-2-fluoro-3-pyridyl)-4-keto-butyl]carbamic acid tert-butyl ester (1.46 g, 3.27 mmol, 1.0 eq. ) was dissolved in MeOH (20 mL). NaBEL (247 mg, 6.53 mmol, 2.0 eq. ) was added at 0 °C. The ice bath was removed, and the reaction was stirred at RT for 1 hour. The reaction mixture was quenched with saturated aqueous NH4CI solution and extracted with EtOAc. The combined organic layers were dried over MgSCU, filtered and concentrated. The crude material was purified by flash chromatography (SiCh, 0% - 40% EtOAc in heptane) to get N-[2-[tert-butyl(dimethyl)silyl]oxy-4-(6-chloro-2-fluoro-3-pyridyl)-4-hydroxy- butyl] carbamic acid tert-butyl ester (1.32 g, 90%) as a light yellow oil. LC-MS: m / z = 449.2 [M+H]+, ESI pos.

[0322] Step 5: 4-[ ter t-butyl(dimethyl) silyl ]oxy-2-( 6-chloro-2-fluoro-3-pyridyl)pyrrolidine-l -carboxylic acid tert-butyl ester

[0323] N-[2-[tert-butyl(dimethyl)silyl]oxy-4-(6-chloro-2-fluoro-3-pyridyl)-4-hydroxy-butyl]carbamic acid tert-butyl ester (800 mg, 1.78 mmol, 1.0 eq. ) was dissolved in DCM (15 mL) and EtsN (2.7 g, 3.72 mL, 26.72 mmol, 15 eq. ) and MsCl (2.65 g, 1.8 mL, 23.16 mmol, 13 eq. ) were added at -60 °C. The mixture was stirred for 1 hours at -60 °C and allowed to warm to rt while stirring overnight. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried over MgSO4 , filtered and concentrated. The crude material was purified by flash chromatography (SiCh, 0 - 40% EtOAc in heptane) to give 4-[tert- butyl(dimethyl)silyl]oxy-2-(6-chloro-2-fluoro-3-pyridyl)pyrrolidine-l-carboxylic acid tert-butyl ester (661 mg, 82%) as a light yellow liquid. LC-MS: m / z = 375.1 [M-'Bu+H] , ESI pos. Step 6: 2-[ 6-chloro-2-(3-cyano-5-methyl-pyrazol-l-yl)-3-pyridyl / -4-hydroxy-pyrrolidine-l- carboxylic acid tert-butyl ester

[0324] 4-[tert-butyl(dimethyl)silyl]oxy-2-(6-chloro-2-fluoro-3-pyridyl)pyrrolidine-l-carboxylic acid tert-butyl ester (636 mg, 1.48 mmol, 1.0 eq. ) was dissolved in DMF (8 mL) and 5-methyl-lH- pyrazole-3 -carbonitrile (190 mg, 1.77 mmol, 1.2 eq.) and CS2CO3 (721.16 mg, 2.21 mmol, 1.5 eq uiv.) were added at rt. The mixture was stirred for 3 hours at 100 °C. The reaction mixture was diluted with water and extracted with EtOAc. The organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography (SiCh, 0 - 100% EtOAc in heptane) to give 2-[6-chloro-2-(3-cyano-5-methyl-pyrazol-l-yl)-3- pyridyl]-4-hydroxy-pyrrolidine-l -carboxylic acid tert-butyl ester (377 mg, 50.6%) as a white solid. LC-MS: m / z = 304.1 [M-Boc+H]+, ESI pos.

[0325] Step 7: racemic mixture of (2S,4S)-2-[6-chloro-2-(3-cyano-5-methyl-pyrazol-l-yl)-3-pyridyl]-4- jluoro-pyrrolidine-l-carboxylic acid tert-butyl ester and (2R,4R)-2-[6-chloro-2-(3-cyano-5- methyl-pyrazol-l-yl)-3-pyridyl]-4-fluoro-pyrrolidine-l -carboxylic acid tert-butyl ester and racemic mixture of (2S,4R)-2-[6-chloro-2-(3-cyano-5-methyl-pyrazol-l-yl)-3-pyridyl]-4-fluoro- pyrrolidine-1 -carboxylic acid tert-butyl ester and 2R,4S)-2-[6-chloro-2-(3-cyano-5-methyl- pyrazol-l-yl)-3-pyridyl]-4-fluoro-pyrrolidine-l-carboxylic acid tert-butyl ester

[0326] 2-[6-chloro-2-(3-cyano-5-methyl-pyrazol-l-yl)-3-pyridyl]-4-hydroxy-pyrrolidine-l -carboxylic acid tert-butyl ester (320 mg, 0.792 mmol, 1.0 eq.) was dissolved in DCM (10 mL) and DAST (1.66 g, 1.36 mL, 10.3 mmol, 13 eq.) was added at -78 °C. After addition, the reaction mixture was stirred for 1 hours at -78 °C, then the dry-ice bath was removed and the reaction was allow to stir overnight at rt. The reaction mixture was quenched at 0 °C with saturated aqueous NaHCOs and extracted with DCM. The organic layers were dried over MgSCU, filtered and concentrated. The crude material was purified by flash chromatography (SiCE, 0 - 50% EtOAc in heptane) give: a racemic mixture of (2R,4R)-2-[6-chloro-2-(3-cyano-5-methyl-pyrazol-l-yl)-3-pyridyl]-4- fluoro-pyrrolidine-l-carboxylic acid tert-butyl ester and (2S,4S)-2-[6-chloro-2-(3-cyano-5- methyl-pyrazol-l-yl)-3 -pyridyl] -4-fluoro-pyrrolidine-l -carboxylic acid tert-butyl ester (114 mg, 35%) as light brown solid. LC-MS: m / z = 306.1 [M-Boc+H]+, ESI pos. and a racemic mixture of (2S,4R)-2-[6-chloro-2-(3-cyano-5-methyl-pyrazol-l-yl)-3-pyridyl]-4- fluoro-pyrrolidine-l-carboxylic acid tert-butyl ester / (2R,4S)-2-[6-chloro-2-(3-cyano-5-methyl- pyrazol-l-yl)-3 -pyridyl] -4-fluoro-pyrrolidine-l -carboxylic acid tert-butyl ester (79 mg, 21%). LC-MS: m / z = 306.1 [M-Boc+H]+, ESI pos.

[0327] (the relative stereochemistry was determined in the next step)

[0328] Step 8: racemic mixure of (2R,4R)-2-[2-(3-cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-pyridyl] -4-fluoro-pyrrolidine-l -carboxylic acid tert-butyl ester and (2S,4S)-2-[2-(3-cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin- 3-yl)amino ]benzimidazol-l-yl ]-3-pyridyl / -4-fluoro-pyrrolidine-l -carboxylic acid tert-butyl ester

[0329] Prepared in analogy to Example 1, step 8, using a racemic mixture of (2R,4R)-2-[6-chloro-2-(3- cyano-5-methyl-pyrazol-l-yl)-3-pyridyl]-4-fluoro-pyrrolidine-l-carboxylic acid tert-butyl ester and (2S,4S)-2-[6-chloro-2-(3-cyano-5-methyl-pyrazol-l-yl)-3-pyridyl]-4-fluoro-pyrrolidine-l- carboxylic acid tert-butyl ester (70 mg, 0.173 mmol, 1 eq.) and lH-benzimidazol-5-yl-(6- m ethyl pyridazin-3-yl)amine (Example 1, step 7) (45 mg, 0.207 mmol, 1.2 eq.) and CS2CO3 (84 mg, 0.259 mmol, 1.5 eq.) to give racemic mixture of (2R,4R)-2-[2-(3-cyano-5-methyl-pyrazol-l- yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-pyridyl]-4-fluoro-pyrrolidine-l- carboxylic acid tert-butyl ester and (2S,4S)-2-[2-(3-cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-pyridyl]-4-fluoro-pyrrolidine-l -carboxylic acid tert-butyl ester (25 mg, 24% yield) as a light brown solid. LC-MS: m / z = 595.2691 [M+H]+, ESI pos.

[0330] Step 9: racemic mixture of l-[3-[(2R,4R)-4-jluoropyrrolidin-2-yl]-6-[5-[(6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl ]-2-pyridyl ]-5-methyl-pyrazole-3-carbonitrile and -[ 3-[ (2S, 4S)-4- jluoropyrrolidin-2-yl ]-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2-pyridyl -5- methyl-pyrazole-3-carbonitrile

[0331] A racemic mixture of (2R,4R)-2-[2-(3-cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-pyridyl]-4-fluoro-pyrrolidine-l-carboxylic acid tert-butyl ester and (2S,4S)-2-[2-(3-cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-pyridyl]-4-fluoro-pyrrolidine-l-carboxylic acid tert-butyl ester (25 mg, 0.041 mmol, 1.0 eq.) was dissolved in DCM (2 mL) and 4 M HC1 in 1,4-dioaxne (155 pL, 0.621 mmol, 15 eq.) was added at 0 °C. The reaction mixture was stirred for 2 hours at 0 °C. The reaction mixture was quenched with saturated aqueous NaHCCh and extracted six times with DCM / MeOH 9: 1. The organic layers were dried over MgSCU, filtered and concentrated. The residue was purified by flash chromatography (SiCh, 0 - 10% MeOH in DCM) to obtain a racemic mixture of the title compounds (10 mg, 50%; also known as 5-methyl-l-[6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-[rac-(2A,4A)-4-fluoropyrrolidin-2-yl]pyridin- 2-yl]pyrazole-3 -carbonitrile) as light brown solid. LC-MS: m / z = 495.2 [M+H]+, ESI pos.JH NMR (600 MHz, CDC13) 8 ppm 8.60 (d, J= 8.4 Hz, 1 H), 8.57 (s, 1 H), 7.98 (d, J = 8.8 Hz, 1 H), 7.76 (d, J= 1.9 Hz, 1H), 7.75 (d, J = 8.5 Hz, 1 H), 7.38 (dd, J= 8.7, 2.1 Hz, 1 H), 7.14 (s, 1 H), 7.06 - 7.11 (m, 1 H), 6.98 - 7.06 (m, 1 H), 6.67 (d, J= 0.7 Hz, 1 H), 5.30 (s, 1 H), 4.37 (br d, J = 3.6 Hz, 1 H), 3.51 (d, J = 21.3 Hz, 1 H), 3.13 (d, J = 36.0 Hz, 1 H), 2.60 (s, 4 H), 2.45 (s, 3 H), 1.85 - 2.01 (m, 2 H). cis-isomery confirmed by ROESY correlations between H-27 and H-28' and between H-24 and H-28' Example 24 l-[3-[(2R,4S)-4-fluoropyrrolidin-2-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol- l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile and l-[3-[(2S,4R)-4-fluoropyrrolidin-2- yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-

[0332] 3-carbonitrile

[0333] Step 1: racemic mixure of (2R,4S)-2-[2-(3-cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-pyridyl]-4-fluoro-pyrrolidine-l-carboxylic acid tert-butyl ester and (2S,4R)-2-[2-(3-cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin- 3-yl)amino ]benzimidazol-l-yl ]-3-pyridyl -4-jluoro-pyrrolidine-l -carboxylic acid tert-butyl ester

[0334] Prepared in analogy to Example 1, step 8, using a racemic mixture of (2R,4S)-2-[6-chloro-2-(3- cyano-5-methyl-pyrazol-l-yl)-3-pyridyl]-4-fluoro-pyrrolidine-l-carboxylic acid tert-butyl ester and (2S,4R)-2-[6-chloro-2-(3-cyano-5-methyl-pyrazol-l-yl)-3-pyridyl]-4-fluoro-pyrrolidine-l- carboxylic acid tert-butyl ester (75 mg, 0.185 mmol, 1.0 eq.) and lH-benzimidazol-5-yl-(6- m ethyl pyridazin-3-yl)amine (Example 1, step 7) (50 mg, 0.222 mmol, 1.2 eq.) and CS2CO3 (90 mg, 0.277 mmol, 1.5 eq.) to give racemic mixure of (2R,4S)-2-[2-(3-cyano-5-methyl-pyrazol-l- yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-pyridyl]-4-fluoro-pyrrolidine-l- carboxylic acid tert-butyl ester and (2S,4R)-2-[2-(3-cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-pyridyl]-4-fluoro-pyrrolidine-l -carboxylic acid tert-butyl ester (23 mg, 18% yield) as a light brown solid. LC-MS: m / z = 595.2691 [M+H]+, ESI pos.

[0335] Step 2: racemic mixture of l-[3-[(2R,4S)-4-jluoropyrrolidin-2-yl]-6-[5-[(6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl ]-2-pyridyl ]-5-methyl-pyrazole-3-carbonitrile and -[ 3-[ (2S, 4R)-4- jluoropyrrolidin-2-yl ]-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2-pyridyl -5- methyl-pyrazole-3-carbonitrile

[0336] (2S,4R)-2-[2-(3-cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-pyridyl]-4-fluoro-pyrrolidine-l-carboxylic acid tert-butyl ester (23 mg, 0.038 mmol, 1.0 eq) was dissolved in DCM (2 mL) and 4 M HC1 in Dioxane (143 uL, 0.570 mmol, 15 eq) was added at 0 °C. The reaction mixture was stirred for 2 hours at 0 °C. The reaction mixture was quenched with saturated NaHCCh solution and extracted six times with DCM / MeOH 9:1. The organic layers were dried over MgSCU, filtered and concentrated. The crude material was purified by flash chromatography (SiCh, 0 - 10% MeOH in DCM) to obtain racemic mixture of the title compounds (11 mg, 59% yield; also known as 5-methyl-l-[6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-[rac-(27?,45)-4-fluoropyrrolidin-2-yl]pyridin- 2-yl]pyrazole-3-carbonitrile). LC-MS: m / z = 495.2 [M+H]+, ESI pos.JH NMR (600 MHz, CDC138 ppm 8.56 (s, 1 H), 8.53 (d, J= 8.5 Hz, 1 H), 7.96 (d, J= 8.8 Hz, 1 H), 7.76 (d, J= 1.8 Hz, 1 H), 7.73 (d, J = 8.4 Hz, 1 H), 7.38 (dd, J = 8.8, 2.1 Hz, 1 H), 7.12 - 7.14 (m, 1 H), 7.05 - 7.07 (m, 1 H), 6.93 - 7.04 (m, 1 H), 6.68 (d, J = 0.8 Hz, 1 H), 5.28 - 5.58 (m, 1 H), 5.15 - 5.30 (m, 1 H), 4.66 (dd, J= 9.4, 7.1 Hz, 1 H), 3.34 - 3.41 (m, 1 H), 3.14 - 3.25 (m, 1 H), 2.60 (s, 3 H), 2.42 (d, .7= 0.7 Hz, 3 H), 2.31 - 2.41 (m, 1 H), 1.59 - 1.71 (m, 1 H). trans-isomery confirmed by ROESY correlations between H-27 and H-28" and between H-24 and H-28'. Example 25

[0337] 1- [3-Chloro-4-(l-hydroxyethyl)-6- [5- [(6-methylpyridazin-3-yl)amino] benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile Step 1: l-(4-acetyl-3-chloro-6-fluoro-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile

[0338] A mixture of l-(3-chloro-2,6-difluoro-4-pyridyl)ethanone (850 mg, 4.44 mmol, 1.0 eq.), 5- methyl-lH-pyrazole-3-carbonitrile (475 mg, 4.44 mmol, 1.0 eq.) and DIPEA (2.32 mL, 13.31 mmol, 3.0 eq.) in DMSO (6 mL) was stirred at 20 °C for 12 hours. The mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (SiCh, 5-35% EtOAc in PE) to give l-(4-acetyl-3-chloro-6-fluoro-2-pyridyl)-5-methyl-pyrazole-3- carbonitrile (300 mg, 1.08 mmol, 24% yield) as a white solid. LC-MS: m / z = 279.0 [M+H]+, ESI pos.

[0339] Step 2: l-[ 4-acetyl-3-chloro-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2- pyridyl ]-5-methyl-pyrazole-3-carbonitrile;trifluoroacetic acid and l-[ 4-acetyl-3-chloro-6-[ 6- [ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl / -2 -pyridyl ]-5-methyl-pyrazole-3-carbonitrile

[0340] Prepared in analogy to Example 1, step 8, using N-(6-methylpyridazin-3-yl)-lH-benzimidazol-5- amine (Example 1, step 7) (364 mg, 1.61 mmol, 1.5 eq.), l-(4-acetyl-3-chloro-6-fluoro-2- pyridyl)-5-methyl-pyrazole-3-carbonitrile (300 mg, 1.08 mmol, 1.0 eq.) followed by preparative HPLC (Phenomenex luna C18 150 mm x 40 mm x 15 pm, water (0.1%TFA) - ACN, hold time 2 min, flow rate 60 ml / min) to give l-[4-acetyl-3-chloro-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (93 mg, 17% yield). LC-MS: m / z = 484.0 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-d6) 5 = 9.97 (br d, J = 2.0 Hz, 1H), 9.07 (s, 1H), 8.56 (s, 1H), 8.53 (br s, 1H), 7.78 (d, J= 8.6 Hz, 1H), 7.67 (br d, J= 8.5 Hz, 1H), 7.53 (dd, J = 2.0, 8.8 Hz, 1H), 7.45 (br d, J = 9.1 Hz, 1H), 7.08 (d, J= 0.6 Hz, 1H), 2.78 (s, 3H), 2.57 (s, 3H), 2.36 (s, 3H); and l-[4-acetyl-3-chloro-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile (59 mg, 11% yield). LC-MS: m / z = 484.0 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-d6) 5 = 10.15 (br s, 1H), 9.15 (s, 1H), 8.57 (s, 1H), 8.29 (d, J= 1.9 Hz, 1H), 8.13 (d, J= 8.9 Hz, 1H), 7.81 (d, J = 9.3 Hz, 1H), 7.60 (d, J= 9.4 Hz, 1H), 7.47 (dd, J = 2.1, 8.9 Hz, 1H), 7.13 (d, J= 0.8 Hz, 1H), 2.77 (s, 3H), 2.59 (s, 3H), 2.36 (s, 3H). Step 3: l-[ 3-chloro-4-( 1 -hydroxyethyl)-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l- y I] -2 -pyridyl ]-5-methyl-pyrazole-3-carbonitrile

[0341] Prepared in analogy to Example 1, step 8, using of l-[4-acetyl-3-chloro-6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (93 mg, 0.190 mmol, 1.0 eq.) and NaBEU (35 mg, 0.930 mmol, 4.8 eq.) in DMF / MeOH (1 :3) followed by purification by preparative HPLC (Phenomenex Synergi Cl 8 150 x 25mm x lOum, water (0.225%FA)-ACN, hold time 2 min, flow rate 25 ml / min) to give l-[3-chloro-4-(l- hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl- pyrazole-3 -carbonitrile (32 mg, 0.060 mmol, 31% yield) as a yellow solid. LC-MS: m / z = 486.0 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-t / 6) 8 = 9.24 (s, 1H), 9.05 (s, 1H), 8.47 (d, J= 2.0 Hz, 1H), 8.33 (s, 1H), 8.27 (s, 1H), 7.99 (d, J= 8.8 Hz, 1H), 7.50 (dd, J= 2.0, 8.8 Hz, 1H), 7.34 (d, J= 9.2 Hz, 1H), 7.13 - 7.07 (m, 2H), 6.12 - 5.88 (m, 1H), 5.16 (q, J= 6.4 Hz, 1H), 2.49 (br s, 3H), 2.33 (s, 3H), 1.50 (d, J= 6.4 Hz, 3H).

[0342] Example 26

[0343] 1- [3-chloro-4-(l-hydroxyethyl)-6- [6- [(6-methylpyridazin-3-yl)amino] benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0344] Prepared in analogy to Example 15, step 3, using l-[4-acetyl-3-chloro-6-[6-[(6-methylpyridazin- 3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (53 mg, 0.110 mmol, 1.0 eq.) and NaBH4 (35 mg, 0.930 mmol, 4.8 eq.) in DMF / MeOH (1 :3) followed by purification by preparative HPLC (Phenomenex Synergi C18 150 x 25mm x lOum, water (0.225%FA)-ACN, flow rate 25 ml / min) to give l-[3-chloro-4-(l-hydroxyethyl)-6-[6-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; formic acid (25 mg, 0.050 mmol, 45% yield) as a yellow solid. LC-MS: m / z = 486.0 [M+H]+, ESI pos.JH NMR (400 MHz, DMSO-t / e) 8 = 9.30 (s, 1H), 8.94 (s, 1H), 8.80 (d, J= 2.0 Hz, 1H), 8.34 - 8.30 (m, 2H), 7.69 (d, J= 8.4 Hz, 1H), 7.43 (dd, J= 2.0, 8.8 Hz, 1H), 7.29 (d, J= 9.2 Hz, 1H), 7.12 - 7.03 (m, 2H), 6.18 - 5.80 (m, 1H), 5.17 (q, J= 6.4 Hz, 1H), 2.50 - 2.48 (m, 3H), 2.36 (d, J= 0.4 Hz, 3H), 1.51 (d, J= 6.5 Hz, 3H).

[0345] Example 27 5-Methyl- 1- [6- [5- [(6-methylpyridazin-3-yl)amino] benzimidazol- 1-yl] -3-methylsulfinyl-2- pyridyl] pyrazole-3-carbonitrile

[0346] Step 1: 6-chloro-2-fluoro-3-methylsulfanyl-pyridine

[0347] To a solution of 2-chloro-6-fluoropyridine (5.0 g, 38.01 mmol, 1.0 eq.) in THF (50 mL) was added LDA (23.0 mL, 46 mmol, 1.2 eq.) dropwise under inert atmosphere at -70 °C. The mixture was stirred at -70 °C for 0.5 hours. Then, a solution of methyl thiocyanate (3.34 g, 45.61 mmol, 1.2 eq.) in THF (20 mL) was added dropwise at -70 °C. The reaction mixture was stirred at -70 °C for 2 hours. The reaction mixture was poured into saturated aqueous NH4CI under stirring, and then extracted with EtOAc. The combined extracts were concentrated and the residue was purified by flash chromatography (SiCL, 10% EtOAc in PE) to give 6-chl oro-2- fhioro-3-methylsulfanyl-pyridine (1.20 g, 6.76 mmol, 18% yield) as white solid. LC-MS: m / z = 178.1 [M+H]+, ESI pos. 'H NMR (400 MHz, CDCI3) 6 = 7.60 (dd, J = 7.9, 9.3 Hz, 1H), 7.20 (dd, J= 1.0, 7.9 Hz, 1H), 2.49 (s, 3H).

[0348] Step 2: 6-chloro-2-fluoro-3-methylsulfmyl-pyridine

[0349] To a solution of 6-chloro-2-fluoro-3-methylsulfanyl-pyridine (1.10 g, 6.19 mmol, 1.0 eq.) in DCM (20 mL) was added mCPBA (1.26 g, 6.19 mmol, 1.0 eq.) in portions. The reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was poured into aqueous 10% ISfeSCh under stirring, and was then extracted with EtOAc. The combined extracts were concentrated and the crude was purified by flash chromatography (SiCh, 50% EtOAc in PE) to yield 6-chloro-2- fhioro-3-methylsulfmyl-pyridine (1.00 g, 5.16 mmol, 83% yield) as colorless oil. LC-MS: m / z = 194.1 [M+H]+, ESI pos. 'H NMR (400 MHz, CDC13) 8 = 8.28 (t, J= 8.4 Hz, 1H), 7.51 (d, J = 7.9 Hz, 1H), 2.88 (s, 3H).

