EP4642773A1

EP4642773A1 - New benzimidazole derivatives

Info

Publication number: EP4642773A1
Application number: EP23840681.3A
Authority: EP
Inventors: Mahendra AWALE; Stefan Berchtold; Julie CHARPENTIER; Héloïse Marie Albine COLOMBANO; Guillaume Stéphane DÉCORET; Katrin Groebke Zbinden; Nicole Denise GROSSMANN; Wolfgang Juergen HAAP; Philip Anthony Harris; Jérôme HERT; Jonah Milton KALLENBACH; Christian Kramer; Lukas Matthias KREIS; Danny KRUMM; Xavier LUCAS CABRÉ; Nenad MANEVSKI; Philippe Pflieger; Amir Mohsen POURMOUSA ABKENAR; Etienne RAUBER; Dazhi TAN
Original assignee: F Hoffmann La Roche AG
Current assignee: F Hoffmann La Roche AG
Priority date: 2022-12-27
Filing date: 2023-12-22
Publication date: 2025-11-05
Also published as: WO2024141444A1; JP2026500715A; CN120418238A

Abstract

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

Description

New Benzimidazole Derivatives

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.

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

R¹ is haloalkoxy, heterocycloalkylcarbonyl, heteroaryl or heterocycloalkyl, wherein heterocycloalkyl carbonyl, heteroaryl and heterocycloalkyl are optionally substituted with 1, 2 or 3 substituents individually selected from R⁴;

R² is hydrogen, alkoxy, alkyl, halogen, haloalkoxy, dialkylaminocarbonylalkoxy, heterocycloalkyloxy, heterocycloalkylalkoxy or alkylheteroarylamino;

R³ is hydrogen, cycloalkylcarbonyl, alkylcarbonyl, heterocycloalkylcarbonyl, heterocycloalkyl or heteroaryl; wherein heterocycloalkylcarbonyl, heterocycloalkyl and heteroaryl are optionally substituted with 1, 2 or 3 substituents individually selected from R⁵; or R² and R³ together with the carbon atoms to which they are attached to form a 4 to 6 membered heterocycloalkyl optionally substituted with alkylheteroaryl; each instance of R⁴ is individually selected from alkyl, amino, alkyl sulfonyl, cyano, halogen, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, dialkylaminocarbonyl, haloalkoxy and haloalkyl; each instance of R⁵ is individually selected from alkyl, alkoxycarbonyl, heterocycloalkyl, cycloalkyl, (hydroxyl)(alkyl)heterocycloalkyl, dialkylaminocarbonyl, heterocycloalkyl alkoxy, alkylheterocycloalkyl, alkylheterocycloalkyl oxy, heterocycloalkylheterocycloalkyloxy, (haloalkyl)(alkyl)aminocarbonyl, dialkylaminocarbonylalkyl, hydroxyalkyl and arylalkoxycarbonylaminoheterocycloalkyl;

A¹ is -N- or -CH-; and

L is absent, -O- or -NH-; or a pharmaceutically acceptable salt thereof.

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 (c AMP -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).

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 HDAC4/5 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.).

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-

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 SIKl-related toxicities.

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.

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.

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).

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.

In the present description the term “alkyl”, alone or in combination, signifies a straightchain or branched-chain alkyl group with 1 to 8 carbon atoms, particularly a straight or branched-chain alkyl group with 1 to 6 carbon atoms and more particularly a straight or branched-chain alkyl group with 1 to 4 carbon atoms. Examples of straight-chain and branched- chain C1-C8 alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, the isomeric pentyls, the isomeric hexyls, the isomeric heptyls and the isomeric octyls, particularly methyl, ethyl, propyl, butyl and pentyl. Particular examples of alkyl are methyl, ethyl, propyl, isopropyl, butyl and isobutyl. Methyl, ethyl, propyl and butyl, like isobutyl, are further particular examples of “alkyl” in the compound of formula (I).

The term “heterocycloalkyl”, alone or in combination, denotes a monovalent saturated or partly unsaturated mono- or bicyclic ring system of 4 to 12 ring atoms, comprising 1, 2, or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Bicyclic means consisting of two cycles having one or two ring atoms in common. “Hetercycloylkyl” may comprise a carbonyl group, wherein the carbon is part of the ring system. The ring system can be attached to the remaining compound via an atom selected from C, N, S and O, in particular via a N atom (“N-heterocycloalkyl). Examples of “heterocycloalkyl” include, but are not limited to, morpholino, morpholin-4-yl, pyrrolidinyl, pyrrolidin-l-yl, pyrrolidin-3-yl, piperidyl, 1 -piperidyl, 3 -piperidyl, 4-piperidyl, 2-oxopyrrolidin-l-yl, piperazinyl, piperazin- 1-yl, azetidinyl, azetidin-1- 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[2.2.1]heptan-2-yl), 2-azabicyclo[2.2.0]hexan-2-yl, 4-oxa-7-azaspiro[2.5]octan-7-yl, (3-azabicyclo[3.1.0]hexan-3-yl), (6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-l-yl), 2-oxa-7- azaspiro[3.4]octan-7-yl, (2-oxo-l -piperidyl), (2,3-dihydropyridazino[4,5-b][l,4]oxazin-8-yl), pyrrolidin-l-yl, 2-oxo-pyrimidin-4-yl, morpholinoethyl, 2-oxa-5-azaspiro[3.4]octan-5-yl, oxetan- 3-yl, (2-oxo-l -piperidyl), 2-oxo-4-piperidyl, 5-oxo-pyrrolidin-3-yl, 2-oxa-5-azaspiro[3.4]octan- 5-yl, (7,8-dihydro-5H-pyrano[4,3-c]pyridazin-3-yl), [rac-(4aS,7aR)-4-methyl-2,3,4a,5,7,7a- hexahydropyrrolo[3,4-b][l,4]oxazin-6-yl], [rac-(3aS,6aS)-6-oxo-2,3,3a,4,5,6a- hexahydropyrrolo[2,3-c]pyrrol-l-yl] diazaspiroheptanyl and 2,6-diazaspiro[3.3]heptanyl. Particular examples of “heterocycloalkyl” are diazaspiroheptanyl, tetrahydrofuranyl, piperidinyl and oxetanyl, more particularly 2,6-diazaspiro[3.3]heptanyl, 6-tetrahydrofuran-3-yl, 4-piperidyl and oxetan-3-yl. In a particular embodiment, heterocycloalkyl is “N-heterocycloalkyl”.

The term “heteroaryl”, alone or in combination, signifies a fully aromatic or partially 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, benzotri azolyl, lH-benzotriazol-4-yl, furanyl, furyl, 2-furyl, 3-furyl, [6-oxo-lH-pyridazin-5-yl], triazolyl, triazol-l-yl, triazol-2-yl, 2-oxo-4- pyridyl. pyrimidin-2-yl, pyrimidin-5-yl, (l,3,4-oxadiazol-2-yl), (l,3,4-thiadiazol-2-yl), (1,2,4- triazin-3-yl), 2-oxo-pyrimidin-4-yl, (l-methyl-2-oxo-3-pyridyl), (2,3-dihydropyridazino[4,5- b][l,4]oxazin-8-yl), 1 -methyl -6-oxo-pyridazin-3-yl, 2,3-dihydropyridazino[4,5-b][l,4]oxazin-8- yl, 6-oxo-pyrrolo[2,3-c]pyridazin-3-yl, 5,7-dihydropyrrolo[3,4-c]pyridazin-3-yl, pyridazin-3-yl and 5,6-dihydropyrrolo[2,3-c]pyridazin-7-yl. Particular examples of “heteroaryl” are pyrazolyl and pyridazinyl, more particularly pyrazol-l-yl, pyrazol-4-yl and pyridazin-3-yl. In one particular embodiment, heteroaryl is “N-heteroaryl”.

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

The term “aryl”, alone or in combination, denotes a monovalent aromatic carbocyclic mono- or bicyclic ring system comprising 6 to 10 carbon ring atoms. Examples of aryl moi eties include phenyl and naphthyl. A particular example of “aryl” is phenyl.

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

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

The term “cyano”, alone or in combination, signifies carbon atom linked to a nitrogen atom via a triple bond; this group is also referred to as carbonitrile group.

The term “sulfonyl”, alone or in combination, denotes a -SO2- group.

In the present description the term “alkylsulfonyl”, alone or in combination, signifies a group of the formula alkyl-sulfonyl- in which the term “alkyl” has the previously given significae.

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

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 trifluoroethyl. 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. A particular “haloalkoxy” is difluoromethoxy.

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

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

The term “heterocycloalkylcarbonyl”, alone or in combination, signifies a” heterocycloalkyl” linked to a “carbonyl” group.

The term “heterocycloalkyloxy”, alone or in combination, signifies a “heterocycloalkyl” group linked to an “oxy” group.

The term “heterocycloalkylalkoxy”, alone or in combination, signifies a “heterocycloalkyl” group linked to an “alkoxy” group.

The term “heterocycloalkyalkoxy”, alone or in combination, signifies a “heterocycloalkyl” group linked to an “alkoxy” group.

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

The term “alkylamino”, alone or in combination, is an alkyl group linked to a -NH- group. The term “dialkylamino” denotes two alkyl groups linked to a -N- atom. An example of a” dialkylamino” group is for instance dimethylamino.

The term “dialkylaminocarbonylalkoxy”, alone or in combination, refers to a “dialkylamino” group linked to a “carbonyl” group, wherein the carbonyl group is further linked to an “alkoxy” group.

The term “alkylheteroarylamino”, alone or in combination, refers to an “alkyl” group linked to a “heteroaryl” group, wherein the heteroaryl is further linked to a “amino” group.

The terhm “cycloalkylcarbonyl”, alone or in combination, signifies a “cycloalkyl” group linked to a “carbonyl” group. Examples of cycloalkylcarbonyl include cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl and cyclohexyl carbonyl. The terhm “cycloalkylalkyl”, alone or in combination, denotes an “alkyl” group wherein at least one of the hydrogen atoms of the alkyl group is replaced by a “cycloalkyl” group. Examples of cycloalkylalkyl include cyclopropylmethyl, cyclopropylethyl, cyclobutylpropyl and cyclopentylbutyl.

The term “alkylcarbonyl”, alone or in combination, signifies an “alkyl” group linked to a “carbonyl” group. Examples of alkylcarbonyl are for instance methylcarbonyl, ethylcarbonyl and propylcarbonyl.

The term “alkylheteroaryl”, alone or in combination, denotes a “heteroaryl” wherein at least one of the hydrogen atoms of the heteroaryl group has been replaced by an alkyl group. Examples of alkylheteroaryl are for instance methylheteroaryl, ethylheteroaryl and propylheteroaryl.

The term “alkoxyalkyl”, alone or in combination, denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by an alkoxy group. Exemplary alkoxyalkyl groups include 2-methoxy ethyl, 3 -methoxypropyl, l-methyl-2-methoxy ethyl, l-(2- methoxyethyl)-3 -methoxypropyl, and 1 -(2-methoxyethyl)-3 -methoxypropyl .

The term “dialkylaminocarbonyl”, alone or in combination, denotes a “carbonyl” group linked to an “dialkylamino” group.

The term “alkoxycarbonyl”, alone or in combination, signifies an “alkoxy” group linked to a “carbonyl” group.

The term “alkylheterocycloalkyl”, alone or in combination, denotes a heterocycloalkyl group wherein one of the hydrogen atoms is replaced by an “alkyl” group. Examples of alkylheterocycloalkyl are for instance methylheterocycloalkyl, ethylheterocycloalkyl and propylheterocycloalkyl.

The term “alkylheterocycloalkyloxy”, alone or in combination, denotes an “oxy” group linked to a “heterocycloalkyl” group, wherein one of the hydrogen atoms of heterocycloalkyl has been replaced by an “alkyl” group.

The term “heterocycloalkylheterocycloalkyloxy”, alone or in combination denotes an “oxy” group linked to a “heterocycloalkyl” group, wherein one of the hydrogen atoms of “heterocycloalkyl” has been replaced by a further “heterocycloalkyl” group. The term “aminocarbonyl”, alone or in combination, signifies an “amino” group linked to a “carbonyl” group.

The term “dialkylaminocarbonylalkyl”, alone or in combination, denotes an “alkyl” group, wherein one of the hydrogen atoms of alkyl has been replaced by a dialkylamino group.

The term “hydroxyalkyl”, alone or in combination, denotes an “alkyl” group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a “hydroxy” group.

Examples of hydroxyalkyl include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl,

3-hydroxypropyl, l-(hydroxymethyl)-2-m ethylpropyl, 2-hydroxybutyl, 3 -hydroxybutyl,

4-hydroxybutyl, 2,3 -dihydroxypropyl, 2-hydroxy- 1 -hydroxymethyl ethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl or 2-(hydroxymethyl)-3 -hydroxypropyl.

The term “arylalkoxycarbonylaminoheterocycloalkyl”, alone or in combination, denotes a “heterocycloalkyl” group wherein a hydrogen atom of heterocycloalkyl has been replaced by a cabonylamino group linked to an “alkoxy” group, and wherein one of the hydrogen of alkoxy has been replaed by an “aryl” group.

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.

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.

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, 3^rd Ed., 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), carbobenzyloxy (Cbz) and p- methoxybenzyloxycarbonyl (Moz).

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.

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.

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). 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.

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.

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 are ²H, ³H, ¹³C, ¹⁴C and ¹⁸F. 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 a ¹³C- or ¹⁴C- enriched carbon are within the scope of this invention.

The invention thus relates to:

A compound according to the invention, wherein the compound is of formula (I) wherein

R¹ is haloalkoxy, heterocycloalkylcarbonyl, heteroaryl or heterocycloalkyl, wherein heterocycloalkyl carbonyl, heteroaryl and heterocycloalkyl are optionally substituted with 1, 2 or 3 substituents individually selected from R⁴; R² is hydrogen, alkoxy, alkyl, halogen, dialkylaminocarbonylalkoxy, heterocycloalkyl oxy, heterocycloalkyl alkoxy or alkylheteroarylamino;

R³ is hydrogen, cycloalkylcarbonyl, alkylcarbonyl, heterocycloalkylcarbonyl, heterocycloalkyl or heteroaryl; wherein heterocycloalkylcarbonyl, heterocycloalkyl and heteroaryl are optionally substituted with 1, 2 or 3 substituents individually selected from R⁵; or R² and R³ together with the carbon atoms to which they are attached to form a 4 to 6 membered heterocycloalkyl optionally substituted with alkylheteroaryl; each instance of R⁴ is individually selected from alkyl, cyano, halogen, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, dialkylaminocarbonyl, haloalkoxy and haloalkyl; each instance of R⁵ is individually selected from alkyl, alkoxycarbonyl, heterocycloalkyl, cycloalkyl, (hydroxyl)(alkyl)heterocycloalkyl, dialkylaminocarbonyl, heterocycloalkyl alkoxy, alkylheterocycloalkyl, alkylheterocycloalkyl oxy, heterocycloalkylheterocycloalkyloxy, (haloalkyl)(alkyl)aminocarbonyl, dialkylaminocarbonylalkyl, hydroxyalkyl and arylalkoxycarbonylaminoheterocycloalkyl;

A¹ is -N- or -CH-; and

L is absent, -O- or -NH-; or a pharmaceutically acceptable salt thereof;

A compound according to the invention, wherein R¹ is haloalkoxy, azetidinylcarbonyl, pyrazolyl, triazolyl or pyrrolidinyl, wherein azetidinylcarbonyl, pyrazolyl, triazolyl and pyrrolidinyl are optionally substituted with 1, 2 or 3 substituents individually selected from R⁴;

A compound according to the invention, wherein R¹ is haloalkoxy, azetidinylcarbonyl, pyrazolyl, triazolyl or pyrrolidinyl, wherein azetidinylcarbonyl, pyrazolyl, triazolyl and pyrrolidinyl are optionally substituted with 1 or 2 substituents individually selected from R⁴;

A compound according to the invention, wherein R¹ is haloalkoxy, azetidinylcarbonyl, pyrazolyl, triazolyl or pyrrolidinyl, wherein azetidinylcarbonyl, pyrazolyl, triazolyl and pyrrolidinyl are optionally substituted with a substituent selected from R⁴;

A compound according to the invention, wherein R¹ is pyrazolyl optionally substituted with 1, 2 or 3 substituents individually selected from R⁴; A compound according to the invention, wherein R¹ is pyrazolyl optionally substituted with a substituent selected from R⁴;

A compound according to the invention, wherein R² is hydrogen, alkoxy, alkyl, halogen, dialkylaminocarbonylalkoxy, oxetanyloxy, tetrahydropyranyl oxy, pyrrolidinyloxy, morpholinylalkoxy or alkylpyridazinylamino; or R² and R³, together with the carbon atoms to which they are attached to, form imidazolidin-2-one substituted with methylpyridazinyl;

A compound according to the invention, wherein R² is hydrogen, methoxy, methyl, fluoro, dimethylaminocarbonylethoxy, oxetanyloxy, tetrahydropyranyl oxy, pyrrolidinyloxy, morpholinylalkoxy or alkylpyridazinylamino; or R² and R³, together with the carbon atoms to which they are attached to, form imidazolidin-2-one substituted with methylpyridazinyl;

A compound according to the invention, wherein R² is hydrogen, alkoxy, alkyl, halogen, haloalkoxy, dialkylaminocarbonylalkoxy, oxetanyloxy, tetrahydropyranyl oxy, pyrrolidinyloxy, morpholinylalkoxy or alkylpyridazinylamino; or R² and R³, together with the carbon atoms to which they are attached to, form imidazolidin-2-one substituted with methylpyridazinyl;

A compound according to the invention, wherein R² is hydrogen, methoxy, methyl, fluoro, difluoromethoxy, dimethylaminocarbonylethoxy, oxetanyloxy, tetrahydropyranyl oxy, pyrrolidinyloxy, morpholinylalkoxy or alkylpyridazinylamino; or R² and R³, together with the carbon atoms to which they are attached to, form imidazolidin-2-one substituted with methylpyridazinyl;

A compound according to the invention, wherein R³ is hydrogen, cyclopropylcarbonyl, piperidinylcarbonyl, diazaspiroheptanyl, piperidyl, dihydro-5H-pyrano[4,3-c]pyridazinyl, 1- methyl-6-oxo-pyridazinyl, dihydropyridazino[4,5-b][l,4]oxazinyl, 6-oxo-pyrrolo[2,3- c]pyridazinyl, 5,7-dihydropyrrolo[3,4-c]pyridazinyl, pyridazinyl or 5,6-dihydropyrrolo[2,3- c]pyridazinyl; wherein piperidinylcarbonyl, diazaspiroheptanyl, piperidyl, dihydro-5H- pyrano[4,3-c]pyridazinyl, l-methyl-6-oxo-pyridazinyl, dihydropyridazino[4,5-b][l,4]oxazinyl, 6-oxo-pyrrolo[2,3-c]pyridazinyl, 5,7-dihydropyrrolo[3,4-c]pyridazinyl, pyridazinyl and 5,6- dihydropyrrolo[2,3-c]pyridazinyl are optionally substituted with 1, 2 or 3 substituents individually selected from R⁵, preferably with 1 or 2 substituents individually selected from R⁵;

A compound according to the invention, wherein R³ is hydrogen, cyclopropylcarbonyl, piperidinylcarbonyl, 2,6-diazaspiro[3.3]heptanyl, 4-piperidyl, 7,8-dihydro-5H-pyrano[4,3- c]pyridazin-3-yl, 1 -methyl -6-oxo-pyridazin-3-yl, 2,3-dihydropyridazino[4,5-b][l,4]oxazin-8-yl, 6-oxo-pyrrolo[2,3-c]pyridazin-3-yl, 5,7-dihydropyrrolo[3,4-c]pyridazin-3-yl, pyridazin-3-yl or 5,6-dihydropyrrolo[2,3-c]pyridazin-7-yl; wherein piperidinylcarbonyl, 2,6- diazaspiro[3.3]heptanyl, 4-piperidyl, 7,8-dihydro-5H-pyrano[4,3-c]pyridazin-3-yl, l-methyl-6- oxo-pyridazin-3-yl, 2,3-dihydropyridazino[4,5-b][l,4]oxazin-8-yl, 6-oxo-pyrrolo[2,3- c]pyridazin-3-yl, 5,7-dihydropyrrolo[3,4-c]pyridazin-3-yl, pyridazin-3-yl and 5,6- dihydropyrrolo[2,3-c]pyridazin-7-yl are optionally substituted with 1, 2 or 3 substituents individually selected from R⁵, preferably with 1 or 2 substituents individually selected from R⁵;

A compound according to the invention, wherein R³ is pyridazin-3-yl substituted with R⁵;

A compound according to the invention, wherein R⁴ is at each instance independently selected from cyano, methyl, amino, methylsulfonyl, fluoro, methoxyethyl, cyclopropylmethyl, dimethylaminocarbonyl, difluoromethoxy, (lR)-2,2-difluoro-l-methyl-ethoxy, difluoromethyl, trifluoromethyl and trifluoroethyl;

A compound according to the invention, wherein R⁴ is at each instance independently selected from cyano, methyl, fluoro, methoxyethyl, cyclopropylmethyl, dimethylaminocarbonyl, difluoromethoxy, (lR)-2,2-difluoro-l-methyl-ethoxy, difluoromethyl, trifluoromethyl and tri fluoroethyl;

A compound according to the invention, wherein R⁴ is amino or methyl sulfonyl.

A compound according to the invention, wherein R⁵ is at each instance independently selected from tert-butyl oxy carbonyl, methyl, ethyl, tetrahydrofuranyl, oxetanyl, 4-hydroxy-3 -methyl - tetrahydrofuranyl, dimethylaminocarbonyl, 5-[rac-(lS,5R)-3-oxa-6-azabicyclo[3.1.1]heptanyl, l-methyl-5-oxo-pyrrolidinyl, 2-morpholinoethoxy, (l-methyl-4-piperidyl)oxy, (3R)-l-methyl-2- oxo-pyrrolidinyl, (3 S)- 1 -methyl-2-oxo-pyrrolidinyl, 1 -(ox etan-3 -yl)-4-piperidyl]oxy, dimethylaminocarbonylmethyl, 5-(benzyloxycarbonylamino)-l,3-dioxan-2-yl, methyl(2,2,2- trifluoroethyl)carbamoyl and l-methylazetidin-3-yl;

A compound according to the invention, wherein R⁵ is at each instance independently selected from tert-butyl oxy carbonyl, methyl, ethyl, 6-tetrahydrofuran-3-yl, oxetan-3-yl, 4-hydroxy-3- m ethyl -tetrahydrofuran-3-yl, dimethylaminocarbonyl, 5-[rac-(l S,5R)-3-oxa-6- azabicyclo[3.1.1]heptan-6-yl, l-methyl-5-oxo-pyrrolidin-2-yl, 2-morpholinoethoxy, (1 -methyl - 4-piperidyl)oxy, (3R)-l-methyl-2-oxo-pyrrolidin-3-yl, (3 S)-l -methyl -2-oxo-pyrrolidin-3-yl, 1- (oxetan-3-yl)-4-piperidyl]oxy, dimethylaminocarbonylmethyl, 5-(benzyl oxycarbonylamino)- 1,3- dioxan-2-yl, methyl(2,2,2-trifluoroethyl)carbamoyl and l-methylazetidin-3-yl;

A compound according to the invention, wherein R⁵ is alkyl, in particular methyl;

A compound according to the invention, wherein A¹ is -CH-;

A compound according to the invention, wherein A¹ is -N-;

A compound according to the invention, wherein L is -NH-;

A compound according to the invention, wherein L is absent; and

A compound according to the invention, wherein L is -O-.

The invention further relates to a compound of formula (I) selected from l-[3-(difluoromethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]- 5-methyl-pyrazole-3-carbonitrile; l-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]- 5-methyl-pyrazole-3-carbonitrile; l-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-2-pyridyl]-N-(6- methylpyridazin-3-yl)-6-(2 -morpholinoethoxy )benzimidazol-5-amine; l-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(ox etan-3- yloxy)benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile;

1 -[5-(difluoromethyl)-6-[3-methyl-l -(2,2, 2-tri fluoroethyl )pyrazol-4-yl]-2-pyri dyl]-N-(6- methylpyridazin-3-yl)benzimidazol-5-amine;

3 -(difluoromethyl)- 1 - [3 -(difluoromethyl)-6- [6-m ethoxy-5 -[(6-methylpyridazin-3 - yl)amino]benzimidazol-l-yl]-2-pyridyl]-N,N,5-trimethyl-pyrazole-4-carboxamide;

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

6-[[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy- benzimidazol-5-yl]amino]-N,N-dimethyl-pyridazine-3-carboxamide;

3-[[l-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-5-(difluoromethyl)-2-pyridyl]-6- methoxy-benzimidazol-5-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide; l-[5-(difluoromethyl)-6-[5-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-N-(6- methylpyridazin-3-yl)benzimidazol-5-amine; l-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-2-pyridyl]-N-(6- methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine; l-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]- 5-fluoro-pyrazole-3-carbonitrile; l-[3-(difluoromethyl)-6-[5-[(6-keto-5,5,7-trimethyl-pyrrolo[2,3-c]pyridazin-3-yl)amino]-6- methoxy-benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[3-(difluoromethyl)-6-[5-[[6-(2-morpholinoethoxy)pyridazin-3-yl]amino]benzimidazol- l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[3-(difluoromethyl)-6-[5-(7,8-dihydro-5H-pyrano[4,3-c]pyridazin-3-ylamino)-6- methoxy-benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]-6-tetrahydropyran-4-yloxy- benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-5-(difluoromethyl)-2-pyridyl]-N-(6- methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine; l-[6-[3,5-bis(difluoromethyl)pyrazol-l-yl]-5-(difluoromethyl)-2-pyridyl]-N-(6- methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine;

(3R,5S)-l-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrrolidine-3-carbonitrile; l-[6-[5-[(7-cyclopropyl-6-keto-5,5-dimethyl-pyrrolo[2,3-c]pyridazin-3-yl)amino]-6- methoxy-benzimidazol-l-yl]-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile; l-[3-(difluoromethyl)-6-[5-[(6-keto-l -methyl -pyridazin-3-yl)amino]-6-methoxy- benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-[(l-methyl-4-piperidyl)oxy]pyridazin-3- yl]amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[5-(difluoromethyl)-6-[l-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-2-pyridyl]-N-(6- methylpyridazin-3-yl)benzimidazol-5-amine; l-[5-(difluoromethyl)-6-[l-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-2-pyridyl]-N-(6- methylpyridazin-3-yl)benzimidazol-5-amine; l-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-[[l-(oxetan-3-yl)-4-piperidyl]oxy]pyridazin-3- yl]amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[3-(difluoromethyl)-6-[6-methoxy-5-[(4-methyl-2,3-dihydropyridazino[4,5- b][l,4]oxazin-8-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[6-[l-(cyclopropylmethyl)-3 -methyl -pyrazol-4-yl]-5-(difluoromethyl)-2-pyridyl]-N-(6- methylpyridazin-3-yl)benzimidazol-5-amine;

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

N-[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2-pyridyl]benzimidazol-5- yl]cyclopropanecarboxamide; l-[6-[l-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(difluoromethyl)-2-pyridyl]-6- methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine;

3-(difluoromethoxy)-l-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-6,7-dihydropyrazolo[4,3-c]pyridin-4- one; 2-[3-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2-pyridyl]-6-[(6- methylpyridazin-3-yl)amino]benzimidazol-5-yl]oxy-N,N-dimethyl-acetamide; l-[5-(difluoromethyl)-6-[l-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-2-pyridyl]-6- methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; l-[5-(difluoromethyl)-6-[l-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-2-pyridyl]-6- methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; l-[5-(difluoromethyl)-6-[3-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-6- methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; l-[6-[l-(cyclopropylmethyl)-3 -methyl -pyrazol-4-yl]-5-(difluoromethyl)-2-pyridyl]-6- fluoro-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; l-[3-(difluoromethyl)-6-[6-fluoro-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[3-(difluoromethyl)-6-[6-methoxy-5-[[5-[(lS)-3-oxa-6-azabicyclo[3.1.1]heptan-6- yl]pyridazin-3-yl]amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile;

3-[[l-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-5-(difluoromethyl)-2-pyridyl]-6- methyl-benzimidazol-5-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide; l-[5-(difluoromethyl)-6-[(lR)-2,2-difluoro-l-methyl-ethoxy]-2-pyridyl]-N-(6- methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine; l-[5-(difluoromethyl)-6-[(lS)-2,2-difluoro-l-methyl-ethoxy]-2-pyridyl]-N-(6- methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine;

N-[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy- benzimidazol-5-yl]-l-(oxetan-3-yl)piperidine-4-carboxamide;

1-[5-(difluoromethyl)-6-[3-(trifluoromethyl)-5,7-dihydro-4H-pyrano[3,4-c]pyrazol-l-yl]-2- pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine;

2-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3- yloxy)benzimidazol-l-yl]-2-pyridyl]-3,5-dimethyl-4H-pyrrolo[3,4-c]pyrazol-6-one; l-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-(l-methyl-5-oxo-pyrrolidin-2-yl)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-(difluoromethyl)-2-pyridyl]-6-methoxy- benzimidazol-5-yl]amino]-N,N,5-trimethyl-pyridazine-4-carboxamide;

3-[[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy- benzimidazol-5-yl]amino]-N,N,5,6-tetramethyl-pyridazine-4-carboxamide;

3-[[l-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-5-(difluoromethyl)-2-pyridyl]-6- methoxy-benzimidazol-5-yl]amino]-N,6-dimethyl-N-(2,2,2-trifluoroethyl)pyridazine-4- carboxamide;

2-[6-[[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy- benzimidazol-5-yl]amino]pyridazin-3-yl]-N,N-dimethyl-acetamide; l-[3-(difluoromethyl)-6-[6-methoxy-5-(3-methyl-5-methylol-5,6-dihydropyrrolo[2,3- c]pyridazin-7-yl)benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[5-(difluoromethyl)-6-[2-methyl-5-(2,2,2-trifluoroethyl)-l,2,4-triazol-3-yl]-2-pyridyl]-6- methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; l-[3-(difluoromethyl)-6-(6-methoxybenzimidazol-l-yl)-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile; l-[5-(difluoromethyl)-6-[l-methyl-5-(2,2,2-trifluoroethyl)-l,2,4-triazol-3-yl]-2-pyridyl]-6- methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; l-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-[(3R)-l-methyl-2-oxo-pyrrolidin-3- yl]pyridazin-3-yl]amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-[(3S)-l -methyl -2-oxo-pyrrolidin-3-yl]pyridazin-

3-yl]amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; benzyl N-[2-[6-[[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2- pyridyl]benzimidazol-5-yl]amino]pyridazin-3-yl]-l,3-dioxan-5-yl]carbamate; l-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl]-2-pyridyl]-4,6-dihydrofuro[3,4-c]pyrazole-3-carbonitrile; l-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-2-pyridyl]-6-methoxy- N-[6-methyl-5-(l-methylazetidin-3-yl)pyridazin-3-yl]benzimidazol-5-amine; l-[3-(difluoromethyl)-6-[5-[(6-ethyl-5,7-dihydropyrrolo[3,4-c]pyridazin-3-yl)amino]-6- methoxy-benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile;

[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]- [2-(trifluoromethyl)azetidin-l-yl]methanone; l-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-2-pyridyl]-N-(6- methylpyridazin-3-yl)-6-pyrrolidin-3-yloxy-benzimidazol-5-amine; l-[3-(difluoromethyl)-6-[3-(6-methylpyridazin-3-yl)-2-oxo-lH-imidazo[4,5- f]benzimidazol-7-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[3-(difluoromethyl)-6-[l-(6-methylpyridazin-3-yl)-2-oxo-3H-imidazo[4,5- f]benzimidazol-7-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile;

6-[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy- benzimidazol-5-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester; l-[6-[5-(2,6-diazaspiro[3.3]heptan-2-yl)-6-methoxy-benzimidazol-l-yl]-3- (difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[5-(difluoromethyl)-6-[l-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]-2-pyridyl]-6-methoxy-N- (6-methylpyridazin-3-yl)benzimidazol-5-amine; l-[3-(difluoromethyl)-6-[5-[[l-[(3R,4R)-4-hydroxy-3-methyl-tetrahydrofuran-3-yl]-4- piperidyl]amino]-6-methoxy-benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile; l-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl]pyrazin-2-yl]-5-methyl-pyrazole-3-carbonitrile;

(3-aminoazetidin-l-yl)-[6-[6-(difluoromethoxy)-5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-(difluoromethyl)-2-pyridyl]methanone;

[6-[6-(difluoromethoxy)-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-

(difluoromethyl)-2-pyridyl]-[2-(trifluoromethyl)azetidin-l-yl]methanone; [6-[6-(difluoromethoxy)-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3- (difluoromethyl)-2-pyridyl]-[(2S,4S)-2,4-dimethylazetidin-l-yl]methanone;

(3-aminoazetidin-l-yl)-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]methanone;

[l-[5-(difluoromethyl)-6-(l-mesyl-3-piperidyl)-2-pyridyl]benzimidazol-5-yl]-(6- methylpyridazin-3-yl)amine; and

2-azabicyclo[2.2.0]hexan-2-yl-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]methanone; or a pharmaceutically acceptable salt thereof.

1 -[5-(difluoromethyl)-6-[3-methyl-l -(2, 2, 2-tri fluoroethyl )pyrazol-4-yl]-2-pyridyl]-N-(6- methylpyridazin-3-yl)benzimidazol-5-amine;

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

N-[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2-pyridyl]benzimidazol-5- yl]cyclopropanecarboxamide; l-[6-[l-(cyclopropylmethyl)-3 -methyl -pyrazol-4-yl]-5-(difluoromethyl)-2-pyridyl]-6- methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine;

6-[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy- benzimidazol-5-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester; l-[6-[5-(2,6-diazaspiro[3.3]heptan-2-yl)-6-methoxy-benzimidazol-l-yl]-3- (difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[5-(difluoromethyl)-6-[l-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]-2-pyridyl]-6-methoxy-N- (6-methylpyridazin-3-yl)benzimidazol-5-amine; l-[3-(difluoromethyl)-6-[5-[[l-[(3R,4R)-4-hydroxy-3-methyl-tetrahydrofuran-3-yl]-4- piperidyl]amino]-6-methoxy-benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile; and l-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl]pyrazin-2-yl]-5-methyl-pyrazole-3-carbonitrile; or a pharmaceutically acceptable salt thereof.

The invention further relates in particular to a compound of formula (I) selected from l-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]- 5-methyl-pyrazole-3-carbonitrile; l-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3- yloxy)benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[3-(difluoromethyl)-6-[5-(7,8-dihydro-5H-pyrano[4,3-c]pyridazin-3-ylamino)-6- methoxy-benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[6-[l-(cyclopropylmethyl)-3 -methyl -pyrazol-4-yl]-5-(difluoromethyl)-2-pyridyl]-6- methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine;

1 -[5-(difluoromethyl)-6-[3-methyl-l -(2, 2, 2-tri fluoroethyl )pyrazol-4-yl]-2-pyridyl]-6- methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; l-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-2-pyridyl]-6-methoxy- N-[6-methyl-5-(l-methylazetidin-3-yl)pyridazin-3-yl]benzimidazol-5-amine; and l-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl]pyrazin-2-yl]-5-methyl-pyrazole-3-carbonitrile; or a pharmaceutically acceptable salt thereof.

The invention further relates in particular to a compound of formula (I) selected from

[6-[6-(difluoromethoxy)-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3- (difluoromethyl)-2-pyridyl]-[2-(trifluoromethyl)azetidin-l-yl]methanone;

[6-[6-(difluoromethoxy)-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3- (difluoromethyl)-2-pyridyl]-[(2S,4S)-2,4-dimethylazetidin-l-yl]methanone;

(3-aminoazetidin-l-yl)-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]methanone; [l-[5-(difluoromethyl)-6-(l-mesyl-3-piperidyl)-2-pyridyl]benzimidazol-5-yl]-(6- methylpyridazin-3-yl)amine; and

One embodiment of the invention relates to a compound according to the invention, wherein the compound is a compound of formula (Ila) wherein A¹, L, R² and R³ are as described herein; and R⁴ is selected from cyano, haloalkyl and haloalkoxy, in particular cyano and difluoromethyl.

One embodiment of the invention relates to a compound according to the invention, wherein the compound is a compound of formula (lib) wherein L, R² and R³ are as described herein; and R⁴ is selected from cycloalkylalkyl and haloalkyl, in particular cyclopropylmethyl and trifluoroethyl.

One embodiment of the invention relates to a compound according to the invention, wherein the compound is a compound of formula (III) wherein A¹, L, R¹, R², R⁴ and R⁵ are as described herein; and R⁶ is at each instance individually selected from alkyl and alkylazetidinyl, in particular methyl and l-methylazetidin-3-yl; or two R⁶ groups together with the carbon they are attached to form a 5 to 7 membered heterocyl cloalkyl.

General synthetic schemes

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.

Scheme 1

In scheme 1, the synthesis of a compound of formula (I-a) or (I-a’) is described. The compound of formula (I-a) is a compound of formula (I), wherein A¹ is C; R¹ is pyrazol optionally substituted with R⁴, R⁴’ and R⁴”; R² is selected from hydrogen, alkoxy, alkyl, halogen, dialkylaminocarbonylalkoxy, heterocycloalkyloxy, heterocycloalkylalkoxy and alkylheteroaryl amino; R³ is methylpyridazinyl; L is -NH-; R⁴ and R⁴” are independently selected from alkyl, cyano, halogen, alkoxyalkyl, cycloalkylalkyl, haloalkoxy and haloalkyl; R4’ is hydrogen or dialkylaminocarbonyl. The compound of formula (I-a’) is a compound of formula (I), wherein A¹ is C; R¹ is pyrazol optionally substituted with R⁴, R⁴’ and R⁴”; R² is methylpyridazinylamino; L is absent; R³ is selected from hydrogen, alkoxy, alkyl, halogen, dialkylaminocarbonylalkoxy, heterocycloalkyloxy, heterocycloalkylalkoxy and alkylheteroaryl amino; R⁴ and R⁴” are independently selected from alkyl, cyano, halogen, alkoxyalkyl, cycloalkylalkyl, haloalkoxy and haloalkyl; R⁴’ is hydrogen or dialkylaminocarbonyl. In the scheme below R2/R3 means that the group is selected from hydrogen, alkoxy, alkyl, halogen, dialkylaminocarbonylalkoxy, heterocycloalkyloxy, heterocycloalkylalkoxy and alkylheteroarylamino.

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 DMF at temperatures from about -78 °C to about 25°C to yield intermediate 2.

Step B: 6-chloro-2-fluoro-pyridine-3-carbaldehyde 2 can be reacted with a substituted pyrazole 3 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 4.

Step C: Intermediate 4 can be reacted with a fluorinated reagent, such as for instance DAST, in a suitable solvent, such as for instance DCM or ACN at temperatures ranging from about -30 °C and about 30 °C to yield intermediate 5. Step D: Intermediates 5 and 6 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 7 and 7’ which can be separated by flash column chromatography or preparative HPLC or preparative TLC or reacted in the next step as a regioisomeric mixture.

Step E: Introduction of the aminopyridazine 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 tBuXPhos Pd G3 or [tBuBrettPhos Pd(allyl)]OTf, in a suitable solvent (such as for instance 1,4-di oxane), at a temperature ranging from around 80 °C to around 100 °C to yield compounds I-a and I-a’ which can be separated by flash column chromatography or preparative HPLC or preparative TLC.

Scheme 2

In scheme 2, the synthesis of a compound of formula 6 is described wherein A is alkyl, dialkylaminoalkyl, heteroaryl or heterocycloalkyl; wherein heteroaryl and heterocycloalkyl are optionally substituted with 1, 2 or 3 substituents individually selected from R5.

Step A: (4-bromo-5-fluoro-2-nitro-phenyl)amine 8 and alcohol 9 can be reacted in the presence of a suitable organic or mineral base (such as for instance NaH, CS2CO3 or DBU), in a suitable solvent (such as THF, MeTHF or dioxane), at temperatures ranging from about -10 °C to about 120 °C to yield the intermediate 10.

Step B: The nitro group of intermediate 10 can be reduced in the presence of a metallic reducing agent (such as for instance Zn or Fe), an acid (such as for instance AcOH or HC1) in a suitable polar protic solvent (such as for instance MeOH or EtOH) at temperatures ranging from about -10 °C and about 120 °C to yield the diamino intermediate 11. Alternatively, the nitro group of intermediate 10 can be reduced in the presence of hydrogen gas, in the presence of a catalyst (such as for instance Pd on charcoal), in a suitable polar protic solvent (such as for instance MeOH or EtOH), at a temperature ranging from about -10 °C to about 65 °C to yield the diamino intermediate 11. Step C: The diamino intermediate 11 can be cyclized in the presence of orthoformate (such as for instance trimethylorthoformate of triethylorthoformate) which can be used as the reaction solvent at temperatures between about 50 °C and about 100 °C to yield the benzimidazol intermediate 6.

Scheme 3 In scheme 3, the synthesis of a compound of formula (I-b) or (I-b’) is described. The compound of formula (I-b) is a compound of formula (I), wherein A¹ is C; R¹ is pyrazol substituted with methyl and R⁴’; R² is selected from hydrogen, alkoxy and halogen; R³ is methylpyridazinyl; L is -NH-; R⁴’ is 1,1,1 -trifluoroethyl, methoxyethyl or cyclopropylmethyl. The compound of formula (I-b’) is a compound of formula (I), wherein A¹ is C; R¹ is pyrazol substituted with methyl and R⁴’; R² is methylpyridazinylamino, R³ is selected from hydrogen, alkoxy and halogen; L is absent; R⁴’ is 1,1,1 -trifluoroethyl, methoxyethyl or cyclopropylmethyl. In the scheme below R2/R3 means that the group is selected from hydrogen, alkoxy and halogen.

Step A: 2,6-dichloronicotinaldehyde 12 and ethane- 1,2-diol can be reacted in the presence of a suitable organic or mineral acid (such as for instance pTSOH), in a suitable solvent (such as toluene), at temperatures between about 80 °C and about 110 °C (reflux) with continuous water removal using a Dean-Stark apparatus to yield the intermediate 13.

Step B: Intermediates 13 and 14 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 ⁰ to about 120 °C to yield the regioisomeric compounds 15 and 15’ which can be separated by flash column chromatography or preparative HPLC or preparative TLC or reacted in the next step as a regioisomeric mixture. Step C: A Palladium-catalyzed cross-coupling reaction ( Suzuki -Miy aura) between intermediate 15 and the corresponding heteroaryl pinacol borane 16, a Pd catalyst (such as for instance P(Ph3)4 or Pd(dppf)C12 CH2C12 or other suitable Pd catalysts) and a suitable base such as for instance K3PO4, CS2CO3, K2CO3, ISfeCCh) in a suitable solvent (such as for instance 1,4- dioxane or a mixture of 1,4-dioxane and water) while heating (e.g. at a temperature between about 80 °C to about 110 °C or via microwave irradiation at a temperature between about 80 °C to about 120 °C) yields the regioisomeric compounds 17 and 17’ which can be separated by flash column chromatography or preparative HPLC or preparative TLC or reacted in the next step as a regioisomeric mixture.

Step D: Intermediates 17 can be deprotected using an acid (such as for instance HC1) in a suitable solvent (such as for instance dioxane, THF, MeTHF), at a temperature between about 0 °C to about 50 °C to yield the regioisomeric compounds 18 and 18’ which can be separated by flash column chromatography or preparative HPLC or preparative TLC or reacted in the next step as a regioisomeric mixture.

Step E: Intermediate 18 can be reacted with a fluorinating reagent (such as for instance DAST), in a suitable solvent (such as for instance DCM) at temperatures ranging from about -30 °C to about 30 °C to yield the compound of formula I-b or I-b’ which can be purified by flash column chromatography or preparative HPLC or preparative TLC.

Scheme 4

In scheme 3, the synthesis of a compound of formula (I-c) is described. The compound of formula (I-c) is a compound of formula (I), wherein A¹ is NH; L is -NH-; R¹ is pyrazol substituted with cyano and methyl; R² is alkoxy; R³ is methylpyridazinyl.

Step A: 3,5-dichloropyrazine-2-carbaldehyde 18 can be reacted with a fluorinating reagent (such as for instance DAST), in a suitable solvent (such as for instance DCM) at temperatures ranging from about -30 °C to about 30 °C to yield the compound of formula 20. Step B: Intermediates 20 and 14 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 compound 21 which can be purified by flash column chromatography or preparative HPLC or preparative TLC. Step C: Intermediates 21 and 22 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 ⁰ to about 120 °C to yield the compound of formula (I-c) which can be purified by flash column chromatography or preparative HPLC or preparative TLC. The invention thus also relates to a process for the preparation of a compound according to the invention, comprising one of the following steps:

(a) the reaction of a compound of formula (Bl) or (B2) with a compound of formula (B3) in presence or a suitable solvent and in presence of a suitable base;

(b) the reaction of a compound of formula (Cl) with a deoxofluorination agent in presence of a suitable solvent; or

(c) the reaction of a compound of formula (DI) with a compound of formula (D2) in presence of a suitable solvent and in presence of a suitable base; wherein X is halogen, OMs or OTs, in particular halogen; L, R¹, R², R³, R⁴ and R⁵ are as described herein;

In step (a), the solvent can be for example toluene, xylene, 1,4-di oxane or a mixture thereof, in particular 1,4-di oxane;

In step (a), the base can be for example CS2CO3, K2CO3 or K3PO4, in particular K3PO4;

In step (a), the catalyst can be a Pd catalyst, such as for instance tBuXPhos Pd G3 or [tBuBrettPhos Pd(allyl)]OTf;

Conveniently, the reaction of step (a) is performed at a temperature from about 50 °C to about 120 °C, in particular from about 70 °C to about 110 °C, more particular from about 80 °C to about 100 °C;

Conveniently, the reaction of step (a) is performed during about 1 hour to about 48 hours, in particular from about 2 hours to about 24 hours, more particular from about 4 hours to about 18 hours or from about 4 to about 16 hours;

Conveniently, the reaction of step (a) is performed in presence of 1,4-di oxane, K3PO4 and tBuXPhos Pd G3, at a temperature from about 70 °C to about 110 °C;

Conveniently, the reaction of step (a) is performed in presence of 1,4-di oxane, CS2CO3 and [tBuBrettPhos Pd(allyl)]OTf, at a temperature from about 70 °C to about 110 °C;

In step (b), the solvent can be for example dichloromethane or diethyl ether, in particular di chloromethane;

In step (b), the deoxofluorination agent can be for example DAST, cesium fluoride, Deoxo-Fluor, or MOST, in particular DAST; Conveniently, the reaction of step (b) is performed at a temperature from about -30 °C to about 30 °C, in particular from about 0 °C to about 30 °C, more particular from about 0 °C to room temperature;

Conveniently, the reaction of step (b) is performed during about 30 minutes to about 48 hours, in particular from about 1 hour to about 24 hours, more particular from about 2 hours to 12 hours;

Conveniently, the reaction of step (b) is performed in presence of dichloromethane, in presence of D AST, at a temperature from about -30 °C to about 30 °C;

In step (c), the solvent can be a polar solvent such as for instance DMF, DMA, NMP, DMSO, THF or 2-MeTHF, in particular DMSO;

In step (c), the base can be an organic or mineral base such as for instance DIPEA, DBU, K2CO3, CS2CO3 or NaH, in particular DIPEA;

Conveniently, the reaction of step (b) is performed at a temperature from about 60 °C to about 140 °C, in particular from about 70 °C to about 130 °C, more particular from about 80 °C to about 120 °C;

Conveniently, the reaction of step (c) is performed during about 1 hour to about 48 hours, in particular from about 3 hour to about 30 hours, more particular from about 3 hours to 18 hours;

Conveniently, the reaction of step (c) is performed in presence of DMSO, in presence of DIPEA, at a temperature from about 80 °C to about 120 °C.

The invention also relates in particular to:

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

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

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);

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

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.

Pharmaceutical Compositions

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.

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.

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.

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.

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). The invention will now be illustrated by the following examples which have no limiting character.

Examples

Abbreviations

2-MeTHF 2-Methyltetrahydrofuran

ACN acetonitrile

ATP adenosine triphosphate aq. aqueous

BINAP [2,2'-bis(diphenylphosphino)-l, 1 '-binaphthyl]

Boc tert-butyl oxy carb onyl

Boc(2)O di-tert-butyl dicarbonate

BrettPhos Pd G4 dicyclohexyl-[3,6-dimethoxy-2-[2,4,6-tri(propan-2- yl)phenyl]phenyl]phosphane;methanesulfonic acid;N-methyl-2- phenylaniline;palladium (CAS# 1599466-83-7)

CAS chemical abstracts service

CDI carbonyldiimidazole

CH₃CN acetonitrile

CO carbon monoxide

Cs₂CO₃ cesium carbonate

DAST diethylaminosulfur trifluoride dba dibenzilideneacetone

DBU l,8-Diazabicyclo(5.4.0)undec-7-ene

DCE 1 ,2-di chloroethane

DCM dichloromethane

DIPEA A,A-diisopropylethylamine

DMF N,N -dimethylformamide DMSO dimethyl sulfoxide dppf 1,1’ -ferrocenediyl -bis(diphenylphosphine) eq. equivalents ESI electrospray ionization Et₂O diethyl ether

Et₃N triethylamine

EtOAc ethyl acetate

EtOH ethanol

FA formic acid

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

Z>]pyridinium 3 -oxide hexafluorophosphate

HC1 hydrogen chloride

HPLC high pressure liquid chromatography iPrOH isopropyl alcohol

K3PO4 tripotassium phosphate

KOH potassium hydroxide

LC-MS high-performance liquid chromatography - mass spectrometry

LiOH lithium hydroxide

MeOH methanol

MOST morpholinosulfur trifluoride

MsCl methanesulfonyl chloride

MTBE methyl tert-butyl ether

N₂ nitrogen

NaH sodium hydride

NBS N-bromosuccinimide NH₄OH ammonium hydroxide

NMP N-methylpyrrolidone

NMR nuclear magnetic resonance

NPLC normal phase liquid chromatography

OMs O-mesylate

OTs O-tosylate

Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0)

PdCh(dppp) (l,3-bis(diphenylphosphino)propane)palladium(II) chloride (CAS# 59831-02-6)

PE petroleum ether psi pounds per square inch

QphosPd(crotyl)Cl chloro(crotyl)[l,2,3,4,5-pentaphenyl-l'-(di-tert- butylphosphino)ferrocene]palladium(II) (CAS# 1252598-33-6)

QToF quadruploe time of flight

RT room temperature

RuPhos Pd G4 methanesulfonato(2-dicyclohexylphosphino-2',6'-di-i-propoxy- 1,1'- biphenyl)(2'-m ethylamino- l,l'-biphenyl-2-yl)palladium(II) (CAS# 1599466-85-9) sat. saturated

SEM-C1 2-(trimethylsilyl)ethoxymethyl chloride sol. solution

Sphos Pd G3 (2-Dicyclohexylphosphino-2 ',6 '-dimethoxybiphenyl) [2-(2'-amino- l,l '-biphenyl)]palladium(II) methanesulfonate (CAS# 1445085- 82-4)

TBAF terabutyl ammonium fluoride

TBTU 2-( IH-benzotri azole- 1 -yl)- 1 , 1 ,3 ,3 -tetramethylaminium tBuBrettPhos 2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-l,l'- biphenyl (CAS# 1160861-53-9)

[tBuBrettPhos Pd(allyl)]Otf allyl(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl- 1 '-biphenyl )palladium(II)triflate (CAS# 1798782-15-6) tBuXPhos Pd G3 [(2-Di-tert-butylphosphino-2 ’ ,4 ’ ,6 ’ -tri i sopropyl- 1,1’ -biphenyl)-2-

(2’ -amino- 1,1 ’ -biphenyl)] palladium(II) methanesulfonate (CAS

# 1447963-75-8)

TEA triethylamine

Tf triflyl

TFA trifluoroacetic acid

TFAA trifluoroacetic anhydride

THF tetrahydrofuran

TLC thin layer chromatography

TMSC1 trimethyl silyl chloride

TMSCN trimethyl silyl cyanide

Ts tosyl

TsOH tosylic acid

Xantphos (9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane)

XantPhos Pd G4 (6-diphenylphosphanyl- 10H-phenoxazin-4-yl)- diphenylphosphane;methanesulfonic acid;N-methyl-2- phenylaniline;palladium (CAS# 1621274-19-8)

Xphos 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl Example 1 l-[3-(difluoromethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-

2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

Step 1: 6-chloro-2-fluoro-nicotinaldehyde

To a solution of diisopropylamine (16.7 g, 23.6 mL, 165.4 mmol, 1.45 eq.) in THF (110 mL) was added 1.6 M BuLi (92.7 mL, 148.2 mmol, 1.3 eq.) at -78 °C over 20 minutes. The solution was cooled to -20 °C and than recooled to -78 °C. A solution of 2-chloro-6-fluoro-pyridine (15 g, 114.0 mmol, 1.0 eq.) in THF (220 mL) was added dropwise over 30 min at -78°C. The reaction mixture was stired at -78 °C for 1 hour. DMF (10.0 g, 10.6 mL, 136.8 mmol, 1.2 eq.) was added dropwise at -78 °C over 10 minutes. After 20 minutes stirring at -78 °C, 4M HC1 in 1,4-di oxane (150ml) was added until pH 1 was reached. The reaction mixture was poured into 400 mL of H2O. The layers were separated and the aqeous layer was washed wiht EtOAc. The organic layers were washed with H2O, dried over with MgSCU, filtered and concentrated in vacuo. The residue was purified by flash column chromatography using EtOAc in heptane (0% to 100%) as an eluent to yield 6-chloro-2-fluoro-nicotinaldehyde (14.6 g, 80.0%) as light yellow solid. LC-ms: m/z = 156.06 [M+H]⁺, ESI pos.

Step 2: l-(6-chloro-3-formyl-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile

Under argon, 6-chloro-2-fluoro-nicotinaldehyde (1.0 g, 6.27 mmol, 1.0 eq.) was dissolved in DMF (10 mL). 5-methyl-lH-pyrazole-3-carbonitrile (738.5 mg, 6.9 mmol, 1.1 eq.) and K2CO3 (1.0 g, 7.5 mmol, 1.2 eq.) were added. The reaction mixture was stirred at RT over 1 hour. The reaction mixture was partitionned between sat. aq. NH4CI solution and EtOAc; the product was extracted and the organic layer was dried over Na2SO4 and the volatiles removed in vacuo. The crude was triturated with EtOAc and a few drops of MeOH, filtered off and washed with ether, The solid was then dried under high vacuum to yield l-(6-chloro-3-formyl-2-pyridyl)-5-methyl- pyrazole-3 -carbonitrile (590 mg, 22.9%) as off-white solid. Flash column chromatography of the mother liquors using 0 - 30 % EtOAc in heptane yielded a second crop of l-(6-chloro-3-formyl- - M -

2-pyridyl)-5-methyl-pyrazole-3-carbonitrile (590 mg, 22.9%) as off-white solid. LC-MS: m/z = 247.0 [M+H]⁺, ESI pos.

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

Under argon, l-(6-chloro-3-formyl-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile (620 mg, 2.5 mmol, 1.0 eq.) was dissolved in DCM (11.8 mL). At 0 °C DAST (486.2 mg, 398.5 pL, 3.0 mmol, 1.2 eq.) was added and the reaction mixture was stirred at RT over 30 minutes. The reaction mixture was partitionned between NaHCO, solution and DCM, extracted and the organic layer was dried over ISfeSCU; filtered and concentrated in vacuo. The crude was purified by flash column chromatography using 0 - 20% EtOAc as an eluent to yield l-[6-chloro-3- (difhioromethyl)-2-pyridyl] -5 -methyl-pyrazole-3 -carbonitrile (597 mg, 88.4%) as white solid. LC-MS: m/z = 269.0 [M+H]⁺, ESI pos.

Step 4: l-[ 6-(5-bromobenzimidazol-l-yl)-3-(dijluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile

Under argon, l-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (820 mg, 3.1 mmol, 1.0 eq.) was dissolved in DMSO (23.4 mL). 5-bromo-lH-benzimidazole (661.5 mg, 3.4 mmol, 1.1 eq.) and DBU (511.2 mg, 506.1 pL, 3.36 mmol, 1.1 eq.) were added and the reaction mixture was stirred at 80 °C over 3 hours. The reaction was cooled to RT and partitionned between H2O and EtOAc. The product was extracted with EtOAc and the organic layers were dried over Na2SO4 and concentrated in vacuo. The crude was purified by flash column chromatography using 0 - 4% MeOH in DCM as eluent. A second flash column chromatography using 0 - 10% EtOAc in DCM allowed to separate the two regioisomeric products yielding l-[6-(5-bromobenzimidazol-l-yl)-3-(difluoromethyl)-2-pyridyl]-5-methyl- pyrazole-3 -carbonitrile (525 mg, 38.1%) and l-[6-(6-bromobenzimidazol-l-yl)-3- (difluoromethyl)-2-pyridyl] -5 -methyl-pyrazole-3 -carbonitrile (497 mg, 36.0%) as white solids. LC-MS: m/z = 429.02 = [M+H]⁺, ESI pos.

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

Under argon, l-[6-(5-bromobenzimidazol-l-yl)-3-(difluoromethyl)-2-pyridyl]-5-methyl- pyrazole-3 -carbonitrile (100 mg, 0.23 mmol, 1.0 eq.) was suspended in 1,4-dioxane (3 mL). (6- methylpyridazin-3-yl)amine (50.9 mg, 0.47 mmol, 2.0 eq.) and CS2CO3 (227.7 mg, 0.70 mmol, 3.0 eq.) were added. The reaction mixture was degassed with argon, then ['BuBrettPhos Pd(allyl)]OTf (18.2 mg, 0.023 mmol, 0.1 eq.) was added and the reaction mixture was stirred at 80 °C over 2 hours. Further ['BuBrettPhos Pd(allyl)]OTf (18.2 mg, 0.023 mmol, 0.1 eq.) was added and the reaction mixture was stirred at 80 °C over one more hour to give full completion. The solvent was evaporated and the crude was purified by flash column chromatography using 0 - 5% MeOH in DCM as an eluent. Further purification by reversed phase chromatography using formic acid yielded l-[3-(difluoromethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; formic acid (25.0 mg, 21.3%) as an off-white lyophilized powder. LC-MS : m/z = 458.2 [M+H]⁺, ESI pos. l-[3-(difhioromethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile; formic acid (15 mg, 12.8%) was also isolated as an off-white lyophilized powder. LC-MS : m/z = 458.2 [M+H]⁺, ESI pos.

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

Step 1: 4-bromo-5-methoxy-2-nitro-aniline

To a yellow suspension of 5-methoxy-2-nitroaniline (49.7 g, 295.6 mmol, 1.0 eq.) in CH3CN (750 mL) was added NBS (57.9 g, 325.2 mmol, 1.1 eq.) in portions. The mixture was stirred at 20 °C for 2 hours. The reaction mixture was poured into a sat. aqueous Na2SCh solution (1 L) under stirring which was subsequently diluted with 2 L of H2O. A yellow solid precipitate. The suspension was then filtered and the filter cake was concentrated under reduced pressure to give the crude. The crude was triturated in MTBE (100 mL) and the resulting suspension was stirred for 30 minutes. The solid was collected by filtration and dried under reduced pressure to yield 4- bromo-5-methoxy-2-nitro-aniline (70.0 g, 95.5%) as a yellow solid. LC-MS: m/z = 247.0/249.0 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 8 = 8.37 (s, 1H), 6.26 (br s, 2H), 6.19 (s, 1H), 3.94 (s, 3H).

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

To a yellow solution of 4-bromo-5-methoxy-2 -nitro-aniline (60.0 g, 242.87 mmol, 1.0 eq.) in THF (1.2 L) and MeOH (600 mL) was added NH4CI (155.9 g, 2.9 mol, 12.0 eq.). The flask was purged with N2. To the mixture was added zinc (111.2 g, 1.7 mol, 7.0 eq.) in portions at 20 °C. After 2 hours stirring at 20 °C for 2 hours, the suspension was filtered and the mother liquid was concentrated to give 4-bromo-5-methoxy-benzene-l,2-diamine (50.0 g, 94.9%) as a dark green solid. (The filter cake was dissolved in 2 L of 2N HC1 and stirred overnight to deactivate the residual zinc powder before discarding.) LC-MS: m/z = 216.8/218.8 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 6 = 6.91 (s, 1H), 6.37 (s, 1H), 3.82 (s, 3H), 3.42 - 3.05 (m, 4H). Step 3: 5-bromo-6-methoxy-lH-benzimidazole

4-Bromo-5-m ethoxy-benzene- 1,2-diamine (8.0 g, 36.86 mmol, 1.0 eq.) was dissolved in trimethyl orthoformate (39.1 g, 368.6 mmol, 10.0 eq.). Formic acid (6.95 mL, 184.3 mmol, 5.0 eq.) was added to the solution. The dark green solution was stirred at 90 °C for 2 hours. The mixture was then quenched with sat. aq. NaHCOs solution (300 mL) and extracted with EtOAc. The combined organic layers were dried over ISfeSCU, filtered and concentrated under reduced pressure to give the crude. The crude was purified by preparative HPLC (Phenomenex Luna Cl 8 (250 mm x 70 mm, 10 pm), 10 - 30% CFECN in FEO (with 0.225% HCOOH) over 15 minutes, flow rate: 140 mL/min) to yield 5-bromo-6-methoxy-lH-benzimidazole (6.7 g, 72.1%) as a yellow solid. LC-MS: 227.0/229.0 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 8 = 8.05 (s, 1H), 7.89 (s, 1H), 7.20 (s, 1H), 3.97 (s, 3H).

Step 4: l-[ 6-(5-bromo-6-methoxy-benzimidazol-l-yl)-3-(difluoromethyl)-2-pyridyl]-5-methyl- pyrazole-3-carbonitrile

To a solution of l-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (300.0 mg, 1.1 mmol, 1.0 eq.) in DMSO (10 mL) was added 5-bromo-6-methoxy-lH- benzimidazole (278.9 mg, 1.2 mmol, 1.1 eq.) and DIPEA (0.55 mL, 3.35 mmol, 3.0 eq.). The reaction mixture was stirred at 120 °C for 30 hours. The reaction was diluted with H2O and with EtOAc. The organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The residue was purified by flash column chromatography using 40% - 60% EtOAc in PE as eluent to yield l-[6-(6-bromo-5-methoxy-benzimidazol-l-yl)-3- (difluoromethyl)-2-pyridyl] -5 -methyl-pyrazole-3 -carbonitrile (110.0 mg, 21.5%) as well as l-[6- (5-bromo-6-m ethoxy -benzimidazol-l-yl)-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile (140.0 mg, 27.3%). l-[6-(6-bromo-5-methoxy-benzimidazol-l-yl)-3-(difluoromethyl)-2-pyridyl]-5-methyl- pyrazole-3-carbonitrile: LC-MS: m/z = 458.8 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 6 = 8.40 (s, 1 H), 8.00 (s, 1 H), 7.71 (d, J= 8.50 Hz, 1 H), 7.53 (s, 1 H), 7.26-6.98 (m, 1 H), 6.63 (d, J= 0.75 Hz, 1 H), 3.83 (s, 3 H), 2.47 (d, J= 0.63 Hz, 3 H). l-[6-(5-bromo-6-methoxy-benzimidazol-l-yl)-3-(difluoromethyl)-2-pyridyl]-5-methyl- pyrazole-3-carbonitrile: LC-MS: m/z = 458.8 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 6 = 8.49 (s, 1 H), 8.37 (d, J= 8.50 Hz, 1 H) 8.21 (s, 1 H), 7.70 (d, J= 8.50 Hz, 1 H), 7.32 (s, 1 H), 7.27-6.99 (m, 1 H), 6.64 (d, J= 0.75 Hz, 1 H), 3.92 (s, 3 H), 2.49 (s, 3 H). Step 5: l-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl / -2 -pyridyl ]-5-methyl-pyrazole-3-carbonitrile

To a clear solution of l-[6-(5-bromo-6-methoxy-benzimidazol-l-yl)-3-(difluoromethyl)-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile (60.0 mg, 0.080 mmol, 1 eq.) in 1,4-dioxane (5 mL) was added l-[6-(5-bromo-6-methoxy-benzimidazol-l-yl)-3-(difluoromethyl)-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile (120.0 mg, 0.26 mmol, 1.0 eq.), ['BuBrettPhos Pd(allyl)]OTf (20.41 mg, 0.03 mmol, 0.1 eq.) and CS2CO3 (255.41 mg, 0.78 mmol, 3.0 eq.). The reaction mixture was stirred at 80 °C for 16 hours under nitrogen atmosphere. The mixture was diluted with H2O andextracted withEtOAc. The organic layers were separated, dried over Na2SO4 and filtered. To the filtrate was added SiCh Thio-met scavenger to remove the palladium. The suspension was then filtered and the filtrate was concentrated to give a residue. Theresidue was purified by preparative HPLC (Phenomenex Synergi C18 (50 x 25 mm, 10 pm), 14 - 44% CH3CN in H2O (with 0.225% HCOOH) over 10 minutes, flow rate: 25 mL/min). After freeze- drying l-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (20.9 mg, 16.4% yield) was obtained as a white solid. LC-MS: m/z = 488.0 [M+H]⁺, ESI pos. 'H NMR (400 MHz, DMSO-d₆) 8 = 9.01 (s, 1 H) 8.80 (s, 1 H) 8.61-8.59 (d, J= 8.56 Hz, 1 H) 8.46 (br d, J= 1.10 Hz, 1 H) 8.37 (d, J= 8.44 Hz, 1 H) 7.83 (s, 1 H) 7.35 (s, 2 H) 7.25-6.98 (m,2 H)3.87 (s, 3 H) 2.51 (s, 3 H) 2.48 (s, 3 H).

Example 4 l-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-2-pyridyl]-

N-(6-methylpyridazin-3-yl)-6-(2-morpholinoethoxy)benzimidazol-5-amine

Step 1: 6-chloro-3-(difluoromethyl)-2-fluoro-pyridine

To a solution of 6-chloro-2-fluoro-pyridine-3-carbaldehyde (2.0 g, 12.54 mmol, 1.0 eq.) in DCM

(20 mL) was added DAST (5.0 mL, 37.6 mmol, 3.0 eq.) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes. The reaction mixture was poured into a sat. aq. NaHCO, solution under stirring, and was extracted with DCM. The combined extracts were concentrated under vacuum to give 6-chloro-3-(difluoromethyl)-2-fluoro-pyridine (2.0 g, 87.9%) as a yellow oil. LC-MS: m/z = 182.0 [M+H]⁺, ESI pos. 'H NMR (400 MHz, DMSO-d₆) 6 = 8.28 (t, J= 8.7 Hz, 1H), 7.68 (d, J= 7.9 Hz, 1H), 7.40 - 7.06 (m, 1H).

Step 2: 6-chloro-3-(difluoromethyl)-2-[ 3-(difluoromethyl)-5-methyl-pyrazol-l-yl] pyridine A solution of 6-chloro-3-(difluoromethyl)-2-fluoro-pyridine (900.0 mg, 5.0 mmol, 1.0 eq.), 3- (difhioromethyl)-5-methyl-lH-pyrazole (655.0 mg, 5.0 mmol, 1.0 eq.) and DIPEA (2.5 mL, 14.9 mmol, 3.0 eq.) in DMSO (10 mL) was stirred at 100 °C for 12 hours. The reaction mixture was poured into H2O and was extracted with EtOAc. The organic phase was washed with brine and the vombined extracts were concentrated under vacuum to give a residue. The residue was purified by flash column chromatography using 10% EtOAc in PE as an eluent to yield a mixture of regioisomers. This mixture was purified by preparative NPLC and concentrated under reduced pressure to give 6-chloro-3-(difluoromethyl)-2-[3-(difluoromethyl)-5-methyl-pyrazol-l- yl]pyridine (200.0 mg, 13.7%) as a white solid. LC-MS: m/z = 294.1 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCI3) 5 = 8.17 (d, J= 8.3 Hz, 1H), 7.51 (d, J= 8.3 Hz, 1H), 7.33- 7.06 (s, 1H), 6.83 - 6.52 (m, 1H), 6.48 (s, 1H), 2.53 (s, 3H).

Step 3: 4-[2-[6-bromo-3-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-2- pyridyl]benzimidazol-5-yl oxyethyl morpholine

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

4-[2-[6-bromo-l-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-2- pyridyl] benzimidazol-5-yl] oxy ethyl] morpholine : LC-MS: 585.1 [M+H]⁺, ESI pos. 'H NMR (400 MHz, DMSO-de) 6 = 9.06 (s, 1H), 8.59 (d, J= 8.7 Hz, 1H), 8.30 (d, J= 8.6 Hz, 1H), 8.04 (s, 1H), 7.90 (s, 1H), 7.34 - 6.90 (m, 2H), 6.70 (s, 1H), 4.11 (t, J = 6.0 Hz, 2H), 3.58 - 3.54 (m, 4H), 2.74 (t, J= 6.1 Hz, 2H), 2.52 (br s, 4H), 2.47 (br s, 3H).

4-[2-[6-bromo-3-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-2- pyridyl] benzimidazol-5-yl] oxy ethyl] morpholine : LC-MS: 585.1 [M+H]⁺, ESI pos. 'H NMR (400 MHz, DMSO-de) 6 = 9.17 (s, 1H), 8.56 (d, J= 8.7 Hz, 1H), 8.46 (s, 1H), 8.29 (d, J= 8.6 Hz, 1H), 7.56 (s, 1H), 7.29 - 6.91 (m, 2H), 6.76 (s, 1H), 4.25 (t, J= 5.6 Hz, 2H), 3.62 - 3.54 (m, 4H), 2.77 (t, J= 5.5 Hz, 2H), 2.56 - 2.53 (m, 4H), 2.49 - 2.49 (m, 3H)

Step 4: l-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-2-pyridyl]-N-(6- methylpyridazin-3-yl)-6-(2-morpholinoethoxy)benzimidazol-5-amine

To a solution of 5-amino-2-methylpyridine (48.2 mg, 0.45 mmol, 2.0 eq.) and 4-[2-[6-bromo-3- [5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-2-pyridyl]benzimidazol-5- yl]oxyethyl]morpholine (130.0 mg, 0.22 mmol, 1.0 eq.) in 1,4-dioxane (4 mL) were added CS2CO3 (217.82 mg, 0.67 mmol, 3.0 eq.). The flask was purged with N2 and ['BuBrettPhos Pd(allyl)]OTf (17.41 mg, 0.02 mmol, 0.1 eq.) was added to the mixture and stirred at 80 °C for 4 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Phenom enex C18 (75 x 30 mm, 3 pm), 8 - 38% CH3CN in H2O (with 0.225% HCOOH) over 7 minutes, flow rate: 25 mL/min) and the fractions lyophilized to afford l-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-2- pyridyl]-N-(6-methylpyridazin-3-yl)-6-(2-morpholinoethoxy)benzimidazol-5-amine (79.2 mg, 58.1%) as a yellow solid. LC-MS: m/z = 612.2 [M+H]⁺, ESI pos. 'H NMR (400 MHz, DMSO- de) 8 = 9.01 (s, 1H), 8.66 (s, 1H), 8.57 (d, J= 8.6 Hz, 1H), 8.33 - 8.26 (m, 2H), 7.90 (s, 1H), 7.37 - 7.32 (m, 1H), 7.31 - 6.94 (m, 3H), 6.72 (s, 1H), 4.16 (t, J= 6.1 Hz, 2H), 3.56 - 3.52 (m, 4H), 2.73 (t, J= 6.0 Hz, 2H), 2.53 (s, 3H), 2.49 (s, 3H), 2.43 - 2.38 (m, 4H). Example 5 l-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3- yloxy)benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

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

To a mixture of oxetan-3-ol (473.0 mg, 6.4 mmol, 1.5 eq.) in THF (50 mL) was added NaH, 60% in mineral oil (256.0 mg, 6.4 mmol, 1.5 eq.) in portions at 0 °C. The reaction mixture was stirred at 0 °C for 30 min under N2 atmosphere. Then 4-bromo-5-fluoro-2-nitro-aniline (1.0 g, 4.3 mmol, 1.0 eq.) was added and the reaction mixture was further stirred at 25 °C for 12 hours. The reaction was quenched with sat. aq. NH4CI and extracted with EtOAc. The organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purifited by flash column chromatography using 0 - 10% EtOAc in PE as eluent to yield 4- bromo-2-nitro-5-(oxetan-3-yloxy)aniline (1.1 g, 89.4%) as a white solid. LC-MS: m/z = 289.1 [M+H]⁺, ESI pos. 'H NMR (400 MHz, DMSO-d₆) 6 = 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).

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

To a solution of 4-bromo-2-nitro-5-(oxetan-3-yloxy)aniline (1.0 g, 3.5 mmol, 1.0 eq.) in EtOH (9 mL) was added iron (965.8 mg, 17.3 mmol, 5.0 eq.), NH4CI (1.85 g, 34.6 mmol, 10.0 eq.) and H2O (3 mL). The reaction mixture was stirred under N2 at 50 °C for 2 hours. The reaction mixture was filtered and the filtrate was poured into H2O and was extracted with EtOAc. The combined organic extracts were concentrated under vacuum to give 4-bromo-5-(oxetan-3- yloxy)benzene-l,2-diamine (800.0 mg, 89.3%) as a brown oil. LC-MS: m/z = 283.1 [M+H]⁺, ESI pos.

Step 3: 5-bromo-6-(oxetan-3-yloxy)-lH-benzimidazole

To a solution of TsOH (47.5 mg, 0.3 mmol, 0.1 eq.) in EtOH (15 mL) were added 4-bromo-5- (ox etan-3 -yl oxy )benzene-l,2-diamine (800.0 mg, 3.1 mmol, 1.0 eq.) and trimethyl orthofomate (3.4 mL, 30.9 mmol, 10.0 eq.), and the mixture was stirred at 80 °C for 2 hours. The reaction mixture was diluted with NaHCOs and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 70% EtOAc as eluent to yield 5-bromo-6-(oxetan-3- yloxy)-lH-benzimidazole (600.0 mg, 72.2%) as a yellow oil. LC-MS: m/z = 271.0 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 8 = 8.02 (s, 1H), 7.88 (s, 1H), 6.78 (s, 1H), 5.29 (quin, J= 5.6 Hz, 1H), 5.04 (t, J= 6.8 Hz, 2H), 4.91 - 4.88 (m, 2H).

Step 4: l-[ 6-[5-bromo-6-(oxetan-3-yloxy)benzimidazol-l-yl]-3-(difluoromethyl)-2-pyridyl]-5- methyl-pyrazole-3-carbonitrile

To a solution of 5-bromo-6-(oxetan-3-yloxy)-lH-benzimidazole (300.5 mg, 1.12 mmol, 1.0 eq.) in DMSO (6 mL) was added l-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile (300.0 mg, 1.12 mmol, 1.0 eq.) and K2CO3 (462.98 mg, 3.35 mmol, 3.0 eq.). The reaction mixture was stirred at 50 °C for 4 hours. The reaction mixture was poured into H2O and extracted with EtOAc. The organic layers were washed with brine, and the combined extracts were concentrated under vacuum. The residue was purified by flash column chromatography using ethyl acetate as a solvent to give l-[6-[6-bromo-5-(oxetan-3-yloxy)benzimidazol-l-yl]-3- (difluoromethyl)-2-pyridyl] -5 -methyl-pyrazole-3 -carbonitrile (200.0 mg, 35.7%) as a white solid and l-[6-[5-bromo-6-(oxetan-3-yloxy)benzimidazol-l-yl]-3-(difluoromethyl)-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile (200.0 mg, 35.7%) as a yellow solid. l-[6-[6-bromo-5-(oxetan-3-yloxy)benzimidazol-l-yl]-3-(difluoromethyl)-2-pyridyl]-5- methyl-pyrazole-3-carbonitrile: LC-MS: m/z = 503.1 [M+H]⁺, ESI pos. 'H NMR (400 MHz, DMSO-de) 6 = 9.11 (s, 1H), 8.64 (d, J= 8.6 Hz, 1H), 8.35 (d, J= 8.5 Hz, 1H), 8.09 (s, 1H), 7.44 (s, 1H), 7.23 (s, 1H), 7.19 (d, J= 0.8 Hz, 1H), 7.10 (s, 1H), 6.96 (s, 1H), 5.24 (quin, J= 5.4 Hz, 1H), 4.74 - 4.67 (m, 2H), 4.61 (dd, J= 5.0, 7.4 Hz, 2H), 2.42 (s, 3H). l-[6-[5-bromo-6-(oxetan-3-yloxy)benzimidazol-l-yl]-3-(difluoromethyl)-2-pyridyl]-5- methyl-pyrazole-3-carbonitrile: LC-MS: 503.1 [M+H]⁺, ESI pos. ^XH NMR (400 MHz, DMSO-de) 6 = 9.18 (s, 1H), 8.60 (d, J= 8.6 Hz, 1H), 8.47 (s, 1H), 8.35 (d, J= 8.6 Hz, 1H), 7.22 (s, 1H), 7.20 (s, 1H), 7.17 (s, 1H), 7.09 (s, 1H), 6.95 (s, 1H), 5.45 (quin, J= 5.4 Hz, 1H), 5.02 (t, J= 6.7 Hz, 2H), 4.60 (dd, J = 5.0, 7.1 Hz, 2H), 2.49 - 2.48 (m, 3H) Step 5: l-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3- yloxy)benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

Prepared according to Example 4, step 4 to afford l-[3-(difluoromethyl)-6-[5-[(6- methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-l-yl]-2-pyridyl]-5-methyl- pyrazole-3 -carbonitrile (19.1 mg, 8.9%) as a yellow solid after purification by preparative HPLC. LC-MS: m/z = 530.2 [M+H]⁺, ESI pos. 'H NMR (400 MHz, DMSO-d₆) 8 = 9.04 (s, 1H), 8.84 (s, 1H), 8.60 (d, J= 8.6 Hz, 1H), 8.40 - 8.30 (m, 2H), 7.38 - 6.95 (m, 5H), 5.24 (quin, J= 5.3 Hz, 1H), 4.72 (br d, J= 5.5 Hz, 4H), 2.53 - 2.51 (m, 3H), 2.44 (s, 3H).

Example 6 l-[5-(difluoromethyl)-6-[3-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2- pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine

Step 1: 2,6-dichloro-3-(l,3-dioxolan-2-yl)pyridine

In a 250 mL three-necked flask equipped with a Dean-Stark trap, an intensive cooler and a thermometer, 2,6-dichloronicotinaldehyde (3.75 g, 19.2 mmol, 1.0 eq.) was dissolved in toluene (100 ml). Then, ethane- 1,2-diol (1.8 g, 1.6 ml, 28.7 mmol, 1.5 eq.) and pTsOH (91.1 mg, 479 pmol, 0.025 eq.) were added. The orange solution was heated to reflux overnight with azeotropic removal of H2O via Dean Stark trap. Once the mixture had cooled down, it was concentrated in vacuum. Residual material was diluted with EtOAc and sat. aq. NaHCOs. The organic layer was separated and washed with H2O. The organic layer was dried with Na2SO4, filtered and evaporated. The crude was purified by flash column chromatography using 0 - 50% EtOAc in heptane as eluent. The title compound 2,6-dichloro-3-(l,3-dioxolan-2-yl)pyridine (3.85 g, 91.3 %) was obtained as a light yellow oil. LC-MS: m/z=220.1 [M+H]⁺, ESI pos. Step 2: l-[6-chloro-5-(l,3-dioxolan-2-yl)-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5- amine

A mixture of N-(6-methylpyridazin-3-yl)-lH-benzimidazol-5-amine (5.12 g, 22.72 mmol, 1.0 eq.), 2,6-dichloro-3-(l,3-dioxolan-2-yl)pyridine (5.0 g, 22.72 mmol, 1.0 eq.), K2CO3 (6.28 g, 45.44 mmol, 2.0 eq.) and DMSO (50 mL) was stirred at 60 °C for 24 hours. The reaction mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 10% MeOH in DCM as eluent to give l-[6-chloro-5-(l,3-dioxolan-2-yl)-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5- amine (1.0 g, 10.8%) as a brown solid. LC-MS: m/z = 409.1 [M+H]⁺, ESI pos.

Step 3: 2-chloro-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]pyridine-3- carbaldehyde

To a solution of l-[6-chloro-5-(l,3-dioxolan-2-yl)-2-pyridyl]-N-(6-methylpyridazin-3- yl)benzimidazol-5-amine (600.0 mg, 1.5 mmol, 1.0 eq.) in HCl\dioxane (8.0 mL, 32.0 mmol, 21.8 eq.) was added HC1 (8.0 mL, 48.0 mmol, 32.71 eq.) at 25 °C and the resulting mixture was stirred at 25 °C for 2 hours. The reaction mixture was filtered and the filter cake was dissolved with H2O and lyophilized to give 2-chloro-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol- l-yl]pyridine-3-carbaldehyde (530.0 mg, 99.0%) as a yellow solid. LC-MS: m/z = 365.1 [M+H]⁺, ESI pos.

Step 4: l-[6-chloro-5-(difluoromethyl)-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5- amine

To a solution of 2-chloro-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]pyridine-3- carbaldehyde (400.0 mg, 1.1 mmol, 1.0 eq.) in DCM (10 mL) was added DAST (2831.5 mg, 17.5 mmol, 16.0 eq.) at 25 °C and the resulting mixture was stirred at 25 °C for 2 hours. More DAST (530.9 mg, 3.29 mmol, 3.0 eq.) was added for 2 hours. The reaction mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layers were dried over anhydrous ISfeSCU, filtered and concentrated under reduced pressure to give the crude l-[6- chloro-5-(difluoromethyl)-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (300.0 mg, 70.7%) as a yellow solid. LC-MS: m/z = 387.1 [M+H]⁺, ESI pos. 'H NMR (400 MHz, DMSO-de) 6 = 9.81 (s, 1H), 9.10 (s, 1H), 8.44 - 8.35 (m, 2H), 8.31 (d, J= 8.8 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.64 (d, J= 9.2 Hz, 1H), 7.52 (dd, J= 2.0, 8.8 Hz, 1H), 7.43 - 7.16 (m, 2H), 2.55 (s, 3H). Step 5: 4-bromo-3-methyl-l-(2,2,2-trifluoroethyl)pyrazole

A mixture of 4-bromo-3-methylpyrazole (15.0 g, 93.2 mmol, 1.0 eq.), 2,2,2-trifluoroethyl trifluoromethanesulfonate (22.7 g, 97.8 mmol, 1.05 eq.) and CS2CO3 (25.3 g, 186.3 mmol, 2.0 eq.) in DMF (150 mL) was stirred at 100 °C for 12 hours. The reaction mixture was filtered and the filtrate was diluted with H2O and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using a gradient of 11 - 17% EtOAc in PE as eluent to give the mixture of 4-bromo-3 -methyl- 1 -(2,2,2- trifluoroethyl)pyrazole and 4-bromo-5-methyl-l-(2,2,2-trifluoroethyl)pyrazole (19.5 g, 86.1%) as a colorless oil. LC-MS: m/z = 242.9 [M+H]⁺, ESI pos. 'H NMR (400 MHz, DMSO-d₆) 8 = 8.00 (s, 1H), 5.09 - 4.99 (m, 2H), 2.14 (s, 3H).

Step 6: 3-methyl-4-(4, 4, 5, 5-tetramethyl-l , 3, 2-dioxaborolan-2-yl)-l-(2, 2, 2- trijluoroethyl)pyrazole

To a mixture of 4-bromo-3-methyl-l-(2,2,2-trifluoroethyl)pyrazole (11.0 g, 45.26 mmol, 1.0 eq.), 4-bromo-5-methyl-l-(2,2,2-trifluoroethyl)pyrazole, KOAc (5.7 mL, 90.5 mmol, 2.0 eq.) and bis(pinacolato)diboron (13.79 g, 54.3 mmol, 1.2 eq.) in 1,4-dioxane (200 mL) was added Pd(dppf)C12’CH2C12 (3.7 g, 4.53 mmol, 0.1 eq.), the mixture was stirred at 100 °C for 16 hours under N2 atmosphere. The mixture was concentrated under reduced pressure to give a residue, which was purified by flash column chromatography using 10 - 20% EtOAc in heptane as eluent to yield a mixture of 3-methyl-4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-l-(2, 2,2- trifluoroethyl)pyrazole and 5-methyl-4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-l -(2,2,2- trifluoroethyl)pyrazole (18.0 g, yield > 100%, crude material) as a yellow gum. LC-MS: m/z = 291.1 [M+H]⁺, ESI pos

Step 7: l-[5-(difluoromethyl)-6-[3-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-N-(6- methylpyridazin-3-yl)benzimidazol-5-amine and l-[5-(difluoromethyl)-6-[5-methyl-l-(2,2,2- trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine To a mixture of 3-methyl-4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-l-(2, 2,2- trifluoroethyl)pyrazole (45.0 mg, 0.16 mmol, 1.5 eq.) and l-[6-chloro-5-(difluoromethyl)-2- pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (40.0 mg, 0.1 mmol, 1.0 eq.) in THF (2 mL) and H2O (0.5 mL) was added Sphos Pd G3 (9.1 mg, 0.01 mmol, 0.1 eq.) and K3PO4 (43.9 mg, 0.21 mmol, 2.0 eq.), the mixture was stirred at 60 °C for 12 hours under N2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give a mixture of l-[5-(difluoromethyl)-6-[3-methyl-l -(2,2,2- trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine and 1- [5-(difluoromethyl)-6-[5-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-N-(6- methylpyridazin-3-yl)benzimidazol-5-amine (20.0 mg, 37.6%) as a yellow solid. LC-MS: m/z = 515.3 [M+H]⁺, ESI pos.

The aformentioned mixture was separated into both its regioisomers by SFC (Daicel Chiralpak AS (250 mm x 30 mm, 10 pm) with MeOH (0.1% NH4OH) in CO2) to give l-[5- (difluoromethyl)-6-[3-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-N-(6- methylpyridazin-3-yl)benzimidazol-5-amine (9.5 mg, 16.1%) and l-[5-(difluoromethyl)-6-[5- methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-N-(6-methylpyridazin-3- yl)benzimidazol-5-amine (3.5 mg, 17.5%) as white solids. l-[5-(difluoromethyl)-6-[3-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-N-(6- methylpyridazin-3-yl)benzimidazol-5-amine: LC-MS: m/z = 515.2 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CD3OD) 8 = 8.92 (s, 1H), 8.36 (d, J = 8.8 Hz, 1H), 8.28 - 8.14 (m, 2H), 8.01 (s, 1H), 7.95 (d, J= 8.8 Hz, 1H), 7.61 (dd, J = 2.0, 8.8 Hz, 1H), 7.35 (d, J= 9.2 Hz, 1H), 7.13 (d, J = 9.2 Hz, 1H), 6.99 - 6.61 (m, 1H), 5.00 (q, J = 8.8 Hz, 2H), 2.53 (s, 3H), 2.42 (s, 3H). l-[5-(difluoromethyl)-6-[5-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-N-(6- methylpyridazin-3-yl)benzimidazol-5-amine: LC-MS: m/z = 515.2 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CD3OD) 8 = 8.91 (s, 1H), 8.36 (d, J = 8.8 Hz, 1H), 8.27 - 8.12 (m, 2H), 7.95 (d, J= 8.4 Hz, 1H), 7.80 (s, 1H), 7.61 (dd, J = 2.0, 9.2 Hz, 1H), 7.35 (d, = 9.2 Hz, 1H), 7.12 (d, J= 9.2 Hz, 1H), 7.01 - 6.67 (m, 1H), 5.05 (q, J= 8.4 Hz, 2H), 2.53 (s, 6H).

Example 7

3-(difluoromethyl)-l-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-

3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-N,N,5-trimethyl-pyrazole-4- carboxamide

Step 1: l-[6-chloro-3-(difluoromethyl)-2-pyridyl]-3-(difluoromethyl)-N,N,5-trimethyl-pyrazole- 4-carboxamide

To a solution of 6-chl oro-3 -(difluoromethyl)-2 -fluoro-pyridine (68 mg, 0.375 mmol, 1.0 eq.) in DMF (0.6 mL) was added 3-(difluoromethyl)-N,N,5-trimethyl-lH-pyrazole-4-carboxamide (83.7 mg, 0.41 mmol, 1.1 eq.) and K2CO3 (51.8 mg, 0.375 mmol, 1.0 eq.). The reaction mixture was stirred at RT over 16 hours. The reaction mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layers were dried over anhydrous MgSCh, filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography using 0 - 50% EtOAc in heptane as eluent to yield l-[6-chloro-3-(difluoromethyl)-2-pyridyl]-3- (difhioromethyl)-N,N,5-trimethyl-pyrazole-4-carboxamide (74.4 mg, 46.8%) as a light yellow liquid. LC-MS: m/z = 365.1 [M+H]⁺, ESI pos.

Step 2: 3-(difluoromethyl)-l-[3-(difluoromethyl)-6-[ 6-methoxy-5-[(6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl / -2 -pyridyl -N,N, 5-trimethyl-pyrazole-4-carboxamide

A suspension of l-[6-chloro-3-(difluoromethyl)-2-pyridyl]-3-(difluoromethyl)-N,N,5-trimethyl- pyrazole-4-carboxamide (64.7 mg, 0.177 mmol, 1.0 eq.), (6-methoxy-lH-benzimidazol-5-yl)-(6- methylpyridazin-3-yl)amine (54.3 mg, 0.21 mmol, 1.2 eq.) and K3PO4 (113.0 mg, 0.53 mmol, 3.0 eq.) at RT in AmOH (1.36 mL) was purged with Argon for 5 minutes. Then TluXPhos Pd G3 (14.09 mg, 0.018 mmol, 0.100 eq.) was added, the vial was locked and the mixture heated to 80 °C for 16 hours. The reaction was cooled to 23 °C and extracted with DCM and H2O. The organic layer was washed with brine, dried over MgSCE; filtered and concentrated in vacuo. The residue was purified by flash column chromatography using 0 - 10% MeOH in DCM as eluent to yield 3 -(difluoromethyl)- l-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-N,N,5-trimethyl-pyrazole-4-carboxamide (36.1 mg, 33.2%) as a light yellow solid. LC-MS: m/z = 584.3 [M+H]⁺, ESI pos.

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

Example 8 5-(difluoromethoxy)-2-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin- 3-yl)amino]benzimidazol-l-yl]-2-pyridyl]pyrazole-3-carbonitrile

Step 1: 3-(difluoromethoxy)-lH-pyrazole-5-carboxamide

To a stirred solution of 3 -(difluoromethoxy)- lH-pyrazole-5-carboxylic acid (200 mg, 1.12 mmol, 1.0 eq.) at RT in DMF (5.25 mL) under an argon atmosphere was added CDI (236.7 mg, 1.5 mmol, 1.3 eq.). After stirring for 3 hours at RT, NH4OH (2.25 g, 2.5 mL, 64.3 mmol, 20 eq.) was added and stirring was continued for 90 minutes. A second batch of CDI (236.73 mg, 1.46 mmol, 1.3 eq.) was added, and the reaction mixture was stirred overnight. The reaction mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layers were dried over anhydrous MgSCL, filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography using 20 - 100% EtOAc in heptane as eluent to yield 3-(difluoromethoxy)-lH-pyrazole-5-carboxamide (133.7 mg, 63.8%) as a white solid. LC-MS: m/z = 178.1 [M+H]+, ESI pos.

Step 2: 3-(difluoromethoxy)-lH-pyrazole-5-carbonitrile

To stirred solution of 3-(difluoromethoxy)-lH-pyrazole-5-carboxamide (133.7 mg, 0.755 mmol, 1.0 eq.) and EtsN (229.2 mg, 316 pL, 2.26 mmol, 3.0 eq.) at RT in DCM (7.3 mL) under an argon atmosphere was added carefully TFAA (475.7 mg, 320 pL, 2.26 mmol, 3.0 eq.). The mixture turned immediately to a clear light yellow solution, with white fumes above. Stirring at RT was continued for 30 minutes. The reaction mixture was concentrated on isolute and purified by flash column chromatography using 0 - 80% EtOAc in heptane as eluent to yield 3- (difhioromethoxy)-lH-pyrazole-5-carbonitrile (98.6 mg, 78.0%) as a colorless liquid. LC-MS: m/z = 160.0 [M+H]⁺, ESI pos.

Step 3: 2-[ 6-chloro-3-(difluoromethyl)-2-pyridyl]-5-(difluoromethoxy)pyrazole-3-carbonitrile To a solution of 6-chl oro-3 -(difluoromethyl)-2 -fluoro-pyridine (101.7 mg, 0.56 mmol, 1.0 eq.) in DMF (0.9 mL) were added 3 -(difluoromethoxy)- lH-pyrazole-5-carbonitrile (98.0 mg, 0.62 mmol, 1.1 eq.) and K2CO3 (77.4 mg, 0.56 mmol, 1.000 eq.). The reaction mixture was heated to 50 °C and stirred for 4 hours. The mixture was cooled to 20 °C, diluted with H2O and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSCE, filtered and concentrated under reduced pressure.

The crude product was added to 1 g isolute HM-N and purified by flash column chromatography using 0 - 50% EtOAc in heptane as eluent to yield 2-[6-chl oro-3 - (difhioromethyl)-2-pyridyl] -5 -(difluorom ethoxy )pyrazole-3 -carbonitrile (138 mg, 76.6%) as a light yellow solid. LC-MS: m/z = 320.0 [M]⁺, ESI pos.

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

Prepared in analogy to Example 7, step 2 to yield 5-(difluoromethoxy)-2-[3-(difluoromethyl)-6- [6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]pyrazole-3- carbonitrile (30.4 mg, 25.2%) as a yellow solid. LC-MS: m/z = 540.3 [M+H]⁺, ESI pos.

Isomer 5-(difluoromethoxy)-2-[3-(difluoromethyl)-6-[5-methoxy-6-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]pyrazole-3-carbonitrile (59.5 mg, 49.9%) was also isolated as a light yellow solid. LC-MS: m/z = 540.3 [M+H]+, ESI pos. Example 9 l-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-tetrahydrofuran-3-ylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile Step 1: l-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-tetrahydrofuran-3-ylpyridazin-3- yl)amino ]benzimidazol-l-yl / -2 -pyridyl ]-5-methyl-pyrazole-3-carbonitrile

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

Example 10

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

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

Example 11 3-[[l-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-5-(difluoromethyl)-2- pyridyl] -6-methoxy-benzimidazol-5-yl] amino] -N,N, 6-trimethyl-pyridazine-4- carboxamide

Step 1: 3-[[ l-[ 6-[ 3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-5-(difluoromethyl)-2-pyridyl]-6- methoxy-benzimidazol-5-yl amino ]-N,N, 6-trimethyl-pyridazine-4-carboxamide

Prepared according to Example 4, step 4 to afford 3-[[l-[6-[3-(difluoromethoxy)-5-methyl- pyrazol-l-yl]-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]amino]-N,N,6- trimethyl-pyridazine-4-carboxamide (6.7 mg, 18.6%) as a yellow solid after purification by preparative HPLC (Phenomenex Cl 8 (150 x 25 mm, 10 pm), 29 - 59% CEECN in H2O (with 0.225% HCOOH) over 10 minutes, flow rate: 25 mL/min). LC-MS: m/z = 600.2 [M+H]⁺, ESI pos. ^XH NMR (400 MHz, DMSO-d₆) 8 = 8.96 (s, 1H), 8.84 (s, 1H), 8.51 (d, J= 8.6 Hz, 1H), 8.38 (s, 1H), 8.22 (d, J= 8.5 Hz, 1H), 7.84 (s, 1H), 7.64 - 7.17 (m, 3H), 6.27 (s, 1H), 3.89 (s, 3H), 3.03 (br d, J= 18.8 Hz, 6H), 2.55 (s, 3H), 2.53 - 2.52 (m, 3H). Example 12 l-[5-(difluoromethyl)-6-[5-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2- pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine l-[5-(difluoromethyl)-6-[5-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-N-(6- methylpyridazin-3-yl)benzimidazol-5-amine (3.5 mg, 17.5% yield) was obtained as a white solid after separation by SFC from its isomer as described in Example 6, step 7. LC-MS: m/z = 515.2 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CD₃OD) 8 = 8.91 (s, 1H), 8.36 (d, J= 8.8 Hz, 1H), 8.27 - 8.12 (m, 2H), 7.95 (d, J= 8.4 Hz, 1H), 7.80 (s, 1H), 7.61 (dd, J= 2.0, 9.2 Hz, 1H), 7.35 (d, J= 9.2 Hz, 1H), 7.12 (d, J= 9.2 Hz, 1H), 7.01 - 6.67 (m, 1H), 5.05 (q, J= 8.4 Hz, 2H), 2.53 (s, 6H).

Example 13 l-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-2-pyridyl]- N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine

Step 1: 5-bromo-l-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-2-pyridyl]- 6-(oxetan-3 -yloxy) benzimidazole

A solution of 6-chloro-3-(difluoromethyl)-2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]pyridine (360.0 mg, 1.23 mmol, 1.0 eq.), 5-bromo-6-(oxetan-3-yloxy)-lH-benzimidazole (329.89 mg, 1.23 mmol, 1.0 eq.) and K2CO3 (508.3 mg, 3.68 mmol, 3.0 eq.) in DMSO (10 mL) was stirred at 50 °C for 16 hours. The reaction mixture was cooled to 23 °C, diluted with H2O (50mL), and extracted with EtOAc (30 mL x 3). The combined organic layers were was washed with brine (50 mL x 3) and concentrated under vacuum. The residue was purified by flash column chromatography using 0 - 50% EtOAc in heptane as eluent to yield 5-bromo-l-[5- (difhioromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-2-pyridyl]-6-(oxetan-3- yloxy)benzimidazole (300.0 mg, 46.5%) as a yellow solid. LC-MS: m/z = 527.7 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 8 = 8.48 (s, 1H), 8.46 (d, J = 8.4 Hz, 1H), 8.11 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.31 (s, 1H), 7.17 (t, J = 55.2 Hz, 1H), 6.77 (t, J = 54.8 Hz, 1H), 6.61 (s, 1H), 5.16 (quin, J = 5.6 Hz, 1H), 4.85 (d, J = 5.7 Hz, 4H), 2.50 (s, 3H).

Isomer 6-bromo-l-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-2-pyridyl]- 5-(oxetan-3-yloxy)benzimidazole (300.0 mg, 46.5%) was also isolated as a white solid. LC-MS: m/z = 527.7 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 6 = 8.59 (s, 1H), 8.44 (br d, J= 8.3 Hz, 1H), 8.35 (s, 1H), 7.73 (br d, J= 8.4 Hz, 1H), 7.25 (t, J= 55.2 Hz, 1H), 6.95 (s, 1H), 6.73 (br t, J= 54.8 Hz, 1H), 6.57 (s, 1H), 5.34 (quin, J= 5.4 Hz, 1H), 5.08 (br t, J= 6.7 Hz, 2H), 4.90 (br t, J= 6.1 Hz, 2H), 2.58 (s, 3H).

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

Prepared acording to Example 4, step 4 to give l-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5- methyl-pyrazol-l-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5- amine (106.7 mg, 0.19 mmol, 32.07% yield) as yellow solid after purification by preparative HPLC (Phenomenex Synergi Max-RP (250 x 50 mm, 10 pm), 15 - 45% CH3CN in H2O (with HCOOH) over 21 minutes, flow rate: 100 mL/min). LC-MS: m/z = 555.2 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 6 = 8.51 (s, 1H), 8.44 (br d, J= 8.1 Hz, 1H), 8.35 (s, 1H), 7.73 (br d, J = 8.2 Hz, 1H), 7.32 - 7.28 (m, 2H), 7.26 - 7.00 (m, 2H), 6.77 (t, J= 54.8 Hz, 1H), 6.61 (s, 1H), 5.22 - 5.16 (m, 1H), 4.90 - 4.84 (m, 2H), 4.83 - 4.76 (m, 2H), 2.64 (s, 3H), 2.51 (s, 3H). Example 14 l-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-

2-pyridyl]-5-fluoro-pyrazole-3-carbonitrile

Step 1: l-(6-chloro-3-formyl-2-pyridyl)-5-fluoro-pyrazole-3-carboxylic acid ethyl ester Prepared according to Example 1, step 2 to yield l-(6-chloro-3-formyl-2-pyridyl)-5-fluoro- pyrazole-3 -carboxylic acid ethyl ester (231 mg, 61.9%) as an off-white solid. LC-MS: m/z = 298.1 [M+H]⁺, ESI pos.

Step 2: l-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-fluoro-pyrazole-3-carboxylic acid ethyl ester

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

Step 3: l-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-fluoro-pyrazole-3-carboxylic acid Under argon, l-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-fluoro-pyrazole-3-carboxylic acid ethyl ester (280 mg, 0.88 mmol, 1.0 eq.) was dissolved in THF (14.5 mL). At RT, IM LiOH in H2O (1.31 mL, 1.31 mmol, 1.5 eq.) was added and the reaction mixture was stirred at RT over 1.5 hours. Sat. aq. NH4CI was added to neutralise the reaction mixture; the volatiles were evaporated and the crude was purified by reverse phase chromatography with formic acid to yield l-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-fluoro-pyrazole-3-carboxylic acid (255 mg, 99.8%) as a yellow lyophilized powder. LC-MS: m/z = 292.1 [M+H]⁺, ESI pos. Step 4: l-[ 6-chloro-3-(difluoromethyl)-2-pyridyl]-5-fluoro-pyrazole-3-carboxamide Under argon, l-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-fluoro-pyrazole-3-carboxylic acid (255 mg, 0.88 mmol, 1.0 eq.) was dissolved in DMF (4.13 mL). 25% NH4OH aq. sol. (65.5 mg, 83.3 pL, 0.96 mmol, 1.1 eq.), DIPEA (226.1 mg, 289.8 pL, 1.75 mmol, 2.0 eq.) and TBTU (505.4 mg, 1.6 mmol, 1.8 eq.) were added. The reaction mixture was stirred at RT over 2 hours. TBTU (505.4 mg, 1.6 mmol, 1.8 eq.) and 25% NH4OH aq. sol. (65.5 mg, 83.3 pL, 0.92 mmol, 1.1 eq.) were added again and the reaction mixture was stirred at RT over 2 hours.