[0350] Step 3: l-( 6-chloro-3-methylsulfinyl-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile

[0351] A solution of 6-chloro-2-fluoro-3-methylsulfmyl-pyridine (500 mg, 2.58 mmol, 1.0 eq.), 5- methyl-lH-pyrazole-3-carbonitrile (277 mg, 2.58 mmol, 1 0 eq.) and DIPEA (0.88 mL, 5.16 mmol, 2 0 eq.) in DMSO (8 mL) was stirred at 30 °C for 2 hours. The reaction mixture was poured into water and extracted with EtOAc. The combined extracts were concentrated and the residue was purified by flash chromatography (SiO2, 30% EtOAc in PE) to yield l-(6-chl oro-3 - methylsulfmyl-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile (220 mg, 0.780 mmol, 30% yield) as yellow oil. LC-MS: m / z = 281.1 [M+H]+, ESI pos. 'H NMR (400 MHz, CDCI3) 6 = 8.65 (d, J = 8.3 Hz, 1H), 7.62 (d, J= 8.3 Hz, 1H), 6.65 (s, 1H), 3.05 (s, 3H), 2.71 (s, 3H). Step 4: 5-methyl-l-[ 6-[5-[ ( 6-methylpyridazin-3-yl)amino ] benzimidazol- 1-yl / -3-methylsulfinyl-2- pyridyl]pyrazole-3-carbonitrile

[0352] A solution of l-(6-chloro-3-methylsulfinyl-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile (200 mg, 0.710 mmol, 1.0 eq.), N-(6-methylpyridazin-3-yl)-lH-benzimidazol-5-amine (Example 1, Step 7) (160 mg, 0.710 mmol, 1.0 eq.) and K2CO3 (295 mg, 2.14 mmol, 3 eq.) in DMSO (4 mL) was stirred at 30 °C for 4 hours. The reaction mixture was diluted with water under stirring upon which a precipitate formed. After filtration, the filter cake was dried and purified by preparative TLC (10% MeOH in DCM). The two regioisomers were further purified by preparative NPLC (Welch Ultimate XB-SiOH 250 mm x 70 mm x 10 pm, gradient 40 - 80% EtOH in hexane over 15 minutes, then 100% EtOH (5 min), flow rate 140 mL / min) to give 5-methyl-l-[6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-methylsulfinyl-2-pyridyl]pyrazole-3- carbonitrile (87 mg, 0.180 mmol, 25% yield) as yellow solid. LC-MS: m / z = 470.2 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-t / 6) 8 = 9.25 (s, 1H), 9.07 (s, 1H), 8.76 (d, J = 8.6 Hz, 1H), 8.47 (d, J= 2.0 Hz, 1H), 8.39 (d, J= 8.6 Hz, 1H), 8.12 (d, J= 8.9 Hz, 1H), 7.55 (dd, J= 2.1, 8.9 Hz, 1H), 7.34 (d, J = 9.0 Hz, 1H), 7.18 (s, 1H), 7.09 (d, J = 9.0 Hz, 1H), 2.96 (s, 3H), 2.64 (s, 3H), 2.48 (s, 3H).

[0353] Example 28 5-Methyl- 1- [6- [6- [(6-methylpyridazin-3-yl)amino] benzimidazol- 1-yl] -3-methylsulfinyl-2- pyridyl] pyrazole-3-carbonitrile

[0354]

[0355] 5-methyl-l-[6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-methylsulfinyl-2- pyridyl]pyrazole-3 -carbonitrile (100 mg, 0.210 mmol, 27% yield) was obtained in Example 27, step 4 as yellow solid after separation of te isomers by preparative NPLC (Welch Ultimate XB- SiOH 250 mm x 70 mm x 10 pm, gradient 40 - 80% EtOH in hexane over 15 minutes, then 100% EtOH (5 min), flow rate 140 mL / min). LC-MS: m / z = 470.1[M+H]+, ESI pos^H NMR (400 MHz, DMSO-t / e) 8 = 9.30 (s, 1H), 8.99 (d, J= 1.8 Hz, 1H), 8.97 (s, 1H), 8.78 (d, J = 8.6 Hz, 1H), 8.35 (d, J= 8.6 Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.48 (dd, J= 1.9, 8.7 Hz, 1H), 7.31 (d, J = 9.0 Hz, 1H), 7.12 (s, 1H), 7.07 (d, J = 9.0 Hz, 1H), 2.97 (s, 3H), 2.62 (s, 3H), 2.48 (s, 3H).

[0356] Example 29 5-Methyl-l- [6- [5- [(6-methylpyridazin-3-yl)amino] benzimidazol-l-yl]-3-(oxetan-3-yloxy)-2- pyridyl] pyrazole-3-carbonitrile

[0357] Step 1: 6-chloro-2-fluoro-3-(oxetan-3-yloxy)pyridine To a white turbid solution of 3-iodooxetane (7.48 g, 40.67 mmol, 2.0 eq.) in 2-butanone (50 mL) was added 6-chl oro-2-fluoro-pyri din-3 -ol (3.00 g, 20.33 mmol, 1.0 eq.) and K2CO3 (7.02 g, 50.84 mmol, 2.5 eq.). The mixture was stirred at 80 °C for 40 hours. The reaction mixture was poured into IN HC1 and further diluted with water. The aqueous phase was extracted with EtOAc and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 10% - 17% EtOAc in PE) to give 6-chl oro-2-fluoro-3-(oxetan-3-yl oxy )pyri dine (1.19 g, 5.85 mmol, 29% yield) as an off-white solid. LC-MS: m / z = 204.1 [M+H]+, ESI pos.1H NMR (400 MHz, CDCI3) 8 = 7.14 (d, J = 8.2 Hz, 1H), 7.04 - 6.96 (m, 1H), 5.23 (t, J = 5.6 Hz, 1H), 4.97 (t, J= 6.9 Hz, 2H), 4.82 (dd, J= 5.3, 7.5 Hz, 2H).

[0358] Step 2: l-[ 6-chloro-3-(oxetan-3-yloxy)-2-pyridyl ]-5-methyl-pyrazole-3-carbonitrile

[0359] A solution of 6-chl oro-2-fluoro-3 -(ox etan-3 -yloxy)pyri dine (1.10 g, 5.4 mmol, 1.0 eq.), 5- methyl-lH-pyrazole-3-carbonitrile (573 mg, 5.4 mmol, 1.0 eq.) and K2CO3 (2.24 g, 16.21 mmol, 3.0 eq.) in DMSO (11 mL) was stirred at 80 °C for 3 hours. The reaction mixture was poured into water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by flash chromatography (silica gel, 11% EtOAc in PE) to give 1 -[6-chl oro-3 -(oxetan-3-yl oxy)-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile (1.00 g, 3.44 mmol, 64% yield) as an off-white solid. LC-MS: m / z = 290.6 [M+H]+, ESI pos. 'H NMR (400 MHz, CDCI3) 6 = 7.48 - 7.43 (m, 1H), 7.08 - 7.04 (m, 1H), 6.60 (s, 1H), 5.22 (t, J = 5.6 Hz, 1H), 4.94 (t, J= 6.9 Hz, 2H), 4.67 (dd, J= 5.1, 7.8 Hz, 2H), 2.34 (s, 3H). Step 3: 5-methyl-l-[ 6-[ 6-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-3-(oxetan-3- yloxy)-2-pyridyl]pyrazole-3-carbonitrile and 5-methyl-l-[6-[5-[(6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl / -3-(oxetan-3-yloxy)-2-pyridyl ]pyrazole-3-carbonitrile; formic acid

[0360] Prepared in analogy to Example 1, step 8, using l-[6-chloro-3-(oxetan-3-yloxy)-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile (500 mg, 1.72 mmol, 1.0 eq.) and N-(6-methylpyridazin-3-yl)- lH-benzimidazol-5-amine (Example 1, step 7) (387 mg, 1.72 mmol, 1.0 eq.). The reaction mixture was poured into H2O and the resulting precipitate was filtered off and dried. The filter cake was purified by flash chromatography (silica gel, 0-10% MeOH in EtOAc) followed by purification by preparative HPLC (Phenomenex C18 75 mm x 30 mm x 3 pm, CH3CN in H2O (with 0.225% FA) over 7 minutes, then 100% CH3CN (2 min), flow rate 25 mL / min) to give 5- methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-(oxetan-3-yloxy)-2- pyridyl]pyrazole-3-carbonitrile;formic acid (26 mg, 0.050 mmol, 3% yield) as an off-white solid. LC-MS: m / z = 479.9 [M+H]+, ESI pos. 'H NMR (400 MHz, CD3OD) 5 = 8.82 (br s, 1H), 8.18 (s, 1H), 8.12 - 8.03 (m, 2H), 7.69 (d, J= 8.9 Hz, 1H), 7.53 (d, J= 9.0 Hz, 2H), 7.31 (d, J = 9.3 Hz, 1H), 6.84 (s, 1H), 5.51 - 5.46 (m, 1H), 5.03 (t, J= 6.9 Hz, 2H), 4.64 (dd, J = 4.7, 7.8 Hz, 2H), 3.31 (td, J= 1.6, 3.3 Hz, 7H), 2.57 (s, 3H), 2.39 (s, 3H).

[0361] Example 30 l-[3-(2,2-Difluoro-l-methyl-ethoxy)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0362] Step 1: (2,2-difluoro-l-methyl-ethyl) trifluoromethane sulfonate

[0363] To a solution of l,l-difluoropropan-2-ol (1.00 g, 10.41 mmol, 1.0 eq.) and TEA (1.9 mL, 13.53 mmol, 1.3 eq.) in DCM (16 mL) was added dropwise TfzO (3.52 g, 12.49 mmol, 1.2 eq.) at -40 °C under inert atmosphere. The mixture was allowed to warm to RT and stirred for 16 hours. The mixture was diluted with DCM and poured into ice water. The organic layer was washed by 20% aqueous ISfeCCh, dried over ISfeSCU, filtered and concentrated. The residue was purified by atmospheric distillation to give the crude product (2,2-difluoro-l-methyl-ethyl) trifluoromethanesulfonate (1.40 g, 6.14 mmol, 47% yield) as brown oil.JH NMR (400 MHz, CDC13) 8 = 5.98 - 5.66 (m, 1H), 4.98 (dqt, J= 3.5, 6.5, 9.8 Hz, 1H), 1.55 (d, J= 6.8 Hz, 3H).

[0364] Step 2: 6-chloro-3-(2, 2-difluoro-l-methyl-ethoxy)-2-fluoro-pyridine

[0365] To a solution of 6-chl oro-2-fluoro-pyri din-3 -ol (500 mg, 3.39 mmol, 1.0 eq.) and (2,2-difluoro- l-methyl-ethyl) trifluoromethanesulfonate (1.45 g, 5.08 mmol, 1.5 eq.) in DMF (10 mL) was added K2CO3 (1.41 g, 10.17 mmol, 3.0 eq.). The mixture was stirred at 80 °C for 12 hours. The mixture was poured into water and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE) to give 6-chl oro-3 -(2, 2-difluoro-l-m ethyl - ethoxy)-2-fluoro-pyridine (400 mg, 1.77 mmol, 52% yield) as colorless oil. LC-MS: m / z = 226.1 [M+H]+, ESI pos. Step 3: l-[ 6-chloro-3-(2, 2-difluoro-l-methyl-ethoxy)-2-pyridyl ]-5-methyl-pyrazole-3-carbonitrile

[0366] To a solution of 5-methyl-lH-pyrazole-3-carbonitrile (166 mg, 1.55 mmol, 1.0 eq.) and 6-chloro- 3-(2,2-difluoro-l-methyl-ethoxy)-2-fluoro-pyridine (350 mg, 1.55 mmol, 1.0 eq.) in DMSO (10 mL) was added K2CO3 (429 mg, 3.1 mmol, 2.0 eq.). The mixture was stirred at 80 °C for 12 hours. The mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0 - 35% EtOAc in PE) to give l-[6-chloro-3-(2,2- difluoro-l-methyl-ethoxy)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (360 mg, 1.15 mmol, 74% yield) as brown solid. LC-MS: m / z = 313.0 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO- tZ6) 5 = 8.10 (d, J= 8.9 Hz, 1H), 7.83 (d, J= 8.8 Hz, 1H), 6.96 (s, 1H), 6.11 (dt, J= 2.9, 54.5 Hz, 1H), 5.04 - 4.89 (m, 1H), 2.18 (s, 3H), 1.22 (d, J= 6.4 Hz, 3H).

[0367] Step 4 l-[3-(2,2-Difluoro-l-methyl-ethoxy)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol- l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0368] Prepared in analogy to Example 1, step 8, using l-[6-chloro-3-(2,2-difluoro-l-methyl-ethoxy)-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile (360 mg, 1.15 mmol, 1.0 eq.) and N-(6- methylpyridazin-3-yl)-lH-benzimidazol-5-amine (Example 1, step7) (389 mg, 1.73 mmol, 1.5 eq.) followed by purification by preparative HPLC (Phenomenex Luna C18 150 mm x 25mm x 10 pm, gradient 27 - 57% CH3CN in H2O (with 0.225% FA) over 10 minutes, then 100% CH3CN (2 min), flow rate 25 mL / min) to give l-[3-(2,2-difluoro-l-methyl-ethoxy)-6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (22.2 mg, 0.040 mmol, 3.8% yield) as an off-white solid. LC-MS: m / z = 502.1 [M+H]+, ESI pos.JH NMR (400 MHz, DMSO-t / 6) 8 = 9.20 (s, 1H), 8.92 (s, 1H), 8.42 (d, J= 1.9 Hz, 1H), 8.32 - 8.20 (m, 2H), 8.13 (s, 1H), 7.99 (d, J= 8.9 Hz, 1H), 7.45 (dd, J = 2.0, 8.9 Hz, 1H), 7.32 (d, J = 9.0 Hz, 1H), 7.07 (d, J= 9.1 Hz, 1H), 7.01 (s, 1H), 6.14 (dt, J= 2.9, 54.6 Hz, 1H), 5.06 - 4.92 (m, 1H), 2.47 (s, 3H), 2.28 (s, 3H), 1.26 (d, J= 6.4 Hz, 3H).

[0369] Example 31 l-[3-Methoxy-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl- pyrazole-3-carbonitrile

[0370] Step 1: 6-chloro-2-fluoro-3-methoxy-pyridine

[0371] To a solution of 6-chl oro-2-fluoro-pyri din-3 -ol (1.30 g, 8.81 mmol, 1.0 eq.) in DMSO (13 mL) were added CS2CO3 (4.31 g, 13.22 mmol, 1.5 eq.) and Mel (1.65 mL, 26.44 mmol, 3.0 eq.), and the mixture was stirred at 60 °C for 1 hour. The reaction mixture was poured into water and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0 - 25% EtOAc in PE) to give 6-chloro-2-fluoro-3-methoxy-pyridine (1.44 g, 8.91 mmol, 100% yield) as a white solid. LC-MS: m / z = 162.0 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-d6) 6 = 7.76 (dd, J = 8.4, 10.4 Hz, 1H), 7.46 (d, J= 8.3 Hz, 1H), 3.90 (s, 3H) Step 2: l-( 6-chloro-3-methoxy-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile

[0372] To a solution of 5-methyl-lH-pyrazole-3-carbonitrile (86 mg, 8.05 mmol, 1.0 eq.), 6-chloro-2- fluoro-3 -methoxy-pyridine (1.3 g, 8.05 mmol, 1.0 eq.) in DMSO (13 mL) was added DIPEA (4.22 mL, 24.14 mmol, 3.0 eq.). The reaction mixture was stirred at 120 °C for 16 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 9 - 50% EtOAc in PE) followed by preparative HPLC (Phenomenex Luna C18 150 mm x 40mm x 15 pm, gradient 30 - 60% CH3CN in H2O over 10 minutes, then 100% CH3CN (2 min), flow rate 60 mL / min) to give l-(6-chl oro-3 -methoxy-2- pyridyl)-5-methyl-pyrazole-3-carbonitrile (45 mg, 0.180 mmol, 2% yield) as a white solid. LC- MS: m / z = 249.1[M+H]+, ESI pos. 'H NMR (400 MHz, METHANOL-d4) 5 = 7.85 (d, J = 8.7 Hz, 1H), 7.65 (d, J= 8.7 Hz, 1H), 7.03 (s, 1H), 3.97 (s, 3H), 2.40 (s, 3H)

[0373] Step 3: l-[ 3-methoxy-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2-pyridyl ]-5- methyl-pyrazole-3-carbonitrile

[0374] Prepared in analogy to Example 1, step 8, using l-(6-chloro-3-methoxy-2-pyridyl)-5-methyl- pyrazole-3 -carbonitrile (45 mg, 0.180 mmol, 1.0 eq.) and N-(6-methylpyridazin-3-yl)-lH- benzimidazol-5-amine (Example 1, step 7) (41 mg, 0.180 mmol, 1.0 eq.) followed by purification by preparative HPLC (Phenomenex Luna Cl 8 150 mm x 40mm x 15 pm, gradient 30 - 60% CH3CN in H2O over 10 minutes, then 100% CH3CN (2 min), flow rate 60 mL / min) to give l-[3-methoxy-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile (3 mg, 4% yield) as an off-white solid. LC-MS: m / z = 438.1 [M+H]+, ESI pos. 'H NMR (400 MHz, METHANOL-d4) 5 = 8.82 (d, J= 1.7 Hz, 1H), 8.75 (s, 1H), 8.49 (br s, 1H), 8.12 (d, J= 3.3 Hz, 2H), 7.71 (d, J= 8.7 Hz, 1H), 7.43 - 7.34 (m, 2H), 7.17 (d, J= 9.2 Hz, 1H), 7.08 (s, 1H), 4.07 (s, 3H), 2.57 (s, 3H), 2.41 (s, 3H). Example 32 l-[3-(Cyanomethoxy)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]- 5-methyl-pyrazole-3-carbonitrile

[0375] Step 1: 2- [(6-chloro-2-fluoro-3-pyridyl)oxy] acetonitrile

[0376] To a solution of 6-chl oro-2-fluoro-pyri din-3 -ol (800 mg, 5.42 mmol, 1.0 eq.) and bromoacetonitrile (1300 mg, 10.85 mmol, 2.0 eq.) in 2-butanone (10 mL) was added K2CO3 (2243 mg, 16.27 mmol, 3.0 eq.). The reaction mixture was stirred at 80 °C for 16 hours. The mixture was diluted with water and extrated with EtOAc. The organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (30% - 50% EtOAc in PE) to give 2-[(6-chloro-2-fluoro-3- pyridyl)oxy]acetonitrile (700 mg, 3.75 mmol, 69% yield) as yellow solid.JH NMR (400 MHz, CDCI3) 8 ppm 7.53-7.50 (dd, J =9.52, 8.32 Hz, 1 H) 7.28 - 7.25 (m, 1 H) 4.88 (s, 1 H).

[0377] Step 2: l-[ 6-chloro-3-(cyanomethoxy)-2-pyridyl ]-5-methyl-pyrazole-3-carbonitrile

[0378] Prepared in analogy to Example 17, step 2, using 2-[(6-chloro-2-fluoro-3- pyridyl)oxy]acetonitrile (700 mg, 3.7 mmol, 1.0 eq.) and 5-methyl-lH-pyrazole-3-carbonitrile (398 mg, 3.7 mmol, 1.0 eq.) to give l-[6-chloro-3-(cyanomethoxy)-2-pyridyl]-5-methyl- pyrazole-3 -carbonitrile (640 mg, 2.34 mmol, 62% yield) as a red solid. LC-MS: m / z = 274.0 [M+H]+, ESI pos. 'H NMR (400 MHz, CDC13) 8 ppm 7.74-7.72 (d, J =8.63 Hz, 1 H) 7.57-7.56 (d, J =8.63 Hz, 1 H) 6.63 (s, 1 H) 4.87 (s, 2 H) 2.40 (s, 3 H).

[0379] Step 3: l-[ 3 -(cyanomethoxy) -6- [ 6-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2- pyridyl] -5-methyl-pyrazole-3-carbonitrile

[0380] Prepared in analogy to Example 1, step 8, using l-[6-chloro-3-(cyanomethoxy)-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile (600 mg, 2.19 mmol, 1.0 eq.) and N-(6-methylpyridazin-3-yl)- lH-benzimidazol-5-amine (Example 1, step 7) (593 mg, 2.63 mmol, 1.2 eq.) followed by purification by preparative HPLC (Phenomenex Luna Cl 8 150 mm x 40mm x 15 pm, gradient 30 - 60% CH3CN in H2O over 10 minutes, then 100% CH3CN (2 min), flow rate 60 mL / min) and preparative NPLC (Welch Ultimate XB-SiOH 250 mm x 50 mm x 10 pm, gradient 15 - 55% EtOH (0.1% FA) - Hexane over 15 minutes then 100% EtOH for 2 minutes, flow rate 100 ml / min) to give l-[3-(cyanomethoxy)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]- 2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (15 mg, 0.030 mmol, 2% yield) as white solid. LC- MS: m / z = 463.1 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-t / 6) 6 ppm 9.27 (s, 1 H) 8.82 (s, 1 H) 8.68 - 8.74 (m, 1 H) 8.30 (s, 2 H) 7.67 - 7.71 (m, 1 H) 7.42 (dd, J =8.76, 2.13 Hz, 1 H) 7.29 (d, J =9.01 Hz, 1 H) 7.08 (d, J =9.01 Hz, 1 H) 7.02 (s, 1 H) 5.40 (s, 2 H) 2.50 (br s, 3 H) 2.34 (s, 3 H) 2.06 - 2.10 (m, 1 H). Example 33 l-[3-(Cyanomethoxy)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]- 5-methyl-pyrazole-3-carbonitrile l-[3-(cyanomethoxy)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile (4 mg, 0.010 mmol, 0.4% yield) was obtained as white solid after purification of the crude in Example 32, step 3. LC-MS: m / z = 463.1 [M+H]+, ESI pos.JH NMR (400 MHz, DMSO-d6) 5 ppm 9.22 (s, 1 H) 8.95 (s, 1 H) 8.41 - 8.49 (m, 1 H) 8.33 (d, J =4.04 Hz, 2 H) 7.97 - 8.04 (m, 1 H) 7.43 - 7.52 (m, 1 H) 7.32 (s, 1 H) 7.04 - 7.12 (m, 2 H) 5.40 (s, 2 H) 2.47 - 2.49 (m, 3 H) 2.32 (s, 3 H).

[0381] Example 34

[0382] 1- [3- [(2R,4R)-4-(difluoromethyl)tetrahydrofuran-2-yl]-6- [5- [(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile and

[0383] 1- [3- [(2S,4S)-4-(difluoromethyl)tetrahydrofuran-2-yl]-6- [5- [(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile Step 1 : l-( 6-chloro-2-fluoro-3-pyridyl)-3-methylol-pent-4-en-l-one

[0384] To a solution of diisopropylamine (325 pL, 2.28 mmol, 1.2 eq.) in THF (4 mL) was added 1.6 M BuLi (1.4 mL, 2.28 mmol, 1.2 eq.) at -78 °C drop wise. The solution was warmed to -20 °C and stirred for 10 minutes. The reaction mixture was cooled to -78 °C. A solution of 2-chloro-6- fluoro-pyridine (250 mg, 1.90 mmol, 1.0 eq.) in THF (2 mL) was added dropwise at -78 °C. The reaction mixture was stirred at -78 °C for 1 hour. 4-vinyltetrahydrofuran-2-one (256 mg, 2.28 mmol, 1.2 eq.) solved in THF (2 mL) was added dropwise at -78 °C. The reaction mixture was quenched with saturated aqueous NH4CI and extracted with EtOAc. The organic layers were dried over MgSCh, filtered and concentrated. The residue was purified by flash chromatography (0-40% EtOAc in Heptan) to give l-(6-chloro-2-fluoro-3-pyridyl)-3-m ethyl ol-pent-4-en-l -one (180 mg, 0.589 mmol, 31% yield) as a light yellow liquid. LC-MS: m / z = 244.1 [M+H]+, ESI pos.

[0385] Step 2: l-(6-chloro-2-fluoro-3-pyridyl)-3-vinyl-butane-l,4-diol l-(6-chloro-2-fluoro-3-pyridyl)-3-methylol-pent-4-en-l-one (1.07 g, 4.391 mmol, 1.0 eq.) was dissolved in methanol (20 mL) and NaBH4 (332 mg, 8.78 mmol, 2.0 eq.) was added portion wise at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours. The reaction mixture was quenched with water and extracted with EtOAc. The organic layers were dried over MgSO4, filtered and concentrated to dryness to obtain the crude title compound l-(6-chloro-2-fluoro-3-pyridyl)-3- vinyl -butane- 1,4-diol (1.02 g, 3.996 mmol, 91% yield) as colorless liquid which was used without further purification. LC-MS: m / z = 246.1 [M+H]+, ESI pos.