Several drops of H2O were added , and the crude was purified by reverse phase chromatography under neutral conditions to yield l-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-fluoro-pyrazole-3- carboxamide (224 mg, 42.3%) as an off-white lyophilized powder. LC-MS: m/z = 291.0 [M+H]⁺, ESI pos.

Step 5: l-[ 6-chloro-3-(difluoromethyl)-2-pyridyl]-5-fluoro-pyrazole-3-carbonitrile

Under argon, l-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-fluoro-pyrazole-3-carboxamide (224 mg, 0.77 mmol, 1.0 eq.) was dissolved in DCM (4.3 mL). TEA (234.0 mg, 322 pL, 2.31 mmol, 3.000 eq.) and TFAA (485.6 mg, 327 pL, 2.31 mmol, 3.0 eq.) were added and the reaction mixture was stirred at RT over 3 hours. The volatiles were evaporated and the crude was purified on reverse phase chromatography under neutral conditions to yield l-[6-chl oro-3 - (difluoromethyl)-2-pyridyl] -5 -fluoro-pyrazole-3 -carbonitrile (140 mg, 60.9%) as a yellow oil. LC-MS: m/z = 272.9 [M+H]⁺, ESI pos.

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

Prepared according to Example 7, step 2 to yield l-[3-(difluoromethyl)-6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-fluoro-pyrazole-3-carbonitrile (4.0 mg, 3.9%) as a white lyophilized powder, after purification by reverse phase flash chromatography column. LC-MS: m/z = 462.2 [M+H]⁺, ESI pos. Example 15 l-[3-(difluoromethyl)-6-[5-[(6-keto-5,5,7-trimethyl-pyrrolo[2,3-c]pyridazin-3- yl)amino]-6-methoxy-benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile

Step 1: 3-(benzhydrylideneamino)-5,5, 7-trimethyl-pyrrolo[2,3-c]pyridazin-6-one

In a sealed glass tube, 3-chloro-5, 5, 7-trimethyl-pyrrolo[2, 3-c]pyridazin-6-one (94 mg, 0.44 mmol, 1.0 eq.), benzophenone imine (127.1 mg, 118 pL, 0.67 mmol, 1.5 eq.) and CS2CO3 (289.4 mg, 0.89 mmol, 2.0 eq.) were combined with 1, 4-dioxane (1.8 mL) and the suspension was purged with argon. Then, BINAP (27.7 mg, 0.04 mmol, 0.1 eq.) and Pd2dba3’CHCh (23.0 mg, 0.022 mmol, 0.05 eq.) was added , the vial was sealed and the mixture was heated to 100 °C for 20 hours. The reaction mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layers were dried over anhydrous MgSCh, filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography using 0 - 80% EtOAc in heptane as eluent to yield 3-(benzhydrylideneamino)-5,5,7-trimethyl-pyrrolo[2,3-c]pyridazin-6-one (131 mg, 78.6%) as an orange liquid. LC-MS: m/z = 357.3 [M+H]⁺, ESI pos.

Step 2: 3-amino-5,5, 7-trimethyl-pyrrolo[2,3-c]pyridazin-6-one; hydrogen chloride

To a solution of 3-(benzhydrylideneamino)-5, 5, 7-trimethyl-pyrrolo[2, 3-c]pyridazin-6-one (131 mg, 0.37 mmol, 1.0 eq.) in THF (5.3 mL) was added 2 M HC1 in Et2O (242.6 mg, 202 pL, 0.40 mmol, 1.1 eq.). The mixture immediately turned cloudy, and was stirred at 23 °C for 2 hours. More 2 M HC1 in Et2O (121.3 mg, 101 pL, 0.20 mmol, 0.55 eq.) was added and the reaction mixture was stirred overnight. The reaction mixture was filtered, washed with Et2O and the resluting solid was dried under vacuum to yield 3-amino-5,5,7-trimethyl-pyrrolo[2,3- c]pyridazin-6-one; hydrogen chloride (61.7 mg, 69.7%) as a white solid. LC-MS: m/z = 193.1 [M+H]⁺, ESI pos. Step 3: l-[3-(difluoromethyl)-6-[5-[(6-keto-5,5, 7-trimethyl-pyrrolo[2,3-c]pyridazin-3- yl)amino ] -6-methoxy-benzimidazol-l-yl / -2 -pyridyl ]-5-methyl-pyrazole-3-carbonitrile

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

Example 16 l-[3-(difluoromethyl)-6-[5-[[6-(2-morpholinoethoxy)pyridazin-3- yl]amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

Step 1: 2 -morpholinoethanol

To a solution of ethylene bromohydrin (9.15 mL, 129.13 mmol, 1.5 eq.) and K2CO3 (0.92 mL, 172.18 mmol, 2.0 eq.) in CH3CN (120 mL) were added morpholine (7.5 g, 86.1 mmol, 1.0 eq.). The yellow suspension was stirred at 80 °C for overnight. The reaction mixture was filtered and concentrated. The crude was purified by flash column chromatography using 0 - 10% MeOH in DCM as eluent to yield 2-morpholinoethanol (11.0 g, 97.4%) as a light yellow oil. LC-MS: m/z = 132.0 [M+H]⁺, ESI pos.

Step 2: 4- [2-(6-chloropyridazin-3-yl)oxyethyl] morpholine

2-morpholinoethanol (1 g, 933 pL, 7.62 mmol, 1.0 eq.) was dissolved in THF (30 mL), cooled to 0 °C, NaH 60% in mineral oil (320.2 mg, 8.0 mmol, 1.05 eq.) was added and stirred for 1 hour.

3, 6-dichloropyridazine (1.25 g, 8.4 mmol, 1.1 eq.) was added and stirred over night at RT. The reaction mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography using 0 - 10% MeOH in DCM as eluent to yield 4-[2-(6-chloropyridazin-3-yl)oxyethyl]morpholine (1.55 g, 83.4%) as a colorless oil. LC- MS: m/z = 244.2 [M+H]⁺, ESI pos.

Step 3: N-[6-(2-morpholinoethoxy)pyridazin-3-yl] carbamic acid tert-butyl ester

To a solution of 4-[2-(6-chloropyridazin-3-yl)oxyethyl]morpholine (1.55 g, 6.36 mmol, 1.0 eq.) in 1, 4-dioxane (20 mL), was added tert-butyl carbamate (1.49 g, 12.7 mmol, 2.0 eq.), CS2CO3 (4.14 g, 12.7 mmol, 2.00eq.), Xantphos (736.1 mg, 1.3 mmol, 0.2 eq.) followed by Pd2dba3 (582.5 mg, 0.64 mmol, 0.1 eq.). This reaction mixture was heated up to 90 °C for 3 hours. The reaction mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography using 0 - 8% MeOH in DCM as eluent to yield N-[6-(2-morpholinoethoxy)pyridazin-3-yl]carbamic acid tert-butyl ester (1.4 g, 67.9%) as a yellow solid. LC-MS: m/z = 325.2 [M+H]⁺, ESI pos.

Step 4: [6-(2-morpholinoethoxy)pyridazin-3-yl] amine; 2 2,2,2-trifluoroacetic acid N-[6-(2-morpholinoethoxy) pyridazin-3-yl]carbamic acid tert-butyl ester (500 mg, 1.54 mmol, 1.0 eq.) was dissolved in DCM (10 mL), TFA (1.76 g, 1.2 mL, 15.4 mmol, 10.0 eq.) was added and stirred for 2 hours. The volatiles were removed under vacuum to yield an orange oil. 10 mL of Et2O was added, and the suspension ultrasonicated for 10 minutes. The solid was filtered off , washed with ether and dried under high vacuum to give [6-(2 -morpholinoethoxy) pyridazin-3- yl]amine; 2 2, 2, 2-trifluoroacetic acid (675 mg, 96.8%) as a white solid. LC-MS: m/z = 225.1 [M+H]⁺, ESI pos.

Step 5: l-[3-(difluoromethyl)-6-[5-[[ 6-(2-morpholinoethoxy)pyridazin-3- yl]amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile Prepared according to Example 4, step 4 to yield l-[3-(difluoromethyl)-6-[5-[[6-(2- morpholinoethoxy)pyridazin-3-yl]amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile (47 mg, 74.%) as a white solid. LC-MS: m/z = 617.4 [M+HCOO]', ESI neg. Example 17 l-[3-(difluoromethyl)-6-[5-(7,8-dihydro-5H-pyrano[4,3-c]pyridazin-3-ylamino)-

6-methoxy-benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

Step 1 : benzhydrylidene ( 7, 8-dihydro-5H-pyrano[ 4, 3-c ]pyridazin-3-yl)amine

Prepared according to Example 15, step 1 using 3-chloro-7,8-dihydro-5H-pyrano[4,3- c]pyridazine (340 mg, 1.9 mmol, 1.0 eq.) , to yield benzhydrylidene(7,8-dihydro-5H-pyrano[4,3- c]pyridazin-3-yl)amine (345 mg, 57.8%) as a yellow foam. LC-MS: m/z = 316.2 [M+H]⁺, ESI pos.

Step 2: 7,8-dihydro-5H-pyrano[4,3-c]pyridazin-3-ylamine; 1:1 hydrogen chloride

To a solution of benzhydrylidene(7,8-dihydro-5H-pyrano[4,3-c]pyridazin-3-yl)amine (345 mg, 1.1 mmol, 1.0 eq.) in THF (10 mL) was added 2 M HC1 in Et2O (602 pL, 1.2 mmol, 1.1 eq.). Immediately, a precipitate formed. After 2 hours, 2 M HC1 in ether (602 pL, 1.2 mmol, 1.1 eq.) was added again, and stirred for furhter 2 hours. Three drops of H2O were added and stirring was continued for 1 hour. The solid was filtered off and washed with Et2O, dried under rhigh vacuume to yield 7,8-dihydro-5H-pyrano[4,3-c]pyridazin-3-ylamine; 1 : 1 hydrogen chloride (195 mg, 95%) as an off-white solid. LC-MS: m/z = 152.0 [M+H]⁺, ESI pos.

Step 3: l-[3-(difluoromethyl)-6-[5-(7,8-dihydro-5H-pyrano[4,3-c]pyridazin-3-ylamino)-6- methoxy-benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

Prepared according to Example 4, step 4 to yield l-[3-(difluoromethyl)-6-[5-(7,8-dihydro-5H- pyrano[4,3-c]pyridazin-3-ylamino)-6-methoxy-benzimidazol-l-yl]-2-pyridyl]-5-methyl- pyrazole-3 -carbonitrile (34 mg, 65.5%) as a white solid. LC-MS: m/z = 574.4 [M+HCOO]', ESI neg. Example 18 l-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]-6-tetrahydropyran-

4-yloxy-benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

Step 1: 4-bromo-2-nitro-5-tetrahydropyran-4-yloxy-aniline

To a mixture of tetrahydro-2H-pyran-4-ol (0.49 mL, 5.11 mmol, 1.2 eq.) in THF (15 mL) was added NaH, 60% in mineral oil (400.0 mg, 10.0 mmol, 2.35 eq.) at 0 °C. The mixture was stirred at 0 °C for 30 minutes. Then, 4-bromo-5-fhioro-2-nitro-aniline (1.0 gg, 4.26 mmol, 1.0 eq.) was added and the mixture was stirred at 0 °C for 1.5 h, warmed to RT and stirred overnight. The reaction mixture was diluted with sat. aq. NH4CI and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 4-bromo-2-nitro-5-tetrahydropyran-4-yl oxy-aniline (603.0 mg, 42.7%) as a yellow oil. LC-MS: m/z = 317.1, 319.1 [M+H]⁺, ESI pos.

Step 2: 4-bromo-5-tetrahydropyran-4-yloxy-benzene-l, 2 -diamine

A mixture of 4-bromo-2-nitro-5-tetrahydropyran-4-yloxy-aniline (600.0 mg, 1.9 mmol, 1.0 eq.), iron (528.3 mg, 9.5 mmol, 5.0 eq.) and NH4CI (1.01 g, 18.9 mmol, 10.0 eq.) in EtOH (8 mL) and H2O (2 mL) was stirred at 50 °C for 2 hours. The mixture was filtered, purified by reversed phase chromatography with formic acid and lyophilized to give 4-bromo-5-tetrahydropyran-4- yloxy-benzene-1, 2-diamine (370.0 mg, 57.9%) as a green oil. LC-MS: m/z = 287.1, 289.1 [M+H]⁺, ESI pos.

Step 3: 5-bromo-6-tetrahydropyran-4-yloxy-lH-benzimidazole

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

Step 4: l-[ 6-(5-bromo-6-tetrahydropyran-4-yloxy-benzimidazol-l-yl)-3-(difluoromethyl)-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile

Prepared according to Example 4, step 3 to yield l-[6-(6-bromo-5-tetrahydropyran-4-yloxy- benzimidazol-l-yl)-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (140.0 mg, 32.8%) and l-[6-(5-bromo-6-tetrahydropyran-4-yloxy-benzimidazol-l-yl)-3-(difluoromethyl)-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile (130.0 mg, 30.4% yield) as yellow solids after purification by flash column chromatography (15% EtOAc in PE to 25% MeOH in EtOAc). l-[6-(6-bromo-5-tetrahydropyran-4-yloxy-benzimidazol-l-yl)-3-(difluoromethyl)-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile: LC-MS: m/z = 529.1, 539.1 [M+H]⁺, ESI pos. ^XH NMR (400 MHz, CD₃OD) 8 = 8.93 (s, 1H), 8.56 (d, J= 8.8 Hz, 1H), 8.21 (d, J= 8.8 Hz, 1H), 7.95 (d, J= 13.8 Hz, 2H), 7.20 - 6.88 (m, 2H), 4.56 - 4.50 (m, 1H), 4.02 - 3.95 (m, 2H), 3.57 - 3.50 (m, 2H), 2.48 (s, 3H), 2.01 - 1.96 (m, 2H), 1.84 - 1.77 (m, 2H). l-[6-(5-bromo-6-tetrahydropyran-4-yloxy-benzimidazol-l-yl)-3-(difluoromethyl)-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile: LC-MS: m/z = 529.0, 539.0 [M+H]⁺, ESI pos. 'l l NMR (400 MHz, CD3OD) 8 = 8.97 (s, 1H), 8.53 (d, J= 8.8 Hz, 1H), 8.47 (s, 1H), 8.18 (d, J= 8.8 Hz, 1H), 7.44 (s, 1H), 7.22 - 6.89 (m, 2H), 4.78 - 4.71 (m, 1H), 4.05 - 3.97 (m, 2H), 3.67 - 3.60 (m, 2H), 2.53 (s, 3H), 2.12 - 2.05 (m, 2H), 1.88 - 1.80 (m, 2H).

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

Prepared according to Example 4, step 4 to yield l-[3-(difluoromethyl)-6-[5-[(6- methylpyridazin-3-yl)amino]-6-tetrahydropyran-4-yloxy-benzimidazol-l-yl]-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile (14.1 mg„ 10.3% yield) as a white solid after purification by preparative HPLC (Phenomenex C18 (75 x 30 mm, 3 pm), 18 - 48% CH3CN in H2O (with 0.225% HCOOH) over 7 minutes, flow rate: 25 mL/min). LC-MS: m/z = 558.3 [M+H]⁺, ESI pos. ^XH NMR (400 MHz, DMSO-d₆) 8 = 9.05 (s, 1H), 8.68 (s, 1H), 8.61 (d, J= 8.8 Hz, 1H), 8.37 (d, J= 8.8 Hz, 1H), 8.18 (s, 1H), 7.89 (s, 1H), 7.38 - 7.26 (m, 2H), 7.25 - 6.93 (m, 2H), 4.45 - 4.37 (m, 1H), 3.90 - 3.82 (m, 2H), 3.31 - 3.27 (m, 2H), 2.48 (s, 3H), 2.46 (s, 3H), 1.96 - 1.89 (m, 2H), 1.76 - 1.66 (m, 2H). Example 19 l-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-5-(difluoromethyl)-2-pyridyl]- N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine

Step 1: 5-bromo-l-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-5-(difluoromethyl)-2- pyridyl]-6-(oxetan-3-yloxy)benzimidazole

Prepared according to Example 4, step 3 to afford 5-bromo-l-[6-[3-(difluoromethoxy)-5-methyl- pyrazol-l-yl]-5-(difluoromethyl)-2-pyridyl]-6-(oxetan-3-yloxy)benzimidazole (110.0 mg, 31.4%) and 6-bromo-l-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-5-(difluoromethyl)-2- pyridyl]-5-(oxetan-3-yloxy)benzimidazole (100.0 mg, 28.6%) as white solids. LC-MS: m/z = 544.0 [M+H]⁺, ESI pos. ^XH NMR (400 MHz, CD3OD) 6 = 8.96 - 8.91 (m, 1H), 8.54 - 8.51 (m, 1H), 8.50 - 8.43 (m, 1H), 8.06 - 8.01 (m, 1H), 7.41 - 6.97 (m, 3H), 6.20 - 6.11 (m, 1H), 5.47 - 5.40 (m, 1H), 5.15 - 5.09 (m, 2H), 4.83 - 4.77 (m, 2H), 2.57 - 2.47 (m, 3H).

Step 2: l-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-5-(difluoromethyl)-2-pyridyl]-N-(6- methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine

Prepared according to Example 4, step 4 to yield l-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-l- yl]-5-(difluoromethyl)-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol- 5-amine (37.0 mg, 35.2%) as a yellow solid after purification by preparative HPLC (Phenomenex luna C18 (150 x 40 mm, 15 pm), 18 - 48% CH3CN in H2O (with 0.225% HCOOH) over 7 minutes, flow rate: 25 mL/min). LC-MS: m/z = 571.1 [M+H]⁺, ESI pos. 'H NMR (400 MHz, DMSO-d₆) 8 = 9.01 - 8.96 (m, 1H), 8.86 - 8.80 (m, 1H), 8.58 - 8.49 (m, 1H), 8.28 - 8.27 (m, 1H), 8.23 - 8.15 (m, 1H), 7.65 - 7.15 (m, 5H), 6.35 - 6.27 (m, 1H), 5.32 - 5.23 (m, 1H), 4.82 - 4.78 (m, 2H), 4.76 - 4.72 (m, 2H), 2.52 - 2.52 (m, 3H), 2.46 - 2.44 (m, 3H). Example 20 l-[6-[3,5-bis(difluoromethyl)pyrazol-l-yl]-5-(difluoromethyl)-2-pyridyl]-N-(6- methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine

Step 1 : 2-[ 3, 5-bis(difluoromethyl)pyrazol-l-yl ]-6-chloro-3-(difluoromethyl )pyridine Prepared according to Example 4, step 1 using 3, 5-bis-(difluoromethyl)-lH-pyrazole (78.7 mg, 0.47 mmol, 1.0 eq.) at 50 °C to afford 2-[3, 5-bis(difluoromethyl)pyrazol-l-yl]-6-chloro-3- (difluoromethyl)pyridine (100.0 mg, 64.8%) as an off-white liquid. LC-MS: m/z = 329.8 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 6 = 8.16 - 8.11 (m, 1H), 7.54 - 7.38 (m, 2H), 7.29 (br d, J= 8.0 Hz, 1H), 6.97 - 6.93 (m, 1H), 6.81 - 6.52 (m, 1H).

Step 2: l-[ 6-[ 3, 5-bis(difluoromethyl)pyrazol-l-yl / -5-(difluoromethyl)-2-pyridyl / -5-bromo-6- (oxetan-3-yloxy)benzimidazole

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

(oxetan-3-yloxy)benzimidazole: LC-MS: m/z = 564.0 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CD₃OD) 8 = 8.91 - 8.88 (m, 1H), 8.63 - 8.57 (m, 1H), 8.18 - 8.13 (m, 1H), 8.02 - 7.99 (m, 1H), 7.44 - 6.84 (m, 5H), 5.32 - 5.25 (m, 1H), 4.87 - 4.84 (m, 2H), 4.78 - 4.73 (m, 2H).

Step 3: l-[ 6-[ 3, 5-bis(difluoromethyl)pyrazol-l-yl / -5-(difluoromethyl)-2-pyridyl ]-N-( 6- methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine

Prepared according to Example 4, step 4 to yield l-[6-[3, 5-bis(difluoromethyl)pyrazol-l-yl]-5- (difluoromethyl)-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5- amine (7.0 mg, 7.8%) as yellow solid after purification by preprative HPLC (Phenomenex luna Cl 8 (150 x 40 mm, 15 pm), 22 - 52% CH3CN in H₂O (with 0.225% HCOOH) over 7 minutes, flow rate: 25 mL/min). LC-MS: m/z = 591.2 [M+H]⁺, ESI pos. 'H NMR (400 MHz, DMSO-d₆) 8 = 8.99 - 8.95 (m, 1H), 8.86 - 8.82 (m, 1H), 8.64 - 8.59 (m, 1H), 8.39 - 8.35 (m, 1H), 8.32 - 8.27 (m, 1H), 7.60 - 7.32 (m, 5H), 7.32 - 7.09 (m, 2H), 5.31 - 5.24 (m, 1H), 4.77 - 4.72 (m, 2H), 4.71 - 4.67 (m, 2H), 2.49 - 2.49 (m, 3H).

Example 21 (3R,5S)-l-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrrolidine-3-carbonitrile

Step 1: tert-butyl (2S,4S)-2-methyl-4-methylspLfonyloxy-pyrrolidine-l -carboxylate

To a solution of tert-butyl (2S,4S)-4-hydroxy-2-methyl-pyrrolidine-l-carboxylate (1000.0 mg, 4.97 mmol, 1.0 eq.) and TEA (3.46 mL, 24.87 mmol, 5.01 eq.) in DCM (16 mL) was added MsCl (0.88 mL, 11.34 mmol, 2.28 eq.) dropwise at 0 °C. The reaction mixture was stirred at 0 °C under N2 for 3 hours. H₂O (100 mL) was added to the mixture which was extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na₂SO4, filtered and concentrated under reduced pressure to give a light yellow oil. The crude was purified by flash column chromatography using 0% - 30% EtOAc in PE to yield tert-butyl (2S,4S)-2-methyl-4- methylspLfonyloxy-pyrrolidine-l-carboxylate (1.27 g, 91.5%) as light yellow oil. LC-MS: m/z = 223 [M+H-C₄H₈]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 6 = 5.22 - 5.13 (m, 1H), 4.02 (br d, J = 5.3 Hz, 1H), 3.83 (br s, 1H), 3.55 (br dd, J= 4.1, 13.1 Hz, 1H), 3.03 (s, 3H), 2.44 (br s, 1H), 1.92 - 1.80 (m, 1H), 1.47 (s, 9H), 1.29 - 1.25 (m, 3H).

Step 2: tert-butyl (2S,4R)-4-cyano-2-methyl-pyrrolidine-l-carboxylate

To a clear, brown solution of tert-butyl (2S,4S)-2-methyl-4-methylspLfonyloxy-pyrrolidine-l- carboxylate (1270.0 mg, 4.55 mmol, 1.0 eq.) in DMSO (13 mL) was added sodium cyanide (646.0 mg, 13.18 mmol, 2.9 eq.). The mixture was stirred at 80 °C for 20 hours. The yellow suspension was coole to 20 °C and sat. aq. NaHCOs sol. (300 ml) was added. The mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na2SO₄, filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography using 0% - 30% EtOAc in PE to yield tert-butyl (2S,4R)-4-cyano-2-methyl- pyrrolidine-1 -carboxylate (820.0 mg, 85.8%) as colorless oil. LC-MS: m/z = 155 [M+H-C₄H₈]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 6 = 3.92 (br s, 2H), 3.53 (dd, J= 7.0, 11.3 Hz, 1H), 2.99 (quin, J= 7.4 Hz, 1H), 2.55 - 2.44 (m, 1H), 1.95 - 1.87 (m, 1H), 1.46 (s, 9H), 1.35 (br d, J= 6.2 Hz, 3H).

Step 3: (3R,5S)-5-methylpyrrolidine-3-carbonitrile; 2, 2, 2 -trifluoroacetic acid

To a solution oftert-butyl (2S,4R)-4-cyano-2-methyl-pyrrolidine-l-carboxylate (820.0 mg, 3.9 mmol, 1.0 eq.) in DCM (10 mL) was added TFA (10.0 mL, 123.25 mmol, 31.6 eq.). The mixture was stirred at 25 °C for 2 hours and concentrated to dryness to yield (3R,5S)-5- methylpyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid (900.0 mg, quant, yield) as a light brown oil. 'H NMR (400 MHz, DMSO-d₆) 8 = 9.53 - 9.29 (m, 1H), 8.99 (br s, 1H), 8.33 - 7.35 (m, 8H), 3.63 - 3.45 (m, 4H), 2.59 - 2.52 (m, 1H), 1.81 (ddd, J= 8.9, 10.4, 12.9 Hz, 1H), 1.32 (d, = 6.6 Hz, 3H).

Step 4: (3R, 5S)-l-[ 6-chloro-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrrolidine-3-carbonitrile To a solution of (3R,5S)-5-methylpyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid (850.0 mg, 3.79 mmol, 1.0 eq.) in DMSO (20 mL) were added 6-chloro-3-(difluoromethyl)-2-fluoro- pyridine (689.0 mg, 3.8 mmol, 1.0 eq.) and K2CO3 (2620.1 mg, 18.96 mmol, 5.0 eq.). The mixture was stirred at 25 °C for 16 hours after which the clear yellow solution had turned to a yellow suspension. The reaction mixture was quenched by the addition of sat. aq. NH₄C1 sol. (100 ml) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography using 0% - 2% EtOAc in PE to yield (3 R, 5 S)-l-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrrolidine-3 -carbonitrile (340.0 mg, 33%) as light yellow oil. LC-MS: m/z = 272.2 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 8 = 7.78 (d, J= 8.1 Hz, 1H), 6.92 (d, J= 8.0 Hz, 1H), 6.73 (t, J= 54.9 Hz, 1H), 4.44 - 4.33 (m, 1H), 3.89 - 3.77 (m, 2H), 3.11 - 2.99 (m, 1H), 2.66 - 2.56 (m, 1H), 1.98 (td, J= 9.5, 12.4 Hz, 1H), 1.28 (d, J= 6.0 Hz, 3H).

Step 5: (3R,5S)-l-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]- 2-pyridyl]-5-methyl-pyrrolidine-3-carbonitrile

To a solution of (3R,5S)-l-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrrolidine-3- carbonitrile (320.0 mg, 1.18 mmol, 1.0 eq) in t-amyl alcohol (15.0 mL) were added N-(6- methylpyridazin-3-yl)-lH-benzimidazol-5-amine (325.0 mg, 1.3 mmol, 1.1 eq), K3PO4 (750.0 mg, 3.54 mmol, 3.0 eq) and 'BuXPhos Pd G3 (94.0 mg, 0.12 mmol, 0.1 eq). The reaction mixture was heated to 100 °C and stirred for 16 hours under a N2 atmosphere. The brown suspension was cooled to 20 °C and quenched by the addition of sat. aq. NH4CI sol. (100 mL). The mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was first purified by preparative HPLC (Phenomenex Luna C18 (150 mm x 40 mm, 15 pm), 17 - 47% CH3CN in H2O (with 0.225% HCOOH) over 10 minutes, flow rate: 60 mL/min) to afford of a mixture of (3R,5S)-1- [3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5- methyl-pyrrolidine-3-carbonitrile and its regioisomer (3R,5S)-l-[3-(difluoromethyl)-6-[6-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrrolidine-3-carbonitrile. This mixture was purified by SFC (Daicel Chiralcel OJ (250 mm x 30 mm, 10 pm) with MeOH (0.1% NH4OH) in CO2) to yield (3R,5S)-l-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrrolidine-3-carbonitrile (70.0 mg, 30.9%) as a yellow solid. LC-MS: m/z = 461.2 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 6 = 8.59 (s, 1H), 8.06 (d, J= 8.3 Hz, 1H), 8.00 (d, J= 8.8 Hz, 1H), 7.76 (d, J= 1.5 Hz, 1H), 7.47 - 7.42 (m, 1H), 7.19 - 7.13 (m, 2H), 7.10 - 7.05 (m, 1H), 6.99 - 6.68 (m, 2H), 4.58 - 4.46 (m, 1H), 4.00 - 3.89 (m, 2H), 3.19 - 3.07 (m, 1H), 2.77 - 2.67 (m, 1H), 2.61 (s, 3H), 2.08 (td, J= 9.5, 12.7 Hz, 1H), 1.38 (d, J= 6.0 Hz, 3H). Example 22 l-[6-[5-[(7-cyclopropyl-6-keto-5,5-dimethyl-pyrrolo[2,3-c]pyridazin-3- yl)amino]-6-methoxy-benzimidazol-l-yl]-3-(difluoromethyl)-2-pyridyl]-5- methyl-pyrazole-3-carbonitrile

Step 1: 3,6-dichloro-N-cyclopropylpyridazin-4-amine

In a 100 mL glass tube, 3,4,6-trichloropyridazine (5 g, 26.7 mmol, Eq: 1.00) was dissolved in THF (50.0 mL). Then cyclopropanamine (15.6 g, 19.1 ml, 267 mmol, Eq: 10) was added to give a brown solution. The tube was sealed and heated at 50 °C for 3 hours. The mixture was cooled to 20 °C. H2O and EtOAc were added. The mixture was extracted 3 times with EtOAc and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The crude material was triturated in heptane/EtOAc 9: 1, collected by filtration, washed with heptane and dried. 3,6-dichloro-N-cyclopropylpyridazin-4-amine (4.965 g) was obtained as an orange solid. LC-MS: m/z = 204.6 [M+H]⁺, ESI pos. (300 MHz, CDCL) 8 = 6.91 (s, 1H), 5.35 (br. s., 1H), 2.53 (br. s., 1H), 0.92-1.01 (m, 2H), 0.64-0.72 (m, 2H).

Step 2: 5, 8-dichloro-l -cyclopropyl- 7-isobutyryl-3, 3-dimethyl-l, 6, 7-triazaspiro[ 3.5 ]nona-5, 8- dien-2-one

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

Step 3: 3-chloro-7-cyclopropyl-5,5-dimethyl-5H-pyrrolo[2,3-c]pyridazin-6(7H)-one In a 5 mL glass tube, 5,8-dichloro-l-cyclopropyl-7-isobutyryl-3,3-dimethyl-l,6,7- triazaspiro[3.5]nona-5,8-dien-2-one (98 mg, 285 pmol, Eq: 1.00) was dissolved in DMF (2.5 ml). Then CS2CO3 (186 mg, 569 pmol, Eq: 2) was added to give a yellow suspension. The tube was closed and heated at 80 °C for 4 hours. The mixture was filtered and concentrated under vacuo. The crude material was purified by preparative HPLC to yield 3-chloro-7-cyclopropyl- 5,5-dimethyl-5H-pyrrolo[2,3-c]pyridazin-6(7H)-one (67 mg) as a white solid. LC-MS: m/z = 238.1 [M+H]⁺, ESI pos. ^XH NMR (300 MHz, CDCh) 8 = 7.20 (s, 1H), 2.95 (s, 1H), 1.41 (s, 6H), 1.10-1.14 (m, 4H).

Step 4: 3-(benzhydrylideneamino)-7-cyclopropyl-5, 5-dimethyl-pyrrolo[2, 3-c]pyridazin-6-one In a sealed glass tube, 3-chloro-7-cyclopropyl-5,5-dimethyl-pyrrolo[2,3-c]pyridazin-6-one (786 mg, 3.31 mmol, 1.0 eq.) , benzophenone imine (946.26 mg, 876.16 pL, 4.96 mmol, 1.5 eq.) and CS2CO3 (2.15 g, 6.61 mmol, 2.0 eq.) were combined with 1,4-dioxane, extra dry (9.96 mL) and Argon was bubbled for 5 minutes. Then BINAP (205.91 mg, 0.331 mmol, 0.1 eq.) and tris(dibenzylideneacetone)dipalladium (0) chloroform adduct (171.14 mg, 0.165 mmol, 0.050 eq.) was added. The vial was sealed, the mixture was heated to 100 °C and stirred for 16 hours. The reaction mixture was cooled to 23 °C, added to 10 g SiCh and concentrated in vacuo. The crude material was purified by flash column chromatography using 0% - 100% EtOAc in heptane to yield 3-(benzhydrylideneamino)-7-cyclopropyl-5,5-dimethyl-pyrrolo[2,3-c]pyridazin- 6-one (957 mg, 75.7%) as a dark red oil. LC-MS: m/z = 383.3 [M+H]⁺, ESI pos.

Step 5: 3-amino-7-cyclopropyl-5,5-dimethyl-pyrrolo[2,3-c]pyridazin-6-one; 1 : 1 hydrogen chloride

To a solution of 3-(benzhydrylideneamino)-7-cyclopropyl-5,5-dimethyl-pyrrolo[2,3-c]pyridazin- 6-one (957 mg, 2.5 mmol, 1.0 eq.) at 23 °C in THF (10 mL) was added HC1 2 M in Et2O (3.75 mL, 7.51 mmol, 3.0 eq.). A solid immediately precipitated out. H2O (90.18 mg, 90.18 pL, 5. mmol, 2.0 eq.), was added and the resulting solution was stirred for 1 hour. The mixture was concentrated to dryness to give a brown oil to which were added Et2O and a few drops of THF. A solid precipitated out. It was collected by filtration, washed with Et2O and dried. 3-amino-7- cyclopropyl-5,5-dimethyl-pyrrolo[2,3-c]pyridazin-6-one; 1:1 hydrogen chloride (349 mg, 54.8%) was obtained as light brown solid. LC-MS: m/z = 219.1 [M+H]⁺, ESI pos.

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

Example 23 l-[3-(difluoromethyl)-6-[5-[(6-keto-l-methyl-pyridazin-3-yl)amino]-6-methoxy- benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

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

Prepared according to Example 4, step 4 to yield l-[3-(difluoromethyl)-6-[5-[(6-keto-l-methyl- pyridazin-3-yl)amino]-6-methoxy-benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile (53 mg, 97.7%) as a light yellow solid. LC-MS: m/z = 504.2 [M+H]⁺, ESI pos.

Example 24 l-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-[(l-methyl-4-piperidyl)oxy]pyridazin- 3-yl] amino] benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

Step 1: 3-chloro-6-[(l-methyl-4-piperidyl)oxy]pyridazine

To a solution of 4-hydroxy-l -methylpiperidine (850.36 mg, 7.38 mmol, 1.1 eq.) in THF (20 mL) was added NaH (402.74 mg, 10.07 mmol, 1.5 eq.). The reaction was stirred at 0 °C for 0.5 hour, then 3,6-dichloropyridazine (1.0 g, 6.71 mmol, 1.0 eq.) was added. And stirring at 25 °C was continued for 4 hours. The mixture was quenched with sat. aq. NH4CI sol. (50 mL) and extracted with EtOAc (50 mLx 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield 3-chloro-6-[(l-methyl-4- piperidyl)oxy]pyridazine (1.3 g, 85.1%) as a white solid, used without further purification. LC- MS: m/z = 228.0 [M+H]⁺, ESI pos.

Step 2: N-[ 6-[(l-methyl-4-piperidyl)oxy]pyridazin-3-yl]-l, 1-diphenyl-methanimine

To a solution of 3-chloro-6-[(l-methyl-4-piperidyl)oxy]pyridazine (400.0 mg, 1.76 mmol, 1.0 eq.) in toluene (4 mL) was added benzophenone imine (0.32 mL, 1.93 mmol, 1.1 eq.). CS2CO3 (2289.43 mg, 7.03 mmol, 4.0 eq.), BINAP (218.61 mg, 0.35 mmol, 0.2 eq.) and Pd2(dba)3 (160.94 mg, 0.18 mmol, 0.1 eq.) were added. The reaction mixture was stirred at 90 ⁰ C under N2 for 6 hours. The mixture cooled to 23 °C, diluted with H2O (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was by preparative HPLC (basic) to yield N-[6-[(l-methyl-4-piperidyl)oxy]pyridazin-3-yl]-l, 1-diphenyl- methanimine (240.0 mg, 36.7%) as a yellow gum. LC-MS: m/z = 373.0 [M+H]⁺, ESI pos. Step 3: 6-[(l-methyl-4-piperidyl)oxy]pyridazin-3-amine

A mixture of N-[6-[(l-methyl-4-piperidyl)oxy]pyridazin-3-yl]-l,l-diphenyl-methanimine (400.0 mg, 1.07 mmol, 1.0 eq) and 4 M HC1 solution in dioxane (3.0 mL) was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure. The residue was suspended in EtOAc (15 mL) and stirred for 15 minutes. The solid was collected by filtration and dried to yield 6-[(l-methyl-4-piperidyl)oxy]pyridazin-3 -amine (200.0 mg, 89.4%) as a brown solid. LC- MS: m/z = 209.1 [M+H]⁺, ESI pos.

Step 4: l-[ 3-(difluoromethyl)-6-[ 6-methoxy-5-[[ 6-[ ( 1 -methyl-4-piperidyl)oxy]pyridazin-3- yl] amino] benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

Prepared according to Example 4, step 4 to yield l-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-[(l- methyl-4-piperidyl)oxy]pyridazin-3-yl]amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole- 3 -carbonitrile (16.9 mg, 25.8%) as a white solid after purification by preparative HPLC (Waters Xbridge (150 mm x 25 mm, 5 pm), 40% - 70% CEECN in H2O (with NH4HCO3) over 8 minutes, flow rate 25 mL / min). LC-MS: m/z = 587.0 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CD₃OD) 8 = 8.74 (S, 1H), 8.59 (S, 1H), 8.43 (d, J= 8.5 Hz, 1H), 8.11 (d, J= 8.5 Hz, 1H), 7.72 - 7.71(m, 1H), 7.26 (d, J= 9.5 Hz, 1H), 7.11 - 6.91 (t, 2H), 6.84 - 6.83 (m, 1H), 4.80(m, 1H), 3.84 (s, 3H), 2.80 (br s, 2H), 2.51 - 2.48 (s, 3H), 2.46 (br s, 2H), 2.34 (s, 3H), 2.16 - 2.04 (m, 2H), 1.93 - 1.80 (m, 2H).

Example 25 l-[5-(difluoromethyl)-6-[l-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-2-pyridyl]- N-(6-methylpyridazin-3-yl)benzimidazol-5-amine

Step 1 : l-(2-methoxyethyl)-3-methyl-4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)pyrazole A solution of 3-methyl-4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-lH-pyrazole (3.0 g, 14.42 mmol, 1.0 eq.), 2-bromoethyl methyl ether (5.85 mL, 62.29 mmol, 4.32 eq.) and potassium carbonate (4.42 g, 32.01 mmol, 2.22 eq.) in CH3CN (40 mL) was stirred at 80 °C for 24 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by flash column chromatography using 0% - 25% EtOAc in PE to yield l-(2-methoxyethyl)-3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyrazole (3.0 g, 78.2%) as a colorless oil (2: 1 mixture of regioisomers). LC-MS: m/z = 267.2 [M+H]⁺, ESI pos.

Step 2: l-[5-(l, 3-dioxolan-2-yl)-6-[ l-(2-methoxyethyl)-3-methyl-pyrazol-4-yl] -2-pyridyl] -N-(6- methylpyridazin-3-yl)benzimidazol-5-amine

To a mixture of l-(2-methoxyethyl)-3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyrazole (195.29 mg, 0.73 mmol, 1.5 eq.) and l-[6-chloro-5-(l,3-dioxolan-2-yl)-2-pyridyl]- N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (200.0 mg, 0.49 mmol, 1.0 eq.) in THF (5 mL) and H2O (0.5 mL) was added Sphos Pd G3 (42.82 mg, 0.05 mmol, 0.1 eq.) and K3PO4 (207.68 mg, 0.98 mmol, 2.0 eq.). The mixture was stirred at 60 °C for 12 hours under N2 atmosphere. The reaction mixture was cooled to 23 °C and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (36% CH3CN in H2O (with 1% FA)) to yield l-[5-(l,3-dioxolan-2-yl)-6-[l-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-2-pyridyl]-N-(6- methylpyridazin-3-yl)benzimidazol-5-amine (200.0 mg, 79.8%) as a yellow solid (mixture of regioisomers). LC-MS: m/z = 513.2 [M+H]⁺, ESI pos.

Step 3: 2-[l-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-6-[5-[(6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl ]pyridine-3-carbaldehyde

A solution of l-[5-(l,3-dioxolan-2-yl)-6-[l-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-2-pyridyl]- N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (250.0 mg, 0.49 mmol, 1.0 eq.) in HC1 4 M solution in dioxane (4.0 mL, 16.0 mmol, 32.8 eq.) was added 6 N HC1 (4.0 mL, 24.0 mmol, 49.21 eq.) at 25 °C and the resulting mixture was stirred at 25 °C for 2 hours. The reaction mixture was filtered and the filter cake was washed with H2O (5 mL) dried to yield 2-[l-(2- methoxyethyl)-3-methyl-pyrazol-4-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl]pyridine-3-carbaldehyde (180.0 mg, 98.5%) as a yellow solid (mixture of regioisomers). LC- MS: m/z = 469.2 [M+H]⁺, ESI pos.

Step 4: l-[5-(difluoromethyl)-6-[ l-(2-methoxyethyl)-5-methyl-pyrazol-4-yl] -2-pyridyl] -N-(6- methylpyridazin-3-yl)benzimidazol-5-amine

To a solution of 2-[l-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]pyridine-3-carbaldehyde (60.0 mg, 0.13 mmol, 1.0 eq.) in DCM (5 mL) was added DAST (62.01 mg, 0.38 mmol, 3.0 eq.) at 0 °C and the resulting mixture was stirred at 25 °C for 12 hours. The reaction mixture was quenched by the addition of H2O (3 mL) at 25 °C and the DCM was removed under reduced pressure. The aqueous mixture was directly purified by reverse-phase HPLC (60% CH3CN in H2O (with 1% FA)) to yield l-[5- (difluoromethyl)-6-[l-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-2-pyridyl]-N-(6- methylpyridazin-3-yl)benzimidazol-5-amine (20.0 mg, 31.8%) as a yellow solid (mixture of regioisomers). LC-MS: m/z = 491.3 [M+H]⁺, ESI pos.

The above mixture of regioisomers was purified by SFC (Daicel Chiralpak AD (250 mm x 30 mm, 10 pm) with MeOH (0.1% NH4OH) in CO2) to yield l-[5-(difluoromethyl)-6-[l-(2- methoxyethyl)-5-methyl-pyrazol-4-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5- amine (5.4 mg, 26.2%) as white solid. LC-MS: m/z = 491.3 [M+H]⁺, ESI pos.

'H NMR (400 MHz, DMSO-d₆) 8 = 9.22 (s, 1H), 9.04 (s, 1H), 8.42 (d, J= 2.0 Hz, 1H), 8.33 (d, J= 8.8 Hz, 1H), 8.23 (d, J= 8.8 Hz, 1H), 8.03 (d, J= 8.8 Hz, 1H), 7.69 (s, 1H), 7.52 (dd, J= 2.0, 8.8 Hz, 1H), 7.33 (d, J= 92 Hz, 1H), 7.19 (s, 1H), 7.13 - 7.03 (m, 2H), 6.91 (s, 1H), 4.34 (t, J= 52 Hz, 2H), 3.76 (t, J= 52 Hz, 2H), 3.28 (s, 3H), 2.48 (d, J= 4.0 Hz, 6H).

Example 26 l-[5-(difluoromethyl)-6-[l-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-2-pyridyl]- N-(6-methylpyridazin-3-yl)benzimidazol-5-amine l-[5-(difluoromethyl)-6-[l-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-2-pyridyl]-N-(6- methylpyridazin-3-yl)benzimidazol-5-amine (8.1 mg, 0.02 mmol, 40.5% yield) was isolated in Example 25, step 4 as the second regioisomer and was obtained as a white solid. LC-MS: m/z = 491.3 [M+H]⁺, ESI pos. 'H NMR (400 MHz, DMSO-d₆) 6 = 9.22 (s, 1H), 9.02 (s, 1H), 8.45 (d, J =2.0 Hz, 1H), 8.33 (d, J = 8.8 Hz, 1H), 8.21 (d, J= 8.8 Hz, 1H), 8.01 (d, J= 8.8 Hz, 1H), 7.94 (s, 1H), 7.51 (dd, J= 2.0, 8.8 Hz, 1H), 7.33 (d, J= 9.2 Hz, 1H), 7.15 (s, 1H), 7.09 (d, J= 9.2 Hz, 1H), 7.01 (s, 1H), 6.88 (s, 1H), 4.31 (t, J= 5.3 Hz, 2H), 3.74 (t, J= 52 Hz, 2H), 3.28 (s, 3H), 2.48 (br s, 3H), 2.35 (s, 3H).

Example 27 l-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-[[l-(oxetan-3-yl)-4- piperidyl]oxy]pyridazin-3-yl] amino] benzimidazol-l-yl]-2-pyridyl]-5-methyl- pyrazole-3-carbonitrile

Step 1: tert-butyl 4-(6-chloropyridazin-3-yl)oxypiperidine-l -carboxylate

To a solution of l-Boc-4-hydroxypiperidine (1621.1 mg, 8.05 mmol, 1.2 eq.) in THF (15 mL) was added NaH (537.0 mg, 13.43 mmol, 2.0 eq.) at 0 °C under N2 atmosphere. The reaction mixture was stirred at 0 °C for 30 minutes. Then to the mixture was added 3,6- dichloropyridazine (1000.0 mg, 6.71 mmol, 1.0 eq.) at 0 °C under N2 atmosphere and stirring was continued for 2 hours. The reaction mixture was poured into sat. aq. NH4CI sol. (100 mL) with stirring, and this was extracted with EtOAc (100 mL x 3). The combined organic extracts were concentrated under vacuum. The crude material was purified by flash column chromatography using 0% - 15% EtOAc in PE to yield tert-butyl 4-(6-chloropyridazin-3- yl)oxypiperidine-l -carboxylate (1.8 g, 85.5%) as a white solid. LC-MS: m/z = 314.2 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 8 = 7.38 (d, J= 92 Hz, 1H), 6.94 (d, J= 92 Hz, 1H), 5.44 (tt, J = 3.9, 8.1 Hz, 1H), 3.90 - 3.75 (m, 2H), 3.31 - 3.22 (m, 2H), 2.12 - 2.04 (m, 2H), 1.83 - 1.68 (m, 2H), 1.48 (s, 9H). Step 2: 3-chloro-6-(4-piperidyloxy)pyridazine;hydrochloride

To a solution of tert-butyl 4-(6-chloropyridazin-3-yl)oxypiperidine-l -carboxylate (1.5 g, 4.78 mmol, 1.0 eq.) in DCM (15 mL) was added HC1 4 M solution in dioxane (5.0 mL, 20.0 mmol, 4.18 eq.). The reaction mixture was stirred at 25 °C for 2 hours. A white solid had precipitated out. The reaction mixture was concentrated to dryness to yield 3-chloro-6-(4- piperidyloxy)pyridazine;hydrochloride (1.1 g, 92.0%) as a white solid. LC-MS: m/z = 214.0 [M+H]⁺, ESI pos. 'H NMR (400 MHz, DMSO-d₆) 8 = 9.25 - 8.94 (m, 2H), 7.83 (d, J= 9.3 Hz, 1H), 7.36 (d, J= 9.2 Hz, 1H), 5.39 (tt, = 3.7, 7.8 Hz, 1H), 3.28 - 3.19 (m, 2H), 3.11 (br dd, J= 3.2, 7.2 Hz, 2H), 2.20 (ddd, J= 3.4, 6.9, 10.1 Hz, 2H), 2.05 - 1.90 (m, 2H).

Step 3: 3-chloro-6-[[ l-(oxetan-3-yl)-4-piperidyl]oxy]pyridazine

A solution of 3-chloro-6-(4-piperidyloxy)pyridazine (1.1 g, 5.15 mmol, 1.0 eq.) and 3-oxetanone (1.11 g, 15.45 mmol, 3.0 eq.) in MeOH (12 mL) was stirred at 20 °C for 10 minutes. Then sodium cyanoborohydride (647.05 mg, 10.3 mmol, 2.0 eq.) was added. Stirring at 20 °C was continued for 1 hour. The reaction mixture was poured into H2O (50 mL) and this was extracted with EtOAc (50 mL x 3). The combined organic extracts were concentrated under vacuum. The crude material was purified by flash column chromatography using 0% - 100% EtOAc in PE to yield 3-chloro-6-[[l-(oxetan-3-yl)-4-piperidyl]oxy]pyridazine (800.0 mg, 57.6%) as a white solid. LC-MS: m/z = 270.0 [M+H]⁺, ESI pos. 'H NMR (400 MHz, DMSO-d₆) 6 = 7.78 (d, J= 9.2 Hz, 1H), 7.31 (d, J= 9.3 Hz, 1H), 5.16 (td, J= 4.2, 8.3 Hz, 1H), 4.56 - 4.51 (m, 2H), 4.43 (t, J= 6.1 Hz, 2H), 3.42 (quin, J= 6.4 Hz, 1H), 2.60 - 2.53 (m, 2H), 2.14 - 2.03 (m, 4H), 1.78 - 1.67 (m, 2H).

Step 4: N-[ 6-[[l -(oxetan-3-yl)-4-piperidyl] oxy]pyridazin-3-yl] -1 , 1-diphenyl-methanimine To a solution of benzophenone imine (0.75 mL, 4.45 mmol, 1.5 eq.) and 3-chloro-6-[[l-(oxetan- 3-yl)-4-piperidyl]oxy]pyridazine (800.0 mg, 2.97 mmol, 1.0 eq.) in 1,4-dioxane (10 mL) were added CS2CO3 (1932.72 mg, 5.93 mmol, 2.0 eq.) and Xantphos Pd G4 (142.72 mg, 0.15 mmol, 0.05 eq.) at 20 °C under N2 atmosphere. The mixture was stirred at 100 °C for 16 hours. The reaction mixture was cooled to 23°C and poured into H2O (50mL). This was extracted with EtOAc (50 mL x 3). The combined organic extracts were concentrated under vacuum. The crude material was purified by flash column chromatography using 0% - 100% EtOAc in PE to yield N-[6-[[l -(ox etan-3-yl)-4-piperidyl]oxy]pyridazin-3-yl]-l, 1-diphenyl-methanimine (700.0 mg, 56.9%) as a yellow solid. LC-MS: m/z = 270.0 [M+H]⁺, ESI pos. 'H NMR (400 MHz, DMSO- d₆) 6 = 7.70 (d, J= 7.2 Hz, 2H), 7.58 (d, J= 7.2 Hz, 1H), 7.55 - 7.47 (m, 2H), 7.37 - 7.32 (m, 3H), 7.15 (dd, J= 2.8, 6.5 Hz, 2H), 7.11 - 7.06 (m, 1H), 7.04 - 6.98 (m, 1H), 5.08 - 4.98 (m, 1H), 4.52 (t, J= 6.4 Hz, 2H), 4.44 - 4.39 (m, 2H), 3.42 - 3.37 (m, 1H), 2.56 (br s, 2H), 2.07 - 1.96 (m, 4H), 1.70 - 1.57 (m, 2H).

Step 5: 6-[[ l-(oxetan-3-yl)-4-piperidyl]oxy]pyridazin-3-amine

To a solution of N-[6-[[l-(oxetan-3-yl)-4-piperidyl]oxy]pyridazin-3-yl]-l,l-diphenyl- methanimine (400.0 mg, 0.97 mmol, 1.0 eq.) inMeOH (8 mL) were added sodium acetate (0.18 mL, 2.41 mmol, 2.5 eq.) and hydroxylamine hydrochloride (134.12 mg, 1.93 mmol, 2.0 eq.). Stirring at 20 °C was continued for 0.5 hour. The reaction mixture was purified by preparative TLC using 10% MeOH in DCM to yield 6-[[l-(oxetan-3-yl)-4-piperidyl]oxy]pyridazin-3-amine (180.0 mg, 74.5%) as a white solid. LC-MS: m/z = 251.1 [M+H]⁺, ESI pos. 'H NMR (400 MHz, DMSO-d₆) 8 = 6.87 - 6.78 (m, 2H), 5.85 (s, 2H), 4.94 (tt, J= 4.1, 8.5 Hz, 1H), 4.55 - 4.50 (m, 2H), 4.42 (t, J= 6.1 Hz, 2H), 2.10 - 1.94 (m, 4H), 1.64 (dtd, J= 3.5, 9.1, 12.5 Hz, 2H).

Step 6: l-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-[[l-(oxetan-3-yl)-4-piperidyl]oxy]pyridazin- 3-yl amino ]benzimidazol-l-yl / -2 -pyridyl ]-5-methyl-pyrazole-3-carbonitrile

Prepared according to Example 4, step 4 to yield l-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-[[l- (oxetan-3-yl)-4-piperidyl]oxy]pyridazin-3-yl]amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl- pyrazole-3 -carbonitrile (68.6 mg, 46.5%) as a brown solid after purification by preparative HPLC (Phenomenex Luna C18 (150 mm x 25 mm, 10 pm), 13 - 43% C LCN in H2O (with 0.225% HCOOH) over 10 minutes, flow rate: 25 mL/min). LC-MS: m/z = 629.3 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CD3OD) 8 = 8.80 (s, 1H), 8.66 (s, 1H), 8.49 (br d, J= 8.3 Hz, 1H), 8.17 (br d, J= 8.4 Hz, 1H), 7.78 (s, 1H), 7.31 (d, = 9.5 Hz, 1H), 7.19 - 6.88 (m, 3H), 5.16 - 5.06 (m, 1H), 4.74 - 4.66 (m, 2H), 4.65 - 4.60 (m, 2H), 3.90 (s, 3H), 3.63 - 3.53 (m, 1H), 2.74 - 2.63 (m, 2H), 2.54 (s, 3H), 2.28 (br s, 2H), 2.19 - 2.11 (m, 2H), 1.96 - 1.78 (m, 2H).

Example 28 l-[3-(difluoromethyl)-6-[6-methoxy-5-[(4-methyl-2,3-dihydropyridazino[4,5- b][l,4]oxazin-8-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile

Step 1: 2-[ (5, 6-dichloropyridazin-4-yl)-methyl-amino] ethanol

To a solution of 3,4,5-trichloropyridazine (11.0 g, 59.97 mmol, 1.0 eq.) in MeOH (80 mL) was added dropwise a solution of 2-(methylamino)ethanol (13.51 g, 179.91 mmol, 3.0 eq.) in MeOH (120 mL) at 20 °C. Stirring at 20 °C was then continued for 16 hours. The mixture was concentrated under vacuum. The crude material was purified by flash column chromatography using 0% - 16% MeOH in EtOAc to yield 2-[(5,6-dichloropyridazin-4-yl)-methyl-amino]ethanol (9.7 g, 72.8%) as a yellow oil. LC-MS: m/z = 222.0 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 6 = 8.59 (s, 1H), 3.94 - 3.88 (m, 2H), 3.75 - 3.69 (m, 2H), 3.21 (s, 3H).

Step 2: 8-chloro-4-methyl-2, 3-dihydropyridazino[ 4, 5-b ][ 1, 4 ] oxazine

To a solution of 2-[(5,6-dichloropyridazin-4-yl)-methyl-amino]ethanol (3.0 g, 13.51 mmol, 1.0 eq.) in THF (270 mL) was added potassium tert-butoxide (1.82 g, 16.21 mmol, 1.2 eq.) at 80 °C The mixture was stirred at 80 °C for 3 hours. The reaction mixture was cooled to 23 °C and concentrated. The residue was treated with sat. aq. NH4CI sol. (250 mL) and this was extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over ISfeSCU, filtered and concentrated under vacuum to give-chloro-4-methyl-2,3- dihydropyridazino[4,5-b][l,4]oxazine (2.2 g, 79.0%) as light brown solid. LC-MS: m/z = 186.0 [M+H]⁺, ESI pos. 'H NMR (400 MHz, DMSO-d₆) 8 = 8.65 (s, 1H), 4.41 - 4.36 (m, 2H), 3.49 - 3.43 (m, 2H), 3.02 (s, 3H). Step 3: benzhydrylidene-(4-methyl-2, 3-dihydropyridazino[ 4, 5-b ] [ 1, 4 ]oxazin-8-yl)amine In a glass tube , 8-chloro-4-methyl-2,3-dihydropyridazino[4,5-b][l,4]oxazine (250 mg, 1.35 mmol, 1.0 eq.) , benzophenone imine (385.42 mg, 356.87 pL, 2.02 mmol, 1.5 eq.) and CS2CO3 (877.7 mg, 2.69 mmol, 2.0 eq.) were combined with 1,4-dioxane, extra dry (4 mL) and Argon was bubbled through the mixture for 5 minutes. Then BINAP (83.87 mg, 0.135 mmol, 0.1 eq.) and tris(dibenzylideneacetone)dipalladium (0) chloroform adduct (69.71 mg, 0.067 mmol, 0.05 eq.) was added, the vial was sealed, the mixture was heated to 100 °C and stirring was continued for 16 hours. More benzophenone imine (385.42 mg, 356.87 pL, 2.02 mmol, 1.5 eq.), CS2CO3 (877.7 mg, 2.69 mmol, 2.0 eq.), BINAP (83.87 mg, 0.135 mmol, 0.1 eq.) and tris(dibenzylideneacetone)dipalladium (0) chloroform adduct (69.71 mg, 0.067 mmol, 0.05 eq.) were added. The mixture was stirred at 100 °C for 2 days. The reaction was cooled to 23 °C, added to 10 g SiCh an d concentrated in vacuo. The crude material was purified by flash column chromatography using 0% - 100% EtOAc in heptane, then 20% EtOAc in MeOH to yield benzhydrylidene-(4-methyl-2,3-dihydropyridazino[4,5-b][l,4]oxazin-8-yl)amine (188 mg, 39.7%) as a brown oil. LC-MS: m/z = 331.2 [M+H]⁺, ESI pos.

Step 4: (4-methyl-2,3-dihydropyridazino[4,5-b] [l,4]oxazin-8-yl)amine dihydrochloride To a solution of benzhydrylidene-(4-methyl-2,3-dihydropyridazino[4,5-b][l,4]oxazin-8- yl)amine (188 mg, 0.535 mmol, 1.0 eq.) in THF (10 mL) were added HC1 2 M in Et2O (2.67 mL, 5.35 mmol, 10.0 eq.) and H2O (9.64 mg, 9.64 pL, 0.535 mmol, 1.0 eq.). The mixture was stirred for 1 hour at 20 °C. The precipitated solid was collected by filtration, washed with Et2O and ried to yield (4-methyl-2,3-dihydropyridazino[4,5-b][l,4]oxazin-8-yl)amine dihydrochloride (100 mg, 78.2%) as a light brown solid. LC-MS: m/z = 167.0 [M+H]⁺, ESI pos.

Step 5: l-[ 3-(difluoromethyl)-6-[ 6-methoxy-5-[ ( 4-methyl-2, 3-dihydropyridazino[ 4, 5- b] [1,4 oxazin-8-yl)amino ]benzimidazol-l-yl ]-2-pyridyl ]-5-methyl-pyrazole-3-carbonitrile Prepared according to Example 4, step 4 using l-[6-(5-bromo-6-methoxy-benzimidazol-l-yl)-3- (difluoromethyl)-2-pyridyl] -5 -methyl-pyrazole-3 -carbonitrile (50 mg, 0.098 mmol, 1.0 eq, prepared in Example 3, step 4), (4-methyl-2,3-dihydropyridazino[4,5-b][l,4]oxazin-8- yl)amine;dihydrochloride (46.9 mg, 0.196 mmol, 2.0 eq.) to yield l-[3-(difluoromethyl)-6-[6- methoxy-5-[(4-methyl-2,3-dihydropyridazino[4,5-b][l,4]oxazin-8-yl)amino]benzimidazol-l-yl]- 2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (18 mg, 27.0%) as a light brown solid. LC-MS: m/z = 589.3 [M+HCOO]', ESI neg. Example 29 l-[6-[l-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(difluoromethyl)-2- pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine

Step 1: l-(cyclopropylmethyl)-3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole and l-(cyclopropylmethyl)-5-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole A mixture of 3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (1.0 g, 4.81 mmol, 1.0 eq.), (bromomethyl)cyclopropane (4.66 mL, 48.06 mmol, 10.0 eq.) and CS2CO3 (3.13 g, 9.61 mmol, 2.0 eq.) in CH3CN (10 mL) was stirred at 80 °C for 12 hours. The reaction mixture was cooled to 23 °C and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Welch pLtimate XB-CN (250 mm x 70 mm, 10 pm), gradient of EtOH in hexane). l-(cyclopropylmethyl)-3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (330 mg, 26.2%) was obtained as a colorless oil. LC-MS: m/z = 263.1 [M+H]⁺, ESI pos. 'H NMR (400 MHz, DMSO-de) 8 = 7.80 (s, 1H), 3.85 (d, J= 7.1 Hz, 2H), 3.34 (s, 1H), 2.23 (s, 3H), 1.24 (s, 12H), 0.49 (br d, J= 7.7 Hz, 2H), 0.32 (br d, J= 4.6 Hz, 2H). l-(cyclopropylmethyl)-5-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (100 mg, 7.9%) was obtained as a colorless oil. LC-MS: m/z = 263.1 [M+H]⁺, ESI pos. 'H NMR (400 MHz, DMSO-de) 6 = 7.45 (s, 1H), 3.89 (d, J= 6.8 Hz, 2H), 3.36 (br s, 1H), 2.38 (s, 3H), 1.24 (s, 12H), 0.46 (br d, J= 7.8 Hz, 2H), 0.31 (br d, J= 4.6 Hz, 2H).

Step 2: l-[ 6-[ 1 -(cyclopropylmethyl)-3-methyl-pyrazol-4-yl ]-5-( 1, 3-dioxolan-2-yl)-2 -pyridyl ]-N- (6-methylpyridazin-3-yl)benzimidazol-5-amine

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

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

Step 4: l-[6-[l-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(difluoromethyl)-2-pyridyl]-N-(6- methylpyridazin-3-yl)benzimidazol-5-amine;formic acid

Prepared according to Example 25, step 4 to yield l-[6-[l-(cyclopropylmethyl)-3-methyl- pyrazol-4-yl]-5-(difluoromethyl)-2-pyridyl]-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; formic acid (31.0 mg, 36.1%) as a yellow solid. LC-MS: m/z = 487.2 [M+H]⁺, ESI pos. ^TH NMR (400 MHz, CD₃OD) 8 = 8.92 (s, 1H), 8.34 (d, J= 8.8 Hz, 1H), 8.29 - 8.19 (m, 2H), 7.93 (s, 1H), 7.91 (d, J= 8.8 Hz, 1H), 7.60 (dd, J = 2.0, 8.8 Hz, 1H), 7.41 (d, J= 9.2 Hz, 1H), 7.19 (d, J = 9.2 Hz, 1H), 6.84 (s, 1H), 4.05 (d, J = 7.2 Hz, 2H), 2.54 (s, 3H), 2.42 (s, 3H), 1.45 - 1.31 (m, 1H), 0.72 - 0.59 (m, 2H), 0.46 (q, J = 4.8 Hz, 2H).

Example 30

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

Step 1: 6-amino-4-methyl-pyridazine-3-carboxylic acid methyl ester

In an autoclave, (6-chloro-5-methyl-pyridazin-3-yl)amine (5.4 g, 36.86 mmol, 1.0 eq.) was dissolved in MeOH (100 mL) under an inert atmosphere of Argon. PdC12(dppp) (1.308 g, 1.83 mmol, 0.05 eq.) and NEts (11.18 g, 15.4 mL, 110.49 mmol, 3 eq.) were added to the mixture which was heated to 100 °C. The reaction mixture was then stirred at 100 °C under CO (60 bars) for 18 hours. The mixture was cooled to 20 °C and purged with Argon. The mixture was mixed with brine and extracted several times with plenty of EtOAc. As a large amount of product was still contained in the aqueous phase, further extraction was performed using DCM. All the organic extracts were combined and concentrated to afford a yellow solution. This crude material was purified by flash column chromatography using 35% - 50% (EtOAc / EtOH / NH4OH 75:25:2) in heptane to yield 6-amino-4-methyl-pyridazine-3-carboxylic acid methyl ester (3.29 g, 51.8%) as a white solid. LC-MS: m/z = 168.1 [M+H]⁺, ESI pos. 'H NMR (300 MHz, CDCh) 8 = 6.56 (d, J = 1.0 Hz, 1H), 5.06 (br s, 2H), 3.99 (s, 3H), 2.52 (d, J= 0.8 Hz, 3H).

Step 2: 6-amino-4-methyl-pyridazine-3-carboxylic acid

Under argon, 6-amino-4-methyl-pyridazine-3-carboxylic acid methyl ester (300 mg, 1.79 mmol, 1.0 eq.) was suspended in THF (15 mL) at 20 °C. LiOH 1 M in H2O (2.69 mL, 2.69 mmol, 1.5 eq.) was added and stirring was continued for 1 hour. The reaction mixture was partitioned between H2O and DCM. The aqueous layer was acidified with 1 M HC1 to pH = 2. After lyophilization, 6-amino-4-methyl-pyridazine-3-carboxylic acid (457 mg) was obtained as a solid and used without further purification. LC-MS: m/z = 154.0 [M+H]⁺, ESI pos.

Step 3: 6-amino-N,N,4-trimethyl-pyridazine-3-carboxamide

Under argon, 6-amino-4-methyl-pyridazine-3-carboxylic acid (167 mg, 0.654 mmol, 1.0 eq.) was suspended in DMF (1 mL) at 20 °C. Dimethylamine 2M in THF (436.75 mg, 490.73 pL, 0.981 mmol, 1.5 eq.) was added, the reaction mixture turning to a solution. DIPEA (169.14 mg, 216.84 pL, 1.31 mmol, 2.0 eq.) and TBTU (252.1 mg, 0.785 mmol, 1.2 eq.) were added. The reaction mixture was stirred at 20 °C for 3 hours and 30 minutes. More dimethylamine 2M in THF (981.45 pL, 1.96 mmol, 3.0 eq.) was added and the reaction mixture was stirred at 20 °C for another 20 minutes. No further conversion was observed. More TBTU (252.1 mg, 0.785 mmol, 1.2 eq.) and dimethylamine 2M in THF (981.45 pL, 1.96 mmol, 3.0 eq.) were added and the reaction mixture was stirred at 50 °C for 18 hours. The mixture was cooled to 20 °C. H2O was added and the mixture was directly purified by reverse phase chromatography column to yield 6-amino-N,N,4-trimethyl-pyridazine-3-carboxamide (777 mg, contaminated by activated ester intermediate, inorganic salts and DMF), which was used without further purification. LC- MS : m/z = 181.1 [M+H]⁺, ESI pos. Step 4: 6-[[ l-[ 6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2-pyridyl]benzimidazol-5- yl] amino] -N,N,4-trimethyl-pyridazine-3-carboxamide

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

Example 31

N-[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2- pyridyl]benzimidazol-5-yl]cyclopropanecarboxamide

Step 1: trimethyl- [2- [ (5-nitrobenzimidazol-l-yl)methoxy] ethyl] silane

To a solution of 5-nitrobenzimidazole (10.0 g, 61.3 mmol, 1.0 eq.) in DMF (50 mL) was added NaH 60 % dispersion in mineral oil (2.94 g, 73.56 mmol, 1.2 eq.) portion wise at 0 °C. The mixture was stirred at 20 °C for 1 hour before it was cooled again to 0 °C. 2- (trimethylsilyl)ethoxym ethyl chloride (15.19 mL, 85.82 mmol, 1.4 eq.) was added dropwise, the cooling bath was removed and stirring 120 °C was continued for 16 hours. The mixture was poured into H2O (200 mL) and extracted with EtOAc (100 mLx 3). The combined organic layers were concentrated under reduced pressure. The crude was purified by flash column chromatography using 0% - 25% EtOAc in PE to yield trimethyl-[2-[(5-nitrobenzimidazol-l- yl)methoxy]ethyl]silane (11.2 g, 62.3%) as a yellow oil (mixture of regioisomers). LC-MS: m/z = 294.2 [M+H]⁺, ESI pos.

Step 2: l-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine

To a solution of trimethyl-[2-[(5-nitrobenzimidazol-l-yl)methoxy]ethyl]silane (2.4 g, 8.18 mmol, 1.0 eq.) (mixture of regioisomers) in EtOH (30 mL) and H2O (10 mL) was added NH4CI (4.38 g, 81.8 mmol, 10.0 eq.) and Fe (2.28 g, 40.9 mmol, 5.0 eq.). The mixture was stirred at 50 °C for 16 hours under N2. The suspension was cooled to 20 °C, filtered through a celite pad and the filter cake was washed with MeOH (50 mL x 5). The combined filtrates were concentrated under reduced pressure. The residue was treated with H2O (300 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous TsfeSCU and concentrated under reduced pressure to yield l-(2- trimethylsilylethoxymethyl)benzimidazol-5-amine (2.05 g, 85.6%) (mixture of regioisomers) as a brown oil. LC-MS: m/z = 264.0 [M+H]⁺, ESI pos.

Step 3: N-[ l-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl] cyclopropanecarboxamide To a solution of cyclopropanecarboxylic acid (196.1 mg, 2.28 mmol, 1.2 eq.) and l-(2- trimethylsilylethoxymethyl)benzimidazol-5-amine (500 mg, 1.9 mmol, 1.0 eq.) (mixture of regioisomers) in DMF (5 mL) was added HATU (669.87 mg, 2.85 mmol, 1.5 eq.) and stirring was contiued for 0.5 hour at 25 °C. DIPEA (736.02 mg, 5.69 mmol, 3.0 eq.) was added and stirring at 25 °C was continued for another 0.5 hour. The reaction mixture was quenched by the addition of H2O (50 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by flash column chromatography using 0% - 50% EtOAc in PE to yield N-[l-(2-trimethylsilylethoxymethyl)benzimidazol-5- yl]cyclopropanecarboxamide (350.0 mg, 50.1%) as a brown solid. LC-MS: m/z = 332.0 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 8 = 8.25 (s, 1H), 7.94 (s, 1H), 7.91 (br s, 1H), 7.68 (br d, J = 8.7 Hz, 1H), 7.05 (br d, J= 8.3 Hz, 1H), 5.48 (s, 2H), 3.51 (d, J= 8.2 Hz, 2H), 1.56 (td, J= 3.8, 7.9 Hz, 1H), 1.12 - 1.07 (m, 2H), 0.90 (d, J= 8.3 Hz, 2H), 0.85 (br dd, J= 3.1, 7.7 Hz, 2H), -0.06 (s, 8H).

N-[3-(2 -trimethylsilyl ethoxymethyl)benzimidazol-5-yl]cyclopropanecarboxamide (200.0 mg, 28.6%) was also obtained as a brown solid. LC-MS: m/z = 332.0 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 6 = 7.99 (s, 1H), 7.88 (br s, 1H), 7.63 (br s, 1H), 7.49 (br d, J= 8.7 Hz, 1H), 5.53 (s, 2H), 3.51 (t, J= 8.2 Hz, 2H), 1.60 - 1.51 (m, 1H), 1.16 - 1.11 (m, 2H), 0.92 (d, J= 8.2 Hz, 2H), 0.90 - 0.86 (m, 2H), -0.04 (s, 9H).

Step 4: N-(lH-benzimidazol-5-yl)cyclopropanecarboxamide ; 2, 2, 2 -trifluoroacetic acid A solution of N-[l -(2 -trimethylsilyl ethoxymethyl)benzimidazol-5-yl] in TFA (1 mL) was stirred at 25 °C for 1 hours. The reaction mixture was concentrated to dryess to yield N-(1H- benzimidazol-5-yl)cyclopropanecarboxamide; 2,2,2-trifluoroacetic acid (500.0 mg, 94.6%) as an orange oil. LC-MS: m/z = 202.1 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CD₃OD) 8 = 9.30 (s, 1H), 8.46 (d, J= 1.3 Hz, 1H), 7.78 (d, J= 8.9 Hz, 1H), 7.59 (dd, J= 1.8, 8.9 Hz, 1H), 1.88 - 1.80 (m, 1H), 1.03 - 0.99 (m, 2H), 0.93 (td, J= 3.1, 7.8 Hz, 2H).

Step 5: N-[ l-[ 6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2-pyridyl]benzimidazol-5- yl cyclopropanecarboxamide

To a solution of l-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile 1- [6-chloro-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (100.0 mg, 0.37 mmol, 1.0 eq.) in t-amyl alcohol (5.0 mL, 45.89 mmol, 123.28 eq.) were added N-(1H- benzimidazol-5-yl)cyclopropanecarboxamide; 2,2,2-trifluoroacetic acid (129.08 mg, 0.41 mmol, 1.1 eq.), K3PO4 (236.74 mg, 1.12 mmol, 3.0 eq.) and ‘BuXPhos Pd G3 (29.56 mg, 0.04 mmol, 0.1 eq.). The reaction mixture was heated to 100 °C and stirring under N2 atmosphere was continued for 3 hours. The mixture was cooled to 25 °C, quenched with H2O (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over ISfeSCU, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (ACS-WH-GX-F, 37 - 67% CH3CN in H₂O (with 0.225% HCOOH) over 10 minutes, flow rate: 25 mL/min) to yield N-[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2- pyridyl]benzimidazol-5-yl]cyclopropanecarboxamide (3.5 mg, 2.2%) as a white solid. LC-MS: m/z = 434.2 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CD3OD) 8 = 8.99 (s, 1H), 8.56 (d, J= 8.6 Hz, 1H), 8.22 (d, J= 8.6 Hz, 1H), 8.16 (dd, J= 3.5, 5.2 Hz, 2H), 7.57 (dd, J= 1.8, 8.9 Hz, 1H), 7.08 (t, J= 54.7 Hz, 1H), 6.91 (d, J= 0.6 Hz, 1H), 2.53 (s, 3H), 1.86 - 1.77 (m, 1H), 1.03 - 0.97 (m, 2H), 0.92 - 0.87 (m, 2H).

Example 32 l-[6-[l-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(difluoromethyl)-2- pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine

Step 1: l-[6-chloro-5-(l,3-dioxolan-2-yl)-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3- yl) benzimidazol-5-amine

A mixture of 6-methoxy-N-(6-methylpyridazin-3-yl)-lH-benzimidazol-5-amine (580.05 mg, 2.27 mmol, 1.0 eq.), 2,6-dichloro-3-(l,3-dioxolan-2-yl)pyridine (500.0 mg, 2.27 mmol, 1.0 eq.) and K2CO3 (626.72 mg, 4.54 mmol, 2.0 eq.) in DMSO (8 mL) was stirred at 120 °C for 12 hours. The reaction mixture was cooled to 23 °C and added to H2O (50 mL). The insoluble material was collected by filtration and dried nder reduced pressure. This crude material was purified by preparative HPLC (Welch pLtimate XB-CN (250 mm x 70 mm, 10 pm), gradient of EtOH in hexane). The collected fractions were combined and concentrated to dryness. The residual solid was triturated in MeOH (5 mL) and the suspension was stirred at 25°C for 30 minutes. The product was collected by filtration, washed with MeOH and dreid to yield l-[6- chloro-5-(l,3-dioxolan-2-yl)-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5- amine (80.0 mg, 8%) as a white solid. LC-MS: m/z = 439.2 [M+H]⁺, ESI pos. 'H NMR (400 MHz, DMSO-de) 8 = 8.89 (s, 1H), 8.78 (s, 1H), 8.39 (s, 1H), 8.20 (d, J= 8.4 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.98 (s, 1H), 7.32 (s, 2H), 6.07 (s, 1H), 4.20 - 4.10 (m, 2H), 4.08 - 4.02 (m, 2H), 3.97 (s, 3H), 2.48 (s, 3H).

Step 2: l-[ 6-[ 1 -(cyclopropylmethyl)-3-methyl-pyrazol-4-yl -5-( 1, 3-dioxolan-2-yl)-2 -pyridyl -6- methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine

To a solution of l-[6-chloro-5-(l,3-dioxolan-2-yl)-2-pyridyl]-6-methoxy-N-(6-methylpyridazin- 3-yl)benzimidazol-5-amine (100.0 mg, 0.23 mmol, 1.0 eq.) and l-(cyclopropylmethyl)-3- methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (71.68 mg, 0.27 mmol, 1.2 eq.) in THF (5 mL) were added K3PO4 (0.46 mL, 0.68 mmol, 3.0 eq.) and Sphos Pd G3 (19.95 mg, 0.02 mmol, 0.1 eq.). Stirring at 60 °C was continued for 12 hours. The reaction mixture was cooled to 23 °C and concentrated under reduced pressure. The crude product was purified by reversed-phase HPLC (50% CH3CN in H2O (with 0.1% HCOOH)) to yield l-[6-[l- (cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(l,3-dioxolan-2-yl)-2-pyridyl]-6-methoxy-N-(6- methylpyridazin-3-yl)benzimidazol-5-amine (100.0 mg, 81.5%) as a yellow solid. LC-MS: m/z = 539.3 [M+H]⁺, ESI pos.

Step 3: 2-[ 1 -(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-6-[ 6-methoxy-5-[ ( 6-methylpyridazin-3- yl)amino]benzimidazol-l-yl ]pyridine-3-carbaldehyde

A solution of l-[6-[l-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(l,3-dioxolan-2-yl)-2- pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (100.0 mg, 0.19 mmol, 1.0 eq.) in HC1 4 M solution in dioxane (0.94 mL, 3.78 mmol, 20.34 eq.) was stirred at 25 °C for 2 hours. The pH of the mixture was adjusted to 6 with sat.aq NaHCCL solution. The precipitated solid was collected by filtration and dissolved in H2O (5 mL). This solution was concentrated to dryness to yiled 2-[l-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-6-[6-methoxy-5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]pyridine-3-carbaldehyde (80.0 mg, 87.1%) as a yellow solid. LC-MS: m/z = 495.3 [M+H]⁺, ESI pos.

Step 4: l-[ 6-[ 1 -(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(difluoromethyl)-2-pyridyl]-6- methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine

To a solution of 2-[l-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-6-[6-methoxy-5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]pyridine-3-carbaldehyde (70.0 mg, 0.14 mmol, 1.0 eq.) in DCM (5 mL) was added DAST (114.22 mg, 0.71 mmol, 5.0 eq.) at 0 °C and the resulting mixture was stirred at 25 °C for 12 hours. The reaction mixture was quenched by the addition of H2O (0.5 mL) at 25 °C, and then concentrated under reduced pressure to remove the DCM. The residual aqueous mixture was purified by preparative HPLC (Phenomenex Luna C18 (150 mm x 25 mm, 10 pm), CH3CN in H2O (with 0.225% HCOOH)) to yield l-[6-[l- (cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(difluoromethyl)-2-pyridyl]-6-methoxy-N-(6- methylpyridazin-3-yl)benzimidazol-5-amine (10.0 mg, 13.4%) as a yellow solid. LC-MS: m/z = 517.3 [M+H]⁺, ESI pos. ^XH NMR (400 MHz, CD3OD) 6 = 8.81 (s, 1H), 8.61 (s, 1H), 8.33 (d, J= 8.8 Hz, 1H), 8.04 - 7.82 (m, 3H), 7.37 (d, J= 92 Hz, 1H), 7.26 (d, J= 92 Hz, 1H), 7.09 - 6.65 (m, 1H), 4.05 (d, J= 22 Hz, 2H), 3.91 (s, 3H), 2.54 (s, 3H), 2.45 (s, 3H), 1.47 - 1.30 (m, 1H), 0.80 - 0.60 (m, 2H), 0.50 - 0.40 (m, 2H).

Example 33 3-(difluoromethoxy)-l-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin- 3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-6,7-dihydropyrazolo[4,3- c]pyridin-4-one

Step 1: 5-methyl-l,2,6, 7-tetrahydropyrazolo[4,3-c]pyridine-3,4-quinone

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

Step 2: 3-hydroxy-4-keto-5-methyl-6, 7-dihydropyrazolo[4,3-c]pyridine-l-carboxylic acid tertbutyl ester

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

To a solution of 3,4-diketo-5-methyl-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-l-carboxylic acid tert-butyl ester (247.77 mg, 0.927 mmol, 1.0 eq.) in DMF (8.43 mL) were added K2CO3 (384.36 mg, 2.78 mmol, 3.0 eq.) and sodium chlorodifluoroacetate (212. mg, 1.39 mmol, 1.5 eq.). The mixture was heated to 80 °C and stirred for 30 minutes. The reaction mixture was cooled to 23 °C, diluted with H2O and extracted with EtOAc. The organic layer was washed with brine, dried with MgSCU, filtered and concentrated in vacuo to yield 3-(difluoromethoxy)-4-keto-5-methyl- 6,7-dihydropyrazolo[4,3-c]pyridine-l -carboxylic acid tert-butyl ester (184 mg, 37.5%) as an orange liquid, which was used without further purification. LC-MS: m/z = 318.2 [M+H]⁺, ESI pos.

Step 4: 3-(difluoromethoxy)-5-methyl-6, 7-dihydro-lH-pyrazolo[4,3-c]pyridin-4-one; 1:1 hydrogen chloride

To a solution of 3-(difluoromethoxy)-4-keto-5-methyl-6,7-dihydropyrazolo[4,3-c]pyridine-l- carboxylic acid tert-butyl ester (183.39 mg, 0.578 mmol, 1.0 eq.) in 1,4-dioxane (2.64 mL)was added HC1 4 M solution in dioxane(5.2 g, 4.34 mL, 17.34 mmol, 30.0 eq.) and the mixture was stirred at 23 °C for 16 hours. The reaction mixture was concentrated to dryness to yield 3- (difluoromethoxy)-5-methyl-6,7-dihydro-lH-pyrazolo[4,3-c]pyridin-4-one 1 : 1 hydrogen chloride (131 mg, 71.5%) as a light yellow solid. LC-MS: m/z = 218.1 [M+H]⁺, ESI pos.

Step 5: 6-chloro-2-[3-(difluoromethoxy)-4-keto-5-methyl-6, 7-dihydropyrazolo [4, 3-c]pyridin-l- yl nicotinaldehyde

To a solution of 6-chloro-2-fluoro-nicotinaldehyde (74.99 mg, 0.470 mmol, 1.0 eq.) in DMF (0.750 mL) were added 3-(difluoromethoxy)-5-methyl-6,7-dihydro-lH-pyrazolo[4,3-c]pyridin-4- one;hydrochloride (131.13 mg, 0.517 mmol, 1.1 eq.) and K2CO3 (194.88 mg, 1.41 mmol, 3.000 eq.). The reaction mixture was stirred at 23 °C for 1 hour. The reaction was diluted with H2O and extracted with EtOAc. The organic layer was washed with brine, dried with MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash column chromatography (first time using 0% - 100% EtOAc in heptane, second time using 20% - 80% EtOAc in heptane) to yield 6-chloro-2-[3-(difluoromethoxy)-4-keto-5-methyl-6,7-dihydropyrazolo[4,3-c]pyridin-l- yl]nicotinaldehyde (115 mg, 63.6%) as a white solid. LC-MS: m/z = 357.1 [M+H]⁺, ESI pos. Step 6: l-[6-chloro-3-(difluoromethyl)-2-pyridyl]-3-(difluoromethoxy)-5-methyl-6, 7- dihydropyrazolo[ 4, 3-c ]pyridin-4-one

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

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

Example 34

2-[3-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2-pyridyl]-6-[(6- methylpyridazin-3-yl)amino]benzimidazol-5-yl]oxy-N,N-dimethyl-acetamide

Step 1: 2-(5-amino-2-bromo-4-nitro-phenoxy)-N,N-dimethyl-acetamide

To a solution of 2-hydroxy-N,N-dimethyl-acetamide (1.0 g, 9.7 mmol, 1.14 eq.) in THF (20 mL) was added NaH 60% dispersion in mineral oil (680.82 mg, 17.02 mmol, 2.0 eq.). The the mixture was stirred at 0 °C for 1 hour. 4-bromo-5-fluoro-2-nitro-aniline (2.0 g, 8.51 mmol, 1.0 eq.) was added and stirring was continued at 25 °C for 12 hours. The reaction mixture was added diluted with H2O (40 mL) and extracted with EtOAc. A solid precipitated out. It was collected by filtration and dried to yield 2-(5-amino-2-bromo-4-nitro-phenoxy)-N,N-dimethyl-acetamide (300.0 mg, 10%) as an orange solid. LC-MS: m/z = 317.8 [M+H]⁺, ESI pos. 'H NMR (400 MHz, DMSO-de) 6 = 8.13 (s, 1H), 7.56 (s, 2H), 6.38 (s, 1H), 4.98 (s, 2H), 3.00 (s, 3H), 2.86 (s, 3H). From the above biphasic filtrate, the layers were separated, the organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography using 80% EtOAc in PE to yield a second crop of 2-(5-amino-2- bromo-4-nitro-phenoxy)-N,N-dimethyl-acetamide (700.0 mg, 23.3%) as a yellow solid. LC-MS: m/z = 317.8 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 8 = 8.28 (s, 1H), 6.29 (s, 1H), 4.73 (s, 2H), 3.07 (s, 3H), 2.91 (s, 3H).

Step 2: 2-(4, 5-diamino-2-bromo-phenoxy)-N,N-dimethyl-acetamide

To a solution of 2-(5-amino-2-bromo-4-nitro-phenoxy)-N,N-dimethyl-acetamide (1.0 g, 3.14 mmol, 1.0 eq.) in EtOH (20 mL) were added Fe (877.66 mg, 15.72 mmol, 5.0 eq.), NH4CI (1681.44 mg, 31.43 mmol, 10.0 eq.) and H2O (5 mL). The mixture was stirred under N2 at 50 °C for 2 hours. The reaction mixture was concentrated under reduced pressure and a mixture of DCM / MeOH 10:1 (50 mL) was added. Stirring at 50 °C was continued for 1 hour. The mixture was filtered on a celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC using DCM / MeOH 10:1 to yileld 2-(4,5-diamino-2-bromo- phenoxy)-N,N-dimethyl-acetamide (500.0 mg, 49.7%) as a grey solid. LC-MS: m/z = 288.0 [M+H]⁺, ESI pos. ^XH NMR (400 MHz, CD3OD) 8 = 6.87 (s, 1H), 6.46 (s, 1H), 4.67 (s, 2H), 3.13 (s, 3H), 2.99 (s, 3H).

Step 3: 2-[(6-bromo-3H-benzimidazol-5-yl)oxy]-N,N-dimethyl-acetamide

To a solution of 2-(4,5-diamino-2-bromo-phenoxy)-N,N-dimethyl-acetamide (500.0 mg, 1.74 mmol, 1.0 eq.) in EtOH (1 mL) were added trimethyl orthofomate (1841.47 mg, 17.35 mmol, 10.0 eq.) and TsOH (26.69 mg, 0.17 mmol, 0.1 eq.). The mixture was stirred at 80 °C for 2 hours. The reaction mixture was concentrated under reduced pressure. The crude material was purified by flash column chromatography using 0% - 10% MeOH in EtOAc to yield 2-[(6- bromo-3H-benzimidazol-5-yl)oxy]-N,N-dimethyl-acetamide (500.0 mg, 87%) as a brown solid. LC-MS: m/z = 299.8 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CD3OD) 8 = 8.13 (s, 1H), 7.84 (s, 1H), 7.24 (s, 1H), 4.91 (s, 2H), 3.18 (s, 3H), 3.01 (s, 3H). Step 4: 2-[ 6-bromo-3-[ 6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2- pyridyl]benzimidazol-5-yl]oxy-N,N-dimethyl-acetamide

To a solution of 2-[(6-bromo-3H-benzimidazol-5-yl)oxy]-N,N-dimethyl-ethanamine (200.0 mg, 0.7 mmol, 1.0 eq.) in DMSO (2 mL) were added l-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile (189.09 mg, 0.7 mmol, 1.0 eq.) and BGCCh (291.84 mg, 2.11 mmol, 3.0 eq.) and stirring at 50 °C was continued for 1 hour. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (5 mL x 3), dried over anhydrous ISfeSCU, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC using DCM / MeOH 10: 1 to yield 2-[6-bromo-3-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2- pyridyl]benzimidazol-5-yl]oxy-N,N-dimethyl-acetamide (80.0 mg, 19.3% ) as a white solid. LC- MS: m/z = 531.7 [M+H]⁺, ESI pos. ^XH NMR (400 MHz, CDCh) 8 = 8.58 (s, 1H), 8.46 (d, J= 8.4 Hz, 1H), 8.31 (s, 1H), 7.79 (d, J= 8.4 Hz, 1H), 7.42 (s, 1H), 7.36 (s, 1H), 7.23 (s, 1H), 7.09 (s, 1H), 6.73 (s, 1H), 4.88 (s, 2H), 3.18 (s, 3H), 3.03 (s, 3H), 2.58 (s, 3H).

2-[6-bromo-l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2-pyridyl]benzimidazol-5- yl]oxy-N,N-dimethyl-acetamide (80.0 mg, 19.3%) was also obtained as a white solid. LC-MS: m/z = 531.7 [M+H]⁺, ESI pos. ^XH NMR (400 MHz, CDCh) 6 = 8.57 (s, 1H), 8.53 (d, J= 8.6 Hz, 1H), 8.10 (s, 1H), 7.85 (d, J= 8.3 Hz, 1H), 7.80 (s, 1H), 7.33 (s, 1H), 7.19 (s, 1H), 7.06 (s, 1H), 6.71 (d, J= 0.6 Hz, 1H), 4.84 (s, 2H), 3.18 (s, 3H), 2.96 (s, 3H), 2.56 (s, 3H).

Step 5: 2-[ 3-[6-( 3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2-pyridyl -6-[ ( 6- methylpyridazin-3-yl)amino]benzimidazol-5-yl]oxy-N,N-dimethyl-acetamide

Prepared according to Example 4, step 4 to yield 2-[3-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5- (difhjoromethyl)-2-pyridyl]-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-5-yl]oxy-N,N- dimethyl-acetamide (12.1 mg, 13.9%) as an off white solid after purification by preparative HPLC (ACS-WH-GX-F, 10 - 40% CH3CN in H₂O (with HCOOH) over 10 minutes, flow rate: 25 mL/min). LC-MS: m/z = 559.3 [M+H]⁺, ESI pos. 'H NMR (400 MHz, DMSO-d₆) 6 = 9.03 (s, 1H), 8.85 (s, 1H), 8.81 (s, 1H), 8.59 (d, J= 8.7 Hz, 1H), 8.34 (d, J= 8.6 Hz, 1H), 7.78 (s, 1H), 7.37 - 7.33 (m, 1H), 7.30 - 7.26 (m, 1H), 7.22 - 6.92 (m, 2H), 4.95 (s, 2H), 2.90 (s, 3H), 2.83 (s, 3H), 2.55 (s, 3H), 2.46 (s, 3H). Example 35 l-[5-(difluoromethyl)-6-[l-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-2-pyridyl]-

6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine

Step 1: 4-bromo-5-methoxy-2-nitro-aniline

To a solution of 5-methoxy-2-nitroaniline (10.0 g, 59.47 mmol, 1.0 eq.) in acetonitrile (150 mL) was added NBS (11.6 g, 65.42 mmol, 1.1 eq.) in portions under N2 at RT and the reaction mixture was stirred at RT for 3 hours. The reaction mixture was poured into sat. NazSOs solution (300 mL) under vigorous stirring and H2O (500 mL) was added. The resulting precipitate was filtered and the filter cake was dried to give 4-bromo-5-methoxy-2-nitro-aniline (13.0 g, 52.62 mmol, 88% yield) as a yellow solid. ESI pos [M+H]⁺ 249.1.

'H NMR (400 MHz, CDCh) 6 = 8.36 (s, 1H), 6.25 (br s, 2H), 6.18 (s, 1H), 3.92 (s, 3H)

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

To a solution of 4-bromo-5-methoxy-2-nitro-aniline (13.0 g, 52.6 mmol, 1.0 eq.) in a mixture of DCM (260 mL) and MeOH (260 mL) was added sat. NH4CI (520 mL, 1052 mmol, 20.0 eq.) at at RT and the mixture was bubbled with N2 for 10 minutes. Zn (34.4 g, 527 mmol, 10.0 eq.) was added in portions at RT and the reaction mixture was stirred at RT for 2 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was dissolved with DCM (600mL) and washed with brine (3 x 200 mL). The combined organic phases were 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. ESI pos [M+H]⁺ 217.0. 'H NMR (400 MHz, DMSO-de) 8 = 6.66 (s, 1H), 6.34 (s, 1H), 4.79 - 4.13 (m, 4H), 3.63 (s, 3H). Step 3: 5-bromo-6-methoxy-lH-benzimidazole

To a solution of 4-bromo-5-methoxy-benzene-l,2-diamine (11.0 g, 50.7 mmol, 1.0 eq.) in trimethyl orthoformate (200 mL, 507 mmol, 10.0 eq.) was added formic acid (10.0 mL, 265 mmol, 5.2 eq.) and the mixture was stirred at 90 °C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (400mL) and washed with sat. NaHCOs (300mL). Then the organic phase was washed with brine (3 x 100 mL), dried over Na2SO4, filtered and concentrated. The crude was purified by flash chromatography (silica gel, EtOAc) to give 5-bromo-6-methoxy-lH-benzimidazole (9.6 g, 42.3 mmol, 83% yield) as a yellow solid. ESI pos [M+H]⁺ 227.0. 'H NMR (400 MHz, DMSO-d₆) 8 = 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).

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

To a solution of 2-(trimethylsilyl)ethoxymethyl chloride (3.27 mL, 18.5 mmol, 1.4 eq.) in DMF (60 mL) was added sodium hydride (60% in oil) (635 mg, 15.9 mmol, 1.2 eq.) in portions at 0 °C. After addition, the mixture was allowed to reach RT and was stirred for 1 hour. The mixture was cooled to 0 °C and 5-bromo-6-methoxy-lH-benzimidazole (3.0 g, 13.2 mmol, 1.0 eq.) was added. The mixture was allowed to reach RT and was stirred for 16 hours. The mixture was poured into sat. aqueous NH4CI (300 mL), extracted with EtOAc (3 x 100 mL) and the combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0% to 20% EtOAc in petroleum ether) to give a mixture of 2-[(5-bromo-6-methoxy-benzimidazol-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. ESI pos [M+H]⁺ 357.0.

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

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.), 3-amino-6-methylpyridazine (1.71 g, 15.7 mmol, 2.0 eq.) and CS2CO3 (7.66 g, 23.5 mmol, 3.0 eq.) in 1,4-di oxane (50 mL) was bubbled with N2 for 10 minutes. [tBuBrettPhos Pd(allyl)]OTf (613 mg, 0.78 mmol, 0.1 eq.) was added and the mixture was stirred at 80 °C for 4 hours under N2. The mixture was poured into sat. aqueous NH4CI (300 mL), extracted with EtOAc (3 x 100 mL) and the combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0% to 100% EtOAc in petroleum ether) to give a mixture of 6-methoxy-N-(6-methylpyridazin- 3-yl)-l -(2 -trimethyl silyl ethoxymethyl)benzimidazol-5-amine and 6-methoxy-N-(6- methylpyridazin-3-yl)-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine (3.0 g, 7.78 mmol, 94% yield) as yellow oil. ESI pos [M+H]⁺ 386.1.

Step 6: 6-methoxy-N-( 6-methylpyridazin-3-yl)-lH-benzimidazol-5-amine To a solution of a mixture of 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 (3.0 g, 7.39 mmol, 1.0 eq.) in trifluoroacetic acid (10 mL, 130 mmol, 18 eq.) at RT was stirred at RT for 3 hours. The mixture was concentrated and the resulting gum was dissolved in MeOH (10 mL). Aqueous NEE (10%) (10 mL) was added carefully until 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 yellow solid. The combined filtrates were concentrated and the resulting residue was purified by preparative HPLC (Kromasil Eternity XT 10 pm, 250 mm x 80 mm, 0.1% NH4HCO3 in water - ACN) to give 6- methoxy-N-(6-methylpyridazin-3-yl)-lH-benzimidazol-5-amine (0.5 g, 1.96 mmol, 26% yield) as yellow solid. ESI pos [M+H]⁺ 256.1. ^XH NMR (400 MHz, CD₃OD) 8 = 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).

Step 7: 6-methoxy-N-( 6-methylpyridazin-3-yl)-lH-benzimidazol-5-amine A solution of 6-methoxy-N-(6-methylpyridazin-3-yl)-l-(2- trimethylsilylethoxymethyl)benzimidazol-5-amine (10.6 g, 27.49 mmol, 1.0 eq.) in TFA (20.0 mL, 259.6 mmol, 9.44 eq.) was stirred at 25 °C for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (CH3CN in H2O (with 0.1% NH4OH)) to yield 6-methoxy-N-(6-methylpyridazin-3-yl)-lH-benzimidazol- 5-amine (10.0 g, 99.7% yield) as a brown solid. LC-MS: m/z = 256.0 [M+H]⁺, ESI pos.

Step 8: l-[5-(l, 3-dioxolan-2-yl)-6-[ l-(2-methoxyethyl)-3-methyl-pyrazol-4-yl] -2-pyridyl] -6- methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine

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

Step 8: 2-[l-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-6-[6-methoxy-5-[(6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl ]pyridine-3-carbaldehyde

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

Step 10: l-[5-(difluoromethyl)-6-[ 1 ~(2-methoxyethyl)-3-methyl-pyrazol-4-yl] -2-pyridyl] -6- methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine

Prepared according to Example 32, step 4 to yield l-[5-(difluoromethyl)-6-[l-(2-methoxyethyl)- 3-methyl-pyrazol-4-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (60.0 mg, 33.8%) as a yellow oil (mixture of regioisomers at pyrazole) after purification by preparative HPLC (Welch pLtimate XB-CN (250 mm x 50 mm, 10 pm), gradient of EtOH in hexane). LC-MS: m/z = 521.3 [M+H]⁺, ESI pos. This regioisomeric mixture was purified by SFC (Daicel Chiralpak AS (250 mm x 30 mm, 10 pm) with EtOH (0.1% NH4OH) in CO2) to yield l-[5-(difluoromethyl)-6-[l-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-2-pyridyl]-6- methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (17.1 mg, 28.5%) as a yellow solid. LC-MS: m/z = 521.3 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CD3OD) 8 = 8.81 (s, 1H), 8.63 (s, 1H), 8.33 (d, J= 8.8 Hz, 1H), 7.98 (s, 1H), 7.93 - 7.83 (m, 2H), 7.35 (d, J= 92 Hz, 1H), 7.23 (d, J= 92 Hz, 1H), 7.01 - 6.64 (m, 1H), 4.34 (t, J= 52 Hz, 2H), 3.91 (s, 3H), 3.79 (t, J= 52 Hz, 2H), 3.37 (s, 2H), 2.53 (s, 3H), 2.45 (s, 3H).

Example 36 l-[5-(difluoromethyl)-6-[l-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-2-pyridyl]- 6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine l-[5-(difluoromethyl)-6-[l-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-2-pyridyl]-6-methoxy-N- (6-methylpyridazin-3-yl)benzimidazol-5-amine (14.2 mg, 23.4%) was obtained in Example 35, step 4 as a yellow solid. LC-MS: m/z = 521.3 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CD₃OD) 8 = 8.93 - 8.31 (m, 2H), 8.23 (d, J= 8.4 Hz, 1H), 8.00 - 7.75 (m, 2H), 7.63 (s, 1H), 7.40 - 7.10 (m, 2H), 6.96 - 6.47 (m, 1H), 4.27 (t, J= 5.2 Hz, 2H), 3.82 (s, 3H), 3.71 (t, J= 5.2 Hz, 2H), 3.25 - 3.23 (m, 3H), 2.43 (d, J = 10.4 Hz, 6H).

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

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

Step 2: 6-[ 6-methoxy-5-[ ( 6-methylpyridazin-3-yl )amino]benzimidazol-l-yl -2-[ 3-methyl-l- (2,2, 2-trifluoroethyl)pyrazol-4-yl]pyridine-3-carbaldehyde and 6-[ 6-methoxy-5-[ ( 6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-[5-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4- yl pyridine-3-carbaldehyde

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

Step 3: l-[5-(difluoromethyl)-6-[3-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-6- methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine

Prepared according to Example 35, step 3 to yield l-[5-(difluoromethyl)-6-[3-methyl-l-(2,2,2- trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5- amine (4.6 mg, 15.1%) as a yellow solid. LC-MS: m/z = 523.2 [M+H]⁺, ESI pos. ^TH NMR (400 MHz, CD₃OD) 8 = 8.84 (s, 1H), 8.66 (s, 1H), 8.35 (d, J= 8.4 Hz, 1H), 8.01 (d, J= 15.6 Hz, 2H), 7.96 (d, J= 8.4 Hz, 1H), 7.35 (d, J= 9.2 Hz, 1H), 7.24 (d, J= 9.2 Hz, 1H), 6.98 - 6.62 (m, 1H), 5.04 - 4.98 (m, 2H), 3.90 (s, 3H), 2.53 (s, 3H), 2.44 (s, 3H). Example 38 l-[6-[l-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(difluoromethyl)-2- pyridyl]-6-fluoro-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine

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

To a solution of 5-bromo-6-fluoro-lH-benzimidazole (5.0 g, 23.25 mmol, 1.0 eq.) and tetrabutylammonium bromide (0.75 g, 2.33 mmol, 0.1 eq.) in DCM (40 mL) was added a solution of KOH (2.6 g, 23.25 mmol, 1.0 eq.) in H₂O (20 mL). SEM-C1 (4.63 g, 27.9 mmol, 1.2 eq.) was added at 0 °C and the resulting mixture was stirred for 1 hour, then at 25 °C for 1 hour. Sat. aq.NaCl sol. (100 mL) was added and the reaction mixture was extracted with EtOAc (50 mL x 3). The combined organic extracts were concentrated under reduced pressure. The residue was purified by flash column chromatography using 10% - 50% EtOAc in PE to yield 2-[(5- bromo-6-fluoro-benzimidazol-l-yl)methoxy]ethyl-trimethyl-silane (8.4 g, 94.2%) as a brown oil. LC-MS: m/z = 347.0 [M+H]⁺, ESI pos.