[0386] Step 3: 6-chloro-2-fluoro-3-(4-vinyltetrahydrofuran-2-yl)pyridine l-(6-chloro-2-fluoro-3-pyridyl)-3 -vinyl -butane- 1,4-diol (1.01 g, 4.111 mmol, 1.0 eq.) was dissolved in toluene (20 mL) and p-toluenesulfonic acid monohydrate (78 mg, 0.411 mmol, 0.1 eq.) was added at rt. The mixture was stirred for 3 hours at 110 °C. The reaction mixture was diluted with saturated aqueous NaHCCh and extracted with EtOAc. The organic layers were dried over MgSCU, filtered and concentrated. The residue was purified by flash chromatography (0 - 30% EtOAc in Heptane) to give 6-chloro-2-fluoro-3-(4-vinyltetrahydrofuran-2-yl)pyridine (507 mg, 2.056 mmol, 50% yield) as a light yellow liquid. LC-MS: m / z = 228.1 [M+H]+, ESI pos.

[0387] Step 4: 5-( 6-chloro-2-fluoro-3-pyridyl)tetrahydrofuran-3-carbaldehyde

[0388] 6-chloro-2-fluoro-3-(4-vinyltetrahydrofuran-2-yl)pyridine (500 mg, 2.196 mmol, 1.0 eq.) was dissolved in dichloromethane (25 mL). Ozone (generated from O2) was bubbled through the reaction mixture at -78 °C until the blue colour of unreacted O3 appeared. PI13P (691 mg, 2.636 mmol, 1.2 eq.) was added and the reaction mixture was stirred for 1 hour at -78 °C followed by 1 hour at RT. The reaction mixture was concentrated to dryness and the residue was purified by flash chromatography (0 - 100% EtOAC in Heptane) to give 5-(6-chloro-2-fluoro-3- pyridyl)tetrahydrofuran-3-carbaldehyde (119 mg, 0.483 mmol, 22% yield) as a colorless oil. LC- MS: m / z = 230.1 [M+H]+, ESI pos.

[0389] Step 5: 6-chloro-3-[ 4-(difluoromethyl)tetrahydrofuran-2-yl / -2-fluoro-pyridine

[0390] 5-(6-chloro-2-fluoro-3-pyridyl)tetrahydrofuran-3-carbaldehyde (115 mg, 0.501 mmol, 1.0 eq.) was dissolved in DCM (4 mL) and DAST (265 pL, 2.00 mmol, 4.0 eq.) was added at 0 °C. The mixture was stirred for 1 hours at 0 °C. The reaction mixture was quenched with saturated aqueous NaHCCL solution and extracted with DCM. The organic layers were dried over MgSCU, filtered and concentrated. The residue was purified by flash chromatography (0 - 30% EtOAc in Heptane) to give 6-chloro-3-[4-(difluoromethyl)tetrahydrofuran-2-yl]-2-fluoro-pyridine (92 mg, 0.366 mmol, 73%) as a light yellow liquid. LC-MS: m / z = 252.1 [M+H]+, ESI pos.

[0391] Step 6: racemic mixture of l-[6-chloro-3-[(2R,4R)-4-(difluoromethyl)tetrahydrofuran-2-yl]-2- pyridyl ]-5-methyl-pyrazole-3-carbonitrile and l-[ 6-chloro-3-[ (2S, 4S)-4-

[0392] (difluoromethyl)tetrahydrofuran-2-yl ]-2-pyridyl ]-5-methyl-pyrazole-3-carbonitrile and racemic mixture of l-[ 6-chloro-3-[ (2S, 4R)-4f difluor omethyl)tetrahydrofuran-2-yl ]-2-pyridyl ]-5-methyl- pyrazole-3-carbonitrile and l-[ 6-chloro-3-[ (2R, 4S)-4f difluor omethyl)tetrahydrofuran-2-yl -2- pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0393] 6-chloro-3-[4-(difluoromethyl)tetrahydrofuran-2-yl]-2-fluoro-pyridine (91 mg, 0.362 mmol, 1.0 eq.) was dissolved in DMF (2 mL) and 5-methyl-lH-pyrazole-3-carbonitrile (46 mg, 0.434 mmol, 1.2 eq.) and K2CO3 (74.97 mg, 0.542 mmol, 1.500 eq.) were added at rt. The mixture was stirred for 18 hours at 70 °C. The reaction mixture was diluted with water and extracted with EtOAc. The organic layers were washed with brine, dried over MgSCh, filtered and concentrated. The crude material was purified by flash chromatography (0 - 60% EtOAc in Heptane) to give racemic mixture of l-[6-chl oro-3 -[(2R,4R)-4-(difluorom ethyl )tetrahydrofuran- 2-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile and l-[6-chloro-3-[(2S,4S)-4- (difhioromethyl)tetrahydrofuran-2-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (42 mg, 0.124 mmol, 35% yield) as a colorless liquid. LC-MS: m / z = 339.1 [M+H]+, ESI pos. and racemic mixture of l-[6-chloro-3-[(2S,4R)-4-(difluoromethyl)tetrahydrofuran-2-yl]-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile and 1 -[6-chloro-3-[(2R,4S)-4-(difluoromethyl)tetrahydrofuran-2- yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (41 mg, 0.117 mmol, 33% yield) as a colorless liquid. LC-MS: m / z = 339.1 [M+H]+, ESI pos.

[0394] Relative stereochemistry confirmed in next step. Step 7: racemic mixture of l-[3-[(2R,4R)-4-(difluoromethyl)tetrahydrofuran-2-yl]-6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile and l-[ 3-[ (2S, 4S)-4f difluor omethyl)tetrahydrofuran-2-yl ]-6-[5-[ ( 6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl / -2 -pyridyl ]-5-methyl-pyrazole-3-carbonitrile

[0395] A racemic mixture of l-[6-chloro-3-[(2R,4R)-4-(difluoromethyl)tetrahydrofuran-2-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile and l-[6-chloro-3-[(2S,4S)-4-

[0396] (difluoromethyl)tetrahydrofuran-2-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (42 mg, 0.125 mmol, 1.0 eq.) was dissolved in DMF (1 mL) and lH-benzimidazol-5-yl-(6-methylpyridazin-3- yl)amine (Example 1, step 7) (31 mg, 0.138 mmol, 1.1 eq.) and Cs2CO3(82 mg, 0.251 mmol, 2.0 eq.) were added at RT. The mixture was stirred at 100 °C for 18 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (0 - 5% MeOH in DCM) to give a racemic mixture of the title compounds (22 mg, 0.040 mmol, 32%; also known as 5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3- [rac-(2A, 4A)-4-(difluoromethyl)oxolan-2-yl]pyri din-2 -yl]pyrazole-3 -carbonitrile) as light brown solid. LC-MS: m / z = 528.3 [M+H]+, ESI pos. 'H NMR (600 MHz, CDC13) d ppm 8.59 (s, 1 H),

[0397] 8.39 - 8.44 (m, 1 H), 7.99 (d, J =8.8 Hz, 1 H), 7.79 (d, J=1.7 Hz, 1 H), 7.77 (d, J =8.5 Hz, 1 H),

[0398] 7.40 (dd, J =8.8, 2.1 Hz, 1 H), 7.14 - 7.16 (m, 1 H), 7.07 - 7.10 (m, 1 H), 6.69 (d, J =0.8 Hz, 1 H), 5.72 - 5.93 (m, 1 H), 4.90 (dd, J =9.3, 6.7 Hz, 1 H), 4.24 (dd, J =9.7, 4.3 Hz, 1 H), 3.95 (dd, J =9.4, 8.3 Hz, 1 H), 2.85 - 2.94 (m, 1 H), 2.61 (s, 3H), 2.53 - 2.59 (m, 1 H), 2.48 (d, J =0.8 Hz, 3 H), 1.71 (ddd, J=13.3, 9.3, 7.1 Hz, 2 H).

[0399] Relative stereochemistry confirmed by NOESY Example 35

[0400] 1- [3- [(2S,4R)-4-(difluoromethyl)tetrahydrofuran-2-yl]-6- [5- [(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile and

[0401] 1- [3- [(2R,4S)-4-(difluoromethyl)tetrahydrofuran-2-yl]-6- [5- [(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile l-[6-chloro-3-[(2R,4S)-4-(difluoromethyl)tetrahydrofuran-2-yl]-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile (41 mg, 0.117 mmol, 1.0 eq.) was dissolved in N,N-dimethylformamide (1 mL) and lH-benzimidazol-5-yl-(6-methylpyridazin-3-yl)amine (Example 1, step 7) (29 mg, 0.129 mmol, 1.100 eq.) and CS2CO3 (76 mg, 0.234 mmol, 2.0 eq.) were added at RT. The mixture was stirred at 100 °C for 18 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layers were washed with brine, dried over MgSCU, filtered and concentrated. The residue was purified by flash chromatography (0 - 5% MeOH in DCM) to give a racemic mixture of the title compounds (18.3 mg, 20.41%; also known as 5-methyl-l-[6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-[rac-(2A,45)-4-(difluoromethyl)oxolan-2- yl]pyridin-2-yl]pyrazole-3-carbonitrile) as light brown solids. LC-MS: m / z = 528.3 [M+H]+, ESI pos. 1H NMR (600 MHz, CHLOROFORM-d) d ppm 8.58 (s, 1 H), 8.35 (dd, J =8.4, 0.6 Hz, 1 H), 7.98 (d, J =8.8 Hz, 1 H), 7.79 (d, J=1.6 Hz, 1 H), 7.76 (d, J=8.4 Hz, 1 H), 7.41 (dd, J =8.8, 2.1 Hz, 1 H), 7.13 - 7.17 (m, 1 H), 6.94 - 7.12 (m, 2 H), 6.69 (d, J=0.8 Hz, 1 H), 5.74 - 5.95 (m, 1 H), 5.00 - 5.04 (m, 1 H), 5.02 (t, .7 =7,6 Hz, 1 H), 4.28 (dd, J =9.2, 8.0 Hz, 1 H), 3.94 (dd, J =9.5, 6.6 Hz, 1 H), 2.81 - 2.90 (m, 1 H), 2.61 (s, 3 H), 2.48 (d, J =0.8 Hz, 3 H), 2.39 - 2.46 (m, 1 H), 1.85 - 1.93 (m, 1 H).

[0402] Relative stereochemistry confirmed by NOESY Example 36 3-[[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethoxy)-2-pyridyl]benzimidazol-5- yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide

[0403] Step 1: methyl 3-chloro-6-methyl-pyridazine-4-carboxylate

[0404] I

[0405] To a suspension of 3-chloro-6-methylpyridazine-4-carboxylic acid (1700.0 mg, 9.85 mmol, 1.0 eq.), K2CO3 (2720 mg, 19.68 mmol, 2.0 eq.) in DMSO (30 mL) was added iodomethane (0.92 mL, 14.85 mmol, 1.51 eq.) at 25 °C. The mixture was stirred at 25 °C for 16 hours. The reaction mixture was diluted with water (200 ml) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (30% EtOAc in PE) give methyl 3-chloro-6- methyl-pyridazine-4-carboxylate (900 mg, 4.82 mmol, 49% yield) as dark red oil. LCMS: 187.0 [M+H]+ESI pos.1H NMR (400 MHz, CDCI3 ) 5 = 7.69 (s, 1H), 4.00 (s, 3H), 2.78 (s, 3H)

[0406] Step 2: methyl 3-(lH-benzimidazol-5-ylamino)-6-methyl-pyridazine-4-carboxylate

[0407] A mixture of methyl 3-chloro-6-methyl-pyridazine-4-carboxylate (950 mg, 5.09 mmol, 1.0 eq.) and 5-aminobenzimidazole (684 mg, 5.14 mmol, 1.01 eq.) in iPrOH (60 mL) was stirred at 120 °C for 24 hours. The reaction mixture was cooled to RT and concentrated. The residue was slurried in MeOH (lOmL) and the solid was collected by filtration. The filter cake was purified by preparative HPLC (Phenom enex Luna Cl 8 150 mm x 40mm x 15 pm, gradient 30 - 60% CH3CN in H2O over 10 minutes, then 100% CH3CN (2 min), flow rate 60 mL / min) to give methyl 3-(lH-benzimidazol-5-ylamino)-6-methyl-pyridazine-4-carboxylate (400 mg, 1.41 mmol, 28% yield) as light yellow solid. LCMS: 284.1[M+H]+ESI pos. 'HNMR (400 MHz, DMSO-d6) 5 = 9.54 (s, 1H), 8.35 - 8.30 (m, 1H), 8.23 (s, 1H), 7.84 (s, 1H), 7.57 (d, J= 8.6 Hz, 1H), 7.30 - 7.25 (m, 1H), 3.95 (s, 3H), 2.57 (s, 3H)

[0408] Step 3: l-[6-chloro-3-(difluoromethoxy)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile and 2-[6- chloro-3-(difluoromethoxy)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0409] A solution of 6-chloro-3-(difhioromethoxy)-2-fhioro-pyridine (2.2 g, 11.14 mmol, 1.0 eq.), 5- methyl-lH-pyrazole-3-carbonitrile (1.2 g, 11.17 mmol, 1.0 eq.) and potassium carbonate (4.62 g, 33.43 mmol, 3.0 eq.) in DMSO (108 mL) was stirred at 80 °C for 3 hours. The colorless solution turned to yellow solution. The reaction mixture was cooled to RT, poured into water (800 mL) and extracted with EtOAc (3 x 100ml). The combined organic layers were washed with brine (2 x lOOmL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (0 - 10% EtOAc in PE) to give 2-[6-chl oro-3 -(difluoromethoxy)-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile (600 mg, 2.11 mmol, 19% yield) as white solid LCMS: 285.1 [M+H]+ESI pos. and l-[6-chloro-3-(difluoromethoxy)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (2.2 g, 7.73 mmol, 69% yield) as white solid. LCMS: 285.1 [M+H]+ESI pos.

[0410] Step 5: 3-[[ l-[ 6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethoxy)-2-pyridyl]benzimidazol-5- yl amino J-N,N, 6-trimethyl-pyridazine-4-carboxamide

[0411] To a solution of 3-[[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethoxy)-2- pyridyl]benzimidazol-5-yl]amino]-6-methyl-pyridazine-4-carboxylic acid (50 mg, 0.07 mmol, 1.0 eq.) in DMF (2 mL) were added dimethylamine hydrochloride (28 mg, 0.34 mmol, 5.0 eq.) and DIPEA (0.09 mL, 0.54 mmol, 8.0 eq.) sequentially 25 °C, followed by HATU (31 mg, 0.08 mmol, 1.2 eq.). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with water (30 ml) and extracted with DCM / MeOH(10 / l) (3 x 10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (Waters Xbridge 150 mm x 25 mm x 5 pm, water (lOmM NH4HCO3) - CH3CN, gradient time 9 minutes, 100% hold time 2 min, flow rate 25 mL / min) to give 3-[[l-[6- (3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethoxy)-2-pyridyl]benzimidazol-5-yl]amino]- N,N,6-trimethyl-pyridazine-4-carboxamide (3 mg) as yellow solid and the crude 3-[[3-[6-(3- cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethoxy)-2-pyridyl]benzimidazol-5-yl]amino]-N,N,6- trimethyl-pyridazine-4-carboxamide (1.2 mg, 0.002 mmol, 3% yield) as light yellow solid. LCMS: 545.2 [M+H]+ESI pos. 'H NMR (400 MHz, DMSO-d6) 5 = 9.01 (s, 1H), 8.39 (s, 1H), 8.34 (s, 2H), 8.18 (d, J= 2.0 Hz, 1H), 8.04 (d, J= 8.9 Hz, 1H), 7.55 - 7.50 (m, 1H), 7.32 (s, 2H), 7.14 (s, 1H), 7.08 (d, J= 0.6 Hz, 1H), 2.98 (s, 3H), 2.90 (s, 3H), 2.53 - 2.52 (m, 3H), 2.37 (s, 3H)

[0412] Example 37 l-[3-(2,2-difluoroethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]- 5-methyl-pyrazole-3-carbonitrile

[0413] Step 1 : l-(3-acetyl-6-chloro-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile

[0414] A solution of l-(6-chloro-2-fluoro-3-pyridyl)ethanone (10.0 g, 57.61 mmol, 1.0 eq.), 5-methyl- lH-pyrazole-3-carbonitrile (5.86 g, 54.73 mmol, 0.95 eq.) and DIPEA (28.57 mL, 172.84 mmol, 3.0 eq.) in DMSO (70 mL) was stirred at 80 °C for 4 hours. The reaction mixture was cooled to RT, poured into water (700mL) and extracted with EtOAc (3 x 400 mL). The ocombined rganic layers were washed with brine (2 x 100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (0 - 30% EtOAc in PE) to give l-(3-acetyl-6- chloro-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile (12.2 g, 46.8 mmol, 69% yield) as light yellow solid. LCMS: 261.0 [M+H]+ESI pos. 'H NMR (400 MHz, CDC13) 8 ppm 2.19 - 2.22 (m, 3 H) 2.61 (s, 3 H) 6.62 - 6.66 (m, 1 H) 7.48 - 7.54 (m, 1 H) 7.98 (d, J= 8.07 Hz, 1 H).

[0415] Step 2: l-[6-chloro-3-(4,4,4-trifluoro-3-oxo-butanoyl)-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile

[0416] To a solution of l-(3-acetyl-6-chloro-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile (3.53 g, 11.51 mmol, 1.0 eq.) in THF (35 mL) was added LiHMDS (23.02 mL, 23.02 mmol, 2.0 eq.) dropwise at -70 °C. The reaction mixture was stirred at -70 °C for 1 hour. To the reaction mixture was added ethyl trifluoroacetate (1.64 g, 11.51 mmol, 1.0 eq.) in THF (10 mL) dropwise at -70 °C. The reaction mixture was allowed to reach 20 °C and was stirred at 20 °C for 2 hours. The reaction mixture was poured into saturated aqueous NH4CI (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (10 - 30% EtOAc in PE) to give l-[6-chloro-3-(4,4,4-trifluoro-3-oxo-butanoyl)-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile (1.4 g, 3.92 mmol, 34% yield) as brown oil. LCMS: 357.1 [M+H]+ESI pos.1!! NMR (400 MHz, CDCI3 ) 8 ppm 2.35 (br s, 3 H) 4.88 - 5.29 (m, 1 H) 6.41 - 6.59 (m, 1 H) 7.32 - 7.56 (m, 1 H) 7.83 - 8.06 (m, 1 H).

[0417] Step 3: l-[ 6-chloro-3-(2, 2 -difluoroacetyl) -2 -pyridyl ]-5-methyl-pyrazole-3-carbonitrile

[0418] To a solution of l-[6-chloro-3-(4,4,4-trifluoro-3-oxo-butanoyl)-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile (3.2 g, 8.07 mmol, 1.0 eq.) in CH3CN (60 mL) was added SelectFluor (7.15 g, 20.19 mmol, 2.5 eq.) in portion at 15 °C. The mixture was stirred at 90 °C for 1 h, then cooled to room temperature. To the mixture was added TEA (5.6 mL, 40.37 mmol, 5.0 eq.) and water (0.29 mL, 16.15 mmol, 2.0 eq.) at 20 °C. The mixture was stirred at 20 °C for 1.5 hours. The reaction mixture was poured into water (60 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered and concentrated to give the crude product l-[6-chloro-3-(2,2-difluoroacetyl)-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile (2.4 g, 8.09 mmol, quant, yield) as brown oil which was used without further purification. LCMS: 296.9 [M+H]+ESI pos.

[0419] Step 4: l-[ 6-chloro-3-(2, 2-dijluoro-l-hydroxy-ethyl)-2-pyridyl / -5-methyl-pyrazole-3- carbonitrile

[0420] To a solution of l-[6-chloro-3-(2,2-difluoroacetyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (2.4 g, 8.09 mmol, 1.0 eq.) in THF (30 mL) was added NaBH4 (918 mg, 24.27 mmol, 3.0 eq.) at 0 °C in portion. The mixture was stirred at 0 °C for 1 hour. The mixture was quenched by addition of saturated aqueous NH4CI (50mL) and extracted with EtOAc (3 x 30mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (0 - 25% EtOAc in PE) to give l-[6-chloro-3-(2,2-difluoro-l-hydroxy-ethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (1.7 g, 5.69 mmol, 70% yield) as light yellow solid. LCMS: 299.0 [M+H]+ESI pos. 'H NMR (400 MHz, CDCI3 ) 8 = 8.21 (d, J= 8.3 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 6.64 (s, 1H), 5.98 (dt, J = 2.9, 55.5 Hz, 1H), 5.07 (ddd, = 2.7, 10.1, 13.3 Hz, 1H), 2.46 (s, 3H).

[0421] Step 5: O-[ 1 -[ 6-chloro-2-(3-cyano-5-methyl-pyrazol-l-yl)-3-pyridyl ]-2, 2 -difluoro-ethyl ] methylsulfanylmethanethioate

[0422] To a solution of l-[6-chloro-3-(2,2-difluoro-l-hydroxy-ethyl)-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile (1.6 g, 5.36 mmol, 1.0 eq.) in THF (30 mL) was added NaH (642.83 mg, 16.07 mmol, 3.0 eq.) at 0 °C. The mixture was stirred at 0 °C for 0.5 hours. Carbondisulfide (1.22 g, 16.07 mmol, 3.0 eq.) was added at 0 °C and the reaction mixture was stirred for 2 hours. Methyl iodide (2.28 g, 16.07 mmol, 3.0 eq.) was added and the mixture was stirred at 25 °C for 12 hours. The mixture was quenched by addition of saturated aqueous NH4CI (200mL) and extracted with EtOAc (2 x 200mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (0 - 25% EtOAc in PE) to give O-[l-[6-chloro-2-(3-cyano-5-methyl-pyrazol-l- yl)-3-pyridyl]-2,2-difluoro-ethyl] methylsulfanylmethanethioate (1.7 g, 4.37 mmol, 82% yield) as light yellow solid.

[0423] Step 6: l-[ 6-chloro-3-(2, 2 -difluoroethyl) -2 -pyridyl ]-5-methyl-pyrazole-3-carbonitrile

[0424] To a solution of O-[l-[6-chloro-2-(3-cyano-5-methyl-pyrazol-l-yl)-3-pyridyl]-2,2-difluoro-ethyl] methylsulfanylmethanethioate (1.7 g, 4.37 mmol, 1.0 eq.) and tri-n-butyl-tin hydride (1.53 g, 5.25 mmol, 1.2 eq.) in toluene (30 mL) was added AIBN (71.79 mg, 0.44 mmol, 0.1 eq.) at 20 °C and the mixture was stirred for 15 minutes. The mixture was heated to 80 °C and stirred for 2 hours. The mixture was quenched by addition of saturated aqueous NH4CI (lOOmL) and extracted with EtOAc (3 x 50mL). The combined organic layers were washed with saturated aqueous KF (lOOmL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (SiO2, 0 - 10% EtOAc in PE) to give l-[6-chloro-3-(2,2-difluoroethyl)-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile (1.2 g, 4.25 mmol, 97% yield) as white solid. LCMS: 299.0 [M+H]+ESI pos. 'H NMR (400 MHz, CDCI3 ) 8 = 7.86 (d, J= 8.2 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H), 6.62 (d, J= 0.6 Hz, 1H), 6.05 (tt, J = 4.0, 56.5 Hz, 1H), 3.19 (dt, J = 4.0, 17.0 Hz, 2H), 2.43 (s, 3H).