Step 2: 6-fluoro-N-( 6-methylpyridazin-3-yl)-l-(2-trimethylsilylethoxymethyl)benzimidazol-5- amine

A mixture of 2-[(5-bromo-6-fluoro-benzimidazol-l-yl)methoxy]ethyl-trimethyl-silane (8.0 g, 23.17 mmol, 1.0 eq.), 3-amino-6-methylpyridazine (3.03 g, 27.8 mmol, 1.2 eq.), [Pd(allyl)(tBuBrettPhos)]OTf (0.91 g, 1.16 mmol, 0.05 eq.) and CS2CO3 (22.65 g, 69.51 mmol, 3.0 eq.) inl,4-dioxane (100 mL) was stirred atlOO °C under N2 atmosphere for 12 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to yield 6- fluoro-N-(6-methylpyridazin-3-yl)-l-(2 -trimethyl silyl ethoxymethyl)benzimidazol-5-amine (11.0 g, 95.3%) as a brown oil. LC-MS: m/z = 374.2 [M+H]⁺, ESI pos. Step 3: 6-fluoro-N-(6-methylpyridazin-3-yl)-lH-benzimidazol-5-amine;formic acid

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

Step 4: l-[6-chloro-5-(l,3-dioxolan-2-yl)-2-pyridyl]-6-fluoro-N-(6-methylpyridazin-3- yl) benzimidazol-5-amine

Prepared according to Example 32, step 1 to yield l-[6-chloro-5-(l,3-dioxolan-2-yl)-2-pyridyl]- 6-fluoro-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (300.0 mg, 9.6%) as a white solid.

LC-MS: m/z = 426.8 [M+H]⁺, ESI pos. 'H NMR (400 MHz, DMSO-d₆) 8 = 9.06 (s, 1H), 8.89 (s, 1H), 8.69 (d, J= 7.8 Hz, 1H), 8.22 - 8.14 (m, 2H), 8.07 (d, J= 8.3 Hz, 1H), 7.38 - 7.33 (m, 1H), 7.29 - 7.24 (m, 1H), 6.05 (s, 1H), 4.16 - 4.01 (m, 4H), 2.48 (s, 3H).

Step 5: l-[ 6-[ 1 -(cyclopropylmethyl)-3-methyl-pyrazol-4-yl -5-( 1, 3-dioxolan-2-yl)-2 -pyridyl -6- fluoro-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine

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

Step 6: 2-[ I -(cyclopropylmethyl)-3-methyl-pyrazol-4-yl -6-[ 6-fluoro-5-[ ( 6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl ]pyridine-3-carbaldehyde

Prepared according to Example 35, step 3 to yield 2-[l-(cyclopropylmethyl)-3-methyl-pyrazol-

4-yl]-6-[6-fluoro-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]pyridine-3-carbaldehyde (80.0 mg, 97.0%) as a yellow solid. LC-MS: m/z = 483.3 [M+H]⁺, ESI pos.

Step 7: l-[ 6-[ I -(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(difluoromethyl)-2-pyridyl]-6- fluoro-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine

Prepared according to Example 35, step 4 to yield l-[6-[l-(cyclopropylmethyl)-3-methyl- pyrazol-4-yl]-5-(difluoromethyl)-2-pyridyl]-6-fluoro-N-(6-methylpyridazin-3-yl)benzimidazol-

5-amine (17.7 mg, 24.8%) as a white solid. LC-MS: m/z = 505.3 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CD3OD) 8 = 8.95 (s, 1H), 8.55 (d, J= 7.6 Hz, 1H), 8.34 (d, J= 8.8 Hz, 1H), 8.20 (d, J= 11.6 Hz, 1H), 8.03 - 7.85 (m, 2H), 7.40 (d, J= 9.2 Hz, 1H), 7.23 (d, J= 9.2 Hz, 1H), 7.01 - 6.60 (m, 1H), 4.05 (d, J= 7.2 Hz, 2H), 2.54 (s, 3H), 2.42 (s, 3H), 1.47 - 1.31 (m, 1H), 0.74 - 0.61 (m, 2H), 0.46 (q, J= 5.2 Hz, 2H).

Example 39 l-[3-(difluoromethyl)-6-[6-fluoro-5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

Step 1: l-[3-(difluoromethyl)-6-[6-fluoro-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-

2-pyridyl]-5-methyl-pyrazole-3-carbonitrile l-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (100 mg, 0.372 mmol, 1.0 eq.) was dissolved in t-amyl alcohol (2.67 mL). (6-fluoro-lH-benzimidazol-5-yl)-(6- methylpyridazin-3-yl)amine (99.6 mg, 0.409 mmol, 1.1 eq.) and tripotassium phosphate (237.04 mg, 1.12 mmol, 3.0 eq.) were added at 23 °C. The suspension was purged with Argon before tBuXPhos Pd G3 (29.57 mg, 0.037 mmol, 0.1 eq.) was added. The vial was closed under Argon and the reaction mixture was heated to 80 °C and stirred overnight. The reaction mixture was cooled to 23 °C, diluted with H2O and extracted with EtOAc (2 x). The combined organic layers were dried over MgSCh, filtered and concentrated to dryness. The crude material was purified by flash column chromatography using 0% - 5% MeOH in DCM to yield l-[3-(difluoromethyl)-6- [6-fluoro-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-

3 -carbonitrile (58.4 mg, 32.9%) as a white solid. LC-MS: m/z = 476.2 [M+H]⁺, ESI pos. Example 40 l-[3-(difluoromethyl)-6-[6-methoxy-5-[[5-(3-oxa-6-azabicyclo[3.1.1]heptan-6- yl]pyridazin-3-yl] amino] benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile

Step 1 : 6-( 6-chloropyridazin-4-yl)-3-oxa-6-azabicyclo[ 3.1.1 ] heptane

To a mixture of 3,5-dichloropyridazine (274.12 mg, 1.84 mmol, 1.0 eq.) and K2CO3 (762.92 mg, 5.52 mmol, 3.0 eq.) in CH3CN (4.35 mL) was added 3-oxa-6-azabicyclo[3.1.1]heptane hydrochloride (299.38 mg, 2.21 mmol, 1.2 eq.). The mixture was stirred at 60 °C for 16 h, cooled to 23 °C and concentrated under reduced pressure. The residue was purified by flash column chromatography using 20% - 100% EtOAc in heptane to yield 6-(6-chloropyridazin-4- yl)-3-oxa-6-azabicyclo[3.1.1]heptane as a light yellow liquid (213 mg, 51.9%). LC-MS: m/z = 212.2 [M+H]⁺, ESI pos.

Step 2: N-[5-[3-oxa-6-azabicyclo[3.1.1]heptan-6-yl]pyridazin-3-yl]carbamic acid tert-butyl ester

To a mixture of 6-(6-chloropyridazin-4-yl)-3-oxa-6-azabicyclo[3.1.1]heptane (160 mg, 0.756 mmol, 1.0 eq.) in 1,4-dioxane (2.38 mL), were added tert-butyl carbamate (177.12 mg, 1.51 mmol, 2.0 eq.), CS2CO3 (492.62 mg, 1.51 mmol, 2.0 eq.), (9,9-dimethyl-9H-xanthene-4,5- diyl)bis(diphenylphosphine) (87.48 mg, 0.151 mmol, 0.2 eq.) and by tris(dibenzylideneacetone)dipalladium (0) chloroform complex (78.25 mg, 0.076 mmol, 0.1 eq.) The vial was sealed and the mixture was heated to 90 °C and stirring was continued for 3 hours. The reaction mixture was cooled to 23 °C, diluted with H2O and extracted with DCM. The organic layer was washed with brine, dried with MgSCU, filtered and concentrated in vacuo. The residue was purified by flash column chromatography using 0% - 100% (DCM / MeOH 9: 1) in DCM to yield N-[5-[3-oxa-6-azabicyclo[3.1. l]heptan-6-yl]pyridazin-3-yl]carbamic acid tertbutyl ester as an orange solid (64.1 mg, 26.1%). LC-MS: m/z = 293.2 [M+H]⁺, ESI pos.

Step 3: [5-[ 3-oxa-6-azabicyclo[ 3.1.1 ]heptan-6-yl]pyridazin-3-yl] amine ; 2, 2, 2-trifluoroacetic acid

N-[5-[3-oxa-6-azabicyclo[3.1.1]heptan-6-yl]pyridazin-3-yl]carbamic acid tert-butyl ester (64.1 mg, 0.219 mmol, 1.0 eq.) was dissolved in DCM (1.42 mL), TFA (250.01 mg, 168.93 pL, 2.19 mmol, 10.0 eq.) was added and stirring was continued for 18 hours at 23 °C. The solution was evaporated to dryness. The residue was triturated in 3 ml of Et2O and the resulting suspension was stirred for 30 minutes. The roduct was collected by filtration, washed with Et2O and dried to yield [5-[3-oxa-6-azabicyclo[3.1.1]heptan-6-yl]pyridazin-3-yl]amine; 2, 2, 2-trifluoroacetic acid as an orange solid (52.3 mg, 62.3%). LC-MS: m/z = 193.2 [M+H]⁺, ESI pos.

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

Example 41 3-[[l-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-5-(difluoromethyl)-2- pyridyl] -6-methyl-benzimidazol-5-yl] amino] -N,N, 6-trimethyl-py ridazine-4- carboxamide Step 1: ethyl 3-(benzhydrylideneamino)-6-methyl-pyridazine-4-carboxylate

Prepared according to Example 27, step 4 to yield ethyl 3-(benzhydrylideneamino)-6-methyl- pyridazine-4-carboxylate (1200.0 mg, 69.7%) as a brown oil. LC-MS: m/z = 346.1 [M+H]⁺, ESI pos.

Step 2: 3-(benzhydrylideneamino)-6-methyl-pyridazine-4-carboxylate; lithium salt To a mixture of ethyl 3-(benzhydrylideneamino)-6-methyl-pyridazine-4-carboxylate (1200.0 mg, 3.47 mmol, 1.0 eq.) in THF (6 mL), MeOH (6 mL) and H2O (6 mL), was added LiOH (249.11 mg, 10.42 mmol, 3.0 eq.), and the reaction mixture was stirred at 30 °C for 12 hours, turning to a clear solution. The mixture was concentrated under vaccum to yield 3-(benzhydrylideneamino)- 6-methyl-pyridazine-4-carboxylate; lithium salt (1000.0 mg, 89%) as a yellow solid. LC-MS: m/z = 318.1 [M+H]⁺, ESI pos.

Step 3: 3-(benzhydrylideneamino)-N,N, 6-trimethyl-pyridazine-4-carboxamide

To a suspension of dimethylamine hydrochloride (323.75 mg, 3.97 mmol, 1.5 eq.) in DMF (10 mL) was added DIPEA (1025.98 mg, 7.94 mmol, 3.0 eq.), 3-(benzhydrylideneamino)-6-methyl- pyridazine-4-carboxylic acid (840.0 mg, 2.65 mmol, 1.0 eq.) and HATU (934.12 mg, 3.97 mmol, 1.5 eq.). The the mixture was heated to 30 °C and stirred for 1 hour. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 30% - 40% EtOAc in PE to yield 3-(benzhydrylideneamino)-N,N,6- trimethyl-pyridazine-4-carboxamide (400.0 mg, 39.5%) as a white solid. LC-MS: m/z = 345.2 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 8 = 7.84 - 7.22 (m, 11H), 3.06 (s, 3H), 3.02 (s, 3H), 2.61 (s, 3H).

Step 4: 3-amino-N,N, 6-trimethyl-pyridazine-4-carboxamide

To a colorless solution of 3-(benzhydrylideneamino)-N,N,6-trimethyl-pyridazine-4-carboxamide (400.0 mg, 1.16 mmol, 1.0 eq.) in MeOH (20 mL) were added hydroxylamine hydrochloride (161.41 mg, 2.32 mmol, 2.0 eq.) and sodium acetate (0.22 mL, 2.9 mmol, 2.5 eq.) and the resulting colorless solution was stirred at 20 °C for 2 hours. The reaction mixture was concentrated under reduce pressure. The residue was taken in H2O (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc) to yield 3-amino-N,N,6-trimethyl-pyridazine-4- carboxamide (220.0 mg, 94.6%) as a brown solid. LC-MS: m/z = 181.1 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 8 = 6.92 (s, 1H), 5.42 (br s, 2H), 3.04 (br s, 3H), 2.94 (br s, 3H), 2.50 (s, 3H).

Step 5: 5-bromo-l-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-5-(difluoromethyl)-2- pyridyl] -6-methyl-benzimidazole

To a solution of 5-bromo-6-methyl-lH-benzimidazole (143.47 mg, 0.68 mmol, 1.0 eq.) in DMSO (3 mL) were added 6-chloro-2-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-3- (difluoromethyl)pyridine (210.0 mg, 0.68 mmol, 1.0 eq.) and K2CO3 (281.18 mg, 2.03 mmol, 3.0 eq.). The reaction mixture was stirred at 50 °C for 12 hours. The reaction mixture was cooled to 23 °C, diluted with H2O (10 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (5 mL x 3), dired over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 20% - 50% EtOAc in PE to yield 5-bromo-l-[6-[3-(difluoromethoxy)-5- methyl-pyrazol-l-yl]-5-(difluoromethyl)-2-pyridyl]-6-methyl-benzimidazole (70.0 mg, 19.2%) as a white solid. LC-MS: m/z = 486.0 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 6 = 8.53 (s, 1H), 8.40 (d, J= 8.4 Hz, 1H), 8.08 (s, 1H), 7.91 (s, 1H), 7.65 (d, J= 8.4 Hz, 1H), 7.46 (s, 1H), 7.32 (s, 1H), 7.18 (s, 1H), 6.93 (t, J= 72.9 Hz, 1H), 6.00 (s, 1H), 2.57 (s, 3H), 2.54 (s, 3H).

Regioisomer 6-bromo-l-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-5-(difluoromethyl)-2- pyridyl]-5-methyl-benzimidazole (110.0 mg, 30.2%) was also obtained as a white solid. LC-MS: m/z = 486.0 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 6 = 8.55 (s, 1H), 8.39 (d, J= 8.4 Hz, 1H), 8.27 (s, 1H), 7.75 (s, 1H), 7.64 (d, J= 8.4 Hz, 1H), 7.46 (s, 1H), 7.32 (s, 1H), 7.18 (s, 1H), 6.93 (t, J= 72.9 Hz, 1H), 6.00 (s, 1H), 2.55 (s, 6H).

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

Prepared according to Example 4, step 4 to yield 3-[[l-[6-[3-(difhioromethoxy)-5-methyl- pyrazol-l-yl]-5-(difluoromethyl)-2-pyridyl]-6-methyl-benzimidazol-5-yl]amino]-N,N,6- trimethyl-pyridazine-4-carboxamide (7.9 mg, 15.9%) as white solid after purification by preparative HPLC (ACS-WH-GX-F, 28 - 58% CH3CN in H₂O (with 0.225% HCOOH) over 10 minutes, flow rate: 25 mL/min). LC-MS: m/z = 584.2 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 6 = 8.61 (br s, 1H), 8.40 (d, J= 8.4 Hz, 1H), 8.33 (br s, 1H), 8.15 - 8.00 (m, 1H), 7.88 (s, 1H), 7.72 (br d, J= 8.3 Hz, 1H), 7.47 (s, 1H), 7.33 (s, 1H), 7.19 (s, 1H), 7.16 - 6.76 (m, 2H), 6.01 (s, 1H), 3.14 (br s, 3H), 3.07 (br s, 3H), 2.66 (s, 3H), 2.56 (s, 3H), 2.48 (s, 3H).

Example 42 l-[5-(difluoromethyl)-6-[(lR)-2,2-difluoro-l-methyl-ethoxy]-2-pyridyl]-N-(6- methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine

Step 1: l,l-difluoropropan-2-ol

To a solution of l,l-difluoropropan-2-one (20.0 g, 212.63 mmol, 1.0 eq.) in Et20 (200 mL)was added NaBHj (8.04 g, 212.63 mmol, 1.0 eq.) at 0 °C. The mixture was then stirred at 15 °C for 1 hour. The reaction mixture was slowly added to sat. aq. NH4CI sol. (500mL). The resulting mixture was stirred at 15 °C for 10 minutes. The layers were separated. The organic phase was dried over Na2SO4 and filtred.The organic phase was evaporated at atmospheric pressure to removed the solvent. Then the residue was distilled at reduced pressure (30 mm Hg, 29°C) to yield l,l-difhioropropan-2-ol (7.3 g, 28.6%) as a colorless oil. 'H NMR (400 MHz, CDCh) 6 = 5.79 - 5.44 (m, 1H), 4.03 - 3.84 (m, 1H), 2.13 (br s, 1H), 1.30 (d, J = 6.6 Hz, 3H).

Step 2: 6-chloro-3-(difluoromethyl)-2-(2, 2-difluoro-l-methyl-ethoxy)pyridine

To a colorless solution of l,l-difhioropropan-2-ol (58.22 mg, 0.61 mmol, 1.1 eq.) in THF (10 mL) was added NaH (33.05 mg, 0.83 mmol, 1.5 eq.) at 0 °C under N2 and stirring was continued for 1 hour. 6-chloro-3-(difluoromethyl)-2-fluoro-pyridine (100.0 mg, 0.55 mmol, 1.0 eq.) was added and stirring at 25 °C was continued for 12 hours under N2. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over ISfeSCU, filtered and concentrated under vacuum to yield 6-chl oro-3 -(difluoromethyl)-2-(2,2-difluoro- 1-m ethyl-ethoxy )pyri dine (130.0 mg, 0.5 mmol, 91.6% yield) as a yellow oil. LC-MS: m/z = 258.0 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 6 = 7.87 (d, J= 7.8 Hz, 1H), 7.09 (d, J= 7.8 Hz, 1H), 6.83 (t, J= 55.0 Hz, 1H), 5.94 (ddd, J= 3.2, 54.8, 56.3 Hz, 1H), 5.58 - 5.42 (m, 1H), 1.37 - 1.16 (m, 3H).

Step 3: 4-bromo-2-nitro-5-(oxetan-3-yloxy)aniline

To a solution of oxetan-3-ol (4.26 g, 57.46 mmol, 1.5 eq.) in THF (90 mL) under N2 cooled to 0 °C was added sodium hydride (60% in oil) (2.3 g, 57.61 mmol, 1.5 eq.) in portions and the mixture was stirred at 0 °C for 30 minutes. 4-bromo-5-fluoro-2-nitro-aniline (9.0 g, 38.3 mmol, 1.0 eq.) was added and the reaction mixture was allowed to warm to RT and was stirred at RT for 12 hours. The reaction was quenched with H2O (100 mL) which formed a precipitate. The mixture was filtered and the filter cake was dried under reduced pressure to give 4-bromo-2-nitro-5-(oxetan-3- yloxy)aniline (4.0 g, 13.84 mmol, 36% yield). The filtrate was extracted with EtOAc (3 x 250 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was triturated in a mixture of petrol ether / EtOAc (10: 1, 30 mL) at RT for 30 minutes . The mixture was filtered and the filter cake was dried under reduced pressure to give 4-bromo-2-nitro-5- (ox etan-3 -yloxy)aniline (7.0 g, 24.21 mmol, 63% yield) as yellow solid. ESI pos [M+H]⁺ 289.0.

'H NMR (400 MHz, DMSO-d₆) 6 = 8.16 (s, 1H), 7.56 (s, 2H), 6.21 (s, 1H), 5.31 (q, J = 5.4 Hz, 1H), 4.93 (t, J= 6.8 Hz, 2H), 4.59 (dd, J= 5.2, 7.6 Hz, 2H).

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

To a solution of 4-bromo-2-nitro-5-(oxetan-3-yloxy)aniline (10.5 g, 36.32 mmol, 1.0 eq.) in EtOH (120 mL) under N2 was added Fe (10.14 g, 181.61 mmol, 5.0 eq.), NH4CI (19.43 g, 363.22 mmol, 10.0 eq.) and H2O (40 mL). The reaction mixture was stirred under N2 at 50 °C for 12 hours. The reaction mixture was cooled to RT and filtered. The filtrate was diluted with H2O (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were concentrated to give 4- bromo-5-(oxetan-3-yloxy)benzene-l,2-diamine (9.4 g, 36.28 mmol, quant, yield) as black solid. ESI pos [M+H]⁺ 259.0.

Step 5: 5-bromo-6-(oxetan-3-yloxy)-lH-benzimidazole;formic acid

A solution of 4-bromo-5-(oxetan-3-yloxy)benzene-l,2-diamine (9.0 g, 34.74 mmol, 1.0 eq.) and formic acid (8.0 mL, 41463.19 mmol, 1193.68 eq.) in triethyl orthoformate (80 mL) was stirred at 80 °C for 12 hours. The reaction mixture was cooled to RT and concentrated. The residue was purified by preparative HPLC (Phenom enex luna Cl 8 10 pm, 150 mm x 40mm, water + 0.1% FA - ACN) to give 5-bromo-6-(oxetan-3-yloxy)-lH-benzimidazole (8.6 g, 31.96 mmol, 91% yield) as a white solid. ESI pos [M+H]⁺ 270.9. 'H NMR (400 MHz, CDCh) 6 = 8.16 (s, 1H), 8.05 (s, 1H), 7.88 (s, 1H), 6.80 (s, 1H), 5.29 (td, J = 5.6, 11.2 Hz, 1H), 5.04 (t, J= 6.8 Hz, 2H), 4.95 - 4.84 (m, 2H).

Step 6: 5-bromo-l-[5-(difluoromethyl)-6-(2, 2-difluoro-l-methyl-ethoxy)-2-pyridyl]-6-(oxetan-3- yloxy) benzimidazole

To a yellow solution of 6-chloro-3-(difluoromethyl)-2-(2,2-difluoro-l-methyl-ethoxy)pyridine (310.0 mg, 1.2 mmol, 1.0 eq.) and 5-bromo-6-(oxetan-3-yloxy)-lH-benzimidazole (prepared in analogy to the procedures described in example 18, step 3) (323.81 mg, 1.2 mmol, 1.0 eq.) in DMSO (10 mL) was added K2CO3 (498.94 mg, 3.61 mmol, 3.0 eq.). The resulting yellow suspension was stirred at 80 °C for 16 hours. The reaction mixture was cooled to 23 °C, poured into H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over ISfeSCU, filtered and concentrated under vacuum. The residue was purified by flash column chromatography using 0% - 100% EtOAc in PE to yield 5-bromo-l-[5-(difluoromethyl)-6-(2,2-difluoro-l-methyl-ethoxy)-2-pyridyl]-6-(oxetan-3- yloxy)benzimidazole (200.0 mg, 33.9%) as a colorless oil. LC-MS: m/z = 492.0 [M+H]⁺, ESI pos. ^XH NMR (400 MHz, CDCh) 6 = 8.40 (s, 1H), 8.17 (br d, J= 7.9 Hz, 1H), 8.12 (d, J= 1.5 Hz, 1H), 7.22 (br d, J = 8.0 Hz, 1H), 7.19 (s, 1H), 6.94 (br t, J= 54.9 Hz, 1H), 6.14 - 5.81 (m, 1H), 5.70 - 5.55 (m, 1H), 5.40 - 5.26 (m, 1H), 5.05 - 4.98 (m, 2H), 4.96 - 4.90 (m, 1H), 4.89 - 4.83 (m, 1H), 1.56 (br d, J= 6.5 Hz, 3H).

Regioisomer 6-bromo-l-[5-(difluoromethyl)-6-(2,2-difluoro-l-methyl-ethoxy)-2-pyridyl]-5- (ox etan-3 -yl oxy )benzimidazole (260.0 mg, 0.53 mmol, 44.07% yield) was also obtained as a yellow solid. LC-MS: m/z = 492.0 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 6 = 8.42 (s, 1H), 8.23 (s, 1H), 8.05 (d, J= 8.0 Hz, 1H), 7.17 (s, 1H), 7.00 - 6.65 (m, 2H), 5.90 (dt, J= 3.2, 55.4 Hz, 1H), 5.56 - 5.41 (m, 1H), 5.30 - 5.20 (m, 1H), 4.99 (t, J= 6.7 Hz, 2H), 4.82 (br t, J= 5.9 Hz, 2H), 1.50 (br d, J= 6.4 Hz, 3H). Step 7: l-[5-(difluoromethyl)-6-(2,2-difluoro-l-methyl-ethoxy)-2-pyridyl]-N-(6-methylpyridazin- 3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine

Prepared according to Example 4, step 4 to yield l-[5-(difluoromethyl)-6-(2,2-difluoro-l- methyl-ethoxy)-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5- amine (85.0 mg, 37.4%) as a yellow solid after after purification by preparative HPLC (Phenomenex Luna C18 (75 mm x 30 mm, 3 pm), 27 - 47% CEECN in H2O (with TFA) over 9 minutes, flow rate: 25 mL/min). LC-MS: m/z = 519.2 [M+H]⁺, ESI pos.

Step 8: l-[5-(difluoromethyl)-6-[(lR)-2,2-difluoro-l-methyl-ethoxy]-2-pyridyl]-N-(6- methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine l-[5-(difluoromethyl)-6-(2,2-difluoro-l-methyl-ethoxy)-2-pyridyl]-N-(6-methylpyridazin-3-yl)- 6-(oxetan-3-yloxy)benzimidazol-5-amine (85.0 mg, 0.16 mmol, 1.0 eq.) was purified by chiral SFC (Daicel Chiralpak AD (250 mm x 30 mm, 10 pm) with EtOH (0.1% NH4OH) in CO2 over 6.5 min, flow rate 70 mL / min) to yield l-[5-(difluoromethyl)-6-[(lR)-2,2-difluoro-l-methyl- ethoxy]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine (23.2 mg, 27.3%) as a white solid. LC-MS: m/z = 519.2 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CD3OD) 8 = 8.74 (s, 1H), 8.60 (s, 1H), 8.23 (d, J= 7.9 Hz, 1H), 7.56 (d, J= 7.9 Hz, 1H), 7.43 - 7.37 (m, 2H), 7.33 - 7.26 (m, 1H), 7.02 (t, J= 55.1 Hz, 1H), 6.18 (dt, J= 3.5, 55.3 Hz, 1H), 5.79 - 5.65 (m, 1H), 5.48 (quin, J= 5.4 Hz, 1H), 5.10 - 5.01 (m, 2H), 4.85 - 4.81 (m, 1H), 4.79 (dd, J = 5.2, 7.0 Hz, 1H), 2.57 (s, 3H), 1.56 (d, J= 6.6 Hz, 3H).

Example 43 l-[5-(difluoromethyl)-6-[(lS)-2,2-difluoro-l-methyl-ethoxy]-2-pyridyl]-N-(6- methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine Step 1: l-[5-(difluoromethyl)-6-[(lS)-2,2-difluoro-l-methyl-ethoxy]-2-pyridyl]-N-(6- methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine l-[5-(difhioromethyl)-6-[(lS)-2,2-difluoro-l -methyl -ethoxy]-2-pyridyl]-N-(6-methylpyridazin- 3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine (24.7 mg, 29.1%) was obtained as a white solid in Example 42, step 5 after chiral SFC purification. LC-MS: m/z = 519.2 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CD3OD) 8 = 8.74 (s, 1H), 8.60 (s, 1H), 8.23 (d, J= 7.9 Hz, 1H), 7.56 (d, J= 7.9 Hz, 1H), 7.43 - 7.37 (m, 2H), 7.33 - 7.26 (m, 1H), 7.02 (t, J= 55.1 Hz, 1H), 6.18 (dt, J= 3.5, 55.3 Hz, 1H), 5.79 - 5.65 (m, 1H), 5.48 (quin, J= 5.4 Hz, 1H), 5.10 - 5.01 (m, 2H), 4.85 - 4.81 (m, 1H), 4.79 (dd, J= 5.2, 7.0 Hz, 1H), 2.57 (s, 3H), 1.56 (d, J= 6.6 Hz, 3H).

Example 44

N-[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2-pyridyl]-6- methoxy-benzimidazol-5-yl]-l-(oxetan-3-yl)piperidine-4-carboxamide

Step 1: methyl l-(oxetan-3-yl)piperidine-4-carboxylate

A solution of methyl 4-piperidinecarboxylate (1.0 g, 6.98 mmol, 1.0 eq.) and 3-oxetanone (1.51 g, 20.95 mmol, 3.0 eq.)in MeOH (10 mL) was stirred at 20 °C for 10 minutes. Then NaBHsCN (877.78 mg, 13.97 mmol, 2.0 eq.) was added. The mixture was stirred at 20 °C for 1 hour. The mixture was then concentrated in vacuo to remove the MeOH. H2O (20 mL) was added to the residue and the mixture was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness to yield methyl 1 -(ox etan-3 -yl)piperidine-4-carboxylate (1000.0 mg, 71.9%) as a colorless oil. LC- MS: m/z = 200.2 [M+H]⁺, ESI pos. Step 2: l-(oxetan-3-yl)piperidine-4-carboxylic acid

To a solution ofmethyl 1 -(ox etan-3 -yl)piperidine-4-carboxylate (1000.0 mg, 5.02 mmol, 1.0 eq.) in THF (2 mL) and H2O (2 mL) was added LiOH hydrate (526.47 mg, 12.55 mmol, 2.5 eq.). The mixture was stirred at 20 °C for 2 hours and concentrated in vacuum to remove the THF. The pH of the residual aqueous mixture was set to 7 by the addition of IN HC1. The mixture was directly purified by preparative HPLC (Waters Atlantis T3 (150 mm x 30 mm, 5 pm), CH3CN in H2O (with TFA) to yield l-(oxetan-3-yl)piperidine-4-carboxylic acid (380.0 mg, 40.9%) as a white solid. LC-MS: m/z = 186.1 [M+H]⁺, ESI pos. 'H NMR (400 MHz, DMSO-d₆) 6 = 4.53 - 4.48 (m, 2H), 4.40 (t, J= 6.1 Hz, 2H), 3.36 - 3.32 (m, 1H), 2.60 (br d, J= 11.3 Hz, 2H), 2.24 - 2.16 (m, 1H), 1.84 - 1.73 (m, 4H), 1.59 - 1.48 (m, 2H).

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

Prepared according to Example 4, step 4 to yield l-[6-(5-amino-6-methoxy-benzimidazol-l-yl)- 3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (15 mg, 13.5%) as a yellow solid. LC-MS: m/z = 396.1, [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 8 = 8.44 - 8.37 (m, 2H), 7.75 (d, J= 8.4 Hz, 1H), 7.47 (s, 1H), 7.29 (s, 1H), 7.27 (s, 1H), 7.16 (s, 1H), 7.02 (s, 1H), 6.69 (s, 1H), 3.87 (s, 3H), 2.54 (s, 3H).

Step 4: N-[ l-[ 6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy- benzimidazol-5-yl]-l-(oxetan-3-yl)piperidine-4-carboxamide

To a light yellow solution of l-[6-(5-amino-6-methoxy-benzimidazol-l-yl)-3-(difluoromethyl)- 2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (15.0 mg, 0.040 mmol, 1 eq.) in DMF (1 mL) were added DIPEA (9.1 mg, 0.070 mmol, 2 eq.) and l-(oxetan-3-yl)piperidine-4-carboxylic acid (7.84 mg, 0.040 mmol, 1.2 eq.) at 25 °C. HATU (12.45 mg, 0.050 mmol, 1.5 eq.) was then added portionwise to give a brown solution. The mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched by the addition of NH4CI (10 ml) and extracted with EtOAc (5 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. Theresidue was purified by preparative HPLC (Waters Xbridge (150 mm x 25 mm, 5 pm), 32% - 62% CH3CN in H2O (with NH4HCO3) over 8 minutes, flow rate 25 mL / min) to yield N-[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy- benzimidazol-5-yl]-l-(oxetan-3-yl)piperidine-4-carboxamide (4.7 mg, 21.1%) as a white solid. LC-MS: m/z = 563.1 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CD3OD) 8 = 8.88 - 8.81 (m, 1H), 8.57 - 8.48 (m, 1H), 8.44 - 8.39 (m, 1H), 8.24 - 8.13 (m, 1H), 7.85 - 7.77 (m, 1H), 7.20 (br d, J= 5.9 Hz, 1H), 7.06 (br d, J= 5.9 Hz, 1H), 6.91 (br s, 1H), 6.89 (s, 1H), 4.75 - 4.69 (m, 2H), 4.68 - 4.62 (m, 2H), 3.91 - 3.86 (m, 3H), 3.70 - 3.61 (m, 1H), 2.98 (br d, J= 11.5 Hz, 2H), 2.67 - 2.57 (m, 1H), 2.53 (d, J= 5.1 Hz, 3H), 2.18 - 2.09 (m, 2H), 2.02 - 1.89 (m, 4H).

Example 45 l-[5-(difluoromethyl)-6-[3-(trifluoromethyl)-5,7-dihydro-4H-pyrano[3,4- c]pyrazol-l-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3- yloxy)benzimidazol-5-amine

Step 1: 3,6-dihydro-2H-pyran-5-yloxy(trimethyl)silane

To a solution of dihydro-2H-pyran-3(4H)-one (1.0 g, 9.99 mmol, 1.0 eq.) inTHF (20 mL) was added TMSC1 (3.2 mL, 24.97 mmol, 2.5 eq.) at 25 °C and the mixture was stirred for 0.2 hour. Then TEA (3.75 mL, 26.97 mmol, 2.7 eq.) was added dropwise at 25 °C. The resulting mixture was stirred at 70 °C for 12 hours. The reaction mixture was cooled to 23 °C and concentrated under reduced pressure. The residue was triturated in PE(20 mL) and the resulting suspension was stirred at 25 °C for 10 minutes. The solid was filtered off and the filtrate was concentrated under reduced pressure to yield 3,6-dihydro-2H-pyran-5-yloxy(trimethyl)silane (1.7 g,98.8%) as a yellow gum. 'H NMR (400 MHz, CDCh) 6 = 4.96 (t, J= 4.0 Hz, 1H), 3.90 (d, J= 1.6 Hz, 2H), 3.70 (t, J= 5.4 Hz, 2H), 2.21 - 2.13 (m, 2H), 0.21 (s, 9H).

Step 2: 3 -(trifluoromethyl) -1,4, 5, 7-tetrahydropyrano[3,4-c]pyrazole

To a solution of 4-(2,2,2-trifluoroacetyl)tetrahydropyran-3-one (1.0 g, 5.1 mmol, 1.0 eq.) in THF (10 mL) was added methyl lithium (3.19 mL, 5.1 mmol, 1.0 eq.) dropwise under N2 at 25°C. After stirring for 1 hour the mixture was cooled to -78 °C and 4-(2,2,2- trifluoroacetyl)tetrahydropyran-3-one (1.0 g, 5.1 mmol, 1.0 eq.) was added. The mixture was allowed to slowly warm to 25 °C for 12 hours. The reaction mixture was quenched by the addition of sat. aq. NH4CI sol. (5 mL), diluted with H2O (15 mL) and extracted with EtOAc (25 mL x 3). The combined organic layers were washed with sat. aq. NaCl sol. (50 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield 4-(2,2,2- trifluoroacetyl)tetrahydropyran-3-one (600.0 mg). To a soltion of 4-(2,2,2- trifluoroacetyl)tetrahydropyran-3-one (600.0 mg, 3.06 mmol, 1 eq.) in EtOH (10 mL) was added hydrazine hydrate (510.74 mg, 10.2 mmol, 2.0 eq.) at 2 5°C and the reaction mixture was stirred at 70 °C for 12 hours. The reaction mixture was cooed to 25 °C and concentrated under reduced pressure. The residue was purified by preparative HPLC (Welch pLtimate XB-SiOH (250 mm x 50 mm, 10 pm), gradient of EtOH (with 0.1% NH4OH) in hexane) to yield 3-(trifluoromethyl)- l,4,5,7-tetrahydropyrano[3,4-c]pyrazole (270.0 mg, 45.0%) as a white solid. No analytical

Step 3: l-[6-chloro-3-(difluoromethyl)-2-pyridyl]-3-(trifluoromethyl)-5, 7-dihydro-4H- pyrano[ 3, 4-c pyrazole

To a solution of 6-chl oro-3 -(difluoromethyl)-2 -fluoro-pyridine (236.21 mg, 1.3 mmol, 1.0 eq.) in DMSO (5 mL) were added 3-(trifluoromethyl)-l,4,5,7-tetrahydropyrano[3,4-c]pyrazole (250.0 mg, 1.3 mmol, 1.0 eq.) and DIPEA (0.66 mL, 3.9 mmol, 3.0 eq.). The mixture was stirred at 70 °C for 12 hours. The reaction mixture was purified by reverse phase HPLC (CH3CN in H2O (with 0.1% FA)) to yield l-[6-chloro-3-(difluoromethyl)-2-pyridyl]-3-(trifluoromethyl)-5,7- dihydro-4H-pyrano[3,4-c]pyrazole (180.0 mg, 0.51 mmol, 39.11% yield) as a white solid. LC- MS: m/z = 354.1 [M+H]⁺, ESI pos. ^XH NMR (400 MHz, CDCh) 6 = 8.19 (d, J= 8.0 Hz, 1H), 7.94 - 7.58 (m, 1H), 7.40 (d, J= 8.0 Hz, 1H), 5.12 (s, 2H), 3.96 (t, J= 5.6 Hz, 2H), 2.81 (t, J= 5.2 Hz, 2H).

Step 4: l-[ 6-[5-bromo-6-(oxetan-3-yloxy)benzimidazol-l-yl]-3-(difluoromethyl)-2-pyridyl]-3- (trifluoromethyl)-5, 7-dihydro-4H-pyrano[ 3, 4-c]pyrazole

To a light yellow solution of l-[6-chloro-3-(difluoromethyl)-2-pyridyl]-3-(trifluoromethyl)-5,7- dihydro-4H-pyrano[3,4-c]pyrazole (155.0 mg, 0.44 mmol, 1.0 eq.) in DMF (5 mL) was added 5- bromo-6-(oxetan-3-yloxy)-lH-benzimidazole (117.93 mg, 0.44 mmol, 1.0 eq.). The brown solution was then treated with K2CO3 (181.71 mg, 1.31 mmol, 3.0 eq.) and stirred at 20 °C for 12 hours. The mixture was poured into H2O (50mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed by brine (30mL x 3), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative TLC (EtOAc) to yield l-[6-[5- bromo-6-(oxetan-3-yloxy)benzimidazol-l-yl]-3-(difluoromethyl)-2-pyridyl]-3-(trifluoromethyl)-

5.7-dihydro-4H-pyrano[3,4-c]pyrazole (55.0 mg, 21.4%) as a yellow solid. LC-MS: m/z = 586.0 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CD₃OD) 8 = 8.89 (s, 1H), 8.56 (d, J= 8.5 Hz, 1H), 8.41 (s, 1H), 8.00 (d, J= 8.5 Hz, 1H), 7.59 (t, J= 55.0 Hz, 1H), 7.05 (s, 1H), 5.50 - 5.40 (m, 1H), 5.11 (t, J= 7.0 Hz, 2H), 5.06 (s, 2H), 4.80 (dd, J= 4.9, 7.8 Hz, 2H), 3.99 (t, J= 5.6 Hz, 2H), 2.84 (t, J= 5.3 Hz, 2H).

Regioisomer l-[6-[6-bromo-5-(oxetan-3-yloxy)benzimidazol-l-yl]-3-(difluoromethyl)-2- pyridyl]-3-(trifluoromethyl)-5,7-dihydro-4H-pyrano[3,4-c]pyrazole (40.0 mg, 15.6%) was also obtained as a brown gum.

LC-MS: m/z = 586.0 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CD3OD) 8 = 8.83 (s, 1H), 8.58 (d, J = 8.4 Hz, 1H), 8.41 - 8.32 (m, 1H), 8.05 - 7.96 (m, 2H), 7.85 - 7.78 (m, 1H), 7.54 (t, J= 54.9 Hz, 1H), 7.35 (s, 1H), 5.44 - 5.32 (m, 1H), 5.05 (s, 2H), 3.98 (t, J= 5.6 Hz, 2H), 3.88 (t, J= 5.6 Hz, 1H), 2.85 (br t, J= 5.3 Hz, 2H), 2.70 (t, J= 5.9 Hz, 1H).

Step 5: l-[5-(difluoromethyl)-6-[3-(trifluoromethyl)-5, 7-dihydro-4H-pyrano[3,4-c]pyrazol-l- yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)benzimidazol-5-amine

Prepared according to Example 4, step 4 to yield l-[5-(difluoromethyl)-6-[3-(trifluoromethyl)-

5.7-dihydro-4H-pyrano[3,4-c]pyrazol-l-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-(oxetan-3- yloxy)benzimidazol-5-amine (20.5 mg, 32.5%) as ayellow solid after purification by preparative HPLC (Phenomenex Luna C18 (150 mm x 25 mm, 10 pm), 24 - 54% CH3CN in H2O (with 0.225% FA) over 10 minutes, flow rate: 25 mL/min). LC-MS: m/z = 615.1 [M+H]⁺, ESI pos. 'H NMR (400 MHz, DMSO-d₆) 8 = 8.86 (d, J= 15.8 Hz, 2H), 8.58 (d, J= 8.5 Hz, 1H), 8.38 (s, 1H), 8.12 (d, J= 8.4 Hz, 1H), 7.62 - 7.31 (m, 3H), 7.27 (s, 1H), 5.41 (quin, J= 5.6 Hz, 1H), 5.04 (s, 2H), 4.84 (t, J= 6.6 Hz, 2H), 4.78 - 4.70 (m, 2H), 3.93 (br t, J= 5.5 Hz, 2H), 2.79 (br s, 2H), 2.50 - 2.49 (m, 3H).

Example 46 2-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3- yloxy)benzimidazol-l-yl]-2-pyridyl]-3,5-dimethyl-4H-pyrrolo[3,4-c]pyrazol-6- one

Step 1: methyl 5-methyl-l-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate

In a 500 mL three-necked round-bottom flask (dried by heating with a heat gun under vacuum), methyl 5-methyl-lH-pyrazole-3-carboxylate (5.0 g, 35.68 mmol, 1.0 eq.) was dissolved in DMF (100 mL). NaH (60% dispersion in mineral oil) (1712.0 mg, 42.8 mmol, 1.2 eq.) was added portionwise at 0 °C under N2. The reaction mixture was stirred at 0 °C for 0.5 hour to give a white suspension. Then 2 -trimethyl silyl)ethoxym ethyl chloride (9.47 mL, 53.52 mmol, 1.5 eq.) was added dropwise using a syringe at 0 °C. The reaction mixture was then stirred at 0 °C for 2 hours, resulting in a yellow suspension. Under a stream of N2, the mixture was carefully quenched by the addition of NH4CI (600 mL). EtOAc (400 mL) was added and the layers were separated. The aqueous phase was back-extracted with EtOAc (400 mL x 2). The combined organic extracts were washed with brine (600 mL), dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by flash column chromatography using 30% EtOAc in PE to yield methyl 5-methyl-l-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (4.0 g,41.5%) as a colorless oil. LC-MS: m/z = 271.2 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 8 = 6.63 (s, 1H), 5.49 (s, 2H), 3.92 (s, 3H), 3.56 (t, J= 8.1 Hz, 2H), 2.39 (s, 3H), 0.88 (t, J= 8.2 Hz, 2H), -0.03 (s, 9H).

Regioisomer methyl 5-methyl-2-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (4.0 g, 41.5%) was also obtained as a colorless oil. LC-MS: m/z = 271.2 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 6 = 6.68 (s, 1H), 5.78 (s, 2H), 3.88 (s, 3H), 3.63 - 3.53 (m, 2H), 2.30 (s, 3H), 0.93 - 0.87 (m, 2H), -0.04 (s, 9H). Step 2: methyl 4-bromo-5-methyl-l-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate To a solution of methyl 5-methyl-l -(2 -trimethyl silyl ethoxymethyl)pyrazole-3-carboxylate (4.0 g, 14.79 mmol, 1 eq.) in CH CN (40 mL) was added NBS (3949.7 mg, 22.19 mmol, 1.5 eq.) at 20 °C under N2. The reaction mixture was stirred at 20 °C for 3 hours. SiCh (6 g) was added to the orange solution. The mixture was concentrated at 23 °C to dryness and the residual yellow solid was purified by flash column chromatography using 0% - 20% EtOAc in PE to yield 4- bromo-5-methyl-l-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (4.5 g,87.1%) as a colorless oil. LC-MS: m/z = 290.9 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 6 = 5.49 (s, 2H), 3.94 (s, 3H), 3.54 (t, J= 8.3 Hz, 2H), 2.38 (s, 3H), 0.87 (t, J= 8.3 Hz, 2H), -0.03 (s, 9H).

Step 3: methyl 4-[(tert-butoxycarbonylamino)methyl]-5-methyl-l-(2- trimethylsilylethoxymethyl)pyrazole-3-carboxylate

To a suspension of methyl 4-bromo-5-methyl-l-(2-trimethylsilylethoxymethyl)pyrazole-3- carboxylate (3.0 g, 8.59 mmol, 1.0 eq.) and potassium N-BOC-aminomethyltrifluoroborate (5.09 g, 21.47 mmol, 2.5 eq.) in 1,4-dioxane (30 mL)were added CS2CO3 (6.99 g, 21.47 mmol, 2.5 eq.), Pd(OAc)2 (385.64 mg, 1.72 mmol, 0.2 eq.), XPhos (1637.73 mg, 3.44 mmol, 0.4 eq.) and H2O (3 mL). The suspension was degassed and back-filled with N2 3 times. The mixture was then heated to 110 °C and stirring was continued for 16 hours. The resulting was dark suspension was cooled to 23 °C. The precipitate was filtered off. The filtrate was diluted with H2O (150 mL) and extracted with EtOAc (100 mL x 3). The combined organic extracts were dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash column chromatography using 20% EtOAc in PE to yield methyl 4-[(tert- butoxycarbonylamino)methyl]-5-methyl-l -(2 -trimethyl silyl ethoxymethyl )pyrazole-3- carboxylate (1.5 g,43.7%) as a colorless oil. LC-MS: m/z = 400.2 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 8 = 5.47 (s, 2H), 4.29 (d, J= 6.4 Hz, 2H), 3.96 (s, 3H), 3.60 - 3.52 (m, 2H), 2.44 (s, 3H), 1.42 (s, 9H), 0.91 - 0.85 (m, 2H), -0.03 (s, 9H).

Step 4: methyl 4-(aminomethyl)-5-methyl-l-(2-trimethylsilylethoxymethyl)pyrazole-3- carboxylate

To a solution of methyl 4-[(tert-butoxycarbonylamino)methyl]-5-methyl-l-(2- trimethylsilylethoxymethyl)pyrazole-3-carboxylate (1.8 g, 4.5 mmol, 1.0 eq.) in DCM (18 mL) was added TFA (1.8 mL). The reaction mixture was stirred at 25 °C for 4 hours. The mixture was quenched by the careful addition of sat. aq. NaHCCh sol. (50 mL). DCM (20 mL) was added and the layers were separated. The aqueous phase was back-extracted with DCM (20 mL x 2). The combined organic extracts were dried over Na2SO4, filtered and concentrated under vacuum to yield methyl 4-(aminomethyl)-5-methyl-l-(2-trimethylsilylethoxymethyl)pyrazole-3- carboxylate (1.2 g, 89.0%) as a yellow oil which was used without further purification. LC-MS: m/z = 300.1 [M+H]⁺, ESI pos.

Step 5: 4-(aminomethyl)-5-methyl-l-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylic acid To a solution of methyl 4-(aminomethyl)-5-methyl-l-(2-trimethylsilylethoxymethyl)pyrazole-3- carboxylate (1.2 g, 4.01 mmol, 1.0 eq.) in a mixture THF (10 mL), MeOH (10 mL) and H2O (1 mL), was added LiOH hydrate (420.79 mg, 10.02 mmol, 2.5 eq.). The mixture was stirred at 25 °C for 1 hour. The pH was adjusted to 7 using 1 M HC1 and the mixture was concentrated under reduced pressure to give 4-(aminomethyl)-5-methyl-l -(2 -trimethyl silyl ethoxymethyl)pyrazole- 3-carboxylic acid (1.0 g, 87.4%) as a yellow oil which was used without further purification. LC-MS: m/z = 286.2 [M+H]⁺, ESI pos.

Step 6: 3-methyl-2-(2-trimethylsilylethoxymethyl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6-one To a solution of 4-(aminomethyl)-5-methyl-l-(2-trimethylsilylethoxymethyl)pyrazole-3- carboxylic acid (1.0 g, 3.5 mmol, 1.0 eq.) in DMF (50 mL) were added DIPEA (0.52 mL, 10.51 mmol, 3.0 eq.) and HATU (989.17 mg, 4.2 mmol, 1.2 eq.). The reaction mixture was stirred at 25 °C for 12 hours, diluted with H2O (200mL) and extracted with EtOAc (150 mL x 2). The combined organic extracts were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC (DCM/MeOH 10: 1) andconcentrated under vacuum to give the crude(200 mg, 50% purity). The crude was purified by revers-phase flash column chromatography to yield 3-methyl-2-(2- trimethylsilylethoxymethyl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6-one (50.0 mg, 5.3%) as a white solid. LC-MS: m/z = 268.2 [M+H]⁺, ESI pos.

Step 7: 3,5-dimethyl-2-(2-trimethylsilylethoxymethyl)-4H-pyrrolo[3,4-c]pyrazol-6-one

To a solution of 3-methyl-2-(2-trimethylsilylethoxymethyl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6- one (50.0 mg, 0.19 mmol, 1.0 eq.) in DMF (3 mL) was added NaH 60% dispersion in mineral oil (12.0 mg, 0.3 mmol, 1.6 eq.) in portions. The mixture was stirred at 0 °C for 30 minutes. Then iodomethane (0.12 mL, 1.87 mmol, 10.0 eq.)was added dropwise. The reaction mixture was stirred at 20 °C for 2 hours. The reaction mixture was poured into sat. aq. NH4CI sol. (40 mL). The mixture was extracted with EtOAc (30 mL x 2). The combined organic extracts were washed with brine (60 mL), dried over Na2SO4, filtered and concentrated under vacuum to give 3, 5-dimethyl-2-(2 -trimethyl silyl ethoxymethyl)-4H-pyrrolo[3,4-c]pyrazol-6-one (40.0 mg, 76.0%) as a colorless oil which was used without further purification. LC-MS: m/z = 282.2 [M+H]⁺, ESI pos.