[0425] Step 7: l-[3-(2,2-difluoroethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl] -5-methyl-pyrazole-3-carbonitrile

[0426] Prepared in analogy to Example 1, step 8, using N-(6-methylpyridazin-3-yl)-lH-benzimidazol-5- amine (Example 1, step 7) (263 mg, 1.17 mmol, 1.1 eq.) and l-[6-chloro-3-(2,2-difluoroethyl)-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile (300 mg, 1.06 mmol, 1.0 eq.) followed by preparative NPLC (Welch Ultimate XB-SiOH 250 mm x 70 mm x 10 pm, gradient 15 - 55% EtOH (with 0.1% ammonium hydroxide) in hexane over 15 minutes, then 100% EtOH (with 0.1% ammonium hydroxide) (3 min), flow rate 100 mL / min) to give l-[3-(2,2-difluoroethyl)-6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (45 mg, 0.095 mmol, 9% yield) as white solid. LC-MS: m / z = 472.2 [M+H]+, ESI pos. 'H NMR (400 MHz, METHANOL-d4) 5 = 8.90 (s, 1H), 8.28 (d, J= 8.4 Hz, 1H), 8.24 (d, J= 1.8 Hz, 1H), 8.10 (dd, J= 2.7, 8.7 Hz, 2H), 7.59 (dd, J= 2.1, 8.9 Hz, 1H), 7.35 (d, J= 9.2 Hz, 1H), 7.12 (d, J = 9.2 Hz, 1H), 6.88 (d, J= 0.6 Hz, 1H), 6.13 (tt, J= 4.0, 56.5 Hz, 1H), 3.29 - 3.19 (m, 2H), 2.53 (s, 3H), 2.43 (s, 3H) Example 38 l-[3-(l,3-dioxolan-2-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]- 5-methyl-pyrazole-3-carbonitrile Step 1: 6-chloro-3-(l,3-dioxolan-2-yl)-2-fluoro-pyridine

[0427] 2,4-dichlorothiazole-5-carbaldehyde (2.0 g, 12.5 mmol, 1.0 eq.) was dissolved in Toluene (50 ml) and 1,2-ethanediol (1.0 ml, 18.3 mmol, 1.5 eq.). p-Toluenesulfonic acid monohydrate (62 mg, 0.330 mmol, 0.03 eq.) was added and the mixture was heated to reflux overnight with azeotropic removal of water via Dean Stark trap. The reaction mixture was cooled to RT and partitionned between saturated aqueous NaHCCh (50 mL) and EtOAc (50 mL). The organic layer was washed with water (20 mL). The aqueous phase was extracted with EtOAc (50 mL) and the combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (SiO2, 40% EtOAc in heptane) to give 6-chl oro-3 -(1,3- dioxolan-2-yl)-2-fluoro-pyridine (2.25 g, 11.07 mmol, 88% yield ) as a yellow oil. LC-MS: m / z

[0428] = 204.0 [M+H]+, ESI pos.

[0429] Step 2: l-[6-chloro-3-(l,3-dioxolan-2-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile and 2- [6- chloro-3-( 1, 3-dioxolan-2-yl)-2-pyridyl ]-5-methyl-pyrazole-3-carbonitrile 6-Chl oro-3 -(1,3 -di ox olan-2-yl)-2-fluoro-pyri dine (1.26 g, 6.19 mmol, 1.0 eq.) was dissolved in DMF (13 mL). 5-methyl-lH-pyrazole-3-carbonitrile (729 mg, 6.81 mmol, 1.1 eq.) and K2CO3 (1.03 g, 7.43 mmol, 1.2 eq.) were added. The reaction mixture was stirred at 50 °C overnight. The reaction mixture was cooled to RT and partitionned between saturated aqueous NH4CI (50 mL) and EtOAc (50 mL). The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (SiO2, 0 to 50% EtOAc in heptane) to give a 8: 1 mixture of l-[6-chloro-3-(l,3-dioxolan-2-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile and 2-[6-chloro-3-(l,3-dioxolan-2-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile () as a light yellow solid. LC-MS: m / z = 291.1 [M+H]+, ESI pos.

[0430] Step 3: l-[ 6-(5-bromobenzimidazol-l-yl)-3-( 1, 3-dioxolan-2-yl)-2-pyridyl / -5-methyl-pyrazole-3- carbonitrile and l-[ 6-(6-bromobenzimidazol-l-yl)-3-(l, 3-dioxolan-2-yl)-2-pyridyl]-5-methyl- pyrazole-3-carbonitrile

[0431] A 8: 1 mixture of l-[6-chloro-3-(l,3-dioxolan-2-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile and 2-[6-chloro-3-(l,3-dioxolan-2-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (1.0 g, 3.44 mmol, 1.0 eq.) was dissolved in DMSO (30 mL). 5-bromo-lH-benzimidazole (745 mg, 3.78 mmol, 1.1 eq.) and l,8-diazabicyclo[5.4.0]undec-7-ene (2.59 mL, 17.2 mmol, 5.0 eq.) were added and the reaction mixture was stirred at 120 °C for 3 hours. The reaction mixture was cooled to RT and partitionned between water (75 mL) and EtOAc (75 mL). The organic layer was dried over MgSCh, filtered and concentrated. The residue was purified by flash chromatography (SiCh, 0 to 100% EtOAc in heptane) to give a 1 :1 mixture of l-[6-(5- bromobenzimidazol-l-yl)-3-(l,3-dioxolan-2-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile and l-[6-(6-bromobenzimidazol-l-yl)-3-(l,3-dioxolan-2-yl)-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile (1.04 g, 2.31 mmol, 67% yield) as off-white solid. LC-MS: m / z = 451.2 [M+H]+, ESI pos. Step 4: l-[3-( 1, 3-dioxolan-2-yl)-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2- pyridyl] -5-methyl-pyrazole-3-carbonitrile

[0432] A mixture of l-[6-(5-bromobenzimidazol-l-yl)-3-(l,3-dioxolan-2-yl)-2-pyridyl]-5-methyl- pyrazole-3 -carbonitrile and l-[6-(6-bromobenzimidazol-l-yl)-3-(l,3-dioxolan-2-yl)-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile (300 mg, 0.665 mmol, 1.0 eq.) was suspended in 1,4-dioxane (8.56 mL). (6-methylpyridazin-3-yl)amine (145 mg, 1.33 mmol, 2.0 eq.) and CS2CO3 (650 mg, 1.99 mmol, 3.0 eq.) were added. The reaction mixture was bubbled with Ar for 10 minutes. [tBuBrettPhos Pd(allyl)]OTf (52 mg, 0.066 mmol, 0.10 eq.) was added and the reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was cooled to RT, concentrated and the residue was purified by flash chromatography (SiCh, 0 to 10% MeOH in DCM) to give l-[3- (l,3-dioxolan-2-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile (93 mg, 0.193 mmol, 29% yield) as a light green solid. LC-MS: m / z = 480.4 [M+H]+, ESI pos. 1H NMR (600 MHz, DMSO-d6) d ppm 9.22 (s, 1 H), 9.06 (s, 1 H), 8.44 (d, J= 2.1 Hz, 1 H), 8.41 (d, J= 8.5 Hz, 1 H), 8.29 (d, J= 8.2 Hz, 1 H), 8.06 (d, J= 9.0

[0433] Hz, 1 H), 7.49 (dd, J = 8.8, 2.2 Hz, 1 H), 7.33 (d, J= 9.1 Hz, 1 H), , 7.06 - 7.09 (m, 2H), 5.70 - 5.71 (m, 1 H), 4.01 - 4.06 (m, 2 H), 3.90 - 3.94 (m, 2 H), 2.48 (s, 3 H), 2.36 (s, 2H), 2.35 (d, J= 0.7 Hz, 3 H).

[0434] Example 39 [l-[6-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-5-(l,3-dioxolan-2-yl)-2- pyridyl]benzimidazol-5-yl]-(6-methylpyridazin-3-yl)amine 6-chloro-2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-3-(l,3-dioxolan-2-yl)pyridine (300 mg, 0.950 mmol, 1.0 eq.) was dissolved in t-amyl alcohol (7 mL) and lH-benzimidazol-5-yl-(6- methylpyridazin-3-yl)amine (Example 1, step 7) (214 mg, 0.950 mmol, 1.0 eq.) and tripotassium phosphate (605 mg, 2.85 mmol, 3.0 eq.) were added. The suspension was bubbled with Argon for 10 minutes. [tBuBrettPhos Pd(allyl)]OTf (75 mg, 0.095 mmol, 0.10 eq.) was added and reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over MgSCU, filtered and concentrated. The residue was purified by flash chromatography (SiO2, 0 - 6% MeOH in DCM) to give [l-[6-[3-(difluoromethyl)-5-methyl- pyrazol-l-yl]-5-(l,3-dioxolan-2-yl)-2-pyridyl]benzimidazol-5-yl]-(6-methylpyridazin-3-yl)amine (120 mg, 25% yield) as light brown solid. LC-MS: m / z = 505.2 [M+H]+, ESI pos.

[0435] Example 40 [l-[5-bromo-6-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-2-pyridyl]benzimidazol-5-yl]-(6- methylpyridazin-3-yl)amine

[0436] 3-bromo-6-chloro-2-fluoro-pyridine (1 g, 4.75 mmol, 1.0 eq.) was dissolved in DMF (25 mL) and 3-(difluoromethyl)-5-methyl-lH-pyrazole (753 mg, 5.7 mmol, 1.2 eq.) and K^CCh (985 mg, 7.13 mmol, 1.5 eq.) were added. The mixture was stirred at RT for 16 hours. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 75 mL). The combined organic layers were washed with brine (75 mL), dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (SiCL, 0 - 40% EtOAc in Heptane) to give a mixture of 3-bromo-6-chloro-2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]pyridine and 3- bromo-6-chloro-2-[5-(difluoromethyl)-3-methyl-pyrazol-l-yl]pyridine. The mixture was purified by preparative SFC (DAICEL CHIRALPAK IC (250 mm x 30 mm, 10 pm), 0.1% NH4OH in MeOH, gradient time 4 minutes, flow rate 80 mL / min) to give the two title compounds 3-bromo- 6-chloro-2-[3-(difhioromethyl)-5-methyl-pyrazol-l-yl]pyridine (1.15 g, 73.53%) as white solid. LC-MS: m / z = 323.9 [M+H]+, ESI pos.

[0437] Step 2: [ l-[5-bromo-6-[ 3-(difluoromethyl)-5-methyl-pyrazol-l-yl ]-2-pyridyl ]benzimidazol-5-yl ]- ( 6-methylpyridazin-3-yl)amine

[0438] 3-bromo-6-chloro-2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]pyridine (120 mg, 0.372 mmol, 1.0 eq.) was dissolved in DMSO (1.8 mL) and lH-benzimidazol-5-yl-(6-methylpyridazin-3- yl)amine (Example 1, step 7) (92 mg, 0.409 mmol, 1.1 eq.) and l,8-diazabicyclo[5.4.0]undec-7- ene (67 pL, 0.446 mmol, 1.2 eq.) were added. The mixture was stirred at 80 °C for 3 hours. The reaction mixture was cooled to RT, diluted with saturated aqueous NaHCCL (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed brine (30 mL), dried over MgSCh, filtered and concentrated. The residue was purified by flash chromatography (SiCL, 0 - 5% MeOH in DCM) to give [l-[5-bromo-6-[3-(difluoromethyl)-5-methyl-pyrazol-l- yl]-2-pyridyl]benzimidazol-5-yl]-(6-methylpyridazin-3-yl)amine (26 mg, 0.051 mmol, 14%) as light brown. LC-MS: m / z = 513.1 [M+H]+, ESI pos. 'H NMR (600 MHz, CDC13) 8 ppm 8.57 (s, 1 H), 8.30 (d, J= 8.5 Hz, 1 H), 7.99 (dd, J= 8.8, 0.6 Hz, 1 H), 7.77 (d, J= 1.7 Hz, 1 H), 7.63 (d, J= 8.6 Hz, 1 H), 7.38 (dd, J= 8.8, 2.2 Hz, 1 H), 7.11 - 7.17 (m, 1 H), 7.08 (s, 1 H), 7.03 (br s, 1 H), 6.63 - 6.85 (m, 1H), 6.52 (d, J= 0.7 Hz, 1 H), 2.60 (s, 3 H), 2.37 (d, J= 0.7 Hz, 3 H).

[0439] Example 41

[0440] 5-methyl- 1- [6- [5- [(6-methylpyridazin-3-yl)amino] benzimidazol- 1-yl] -3-(trifluoromethoxy)- 2-pyridyl]pyrazole-3-carbonitrile Step J: 2,6-dichloro-3-(trifluoromethoxy)pyridine

[0441] To a solution of 2, 6-di chi oro-3 -(trifluorom ethoxy )pyri dine (500 mg, 2.16 mmol, 1.0 eq.) in DMSO (10 mL) was added 5-methyl-lH-pyrazole-3-carbonitrile (277 mg, 2.59 mmol, 1.2 eq.) and K2CO3 (892 mg, 6.47 mmol, 3.0 eq.). The reaction was stirred at 25 °C for 4 hours. The mixture was diluted with water (50 mL) and extrated with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography(10 to 30 % EtOAc in PE) to give l-[6-chloro- 3-(trifluoromethoxy)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (100 mg, 0.33 mmol, 15% yield) as off-white solid. LC-MS: m / z = 302.9 [M+H]+, ESI pos. 'H NMR (400 MHz, CDCI3) 8 = 7.84 (dd, J= 1.2, 8.6 Hz, 1H), 7.58 (d, J= 8.6 Hz, 1H), 6.61 (d, J= 0.6 Hz, 1H), 2.38 (d, J = 0.6 Hz, 3H).

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

[0443] To a solution of l-[6-chloro-3-(trifluoromethoxy)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (40 mg, 0.13 mmol, 1.0 eq.) in DMSO (2 mL) was added N-(6-methylpyridazin-3-yl)-lH- benzimidazol-5-amine (60 mg, 0.26 mmol, 2.0 eq.) and K2CO3 (91.33 mg, 0.66 mmol, 5.0 eq.). The reaction mixture was stirred at 50 °C for 16 hours. The mixture was cooled to RT and diluted with EtOAc (20 mL), filtered and the filtrate was concentrated. The residue was purified by preparative TLC (DCM / MeOH 10: 1) followed by preparative SFC (DAICEL CHIRALPAK IC (250 mm x 30 mm, 10 pm), 0.1% NH4OH in MeOH, gradient time 4 minutes, flow rate 80 mL / min) to give 5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3- (trifluoromethoxy)-2-pyridyl]pyrazole-3-carbonitrile (6 mg, 0.01 mmol, 8% yield) as yellow solid. LC-MS: m / z = 492.1 [M+H]+, ESI pos. 'H NMR (400 MHz, METHANOL-d4) 5 = 8.98 (s, 1H), 8.43 - 8.37 (m, 1H), 8.28 (dd, J= 3.4, 5.4 Hz, 2H), 8.20 (d, J= 9.0 Hz, 1H), 7.61 (dd, J = 2.0, 8.9 Hz, 1H), 7.53 (d, J = 92 Hz, 1H), 7.31 (d, J = 92 Hz, 1H), 6.90 (s, 1H), 2.59 (s, 3H), 2.45 (s, 3H).

[0444] Example 42 [l-[5-amino-6-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-2-pyridyl]benzimidazol-5-yl]-(6- methylpyridazin-3-yl)amine

[0445] Step 1: 6-chloro-2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]nicotinic acid methyl ester

[0446] 6-chloro-2-fluoro-nicotinic acid methyl ester (1.00 g, 5.28 mmol, 1.0 eq.) was dissolved in DMF (25 mL) and 3-(difluoromethyl)-5-methyl-lH-pyrazole (836 mg, 6.33 mmol, 1.2 eq.) and K2CO3 (1.09 g, 7.91 mmol, 1.5 eq.) were added. The mixture was stirred at RT for 16 hours. The reaction mixture was diluted with water (75 mL) and extracted with EtOAc (3 x 75 mL). The combined organic layers were washed with brine (50 mL), dried over MgSCU, filtered and concentrated. The residue was purified by flash chromatography (SiCL, 0 - 40% EtOAc in Heptane). The material was further purified by preparative SFC (column achiral 100 PEI (250mm x 20 mm x 5pm). 30% (0.2% diethylamine in MeOH) in scCO?) to obtain the two title compounds 6-chloro-2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]nicotinic acid methyl ester (943 mg, 59%) as colorless liquid. LC-MS: m / z = 302.1 [M+H]+, ESI pos. 'H NMR (600 MHz, CDC13) 8 ppm 8.11 (d, J= 8.2 Hz, 1 H), 7.44 (d, J= 8.1 Hz, 1 H), 6.61 (t, J= 55.0 Hz, 1 H), 6.43 (d, J= 0.7 Hz, 1 H), 3.72 (s, 3 H), 2.54 (d, J= 0.7 Hz, 3 H).

[0447] Step 2: 6-chloro-2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl] nicotinic acid

[0448] 6-chloro-2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]nicotinic acid methyl ester (940 mg, 3.12 mmol, 1.0 eq.) was dissolved in THF (8 mL) and MeOH (4 mL) and lithium hydroxide monohydrate (262 mg, 6.23 mmol, 2.0 eq.) dissolved in water (4 mL) was added. The mixture was stirred at RT for 16 hours. The reaction mixture was concentated to give 6-chloro-2-[3- (difluoromethyl)-5-methyl-pyrazol-l-yl]nicotinic acid (1.27 g, 3.09 mmol, 99%) as light yellow solid which was used without further purification. LC-MS: m / z = 288.1 [M+H]+, ESI pos.

[0449] Step 3: N-tert-butoxycarbonyl-N-[ 6-chloro-2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-3- pyridyl] carbamic acid tert-butyl ester

[0450] 6-chloro-2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]nicotinic acid (100 mg, 0.348 mmol, 1.0 eq.) was dissolved in tert-butanol (2 mL) followed by the addition of EtsN (58 pL, 0.417 mmol, 1.2 eq.) and diphenylphosphoryl azide (90 pL, 0.417 mmol, 1.2 eq.) at RT. The mixture was stirred at 80 °C for 16 hours. The reaction mixture was cooled to RT, diluted with water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over MgSCU , filtered and and concentrated. The crude material was dissolved in DCM (2 mL). DIPEA (36 pL, 0.209 mmol, 0.6 eq.), 4-dimethylaminopyridine (4.25 mg, 0.035 mmol, 0.1 eq.) and (Boc)2O (46 mg, 0.209 mmol, 0.6 eq.) were added at RT. The reaction mixture was stirred at RT for 16 hours. The reaction mixture was diluted with water (30 mL) and extracted two times with DCM (3 x 20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (SiCh, 0 - 30% EtOAc in Heptane) to give N-tert-butoxycarbonyl-N-[6-chloro-2-[3-(difluoromethyl)-5- methyl-pyrazol-l-yl]-3-pyridyl]carbamic acid tert-butyl ester (42 mg, 25%) as colorless oil. LC- MS: m / z = 481.1423 [M+Na+H]+, ESI pos.

[0451] Step 4: N-tert-butoxycarbonyl-N-[ 2-[ 3-(difluoromethyl)-5-methyl-pyrazol-l-yl ]-6-[5-[ ( 6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-pyridyl] carbamic acid tert-butyl ester

[0452] N-tert-butoxycarbonyl-N-[6-chloro-2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-3- pyridyl] carbamic acid tert-butyl ester (40 mg, 0.087 mmol, 1.0 eq.) was dissolved in tert-amyl alcohol (3 mL). lH-benzimidazol-5-yl-(6-methylpyridazin-3-yl)amine (Example 1, step 7) (24 mg, 0.105 mmol, 1.2 eq.) and tripotassium phosphate (56 mg, 0.262 mmol, 3.0 eq.) were added. The mixture was bubbled with argon for 10 minutes. tBuxphosPdG3 (7 mg, 0.009 mmol, 0.1 eq.) was added. The reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was cooled to RT, diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over MgSCU, filtered and concentrated. The residue was purified by flash chromatography (SiCL, 0 - 5% MeOH in DCM) to give N-tert-butoxycarbonyl-N-[2-[3- (difhioromethyl)-5-methyl-pyrazol-l-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl]-3-pyridyl]carbamic acid tert-butyl ester (15 mg, 27%) as light brown solid. LC-MS: m / z = 548.4 [M-Boc+H]+, ESI pos. Step 5: [ l-[5-amino-6-[ 3-(difluoromethyl)-5-methyl-pyrazol-l-yl ]-2-pyridyl ]benzimidazol-5-yl ]- ( 6-methylpyridazin-3-yl)amine

[0453] N-tert-butoxycarbonyl-N-[2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-pyridyl]carbamic acid tert-butyl ester (15 mg, 0.023 mmol, 1.0 eq.) was dissolved in DCM (2 mL) and 4 M HC1 in Dioxane 4M (58 pL, 0.232 mmol, 10 eq.) was added. The reaction mixture was stirred at RT for 1 hour. The reaction mixture was diluted with saturated aqueous NaHCCL (10 mL) and extracted wih DCM (3 x 10 mL). The combined organic layers were dried over MgSCh, filtered and concentrated. The crude material was purified by flash chromatography (SiCL, 0 - 6% MeOH in DCM to give [l-[5- amino-6-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-2-pyridyl]benzimidazol-5-yl]-(6- m ethyl pyridazin-3-yl)amine (7 mg, 66%) as light brown solid. LC-MS: m / z = 448.4 [M+H]+, ESI pos. 'HNMR (600 MHz, CDC13) 8 ppm 8.43 (s, 1 H), 7.84 (d, J= 8.7 Hz, 1 H), 7.75 (d, J= 1.9 Hz, 1 H), 7.44 (s, 2 H), 7.32 (dd, J= 8.7, 2.1 Hz, 1 H), 7.11 - 7.13 (m, 1 H), 7.06 - 7.08 (m, 1 H), 6.93 - 7.19 (m, 1 H), 6.63 - 6.84 (m, 1 H), 6.51 (s, 1 H), 4.98 (s, 2H), 2.60 (s, 3 H), 2.55 (s, 3 H).

[0454] Example 43 l-[3-(l-cyanocyclopropoxy)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile Step 1: methyl 4-bromo-2-[(6-chloro-2-fluoro-3-pyridyl)oxy]butanoate

[0455] 6-chl oro-2-fluoro-pyri din-3 -ol (1.0 g, 6.78 mmol, 1.0 eq.) was dissolved in dry DMF (10 mL). K2CO3 (1.87 g, 13.56 mmol, 2.0 eq.) was added and the mixture was stirred at RT for 30 mins. Methyl 2,4-dibromo-butyrate (1.76 g, 6.78 mmol, 1.0 eq.) was added dropwise and the reaction mixture was stirred at RT for 12 hours. The reaction mixture was cooled to RT, poured into water (20 mL) and ectracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentracted. The residue was purified by preparative TLC (PE / EtOAc 3: 1, Rf=0.6, UV) to give methyl 4-bromo-2-[(6-chloro-2-fluoro-3- pyridyl)oxy]butanoate (1.0 g, 3.06 mmol, 45% yield) as colorless oil. LC-MS: m / z = 327.8 [M+H]+, ESI pos.

[0456] Step 2: methyl l-[(6-chloro-2-fluoro-3-pyridyl)oxy] cyclopropanecarboxylate

[0457] Methyl 4-bromo-2-[(6-chloro-2-fluoro-3-pyridyl)oxy]butanoate (1.0 g, 3.06 mmol, 1.0 eq.) was dissolved in dry THF (60 mL) under N2 and cooled to -10 °C. Potassium tert-butoxide (344 mg, 3.06 mmol, 1.0 eq.) was added in portions. The resulting mixture was stirred at -10 °C for 30 minutes then at RT for 16 hours. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (SiO2, 0 - 20% EtOAc in PE) to give methyl l-[(6-chloro-2-fluoro-3- pyridyl)oxy]cyclopropanecarboxylate (750.0 mg, 3.05 mmol, 99% yield) as colorless oil. LC- MS: m / z = 245.9 [M+H]+, ESI pos. Step 3: l-[(6-chloro-2-fluoro-3-pyridyl)oxy] cyclopropanecarboxylic acid

[0458] To a mixture of methyl l-[(6-chloro-2-fluoro-3-pyridyl)oxy]cyclopropanecarboxylate (750 mg, 3.05 mmol, 1.0 eq.) in THF (5 mL) / methanol (5 mL) / water (5 mL) was added LiOH (183 mg, 7.64 mmol, 2.5 eq.) . The mixture was stirred at RT for 1 hour. The pH of the reaction mixture was adjusted to 7 with IM HC1. The reaction mixture was concentrated and the residue was purified by preparative HPLC (Phenomenex luna C18 150 mm x 40 mm x 15 pm, water (0.1% TFA) - ACN, flow rate 60 ml / min) to give l-[(6-chloro-2-fluoro-3- pyridyl)oxy]cyclopropanecarboxylic acid (150 mg, 0.65 mmol, 21% yield) as light brown solid. LC-MS: m / z = 231.9 [M+H]+, ESI pos. 'H NMR (400 MHz, METHANOL-d4) 5 = 7.63 (dd, J= 8.4, 9.9 Hz, 1H), 7.28 (d, J= 8.3 Hz, 1H), 1.69 - 1.65 (m, 2H), 1.43 - 1.38 (m, 2H).