Step 8: 3,5-dimethyl-2,4-dihydropyrrolo[3,4-c]pyrazol-6-one

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

Step 9: 2-[ 6-chloro- 3 -(difluoromethyl) -2 -pyridyl J -3, 5-dimethyl-4H -pyrrolo[ 3, 4-c ]pyrazol-6-one To a solution of 6-chl oro-3 -(difluoromethyl)-2 -fluoro-pyridine (20.0 mg, 0.110 mmol, 1 eq.) and

3.5-dimethyl-2,4-dihydropyrrolo[3,4-c]pyrazol-6-one (16.65 mg, 0.110 mmol, 1 eq.) in DMSO (1 mL) was added K2CO3 (0.04 mL, 0.220 mmol, 2 eq.). The reaction mixture was stirred at 30 °C for 1 hour. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (30 mL x 3) and concentrated under vacuum. The residue was purified by preparative TLC using 20% EtOAc in PE to yield 2- [6-chloro-3-(difluoromethyl)-2-pyridyl]-3,5-dimethyl-4H-pyrrolo[3,4-c]pyrazol-6-one (20.0 mg, 58.1%) as a white solid. LC-MS: m/z = 313.0 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 8 = 8.16 (d, J= 8.2 Hz, 1H), 7.57-7.29 (t, 1H), 7.50 (d, J= 8.2 Hz, 1H), 4.30 (s, 2H), 3.20 (s, 3H), 2.53 (s, 3H).

Step 10: 2-[ 6-[5-bromo-6-(oxetan-3-yloxy)benzimidazol-l-yl]-3-(difluoromethyl)-2-pyridyl]-3, 5- dimethyl-4H-pyrrolo[3,4-c]pyrazol-6-one

To a solution of 2-[6-chloro-3-(difluoromethyl)-2-pyridyl]-3,5-dimethyl-4H-pyrrolo[3,4- c]pyrazol-6-one (20.0 mg, 0.06 mmol, 1.0 eq.) and 5-bromo-6-(oxetan-3-yloxy)-lH- benzimidazole (21.0 mg, 0.08 mmol, 1.22 eq.) in DMSO (1 mL) was added K2CO3 (26.52 mg, 0.19 mmol, 3.0 eq.) at 20 °C. The reaction mixture was stirred at 40 °C for 12 hours. The reaction mixture was cooled to 23 °C. EtOAc (10 mL) and H2O (10 mL) were added and the layers were separated. The aqueous phase was back-extracted with EtOAc (10 mL x 2). The combined organic extracts were washed with brine (20 mL x 3), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC using 10% MeOH to yield 2-[6-[5-bromo-6-(oxetan-3-yloxy)benzimidazol-l-yl]-3-(difluoromethyl)-2-pyridyl]-3,5- dimethyl-4H-pyrrolo[3,4-c]pyrazol-6-one (15.0 mg, 43.0%). LC-MS: m/z = 545.1 [M+H]⁺, ESI pos. ^XH NMR (400 MHz, DMSO-d₆) 6 = 9.09 (s, 1H), 8.61 (d, J= 8.6 Hz, 1H), 8.29 (d, J = 8.5 Hz, 1H), 8.09 (s, 1H), 7.48 (s, 1H), 7.33 - 7.01 (m, 1H), 5.25 (t, J= 5.6 Hz, 1H), 4.75 - 4.67 (m, 2H), 4.61 (dd, J= 5.2, 7.3 Hz, 2H), 4.40 (s, 2H), 3.09 (s, 3H), 2.46 (s, 3H).

Regioisomer 2-[6-[6-bromo-5-(oxetan-3-yloxy)benzimidazol-l-yl]-3-(difluoromethyl)-2- pyridyl]-3,5-dimethyl-4H-pyrrolo[3,4-c]pyrazol-6-one (10.0 mg, 28.7 was also isolated )as a yellow oil. LC-MS: m/z = 545.1 [M+H]⁺, ESI pos. 'H NMR (400 MHz, DMSO-d₆) 6 = 9.16 (s, 1H), 8.57 (d, J= 8.7 Hz, 1H), 8.50 (s, 1H), 8.30 (d, J= 8.4 Hz, 1H), 7.19 (s, 1H), 7.25 -6.98 (m, 1H), 5.48 - 5.40 (m, 1H), 5.02 (t, J= 6.7 Hz, 2H), 4.61 (dd, J= 5.1, 7.0 Hz, 2H), 4.42 (s, 2H), 3.08 (s, 3H), 2.52 - 2.51 (m, 3H). Step 11: 2-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3- yloxy)benzimidazol-l-yl] -2-pyridyl] -3, 5-dimethyl-4H-pyrrolo[ 3, 4-c]pyrazol-6-one Prepared according to Example 4, step 4 to yield 2-[3-(difluoromethyl)-6-[5-[(6- methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-l-yl]-2-pyridyl]-3,5-dimethyl- 4H-pyrrolo[3,4-c]pyrazol-6-one (2.65 mg, 15.1% yield) as a white solid after purification by preparative HPLC (Phenomenex Cl 8 (75 mm x 30 mm, 3 pm), 8 - 38% CH3CN in H2O (with 0.225% FA) over 7 minutes, flow rate: 25 mL/min). LC-MS: m/z = 574.3 [M+H]⁺, ESI pos. ^TH NMR (400 MHz, CD3OD) 8 = 8.91 (br s, 1H), 8.64 (br s, 1H), 8.53 (br d, J= 8.5 Hz, 1H), 8.17 (br d, J= 8.3 Hz, 1H), 7.49 (br s, 1H), 7.39 (br s, 1H), 7.29-7.01 (m, 2H), 5.25 (br d, J= 3.8 Hz, 1H), 4.79 (br d, J= 4.8 Hz, 4H), 4.50 (s, 2H), 3.23 (s, 3H), 2.61 - 2.48 (m, 6H).

Example 47 l-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-(l-methyl-5-oxo-pyrrolidin-2- yl)pyridazin-3-yl] amino] benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile

Step 1: tert-butyl N-(6-formyllpyridazin-3-yl)carbamate

To a solution of tert-butyl N-(6-vinylpyridazin-3-yl)carbamate (500.0 mg, 2.26 mmol, 1.0 eq.) in MeOH (5 mL) and H2O (2 mL) was added OsC (58.49 mg, 0.23 mmol, 0.1 eq.). After stirring 5 minutes, NalCh (1.45 g, 6.78 mmol, 3.0 eq.) was added and stirring at 20 °C was continued for 2 hours. The reaction mixture was poured into H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were concentrated under vacuum. The residue was purified by flash column chromatography using 30% EtOAc in PE to yield tert-butyl N-(6-formylpyridazin- 3-yl)carbamate (250.0 mg, 49.6%) as a white solid. LC-MS: m/z = 167.8 [M+H-56]⁺, ESI pos. Step 2: methyl 4-[6-(tert-butoxycarbonylamino)pyridazin-3-yl]-4-oxo-butanoate

To a solution of methyl acrylate (578.48 mg, 6.72 mmol, 1.5 eq.) at 23 °C in THF (10 mL), were added 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazoliumbromide (241.63 mg, 0.9 mmol, 0.2 eq.) and TEA (1.87 mL, 13.44 mmol, 3.0 eq.), Then tert-butyl N-(6-formylpyridazin-3-yl)carbamate (1.0 g, 4.48 mmol, 1.0 eq.) was added and stirring at 70 °C was continued for 2 hours. The reaction mixture was poured into FLO (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash column chromatography using 30% EtOAc in PE to yield methyl 4-[6-(tert- butoxycarbonylamino)pyridazin-3-yl]-4-oxo-butanoate (400.0 mg, 28.9%) as a white solid. LC- MS: m/z = 310.1 [M+H]⁺, ESI pos.

Step 3: tert-butyl N-[6-(l-methyl-5-oxo-pyrrolidin-2-yl)pyridazin-3-yl] carbamate To a solution of methyl 4-[6-(tert-butoxycarbonylamino)pyridazin-3-yl]-4-oxo-butanoate (400.0 mg, 1.29 mmol, 1.0 eq.) in MeOH (5 mL), were added HO Ac (7.77 mg, 0.13 mmol, 0.1 eq.) and methylamine 2 M sol. in THF (3.23 mL, 6.47 mmol, 5.0 eq.). The reaction mixture was stirred at 30 °C for 12 hours. NaBHsCN (243.79 mg, 3.88 mmol, 3.0 eq.) was added and stirring at 30 °C was continued for 12 hours. The reaction mixture was poured into H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under vacuum.

The residue was purified by preparative TLC using 10% MeOH in DCM to yield tert-butyl N-[6- (l-methyl-5-oxo-pyrrolidin-2-yl)pyridazin-3-yl]carbamate (80.0 mg, 21.2%) as a brown solid. LC-MS: m/z = 292.9 [M+H]⁺, ESI pos.

Step 4: 5-( 6-aminopyridazin-3-yl)-l-methyl-pyrrolidin-2-one

A solution of tert-butyl N-[6-(l-methyl-5-oxo-pyrrolidin-2-yl)pyridazin-3-yl]carbamate (80.0 mg, 0.27 mmol, 1.0 eq.) in HC1 4M sol. in dioxane (1.0 mL) was stirred at 40 °C for 1 hour. The reaction mixture was concentrated under vaccum. The residue was purified by preparative HPLC (Phenomenex Luna C18 (150 mm x 40 mm, 15 pm), 4% - 30% CH3CN in H2O (with 0.225% FA) over 10 minutes, flow rate: 20 mL/min) to yield 5-(6-aminopyridazin-3-yl)-l-methyl- pyrrolidin-2-one (40.0 mg, 76.0%) as a brown solid. LC-MS: m/z = 193.0 [M+H]⁺, ESI pos. Step 5: l-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-(l-methyl-5-oxo-pyrrolidin-2-yl)pyridazin-3- yl]amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

Prepared according to Example 4, step 4 to yield l-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-(l- methyl-5-oxo-pyrrolidin-2-yl)pyridazin-3-yl]amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl- pyrazole-3 -carbonitrile (6.0 mg, 11.7%) as a yellow solid after purification by preparative HPLC. LC-MS: m/z = 571.1 [M+H]⁺, ESI pos. ^XH NMR (400 MHz, DMSO-d₆) 8 = 9.07 - 8.98 (m, 1H), 8.84 - 8.72 (m, 1H), 8.70 - 8.53 (m, 2H), 8.48 - 8.29 (m, 1H), 7.91 - 7.81 (m, 1H), 7.49 - 7.37 (m, 2H), 7.08 (m, 2H), 4.86 - 4.69 (m, 1H), 3.92 - 3.84 (m, 3H), 3.30 (br s, 3H), 2.56 (br s, 3H), 2.42 - 2.31 (m, 3H), 1.98 - 1.86 (m, 1H).

Example 48

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

Step 1: 3-chloro-N,N,5-trimethyl-pyridazine-4-carboxamide

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

In a glass tube, 3-chloro-N,N,5-trimethyl-pyridazine-4-carboxamide (175 mg, 0.877 mmol, 1.0 eq.), benzophenone imine (250.84 mg, 232.25 pL, 1.31 mmol, 1.5 eq.) and CS2CO3 (571.21 mg, 1.75 mmol, 2.0 eq.) were combined with 1,4-dioxane (2.6 mL) and argon was bubbled through the mixture for 5 minutes. Then BINAP (54.58 mg, 0.088 mmol, 0.1 eq.) and tris(dibenzylideneacetone)dipalladium (0) (45.37 mg, 0.044 mmol, 0.05 eq.) were added, the vial was sealed and the reaction mixture was stirred at 100 ⁰ C over night. The mixture was cooled to 23 °C and concentrated. The residue was purified by flash column chromatography using 50% - 100% EtOAc in heptane to yield 3-(benzhydrylideneamino)-N,N,5-trimethyl-pyridazine-4- carboxamide ( 217 mg, 70.7%) as a yellow viscous oil. LC-MS: m/z = 345.1 [M+H]⁺, ESI pos.

Step 3: 3-amino-N,N,5-trimethyl-pyridazine-4-carboxamide

To a solution of 3-(benzhydrylideneamino)-N,N,5-trimethyl-pyridazine-4-carboxamide (207 mg, 0.601 mmol, 1.0 eq.) intetrahydrofuran (11.24 mL) were added HC1 2 M sol. in Et2O (3.01 mL, 6.01 mmol, 10.0 eq.) and H2O (10.83 mg, 10.83 pL, 0.601 mmol, 1.0 eq.). The reaction mixture was stirred at 23 °C over night. More HC1 2 M sol. in Et2O (1.5 mL, 3.01 mmol, 5.0 eq.) was added and stirring was continued for another 4 hours. The solid was collected by filtration, washed with Et2O and dried to yield 3-amino-N,N,5-trimethyl-pyridazine-4-carboxamide (76.5 mg, 70.6%) as a white solid. LC-MS: m/z = 181.0 [M+H]⁺, ESI pos.

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

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

Example 49 3-[[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2-pyridyl]-6- methoxy-benzimidazol-5-yl]amino]-N,N,5,6-tetramethyl-pyridazine-4- carboxamide

Step 1: 3-chlor o-5, 6-dimethyl-pyridazine-4-carboxylic acid

Under argon, 3-chloro-5,6-dimethyl-pyridazine-4-carboxylic acid ethyl ester (300 mg, 1.33 mmol, 1.0 eq.) was dissolved at 23 °C in THF (9 mL). 1 M Li OH aq. sol. (1.99 mL, 1.99 mmol, 1.5 eq.)was added and the dark reaction mixture was stirred at 70 °C over night. The mixture was cooled to 23 °C and treated with HCOOH (244.46 mg, 203.72 pL, 5.31 mmol, 4 eq.) to adjust pH to 3. The mixture was concentrated to dryness. The residue was purified by flash column chromatography using a gradient of (DCM/MeOH/HCOOH 8:2:1) in DCM to yield 3- chloro-5,6-dimethyl-pyridazine-4-carboxylic acid (140.8mg, 55.7%) as a light brown solid. LC- MS: m/z = 187.0 [M+H]⁺, ESI pos.

Step 2: 3-chloro-N,N,5, 6-tetramethyl-pyridazine-4-carboxamide

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

Step 3: 3-(benzhydrylideneamino)-N,N,5, 6-tetramethyl-pyridazine-4-carboxamide

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

Step 4: 3-amino-N,N, 5, 6-tetramethyl-pyridazine-4-carboxamide

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

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

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

Example 50

3-[[l-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-5-(difluoromethyl)-2- pyridyl]-6-methoxy-benzimidazol-5-yl] amino] -N,6-dimethyl-N-(2, 2,2- trifluoroethyl)pyridazine-4-carboxamide Step 1: 2-[ (5-bromo-6-methoxy-benzimidazol-l-yl)methoxy]ethyl-trimethyl-silane

To a mixture of 5-bromo-6-methoxy-lH-benzimidazole (7.0 g, 30.83 mmol, 1.0 eq.) and NaH (3.4 mL, 61.66 mmol, 2.0 eq.) at 0 °C in DMF (70 mL) was added SEM-C1 (7.71 g, 46.24 mmol, 1.5 eq.). The reaction mixture was stirred at 0 °Cwas stirred at 0 °C for 0.5 hour. The mixture was quenched by the addition of sat.aq. NH4CI sol. (200 mL) and extracted with EtOAc (lOOmL x 3). The combined organic layers were dried over ISfeSCU, filtered and concentrated in vacuo. The residue was purified by flash column chromatography using 20% - 50% EtOAc in PE to yield 2-[(5-bromo-6-methoxy-benzimidazol-l-yl)methoxy]ethyl-trimethyl-silane (10.0 g, 90.8%) as a yellow oil (mixture of regioisomers). LC-MS: m/z = 359.0 [M+H]⁺, ESI pos.

Step 2: 3-[[ 6-methoxy-l -(2-trimethylsilylethoxymethyl)benzimidazol-5-yl] amino] -6-methyl- pyridazine-4-carboxylic acid

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

Step 3: 3-[[ 6-methoxy-l -(2-trimethylsilylethoxymethyl)benzimidazol-5-yl] amino] -N, 6-dimethyl- N-(2, 2, 2-trifluoroethyl)pyridazine-4-carboxamide

To a mixture of 3-[[6-methoxy-l-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]amino]-6- methyl-pyridazine-4-carboxylic acid (70.0 mg, 0.160 mmol, 1 eq.), methyl-(2,2,2-trifluoro- ethyl)-amine hydrochloride (48.74 mg, 0.330 mmol, 2 eq.) and DIPEA (0.09 mL, 0.490 mmol, 3 eq.) in DMF (3 mL) was added HATU (115.02 mg, 0.490 mmol, 3 eq.) at 30 °C. The mixture was stirred at 30 °C for 2 hours. The reaction mixture was diluted with H2O (50 mL), and extracted with EtOAc (30 mL x 3). The combined organic extracts were washed with brine (60 mL x 3), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by reversed phase flash chromatography (column: Spherical C18 20-45 pm, 120 g; 30% - 40% CH3CN in H2O (with 0.1% FA) over 25 minutes, flow rate: 50 mL/min to yield 3-[[6-methoxy- l-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]amino]-N,6-dimethyl-N-(2,2,2- trifluoroethyl)pyridazine-4-carboxamide (80.0 mg, 93.5%) as a yellow solid (mixture of regioisomers). LC-MS: m/z = 525.3 [M+H]⁺, ESI pos. Step 4: 3-[(6-methoxy-lH-benzimidazol-5-yl)amino]-N,6-dimethyl-N-(2,2,2- trifluoroethyl)pyridazine-4-carboxamide; 2, 2, 2-trifluoroacetic acid 3-[[6-methoxy- 1 -(2 -trimethyl silyl ethoxym ethyl)benzimidazol-5-yl]amino]-N, 6-dimethyl-N- (2,2,2-trifluoroethyl)pyridazine-4-carboxamide (100.0 mg, 0.19 mmol, 1.0 eq.)was dissolved in TFA (1.0 mL). The resulting yellow solution was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in a mixture of CH3CN (1 mL) and H2O (15 mL) and the solution was lyophilized to yield 3-[(6-methoxy-lH- benzimidazol-5-yl)amino]-N,6-dimethyl-N-(2,2,2-trifluoroethyl)pyridazine-4-carboxamide;

2, 2, 2-trifluoroacetic acid (65.0 mg, 67.1%) as a yellow solid. LC-MS: m/z = 395.1 [M+H]⁺, ESI pos.

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

Prepared according to Example 31, step 5 to yield 3-[[l-[6-[3-(difhioromethoxy)-5-methyl- pyrazol-l-yl]-5-(difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]amino]-N,6- dimethyl-N-(2,2,2-trifluoroethyl)pyridazine-4-carboxamide (6.23 mg, 6.5% as a yellow solid, after purification by preparative TLC using 10% MeOH in DCM. LC-MS: m/z = 668.3 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CD3OD) 8 = 8.88 (br s, 1H), 8.83 (s, 1H), 8.48 (br d, J= 8.3 Hz, 1H), 8.07 (d, J= 8.3 Hz, 1H), 7.88 (s, 1H), 7.45 (br s, 1H), 7.39 (s, 1H), 7.32 (s, 1H), 7.25 (s, 1H), 7.14 (s, 1H), 7.11 (s, 1H), 6.96 (s, 1H), 6.12 (s, 1H), 4.48 - 4.17 (m, 2H), 3.93 (s, 3H), 3.19 (br s, 3H), 2.62 (s, 3H), 2.54 (s, 3H).

Regioisomer 3-[[3-[6-[3-(difluoromethoxy)-5-methyl-pyrazol-l-yl]-5-(difluoromethyl)-2- pyridyl]-6-methoxy-benzimidazol-5-yl]amino]-N,6-dimethyl-N-(2,2,2-trifluoroethyl)pyridazine- 4-carboxamide (19.72 mg, 21.0%) was also isolated as a yellow solid. LC-MS: m/z = 668.3 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CD₃OD) 8 = 9.35 (br s, 1H), 8.79 (s, 1H), 8.53 (br d, J= 8.4 Hz, 1H), 8.04 (br d, J= 8.4 Hz, 1H), 7.46 (br s, 1H), 7.43 (s, 1H), 7.36 (br s, 1H), 7.31 (s, 1H), 7.29 (s, 1H), 7.15 (s, 1H), 7.13 (s, 1H), 6.95 (s, 1H), 6.03 (s, 1H), 4.48 - 4.24 (m, 2H), 4.00 (s, 3H), 3.18 (br s, 3H), 2.63 (s, 3H), 2.51 (br s, 3H).

Example 51

2-[6-[[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2-pyridyl]-6- methoxy-benzimidazol-5-yl]amino]pyridazin-3-yl]-N,N-dimethyl-acetamide

Step 1: diethyl 2-(6-chloropyridazin-3-yl)propanedioate

To a colorless solution of 3,6-dichloropyridazine (2.0 g, 13.42 mmol, 1.0 eq.), diethyl malonate (3.06 mL, 20.14 mmol, 1.5 eq.) in DMSO (20 mL) was added CS2CO3 (8.75 g, 26.85 mmol, 2.0 eq.). The mixture was heated to 110 °C and stirred for 1 hour. The reaction mixture was cooled to 23 °C, diluted with H2O (100 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (40 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash column chromatography using 10% - 30% EtOAc in PE to yield diethyl 2-(6-chloropyridazin-3-yl)propanedioate (3.3 g, 81.1%) as a yellow oil. LC-MS: m/z = 273.0 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 8 = 7.85 (d, = 8.9 Hz, 1H), 7.58 (d, = 9.0 Hz, 1H), 5.28 (s, 1H), 4.33 - 4.24 (m, 4H), 1.31 (t, J= 7.1 Hz, 6H).

Step 2: diethyl 2-[6-(tert-butoxycarbonylamino)pyridazin-3-yl]propanedioate

To a solution of diethyl 2-(6-chloropyridazin-3-yl)propanedioate (2.7 g, 9.9 mmol, 1.0 eq.) and tert-butyl carbamate (1.74 g, 14.85 mmol, 1.5 eq.) in 1,4-dioxane (30 mL) were added CS2CO3 (6.45 g, 19.8 mmol, 2.0 eq.), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (1.15 g, 1.98 mmol, 0.2 eq.) and tris(dibenzylideneacetone)dipalladium(0) (0.91 g, 0.99 mmol, 0.1 eq.). The mixture was degassed by and back-filled with N2 three times, then it was heated to 90 °C and stirred for 12 hours. The resulting brown suspension was cooled to 23 °C and filtered. The filtrate was diluted with H2O (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed by brine (50 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, was purified by flash column chromatography using 20% - 40% EtOAc in PE. The isolqted material was purified by preparative HPLC (ACS-WH-GX-S, 35% - 65% CH3CN in H2O (with NH4CO3) over 10 minutes, flow rate: 60 mL/min) to yield diethyl 2-[6-(tert-butoxycarbonylamino)pyridazin-3-yl]propanedioate (200.0 mg, 5.7%) as a white solid. LC-MS: m/z = 354.0 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 8 = 8.27 (d, J= 9.3 Hz, 1H), 7.79 - 7.73 (m, 2H), 5.17 (s, 1H), 4.30 - 4.20 (m, 4H), 1.55 (s, 9H), 1.28 (t, J= 7.2 Hz, 6H).

Step 3: 2- [6-(tert-butoxycarbonylamino)pyridazin-3-yl] acetic acid To a suspension of diethyl 2-[6-(tert-butoxycarbonylamino)pyridazin-3-yl]propanedioate (160.0 mg, 0.45 mmol, 1.0 eq.) in a mixture of MeOH (2 mL) and H2O (1 mL), was added Li OH monohydrate (38.0 mg, 0.91 mmol, 2.0 eq.). Then the mixture was heated to 30 °C and stirred for 12 hours. The reaction mixture was concentrated to dryness to yield 2-[6-(tert- butoxycarbonylamino)pyridazin-3-yl]acetic acid (110.0 mg, 86.3%) as a white solid. LC-MS: m/z = 254.1 [M+H]⁺, ESI pos.

Step 4: tert-butyl N-[6-[2-(dimethylamino)-2-oxo-ethyl]pyridazin-3-yl] carbamate To a suspension of dimethylamine hydrochloride (77.27 mg, 0.95 mmol, 2.0 eq.) in DMF (2 mL) were added DIPEA (244.98 mg, 1.9 mmol, 4.0 eq.), HATU (222.96 mg, 0.95 mmol, 2.0 eq.), and 2-[6-(tert-butoxycarbonylamino)pyridazin-3-yl]acetic acid (120.0 mg, 0.47 mmol, 1.0 eq.). The mixture was heated to 30 °C and stirred for 12 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC using 10% MeOH in DCM to yiled tertbutyl N-[6-[2-(dimethylamino)-2-oxo-ethyl]pyridazin-3-yl]carbamate (20 mg, 96.4%) as a white solid. LC-MS: m/z = 225.1 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 6 = 8.19 (d, J= 9.3 Hz, 1H), 7.58 (d, J= 9.3 Hz, 2H), 4.03 (s, 2H), 3.14 (s, 3H), 2.97 (s, 3H), 1.54 (s, 9H).

Step 5: 2-(6-aminopyridazin-3-yl)-N,N-dimethyl-acetamide

A solution of tert-butyl N-[6-[2-(dimethylamino)-2-oxo-ethyl]pyridazin-3-yl]carbamate (60.0 mg, 0.21 mmol, 1.0 eq.) in HC1 4M sol. in dioxane (1.0 mL was stirred at 40 °C for 13 hours. The resulting white suspension was concentrated to dryness and the residue was lyophilized to yield 2-(6-aminopyridazin-3-yl)-N,N-dimethyl -acetamide (40.0 mg, 93.3%) as a white solid. LC-MS: m/z = 225.1 [M+H]⁺, ESI pos.

Step 6: 2-[ 6-[[ l-[ 6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy- benzimidazol-5-yl] amino]pyridazin-3-yl] -N,N-dimethyl-acetamide

Prepared according to Example 4, step 4 to yield 2-[6-[[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5- (difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]amino]pyridazin-3-yl]-N,N-dimethyl- acetamide (5.5 mg, 21.5%) as a white solid after purificatio by preparative HPLC (ACS-WH- GX-F, 17% - 47% CH3CN in H2O (with FA) over 10 minutes, flow rate: 25 mL/min). LC-MS: m/z = 560.3 [M+H]⁺, ESI pos. 'H NMR (400 MHz, DMSO-d₆) 8 = 9.00 (s, 1H), 8.80 (s, 1H), 8.60 (d, J= 8.7 Hz, 1H), 8.47 (s, 1H), 8.37 (d, J= 8.6 Hz, 1H), 7.83 (s, 1H), 7.37 - 7.29 (m, 2H), 7.26 - 6.97 (m, 2H), 3.90 (s, 2H), 3.87 (s, 3H), 3.09 (s, 3H), 2.85 (s, 3H), 2.53 (br s, 3H).

Example 52 l-[3-(difluoromethyl)-6-[6-methoxy-5-(3-methyl-5-methylol-5,6- dihydropyrrolo[2,3-c]pyridazin-7-yl)benzimidazol-l-yl]-2-pyridyl]-5-methyl- pyrazole-3-carbonitrile

Step 1: 3,6-dichloro-4-(oxetan-3-yl)pyridazine

In a sealed tube, a mixture of 3,6-dichloro-l,2,4,5-tetrazine (919.31 mg, 6.09 mmol, 1.0 eq.) and 3-ethynyloxetane (710 mg, 8.65 mmol, 1 eq.) in toluene (7.04 mL) was heated to 140 °C and stirring was continued for 2 hours. The reaction mixture was cooled to 23 °C and concentrated. The residue was purified by flash column chromatography using 0% - 30% EtOAc in cyclohexane to yield 3,6-dichloro-4-(oxetan-3-yl)pyridazine (897 mg, 71.8%) as a pink solid.

LC-MS: m/z = 205.0 [M+H]⁺, ESI pos.

Step 2: 3-chloro-6-methyl-4-(oxetan-3-yl)pyridazine

To a solution of 3, 6-di chi oro-4-(ox etan-3 -yl)pyridazine (342 mg, 1.67 mmol, 1.0 eq.) in a mixture of dry 1,4-dioxane (2.78 mL), H2O (2.78 mL) and 2 M ISfeCCh aq. sol. (150. pL, 0.30 mmol, 0.180 eq.), was added 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (209.38 mg, 233.16 pL, 1.67 mmol, 1.0 eq.). Argon was bubbled through the solution for 5 minutes. Then, 1,1'- bis(diphenylphosphino)ferrocene-palladium(ii)dichloride dichloromethane complex (137.89 mg, 0.167 mmol, 0.1 eq.) was added and the mixture was heated to 90 °C. Stirring was continued for 4.5 hours. The mixture was cooled to 23 °C and concentrated. The residue was purified by flash column chromatography using 0% - 3.5% MeOH in DCM to yield a mixture of regioisomers which was further purified by revers-phase preparative HPLC to yield 3-chloro-6-methyl-4- (ox etan-3 -yl)pyridazine (61 mg, 19.2%) as a light red solid. LC-MS: m/z = 185.0 [M+H]⁺, ESI pos.

Step 3: benzhydrylidene- [ 6-methyl-4-(oxetan-3-yl)pyridazin-3-yl] amine

In a glass tube, 3 -chi oro-6-methyl-4-(ox etan-3 -yl)pyridazine (61 mg, 0.321 mmol, 1.0 eq.), benzophenone imine (87.13 mg, 80.67 pL, 0.481 mmol, 1.5 eq.) and CS2CO3 (208.85 mg, 0.641 mmol, 2.0 eq.) were combined with dry 1,4-dioxane (1.6 mL) and Argon was bubbled through the mixture for 5 minutes. Then BINAP (19.96 mg, 0.032 mmol, 0.10 eq.) and tris (dibenzylideneacetone)dipalladium (0) chlorofom adduct (16.59 mg, 0.016 mmol, 0.050 eq.) were added, the vial was sealed and the mixture was heated to 100 °C. Stirring was continued for 16 hours. The mixture was cooled to 23 °C and concentrated. The residue was purified by flash column chromatography using 0% - 35% EtOAc in heptane then using 0% - 7.5% MeOH in DCM to yield benzhydrylidene-[6-methyl-4-(oxetan-3-yl)pyridazin-3-yl]amine (93 mg, 86.3%) as light a yellow oil. LC-MS: m/z = 330.2 [M+H]⁺, ESI pos.

Step 4: (3-methyl-6, 7-dihydro-5H-pyrrolo[2,3-c]pyridazin-7-ium-5-yl)methanol; 2,2,2- trijluoroacetate

TFA (630.95 mg, 426.32 pL, 5.53 mmol, 20.0 eq.) was added dropwise to a solution of benzhydrylidene-[6-methyl-4-(oxetan-3-yl)pyridazin-3-yl]amine (93 mg, 0.277 mmol, 1.0 eq.) in DCM (1.84 mL) H2O (14.96 mg, 14.96 pL, 0.830 mmol, 3.0 eq.) was added and the mixture was stirred at 23 °C for 1 hour. The mixture was diluted with H2O and washed 3 times with DCM. The aqueous layer was evaporated to dryness to yield (3-methyl-6,7-dihydro-5H- pyrrolo[2,3-c]pyridazin-7-ium-5-yl)methanol; 2,2,2-trifluoroacetate (65 mg, 75.7%) as dark green crystals. LC-MS: m/z = 166.0 [M+H]⁺, ESI pos.

Step 5: l-[3-(difluoromethyl)-6-[6-methoxy-5-(3-methyl-5-methylol-5,6-dihydropyrrolo[2,3- c pyridazin- 7-yl) benzimidazol-l-yl / -2 -pyridyl ]-5-methyl-pyrazole-3-carbonitrile

Prepared according to Example 4, step 4 to yield the title compound as a white lyophilized solid (14.8 mg, 16.4%. LC-MS: m/z = 544.2 [M+H]⁺, ESI pos.

Example 53 l-[5-(difluoromethyl)-6-[2-methyl-5-(2,2,2-trifluoroethyl)-l,2,4-triazol-3-yl]-2- pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine

Step 1: N-amino-3-(difluoromethyl)pyridine-2-carboxamidine

A mixture of 3-(difluoromethyl)pyridine-2-carbonitrile (5.0 g, 32.44 mmol, 1.0 eq.) and hydrazine hydrate (31.47 mL, 648.85 mmol, 20.0 eq.) was stirred at 20 °C for 2 hours. The reaction mixture was poured into H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash column chromatography using 0% - 50% EtOAc in PE to yield N-amino-3-(difluoromethyl)pyridine-2- carboxamidine (5.3 g, 87.8%) as a yellow solid. LC-MS: m/z = 187.0 [M+H]⁺, ESI pos.

NMR (400 MHz, CDCI3) 5 = 8.67 - 8.62 (m, 1H), 8.16 - 8.11 (m, 1H), 8.00 - 7.71 (m, 1H), 7.43 - 7.38 (m, 1H). Step 2: N-[ (Z)-[amino-[ 3 -(difluoromethyl) -2 -pyridyl] methylene] amino] -3, 3, 3-trifluoro- propanamide

To a solution of 3,3,3-trifluoropropionic acid (4.37 g, 34.16 mmol, 1.2 eq.) in DMF (50 mL) were added N'-amino-3-(difluoromethyl)pyridine-2-carboxamidine (5.3 g, 28.47 mmol, 1.0 eq.), HATU (10.05 g, 42.71 mmol, 1.5 eq.) and DIPEA (9.92 mL, 56.94 mmol, 2.0 eq.) and the reaction mixture was stirred at 30 °C for 1 hour. The reaction mixture was poured into H2O (200 mL) and extracted with EtOAc (200 mL x 3). , the organic phase was washed with sat. brine (200 mL x 3), and the combined organic phases were dried over anhydrous ISfeSCU, then concentrated under vacuum. The residue was purified by flash column chromatography using 100% EtOAc to yield N-[(Z)-[amino-[3-(difluoromethyl)-2-pyridyl]methylene]amino]-3,3,3- trifluoro-propanamide (6.0 g, 71.1%) as a white solid. LC-MS: m/z = 297.0 [M+H]⁺, ESI pos. NMR (400 MHz, CDCh) 8 = 8.64 - 8.60 (m, 1H), 8.66 - 8.59 (m, 1H), 7.63 - 7.33 (m, 2H), 3.63 - 3.54 (m, 2H).

Step 3: 3-(difluoromethyl)-2-[3-(2,2,2-trifluoroethyl)-lH-l,2,4-triazol-5-yl]pyridine

A solution of N-[(Z)-[amino-[3-(difluoromethyl)-2-pyridyl]methylene]amino]-3,3,3-trifluoro- propanamide (5.0 g, 16.88 mmol, 1.0 eq.) in ethylene glycol (10.48 g, 168.8 mmol, 10.0 eq.) was stirred at 180 °C for 1 hour. The reaction mixture was cooled to 23 °C, poured into H2O (300 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (300 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash column chromatography using 33% EtOAc in PE to yield 3- (difluoromethyl)-2-[3-(2,2,2-trifluoroethyl)-lH-l,2,4-triazol-5-yl]pyridine (3.0 g, 63.9%) as a white solid. LC-MS: m/z = 279.1 [M+H]⁺, ESI pos.

Step 4: 3-(difluoromethyl)-2-[2-methyl-5-(2, 2, 2-trifluoroethyl)-l, 2, 4-triazol-3-yl] pyridine To a solution of 3-(difluoromethyl)-2-[3-(2,2,2-trifluoroethyl)-lH-l,2,4-triazol-5-yl]pyridine (3.0 g, 10.78 mmol, 1.0 eq.) in DMF (20 mL) were added K2CO3 (2.25 g, 16.18 mmol, 1.5 eq.) and iodomethane (2.3 g, 16.18 mmol, 1.5 eq.). The resulting clear solution was stirred at 30 °C for 2 hours. The reaction mixture was cooled to 23 °C, poured into H2O (200 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (200 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash column chromatography using EtOAc to yield 3-(difluoromethyl)-2-[2-methyl-5-(2,2,2- trifluoroethyl)-l,2,4-triazol-3-yl]pyridine (1.5 g, 47.6%) as a yellow solid. LC-MS: m/z = 293.0 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 6 = 8.86 - 8.78 (m, 1H), 8.27 - 8.17 (m, 1H), 7.85 - 7.57 (m, 1H), 7.57 - 7.48 (m, 1H), 4.21 - 4.18 (m, 3H), 4.16 - 4.10 (m, 2H).

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

Step 5: 3-(difluoromethyl)-2-[2-methyl-5-(2,2,2-trifluoroethyl)-l,2,4-triazol-3-yl]-l-oxido- pyridin-l-ium

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

Step 6: l-[5-(difluoromethyl)-6-[2-methyl-5-(2,2,2-trifluoroethyl)-l ,2,4-triazol-3-yl] -2-pyridyl] - 6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine

Prepared according to Example 31, step 5 to first yield a mixture of regioisomers (100.0 mg„ 29.94%) as a yellow solid. LC-MS: m/z = 546.0 [M+H]⁺, ESI pos after purification by reverse phase preparative HPLC. This mixture was further purified by chiral SFC to yield l-[5- (difluoromethyl)-6-[2-methyl-5-(2,2,2-trifluoroethyl)-l,2,4-triazol-3-yl]-2-pyridyl]-6-methoxy- N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (40.0 mg, 25.9%) as a white solid. LC-MS: m/z = 546.2 [M+H]⁺, ESI pos. 'H NMR (400 MHz, DMSO-d₆) 8 = 9.27 (s, 1H), 8.99 - 8.92 (m, 1H), 8.58 - 8.51 (m, 1H), 8.49 - 8.40 (m, 1H), 8.25 - 8.20 (m, 1H), 7.71 - 7.67 (m, 1H), 7.58 - 7.53 (m, 1H), 7.33 - 7.26 (m, 2H), 4.14 - 4.08 (m, 3H), 4.00 - 3.95 (m, 3H), 3.94 - 3.85 (m, 2H), 2.47 - 2.41 (m, 3H).

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

Example 54 l-[3-(difluoromethyl)-6-(6-methoxybenzimidazol-l-yl)-2-pyridyl]-5-methyl- pyrazole-3-carbonitrile

Step 1 : l-[ 3-(difluoromethyl)-6-( 6-methoxybenzimidazol-l-yl)-2-pyridyl ]-5-methyl-pyrazole-3- carbonitrile

In a glass tube, l-[6-(5-bromo-6-methoxy-benzimidazol-l-yl)-3-(difluoromethyl)-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile (50 mg, 0.109 mmol, 1.0 eq.) (obtained in Example 15, step 3) was dissolved in 1,4-dioxane (1 m ) under Argon. 2-(oxetan-3-yl)-2,6-diazaspiro[3.3]heptane; tosylic acid (81.43 mg, 0.163 mmol, 1.5 eq.), CS2CO3 (177.37 mg, 0.544 mmol, 5.0 eq.) and H2O (30.47 mg, 30.47 pL, 1.69 mmol, 15.53 eq.) were added. The reaction mixture was purged with Argon, QphosPd(crotyl)Cl (7.91 mg, 0.009 mmol, 0.08 eq.) was added, the vial was sealed and the reaction mixture was stirred at 80 °C for 18 hours. The reaction mixture was cooled to 23 °C and concentrated. The residue was purified by flash column chromatography using 0% - 50% (DCM / MeOH 9: 1) in DCM to yield l-[3-(difluoromethyl)-6-(6-methoxybenzimidazol-l-yl)-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile (5 mg, 12.1%) as a white powder (side product from the reaction). LC-MS: m/z = 381.1 [M+H]⁺, ESI pos. Example 55 l-[5-(difluoromethyl)-6-[l-methyl-5-(2,2,2-trifluoroethyl)-l,2,4-triazol-3-yl]-2- pyridyl] -6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine

Step 1: l-[5-(difluoromethyl)-6-[l-methyl-5-(2,2,2-trifluoroethyl)-l,2,4-triazol-3-yl]-2-pyridyl]- 6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine

Prepared according to Example 53, step 6 to yield l-[5-(difluoromethyl)-6-[l-methyl-5-(2,2,2- trifluoroethyl)-l,2,4-triazol-3-yl]-2-pyridyl]-6-methoxy-N-(6-methylpyridazin-3- yl)benzimidazol-5-amine (20.0 mg, 5.7%) as a yellow solid after purification by preparative HPLC (Phenomenex Luna C18 (150 mm x 40 mm, 15 pm), 2 - 22% CH3CN in H2O (with 0.225% FA) over 10 minutes, flow rate: 25 mL/min). LC-MS: m/z = 546.3 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CD₃OD) 8 = 8.69 - 8.62 (m, 1H), 8.52 - 8.41 (m, 2H), 8.17 - 8.09 (m, 1H), 8.05 - 7.72 (m, 2H), 7.42 - 7.35 (m, 1H), 7.29 - 7.21 (m, 1H), 4.05 - 3.99 (m, 2H), 3.98 - 3.96 (m, 3H), 3.96 - 3.92 (m, 3H), 2.59 - 2.53 (m, 3H).

Regioisomer 3-[5-(difluoromethyl)-6-[l-methyl-5-(2,2,2-trifluoroethyl)-l,2,4-triazol-3-yl]-2- pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (43.0 mg, 11.6%) was also isolated as a yellow solid. LC-MS: m/z = 546.3 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CD3OD) 8 = 9.27 - 9.22 (m, 1H), 9.01 - 8.95 (m, 1H), 8.47 - 8.39 (m, 1H), 8.05 - 7.73 (m, 2H), 7.37 - 7.21 (m, 3H), 4.09 - 4.02 (m, 2H), 4.01 - 3.99 (m, 3H), 3.98 - 3.95 (m, 3H), 2.57 - 2.48 (m, 3H). Example 56 l-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-[( 1?)-l-methyl-2-oxo-pyrrolidin-3- yl]pyridazin-3-yl] amino] benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile

Step 1: benzyl l-methyl-2-oxo-pyrrolidine-3-carboxylate

A solution of NMP (4.86 mL, 50.44 mmol, 1 eq) (extra dry) in THF (75 mL) was cooled to - 78 °C under N2. LDA (53.0 mL, 106 mmol, 2.1 eq) was added slowly at -78 °C. When the addition was complete, stirring at - 78 °C was continued for 30 minutes. Benzyl chloroformate (8.6 g, 50.44 mmol, 1 eq)was then added dropwise over 15 min under a N2 atmosphere to give a green suspension. The reaction mixture was stirred at -75°C for another 1 hour. The reaction mixture was poured into sat. aq. NH4CI sol. (300 mL) and extracted with EtOAc (100 mL x 3). Tthe combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 0% - 35% EtOAc in PE to yield benzyl l-methyl-2-oxo-pyrrolidine-3 -carboxylate (8 g, mmol, 68%) as a dark brown oil. LC-MS: m/z = 234.1 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 8 = 7.47 - 7.27 (m, 5H), 5.20 (s, 2H), 3.53 - 3.44 (m, 2H), 3.34 (dt, J = 5.8, 8.9 Hz, 1H), 2.87 (s, 3H), 2.45 - 2.35 (m, 1H), 2.32 - 2.20 (m, 1H).

Step 2: benzyl 3-(6-chloropyridazin-3-yl)-l-methyl-2-oxo-pyrrolidine-3-carboxylate

To a solution of 3,6-dichloropyridazine (7.68 g, 51.55 mmol, 1.5 eq) in DMSO (100 mL) were added CS2CO3 (22.4 g, 68.75 mmol, 2.0 eq) and benzyl 1 -methyl -2-oxo-pyrrolidine-3- carboxylate (8.0 g, 34.3 mmol, 1.0 eq) at 23 °C. The reaction mixture was stirred at 110 °C for 2 hours under N2. The reaction mixture was cooled to 23 °C, filtered and the filter cake was washed with DMSO (10 mL x 3). The filtrate was poured into sat. aqueous NH4CI sol. (1 L) and this was extracted with EtOAc (500mL x 3). The combined organic layers were washed with brine (500 mL x 3), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography using 0% - 50% EtOAc in PE to yield benzyl 3-(6- chloropyridazin-3-yl)-l -methyl -2-oxo-pyrrolidine-3 -carboxylate (3.0 g, 23.0%) as a colorles oil.

LC-MS: m/z = 346.0 [M+H]⁺, ESI pos.

Step 3: 3-(6-chloropyridazin-3-yl)-l-methyl-pyrrolidin-2-one

To a solution of benzyl 3-(6-chloropyridazin-3-yl)-l-methyl-2-oxo-pyrrolidine-3-carboxylate (3.0 g, 8.68 mmol, 1 eq) in EtOH (180 mL) was added IN NaOH (60.0 mL, 60 mmol, 6.92 eq) at 20 °C. The reaction mixture was stirred at 20 °C for 2 hours. The mixture was diluted with H2O (200 mL) and extracted with DCM (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 0% - 100% EtOAc in PE, then 15% MeOH in EtOAc to yield 3-(6-chloropyridazin-3-yl)-l-methyl-pyrrolidin-2-one (1.8 g, 98.0%) as a purple solid. LC- MS: m/z = 212.0 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 8 = 7.72 (d, J = 8.9 Hz, 1H), 7.48 (d, J = 8.9 Hz, 1H), 3.95 (t, J = 8.5 Hz, 1H), 3.61 (dt, J = 4.3, 9.2 Hz, 1H), 3.55 - 3.46 (m, 1H), 2.91 (s, 3H), 2.88 - 2.80 (m, 1H), 2.55 (dtd, J = 4.3, 8.7, 13.0 Hz, 1H).

Step 4: tert-butyl N-[6-(l-methyl-2-oxo-pyrrolidin-3-yl)pyridazin-3-yl] carbamate

To a solution of 3-(6-chloropyridazin-3-yl)-l-methyl-pyrrolidin-2-one (400.0 mg, 1.88 mmol, 1 eq) in 1,4-dioxane (40 mL) were added tert-butyl carbamate (661.31 mg, 5.64 mmol, 3 eq), CS2CO3 (1.84 g, 5.64 mmol, 3 eq), Pd2(dba)3 (344.72 mg, 0.380 mmol, 0.200 eq) and XantPhos (435.79 mg, 0.750 mmol, 0.4 eq). The reaction mixture was purged with N2, before it was heated to 100 °C. Stirring was then continued for 2 hours. The mixture was cooled to 23 °C, poured into sat. aq. NH4CI sol. (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 0% - 100% EtOAc in PE, then 10% MeOH in EtOAc to yield tert-butyl N-[6-(l-methyl-2-oxo-pyrrolidin-3-yl)pyridazin-3-yl]carbamate (250 mg, 45.5%) as a brown gum. LC-MS: m/z = 293.1 [M+H]⁺, ESI pos.

Step 5: 3-(6-aminopyridazin-3-yl)-l-methyl-pyrrolidin-2-one; hydrochloride

A solition of tert-butyl N-[6-(l-methyl-2-oxo-pyrrolidin-3-yl)pyridazin-3-yl]carbamate (240.0 mg, 0.820 mmol, 1 eq.) in HC1 4M sol. in dioxane (10.0 mL, 40 mmol, 48.72 eq.) was stirred at 30 °C for 16 hours. The reaction mixture was diluted with H2O and extracted with EtOAc (10 mL x 3). The combined organic layers were concentrated under reduced pressure to yield 3-(6- aminopyridazin-3-yl)-l-methyl-pyrrolidin-2-one;hydrochloride (158.0 mg, 84.2%) as a brown gum. LC-MS: m/z = 193.0 [M+H]⁺, ESI pos. Step 6: l-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-[rac-(3R)-l-methyl-2-oxo-pyrrolidin-3- yl ]pyridazin-3-yl amino] benzimidazol-l-yl ]-2-pyridyl ]-5-methyl-pyrazole-3-carbonitrile

Prepared according to Example 4, step 4 to yield a racemic mixture of l-[3-(difluoromethyl)-6- [6-methoxy-5-[[6-[rac-l -methyl -2-oxo-pyrrolidin-3-yl]pyridazin-3-yl]amino]benzimidazol- 1- yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (60 mg in total) after trituration in DMSO (2 mL) followed by purification by preparative HPLC (Phenomenex Luna C18 (150 mm x 25 mm, 10 pm), 22 - 52% CH3CN in H2O (with 0.225% FA) over 10 minutes, flow rate: 25 mL/min). This racemic mixture was then purified by chiral SFC (REGIS(S,S)WHELK-O1 (250 mm x 25 mm, 10 pm), 70% CO2 in MeOH (with 0.1% NH4OH) over 4.5 minutes, flow rate: 80 mL/min) to yield l-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-[(3R)-l-methyl-2-oxo-pyrrolidin-3- yl]pyridazin-3-yl]amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (or enantiomer) (11.7 mg, 3.6% yield, 87% ee) as a yellow solid as the first eluting enantiomer (absolute stereochemistry was not determined). LC-MS: m/z = 571.1 [M+H]⁺, ESI pos. ^TH NMR (400 MHz, DMSO-de) 8 = 9.00 (s, 1H), 8.79 (s, 1H), 8.60 (d, J= 8.7 Hz, 1H), 8.52 (s, 1H), 8.37 (d, J= 8.6 Hz, 1H), 7.83 (s, 1H), 7.43 - 7.33 (m, 2H), 7.27 - 6.95 (m, 2H), 3.87 (s, 3H), 3.84 (s, 1H), 3.54 - 3.42 (m, 2H), 2.79 (s, 3H), 2.53 (s, 3H), 2.45 - 2.37 (m, 2H).

Example 57 l-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-[(3S)-l-methyl-2-oxo-pyrrolidin-3- yl]pyridazin-3-yl] amino] benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile

Step 1: l-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-[(3S)-l-methyl-2-oxo-pyrrolidin-3- yl ]pyridazin-3-yl amino] benzimidazol-l-yl ]-2-pyridyl ]-5-methyl-pyrazole-3-carbonitrile The title compound was obtained from the racemic mixture described in Example 56 after separation of the enantiomers by chiral SFC (REGIS(S,S)WHELK-O1 (250 mm x 25 mm, 10 pm), 70% CO2 in MeOH (with 0.1% NH4OH) over 4.5 minutes, flow rate: 80 mL/min) followed by a second chiral purification using the same conditions yielding l-[3-(difluoromethyl)-6-[6- methoxy-5-[[6-[(3 S)-l-methyl-2-oxo-pyrrolidin-3-yl]pyridazin-3-yl]amino]benzimidazol-l-yl]- 2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (or enantiomer, absolute stereochemistry was not determined; 11.6 mg, 3.6% yield, 89% ee) as a yellow solid as the second eluting enantiomer. LC-MS: m/z = 571.1 [M+H]⁺, ESI pos. 'H NMR (400 MHz, DMSO-d₆) 8 = 9.00 (s, 1H), 8.79 (s, 1H), 8.60 (d, J= 8.7 Hz, 1H), 8.52 (s, 1H), 8.37 (d, J= 8.6 Hz, 1H), 7.83 (s, 1H), 7.43 - 7.33 (m, 2H), 7.27 - 6.95 (m, 2H), 3.87 (s, 3H), 3.84 (s, 1H), 3.54 - 3.42 (m, 2H), 2.79 (s, 3H), 2.53 (s, 3H), 2.45 - 2.37 (m, 2H).