[0459] Step 4: l-[( 6-chloro-2-fluoro-3-pyridyl)oxy ] cyclopropanecarboxamide l-[(6-chloro-2-fluoro-3-pyridyl)oxy]cyclopropanecarboxylic acid (130 mg, 0.56 mmol, 1.0 eq.) was added to a solution of isobutyl carb onochlori date (76 mg, 0.56 mmol, 1.0 eq.) and triethylamine (0.23 mL, 1.68 mmol, 3.0 eq.) in DCM (2.5 mL) at 0 °C. The ice bath was removed and the mixture was stirred at RT for 30 minutes. Ammonia in MeOH (0.8 mL, 5.61 mmol, 10.0 eq.) was added and the mixture was stirred at RT for 16 hours. The mixture was poured into water (10 ml) and extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated. The residue was purified by preparative TLC (PE / EtOAc 2:3) to give l-[(6-chloro-2-fluoro-3- pyridyl)oxy]cyclopropanecarboxamide (100 mg, 0.43 mmol, 77% yield) as off white solid. LC- MS: m / z = 230.9 [M+H]+, ESI pos. Step 5: l-[( 6-chloro-2-fluoro-3-pyridyl)oxy ] cyclopropanecarbonitrile

[0460] To a solution of l-[(6-chloro-2-fluoro-3-pyridyl)oxy]cyclopropanecarboxamide (50 mg, 0.22 mmol, 1.0 eq.) in DMF (2 mL) was added cyanuric chloride (200 mg, 1.08 mmol, 5.0 eq.) and then reaction mixture was stirred at RT for 1 hour. The mixture was poured into water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine (20 mL), dried over ISfeSCU, filtered, and concentracted. The residue was purifed by preparative TLC (PE / EtOAc 3: 1, Rf=0.66, UV) to provide l-[(6-chloro-2-fluoro-3- pyridyl)oxy]cyclopropanecarbonitrile (46.0 mg, 0.22 mmol, 99.79% yield) as colorless oil. LC- MS: m / z = 212.9 [M+H]+, ESI pos.

[0461] Step 6: l-[ 6-chloro-3-( 1 -cyanocyclopropoxy)-2-pyridyl ]-5-methyl-pyrazole-3-carbonitrile l-[(6-chloro-2-fluoro-3-pyridyl)oxy]cyclopropanecarbonitrile (45 mg, 0.21 mmol, 1.0 eq.) was dissolved DMSO (2 mL) and 5-methyl-lH-pyrazole-3-carbonitrile (25 mg, 0.23 mmol, 1.1 eq.) and K2CO3 (44 mg, 0.32 mmol, 1.5 eq.) were added. The mixture was stirred at RT for 12 hours. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered and concentracted. The residue product was purified by flash chromatography (PE / EtOAc 3: 1 Rf=0.33, UV) to give l-[6-chloro-3-(l-cyanocyclopropoxy)-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile (60 mg, 0.2 mmol, 95% yield) as off white solid. LC-MS: m / z = 300.0 [M+H]+, ESI pos. 'H NMR (400 MHz, METHANOL-d4) 5 = 8.27 - 8.23 (m, 1H), 7.83 - 7.78 (m, 1H), 6.78 (d, J= 0.7 Hz, 1H), 2.28 (d, J= 0.6 Hz, 3H), 1.73 - 1.65 (m, 2H), 1.56 - 1.49 (m, 2H).

[0462] Step 7: l-[ 3-( I -cyanocyclopropoxy)-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0463] To a solution of l-[6-chloro-3-(l-cyanocyclopropoxy)-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile (35 mg, 0.12 mmol, 1.0 eq.) in t-amyl alcohol (5.0 mL) was added N-(6- methylpyridazin-3-yl)-lH-benzimidazol-5-amine (32 mg, 0.14 mmol, 1.22 eq.) and K3PO4 (74.27 mg, 0.35 mmol, 3.0 eq.). The reaction mixture was bubbled with argon for 10 minutes followed by the addition of tBuXPhosPdG3 (9 mg, 0.01 mmol, 0.1 eq.). The reaction mixture was stirred at 100 °C for 3 hours under argon. The reaction mixture was cooled to RT, diluted with water (20 ml) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over ISfeSCU, filtered and concentrated. The residue was purified by preparative HPLC (Phenomenex Luna Cl 8 150 mm x 25mm x 10 pm, gradient 27 - 57% CH3CN in H2O (with 0.225% FA) over 10 minutes, then 100% CH3CN (2 min), flow rate 25 mL / min) to give l-[3-(l-cyanocyclopropoxy)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (7.3 mg, 0.01 mmol, 11% yield) as off white solid. LC-MS: m / z = 489.2 [M+H]+, ESI pos. 'H NMR (400 MHz, METHANOL-d4) 5 = 8.87 (s, 1H), 8.47 (d, J = 8.9 Hz, 1H), 8.38 (br d, J= 2.8 Hz, 1H), 8.27 - 8.22 (m, 2H), 8.11 (d, J= 8.9 Hz, 1H), 7.64 - 7.60 (m, 1H), 7.38 (d, J= 9.3 Hz, 1H), 7.18 - 7.13 (m, 1H), 6.85 (d, J= 0.7 Hz, 1H), 2.55 (s, 3H), 2.37 (d, J = 0.6 Hz, 3H), 1.77 - 1.71 (m, 2H), 1.62 - 1.57 (m, 2H).

[0464] Example 44 l-[3-[(2S,4S)-4-fluorotetrahydrofuran-2-yl]-6-[6-methoxy-5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile and l-[3-[(2R,4R)-4-fluorotetrahydrofuran-2-yl]-6-[6-methoxy-5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0465] Step 1: 4-bromo-5-methoxy-2-nitro-aniline

[0466] To a solution of 5-methoxy-2-nitroaniline (10.0 g, 59.47 mmol, 1.0 eq.) in ACN (150 mL) was added NBS (11.6 g, 65.42 mmol, 1.1 eq.) in portions under N2 at 20 °C. The reaction was stirred at 20 °C for 3 hours. The reaction mixture was poured into 10% aqueous ISfeSCL solution (300 mL) under stirring. Water (500 mL) was added and the yellow precipitate was filtered and dried to give 4-bromo-5-methoxy-2-nitro-aniline (13.0 g, 52.62 mmol, 88% yield) as yellow solid. LC- MS: m / z = 249.1 [M+H]+, ESI pos. 'H NMR (400 MHz, CDCI3) 8 = 8.36 (s, 1H), 6.25 (br s, 2H), 6.18 (s, 1H), 3.92 (s, 3H).

[0467] Step 2: 4-bromo-5-methoxy-benzene-l,2-diamine

[0468] To a solution of 4-bromo-5-methoxy-2-nitro-aniline (13.0 g, 52.62 mmol, 1.0 eq.) in DCM (260 mL) / methanol (260 mL) was added saturated aqueous NH4CI solution (520 mL) at 20 °C. The reaction mixture was purged with N2. Zn (34.4 mg, 526.19 mmol, 10.0 eq.) was added in portions at 20 °C. The reaction mixture was stirred at 20 °C for 2 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was dissolved in DCM (600mL), washed with brine (3 x 100 mL). The organic layer was dried over ISfeSCL, filtered and concentrated to give 4-bromo-5-methoxy-benzene-l,2-diamine (11.0 g, 50.68 mmol, 96% yield) as black solid which was used without further purification. LC-MS: m / z = 217.0 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-d6) 5 = 6.66 (s, 1H), 6.34 (s, 1H), 4.79 - 4.13 (m, 4H), 3.63 (s, 3H).

[0469] Step 3: 5-bromo-6-methoxy-lH-benzimidazole

[0470] To a solution of 4-bromo-5-methoxy-benzene-l,2-diamine (11.0 g, 50.68 mmol, 1.0 eq.) in trimethyl orthoformate (200 mL, 506.77 mmol, 10.0 eq.) was added formic acid (10.0 mL, 265.07 mmol, 5.23 eq.) and the reaction mixture was stirred at 90 °C for 2 hours. The reaction mixture was cooled to RT and concentrated. The residue was dissolved with EtOAc (400mL) and washed with saturated aqueous NaHCCh (2x lOOmL). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (0 - 100% EtOAC in PE) to give 5-bromo-6-methoxy-lH-benzimidazole (9.60 g, 42.28 mmol, 83% yield) as yellow solid. . LC-MS: m / z = 227.0 [M+H]+, ESI pos.JH NMR (400 MHz, DMSO-d6) 5 = 12.53 - 12.20 (m, 1H), 8.14 (br s, 1H), 7.90 - 7.68 (m, 1H), 7.40 - 7.09 (m, 1H), 3.86 (s, 3H).

[0471] Step 4: 2-[(5-bromo-6-methoxy-benzimidazol-l-yl)methoxy]ethyl-trimethyl-silane and 2-[(6- bromo-5-methoxy-benzimidazol-l-yl)methoxy]ethyl-trimethyl-silane

[0472] To a solution of 2-(trimethylsilyl)ethoxymethyl chloride (3.27 mL, 18.5 mmol, 1.4 eq.) in DMF (60 mL) was added sodium hydride (635 mg, 15.88 mmol, 1.2 eq.) in portions at 0 °C. After addition, the mixture was stirred at 20 °C for 1 hour. Then the mixture was cooled to 0 °C and 5- bromo-6-methoxy-lH-benzimidazole (3.00 g, 13.21 mmol, 1.0 eq.) was added dropwise. The mixture was stirred at 20 °C for 16 hours. The reaction mixture was poured into saturated aqueous NH4CI solution (300 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (0 - 20% EtOAc in PE) to give a mixture of 2-[(5-bromo-6-methoxy- benzimidazol-l-yl)methoxy]ethyl-trimethyl-silane and 2-[(6-bromo-5-methoxy-benzimidazol-l- yl)methoxy]ethyl-trimethyl-silane (2.8 g, 7.84 mmol, 59% yield) as a yellow oil. LC-MS: m / z = 357.0 [M+H]+, ESI pos.

[0473] Step 5: 6-methoxy-N-(6-methylpyridazin-3-yl)-l-(2-trimethylsilylethoxymethyl)benzimidazol-5- amine and 6-methoxy-N-(6-methylpyridazin-3-yl)-3-(2-trimethylsilylethoxymethyl)benzimidazol- 5-amine

[0474] To a solution of a mixture of 2-[(5-bromo-6-methoxy-benzimidazol-l-yl)methoxy]ethyl- trimethyl-silane and 2-[(6-bromo-5-methoxy-benzimidazol-l-yl)methoxy]ethyl-trimethyl-silane (2.8 g, 7.84 mmol, 1.0 eq.) and 3-amino-6-methylpyridazine (1.71 g, 15.67 mmol, 2.0 eq.) in 1,4- dioxane (50 mL) was added cesium carbonate (7.66 g, 23.51 mmol, 3.0 eq.). The mixture was bubbled with argon for 10 minutes. [tBuBrettPhos Pd(allyl)]OTf (613 mg, 0.78 mmol, 0.1 eq.) was added and the reaction mixture was stirred at 80 °C for 4 hours. The mixture was cooled to RT, poured into saturated aqueous NH4CI solution (300 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over ISfeSCU, filtered and concentrated. The residue was purified by flash chromatography (SiCh, 0 - 100% EtOAc in PE) to give a mixture of 6-methoxy-N-(6-methylpyridazin-3-yl)-l-(2- trimethylsilylethoxymethyl)benzimidazol-5-amine and 6-m ethoxy-N-(6-m ethyl pyridazin-3-yl)-3- (2-trimethylsilylethoxymethyl)benzimidazol-5-amine (3.0 g, 7.78 mmol, 94% yield) as a yellow oil. LC-MS: m / z = 386.1 [M+H]+, ESI pos.

[0475] Step 6: 6-methoxy-N-( 6-methylpyridazin-3-yl)-lH-benzimidazol-5-amine A solution of a mixture of 6-methoxy-N-(6-methylpyridazin-3-yl)-l-(2- trimethylsilylethoxymethyl)benzimidazol-5-amine and 6-m ethoxy-N-(6-m ethyl pyridazin-3-yl)-3- (2-trimethylsilylethoxymethyl)benzimidazol-5-amine (3.0 g, 7.39 mmol, 1.0 eq.) in trifluoroacetic acid (10 mL, 129.8 mmol, 17.6 eq.) was stirred at RT for 2 hours. The reaction mixture was concentrated and the resulting brown gum was dissolved in MeOH (10 mL). 10% of aqueous NH4OH solution (10 ml) was added carefully to pH 7 and the resulting yellow precipitate was filtered. The filter cake was washed with PE (3 x 10 mL) and dried to give 6- methoxy-N-(6-methylpyridazin-3-yl)-lH-benzimidazol-5-amine (1.0 g, 3.92 mmol, 52% yield) as a yellow solid. The combined filtrates were lyophilized to dryness to give a brown solid. LC- MS: m / z = 256.1 [M+H]+, ESI pos. 'H NMR (400 MHz, METHANOL-d4) 5 = 8.61 (s, 1H), 8.36 (s, 1H), 7.41 (d, J= 9.3 Hz, 1H), 7.33 - 7.28 (m, 1H), 7.26 (s, 1H), 3.98 (s, 3H), 2.54 (s, 3H).

[0476] Step 7: racemic mixture of 6-chloro-2 fluoro-3-[(2R, 4R)-4 fluor otetrahydrofuran-2-yl] pyridine and 6-chloro-2-fluoro-3-[ (2S, 4S)-4-jluorotetrahydrofuran-2-yl pyridine and racemic mixture of 6-chloro-2-fluoro-3-[(2R,4S)-4-fluorotetrahydrofuran-2-yl] pyridine and 6- chloro-2-fluoro-3-[ (2S, 4R)-4 fluor otetrahydrofuran-2-yl pyridine l-[6-chloro-3-(4-hydroxytetrahydrofuran-2-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (985 mg, 3.23 mmol, 1.0 eq.) was dissolved in dichloromethane (25 mL) and DAST (1.04 g, 854.14 pL, 6.46 mmol, 2.0 eq.) was added at -78 °C. After addition the mixture was warmed to RT and stirred at RT for 16 hours. The reaction mixture was quenched with saturated aqueous NaHCCL (50 mL) and extracted DCM (2 x 50 mL). The combined organic layers were dried over MgSCU, filtered and concentrated. The residue was purified by flash chromatography (SiO2, 0 - 30% EtOAC in Heptane) to obtain a racemic mixture of 1 -[6-chl oro-3 -[(2R,4R)-4- fluorotetrahydrofuran-2-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile and 6-chl oro-2-fhioro-3- [(2S,4S)-4-fluorotetrahydrofuran-2-yl]pyridine (382 mg, 37.76%) as light yellow liquid. LC-MS: m / z = 307.1 [M+H]+, ESI pos. and racemix mixture of l-[6-chloro-3-[(2R,4S)-4-fluorotetrahydrofuran-2-yl]-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile and 6-chloro-2-fluoro-3-[(2S,4R)-4-fluorotetrahydrofuran-2- yl]pyridine (268 mg, 27.03%) as off-white solid. LC-MS: m / z = 307.1 [M+H]+, ESI pos.

[0477] Step 8: racemic mixture of l-[3-[(2S,4S)-4-jluorotetrahydrojuran-2-yl]-6-[6-methoxy-5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile and l-[ 3-[ (2R, 4R)-4-jluorotetrahydrofuran-2-yl -6-[ 6-methoxy-5-[ ( 6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl / -2 -pyridyl ]-5-methyl-pyrazole-3-carbonitrile

[0478] A racemic mixture of l-[6-chloro-3-[(2R,4S)-4-fluorotetrahydrofuran-2-yl]-2-pyridyl]-5-methyl- pyrazole-3 -carbonitrile and 6-chloro-2-fluoro-3-[(2S,4R)-4-fluorotetrahydrofuran-2-yl]pyridine (40 mg, 0.130 mmol, 1.0 eq.) was dissolved in t-amyl alcohol (1 mL) and (6-m ethoxy- 1H- benzimidazol-5-yl)-(6-methylpyridazin-3-yl)amine (40 mg, 0.156 mmol, 1.200 eq.) and tripotassium phosphate (83 mg, 0.391 mmol, 3.000 eq.) were added. Suspension was bubbled with argon for 10 minutes. tBuXPhosPdG3 (10 mg, 0.013 mmol, 0.1 eq.) was added and the reaction mixture was stirred at 80 °C for 16 hours under argon. The reaction mixture was cooled to RT, diluted with water (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over MgSCh, filtered and concentrated. The residue was purified by flash chromatography (SiCh, 0 - 5% MeOH in DCM) to obtain a racemic mixture of the title compounds (11.9 mg, 17.36%; also known as l-[6-[6-methoxy-5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-[rac-(2A,4A)-4-fluorooxolan-2-yl]pyri din-2- yl]-5-methylpyrazole-3-carbonitrile) as light brown solid. LC-MS: m / z = 526.4 [M+H]+, ESI pos. iH NMR (600 MHz, CDC13) 8 ppm 8.49 (d, J= 8.5 Hz, 1 H), 8.45 (s, 1 H), 8.37 (s, 1 H), 7.74 (d, J= 8.5 Hz, 1 H), 7.59 (s, 1 H), 7.20 (br s, 1 H), 7.16 - 7.18 (m, 1 H), 7.12 - 7.14 (m, 1 H), 6.68 (d, J= 0.9 Hz, 1 H), 5.29 - 5.41 (m, 1 H), 5.06 (dd, J= 9.2, 5.3 Hz, 1 H), 4.41 - 4.51 (m, 1 H), 3.80 - 3.95 (m, 4 H), 3.50 (s, 2 H), 2.66 - 2.82 (m, 1 H), 2.62 (s, 3 H), 2.53 (d, J= 0.7 Hz, 3 H), 2.11 - 2.25 (m, 1 H). Example 45 3-[[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-[(2S,4S)-4-fluorotetrahydrofuran-2-yl]-2- pyridyl] benzimidazol-5-yl] amino] -N,N,6-trimethyl-pyridazine-4-carboxamide and

[0479] 3-[[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-[(2R,4R)-4-fluorotetrahydrofuran-2-yl]-2- pyridyl] benzimidazol-5-yl] amino] -N,N,6-trimethyl-pyridazine-4-carboxamide

[0480] Step 1: racemic mixture of l-[6-(5-bromobenzimidazol-l-yl)-3-[(2R,4R)-4- jluorotetrahydrofuran-2-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile and l-[ 6-(5- bromobenzimidazol-l-yl)-3-[ (2S, 4S)-4 fluor otetrahydrofuran-2-yl ]-2-pyridyl ]-5-methyl- pyrazole-3-carbonitrile

[0481] A racemic mixture of l-[6-chloro-3-[(2R,4R)-4-fluorotetrahydrofuran-2-yl]-2-pyridyl]-5-methyl- pyrazole-3 -carbonitrile and 1 -[6-chloro-3-[(2S,4S)-4-fluorotetrahydrofuran-2-yl]-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile (Example 44, step 7) (200 mg, 0.652 mmol, 1.0 eq.) was dissolved in DMF (5 mL). 5-bromo-lH-benzimidazole (154 mg, 0.782 mmol, 1.2 eq.) and cesium carbonate (425 mg, 1.3 mmol, 2.0 eq.) were added and the reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was cooled to RT, diluted with water (30 mL) and extracted EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over MgSCh, filtered and concentrated. The residue was purified by flash chromatography (SiCL, 0 - 100% EtOAC in Heptane) to give a racemic mixture of l-[6-(5-bromobenzimidazol-l- yl)-3-[(2R,4R)-4-fluorotetrahydrofuran-2-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile and 1- [6-(5-bromobenzimidazol-l-yl)-3-[(2S,4S)-4-fluorotetrahydrofuran-2-yl]-2-pyridyl]-5-methyl- pyrazole-3 -carbonitrile (73 mg, 22%) as white solid. LC-MS: m / z = 469.3 [M+H]+, ESI pos. 'H NMR (600 MHz, CDC13) 8 ppm 8.56 (s, 1 H), 8.50 (d, J= 8.7 Hz, 1 H), 8.04 (d, J = 1.5 Hz, 1 H), 7.90 (d, J= 8.7 Hz, 1H), 7.74 (d, J= 8.0 Hz, 1 H), 7.51 (dd, J= 8.7, 1.7 Hz, 1 H), 6.66 - 6.71 (m, 1 H), 5.28 - 5.41 (m, 1 H), 5.06 (dd, J= 9.1, 5.2 Hz, 1 H), 4.41 - 4.49 (m, 1 H), 3.82 - 3.91 (m, 1 H), 2.66 - 2.78 (m, 1 H), 2.49 (d, J= 0.8 Hz, 3 H), 2.10 - 2.20 (m, 1 H).

[0482] Step 2: racemic mixture of 3-[[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-[(2S,4S)-4- jluorotetrahydrofuran-2-yl] -2-pyridyl] benzimidazol-5-yl] amino] -N,N,6-trimethyl-pyridazine-4- carboxamide and 3-[[ l-[ 6-(3-cyano-5-methyl-pyrazol-l-yl)-5-[ (2R, 4R)-4-jluorotetrahydrofuran- 2-yl / -2-pyridyl ]benzimidazol-5-yl amino ]-N,N, 6-trimethyl-pyridazine-4-carboxamide i

[0483] A racemic mixture of l-[6-(5-bromobenzimidazol-l-yl)-3-[(2R,4R)-4-fluorotetrahydrofuran-2- yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile and l-[6-(5-bromobenzimidazol-l-yl)-3- [(2S,4S)-4-fluorotetrahydrofuran-2-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (40 mg, 0.086 mmol, 1.0 eq.) was suspended in 1,4-dioxane (1.2 mL). 3-amino-N,N,6-trimethyl- pyridazine-4-carboxamide (31 mg, 0.171 mmol, 2.0 eq.) and cesium carbonate (84 mg, 0.257 mmol, 3.0 eq.) were added and the reaction mixture was bubbled with argon for 10 minutes. [tBuBrettPhos Pd(allyl)]OTf (7 mg, 0.009 mmol, 0.1 eq.) was added and the reaction mixture was stirred 80 °C for 3 hours. The reaction mixture was cooled to RT, diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over MgSCU, filtered and concentrated. The residue was purified by flash chromatography (SiCL, 0 - 7% MeOH in DCM) to give racemic mixture of the title compounds (16 mg, 33%; also known as 3-[[l-[6-(3-cyano-5-methylpyrazol-l-yl)-5-[rac-(2A,4A)-4- fluorooxolan-2-yl]pyri din-2 -yl]benzimidazol-5-yl]amino]-N,N,6-trimethylpyridazine-4- carboxamide) as yellow solid. LC-MS: m / z = 567.3 [M+H]+, ESI pos.

[0484] Example 46 l-[6-[5-[(4aS,7aR)-4-methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][l,4]oxazin-6- yl]benzimidazol-l-yl]-3-(l,3-dioxolan-2-yl)-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile

[0485] A 1 : 1 mixture of l-[6-(5-bromobenzimidazol-l-yl)-3-(l,3-dioxolan-2-yl)-2-pyridyl]-5-methyl- pyrazole-3 -carbonitrile and l-[6-(6-bromobenzimidazol-l-yl)-3-(l,3-dioxolan-2-yl)-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile (Example 38, step 3) (150 mg, 0.332 mmol, 1.0 eq.) was dissolved in 1,4-dioxane (1.6 mL). (4aS,7aR)-4-methyl-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4- b][l,4]oxazine (52 mg, 0.366 mmol, 1.1 eq.) and cesium carbonate (325 mg, 0.997 mmol, 3.0 eq.) were added. The reaction mixture bubbled with argon for 10 minutes. QPhosPd(crotyl)Cl (24 mg, 0.027 mmol, 0.08 eq.) was added. The reaction mixture was stirred at 60 °C for 16 hours. The reaction mixture was cooled to RT and partitionned between water (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (2x 20 mL). The combined organic layer were washed with brine (20 mL), dried over MgSCU, filtered and concentrated. The residue was purified by flash chromatography (SiCL, 0 - 10% MeOH in DCM) to give l-[6-[5- [(4aS,7aR)-4-methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][l,4]oxazin-6-yl]benzimidazol-l-yl]- 3-(l,3-dioxolan-2-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (51 mg, 0.100 mmol, 30% yield) as a red solid. LC-MS: m / z = 513.3 [M+H]+, ESI pos. 'H NMR (600 MHz, DMSO-d6) 5 ppm 8.96 (s, 1 H), 8.36 (d, J = 8.6 Hz, 1 H), 8.24 (d, J= 8.5 Hz, 1 H), 7.98 (d, J= 8.9 Hz, 1 H), 7.08 (d, J= 0.8 Hz, 1 H), 6.80 (d, J= 2.2 Hz, 1 H), 6.68 (dd, J= 9.0, 2.3 Hz, 1 H), 5.69 (s, 1 H), 4.13 (t, J= 3.4 Hz, 1 H), 4.00 - 4.04 (m, 2 H), 3.88 - 3.92 (m, 2 H), 3.76 (dt, J= 11.1, 2.7 Hz, 1 H), 3.52 - 3.58 (m, 1 H), 3.50 (dd, J= 10.6, 4.4 Hz, 1 H), 3.44 - 3.48 (m, 1 H), 3.38 (td, J= 7.9, 3.6 Hz, 1 H), 3.21 - 3.28 (m, 2 H), 2.62 - 2.68 (m, 1 H), 2.38 - 2.42 (m, 1 H), 2.36 (s, 3 H), 2.33 (d, J = 0.6 Hz, 3 H). Example 47 l-[3-(l,l-difluoroethyl)-6-[5-[[6-[(3-methoxyazetidin-l-yl)methyl]pyridazin-3- yl]amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0486] Step 1: 6-chloro-3-(l,l-difluoroethyl)-2-fluoro-pyridine

[0487] To a solution of l-(6-chloro-2-fluoro-3-pyridyl)ethanone (1.0 g, 5.76 mmol, 1.0 eq.) in toluene (10 mL) was added BAST (6.37 g, 28.81 mmol, 5.0 eq.). The mixture was stirred at 80 °C for 16 hours. The reaction mixture was cooled to RT, poured into water (50mL) and extracted with EtOAc (3 x 30mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromtography (0 - 20%

[0488] EtOAc in PE) to give 6-chl oro-3 -(l,l-difluoroethyl)-2-fluoro-pyri dine (640.0 mg, 3.27 mmol, 56.8% yield) as light yellow solid. LC-MS: m / z = 196.1 [M+H]+, ESI pos. 'H NMR (400 MHz, CDC13) 8 = 7.95 (t, J= 8.6 Hz, 1H), 7.32 (d, J= 7.9 Hz, 1H), 2.01 (dt, J= 0.9, 18.6 Hz, 3H). Step 2: l-[6-chloro-3-(l, 1 -difluor oethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0489] To a solution of 6-chl oro-3 -(l,l-difluoroethyl)-2-fluoro-pyri dine (590 mg, 3.02 mmol, 1.0 eq.) and 5-methyl-lH-pyrazole-3-carbonitrile (485 mg, 4.53 mmol, 1.5 eq.) in DMSO (5 mL) was added DIPEA (1.17 g, 9.05 mmol, 3.0 eq.). The mixture was stirred at 80 °C for 48 hours. The mixture was cooled to RT, poured into water (50mL) and extracted with EtOAc (3 x 50mL). The combined organic layers were washed by brine (50mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (0 to 25% EtOAc in PE) to give l-[6-chloro-3-(l,l-difluoroethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (320 mg, 1.13 mmol, 38% yield) as off-white solid. LC-MS: m / z = 283.0 [M+H]+, ESI pos.JH NMR (400 MHz, CDC13) 8 = 8.06 (d, J= 8.3 Hz, 1H), 7.62 (d, J = 8.3 Hz, 1H), 6.59 (s, 1H), 2.29 (s, 3H), 2.00 (t, J= 18.9 Hz, 3H).

[0490] Step 3: l-[ 6-(5-bromobenzimidazol-l-yl)-3-( I, l-dijluoroethyl)-2-pyridyl / -5-methyl-pyrazole-3- carbonitrile

[0491] To a solution of l-[6-chloro-3-(l,l-difluoroethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (270 mg, 0.96 mmol, 1.0 eq.) in DMSO (4 mL) was added 5-bromo-lH-benzimidazole (188 mg, 0.96 mmol, 1.0 eq.) and K2CO3 (264 mg, 1.91 mmol, 2.0 eq.). The reaction mixture was stirred at 50 °C for 48 hours. The reaction mixture was cooled to RT, poured into water (40mL) and extracted with EtOAc (3 x 30mL x 3). The combined organic layers were washed by brine (30mL), dried over Na2SO4, filtered concentrated. The residue was purified by preparative NPLC (Welch Ultimate XB-SiOH 250 mm x 50 mm x 10 pm, gradient 15 - 55% EtOH (0.1% FA) - Hexane over 15 minutes then 100% EtOH for 2 minutes, flow rate 100 ml / min) followed by preparative SFC (DAICEL CHIRALPAK IC (250 mm x 30 mm, 10 pm), 0.1% NH4OH in MeOH, gradient time 4 minutes, flow rate 80 mL / min) to give The residue was dissolved in ACN and water, the suspension was lyophilized to give l-[6-(5-bromobenzimidazol-l-yl)-3-(l,l- difluoroethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (113 mg, 0.26 mmol, 27% yield) as off-white solid. LC-MS: m / z = 444.8 [M+H]+, ESI pos. 'H NMR (400 MHz, CDCI3) 5 = 9.41 - 9.04 (m, 1H), 8.38 (br d, J= 7.8 Hz, 1H), 8.10 (br s, 2H), 8.04 - 7.94 (m, 1H), 7.58 (br d, J= 92 Hz, 1H), 6.67 (s, 1H), 2.33 (s, 3H), 2.07 (t, J = 18.9 Hz, 3H).

[0492] Step 4: l-[3-( 1, 1 -difluor oethyl)-6-[ 5- [ [ 6-[ (3-methoxyazetidin-l-yl)methyl ]pyridazin-3- yl amino ]benzimidazol-l-yl / -2 -pyridyl ]-5-methyl-pyrazole-3-carbonitrile

[0493] To a suspension of l-[6-(5-bromobenzimidazol-l-yl)-3-(l,l-difluoroethyl)-2-pyridyl]-5-methyl- pyrazole-3 -carbonitrile (30 mg, 0.068 mmol, 1.0 eq.) in dry 1,4-dioxane (1 mL) were added [6- [(3-methoxyazetidin-l-yl)methyl]pyridazin-3-yl]amine (39 mg, 0.102 mmol, 1.5 eq.) and cesium carbonate (66 mg, 0.203 mmol, 3.0 eq.). The reaction mixture was bubbled with argon for 5 minutes. [tBuBrettPhos Pd(allyl)]OTf (5 mg, 0.007 mmol, 0.1 eq.) was added and the reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was cooled to RT and concentrated. The residue was purified by flash chromatography (SiCh, 0 - 10% MeOH in DCM) to give l-[3-(l,l-difluoroethyl)-6-[5-[[6-[(3-methoxyazetidin-l-yl)methyl]pyridazin-3- yl]amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (6 mg, 0.011 mmol, 16% yield) as a white solid. LC-MS: m / z = 558.3 [M+H]+, ESI pos. 'H NMR (600 MHz, CDC13) 5 ppm 8.61 (s, 1 H), 8.31 (d, J= 8.5 Hz, 1 H), 8.01 (d, J= 8.7 Hz, 1 H), 7.85 (d, J= 8.5 Hz, 1H), 7.81 (d, J= 2.0 Hz, 1 H), 7.42 - 7.46 (m, 1 H), 7.38 (d, J= 9.3 Hz, 1 H), 7.08 - 7.14 (m, 1 H), 6.97 - 7.05 (m, 1 H), 6.66 (d, J= 0.8 Hz, 1 H), 4.09 (br t, J= 5.6 Hz, 1 H), 3.91 (s, 1 H), 3.89 (br s, 1 H), 3.68 (br t, J= 6.0 Hz, 3 H), 3.27 (s, 3 H), 3.12 - 3.21 (m, 2 H), 2.35 (d, J= 0.7 Hz, 3 H), 2.07 (t, J= 18.8 Hz, 3 H). Example 48 l-[6-[5-fluoro-6-(pyridazin-3-ylamino)benzimidazol-l-yl]-3-[(2S,4S)-4- fluorotetrahydrofuran-2-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile and l-[6-[5-fluoro-6-(pyridazin-3-ylamino)benzimidazol-l-yl]-3-[(2R,4R)-4- fluorotetrahydrofuran-2-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0494] Step 1: 2-[(5-bromo-6-fluoro-benzimidazol-l-yl)methoxy]ethyl-trimethyl-silane and2-[(6- bromo-5-fluoro-benzimidazol-l-yl)methoxy]ethyl-trimethyl-silane

[0495] To a solution of 5-bromo-6-fluoro-lH-benzimidazole (1.9 g, 8.84 mmol, 1.0 eq.) and tetrabutylammonium bromide (0.28 g, 0.88 mmol, 0.1 eq.) in DCM (20 mL) was added KOH (0.99 g, 8.84 mmol, 1.0 eq.) in water (10 mL). The reaction mixture was cooled to 0 °C and SEM-C1 (1.76 g, 10.6 mmol, 1.2 eq.) was added. The reaction mixture was stirred at 0 °C for 1 hour and at RT for 1 hour. The reaction mixture was diluted with brine (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (0 - 60% EtOAc in PE) to give a 1 :1 mixture of 2-[(5-bromo-6-fluoro-benzimidazol-l- yl)methoxy]ethyl-trimethyl-silane and 2-[(6-bromo-5-fluoro-benzimidazol-l-yl)methoxy]ethyl- trimethyl-silane (2.88 g, 8.34 mmol, 94% yield) as a yellow oil. LC-MS: m / z = 344.9 [M+H]+, ESI pos. Step 2: 6-fluoro-N-pyridazin-3-yl-l-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine and 6- fluoro-N-pyridazin-3-yl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine

[0496] To a solution of a mixture of 2-[(5-bromo-6-fluoro-benzimidazol-l-yl)methoxy]ethyl-trimethyl- silane and 2-[(6-bromo-5-fluoro-benzimidazol-l-yl)methoxy]ethyl-trimethyl-silane (300 mg, 0.869 mmol, 1.000 eq.) in 1,4-dioxane (6 mL) were added pyridazin-3-ylamine (124 mg, 1.3 mmol, 1.5 eq.) and cesium carbonate (849 mg, 2.61 mmol, 3.0 eq.). The suspension was bubbled with argon for 10 minutes. [tBuBrettPhos Pd(allyl)]OTf (136 mg, 0.174 mmol, 0.2 eq.) was added and the reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was cooled to RT, poured into water (30 mL) and extracted with EtoAc (3 x 30 mL). The combined organic layers were dried over MgSCh, filtered and concentrated. The residue was purified by flash chromatography (SiCh, 0 - 6% MeOH in DCM) to give a 1 :1 mixture of 6-fluoro-N-pyridazin-3- yl-1 -(2 -trimethylsilyl ethoxymethyl)benzimidazol-5-amine and 6-fluoro-N-pyridazin-3-yl-3-(2- trimethylsilylethoxymethyl)benzimidazol-5-amine (248 mg, 78%) as light brown solid. LC-MS: m / z = 360.1 [M+H]+, ESI pos.

[0497] Step 3: (6-fluoro-lH-benzimidazol-5-yl)-pyridazin-3-yl-amine

[0498] A 1 :1 mixture of 6-fluoro-N-pyridazin-3-yl-l-(2-trimethylsilylethoxymethyl)benzimidazol-5- amine and 6-fluoro-N-pyridazin-3-yl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine (245 mg, 0.682 mmol, 1.0 eq.) was dissolved in DCM (4 mL) and TFA (1.05 mL, 13.63 mmol, 20 eq.) was added. The mixture was stirred at RT for 16 hours The reaction mixture was concentrated and the residue was purified by flash chromatography (Isolute Flash -NEE, 0 - 10% MeOH in DCM) to give (6-fluoro-lH-benzimidazol-5-yl)-pyridazin-3-yl-amine (60 mg, 36%) as off-white solid. LC-MS: m / z = 230.0 [M+H]+, ESI pos. Step 4: racemic mixture of l-[6-[5-jluoro-6-(pyridazin-3-ylamino)benzimidazol-l-yl]-3-

[0499] [ (2S, 4S)-4-fluorotetrahydrofuran-2-yl ]-2-pyridyl ]-5-methyl-pyrazole-3-carbonitrile and l-[ 6-[5- jluoro-6-(pyridazin-3-ylamino)benzimidazol-l-yl -3-[ (2R, 4R)-4 fluor otetrahydrofuran-2-yl -2- pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0500] A racemic mixture of l-[6-chloro-3-[(2R,4R)-4-fluorotetrahydrofuran-2-yl]-2-pyridyl]-5-methyl- pyrazole-3 -carbonitrile and 1 -[6-chloro-3-[(2S,4S)-4-fluorotetrahydrofuran-2-yl]-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile (30 mg, 0.098 mmol, 1.0 eq.) was dissolved in t-amyl alcohol (1 mL) and (6-fluoro-lH-benzimidazol-5-yl)-pyridazin-3-yl-amine (22 mg, 0.098 mmol, 1.0 eq.) and tripotassium phosphate (62 mg, 0.293 mmol, 3.0 eq.) were added. The suspension was bubbled with argon for 10 minutes. tBuXPhos-Pd-G3 (8 mg, 0.010 mmol, 0.1 eq.) was added. The reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was cooled to RT, poured into water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over MgSCU, filtered and concentrated. The residue was purified by flash chromatography (SiCh, 0 - 10% MeOH in DCM) to give a racemic mixture of the title compounds (7 mg, 0.014 mmol, 14%; also known as l-[6-[5-fluoro-6-(pyridazin-3- ylamino)benzimidazol-l -yl]-3-[rac-(2A, 4 ’)-4-fluorooxolan-2-yl]pyri din-2 -yl]-5-methylpyrazole- 3 -carbonitrile) as white solid. LC-MS: m / z = 500.2 [M+H]+, ESI pos.JH NMR (600 MHz, CDC13) 8 ppm 9.02 (d, J= 7.4 Hz, 1 H), 8.77 (dd, J = 4.5, 1.3 Hz, 1 H), 8.55 (s, 1 H), 8.52 (d, J = 8.4 Hz, 1 H), 7.83 (d, J = 8.4 Hz, 1 H), 7.64 (d, J= 11.0 Hz, 1 H), 7.30 (dd, J= 9.0, 4.5 Hz, 1 H), 6.97 (dd, J = 9.0, 1.3 Hz, 1 H), 6.89 (br s, 1H), 6.64 (d, J = 0.8 Hz, 1 H), 5.30 (s, 2 H), 5.01 (dd, J= 9.1, 5.3 Hz, 1 H), 4.37 - 4.48 (m, 1 H), 3.75 - 3.91 (m, 1 H), 3.49 (s, 2 H), 2.59 - 2.76 (m, 1 H), 2.51 (d, J= 0.7 Hz, 3 H), 2.05 - 2.28 (m, 1 H), 0.07 (s, 1 H). Example 49 l-[6-[6-fluoro-5-(pyridazin-3-ylamino)benzimidazol-l-yl]-3-[(2S,4S)-4- fluorotetrahydrofuran-2-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile and l-[6-[6-fluoro-5-(pyridazin-3-ylamino)benzimidazol-l-yl]-3-[(2R,4R)-4- fluorotetrahydrofuran-2-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0501] A racemic mixture of l-[6-[6-fluoro-5-(pyridazin-3-ylamino)benzimidazol-l-yl]-3-[(2S,4S)-4- fluorotetrahydrofuran-2-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile and l-[6-[6-fluoro-5- (pyridazin-3-ylamino)benzimidazol-l-yl]-3-[(2R,4R)-4-fluorotetrahydrofuran-2-yl]-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile was obtained in Example 48, step 4 after flash chromatography (5 mg, 0.01 mmol, 10% yield ) as a white solid. The compound is also known as l-[6-[6-fluoro-5- (pyridazin-3-ylamino)benzimidazol-l -yl]-3-[rac-(2A,4A)-4-fluorooxolan-2-yl]pyri din-2 -yl]-5- methylpyrazole-3-carbonitrile. LC-MS: m / z = 500.2 [M+H]+, ESI pos.

[0502] Example 50 5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-l-yl]-3- (trifluoromethyl)-2-pyridyl]pyrazole-3-carbonitrile

[0503] Step 1: 4-bromo-2-nitro-5-(oxetan-3-yloxy)aniline

[0504] To a solution of oxetan-3-ol (473 mg, 6.38 mmol, 1.5 eq.) in THF (50 mL) was added sodium hydride (60% in oil) (256 mg, 6.4 mmol, 1.5 eq.) in portions at 0 °C and the reaction mixture was stirred at 0 °C for 30 minutes. 4-Bromo-5-fluoro-2-nitro-aniline (1.00 g, 4.26 mmol, 1.0 eq.) was added. The reaction mixture was stirred at 25 °C for 12 hours. The reaction was quenched with saturated aqueous NH4CI (100 mL). The aqueous solution was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated. The residue was purifited by flash chromatography (0 - 90% EtOAc in PE) to give 4-bromo-2-nitro-5-(oxetan-3-yloxy)aniline (1.10 g, 3.81 mmol, 89% yield) as white solid. LC-MS: m / z = 289.1 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-d6) 5 = 8.15 (s, 1H), 7.56 (br s, 2H), 6.20 (s, 1H), 5.31 (br t, J= 5.3 Hz, 1H), 4.93 (t, J= 6.8 Hz, 2H), 4.64 - 4.54 (m, 2H).

[0505] Step 2: 4-bromo-5-(oxetan-3-yloxy)benzene-l,2-diamine

[0506] To a solution of 4-bromo-2-nitro-5-(oxetan-3-yloxy)aniline (1.00 g, 3.46 mmol, 1.0 eq.) in ethanol (9 mL) was added Fe (966 mg, 17.3 mmol, 5.0 eq.), NH4CI (1.85 g, 34.59 mmol, 10 eq.) and water (3 mL). The reaction mixture was stirred under N2 at 50 °C for 2 hours. The reaction mixture was filtered. The filtrate was poured into water (30mL), extracted with EtOAc (3 x 30 mL). The combined organic layers were concentrated to give 4-bromo-5-(oxetan-3- yloxy)benzene-l,2-diamine (800 mg, 3.09 mmol, 89% yield) as brown oil which was used without further purification. LC-MS: m / z = 259.0 [M+H]+, ESI pos.

[0507] Step 3: 5-bromo-6-(oxetan-3-yloxy)-lH-benzimidazole To a solution of TsOH (0.11 g, 0.73 mmol, 0.1 eq.) in ethanol (15 mL) were added 4-bromo-5- (ox etan-3 -yloxy)benzene-l,2-diamine (1.9 g, 7.33 mmol, 1.0 eq.) and trimethyl orthoformate (8.0 mL, 73.33 mmol, 10 eq.). The reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was quenched with saturated aqueous NaHCCL (50 ml) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chormatography (50% EtAOc in PE) to give 5-bromo-6-(oxetan-3-yloxy)-lH-benzimidazole (1.8 g, 6.69 mmol, 91% yield) as a yellow oil. LC-MS: m / z = 268.7 [M+H]+, ESI pos.

[0508] Step 4: l-[6-chloro-3-(trifluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile and 2-[6- chloro-3-(trifluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0509] To a solution of 5-methyl-lH-pyrazole-3-carbonitrile (161 mg, 1.5 mmol, 1.0 eq.) and 6-chloro- 2-fluoro-3-(trifluoromethyl)pyridine (300 mg, 1.5 mmol, 1.0 eq.) in DMSO (10 mL) was added potassium carbonate (623 mg, 4.51 mmol, 3.0 eq.). The suspension was stirred at 30 °C for 16 hours. The reaction was poured into water (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over ISfeSCU, filtered and concentrated. The residue was purified by flash chromatography (0 - 20% EtOAc in PE) to afford l-[6-chloro-3-(trifluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (300 mg, 1.05 mmol, 70% yield) as colorless oil. LC-MS: m / z = 287.1 [M+H]+, ESI pos. 'H NMR (400 MHz, CDC13) 8 = 8.22 (d, J= 8.3 Hz, 1H), 7.69 (d, J= 8.3 Hz, 1H), 6.62 (s, 1H), 2.37 (s, 3H). and 2-[6-chloro-3-(trifluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (100 mg, 0.35 mmol, 23% yield) as white solid. LC-MS: m / z = 287.1 [M+H]+, ESI pos. 'H NMR (400 MHz, CDCI3 ) 6 = 8.20 (d, J= 8.3 Hz, 1H), 7.61 (d, J= 8.2 Hz, 1H), 6.89 (s, 1H), 2.42 (s, 3H). Step 5: l-[6-[6-bromo-5-(oxetan-3-yloxy)benzimidazol-l-yl]-3-(trifluoromethyl)-2-pyridyl]-5- methyl-pyrazole-3-carbonitrile and l-[6-[5-bromo-6-(oxetan-3-yloxy)benzimidazol-l-yl]-3- (trifluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0510] To of l-[6-chloro-3-(trifluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (150 mg, 0.52 mmol, 1.0 eq.) and 5-bromo-6-(oxetan-3-yloxy)-lH-benzimidazole (141 mg, 0.52 mmol, 1.0 eq.) in DMSO (8 mL) was added potassium carbonate (217 mg, 1.57 mmol, 3.0 eq.). The suspension was stirred at 30 °C for 16 hours. The mixture was cooled to RT, poured into water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (SiCh, 0 - 50% EtOAc in PE) to give l-[6-[5-bromo-6-(oxetan-3- yloxy)benzimidazol-l-yl]-3-(trifluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (120.0 mg, 0.23 mmol, 44% yield) as yellow solid. LC-MS: m / z = 519.1 [M+H]+, ESI pos.JH NMR (400 MHz, CDC13) 8 = 8.52 - 8.44 (m, 2H), 8.11 (s, 1H), 7.85 (d, J= 8.7 Hz, 1H), 7.33 (s, 1H), 6.75 (s, 1H), 5.12 (quin, J= 5.7 Hz, 1H), 4.82 (dd, J= 1.7, 5.6 Hz, 4H), 2.37 (s, 3H) and l-[6-[6-bromo-5-(oxetan-3-yloxy)benzimidazol-l-yl]-3-(trifluoromethyl)-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile (120 mg, 0.23 mmol, 44% yield) as white solid. LC-MS: m / z = 519.1 [M+H]+, ESI pos. 'HNMR (400 MHz, CDCI3 ) 6 = 8.61 (s, 1H), 8.47 (d, J= 8.6 Hz, 1H), 8.32 (s, 1H), 7.87 (d, J = 8.6 Hz, 1H), 6.96 (s, 1H), 6.72 (d, J = 0.6 Hz, 1H), 5.35 (quin, J = 5.7 Hz, 1H), 5.08 (t, J= 7.0 Hz, 2H), 4.90 (dd, J= 5.4, 7.5 Hz, 2H), 2.43 (s, 3H)

[0511] Step 6: 5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-l- yl] -3-(trifluoromethyl)-2-pyridyl] pyrazole-3-carbonitrile

[0512] To a solution of 3-amino-6-methylpyridazine (50 mg, 0.46 mmol, 2.0 eq.) and l-[6-[5-bromo-6- (oxetan-3-yloxy)benzimidazol-l-yl]-3-(trifluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile (120 mg, 0.23 mmol, 1.0 eq.) in 1,4-dioxane (6 mL) was added cesium carbonate (226 mg, 0.69 mmol, 3.0 eq.). The reaction mixture was bubbled with argon for 10 minutes. [tBuBrettPhos Pd(allyl)]OTf (36 mg, 0.05 mmol, 0.2 eq.) was added and the reaction mixture was stirred at 80 °C for 4 hours under argon. The mixture was cooled to RT, poured into water (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were concentrated. The residue was triturated with MeOH (10 mL) for 30 minutes. The mixture was filtered. The cake was washed with MeOH (10 mL) and dried. The resulting solid was triturated with DMSO (10 mL) for 30 minutes and the mixture was filitered. The cake was washed with DMSO (10 mL) and concentration to give 5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3- yloxy)benzimidazol-l-yl]-3-(trifluoromethyl)-2-pyridyl]pyrazole-3-carbonitrile (53 mg, 0.1 mmol, 42% yield) as white solid. LC-MS: m / z = 548.2 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-d6) 5 = 9.14 (s, 1H), 8.90 - 8.85 (m, 1H), 8.79 (d, J = 8.8 Hz, 1H), 8.49 (d, J = 8.9 Hz, 1H), 8.38 (s, 1H), 7.39 - 7.35 (m, 3H), 7.20 (s, 1H), 5.23 - 5.15 (m, 1H), 4.74 - 4.64 (m, 4H), 3.31 (s, 3H), 2.37 (s, 3H).