Example 58 benzyl N-[2-[6-[[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2- pyridyl]benzimidazol-5-yl] amino] pyridazin-3-yl]-l,3-dioxan-5-yl] carbamate

Step 1: benzyl N-[2-(6-chloropyridazin-3-yl)-l ,3-dioxan-5-yl] carbamate

To a solution of 6-chloropyridazine-3-carbaldehyde (1.0 g, 7.02 mmol, 1.0 eq.) intoluene (30 mL), were added benzyl N-[2-hydroxy-l-(hydroxymethyl)ethyl]carbamate (3.16 g, 14.03 mmol, 2.0 eq.) and TosOH (175.61 mg, 0.7 mmol, 0.1 eq.). The reaction was heated to 130 °C and stirred for 16 hours using a Dean Stark trap. The reaction mixture was cooled to 23 °C, poured into sat. aq.NaHCCh sol. (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash column chromatography using 0% - 80% EtOAc in PE to yield benzyl N-[2-(6-chloropyridazin-3-yl)-l,3-dioxan-5- yl]carbamate (460.0 mg, 18.7%) as a brown solid. LC-MS: m/z = 350.0 [M+H]⁺, ESI pos. ^TH NMR (400 MHz, CD₃OD) 8 = 7.81 (br s, 1H), 7.64 - 7.57 (m, 1H), 7.36 (br s, 2H), 7.27 - 7.18 (m, 2H), 6.88 (br d, J= 5.4 Hz, 1H), 6.23 (br s, 1H), 5.17 - 5.08 (m, 2H), 4.30 (br d, J= 5.3 Hz, 2H), 4.25 - 4.19 (m, 1H), 3.79 (br d, J= 9.6 Hz, 2H).

Step 2: l-[ 6-(5-aminobenzimidazol-l-yl)-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile

To a solution of l-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (300.0 mg, 1.12 mmol, 1.0 eq) in DMSO (100 mL) were added 5 -aminobenzimidazole (148.69 mg, 1.12 mmol, 1.0 eq) and K2CO3 (462.98 mg, 3.35 mmol, 3.0 eq). The reaction mixture was heated to 80 °C and stirred for 5 hours. The mixture was cooled to 23 °C, diluted with H2O (100 mL) and xtracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC using 10% MeOH in EtOAc to yield l-[6-(5- aminobenzimidazol-l-yl)-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (200.0 mg, 49.0%) as a yellow solid. LC-MS: m/z = 365.9 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CD₃OD) 8 = 8.99 - 8.85 (m, 1H), 8.62 - 8.50 (m, 1H), 8.27 - 8.13 (m, 1H), 8.05 - 7.94 (m, 1H), 7.27 - 6.97 (m, 2H), 6.90 (br d, J = 10.8 Hz, 2H), 2.60 - 2.54 (m, 3H).

Step 3: benzyl N-[2-[6-[[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2- pyridyl]benzimidazol-5-yl amino ]pyridazin-3-yl -l, 3-dioxan-5-yl carbamate

To a solution of l-[6-(5-aminobenzimidazol-l-yl)-3-(difluoromethyl)-2-pyridyl]-5-methyl- pyrazole-3 -carbonitrile (30.0 mg, 0.08 mmol, 1.0 eq.) in 2-methyl-2 -butanol (2.0 mL, 0.08 mmol, 1.0 eq.), were added benzyl N-[2-(6-chloropyridazin-3-yl)-l,3-dioxan-5-yl]carbamate (43.08 mg, 0.12 mmol, 1.5 eq.), CS2CO3 (80.26 mg, 0.25 mmol, 3.0 eq.) and RuPhos Pd G4 (3.49 mg, 0.0 mmol, 0.05 eq.). The reaction was heated to 100 °C and stirred for 3 hours under N2 atmosphere. The reaction mixture was cooled to 23 °C, poured into H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous ISfeSCU, filtered and concentrated under vacuum. The residue was purified by preparative HPLC (Phenomenex Luna C18 (150 mm x 40 mm, 15 pm), 5 - 12% CH3CN in H2O (with 0.225% FA) over 10 minutes, flow rate: 25 mL/min) to yield benzyl N-[2- [6-[[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2-pyridyl]benzimidazol-5- yl]amino]pyridazin-3-yl]-l,3-dioxan-5-yl]carbamate (10.0 mg, 16.7% yield) as a yellow solid. LC-MS: m/z = 679.2 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CD3OD) 8 = 9.02 - 8.93 (m, 1H), 8.61 - 8.49 (m, 1H), 8.33 - 8.24 (m, 1H), 8.23 - 8.12 (m, 2H), 7.81 - 7.70 (m, 1H), 7.66 - 7.58 (m, 1H), 7.44 - 7.29 (m, 5H), 7.24 - 7.06 (m, 2H), 6.95 - 6.87 (m, 1H), 5.82 - 5.69 (m, 1H), 5.19 - 5.13 (m, 2H), 4.32 - 4.23 (m, 2H), 3.69 - 3.61 (m, 1H), 2.50 (br s, 3H).

Example 59 l-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-4,6-dihydrofuro[3,4-c]pyrazole-3- carbonitrile

Step 1: 4,6-dihydro-lH-furo[3,4-c]pyrazole-3-carboxamide

To a stirred solution of 4,6-dihydro-lH-furo[3,4-c]pyrazole-3-carboxylic acid (500 mg, 3.24 mmol, 1.0 eq.) at 20 °C in DMF (16.22 mL) under an argon atmosphere was added CDI (683.87 mg, 4.22 mmol, 1.3 eq.). After stirring for 3 hours, ammonium hydroxide (2.27 g, 2.53 mL, 64.88 mmol, 20.0 eq.) was added and stirring was continued over the weekend. The mixture was diluted with H2O and washed with EtOAc. The aqueous layer was concentrated to dryness to yield 4,6-dihydro-lH-furo[3,4-c]pyrazole-3-carboxamide (700 mg, 42.3%) as a brown semisolid. LC-MS: m/z = 152.0 [M-H]', ESI neg. The product was used in the bext step without further purification.

Step 2: 4,6-dihydro-lH-furo[3,4-c]pyrazole-3-carbonitrile

To stirred mixture of 4,6-dihydro-lH-furo[3,4-c]pyrazole-3-carboxamide (700 mg, 4.57 mmol, 1.0 eq.) and EtsN (1.39 g, 1.91 mL, 13.71 mmol, 3.0 eq.) at 20 °C in DCM (22.85 mL) under an argon atmosphere was added carefully TFAA (2.88 g, 1.94 mL, 13.71 mmol, 3.0 eq.) The mixture immediately turned to a clear, light yellow solution, with white fumes above it. Stirring at 20 °C was then continued for 18 hours. The reaction mixture was diluted with DCM and washed with aq. sat. NaHCCL sol. and then with brine. The aqueous phase was again extracted with DCM after pH adjustement to acidic. The organic layers were combined, dried, filtered and concentrated under reduced pressure to yield 4,6-dihydro-lH-furo[3,4-c]pyrazole-3-carbonitrile (550 mg, 72.1%) as a brown liquid. LC-MS: m/z = 136.0 [M+H]⁺, ESI pos. The product was used in the bext step without further purification. Step 3: l-[6-chloro-3-(difluoromethyl)-2-pyridyl]-4,6-dihydrofuro[3,4-c]pyrazole-3-carbonitrile Under argon,4,6-dihydro-lH-furo[3,4-c]pyrazole-3-carbonitrile (198.48 mg, 1.32 mmol, 1.2 eq.), 6-chl oro-3 -(difluoromethyl)-2 -fluoro-pyridine (200 mg, 1.1 mmol, 1.0 eq.)and CS2CO3 (1.08 g, 3.31 mmol, 3.0 eq.) were mixed in DMF (5 mL). The reaction mixture was stirred at 20 °C overnight. After extraction work up using DCM and H2O, the residue was purified by flash column chromatography using 20% - 80% (EtOAcZEtOH 3 : 1) in heptane to yield l-[6-chloro-3- (difluoromethyl)-2-pyridyl]-4,6-dihydrofuro[3,4-c]pyrazole-3-carbonitrile (50 mg, 13.2%) as light yellow powder. LC-MS: m/z = 295.0 [M-H]', ESI neg.

Step 4: l-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl / -2 -pyridyl -4, 6-dihydrofuro[ 3, 4-c ]pyrazole-3-carbonitrile

Prepared according to Example 31, step 5 to yield l-[3-(difluoromethyl)-6-[6-methoxy-5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-4,6-dihydrofuro[3,4-c]pyrazole-3- carbonitrile (9 mg, 27.4%) as an amorphous freeze-dried solid after purification by preparative HPLC. LC-MS: m/z = 516.2 [M+H]⁺, ESI pos.

Regioisomer l-[3-(difluoromethyl)-6-[6-methoxy-6-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-4,6-dihydrofuro[3,4-c]pyrazole-3-carbonitrile (14 mg, 43.1%) was also obtained as as an amorphous freeze-dried solid. LC-MS: m/z = 516.2 [M+H]⁺, ESI pos.

Example 60 l-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-2-pyridyl]-

6-methoxy-N-[6-methyl-5-(l-methylazetidin-3-yl)pyridazin-3-yl]benzimidazol- 5-amine Step 1: tert-butyl 3-(3,6-dichloropyridazin-4-yl)azetidine-l-carboxylate

To a solution of 3,6-dichloro-l,2,4,5-tetrazine (1.5 g, 9.9 mmol, 1.0 eq) in toluene (20 mL) was added tert-butyl 3 -ethynylazetidine-1 -carboxylate (1.8 g, 9.9 mmol, 1.0 eq). Then the mixture was degassed and back-filled with N2 three times before it was heated to 140 °C and stirred for 3 hours. The reaction mixture was coole to 23 °C, diluted with H2O (40 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 20% - 50% EtOAc in PE to yield tert-butyl 3-(3,6-dichloropyridazin-4- yl)azetidine-l -carboxylate (2.4 g g, 78.6%) as a red oil. LC-MS: m/z = 304.2 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 8 = 7.54 (s, 1H), 4.45 - 4.37 (m, 2H), 4.03 - 3.95 (m, 3H), 1.47 (s, 9H).

Step 2: tert-butyl 3-(6-chloro-3-methyl-pyridazin-4-yl)azetidine-l-carboxylate To a solution of tert-butyl 3 -(3, 6-di chi oropyridazin-4-yl)azeti dine- 1 -carboxylate (2.4 g, 7.89 mmol, 1.0 eq) in a mixture of 1,4-dioxane (20 mL) and H2O (20 mL) were added NazCCh (2.51 g, 23.67 mmol, 3.0 eq), trimethylboroxine (1.98 g, 7.89 mmol, 1.0 eq) and 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (643.85 mg, 0.79 mmol, 0.1 eq). The mixture was degassed and back-filled with N2 three times before it was heatead to 90 °C and then stirred for 2 hours. The reaction mixture was cooled to 23 °C, diluted with H2O (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 50% - 70% EtOAc in PE to yield a mixture of tert-butyl 3 -(6-chl oro-3 -m ethyl-pyridazin-4-yl)azeti dine- 1 -carboxylate and tert-butyl 3-(3-chloro-6- methyl-pyridazin-4-yl)azetidine-l -carboxylate (700.0 mg). Further purification by chiral SFC (Daicel Chiralpak IC (250 mm x 30 mm, 10 pm) with EtOH (0.1% NH4OH) in CO2 over 3.5 min, flow rate 65 mL / min) to yield tert-butyl 3 -(6-chl oro-3 -m ethyl-pyridazin-4-yl)azeti dine- 1- carboxylate (240 mg, 10.6%) as a light yellow oil. LC-MS: m/z = 284.0 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 6 = 7.44 (s, 1H), 4.37 (t, J = 8.6 Hz, 2H), 3.98 (dd, J = 6.3, 8.4 Hz, 2H), 3.89 - 3.80 (m, 1H), 2.59 (s, 3H), 1.47 (s, 10H).

Isomer tert-butyl 3-(3-chloro-6-methyl-pyridazin-4-yl)azetidine-l-carboxylate (310 mg, 13.7%) was also isolated as a light yellow oil. LC-MS: m/z = 284.0 [M+H]+, ESI pos. 'H NMR (400 MHz, CDCh) 6 = 7.35 (s, 1H), 4.43 - 4.35 (m, 2H), 4.04 - 3.93 (m, 3H), 2.74 (s, 3H), 1.46 (s, 10H). Step 3: 4-(azetidin-3-yl)-6-chloro-3-methyl-pyridazine; 2, 222 -trifluoroacetic acid

To a solution of tert-butyl 3-(6-chloro-3-methyl-pyridazin-4-yl)azetidine-l-carboxylate (370.0 mg, 1.3 mmol, 1.0 eq) in DCM (2 mL) was added TFA (1.0 mL, 12.98 mmol, 9.95 eq) and stirring was continued at 20 °C for 3 hours. The reaction mixture was concentrated under vacuo. The residue was dissolved in a mixture of CH CN (2 mL) and H2O (10 mL) and lyophilized to yield 4-(azeti din-3 -yl)-6-chl oro-3 -methyl-pyridazine; 2,2,2-trifluoroacetic acid (440.0 mg, 90.7%) as a red solid. LC-MS: m/z = 184.0 [M+H]+, ESI pos.

Step 4: 6-chloro-3-methyl-4-( I -methylazetidin-3-yl)pyridazine

To a solution of 4-(azeti din-3 -yl)-6-chloro-3 -methyl-pyridazine; 2,2,2-trifluoroacetic acid (506.0 mg, 1.7 mmol, 1.0 eq.) at 0 °C in MeOH (5 mL) were added CH3COOH (0.29 mL, 5.1 mmol, 3.0 eq.) and formaldehyde (413.85 mg, 5.1 mmol, 3.0 eq.). Stirring at 0 °C was continued for 0.25 hour. Then NaBEECN (213.65 mg, 3.4 mmol, 2.0 eq.) was added. The cooling bath was removed and stirring at 20 °C was continued for 1 hour. The reaction mixture was filtered and concentrated. The residue was purified by preparative TLC using 10 % MeOH in DCM (with 1% NH4OH) to yield 6-chl oro-3 -methyl-4-( 1-methylazeti din-3 -yl)pyridazine (241.0 mg, 64.5%) as a colorless oil. LC-MS: m/z = 198.0 [M+H]+, ESI pos. 'H NMR (400 MHz, CDCh) 8 = 7.42 (s, 1H), 3.77 - 3.72 (m, 2H), 3.71 - 3.62 (m, 1H), 3.17 - 3.12 (m, 2H), 2.54 (s, 3H), 2.35 (s, 3H).

Step 5: N-[ 6-methyl-5-(l -methylazetidin-3-yl)pyridazin-3-yl] -1 , 1-diphenyl-methanimine Prepared according to Example 52, step 3 to yield N-[6-methyl-5-(l-methylazetidin-3- yl)pyridazin-3-yl]-l, 1-diphenyl-methanimine (140.0 mg, 33.1%) as a colorless oil, after purification by preparative HPLC (ACS-WH-GX-D, 30% - 60% CH3CN in H2O (with NH4CO3) over 10 minutes, flow rate: 30 mL/min). LC-MS: m/z = 343.0 [M+H]+, ESI pos. 'H NMR (400 MHz, CDCh) 6 = 7.83 - 7.27 (m, 8H), 7.23 - 7.17 (m, 2H), 6.64 (s, 1H), 3.72 - 3.65 (m, 2H), 3.63 - 3.53 (m, 1H), 2.87 - 2.75 (m, 2H), 2.44 (s, 3H), 2.27 (s, 3H).

Step 6: 6-methyl-5-( I -methylazetidin-3-yl)pyridazin-3-amine

Prepared according to Example 41, step 4 to yield 6-methyl-5 -(1-methylazeti din-3 -yl)pyridazin- 3-amine (30.0 mg, quantitative) after purification by preparative HPLC (ACS-WH-GX-D, 1% - 10% CH3CN in H2O (with NH4CO3) over 10 minutes, flow rate: 30 mL/min). LC-MS: m/z = 179.1 [M+H]+, ESI pos. 'H NMR (400 MHz, CD3OD) 8 = 6.93 (s, 1H), 4.30 - 4.21 (m, 2H), 4.08 (quin, J= 8.3 Hz, 1H), 3.97 - 3.88 (m, 2H), 2.77 (s, 3H), 2.34 (s, 3H), 2.00 - 1.91 (m, 4H). Step 7: l-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-2-pyridyl]-6- methoxy-N-[ 6-methyl-5-( 1 -methylazetidin-3-yl)pyridazin-3-yl ]benzimidazol-5-amine

Prepared according to Example 4, step 4 to yield l-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5- methyl-pyrazol-l-yl]-2-pyridyl]-6-methoxy-N-[6-methyl-5-(l-methylazetidin-3-yl)pyridazin-3- yl]benzimidazol-5-amine (5.0 mg, 7.0%) as a white solid after purification by preparative HPLC (ACS-WH-GX-F, 7% - 37% CEECN in H2O (with FA) over 10 minutes, flow rate: 25 mL/min). LC-MS: m/z = 582.3 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-d₆) 8 = 8.97 (s, 1H), 8.91 (s, 1H), 8.55 (d, J= 8.7 Hz, 1H), 8.37 (s, 1H), 8.30 (d, J= 8.6 Hz, 1H), 8.22 (br s, 1H), 7.83 (s, 1H), 7.40 (s, 1H), 7.12 (dt, J= 31.7, 54.5 Hz, 2H), 6.72 (s, 1H), 3.89 (s, 3H), 3.67 (br s, 3H), 3.10 (br s, 2H), 2.55 (s, 3H), 2.35 (s, 3H), 2.27 (s, 3H).

Example 61 l-[3-(difluoromethyl)-6-[5-[(6-ethyl-5,7-dihydropyrrolo[3,4-c]pyridazin-3- yl)amino]-6-methoxy-benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile

Step 1: 3-chloro-6-ethyl-5, 7-dihydropyrrolo[3,4-c]pyridazine

To a solution of 3-chloro-6,7-dihydro-5H-pyrrolo[3,4-c]pyridazin-6-ium; 2,2,2-trifluoroacetate (489 mg, 1.9 mmol, 1.0 eq.) and DIPEA (980.88 mg, 1.33 mL, 7.59 mmol, 4.0 eq.) in DMF (6.32 mL) was added ethyl iodide (295.94 mg, 153.34 pL, 1.9 mmol, 1.0 eq.) at 20 °C. The reaction mixture was heated to 50 °C and stirred for 2 hours. The mixture was cooled to 20 °C, poured into H2O and extracted three times with DCM. The combined organic layers were washed with with brine and concentrated. The residue was purified by flash column chromatography using 0% - 10% MeOH in DCM to yield 3-chloro-6-ethyl-5,7- dihydropyrrolo[3,4-c]pyridazine (175 mg, 48.7%) 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 To a solution of 3-chloro-6-ethyl-5,7-dihydropyrrolo[3,4-c]pyridazine (175 mg, 924.36 umol, 1.0 eq.) inl,4-dioxane (3.7 mL), were added tert-butyl carbamate (216.58 mg, 1.85 mmol, 2.0 eq.) and CS2CO3 (602.35 mg, 1.85 mmol, 2.0 eq.). Ar was bubbled through the solution for 5 minutes and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (106.97 mg, 184.87 umol, 0.2 eq.) was added, followed by tris(dibenzylideneacetone)dipalladium(0) DCM complex (95.68 mg, 92.44 umol, 0.1 eq.). The mixture was heated to 80 °C and stirred for 1.5 hours. The mixture was cooled to 20 °C, poured into H2O and extracted with EtOAc (2 x). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography using 0% - 10% MeOH in DCM to yield N-(6-ethyl-5,7- dihydropyrrolo[3,4-c]pyridazin-3-yl)carbamic acid tert-butyl ester (149 mg, 60.4%) as off-white crystals. LC-MS: m/z = 265.2 [M+H]+, ESI pos.

Step 3: (6-ethyl-6, 7-dihydro-5H-pyrrolo[3,4-c]pyridazin-6-ium-3-yl)ammonium; 2,2,2- trijluoroacetate

To a solution of N-(6-ethyl-5,7-dihydropyrrolo[3,4-c]pyridazin-3-yl)carbamic acid tert-butyl ester (150 mg, 567.49 umol, 1.0 eq.) in DCM (2.84 mL) was added TFA (1.62 g, 1.09 mL, 14.19 mmol, 25.0 eq.) and the mixture was stirred for 50 minutes at 20 °C. The mixture was poured into H2O and the aqueous layer was washed with DCM (3 x) and concentrated to dryness to yield (6-ethyl-6,7-dihydro-5H-pyrrolo[3,4-c]pyridazin-6-ium-3-yl)ammonium; 2,2,2- trifluoroacetate (194 mg, 86.3%) as a white solid. LC-MS: m/z = 165.0 [M+H]+, ESI pos.

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

Prepared according to Example 4, step 4 to yield l-[3-(difluoromethyl)-6-[5-[(6-ethyl-5,7- dihydropyrrolo[3,4-c]pyridazin-3-yl)amino]-6-methoxy-benzimidazol-l-yl]-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile (94 mg, 68.0%) as a white lyophilized solid. LC-MS: m/z = 543.3 [M+H]⁺, ESI pos. Example 62 [3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-[2-(trifluoromethyl)azetidin-l-yl] methanone

Step 1: 2-bromo-3-(difluoromethyl)pyridine

To a solution of 2-bromo-3 -foreaction mixtureylpyridine (10.0 g, 53.76 mmol, 1.0 eq.) in DCM (100 mL) was added DAST (17.76 mL, 134.4 mmol, 2.5 eq.) at - 40 °C. Then the mixture was warmed to 20 °C and stirred for another 2 hours. The mixture was added slowly to sat. aq. NaHCOs sol. (200mL). The resulting suspension was extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (lOOmL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography using 10% EtOAc in PE to yield 2-bromo-3-(difluoromethyl)pyridine (8.0 g, 70.0%) as a colorless oil. LC-MS: m/z = 209.8 [M+H]⁺, ESI pos. 'H NMR (400 MHz, DMSO-d₆) 8 = 8.57 (br d, J= 4.4 Hz, 1H), 8.11 (d, J= 7.1 Hz, 1H), 7.63 (dd, J= 4.8, 7.7 Hz, 1H), 7.39 - 6.97 (m, 1H).

Step 2: methyl 3-(difluoromethyl)pyridine-2-carboxylate

To a solution of 2-bromo-3-(difluoromethyl)pyridine (2.0 g, 9.62 mmol, 1.0 eq.) in MeOH (20 mL) were added NEt3 (4.02 mL, 28.85 mmol, 3.0 eq.) and 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (784.62 mg, 0.96 mmol, 0.1 eq.). The mixture was degassed and back-filled with CO three times, then it was heated to 80 °C and stirred for 12 hours. The reaction mixture was cooled to 20 °C and filtered.

The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography using 10% - 30% EtOAc in PE to yield methyl 3-(difluoromethyl)pyridine-2- carboxylate (1.7 g, 75.6% yield) as a white solid. LC-MS: m/z = 188.0 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 6 = 8.83 (d, J= 4.6 Hz, 1H), 8.19 (d, J= 7.9 Hz, 1H), 7.71 - 7.40 (m, 2H), 4.04 (s, 3H).

Step 3: methyl 3-(difluoromethyl)-l-oxido-pyridin-l-ium-2-carboxylate

To a solution of methyl 3-(difluoromethyl)pyridine-2-carboxylate (1.7 g, 9.08 mmol, 1.0 eq.) in CH3COOH (10.0 mL) was added hydrogen peroxide (20.0 mL, 195.82 mmol, 21.56 eq.). The reaction mixture was heated to 85 °C and stirred for 4 hours. The reaction mixture was cooled to 20 °C, quenched by the addition of sat. aq. Na2SCh sol. (200 mL). Stirring was then contiuned for 1 hour. The mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous ISfeSCU, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 30% - 50% EtOAc in PE to yield methyl 3 -(difluoromethyl)- 1-oxido-pyri din- l-ium-2-carboxylate (800.0 mg, 39.0%) as a white solid. LC-MS: m/z = 204.0 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 8 = 8.29 (d, J= 6.4 Hz, 1H), 7.50 - 7.39 (m, 2H), 6.71 (t, J= 54.9 Hz, 1H), 4.04 (s, 3H).

Step 4: methyl 6-chloro-3-(difluoromethyl)pyridine-2-carboxylate

A mixture of methyl 3 -(difluoromethyl)- 1-oxido-pyri din- l-ium-2-carboxylate (800.0 mg, 3.94 mmol, 1.0 eq.) and POCh (8.0 mL, 85.84 mmol, 21.8 eq.) was heated to 80 °C and stirred for 4 hours. The reaction mixture was cooled to 20 °C and concentrated under vacum. The residue was dissolve in EtOAc and added dropwise to H2O. NaOH solid was added to adjust the pH to ~ 8. The organic layer was concentrated to dryness. The residue was purified by flash column chromatography using 10% - 70% EtOAc in PE to yield methyl 6-chloro-3- (difluoromethyl)pyridine-2-carboxylate (700 mg, 72.2%) as a white solid. LC-MS: m/z = 222.0 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 6 = 8.13 (d, J= 8.3 Hz, 1H), 7.65 - 7.35 (m, 2H), 4.02 (s, 3H).

Step 5: 6-chloro-3-(difluoromethyl)pyridine-2-carboxylic acid

To a solution of methyl 6-chloro-3-(difluoromethyl)pyridine-2-carboxylate (700.0 mg, 3.16 mmol, 1.0 eq.) in a mixture of MeOH (2 mL), THF (6 mL) and H2O (2 mL) was added LiOH hydrate (397.65 mg, 9.48 mmol, 3.0 eq.) and stirring at 20 °C was continued for 12 hours. The reaction mixture was treated with IN HC1 (pH adjusted to ~ 4) and freeze-dried to give a residue (600 mg) which was further purified by preparative HPLC (ACS-WH-GX-V, 16% - 46% CH3CN in H2O (with FA) over 10 minutes, flow rate: 60 mL/min) to yield 6-chloro-3- (difluoromethyl)pyridine-2-carboxylic acid (150.0 mg, 20.6%) as a white solid. LC-MS: m/z = 207.9 [M+H]⁺, ESI pos. ^XH NMR (400 MHz, DMSO-d₆) 6 = 14.63 - 13.70 (m, 1H), 8.26 (d, J= 8.4 Hz, 1H), 7.89 (d, J= 8.3 Hz, 1H), 7.51 (t, J= 54.7 Hz, 1H).

Step 6: [ 6-chloro-3-(difluoromethyl)-2-pyridyl]-[2-(trifluoromethyl)azetidin-l-yl]methanone To a solution of 6-chloro-3-(difluoromethyl)pyridine-2-carboxylic acid (148.0 mg, 0.71 mmol, 1.0 eq.) in DMF (2 mL) were added 2-(trifluoromethyl)azetidine; 4-methylbenzenesulfonic acid (254.38 mg, 0.86 mmol, 1.2 eq.), DIPEA (368.62 mg, 2.85 mmol, 4.0 eq.), HATU (251.63 mg, 1.07 mmol, 1.5 eq.) and stirring at 20 °C was continued for 1 hour. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous TsfeSCU, filtered and concentrated under vacuum. The residue was purified by preparative TLC using 25% EtOAc in PE to yield [6-chloro-3-(difhioromethyl)-2-pyridyl]-[2-(trifluoromethyl)azetidin-l-yl]methanone (230.0 mg, 92.3%) as a colorless oil. LC-MS: m/z = 315.0 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 8 = 8.15 - 8.03 (m, 1H), 7.75 (s, 1H), 7.61 (s, 1H), 7.57 - 7.50 (m, 1H), 7.47 (s, 1H), 7.44 (s, 1H), 7.30 (s, 1H), 7.17 (s, 1H), 5.61 - 4.89 (m, 1H), 4.79 - 4.37 (m, 1H), 4.33 - 4.07 (m, 1H), 2.83 - 2.57 (m, 1H), 2.51 - 2.29 (m, 1H).

Step 7: [3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]- [ 2-(trifluoromethyl)azetidin-l-yl methanone

To a solution of [6-chloro-3-(difluoromethyl)-2-pyridyl]-[2-(trifluoromethyl)azetidin-l- yl]methanone (230.0 mg, 0.73 mmol, 1.0 eq.) in DMSO (5 mL) were added N-(6- methylpyridazin-3-yl)-lH-benzimidazol-5-amine (164.66 mg, 0.73 mmol, 1.0 eq.) and BGCCL (303.08 mg, 2.19 mmol, 3.0 eq.). The mixture was heated to 100 °C and stirring was continued for 14 hours. The reaction mixture was cooled to 20 °C, diluted with H2O (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC using 10% DCM in MeOH to afford 2 isomers.

The first isolated isomer (100 mg) was further purified by preparative HPLC (ACS-WH-GX-F, 19% - 39% CH3CN in H2O (with FA) over 10 minutes, flow rate: 25 mL/min) to yield [3- (difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-[2- (trifluoromethyl)azetidin-l-yl]methanone (47.1 mg, 12.7%) as a yellow solid. LC-MS: m/z = 504.2 [M+H]⁺, ESI pos. 'H NMR (400 MHz, DMSO-d₆) 6 = 9.26 (s, 1H), 9.12 - 9.05 (m, 1H), 8.50 - 8.44 (m, 2H), 8.32 - 8.25 (m, 2H), 8.15 (s, 1H), 7.66 - 7.59 (m, 1H), 7.58 (br s, 1H), 7.44 (s, 1H), 7.36 (d, J= 9.2 Hz, 1H), 7.30 (s, 1H), 7.11 - 7.07 (m, 1H), 5.19 - 5.07 (m, 1H), 4.50 - 4.38 (m, 1H), 4.22 - 4.10 (m, 1H), 2.68 (br s, 1H), 2.50 - 2.49 (m, 3H), 2.38 - 2.33 (m, 1H).

The second isolated isomer was further purified by preparative HPLC (ACS-WH-GX-F, 13% - 43% CH3CN in H2O (with FA) over 10 minutes, flow rate: 25 mL/min) to yield [3- (difluoromethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-[2- (trifluoromethyl)azetidin-l-yl]methanone (48.4 mg, 13.1%) as a yellow solid. LC-MS: m/z = 504.2 [M+H]⁺, ESI pos. 'H NMR (400 MHz, DMSO-d₆) 8 = 9.44 - 9.24 (m, 1H), 9.04 - 8.96 (m, 1H), 8.89 (s, 1H), 8.53 - 8.42 (m, 1H), 8.29 - 8.20 (m, 1H), 8.19 (s, 1H), 7.72 (d, J= 8.7 Hz, 1H), 7.57 - 7.26 (m, 3H), 7.17 - 7.06 (m, 1H), 5.78 - 5.09 (m, 1H), 4.61 - 4.07 (m, 2H), 2.55 (br s, 1H), 2.47 (s, 3H), 2.26 - 2.13 (m, 1H).

Example 63 l-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-2-pyridyl]-

N-(6-methylpyridazin-3-yl)-6-pyrrolidin-3-yloxy-benzimidazol-5-amine

Step 1: tert-butyl 3-(5-amino-2-bromo-4-nitro-phenoxy)pyrrolidine-l -carboxylate

To a solution of tert-butyl 3 -hydroxypyrrolidine- 1 -carboxylate (2629.22 mg, 14.04 mmol, 1.1 eq.) in THF (30 mL) was added NaH 60% dispersion in mineral oil (765.85 mg, 19.15 mmol, 1.5 eq.) at 0 °C under N2. Stirring was continued for 0.5 hour. A solution of 4-bromo-5-fluoro-2- nitro-aniline (3.0 g, 12.77 mmol, 1.0 eq.) in THF (20 mL) was added to the reaction mixture at 0 °C. The mixture was then stirred at 20 °C for 16 hours. The mixture was poured into H2O (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over TsfeSCU, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 0% - 50% EtOAc in PE to yield tert-butyl 3-(5-amino-2-bromo-4-nitro-phenoxy)pyrrolidine-l-carboxylate (4.0 g, 77.9%) as a yellow solid. LC-MS: m/z = 304.2 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 8 = 8.28 (s, 1H), 6.08 (s, 1H), 4.83 (br s, 1H), 4.38 (tt, J= 2.3, 4.4 Hz, 1H), 2.23 - 2.06 (m, 2H), 1.96 - 1.85 (m, 2H), 1.40 (d, J = 3.8 Hz, 9H).

Step 2: tert-butyl 3-(4,5-diamino-2-bromo-phenoxy)pyrrolidine-l-carboxylate

To a suspension of tert-butyl 3 -(5-amino-2-bromo-4-nitro-phenoxy)pyrrolidine-l -carboxylate (4.0 g, 9.94 mmol, 1.0 eq.) in EtOH (40 mL) were added iron (2776.7 mg, 49.72 mmol, 5.0 eq.), NH4CI (5270.49 mg, 99.44 mmol, 10.0 eq.) and H2O (20 mL). The reaction mixture was stirred at 50 °C for 2 hours. MeOH (100 mL) was added to the reaction mixture which was stirred at 50 °C for another 0.5 hour. The mixture was filtered and concentrated under reduced pressure. The residue was dissolved in sat. aq. NaHCOs sol. (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over ISfeSCU, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 0% - 100% EtOAc in PE to yield tert-butyl 3-(4,5-diamino-2 -bromophenoxy )pyrrolidine-l -carboxylate (2.5 g, 67.5%) as a green oil. LC-MS: m/z = 273.9 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 6 = 6.93 (s, 1H), 6.46 - 6.33 (m, 1H), 4.84 - 4.67 (m, 1H),

3.72 - 3.55 (m, 4H), 2.25 - 2.00 (m, 2H), 1.49 (s, 9H).

Step 3: tert-butyl 3-[(6-bromo-3H-benzimidazol-5-yl)oxy]pyrrolidine-l-carboxylate

To a solution of tert-butyl 3 -(4,5-diamino-2-bromo-phenoxy)pyrrolidine-l -carboxylate (2.5 g,

6.72 mmol, 1.0 eq.) in EtOH (15 mL) were added trimethyl orthofomate (7126.74 mg, 67.16 mmol, 10.0 eq.) and TsOH (115.64 mg, 0.67 mmol, 0.1 eq.). The reaction mixture was stirred at 80 °C for 2 hours under N2. The mixture was cooled to 23 °C, quenched by the addition of sat. aq. NaHCOs sol. (50 ml) and extracted with EtOAc (30 mL x 4). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 0% - 10% MeOH in EtOAc to yield tert-butyl 3- [(6-bromo-3H-benzimidazol-5-yl)oxy]pyrrolidine-l -carboxylate (2.54 g, 98.9%) as a yellow solid. LC-MS: m/z = 328.2 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 6 = 8.04 (br d, J= 6.5 Hz, 1H), 7.86 (br s, 1H), 7.25 - 7.11 (m, 1H), 4.93 (br s, 1H), 3.78 - 3.50 (m, 4H), 2.40 - 2.08 (m, 2H), 1.50 (br d, J= 10.5 Hz, 9H). Step 4: tert-butyl 3-[6-bromo-3-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-l- yl ]-2-pyridyl]benzimidazol-5-yl oxypyrrolidine- 1 -carboxylate

To a solution of 6-chloro-3-(difluoromethyl)-2-[3-(difluoromethyl)-5-methyl-pyrazol-l- yl]pyridine (550.0 mg, 1.87 mmol, 1.0 eq.) in DMSO (10 mL) were addedtert-butyl 3-[(6- bromo-3H-benzimidazol-5-yl)oxy]pyrrolidine-l -carboxylate (715.95 mg, 1.87 mmol, 1.0 eq.) and K2CO3 (776.57 mg, 5.62 mmol, 3.0 eq.). The mixture was degassed and back-filled with N2 three times. Then the reaction mixture was heated to 50 °C and stirred for 16 hours. The mixture was poured into H2O (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 0% - 10% EtOAc in PE to yield tert-butyl 3-[6-bromo-3-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5- methyl-pyrazol-l-yl]-2-pyridyl]benzimidazol-5-yl]oxypyrrolidine-l -carboxylate (500.0 mg, 41.8%) as a white solid. LC-MS: m/z = 641.0 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 8 = 8.50 (s, 1H), 8.44 (d, J= 8.4 Hz, 1H), 8.07 (s, 1H), 7.72 - 7.60 (m, 2H), 7.33 (s, 1H), 7.20 (s, 1H), 7.06 (s, 1H), 6.72 (t, J= 54.8 Hz, 1H), 6.55 (s, 1H), 4.90 - 4.74 (m, 1H), 3.79 - 3.42 (m, 4H), 2.54 (br s, 3H), 2.32 - 2.18 (m, 1H), 2.16 - 2.05 (m, 1H), 1.48 (br d, J= 6.8 Hz, 9H).

The other regioisomer tert-butyl 3-[6-bromo-l-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5- methyl-pyrazol-l-yl]-2-pyridyl]benzimidazol-5-yl]oxypyrrolidine-l -carboxylate (600.0 mg, 50.1%) was also isolated as a white solid. LC-MS: m/z = 641.0 [M+H]⁺, ESI pos.

Step 5: tert-butyl 3-[3-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-2- pyridyl ]-6-[ ( 6-methylpyridazin-3-yl )amino ]benzimidazol-5-yl oxypyrrolidine- 1 -carboxylate Prepared according to Example 4, step 4 to yield tert-butyl 3-[3-[5-(difluoromethyl)-6-[3- (difluoromethyl)-5-methyl-pyrazol-l-yl]-2-pyridyl]-6-[(6-methylpyridazin-3- yl)amino]benzimidazol-5-yl]oxypyrrolidine-l-carboxylate (50.0 mg, 95.8%) as a yellow solid. LC-MS: m/z = 668.2 [M+H]⁺, ESI pos.

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

To a solution oftert-butyl 3-[3-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-l- yl]-2-pyridyl]-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-5-yl]oxypyrrolidine-l- carboxylate (27.0 mg, 0.04 mmol, 1.0 eq.) in 1,4-dioxane (1 mL) was added HC1 4M solution in dioxane (1.0 mL, 2.0 mmol, 49.46 eq.). The reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex Luna C18 (150 mm x 25 mm, 10 pm), 5 - 35% CH3CN in H2O (with FA) over 10 minutes, flow rate: 25 mL/min) to yield l-[5-(difluoromethyl)-6-[3- (difluoromethyl)-5-methyl-pyrazol-l-yl]-2-pyridyl]-N-(6-methylpyridazin-3-yl)-6-pyrrolidin-3- yloxy-benzimidazol-5-amine (7.8 mg, 34.0%) as a white lyophilized solid. LC-MS: m/z = 568.1 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CD3OD) 8 = 8.97 - 8.87 (m, 1H), 8.58 - 8.53 (m, 1H), 8.52 (s, 1H), 8.48 - 8.44 (m, 1H), 8.23 - 8.12 (m, 1H), 7.94 - 7.83 (m, 1H), 7.41 (br d, J= 7.3 Hz, 1H), 7.27 - 6.99 (m, 2H), 6.98 - 6.71 (m, 1H), 6.66 (s, 1H), 5.17 (br s, 1H), 3.74 - 3.61 (m, 1H), 3.45 - 3.39 (m, 3H), 2.58 - 2.55 (m, 3H), 2.53 (s, 3H), 2.38 - 2.14 (m, 2H).

Example 64 l-[3-(difluoromethyl)-6-[3-(6-methylpyridazin-3-yl)-2-oxo-lH-imidazo[4,5- f]benzimidazol-7-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

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

To a solution of l-[6-chloro-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (1150.0 mg, 4.28 mmol, 1.0 eq.) and 6-bromo-3H-benzimidazol-5-amine (907.71 mg, 4.28 mmol, 1.0 eq.) in DMSO (20 mL) was added K2CO3 (1774.76 mg, 12.84 mmol, 3.0 eq.). The reaction mixture was stirred at 80 °C for 5 hours. The reaction mixture was cooled to 23 °C and diluted with H2O (lOOmL). A brown solid precipitated out. The solid was collected by filtration and purified by preparative NPLC (Welch pLtimate XB-SiOH (250 mm x 70 mm, 10 pm), 15%

- 55% EtOH in heptane) to yield l-[6-(6-amino-5-bromo-benzimidazol-l-yl)-3- (difhioromethyl)-2-pyridyl] -5 -methyl-pyrazole-3 -carbonitrile (600.0 mg, 31.5%) as a yellow solid. LC-MS: m/z = 445.9 [M+H]⁺, ESI pos^H NMR (400 MHz, DMSO-d₆) 8 = 8.88 (s, 1H), 8.57 (d, J= 8.6 Hz, 1H), 8.25 (d, J= 8.6 Hz, 1H), 7.81 (s, 1H), 7.66 (s, 1H), 7.19 - 6.89 (m, 2H), 5.48 - 5.41 (m, 2H), 2.46 (s, 3H). l-[6-(5-amino-6-bromo-benzimidazol-l-yl)-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile (600.0 mg, 31.5%) was also isolated as a yellow solid. LC-MS: m/z = 445.9 [M+H]⁺, ESI pos. 'H NMR (400 MHz, DMSO-d₆) 8 = 9.05 (s, 1H), 8.55 (d, J= 8.6 Hz, 1H), 8.31 (d, J= 8.6 Hz, 1H), 8.26 (s, 1H), 7.20 - 6.92 (m, 3H), 5.27 - 5.21 (m, 2H), 2.49 (br s, 3H).

Step 2: phenyl N-(6-methylpyridazin-3-yl)carbamate

To a suspension of 3-amino-6-methylpyridazine (1500.0 mg, 13.75 mmol, 1.0 eq) and pyridine (2.45 mL, 30.24 mmol, 2.2 eq) in ACN (60 mL) was added phenyl chloroformate (2.07 mL, 16.49 mmol, 1.2 eq) dropwise at 0 °C. The reaction mixture was then stirred at 20 °C for 1 hour. To the reaction mixture was added H2O (150 mL) and and stirring at 20 °C was continued for 30 minutes. The mixture was cooled in an ice bath and stirred for 1 hour. The solid was collected by filtration and dried to yield phenyl N-(6-methylpyridazin-3-yl)carbamate (2.5 g, 79.3%) as a white solid. LC-MS: m/z = 230.0 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 6 = 8.42 - 8.24 (m, 1H), 8.17 (d, J = 9.1 Hz, 1H), 7.47 - 7.40 (m, 2H), 7.37 (d, J = 9.3 Hz, 1H), 7.29 (d, J = 7.4 Hz, 1H), 7.25 - 7.20 (m, 2H), 2.69 (s, 3H).8te/? 3: l-[6-bromo-3-[6-(3-cyano-5-methyl-pyrazol- l-yl)-5-(difluoromethyl)-2-pyridyl]benzimidazol-5-yl]-3-(6-methylpyridazin-3-yl)urea

To a solution of l-[6-(6-amino-5-bromo-benzimidazol-l-yl)-3-(difluoromethyl)-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile (200.0 mg, 0.45 mmol, 1.0 eq.) and TEA (0.31 mL, 2.25 mmol, 5.0 eq.) in DMF (5 mL) was added phenyl N-(6-methylpyridazin-3-yl)carbamate (206.4 mg, 0.9 mmol, 2.0 eq.). The reaction mixture was stirred at 30 °C for 16 hours. The reaction mixture was diluted with H2O (20 mL) and stirred at 20 °C for 30 minutes. A white solid precipitate out. The solid was collected by filtration, washed with PE (lOmL x 2) and and dried. The solid was then triturated in in DCM (1 mL), collected by filtration and dried to yield l-[6-bromo-3-[6-(3-cyano- 5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2-pyridyl]benzimidazol-5-yl]-3-(6-methylpyridazin- 3-yl)urea (150.0 mg, 57.5%) as a yellow solid. LC-MS: m/z = 581.1 [M+H]⁺, ESI pos.

Step 4: l-[ 3-(difluoromethyl)-6-[ 3-( 6-methylpyridazin-3-yl)-2-oxo-lH-imidazo[ 4, 5- j]benzimidazol-7-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

To a solution of l-[6-bromo-3-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2- pyridyl]benzimidazol-5-yl]-3-(6-methylpyridazin-3-yl)urea (50.0 mg, 0.09 mmol, 1.0 eq.) in toluene (1 mL) was added CS2CO3 (84.36 mg, 0.26 mmol, 3.0 eq.). The mixture was degassed and back-filled with N2 three times. Then phenanthroline (6.22 mg, 0.03 mmol, 0.4 eq.) and [BU₄NCUI₂]2 (19.33 mg, 0.02 mmol, 0.2 eq.) were added to the mixture. Again, the mixture was degassed and back-filled with N2 three times. The reaction mixture was heated to 120 °C and stirred for 16 hours. The mixture was cooled to 23 °C and concentrated under reduced pressure. The residue was purified by preparative HPLC (Shim-Pack C18 (150 mm x 25 mm, 10 pm), 28 - 58% CH3CN in H2O (with 0.225% FA) over 10 minutes, flow rate: 25 mL/min) to yield l-[3- (difluoromethyl)-6-[3-(6-methylpyridazin-3-yl)-2-oxo-lH-imidazo[4,5-f]benzimidazol-7-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile (3.8 mg, 8.7%) as a white solid. LC-MS: m/z = 499.0 [M+H]⁺, ESI pos. ^XH NMR (400 MHz, DMSO-d₆) 6 = 11.59 (s, 1H), 9.12 (s, 1H), 8.61 (d, J= 8.7 Hz, 1H), 8.41 - 8.32 (m, 3H), 7.96 (s, 1H), 7.78 (d, J= 9.0 Hz, 1H), 7.22 - 6.92 (m, 2H), 2.69 (s, 3H), 2.51 - 2.51 (m, 3H).

Example 65 l-[3-(difluoromethyl)-6-[l-(6-methylpyridazin-3-yl)-2-oxo-3H-imidazo[4,5- f]benzimidazol-7-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

Step 1: l-[ 6-bromo-l-[ 6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2- pyridyl]benzimidazol-5-yl -3-( 6-methylpyridazin-3-yl)urea

Prepared according to Example 64, step 3 to yield l-[6-bromo-l-[6-(3-cyano-5-methyl-pyrazol- l-yl)-5-(difluoromethyl)-2-pyridyl]benzimidazol-5-yl]-3-(6-methylpyridazin-3-yl)urea (500.0 mg, 76.7%) as a white solid. LC-MS: m/z = 581.2 [M+H]⁺, ESI pos.

Step 2: l-[ 3-(difluoromethyl)-6-[ 1 -( 6-methylpyridazin-3-yl)-2-oxo-3H-imidazo[ 4, 5- j]benzimidazol-7-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

Prepared according to Example 64, step 4 to yield l-[3-(difluoromethyl)-6-[l-(6- methylpyridazin-3-yl)-2-oxo-3H-imidazo[4,5-f]benzimidazol-7-yl]-2-pyridyl]-5-methyl- pyrazole-3 -carbonitrile (4.7 mg, 22.0%) as a white solid. LC-MS: m/z = 499.2 [M+H]⁺, ESI pos. ^XH NMR (400 MHz, DMSO-d₆) 6 = 9.18 (s, 1H), 8.93 (s, 1H), 8.58 (d, J= 8.6 Hz, 1H), 8.39 (d, J= 8.8 Hz, 1H), 8.22 (d, J= 9.0 Hz, 1H), 7.76 (d, J= 9.1 Hz, 1H), 7.43 (s, 1H), 7.19 (s, 1H), 7.10 (s, 1H), 7.06 (s, 1H), 6.92 (s, 1H), 3.30 (br s, 3H), 2.75 (s, 3H).

Example 66 6-[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2-pyridyl]-6- methoxy-benzimidazol-5-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tertbutyl ester

Step 1: tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate tert-Butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate oxalate (1.19 g, 4.13 mmol, Eq: 1.00) was poured into ice-cold H2O and basified with 2M NaOH (120 m , pH = 10). The aqueous phase was then extracted with CHCE (2 x). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness to yield tert-butyl 2,6- diazaspiro[3.3]heptane-2-carboxylate (776 mg, 92.9%) as a light yellow liquid. LC-MS: m/z = 199.2 [M+H]⁺, ESI pos.

Step 2: 6-[ l-[6-( 3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2-pyridyl ]-6-methoxy- benzimidazol-5-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

Prepared according to Example 54, step 1 to yield 6-[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5- (difluoromethyl)-2-pyridyl]-6-methoxy-benzimidazol-5-yl]-2,6-diazaspiro[3.3]heptane-2- carboxylic acid tert-butyl ester (35 mg, 94.1%) as a yellow powder. LC-MS: m/z = 577.3 [M+H]⁺, ESI pos. Example 67 l-[6-[5-(2,6-diazaspiro[3.3]heptan-2-yl)-6-methoxy-benzimidazol-l-yl]-3- (difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile Step 1: l-[6-[5-(2,6-diazaspiro[3.3]heptan-2-yl)-6-methoxy-benzimidazol-l-yl]-3- (difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

Under argon, 6-[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2-pyridyl]-6- methoxy-benzimidazol-5-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (45 mg, 78.04 umol, 1.0 eq.) (obtained in Example 66, step 2) was dissolved in DCM (1 mL). TFA (88.99 mg, 60.13 pL, 780.44 umol, 10.0 eq.) was added and the reaction mixture was stirred at 20 °C overnight. More TFA (88.99 mg, 60.13 pL, 780.44 umol, 10.0 eq.) was added and the reaction mixture was stirred at 20 °C for another 6 hours. The mixture was neutralized with DCM/MeOH/NFE: 9/1/0.1. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase flash column chromatography using CEECN in FEO (with FA) to yield l-[6-[5-(2,6-diazaspiro[3.3]heptan-2-yl)-6-methoxy-benzimidazol-l-yl]-3- (difhioromethyl)-2-pyridyl] -5 -methyl-pyrazole-3 -carbonitrile (35 mg) as a yellow powder. LC- MS: m/z = 477.3 [M+H]⁺, ESI pos.

Example 68 l-[5-(difluoromethyl)-6-[l-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]-2-pyridyl]-6- methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine

Step 1: tert-butyl 3-[3-(difluoromethyl)-2-pyridyl]-2,5-dihydropyrrole-l-carboxylate To a solution of 2-bromo-3 -(difluoromethyl )pyri dine (300.0 mg, 1.44 mmol, 1.0 eq.) and tertbutyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,5-dihydro-lH-pyrrole-l-carboxylate (468.31 mg, 1.59 mmol, 1.1 eq.) in a mixture of 1,4-dioxane (5 mL) and H2O (1 mL), were added Pd(dppf)C12 DCM complex (117.78 mg, 0.14 mmol, 0.1 eq.) and lSfeCCh (382.18 mg, 3.61 mmol, 2.5 eq.). The mixture was degassed and back-filled with N2 three time before it was heated to 100 °C and stirred for 3 hours. The mixture was cooled to 23 °C and concentrated in vacuo. The residue was purified by and purified by flash column chromatography using 30% - EtOAc in PE to yield tert-butyl 3-[3-(difluoromethyl)-2-pyridyl]-2,5-dihydropyrrole-l- carboxylate (260.0 mg, 60.8%) as a yellow oil. LC-MS: m/z = 241.0 [M-56+H]⁺, ESI pos. ^TH NMR (400 MHz, CDCh) 8 = 8.71 (br d, J= 4.2 Hz, 1H), 8.16 - 8.01 (m, 1H), 7.40 - 7.33 (m, 1H), 7.04 - 6.61 (m, 1H), 6.28 - 6.06 (m, 1H), 4.72 - 4.61 (m, 2H), 4.52 - 4.37 (m, 2H), 1.51 (s, 9H).