[0513] Example 51 l-[3-cyclopropyl-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile Step 1: 6-chloro-3-cyclopropyl-2 -fluoro-pyridine

[0514] To a solution of cyclopropylboronic acid (245 mg, 2.85 mmol, 1.2 eq.) was added 3-bromo-6- chloro-2-fluoropyridine (500 mg, 2.38 mmol, 1.0 eq.), tetrakis(triphenylphosphine)palladium(0) (137 mg, 0.12 mmol, 0.05 eq.) and cesium carbonate (2.32 g, 7.13 mmol, 3.0 eq.). The suspension was bubbled with argon for 10 minutes and stirred at 100 °C for 1 hour. The reaction mixture was cooled to RT, poured into water (30 mL) and extracted with EtOAc (4 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (10% EtOAc in PE, Rf=0. 6 UV) to give 6-chloro-3-cyclopropyl-2-fluoro-pyridine (280 mg, 1.63 mmol, 69% yield) as colorless oil. LC-MS: m / z = 172.0 [M+H]+, ESI pos. 'H NMR (400 MHz, CDC13) 8 = 7.32 - 7.27 (m, 1H), 7.13 (d, J= 7.8 Hz, 1H), 2.05 - 1.97 (m, 1H), 1.10 - 1.03 (m, 2H), 0.77 - 0.71 (m, 2H).

[0515] Step 2: l-( 6-chloro-3-cyclopropyl-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile To a solution of 6-chloro-3-cyclopropyl-2-fluoro-pyridine (280 mg, 1.63 mmol, 1.0 eq.) in DMF (5 mL) was added 5-methyl-lH-pyrazole-3-carbonitrile (175 mg, 1.63 mmol, 1.0 eq.) and potassium carbonate (677 mg, 4.9 mmol, 3.0 eq.). The suspension was stirred at RT for 2 hours. The mixture was poured into water (50 mL) and extracted with EtOAc (4 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over ISfeSCU, filtered and concentrated. The residue was purified by flah chromatography (SiCh, 0 - 20% EtOAc in PE) to give l-(6-chloro-3-cyclopropyl-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile (220 mg, 0.85 mmol, 52% yield) as white solid. LC-MS: m / z = 259.0 [M+H]+, ESI pos. 'H NMR (400 MHz, CDC13) 5 = 7.42 (d, J= 2.3 Hz, 2H), 6.62 (s, 1H), 2.34 (s, 3H), 1.79 - 1.70 (m, 1H), 1.03 - 0.98 (m, 2H), 0.69 - 0.64 (m, 2H).

[0516] Step 3: l-[ 3-cyclopropyl-6-[ 6-methoxy-5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl -2- pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0517] To a solution of l-(6-chloro-3-cyclopropyl-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile (200 mg, 0.77 mmol, 1.0 eq.) in t-amyl alcohol (10 mL) was added 6-methoxy-N-(6-methylpyridazin-3- yl)-lH-benzimidazol-5-amine (Example 44, step 6) (217 mg, 0.85 mmol, 1.1 eq.). The reaction mixture was bubbled with argon for 10 minutes. t-BuXphos Pd G3 (123 mg, 0.15 mmol, 0.2 eq.) and tripotassium phosphate (212 mg, 1.55 mmol, 2.0 eq.) were added. The suspension was stirred at 90 °C for 16 hours under argon. The reaction mixture was cooled to RT, poured into water (50 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by preparative NPLC (Welch Ultimate XB-SiOH 250 mm x 70 mm x 10 pm, gradient 15 - 55% EtOH (with 0.1% ammonium hydroxide) in hexane over 15 minutes, then 100% EtOH (with 0.1% ammonium hydroxide) (3 min), flow rate 100 mL / min) followed by preparative HPLC (Phenomenex Luna C18 150 mm x 25mm x 10 pm, gradient 27 - 57% CH3CN in H2O (with 0.225% FA) over 10 minutes, then 100% CH3CN (2 min), flow rate 25 mL / min) to give 1- [3-cyclopropyl-6-[5-methoxy-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]- 5-methyl-pyrazole-3-carbonitrile (37 mg, 0.08 mmol, 10% yield) as yellow solid. LC-MS: m / z = 478.4 [M+H]+, ESI pos. 'H NMR (400 MHz, CDCh ) 6 = 8.41 (s, 1H), 8.35 (s, 1H), 7.70 - 7.65 (m, 3H), 7.21 - 7.10 (m, 2H), 6.69 (s, 1H), 3.92 (s, 3H), 2.63 (s, 3H), 2.43 (s, 3H), 1.89 - 1.84 (m, 1H), 1.11 - 1.02 (m, 2H), 0.75 (q, J= 5.2 Hz, 2H).

[0518] Example 52

[0519] 1- [3-amino-6- [5- [(6-methylpyridazin-3-yl)amino] benzimidazol-l-yl]-2-pyridyl]-5-methyl- pyrazole-3-carbonitrile

[0520] This example was obtained in analogy to Example 42, using 5-methyl-lH-pyrazole-3- carbonitrile in step 1 to give l-[3-amino-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (57 mg, 0.135 mmol) as a yellow solid. LC-MS: m / z = 423.2 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-d6) 5 = 9.17 (s, 1H), 8.71 (s, 1H), 8.41 - 8.37 (m, 1H), 8.16 (s, 1H), 7.86 (d, J = .1 Hz, 1H), 7.84 (d, J = 3.8 Hz, 1H), 7.60 (d, J= 8.7 Hz, 1H), 7.45 - 7.41 (m, 1H), 7.31 (d, J= 9.0 Hz, 1H), 7.06 (d, J= 9.0 Hz, 1H), 7.04 (s, 1H), 5.76 - 5.70 (m, 2H), 2.47 (s, 3H), 2.34 (s, 3H).

[0521] Example 53 l-[5-cyclopropyl-6-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-2-pyridyl]-6-methoxy-N- (6-methylpyridazin-3-yl)benzimidazol-5-amine Step 1: 6-chloro-3-cyclopropyl-2-[3-(difluoromethoxy)-5-methyl-pyr azol- 1-yl] pyridine

[0522] To a solution of 3-(difluoromethoxy)-5-methyl-lH-pyrazole (40 mg, 0.27 mmol, 1.0 eq.) in DMSO (1 mL) were added 6-chloro-3-cyclopropyl-2-fluoro-pyridine (Example 51, step 1) (56 mg, 0.32 mmol, 1.2 eq.) and K2CO3 (112 mg, 0.81 mmol, 3.0 eq.). The reaction mixture was stirred at 50 °C for 16 hours. The mixture was cooled to RT, poured into water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (10% EtOAc in PE, Rf=0.5 UV) to give 6-chloro-3-cyclopropyl-2-[3-(difluoromethoxy)-5- methyl-pyrazol-l-yl]pyridine (55 mg, 0.18 mmol, 68% yield) as a white solid. LC-MS: m / z = 300.1 [M+H]+, ESI pos. 'H NMR (400 MHz, CDCI3 ) 8 = 7.34 (s, 2H), 6.93 (t, J= 73.4 Hz, 1H), 5.88 (s, 1H), 2.29 (s, 3H), 1.88 (tt, J= 5.2, 8.5 Hz, 1H), 1.06 - 0.94 (m, 2H), 0.71 - 0.62 (m, 2H). Step 2: l-[5-cyclopropyl-6-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-2-pyridyl]-6-methoxy-

[0523] N-(6-methylpyridazin-3-yl)benzimidazol-5-amine

[0524] To a solution of 6-chloro-3-cyclopropyl-2-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]pyridine (50 mg, 0.17 mmol, 1.0 eq.) in tert-amyl Alcohol (2.0 mL) was added 6-methoxy-N-(6- methylpyridazin-3-yl)-lH-benzimidazol-5-amine (Example 44, step 6) (43 mg, 0.17 mmol, 1.0 eq.). The mixture was bubbled with argon for 10 minutes. tBuXPhosPdG3 (13 mg, 0.02 mmol, 0.1 eq.) and tripotassium phosphate (106 mg, 0.5 mmol, 3.0 eq.) were added. The reaction mixture was stirred at 80 °C for 2 hours under argon. The reaction mixture was cooled to RT, poured into water (20 mL) and extracted with EtOAc(3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over ISfeSCL, filtered and concentrated. The residue was purified by preparative TLC (10% MeOH in DCM, Rf=0.4;0.5 UV) followed by to give the product. But the purity of the product was lower than 80%. The product was further purified by preparative HPLC (Shim-pack C18 150 mm x 25 mm x 10 pm, water (with 0.225% FA)-ACN, gradient time 10 minutes, hold time 2 min, flow rate 25 mL / min) to give l-[5-cyclopropyl-6-[3- (difhioromethoxy)-5-methyl-pyrazol-l-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3- yl)benzimidazol-5-amine (7 mg, 0.01 mmol, 8% yield) as yellow solid. LC-MS: m / z = 519.2 [M+H]+, ESI pos. 'H NMR (400 MHz, METHANOL-d4) 5 = 8.75 (s, 1H), 8.61 (s, 1H), 8.00 - 7.89 (m, 2H), 7.81 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 92 Hz, 1H), 7.30 - 6.87 (m, 2H), 6.09 (s, 1H), 3.93 (s, 3H), 2.55 (s, 3H), 2.37 (s, 3H), 1.97 - 1.84 (m, 1H), 1.11 - 0.99 (m, 2H), 0.88 - 0.76 (m, 2H). Example 54

[0525] 1- [3-cyclopropyl-6- [5- [(6-ethyl-5,7-dihydropyrrolo [3,4-c]pyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile Step 1: 3-chloro-6-ethyl-5, 7-dihydropyrrolo[3,4-c]pyridazine

[0526] To a solution of 3-chloro-6,7-dihydro-5H-pyrrolo[3,4-c]pyridazine hydrochloride (365 mg, 1.9 mmol, 1.0 eq.) and DIPEA (1.33 mL, 7.59 mmol, 4.0 eq.) in DMF (6 mL) was added ethyl iodide (153 pL, 1.9 mmol, 1.0 eq.). The reaction mixture was stirred at 50 °C for 2 hours. The reaction mixture was cooled to RT, poured into water (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (30 mL), dried over ISfeSCU, filtered and concentrated. The residue was purified by flash chromatography (SiCL, 0 - 10% MeOH in DCM) to give 3-chloro-6-ethyl-5,7-dihydropyrrolo[3,4-c]pyridazine (175 mg, 49%) as a dark brown oil. LC-MS: m / z = 184.0 [M+H]+, ESI pos. Step 2: N-( 6-ethyl-5, 7-dihydropyrrolo[ 3, 4-c ]pyridazin-3-yl)carbamic acid tert-butyl ester

[0527] To a solution of 3-chloro-6-ethyl-5,7-dihydropyrrolo[3,4-c]pyridazine (175 mg, 924 pmol, 1.0 eq.) in 1,4-dioxane (4 mL) was added tert-butyl carbamate (217 mg, 1.85 mmol, 2.0 eq.), cesium carbonate (602 mg, 1.85 mmol, 2.0 eq.). The mixture was bubbled with argon for 10 minutes. (9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (107 mg, 185 pmol, 0.2 eq.) followed by tris(dibenzylideneacetone)dipalladium(0) - DCM complex (97 mg, 92 pmol, 0.1 eq.) were added and the reaction mixture was stirred at 80 °C for 1.5 hours under argon. The reaction mixture was cooled to RT, poured into water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over ISfeSCU, filtered and concentrated. The residue was purified by flash chromatography (SiCL, 0 - 10% MeOH in DCM) to give N-(6-ethyl-5,7-dihydropyrrolo[3,4-c]pyridazin-3-yl)carbamic acid tert-butyl ester (149 mg, 60.37%) as an off-white crystalline solid. LC-MS: m / z = 265.2 [M+H]+, ESI pos.

[0528] Step 3: 6-ethyl-5, 7-dihydropyrrolo[3,4-c]pyridazin-3-amine;2,2,2-trifluoroacetic acid

[0529] To a solution of N-(6-ethyl-5,7-dihydropyrrolo[3,4-c]pyridazin-3-yl)carbamic acid tert-butyl ester (150 mg, 567 pmol, 1.0 eq.) in DCM (3 mL) was added TFA (1.09 mL, 14.19 mmol, 25 eq.) and the mixture was stirred for at RT for 50 minutes. The reaction mixture was poured into water (30 mL) and the aqueous layerwas extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated to give 6-ethyl-5,7-dihydropyrrolo[3,4-c]pyridazin-3-amine;2,2,2-trifluoroacetic acid (194 mg, 86%) as white solid which was used without further purification. LC-MS: m / z = 165.0 [M+H]+, ESI pos.

[0530] Step 4: l-[3-cyclopropyl-6-[5-[(6-ethyl-5, 7-dihydropyrrolo[3,4-c]pyridazin-3- yl)amino ]benzimidazol-l-yl / -2 -pyridyl ]-5-methyl-pyrazole-3-carbonitrile

[0531] To a solution of l-[6-(5-bromobenzimidazol-l-yl)-3-cyclopropyl-2-pyridyl]-5-methyl-pyrazole- 3 -carbonitrile (32 mg, 76 pmol, 1.2 eq.) and 6-ethyl-5,7-dihydropyrrolo[3,4-c]pyridazin-3- amine;2,2,2-trifluoroacetic acid (25 mg, 64 pmol, 1.0 eq.) in 1,4-dioxane (0.5 mL) was added CS2CO3 (104 mg, 319 pmol, 5.0 eq.). The suspension was bubbled with argon for 10 minutes. [tBuBrettPhos Pd(allyl)]OTf (7 mg, 9 pmol, 0.15 eq.) was added and the reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was cooled to RT and concentrated. The residue was purified by flash chromatography (SiCL, 0 - 10% MeOH in DCM) to give l-[3- cyclopropyl-6-[5-[(6-ethyl-5,7-dihydropyrrolo[3,4-c]pyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile (25 mg, 0.050 mmol, 76%) as an off-white solid. LC- MS: m / z = 503.2 [M+H]+, ESI pos.

[0532] Example 55 3-[[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethoxy)-2-pyridyl]benzimidazol-5- yl]amino]-N,6-dimethyl-pyridazine-4-carboxamide

[0533] Step 1: methyl 3-[[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethoxy)-2- pyridyl ]benzimidazol-5-yl amino ]-6-methyl-pyridazine-4-carboxylic acid

[0534] To a solution of l-[6-chloro-3-(difluoromethoxy)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (Example 36, step 3) (200 mg, 0.7 mmol, 1.0 eq.) in t-amyl alcohol (5.0 mL) was added methyl 3-(lH-benzimidazol-5-ylamino)-6-methyl-pyridazine-4-carboxylate (Example 36, step 2) (300 mg, 0.85 mmol, 1.2 eq.) and tripotassium phosphate (460 mg, 2.17 mmol, 3.1 eq.). The suspension was bubbled with argon for 10 minutes. tBuXPhosPdG3 (56 mg, 0.07 mmol, 0.1 eq.) was added and the reaction mixture was stirred at 80 °C for 3h under argon. The reaction mixture was cooled to RT, diluted with water (50 ml) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (Waters Xbridge 150 mm x 25 mm x 5 pm, water (lOmM NH4HCO3) - CH3CN, gradient time 9 minutes, 100% hold time 2 min, flow rate 25 mL / min) to give 3-[[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethoxy)-2- pyridyl]benzimidazol-5-yl]amino]-6-methyl-pyridazine-4-carboxylic acid (65 mg, 0.13 mmol, 19% yield) as yellow solid. LC-MS: m / z = 532.1 [M+H]+, ESI pos.

[0535] Step 2: 3-[[ l-[ 6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethoxy)-2-pyridyl]benzimidazol-5- yl amino ]-N, 6-dimethyl-pyridazine-4-carboxamide

[0536] To a solution of 3-[[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethoxy)-2- pyridyl]benzimidazol-5-yl]amino]-6-methyl-pyridazine-4-carboxylic acid (80 mg, 0.15 mmol, 1.0 eq.) in pyridine (3 mL) at 0 °C was added methylamine hydrochloride (104 mg, 1.55 mmol, 10 eq.) followed by EDCI (44 mg, 0.23 mmol, 1.5 eq.). The reaction mixture was stirred at 50 °C for 2 hours. The reaction mixture was cooled to RT, poured into water (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (Waters Xbridge 150 mm x 25 mm x 5 pm, water (lOmM NH4HCO3) - CH3CN, gradient time 9 minutes, 100% hold time 2 min, flow rate 25 mL / min) to give 3-[[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)- 5-(difluoromethoxy)-2-pyridyl]benzimidazol-5-yl]amino]-N,6-dimethyl-pyridazine-4- carboxamide (3 mg, 0.003 mmol, 2% yield) as yellow solid. LC-MS: m / z = 531.2 [M+H]+, ESI pos.XH NMR (400 MHz, DMSO-d6) 5 = 10.25 (s, 1H), 9.13 (br d, J= 3.9 Hz, 1H), 9.03 (s, 1H), 8.49 (d, J= 2.0 Hz, 1H), 8.44 (br d, J= 4.2 Hz, 1H), 8.34 (s, 2H), 8.06 (d, J= 8.9 Hz, 1H), 7.69 (s, 1H), 7.50 (s, 1H), 7.45 (dd, J= 2.0, 8.7 Hz, 1H), 7.32 (s, 1H), 7.14 (s, 1H), 7.09 (s, 1H), 2.84 (d, J= 4.5 Hz, 3H), 2.56 (s, 3H), 2.36 (s, 3H). Example 56 l-[4-(difluoromethoxy)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]- 5-methyl-pyrazole-3-carbonitrile Step 1: 4-allyloxy-2,6-difluoro-pyridine

[0537] To a solution of 2,4,6-trifluoropyridine (5.00 g, 37.57 mmol, 1.0 eq.) in DMF (50 mL) was added NaH (1.80 g, 45.0 mmol, 1.2 eq.) at 0 °C under N2 and the reaction mixture was stirred at 0 °C for 10 minutes. Allyl alcohol (2.55 mL, 37.53 mmol, 1.0 eq.) was added dropwise at 0 °C under N2. The reaction mixture was stirred at RT for 2 hours. The reaction mixture was poured into saturated aqueous NH4CI (300 mL) under stirring and was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (SiCh, 10% EtOAc in PE) to give 4-allyloxy-2,6-difluoro-pyridine (4.6 g, 26.88 mmol, 72% yield) as colorless oil. LC-MS: m / z = 172.1 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-d6) 5 = 6.78 (s, 2H), 6.09 - 5.96 (m, 1H), 5.43 (dd, J= 1.5, 17.3 Hz, 1H), 5.32 (dd, J= 1.2, 10.5 Hz, 1H), 4.74 (d, J= 5.4 Hz, 2H).

[0538] Step 2: l-(4-allyloxy-6-fluoro-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile To a solution of 5-methyl-lH-pyrazole-3-carbomtnle (1.43 g, 13.36 mmol, 1.0 eq.) in DMSO (30 mL) was added 4-allyloxy-2,6-difluoro-pyridine (2.30 g, 13.44 mmol, 1.0 eq.) and K2CO3 (3.71 g, 26.88 mmol, 2.0 eq.). The reaction mixture was stirred at 30 °C for 12 hours. The reaction mixture was poured into water (200mL) under stirring and was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (100 mL), dried over ISfeSCU, filtered and concentrated. The residue was purified by flash chromatography (SiCh, 10% EtOAc in PE) to give l-(4-allyloxy-6-fluoro-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile (850 mg, 3.29 mmol, 24% yield) as white solid. LC-MS: m / z = 259.0 [M+H]+, ESI pos.JH NMR (400 MHz, DMSO-d6) 5 = 7.34 (d, J= 1.8 Hz, 1H), 7.02 (d, J= 0.8 Hz, 1H), 6.96 (d, J= 1.8 Hz, 1H), 6.05 (tdd, J= 5.3, 10.6, 17.3 Hz, 1H), 5.46 (qd, J= 1.6, 17.3 Hz, 1H), 5.34 (qd, J= 1.4, 10.6 Hz, 1H), 4.82 (td, J= 1.5, 5.3 Hz, 2H), 2.58 (d, J= 0.6 Hz, 3H).

[0539] Step 3: l-[ 4-allyloxy-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2-pyridyl -5- methyl-pyrazole-3-carbonitrile

[0540] To a solution of N-(6-methylpyridazin-3-yl)-lH-benzimidazol-5-amine (741 mg, 3.29 mmol, 1.0 eq.) in DMSO (10 mL) was added l-(4-allyloxy-6-fluoro-2-pyridyl)-5-methyl-pyrazole-3- carbonitrile (850 mg, 3.29 mmol, 1.0 eq.) and K2CO3 (910 mg, 6.58 mmol, 2.0 eq.). The reaction mixture was stirred at 30 °C for 12 hours. The reaction mixture was poured into water (50 mL) and was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by preparative NPLC (Welch Ultimate XB-SiOH 250 mm x 70 mm x 10 pm, gradient 15 - 55% EtOH (with 0.1% ammonium hydroxide) in hexane over 15 minutes, then 100% EtOH (with 0.1% ammonium hydroxide) (3 min), flow rate 100 mL / min) to givel-[4-allyloxy-6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (150 mg, 0.32 mmol, 10% yield) as grey solid. LC-MS: m / z = 464.2 [M+H]+, ESI pos. 'HNMR (400 MHz, DMSO-d6) 5 = 9.21 (s, 1H), 8.93 (s, 1H), 8.43 (d, J= 1.6 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.59 (d, J= 1.5 Hz, 1H), 7.52 (dd, J= 1.7, 8.9 Hz, 1H), 7.39 (d, J= 1.5 Hz, 1H), 7.33 (d, J = 9.2 Hz, 1H), 7.11 - 7.03 (m, 2H), 6.19 - 6.06 (m, 1H), 5.52 (dd, J = 1.1, 17.4 Hz, 1H), 5.38 (br d, J= 10.4 Hz, 1H), 4.93 (br d, J= 5.1 Hz, 2H), 2.66 (s, 3H), 2.48 (br s, 3H).

[0541] Step 4: l-[ 4-hydroxy-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2-pyridyl ]-5- methyl-pyrazole-3-carbonitrile

[0542] To a suspension of l-[4-allyloxy-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile (150 mg, 0.32 mmol, 1.0 eq.) and K2CO3 (89 mg, 0.65 mmol, 2.0 eq.) in 1,4-dioxane (2 mL) / DMF (0.5 mL) under N2 was aded Pd(PPhs)4 (37 mg, 0.03 mmol, 0.1 eq.). The reaction mixture was stirred at RT for 2 hours under N2. The reaction mixture was concentrated and the residue was purified by preparative HPLC (Waters Xbridge 150 mm x 25 mm x 5 pm, water (10 mM NH4HCO3) - CH3CN, gradient time 9 minutes, 100% hold time 2 min, flow rate 25 mL / min) to give l-[4-hydroxy-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (20 mg, 0.05 mmol, 15% yield) as yellow solid. LC-MS: m / z = 424.1 [M+H]+, ESI pos.

[0543] Step 5: l-[ 4-(difluoromethoxy)-6-[5-[ ( 6-methylpyridazin-3-yl)amino ]benzimidazol-l-yl ]-2- pyridyl] -5-methyl-pyrazole-3-carbonitrile

[0544] To a solution of l-[4-hydroxy-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile (20 mg, 0.05 mmol, 1.0 eq.) in DMF (1 mL) were added CS2CO3 (31 mg, 0.09 mmol, 2.0 eq.) and sodium chlorodifluoroacetate (14 mg, 0.09 mmol, 2.0 eq.). The reaction mixture was stirred at 80 °C for 2 hours. The mixture was filtered and the filter cake was washed with DCM (3 x 5mL). The filtrate was concentrated and the residue was purified by preparative HPLC (Waters Xbridge 150 mm x 25 mm x 5 pm, water (lOmM NH4HCO3) - CH3CN, gradient time 9 minutes, 100% hold time 2 min, flow rate 25 mL / min) to give l-[4-(difluoromethoxy)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (1.7 mg, 0.0 mmol, 7% yield) as yellow solid. LC-MS: m / z = 474.1 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-d6) 5 = 9.27 (s, 1H), 8.95 (s, 1H), 8.46 (d, J= 1.9 Hz, 1H), 8.10 (d, J= 8.9 Hz, 1H), 7.97 (s, 1H), 7.85 (d, J= 1.6 Hz, 1H), 7.79 (s, 1H), 7.64 (d, J= 1.3 Hz, 1H), 7.61 (s, 1H), 7.54 (dd, J= 1.9, 8.8 Hz, 1H), 7.34 (d, J = 9.1 Hz, 1H), 7.13 - 7.05 (m, 2H), 2.69 (s, 3H), 2.48 (br s, 3H).

[0545] Example 57

[0546] 1- [3- [2-(azetidin- l-yl)-2-oxo-ethoxy]-6- [5- [(6-methylpyridazin-3-yl)amino] benzimidazol- 1- yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0547] Step 1: l-(azetidin-l-yl) -2 -chloro-ethanone

[0548] To a mixture of K2CO3 (8.12 g, 58.79 mmol, 2.2 eq.) in water (30 mL) and DCM (30 mL) was added azetidine hydrochloride (2.5 g, 26.72 mmol, 1.0 eq.) and the mixture was stirred for at 25 °C for 30 minutes. The reaction mixture was cooled to 0 °C and a solution of chloroacetyl chloride (3.62 g, 32.06 mmol, 1.2 eq.) in DCM (25 mL) was added over 15 minutes and was stirred further at RT for 2 hours. The reaction mixture was poured into water (100 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered anc concentrated. The residue was purified by flash chromatography (SiCL, 50% EtOAc in PE) to give l-(azetidin-l-yl)-2-chloro-ethanone (1.80 g, 13.48 mmol, 50% yield) as a colorless oil. LC-MS: m / z = 474.1 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-d6) 5 = 4.19 (t, J= 7.7 Hz, 2H), 4.09 (s, 2H), 3.90 (t, J= 7.8 Hz, 2H), 2.22 (t, J= 7.8 Hz, 2H).

[0549] Step 2: l-(azetidin-l-yl)-2-[(6-chloro-2-fluoro-3-pyridyl)oxy] ethanone Cl

[0550] To a solution of 6-chl oro-2-fluoro-pyri din-3 -ol (100 mg, 0.68 mmol, 1.0 eq.) in DMF (1 mL) was added l-(azetidin-l-yl)-2-chloro-ethanone (91 mg, 0.68 mmol, 1.0 eq.) and K2CO3 (103 mg, 0.75 mmol, 1.1 eq.). The reaction mixture was stirred at RT for 16 hours. The reaction mixture was poured into stirring saturated aqueous NH4CI (30 ml) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (SiO2, 0 - 70% EtOAc in PE) to give l-(azetidin-l-yl)-2-[(6-chloro-2-fluoro-3-pyridyl)oxy]ethanone (90 mg, 0.37 mmol, 54% yield) as an off-white solid. LC-MS: m / z = 245.2 [M+H]+, ESI pos.JH NMR (400 MHz, CDCI3) 8 = 7.34 (t, J = 9.0 Hz, 1H), 7.16 (d, J = 8.2 Hz, 1H), 4.62 (s, 2H), 4.37 (br t, J= 7.7 Hz, 2H), 4.11 (br t, J= 7.8 Hz, 2H), 2.36 (quint, J= 7.8 Hz, 2H).

[0551] Step 3: l-[3-[2-(azetidin-l-yl)-2-oxo-ethoxy]-6-chloro-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile

[0552] To a solution of l-(azetidin-l-yl)-2-[(6-chloro-2-fluoro-3-pyridyl)oxy]ethanone (90 mg, 0.37 mmol, 1.0 eq.) in DMSO (1 mL) were added 5-methyl-lH-pyrazole-3-carbonitrile (39 mg, 0.37 mmol, 1.0 eq.) and K2CO3 (153 mg, 1.1 mmol, 3.0 eq.). The reaction mixture was stirred at 30

[0553] C for 16 hours. The reaction mixture was poured into saturated aqueous NH4CI (50 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (0 - 30% EtOAc in PE) to give l-[3-[2-(azetidin-l-yl)-2-oxo-ethoxy]-6-chloro- 2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (120 mg, 0.36 mmol, 98% yield) as a light yellow oil. LC-MS: m / z = 332.0 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-d6) 5 = 7.85 - 7.81 (m, 1H), 7.80 - 7.77 (m, 1H), 6.95 (s, 1H), 4.83 (s, 2H), 4.10 - 4.04 (m, 2H), 3.88 (t, J= 7.7 Hz, 2H), 2.27 - 2.19 (m, 5H).

[0554] Step 4: l-[3-[ 2 -(azetidin-l-yl) -2 -oxo-ethoxy ]-6-[5-[ ( 6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl / -2 -pyridyl ]-5-methyl-pyrazole-3-carbonitrile

[0555] To a solution of l-[3-[2-(azetidin-l-yl)-2-oxo-ethoxy]-6-chloro-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile (110 mg, 0.33 mmol, 1.0 eq.) in t-amyl alcohol (1.0 mL) were added N-(6- methylpyridazin-3-yl)-lH-benzimidazol-5-amine (100 mg, 0.4 mmol, 1.21 eq.) and K3PO4 (211 mg, 1.0 mmol, 3.0 eq.). The reaction mixture was bubbled with argon for 10 minutes. tBuXPhosPdG3 (27 mg, 0.03 mmol, 0.1 eq.) was added and the reaction mixture was stirred at 80 °C for 16 hours under argon. The reaction mixture was cooled to RT, poured into saturated aqueous NH4CI (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (Phenomenex Luna C18 150 mm x 25mm x 10 pm, gradient 27 - 57% CH3CN in H2O (with 0.225% FA) over 10 minutes, then 100% CH3CN (2 min), flow rate 25 mL / min) to give 1- [3-[2-(azetidin-l-yl)-2-oxo-ethoxy]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile (The mixture of two regioisomers) (40 mg, 0.08 mmol, 23% yield) as a light yellow solid. LC-MS: m / z = 521.2 [M+H]+, ESI pos.

[0556] Example 58 - Phosphorylation assay SIK1-3: In the presence of SIK2 (resp. SIK1 or SIK3) and ATP the CHK-peptide (KKKVSRSGLYRSPSMPENLNRPR with C-terminal arginine amide modification) were phosphorylated at one of the four feasible serine’s. Only one phosphorylation is observed under the assay conditions. 60 nl of each compound dilution series (12 point; dilution factor 3, generally 30 pM to 170 pM) in DMSO were transferred by acoustic dispensing to the assay plate and 30 minutes pre-incubated (ambient temperature) after the addition of 5 pl SIK1 (5 nM) resp. 5 pl SIK2 (0.5 nM) or 7 pl SIK3 (1.5 nM) in assay-buffer (12.5 mM HEPES (pH 7.0), 10 mM magnesium acetate, 0.005% BSA). 10 pM CHK-peptide solution and 5 pl of 100 pM ATP for SIK1 & SIK2 resp. 3 pl for SIK3 in assay-buffer were added and incubated ambient for 45 minutes. 40 pl of 0.125% formic acid in water were added to quench the reaction. RapidFire (RF) Mass Spectrometry was utilized for data generation as described below. The multiple charged species (3-5 charges) for the phosphorylated and non-phosphorylated form measured by MRM (Multiple Reaction Monitoring; API5000 or 6500+) or EIC (Extracted Ion Current; QToF) were summed up and the ratio calculated (sum phosphorylated species / sum all species) for data evaluation. Normalization was performed by Genedata software based on the non-inhibition control DMSO and the commercially available SIK inhibitor @ IpM YKL-05-099 (CAS number 1936529-65-5). The results of the assay are expressed in half-maximal inhibitory concentrations (IC50s) and are summarized below in Table 1.

[0557] RapidFire Setup:

[0558] Samples were aspirated by vacuum for max. 600ms and loaded to C4-cartridge (Agilent; #G9203A) for 3000ms@1.5ml / min with 0.1% formic acid in water. Afterwards samples were transferred to the API5000 (API6500+) or QToF mass spectrometer for 4000ms@1.25ml / min with 90% acetonitrile; 10% water; 0.007% TFA; 0.093 formic acid. The cartridge was reconditioned for additional 500ms with 0.1% formic acid in water.

[0559] MS-Setup Sciex API5000 / API6500+:

[0560] All MS analyses using the following MS-setup in MRM mode: Electrospray positive; Ion Spray Voltage: 4000V; Temperature: 550 °C; Collision Gas: 5; Curtain Gas: 15; Gas 1 : 40; Gas 2: 42; EP: 10. DP = declustering potential; CE = collision energy; CXP = cell exit potential.

[0561] MS-Setup Agilent QToF 6545

[0562] All MS analyses using the following MS-setup in Mode MS: Dual AJS Electrospray positive;

[0563] VCap: 3000V; Drying & Sheath gas: 340 °C@81 / min; Nebulizer: 60psig; Nozzle Voltage: 2000V; Fragmentor: 130V; Skimmer: 35V; Octi RF Vpp: 700V; Ref masses on@5spectra / s

[0564] Table 1: IC50 values for inhibition of SIK1, SIK2 and SIK3:

[0565] Example A

[0566] Film coated tablets containing the following ingredients can be manufactured in a conventional manner:

[0567] 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 aqueous solution / suspension of the above mentioned film coat.

[0568] Example B

[0569] Capsules containing the following ingredients can be manufactured in a conventional manner:

[0570] The components are sieved and mixed and filled into capsules of size 2.

[0571] Example C

[0572] Injection solutions can have the following composition:

[0573] 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.

Claims

Claims1. A compound of formula (I)whereinL is absent, -NH- or -O-;R1is hydrogen, hydroxyalkyl or haloalkoxy;R2is cyanoalkyl, haloalkoxy, hydrogen, alkylsulfinyl, cyanoalkoxy, haloalkyl, alkoxy, halogen, amino, haloalkoxyallylamino, azetidinyl-2-oxo-alkoxy, cycloalkyl, cycloalkyloxy, heterocycloalkyl or heterocycloalkyloxy; wherein cycloalkyl, cycloalkyloxy, heterocycloalkyl and heterocycloalkyloxy are optionally substituted with 1, 2 or 3 substituents individually selected from R7;R3and R4are independently selected from cyano, alkyl, haloalkyl and haloalkoxy;R5is hydrogen, alkoxy, halogen, heterocycloalkyloxy or heteroarylamino; wherein heteroarylamino is optionally substituted with 1, 2 or 3 substituents individually selected from R8;R6is alkyl, heterocycloalkyl or heteroaryl; wherein heterocycloalkyl and heteroaryl are optionally substituted with 1, 2 or 3 substituents individually selected from R9; if L is absent, then R6can also be hydrogen or halogen; each R7is individually selected from halogen, haloalkyl, hydroxy and cyano; each R8is individually selected from alkyl and alkoxyheterocycloalkylalkyl;each R9is individually selected from alkyl, halogen, dialkylaminocarbonyl, alkoxyheterocycloalkylalkyl, alkylheterocycloalkyl and alkylaminocarbonyl; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein R1is hydrogen, 1 -hydroxy ethyl or difluoromethoxy.

3. The compound according to claim 1 or 2, wherein R2is 1 -cyanoethyl, difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2-difluoro-l -methyl-ethoxy, hydrogen, methylsulfmyl, cyanomethoxy, 1,1 -difluoroethyl, 2,2-difluoroethyl, trifluoromethyl, methoxy, chloro, bromo, amino, 2-(difluoromethoxy)allylamino, azetidinyl-2-oxo-ethoxy, cyclopropyl, cyclopropyl oxy, tetrahydrofuran-2-yl, oxetan-3-yl, pyrrolidin-2-yl, l,3-dioxolan-2-yl or ox etan-3 -yl oxy; wherein cyclopropyl, cyclopropyl oxy, tetrahydrofuran-2-yl, oxetan-3-yl, pyrrolidin-2-yl, 1,3 -di oxolaneyl and (oxetan-3-yl)oxy are optionally substituted with a substituent selected from R7.

4. The compound according to any one of claims 1 to 3, wherein R3and R4are independently selected from cyano, methyl, difluoromethyl and difluoromethoxy.

5. The compound according to any one of claims 1 to 4, wherein R4is methyl and R3is selected from cyano, methyl, difluoromethyl and difluoromethoxy.

6. The compound according to any one of claims 1 to 5, wherein R5is hydrogen, methoxy, fluoro, (ox etan-3 -yl)oxy or (pyridazin-3-yl)amino; and wherein (pyridazin-3-yl)amino is optionally substituted a substituent selected from R8.

7. The compound according to any one of claims 1 to 6, wherein R6is methyl, heterocycloalkyl or heteroaryl; wherein heterocycloalkyl and heteroaryl are at each instance optionally substituted with 1 or 2 substituents individually selected from R9; wherein heterocylcloalkyl is selected from 2,6-diazaspiro[3.4]octan-6-yl, 2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][l,4]oxazin-6-yl, pyrrolidin- 3 -yl and 5,7-dihydropyrrolo[3,4-c]pyridazin-3-yl; wherein heteroaryl is selected from triazol-4-yl and pyridazin-3-yl; and wherein if L is absent, then R6can also be hydrogen or fluoro.

8. The compound according to any one of claims 1 to 7, wherein R7is at each instance individually selected from hydroxy, fluoro, cyano and difluoromethyl.

9. The compound according to any one of claims 1 to 8, wherein R8is at each instance individually selected from methyl and (3-methoxyazetidin-l-yl)methyl.

10. The compound according to any one of claims 1 to 9, wherein R9is at each instance individually selected from methyl, ethyl, fluoro, (3-methoxyazetidin-l-yl)methyl, methylaminocarbonyl, 1-methylazeti din-3 -yl and dimethylaminocarbonyl.

11. The compound according to any one of claims 1 to 10, wherein L is -NH-.

12. The compound of formula (I) according to any one of claims 1 to 11, selected from5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-tetrahydrofuran-2- yl-2-pyridyl]pyrazole-3-carbonitrile;5-methyl-l-[6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-tetrahydrofuran-2- yl-2-pyridyl]pyrazole-3-carbonitrile;1-[3-(3-hydroxyoxetan-3-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile;5-methyl-l-[6-[5-[(l -methyltri azol -4-yl)amino]benzimidazol-l -yl]-3-tetrahydrofuran-2 -yl-2-pyridyl]pyrazole-3-carbonitrile; l-[6-[5-(2,6-diazaspiro[3.4]octan-6-yl)benzimidazol-l-yl]-3-tetrahydrofuran-2-yl-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile;5-methyl-l-[6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-[rac-(2R,4R)-4- hydroxyoxolan-2-yl]pyridin-2-yl]pyrazole-3-carbonitrile;5-methyl-l-[6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-[rac-(2R,4S)-4- hydroxyoxolan-2-yl]pyridin-2-yl]pyrazole-3-carbonitrile;5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-[rac-(2R,4R)-4- hydroxyoxolan-2-yl]pyridin-2-yl]pyrazole-3-carbonitrile;5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-[rac-(2R,4S)-4- hydroxyoxolan-2-yl]pyridin-2-yl]pyrazole-3-carbonitrile; l-[6-[5-[[(3R,4S)-4-fluoropyrrolidin-3-yl]amino]benzimidazol-l-yl]-3-tetrahydrofuran-2- yl-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile;5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-[rac-(2R,4R)-4- fluorooxolan-2-yl]pyridin-2-yl]pyrazole-3-carbonitrile;5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-[rac-(2R,4S)-4- fluorooxolan-2-yl]pyridin-2-yl]pyrazole-3-carbonitrile; l-[6-[5-[[6-[(3-methoxyazetidin-l-yl)methyl]pyridazin-3-yl]amino]benzimidazol-l-yl]-3- tetrahydrofuran-2-yl-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[6-[6-[[6-[(3-methoxyazetidin-l-yl)methyl]pyridazin-3-yl]amino]benzimidazol-l-yl]-3- tetrahydrofuran-2-yl-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile;1-[3-(l-cyanoethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5- m ethyl -pyrazole-3 -carbonitrile;2-[3-(l-cyanocyclopropyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[3-(difluoromethoxy)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[3-(difluoromethoxy)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[4-(l-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5 -methyl -pyrazol e-3 -carb onitril e; l-[4-(l-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5 -methyl -pyrazol e-3 -carb onitril e; l-[3-(2,2-difluoroethoxy)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[3-(2,2-difluoroethoxy)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile;5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-[rac-(2R,4R)-4- fluoropyrroli din-2 -yl]pyridin-2-yl]pyrazole-3-carbonitrile;5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-[rac-(2R,4S)-4- fluoropyrroli din-2 -yl]pyridin-2-yl]pyrazole-3-carbonitrile;1-[3-chloro-4-(l-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile;1-[3-chloro-4-(l-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile;5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-methylsulfinyl-2- pyridyl]pyrazole-3-carbonitrile;5-methyl-l-[6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-methylsulfinyl-2- pyridyl]pyrazole-3-carbonitrile; formic acid;5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3- (oxetan-3-yloxy)-2-pyridyl]pyrazole-3-carbonitrile; l-[3-(2,2-difluoro-l-methyl-ethoxy)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[3-methoxy-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5- m ethyl -pyrazole-3 -carbonitrile; l-[3-(cyanomethoxy)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5 -methyl -pyrazol e-3 -carb onitril e; l-[3-(cyanomethoxy)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5 -methyl -pyrazol e-3 -carb onitril e;5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-[rac-(2R,4S)-4- cyanooxolan-2-yl]pyridin-2-yl]pyrazole-3-carbonitrile;5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-[rac-(2R,4R)-4- cyanooxolan-2-yl]pyridin-2-yl]pyrazole-3-carbonitrile;5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-[rac-(2R,4R)-4-(difluoromethyl)oxolan-2-yl]pyridin-2-yl]pyrazole-3-carbonitrile;5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-[rac-(2R,4S)-4- (difluoromethyl)oxolan-2-yl]pyridin-2-yl]pyrazole-3-carbonitrile;3-[[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethoxy)-2-pyridyl]benzimidazol-5- yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide; l-[3-(2,2-difluoroethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[3-(l,3-dioxolan-2-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile;[l-[6-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-5-(l,3-dioxolan-2-yl)-2- pyridyl]benzimidazol-5-yl]-(6-methylpyridazin-3-yl)amine; l-[5-bromo-6-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-2-pyridyl]benzimidazol-5-yl]-(6- methylpyridazin-3-yl)amine;5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3- (trifluoromethoxy)-2-pyridyl]pyrazole-3-carbonitrile;[l-[5-amino-6-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-2-pyridyl]benzimidazol-5-yl]- (6-methylpyridazin-3-yl)amine; l-[3-(l-cyanocyclopropoxy)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[6-[5-methoxy-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-[rac-(2R,4R)-4- fluoroox olan-2-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-[rac-(2R,4R)-4- fluoroox olan-2-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile;3-[[l-[6-(3-cyano-5-methylpyrazol-l-yl)-5-[rac-(2R,4R)-4-fluorooxolan-2-yl]pyri din-2- yl]benzimidazol-5-yl]amino]-N,N,6-trimethylpyridazine-4-carboxamide; l-[6-[5-[(4aS,7aR)-4-methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][l,4]oxazin-6- yl]benzimidazol-l-yl]-3-(l,3-dioxolan-2-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile;l-[3-(l,l-difluoroethyl)-6-[5-[[6-[(3-methoxyazetidin-l-yl)methyl]pyridazin-3- yl]amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[3-[2-(difluoromethoxy)prop-2-enylamino]-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol- 1 -yl]pyri din-2 -yl]-5-methylpyrazole-3-carbonitrile;1-[6-[5-fluoro-6-(pyridazin-3-ylamino)benzimidazol-l-yl]-3-[rac-(2R,4R)-4-fluorooxolan-2-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile;1-[6-[6-fluoro-5-(pyridazin-3-ylamino)benzimidazol-l-yl]-3-[rac-(2R,4R)-4-fluorooxolan-2-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile;5-methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-l-yl]-3 -(trifluoromethyl)-2-pyridyl]pyrazole-3 -carbonitrile; l-[3-cyclopropyl-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[3-amino-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl- pyrazole-3 -carbonitrile; l-[5-cyclopropyl-6-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-2-pyridyl]-6-methoxy-N- (6-methylpyridazin-3-yl)benzimidazol-5-amine; l-[3-cyclopropyl-6-[5-[[6-methyl-5-(l-methylazetidin-3-yl)pyridazin-3- yl]amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[3-cyclopropyl-6-[5-[(6-ethyl-5,7-dihydropyrrolo[3,4-c]pyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile;3-[[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethoxy)-2-pyridyl]benzimidazol-5- yl]amino]-N,6-dimethyl-pyridazine-4-carboxamide; l-[4-(difluoromethoxy)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile; and l-[3-[2-(azetidin-l-yl)-2-oxo-ethoxy]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol- l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile;or a pharmaceutically acceptable salt thereof.

13. A process for the preparation of a compound according to any one of claims 1 to 12, comprising at least one of the following steps:(a) the reaction of a compound of formula (Al)with a compound of formula (A2)in presence of a suitable solvent and a suitable base;(b) the reaction of a compound of formula (Bl)with a compound of formula (B2)in presence of a suitable catalyst, a suitable solvent and a suitable solvent; in the above process, L and I -R6are as defined in any one of claims 1 to 12.

14. A compound according to any one of claims 1 to 12 when manufactured according to a process of claim 13.

15. A compound of formula (I) according to any one of claims 1 to 12 or a pharmaceutcically acceptable salt thereof, for use as therapeutically active substance.

16. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

17. The use of a compound of formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, for the treatment or prophylaxis of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel diseases (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis.

18. The use of a compound of formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prophylaxis rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel diseases (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis.

19. A compound of formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel diseases (IBD), atherosclerosis, type 2 diabetes or gl omerul onephriti s .

20. A method for the treatment or prophylaxis of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel diseases (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis, which method comprises administering an effective amount of a compound of formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

21. The invention as hereinbefore described.

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