Step 2: tert-butyl 3-[3-(difluoromethyl)-2-pyridyl]pyrrolidine-l-carboxylate

To a solution of tert-butyl 3-[3-(difluoromethyl)-2-pyridyl]-2,5-dihydropyrrole-l-carboxylate (450.0 mg, 1.52 mmol, 1.0 eq.) in EtOAc (20 mL) was added PtO2 (100.0 mg.). Then the mixture was degassed and back-filled with H2 three times. Stirring at 20 °C under a H2 atmosphere (15 psi) was then continued for 16 hours. The mixture was filtered through a pad of diatomaceous earth and the filter cake was washed with MeOH (15 mL x 5). The filtrate was concentrated under vacuum to yield tert-butyl 3-[3-(difluoromethyl)-2-pyridyl]pyrrolidine-l- carboxylate (370.0 mg, 78.4%) as a yellow oil. LC-MS: m/z = 243.2 [M-56+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 6 = 8.69 (br s, 1H), 7.83 (br d, J= 7.6 Hz, 1H), 7.27 - 7.21 (m, 1H), 7.02 - 6.69 (m, 1H), 3.83 - 3.60 (m, 4H), 3.43 (br dd, J = 6.2, 8.9 Hz, 1H), 2.41 - 2.31 (m, 1H), 2.22 - 2.14 (m, 1H), 1.47 (br s, 9H).

Step 3: 3-(difluoromethyl)-l-oxido-2-pyrrolidin-3-yl-pyridin-l-ium

To a mixture of tert-butyl 3-[3-(difluoromethyl)-2-pyridyl]pyrrolidine-l-carboxylate (500.0 mg, 1.68 mmol, 1.0 eq.) in CHCh (5 mL) were added urea hydrogen peroxide (320.0 mg, 3.4 mmol, 2.03 eq.) and TFAA (0.47 mL, 3.35 mmol, 2.0 eq.) at 20 °C. The mixture was then heated to 50 °C and stirred for 16 hours. The mixture was cooled to 23 °C, poured into H2O (20 mL) and washed with DCM (15 mL x 2). The aqueous phase was purified by reverse phase chromatography (column: Spherical C18 20-45 pm, 80g; 30% - 42% CH3CN in H2O (with 0.1% FA) over 20 minutes, flow rate: 50 mL/min) to yield 3-(difluoromethyl)-l-oxido-2- pyrrolidin-3-yl-pyridin-l-ium (53.0 mg, 14.8%) as a yellow oil. LC-MS: m/z = 215.0 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 8 = 8.39 (d, J = 5.4 Hz, 1H), 7.59 - 7.53 (m, 1H), 7.47 - 7.41 (m, 1H), 6.95 - 6.65 (m, 1H), 4.23 - 4.08 (m, 1H), 3.88 - 3.79 (m, 1H), 3.75 - 3.67 (m, 2H), 3.50 - 3.46 (m, 1H), 2.50 - 2.37 (m, 2H).

Step 4: 3-(difluoromethyl)-l-oxido-2-[l-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]pyridin-l-ium To a solution of 3 -(difluoromethyl)- l-oxido-2-pyrrolidin-3-yl-pyri din- 1-ium (45.0 mg, 0.21 mmol, 1.0 eq.) (5 mL) were added N,N-diisopropylethylamine (0.11 mL, 0.63 mmol, 3.0 eq.) and 3-(difluoromethyl)-l-oxido-2-pyrrolidin-3-yl-pyridin-l-ium (45.0 mg, 0.21 mmol, 1.0 eq.). The mixture was stirred at 20 °C for 3 hours. The mixture was poured into H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC using 10% MeOH in DCM to 3-(difluoromethyl)-l-oxido-2-[l-(2,2,2- trifluoroethyl)pyrrolidin-3-yl]pyridin-l-ium (32.0 mg, 51.4%) as a yellow solid. LC-MS: m/z = 297.1 [M+H]⁺, ESI pos.

Step 5: 6-chloro-3-(difluoromethyl)-2-[ l-(2,2, 2-trifluoroethyl)pyrrolidin-3-yl pyridine

A mixture of 3-(difluoromethyl)-l-oxido-2-[l-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]pyridin-l- ium (76.0 mg, 0.26 mmol, 1.0 eq.) and phosphorus oxychloride (5.0 mL, 53.64 mmol, 209.09 eq.) was stirred at 80 °C for 4 hours. The mixture was cooled to 23 °C and concentrated. The residue was taken in ice-cold H2O and purified by reverse phase chromatography (column: Spherical C18 20-45 pm, 80g; 70% - 82% CH3CN in H2O (with 0.1% FA) over 20 minutes, flow rate: 50 mL/min) to yield 6-chloro-3-(difluoromethyl)-2-[l-(2,2,2-trifluoroethyl)pyrrolidin- 3-yl]pyridine (12.0 mg, 14.9%) as a yellow oil. LC-MS: m/z = 315.0 [M+H]⁺, ESI pos.

Step 6: l-[5-(difluoromethyl)-6-[ I -(2, 2, 2-trifluoroethyl )pyrrolidin-3-yl ]-2-pyridyl ]-6-methoxy- N-(6-methylpyridazin-3-yl)benzimidazol-5-amine

To a mixture of 6-chl oro-3 -(difluoromethyl)-2-[l -(2, 2, 2-trifluoroethyl )pyrrolidin-3-yl]pyri dine (176.0 mg, 0.56 mmol, 1.0 eq.) and 6-methoxy-N-(6-methylpyridazin-3-yl)-lH-benzimidazol-5- amine (171.33 mg, 0.67 mmol, 1.2 eq.) in 2-methylbutan-2-ol (10.0 mL) were added K3PO4 (0.14 mL, 1.68 mmol, 3.0 eq.) and tBuXPhos Pd G3 (44.43 mg, 0.06 mmol, 0.1 eq.). The mixture was degassed and back-filled with N2 three times before it was heated to 100 °C. Stirring was then continued for 16 hours. The mixture was cooled to 23 °C, taken in DMSO (30 mL), filtered and purified by reversed phase chromatography (column: Spherical C18 20-45 pm, 80g; 40% - 52% CH3CN in H2O (with 0.1% FA) over 20 minutes, flow rate: 50 mL/min) to yield l-[5-(difluoromethyl)-6-[l-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]-2-pyridyl]-6-methoxy-N- (6-methylpyridazin-3-yl)benzimidazol-5-amine (37.0 mg, 12.3%) as a yellow solid (mixture of regioisomers). LC-MS: m/z = 534.3 [M+H]⁺, ESI pos.

This mixture of regioisomers was further purified by chiral SFC (REGIS(S,S)WHELK-O1 (250 mm x 25 mm, 10 pm), 55% CO2 in (IPA + CH3CN) (with 0.1% NH4OH) over 3.9 minutes, flow rate: 70 mL/min) to yield l-[5-(difluoromethyl)-6-[l-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]-2- pyridyl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (6.0 mg, 15.5%) as a yellow solid. LC-MS: m/z = 534.3 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CD3OD) 8 = 8.79 (s, 1H), 8.64 (s, 1H), 8.16 (d, J= 8.9 Hz, 1H), 8.11 (s, 1H), 7.84 (d, J= 8.4 Hz, 1H), 7.39 - 7.34 (m, 1H), 7.32 (s, 1H), 7.25 (d, J= 9.0 Hz, 1H), 7.19 (s, 1H), 7.05 (s, 1H), 4.07 - 3.95 (m, 4H), 3.38 - 3.34 (m, 1H), 3.26 - 3.07 (m, 5H), 2.56 - 2.47 (m, 4H), 2.39 - 2.31 (m, 1H).

Regioisomer 3-[5-(difluoromethyl)-6-[l-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]-2-pyridyl]-6- methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (8.6 mg, 23.2%) wasalso isolated as a yellow solid. LC-MS: m/z = 534.3 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CD3OD) 8 = 9.28 (s, 1H), 8.78 (s, 1H), 8.20 (d, J= 8.4 Hz, 1H), 7.82 (d, J= 8.4 Hz, 1H), 7.40 - 7.32 (m, 3H), 7.30 - 7.04 (m, 1H), 4.02 (s, 3H), 3.98 - 3.90 (m, 1H), 3.36 (br s, 1H), 3.16 - 3.08 (m, 1H), 3.07 - 2.98 (m, 3H), 2.78 - 2.69 (m, 1H), 2.53 (s, 3H), 2.33 - 2.25 (m, 2H). Example 69 l-[3-(difluoromethyl)-6-[5-[[l-[(3R,4R)-4-hydroxy-3-methyl-tetrahydrofuran-3- yl] -4-piperidyl] amino] -6-methoxy-benzimidazol- l-yl]-2-pyridyl] -5-methyl- pyrazole-3-carbonitrile

Step 1: 4- [tert-butyl (diphenyl) silyl] oxytetrahydrofuran-3-ol

To a solution of tetrahydrofuran-3,4-diol (11.5 g, 110.47 mmol, 1.0 eq) in ACN (300 mL) were added tert-butylchlorodiphenylsilane (30.36 g, 110.47 mmol, 1.0 eq) and imidazole (11.28 g, 165.71 mmol, 1.5 eq). The reaction mixture was degassed and back-filled with N2 three times before it was heated to 70 °C and stirred for 12 hours. The mixture was cooled to 23 °C and concentrated. The residue was taken in H2O (1 L) and extracted wtih EtOAc (700 mL x 3). The combined organic layers were washed with brine (1 L x 3), dried over ISfeSCU, filtered and concentrated under vacuum. The residue was purified by flash column chromatography using 33% - 41% EtOAc in PE to yield 4-[tert-butyl(diphenyl)silyl]oxytetrahydrofuran-3-ol (30.0 g, 79.3%) a colorless oil. 'H NMR (400 MHz, CDCh) 8 = 7.66 (d, J = 7.3 Hz, 4H), 7.51 - 7.38 (m, 6H), 4.28 (q, J = 6.0 Hz, 1H), 4.11 - 4.04 (m, 1H), 3.88 - 3.76 (m, 2H), 3.59 (d, J = 6.1 Hz, 2H), 3.00 (d, J = 4.1 Hz, 1H), 1.11 (s, 9H).

Step 2: 4-[tert-butyl(diphenyl)silyl]oxytetrahydrofuran-3-one

To a solution of 4-[tert-butyl(diphenyl)silyl]oxytetrahydrofuran-3-ol (30.0 g, 87.59 mmol, 1.0 eq.) in DCM (300 mL) was added Dess-Martin periodinane (40.87 g, 96.35 mmol, 1.1 eq.). The mixture was stirred at 20 °C for 16 hours. The mixture was concentrated and the residue was purified by flash column chromatography using 35% - 52% EtOAc in PE to yield 4-[tert- butyl(diphenyl)silyl]oxytetrahydrofuran-3-one (30.0 g, 95.6%) as a colorless oil. ^XH NMR (400 MHz, CDCh) 6 = 7.78 (d, J= 7.3 Hz, 2H), 7.66 (d, J= 1A Hz, 2H), 7.50 - 7.38 (m, 6H), 4.28 (t, J= 8.8 Hz, 1H), 4.09 - 3.99 (m, 2H), 3.95 - 3.86 (m, 1H), 3.73 (t, J= 9.3 Hz, 1H), 1.10 (s, 9H). Step 3: benzyl N-[l-[(3R,4R)-4-[tert-butyl(diphenyl)silyl]oxy-3-cyano-tetrahydrofuran-3-yl]-4- piperidyl] carbamate and benzyl N-[l-[(3S,4S)-4-[tert-butyl(diphenyl)silyl]oxy-3-cyano- tetrahydrofuran-3-yl] -4-piperidyl] carbamate (racemic mixture)

A mixture of 4-CBZ-aminopiperidine (6.88 g, 29.37 mmol, 1.0 eq.) and CH3COOH (1.94 g, 32.31 mmol, 1.1 eq.) in DCE (100 mL) was stirred at 50 °C for 1 hour under N2 atmosphere. Then4-[tert-butyl(diphenyl)silyl]oxytetrahydrofuran-3-one (10.0 g, 29.37 mmol, 1.0 eq.) was added at 20 °C. The above mixture was stirred at 50 °C for 1 hour. Then TMSCN (5.51 mL, 44.05 mmol, 1.5 eq.) was added and the mixture was stirred at 50 °C for another 14 hours. The mixture was cooled to 23 °C, poured into sat. aq. NaHCCh sol. (100 mL) and extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purifed by flash column chromatography using 45% - 81% EtOAc in PE to yield a racemic mixture of benzyl N-[l- [(3R,4R)-4-[tert-butyl(diphenyl)silyl]oxy-3-cyano-tetrahydrofuran-3-yl]-4-piperidyl]carbamate and N-[l-[(3S,4S)-4-[tert-butyl(diphenyl)silyl]oxy-3-cyano-tetrahydrofuran-3-yl]-4- piperidyl]carbamate (9.1 g, 53.1% ) as a colorless oil. LC-MS: m/z = 584.3 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 8 = 7.78 - 7.61 (m, 5H), 7.49 - 7.36 (m, 11H), 5.10 (s, 2H), 4.35 (d, J= 2.7 Hz, 1H), 4.29 - 4.21 (m, 1H), 4.18 - 4.09 (m, 2H), 4.09 - 4.03 (m, 1H), 4.01 - 3.95 (m, 1H), 2.60 - 2.37 (m, 3H), 2.30 - 2.17 (m, 1H), 1.98 (br d, J= 10.8 Hz, 1H), 1.86 - 1.71 (m, 1H),

1.54 - 1.42 (m, 1H), 1.37 - 1.29 (m, 1H), 1.08 (s, 8H).

The racemic mixture of benzyl N-[l-[(3R,4S)-4-[tert-butyl(diphenyl)silyl]oxy-3-cyano- tetrahydrofuran-3-yl]-4-piperidyl]carbamate and benzyl N-[l-[(3S,4R)-4-[tert- butyl(diphenyl)silyl]oxy-3-cyano-tetrahydrofuran-3-yl]-4-piperidyl]carbamate (1.1 g, 5.3%) was also isolated as a colorless oil. LC-MS: m/z = 584.3 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CDCh) 6 = 7.73 - 7.62 (m, 4H), 7.49 - 7.35 (m, 11H), 5.09 (s, 1H), 5.06 - 5.05 (m, 1H), 4.66 -

4.55 (m, 1H), 4.31 - 4.20 (m, 2H), 3.81 (d, J= 9.4 Hz, 1H), 3.75 - 3.67 (m, 1H), 3.62 (dd, J= 5.6, 9.7 Hz, 1H), 2.76 - 2.53 (m, 2H), 2.44 - 2.27 (m, 2H), 1.97 - 1.79 (m, 2H), 1.56 - 1.49 (m, 1H), 1.44 - 1.32 (m, 1H), 1.12 (s, 9H).

Step 4: benzyl N-[ l-[(3R,4R)-4-[tert-butyl(diphenyl)silyl] oxy-3-methyl-tetrahydrofuran-3-yl] -4- piperidyl] carbamate and benzyl N-[l-[(3S,4S)-4-[tert-butyl(diphenyl)silyl]oxy-3-methyl- tetrahydrofuran-3-yl] -4-piperidyl] carbamate (racemic mixture)

To methyl magnesium bromide (130.0 mL, 390.0 mmol, 25.02 eq.) was added a solution of benzyl N-[l-[(3R,4R)-4-[tert-butyl(diphenyl)silyl]oxy-3-cyano-tetrahydrofuran-3-yl]-4- piperidyl]carbamate and N-[l-[(3S,4S)-4-[tert-butyl(diphenyl)silyl]oxy-3-cyano- tetrahydrofuran-3-yl]-4-piperidyl]carbamate (racemic mixture) (9.1 g, 15.59 mmol, 1.0 eq.) in THF (20 mL) at 0 °C under N2. The mixture was then stirred at 0 °C for 3 hours. The mixture was poured into ice-cold sat. aq. NaHCOs sol. (300 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with sat. aq. NaHCOs sol. (200 mL x 2), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash column chromatography using 35% - 51% EtOAc in PE to yield a racemic mixture of benzyl N-[l- [(3R,4R)-4-[tert-butyl(diphenyl)silyl]oxy-3-methyl-tetrahydrofuran-3-yl]-4-piperidyl]carbamate and benzyl N-[l-[(3S,4S)-4-[tert-butyl(diphenyl)silyl]oxy-3-methyl-tetrahydrofuran-3-yl]-4- piperidyl]carbamate (4.9 g, 54.9%) as a colorless oil. LC-MS: m/z = 573.3 [M+H]⁺, ESI pos. ^TH NMR (400 MHz, CDCh) 8 = 7.80 - 7.75 (m, 2H), 7.68 (dd, J= 1.3, 7.8 Hz, 2H), 7.44 - 7.34 (m, 12H), 5.09 (s, 2H), 4.02 (d, J= 6.8 Hz, 1H), 3.97 (d, J= 2.4 Hz, 1H), 3.86 - 3.75 (m, 2H), 3.63 (d, J= 6.8 Hz, 1H), 3.52 - 3.35 (m, 1H), 2.56 - 2.35 (m, 3H), 2.23 - 2.11 (m, 1H), 1.95 - 1.83 (m, 1H), 1.73 - 1.67 (m, 1H), 1.50 - 1.38 (m, 1H), 1.25 - 1.18 (m, 1H), 1.07 (s, 9H), 0.89 (s, 3H).

Step 5: 1-[(3R, 4R)-4-[ tert-butyl(diphenyl)silyl]oxy-3-methyl-tetrahydrofuran-3-yl] piperidineamine and 1-[(3S, 4S)-4-[ tert-butyl(diphenyl)silyl]oxy-3-methyl-tetrahydrofuran-3-yl]piperidin- 4-amine (racemic mixture)

To a solution of benzyl N-[l-[(3R,4R)-4-[tert-butyl(diphenyl)silyl]oxy-3-methyl- tetrahydrofuran-3-yl]-4-piperidyl]carbamate and benzyl N-[l-[(3S,4S)-4-[tert- butyl(diphenyl)silyl]oxy-3-methyl-tetrahydrofuran-3-yl]-4-piperidyl]carbamate (racemic mixture) (2.7 g, 4.71 mmol, 1.0 eq.) in MeOH (50 mL) was added Pd/C (10%) (700.0 mg.) under N2.The mixture was degassed and back-filled with H2 three times and stirred at 20 °C under a H2 atmosphere (50 psi) for 16 hours. The mixture was filtered through a pad of diatomaceous earth and the cake was washed with MeOH (50 mL x 5). The filtrate was concentrated to yield a racemic mixture of l-[(3R,4R)-4-[tert-butyl(diphenyl)silyl]oxy-3-methyl- tetrahydrofuran-3-yl]piperidin-4-amine and 1 -[(3 S,4S)-4-[tert-butyl(diphenyl)silyl]oxy-3- methyl-tetrahydrofuran-3-yl]piperidin-4-amine (2.1 g, 95.5%) as a colorless oil. LC-MS: m/z = 439.4 [M+H]⁺, ESI pos. 'H NMR (400 MHz, CD3OD) 5 = 7.81 - 7.75 (m, 2H), 7.73 - 7.68 (m, 2H), 7.47 - 7.38 (m, 6H), 7.36 - 7.29 (m, 1H), 4.07 (dd, J= 1.3, 2.8 Hz, 1H), 4.01 (d, J= 6.9 Hz, 1H), 3.79 - 3.72 (m, 2H), 3.66 (d, J= 6.9 Hz, 1H), 2.74 - 2.66 (m, 1H), 2.58 - 2.48 (m, 2H), 2.46 - 2.37 (m, 1H), 2.21 (dt, J = 2.6, 11.3 Hz, 1H), 1.84 - 1.75 (m, 1H), 1.67 - 1.57 (m, 1H), 1.44 (dq, J = 4.2, 11.5 Hz, 1H), 1.36 - 1.26 (m, 1H), 1.08 (s, 9H), 0.92 (s, 3H). Step 6: l-[3-(difluoromethyl)-6-[6-methoxy-5-[[l-[(3R,4R)-4-[tert-butyl(diphenyl)silyl]oxy-3- methyl-tetrahydrofuran-3-yl]-4-piperidyl] amino] benzimidazol-l-yl]-2-pyridyl]-5-methyl- pyrazole-3-carbonitrile and l-[ 3 -(difluoromethyl) -6- [ 6-methoxy-5-[ [l-[( 3S, 4S)-4-[ tert- butyl(diphenyl) silyl (oxy-3-methyl-tetrahydrofuran-3-yl / -4-piperidyl (amino ]benzimidazol-l-yl /-

2 -pyridyl (-5-methyl-pyrazole-3-carbonitrile (racemic mixture )

To a solution of l-[rac-(3R,4R)-4-[tert-butyl(diphenyl)silyl]oxy-3-methyl-tetrahydrofuran-3- yl]piperidin-4-amine and 1 -[(3 S,4S)-4-[tert-butyl(diphenyl)silyl]oxy-3-methyl-tetrahydrofuran-

3-yl]piperidin-4-amine (racemic mixture) (600.0 mg, 1.37 mmol, 1.0 eq.) and l-[6-(5-bromo-6- methoxy-benzimidazol-l-yl)-3-(difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (628.13 mg, 1.37 mmol, 1.0 eq.) in 1,4-dioxane (10 mL) were added CS2CO3 (1336.91 mg, 4.1 mmol, 3.0 eq.) and BrettPhos Pd G4 (125.9 mg, 0.14 mmol, 0.1 eq.) at 20 °C. The mixture was degassed and back-filled with N2 three times before it was heated to 90 °C and stirred for 16 hours. The mixture was cooled to 23 °C, dissoved in DMSO and directly purified by reverse phase chromatography (spherical C18 20-45 pm, 330g; 40% - 62% CH3CN in H2O (with 0.1% FA) over 50 minutes, flow rate: 70 mL/min). The isolated material was further purified by flash column chromatography using 78% - 97% EtOAc in PE, and finally by preparative HPLC (Phenomenex C18 (75 mm x 30 mm, 3 pm), 10 - 40% CH3CN in H2O (with 0.225% FA) over 7 minutes, flow rate: 25 mL/min) to yield a racemic mixture of l-[3-(difluoromethyl)-6-[6- methoxy-5-[[l-[(3R,4R)-4-[tert-butyl(diphenyl)silyl]oxy-3-methyl-tetrahydrofuran-3-yl]-4- piperidyl]amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile and l-[3- (difhioromethyl)-6-[6-methoxy-5-[[l-[(3S,4S)-4-[tert-butyl(diphenyl)silyl]oxy-3-methyl- tetrahydrofuran-3-yl]-4-piperidyl]amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile (10.0 mg, 0.89%) as a yellow solid. LC-MS: m/z = 817.5 [M+H]⁺, ESI pos.

Step 7: l-[3-(difluoromethyl)-6-[5-[[ 1-[(3R, 4R)-4-hydroxy-3-methyl-tetrahydrofuran-3-yl]-4- piperidyl (amino ]-6-methoxy-benzimidazol-l-yl (-2-pyridyl (-5-methyl-pyrazole-3-carbonitrile and l-[3-(difluoromethyl)-6-[5-[[l-[(3S,4S)-4-hydroxy-3-methyl-tetrahydrofuran-3-yl]-4- piperidyl (amino ]-6-methoxy-benzimidazol-l-yl (-2-pyridyl (-5-methyl-pyrazole-3-carbonitrile (racemic mixture)

To a solution of l-[6-[5-[[l-[(3R,4R)-4-[tert-butyl(diphenyl)silyl]oxy-3-methyl-tetrahydrofuran- 3-yl]-4-piperidyl]amino]-6-methoxy-benzimidazol-l-yl]-3-(difluoromethyl)-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile and l-[6-[5-[[l-[(3S,4S)-4-[tert-butyl(diphenyl)silyl]oxy-3- methyl-tetrahydrofuran-3-yl]-4-piperidyl]amino]-6-methoxy-benzimidazol-l-yl]-3- (difhioromethyl)-2-pyridyl] -5 -methyl-pyrazole-3 -carbonitrile (racemic mixture) (10.0 mg, 0.01 mmol, 1.0 eq.) in THF (1 mL) was added TBAF (0.04 mL, 0.04 mmol, 3.0 eq.). The mixture was stirred at 20 °C for 3 hours. The mixture was concentrated and the residue was purified by preparative TLC using 10% MeOH in DCM and then by preparative HPLC (Phenom enex C18 (75 mm x 30 mm, 3 pm), 12 - 42% CH3CN in H2O (with 0.225% FA) over 7 minutes, flow rate: 25 mL/min) to yield a racemic mixture of l-[3-(difluoromethyl)-6-[5-[[l-[(3R,4R)-4-hydroxy-3- methyl-tetrahydrofuran-3-yl]-4-piperidyl]amino]-6-methoxy-benzimidazol-l-yl]-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile and l-[3-(difluoromethyl)-6-[5-[[l-[(3S,4S)-4-hydroxy-3- methyl-tetrahydrofuran-3-yl]-4-piperidyl]amino]-6-methoxy-benzimidazol-l-yl]-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile (1.9 mg, 25.9%) as a yellow solid. LC-MS: m/z = 579.4 [M+H]⁺, ESI pos. ^XH NMR (400 MHz, CD3OD) 6 = 8.77 (s, 1H), 8.51 (d, = 8.3 Hz, 1H), 8.18 (d, J= 8.7 Hz, 1H), 7.71 (s, 1H), 7.19 - 6.89 (m, 3H), 4.16 - 4.10 (m, 1H), 4.00 - 3.93 (m, 1H), 3.89 - 3.83 (m, 5H), 3.74 - 3.69 (m, 1H), 3.57 - 3.50 (m, 1H), 3.35 (br s, 1H), 2.54 (s, 3H), 2.29 - 2.15 (m, 2H), 1.81 - 1.55 (m, 3H), 1.35 - 1.22 (m, 4H).

Example 70 l-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]pyrazin-2-yl]-5-methyl-pyrazole-3-carbonitrile

Step 1: 3,5-dichloro-2-(difluoromethyl)pyrazine

To a solution of 3,5-dichloropyrazine-2-carbaldehyde (500.0 mg, 2.83 mmol, 1 eq.) in DCM (10 mL) were added (diethylamino)sulfur trifluoride (1138.41 mg, 7.06 mmol, 2.5 eq.) and triethylamine trihydrofluoride (455.42 mg, 2.83 mmol, 1 eq.) at 20 °C. The mixture was stirred at 20 °C for 16 hours. The mixture was poured into H2O (40 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash column chromatography using 15% - 25% EtOAc in PE to yield 3,5-dichloro-2- (difluoromethyl)pyrazine (510 mg, 86.2%) as a colorless liquid. 'H NMR (400 MHz, CDCh) 6 = 8.61 (s, 1H), 7.07 - 6.74 (m, 1H).

Step 2: l-[6-chloro-5-(difluoromethyl)pyrazin-2-yl]-6-methoxy-N-(6-methylpyridazin-3- yl) benzimidazol-5-amine

To a solution of 6-methoxy-N-(6-methylpyridazin-3-yl)-lH-benzimidazol-5-amine (128.29 mg, 0.500 mmol, 1 eq.) and 3,5-dichloro-2-(difluoromethyl)pyrazine (100.0 mg, 0.500 mmol, 1 eq.) in DMSO (3 mL) was added N,N-diisopropylethylamine (0.26 mL, 1.51 mmol, 3 eq.) at 20 °C. The mixture was heated to 80 °C and stirred for 3 hours. The mixture was cooled to 23 °C and directly purified by reverse phase chromatography (spherical Cl 8 20-45 pm, 80 g; 51% - 64% CH3CN in H2O (with 0.1% FA) over 20 minutes, flow rate: 50 mL/min) to yield l-[6-chloro-5- (difhjoromethyl)pyrazin-2-yl]-6-methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine (30 mg, 14.3%) as a yellow solid. LC-MS: m/z = 481.1 [M+H]⁺, ESI pos. 'H NMR (400 MHz, DMSO-de) 8 = 9.48 (s, 1H), 9.09 (s, 1H), 8.92 - 8.84 (m, 1H), 8.44 (s, 1H), 7.99 (s, 1H), 7.54 - 7.16 (m, 4H), 4.00 (s, 3H).

Isomer 3-[6-chloro-5-(difluoromethyl)pyrazin-2-yl]-6-methoxy-N-(6-methylpyridazin-3- yl)benzimidazol-5-amine (15 mg, 7.2%) was also isolated as a yellow solid. LC-MS: m/z = 481.1 [M+H]⁺, ESI pos. ¹ H NMR (400 MHz, DMSO-d₆) 6 = 9.42 (s, 1H), 9.18 - 9.07 (m, 2H), 8.99 - 8.73 (m, 1H), 7.49 (s, 1H), 7.47 - 7.43 (m, 1H), 7.41 - 7.36 (m, 1H), 7.34 - 7.16 (m, 1H), 3.94 (s, 3H).

Step 3: l-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl ]pyrazin-2-yl ]-5-methyl-pyrazole-3-carbonitrile;2-[ 3 -(difluoromethyl) -6- [ 6-methoxy-5-[ ( 6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]pyrazin-2-yl]-5-methyl-pyrazole-3-carbonitrile To a yellow solution of l-[6-chloro-5-(difluoromethyl)pyrazin-2-yl]-6-methoxy-N-(6- methylpyridazin-3-yl)benzimidazol-5-amine (30.0 mg, 0.070 mmol, 1 eq.) and 5-methyl-lH- pyrazole-3 -carbonitrile (7.69 mg, 0.070 mmol, 1.0 eq.) in DMSO (1 mL) was added N,N- diisopropylethylamine (0.04 mL, 0.220 mmol, 3 eq.) at 20 °C. The mixture was heated to 50 °C and stirred for 16 hours. The mixture was heated to 80 °C and stirred for 4 hours. To the reaction mixture was added 5-methyl-lH-pyrazole-3-carbonitrile (7.69 mg, 0.070 mmol, 1 eq.) and stirring at 80 °C was continued for 16 hours. The mixture was cooled to 23 °C and directly purified by preparative HPLC (Phenomenex C18 (75 mm x 30 mm, 3 pm), 15 - 45% CH3CN in H2O (with 0.225% FA) over 7 minutes, flow rate: 25 mL/min) to yield a mixture of l-[3- (difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]pyrazin-2- yl]-5-methyl-pyrazole-3 -carbonitrile and 2-[3-(difluoromethyl)-6-[6-methoxy-5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]pyrazin-2-yl]-5-methyl-pyrazole-3-carbonitrile (15 mg, 21.4%) as a yellow solid. LC-MS: m/z = 489.1 [M+H]⁺, ESI pos.

This mixture was further purified by SFC (Phenomenex-Cellulose-2 (250 mm x 30 mm, 10 pm), 70% CO2 in MeOH (with 0.1% NH4OH) over 4.6 minutes, flow rate: 80 mL/min) to yield l-[3- (difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]pyrazin-2- yl]-5-methyl-pyrazole-3-carbonitrile (2 mg, 26.6%) as a yellow solid. LC-MS: m/z = 489.1 [M+H]⁺, ESI pos. 'H NMR (400 MHz, DMSO-d₆) 8 = 9.68 (s, 1H), 9.15 (s, 1H), 8.76 - 8.58 (m, 1H), 7.85 (s, 1H), 7.52 (br s, 2H), 7.30 - 6.98 (m, 2H), 3.89 (s, 3H), 2.59 (s, 3H), 2.43 (br d, J= 3.1 Hz, 3H).

Example 71 (3-aminoazetidin-l-yl)-[6-[6-(difluoromethoxy)-5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-(difluoromethyl)-2-pyridyl] methanone

Step 1: [2-amino-4-bromo-5-(difluoromethoxy)phenyl] amine

Prepared according to Example 3, step 2, with [2-amino-4-bromo-5- (difluoromethoxy)phenyl] amine (135 mg, 0.534 mmol) (CAS 2091036-84-7) to afford[2-amino- 4-bromo-5-(difluoromethoxy)phenyl]amine (135 mg, 0.498 mmol, 50% yield) as a light brown solid. LC-MS: m/z = 253.0 [M+H]⁺, ESI pos.

Step 2: 5-bromo-6-(difluoromethoxy)-lH-benzimidazole

Prepared according to Example 35, step 3, with [2-amino-4-bromo-5- (difluoromethoxy)phenyl] amine (135 mg, 0.534 mmol) to afford 5-bromo-6-(difluoromethoxy)- IH-benzimidazole (138 mg, 0.529 mmol, 98% yield) as a off-white solid. LC-MS: m/z = 362.2 [M+H]⁺, ESI pos. Step 3: N-[ l-[6-chloro-3-(difluoromethyl)picolinoyl] azetidin-3-yl] carbamic acid tert-butyl ester

Prepared according to Example 62, step 6, with 6-chl oro-3 -(difluoromethyl)picolinic acid (prepared in Example 62, step 5) (250 mg, 1.205 mmol) and N-(azeti din-3 -yl)carbamic acid tertbutyl ester (249 mg, 1.445 mmol) to afford N-[l-[6-chloro-3- (difluoromethyl)picolinoyl]azetidin-3-yl]carbamic acid tert-butyl ester (123 mg, 0.340 mmol, 27% yield) as a white solid. LC-MS: m/z = 362.2 [M+H]⁺, ESI pos.

Step 4: N-[ l-[ 6-[5-bromo-6-(difhwromethoxy)benzimidazol-l-yl]-3- (difluoromethyl)picolinoyl]azetidin-3-yl] carbamic acid tert-butyl ester

Prepared according to Example 1, step 4, with 5-bromo-6-(difluoromethoxy)-lH-benzimidazole (56 mg, 0.056 mmol) and N-[l-[6-chloro-3-(difluoromethyl)picolinoyl]azetidin-3- yl]carbamic acid tert-butyl ester (55 mg, 0.152 mmol) to afford N-[l -[6-[5-bromo-6- (difhioromethoxy)benzimidazol-l-yl]-3-(difluoromethyl)picolinoyl]azetidin-3-yl]carbamic acid tert-butyl ester (28 mg, 0.048 mmol, 32% yield) as a white crystalline solid. LC-MS: m/z =

534.1 [M+H]⁺, ESI pos.

Step 5: N-[ l-[ 6-[ 6-(difluoromethoxy)-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3- (difluoromethyl)picolinoyl]azetidin-3-yl] carbamic acid tert-butyl ester

Prepared according to Example 39, step 1, with N-[l-[6-[5-bromo-6- (difluoromethoxy)benzimidazol-l-yl]-3-(difluoromethyl)picolinoyl]azetidin-3-yl]carbamic acid tert-butyl ester (27 mg, 0.046 mmol) and (6-methylpyridazin-3-yl)amine (10 mg, 0.092 mmol) to afford N-[l-[6-[6-(difluoromethoxy)-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3- (difluoromethyl)picolinoyl]azetidin-3-yl]carbamic acid tert-butyl ester (22 mg, 0.036 mmol, 76% yield) as a white crystalline solid. LC-MS: m/z = 617.3 [M+H]⁺, ESI pos.

Step 6: (3-aminoazetidin-l-yl)-[ 6-[ 6-(difluoromethoxy)-5-[(6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl / -3-(difluoromethyl) -2 -pyridyl methanone

Prepared according to Example 16, step 4, with N-[l-[6-[6-(difhioromethoxy)-5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-(difluoromethyl)picolinoyl]azeti din-3- yl]carbamic acid tert-butyl ester (22 mg, 0.036 mmol) to afford (3-aminoazetidin-l-yl)-[6-[6- (difluoromethoxy)-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-(difluoromethyl)-2- pyridyl]methanone (9 mg, 0.017 mmol, 46% yield) as a white crystalline solid. LC-MS: m/z =

517.2 [M+H]⁺, ESI pos. Example 72 [6-[6-(difluoromethoxy)-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]- 3-(difluoromethyl)-2-pyridyl]-[2-(trifluoromethyl)azetidin-l-yl] methanone

Step 1 : [ 6-chloro-3-(difluoromethyl)-2-pyridyl -[ 2-( trifluoromethyl)azetidin-l-yl ] methanone

Prepared according to Example 71, step 3, with 6-chl oro-3 -(difluoromethyl)picolinic acid (75 mg, 0.361 mmol) and 2-(trifluoromethyl)azetidine (54 mg, 0.433 mmol) and [6-chloro-3- (difluoromethyl)-2-pyridyl]-[2-(trifluoromethyl)azetidin-l-yl]methanone (93 mg, 0.296 mmol) to afford [6-chloro-3-(difluoromethyl)-2-pyridyl]-[2-(trifluoromethyl)azetidin-l-yl]methanone (95 mg, 0.303 mmol, 84% yield) as a white solid. LC-MS: m/z = 315.0 [M+H]⁺, ESI pos.

Step 2: [ 6-[5-bromo-6-(difluoromethoxy)benzimidazol-l-yl]-3-(difluoromethyl)-2-pyridyl]-

[ 2-(trifluoromethyl)azetidin-l-yl methanone

Prepared according to Example 71, step 4, with 5 -bromo-6-(difluorom ethoxy)- 1H- benzimidazole (prepared in Example 71, step 2) (60 mg, 0.228 mmol) and (6-methylpyridazin-3- yl)amine (11 mg, 0.100 mmol) and [6-chloro-3-(difhioromethyl)-2-pyridyl]-[2- (trifluoromethyl)azetidin-l-yl]methanone (93 mg, 0.296 mmol) to afford [6-[5-bromo-6- (difluoromethoxy)benzimidazol-l-yl]-3-(difluoromethyl)-2-pyridyl]-[2- (trifluoromethyl)azetidin-l-yl]methanone (40 mg, 0.074 mmol, 29% yield) as a colorless oil. LC-MS: m/z = 541.2 [M+H]⁺, ESI pos.

Step 3: [ 6-[ 6-(difluoromethoxy)-5-[ ( 6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3- (difluoromethyl)-2-pyridyl -[ 2-(trifluoromethyl)azetidin-l-yl methanone

Prepared according to Example 71, step 5, with [6-[5-bromo-6-(difluoromethoxy)benzimidazol- l-yl]-3-(difluoromethyl)-2-pyridyl]-[2-(trifluoromethyl)azetidin-l-yl]methanone (27 mg, 0.050 mmol) and (6-methylpyridazin-3-yl)amine (11 mg, 0.100 mmol) to afford [6-[6- (difluoromethoxy)-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-(difluoromethyl)-2- pyridyl]-[2-(trifluoromethyl)azetidin-l-yl]methanone (12 mg, 0.498 mmol, 39% yield) as a white solid. LC-MS: m/z = 570.2 [M+H]⁺, ESI pos. Example 73 [6-[6-(difluoromethoxy)-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]- 3-(difluoromethyl)-2-pyridyl]-[(2S,4S)-2,4-dimethylazetidin-l-yl] methanone

Prepared in analogy to Example 72 using (2S,4S)-2,4-dimethylazetidine (53 mg, 0.433 mmol) and 6-chloro-3-(difluoromethyl)picolinic acid (75 mg, 0.361 mmol) in step 1 to afford [6-[6- (difluoromethoxy)-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-(difluoromethyl)-2- pyridyl]-[(2S,4S)-2,4-dimethylazetidin-l-yl]methanone (29 mg, 0.055 mmol) as a white solid. LC-MS: m/z = 530.3 [M+H]⁺, ESI pos.

Example 74 (3-aminoazetidin-l-yl)-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl] methanone

Prepared in analogy to Example 71 using lH-benzimidazol-5-yl-(6-methylpyridazin-3-yl)amine (30 mg, 0.134 mmol) and N-[l-[6-chloro-3-(difluoromethyl)picolinoyl]azetidin-3-yl]carbamic acid tert-butyl ester (48 mg, 0.134 mmol) in step 1 to afford (3-aminoazetidin-l-yl)-[3- (difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]methanone (17 mg, 0.038 mmol) as an off-white solid. LC-MS: m/z = 451.3 [M+H]⁺, ESI pos. Example 75 (3-aminoazetidin-l-yl)-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl] methanone

Step 1: 5-[3-(difluoromethyl)-2-pyridyl]-3,6-dihydro-2H-pyridine-l-carboxylic acid tertbutyl ester

To a solution of 2-bromo-3 -(difluoromethyl )pyri dine (1.59 g, 7.64 mmol, 1.0 eq.) in 1,4-dioxane (24 mL) were added 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-l- carboxylic acid tert-butyl ester (3.55 g, 11.47 mmol, 1.5 eq.), K2CO3 (2.11 g, 15.29 mmol, 2.0 eq.) and water (2.4 mL). The reaction mixture was bubbled with argon for 10 min. [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (624 mg, 764 pmol, 0.10 eq.). The vial was sealed and the brown mixture was stirred at 100°C for 2 hours. The reaction mixture was cooled to RT and diluted with EtOAc (20 mL) and water (20 mL) and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue product was purified by flash chromatography (SiO2, 0-100% EtOAc in heptane) to give 5-[3-(difluoromethyl)-2-pyridyl]-3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester (665 mg, 25% yield, 90% purity). LC-MS: m/z = 311.2 [M+H]⁺, ESI pos.

Step 2: 3-[3-(difluoromethyl)-2-pyridyl]piperidine-l-carboxylic acid tert-butyl ester

To a solution of 5-[3-(difluoromethyl)-2-pyridyl]-3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester (665 mg, 2.14 mmol, 1.0 eq.) in EtOAc (11 mL) was added platinum (IV) oxide (66 mg, 291 pmol, 0.14 eq.) and the reaction mixture was stirred under Th for 16 hours at RT. The reaction mixture was filtered off. The filter cake was rinsed with EtOAc (30 mL) and the combined filtrate was evaporated to dryness. The crude product was added to 3 g isolute HM-N and purified by flash chromatography (SiO2, 20 - 50 % EtOAc in heptane) to yield 3-[3- (difhioromethyl)-2-pyridyl]piperidine-l -carboxylic acid tert-butyl ester (298 mg, 40% yield, 90 % purity) as light yellow liquid. LC-MS: m/z = 313.3 [M+H]⁺, ESI pos. Step 3: 3-(difluoromethyl)-2-(3-piperidyl)pyridine hydrochloride

To a solution of 3-[3-(difluoromethyl)-2-pyridyl]piperidine-l-carboxylic acid tert-butyl ester (298 mg, 0.954 pmol, 1.0 eq.) in MeOH (5 mL) was added 4 M HC1 in dioxane (16 mL) and the mixture was stirred at RT for 1 hour. The reaction mixture was evaporated to dryness to yield 3- (difluoromethyl)-2-(3-piperidyl)pyridine hydrochloride (301 mg, 0.944 mmol, 90% purity, 99% yield) as light yellow solid which was used in the next step without further purification. LC-MS: m/z = 213.2 [M+H]⁺, ESI pos.

Step 4: 3-(difluoromethyl)-2-(l-mesyl-3-piperidyl)pyridine

To a mixture of 3-(difluoromethyl)-2-(3-piperidyl)pyridine dihydrochloride (301 mg, 1.05 mmol, 1.0 eq.) in DCM (23 mL) was added DIEA (736 pL, 4.22 mmol, 4.0 eq.) and methanesulfonic anhydride (275 mg, 1.58 mmol, 1.5 eq.) and the resulting solution was stirred at RT for 12 hours. The solution was added to 3 g isolute HM-N, concentrated and purified by flash chromatography (SiCh, 20-80% EtOAc in heptane) to yield 3-(difluoromethyl)-2-(l-mesyl- 3-piperidyl)pyridine (242 mg, 0.830 mmol, 79% yield) as light yellow liquid. LC-MS: m/z = 291.2 [M+H]⁺, ESI pos.

Step 5: 3 -(difluoromethyl) -2 -( I -mesyl-3-piperidyl)-l-oxido-pyridin-l-ium

To a solution of 3 -(difluoromethyl)-2-(l-mesyl-3 -piperidyl )pyri dine (267 mg, 0.920 mmol, 1.0 eq.) in DCM (3 mL) was added 3 -chloroperoxybenzoic acid (413 mg, 1.84 mmol, 2.0 eq.) and the solution was stirred at 23 °C for 12 hours. The reaction mixture was poured into a solution of 10% aqueous ISfeSCL (25 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were washed with saturated aqueous NaHCCL, dried over MgSCU, filtered and concentrated to give 3-(difluoromethyl)-2-(l-mesyl-3-piperidyl)-l-oxido-pyridin-l-ium (254 mg, 0.902 mmol, 98% yield,) as light yellow liquid, used directly without any further purification in the next step. LC-MS: m/z = 307.1 [M+H]⁺, ESI pos.

Step 6: 6-chloro-3-(difluoromethyl)-2-(l -mesyl-3-piperidyl)pyridine

Prepared according to Example 68, step 5, with 3-(difluoromethyl)-2-(l-mesyl-3-piperidyl)-l- oxido-pyridin-l-ium (308 mg, 1.005 mmol) to afford 6-chloro-3-(difluoromethyl)-2-(l-mesyl-3- piperidyl)pyridine (128 mg, 0.395 mmol, 25% yield) as a light yellow solid. LC-MS: m/z = 325.1 [M+H]⁺, ESI pos. Step 7: [l-[5-(difluoromethyl)-6-(l-mesyl-3-piperidyl)-2-pyridyl]benzimidazol-5-yl]-(6- methylpyridazin-3-yl)amine

Prepared according to Example 71, step 4, with lH-benzimidazol-5-yl-(6-methylpyridazin-3- yl)amine (17 mg, 0.077 mmol) and (6-methylpyridazin-3-yl)amine (11 mg, 0.100 mmol) and 6- chloro-3-(difluoromethyl)-2-(l-mesyl-3-piperidyl)pyridine (25 mg, 0.077 mmol) to afford [l-[5- (difluoromethyl)-6-(l -mesyl -3-piperidyl)-2-pyridyl]benzimidazol-5-yl]-(6-methylpyridazin-3- yl)amine (11 mg, 0.021 mmol, 28% yield) as a white solid. LC-MS: m/z = 514.2 [M+H]⁺, ESI pos.

Example 76

2-azabicyclo[2.2.0]hexan-2-yl-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl] methanone

Step 1 : 2-azabicyclo[ 2.2.0 ]hexan-2-yl-[ 6-chloro-3-(difluoromethyl)-2-pyridyl / methanone

Prepared according to Example 62, step 6, with 6-chl oro-3 -(difluoromethyl)picolinic acid (prepared in Example 62, step 5) (40 mg, 0.125 mmol) and 2-azabicyclo[2.2.0]hexane;oxalic acid (26 mg, 0.085 mmol) to afford 2-azabicyclo[2.2.0]hexan-2-yl-[6-chloro-3-(difluoromethyl)- 2-pyridyl]methanone (23 mg, 0.340 mmol, 68% yield) as a colorless oil. LC-MS: m/z = 273.1 [M+H]+, ESI pos.

Step 2: 2-azabicyclo[ 2.2.0]hexan-2-yl-[ 3-(difluoromethyl)-6-[5-[ ( 6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl / -2 -pyridyl methanone

Prepared in analogy to Example 71 using lH-benzimidazol-5-yl-(6-methylpyridazin-3-yl)amine (19 mg, 0.085 mmol) and 2-azabicyclo[2.2.0]hexan-2-yl-[6-chloro-3-(difluoromethyl)-2- pyridyl]methanone (23 mg, 0.085 mmol) in step 1 to afford 2-azabicyclo[2.2.0]hexan-2-yl-[3- (difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]methanone (13 mg, 0.028 mmol, 32% yield) as a white solid. LC-MS: m/z = 462.2 [M+H]+, ESI pos. Example 77 - 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 noninhibition 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.

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.

MS-Setup Sciex API5000/API6500+:

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.

MS-Setup Agilent QToF 6545

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

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

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

Example A

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

The active ingredient is sieved and mixed with microcrystalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidone in water. The granulate is then mixed with sodium starch glycolate and magnesium stearate and compressed to yield kernels of 120 or 350 mg respectively. The kernels are lacquered with an aq. solution / suspension of the above mentioned film coat.

Example B

Capsules containing the following ingredients can be manufactured in a conventional manner: The components are sieved and mixed and filled into capsules of size 2. Example C

Injection solutions can have the following composition:

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

Claims

1. A compound of formula (I) wherein

R³ is hydrogen, cycloalkylcarbonyl, alkylcarbonyl, heterocycloalkylcarbonyl, heterocycloalkyl or heteroaryl; wherein heterocycloalkylcarbonyl, heterocycloalkyl and heteroaryl are optionally substituted with 1, 2 or 3 substituents individually selected from R⁵; or R² and R³ together with the carbon atoms to which they are attached to form a 4 to 6 membered heterocycloalkyl optionally substituted with alkylheteroaryl; each instance of R⁴ is individually selected from alkyl, amino, alkylsulfonyl, cyano, halogen, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, dialkylaminocarbonyl, haloalkoxy and haloalkyl; each instance of R⁵ is individually selected from alkyl, alkoxycarbonyl, heterocycloalkyl, cycloalkyl, (hydroxyl)(alkyl)heterocycloalkyl, dialkylaminocarbonyl, heterocycloalkyl alkoxy, alkylheterocycloalkyl, alkylheterocycloalkyl oxy, heterocycloalkylheterocycloalkyloxy, (haloalkyl)(alkyl)aminocarbonyl, dialkylaminocarbonylalkyl, hydroxyalkyl and arylalkoxycarbonylaminoheterocycloalkyl;

A¹ is -N- or -CH-; and

L is absent, -O- or -NH-; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein R¹ is haloalkoxy, azetidinylcarbonyl, pyrazolyl, triazolyl or pyrrolidinyl, wherein azetidinylcarbonyl, pyrazolyl, triazolyl and pyrrolidinyl are optionally substituted with 1, 2 or 3 substituents individually selected from R⁴.

3. The compound according to claim 1 or 2, wherein R¹ is pyrazolyl optionally substituted with 1, 2 or 3 substituents individually selected from R⁴.

4. The compound according to any one of claims 1 to 3, wherein R² is hydrogen, alkoxy, alkyl, halogen, haloalkoxy, dialkylaminocarbonylalkoxy, oxetanyloxy, tetrahydropyranyl oxy, pyrrolidinyloxy, morpholinylalkoxy or alkylpyridazinylamino; or R² and R³, together with the carbon atoms to which they are attached to, form imidazolidin-2-one substituted with methylpyridazinyl .

5. The compound according to any one of claims 1 to 4, wherein R² is hydrogen, methoxy, methyl, fluoro, difluoromethoxy, dimethylaminocarbonylethoxy, oxetanyloxy, tetrahydropyranyl oxy, pyrrolidinyloxy, morpholinylalkoxy or alkylpyridazinylamino; or R² and R³, together with the carbon atoms to which they are attached to, form imidazolidin-2-one substituted with methylpyridazinyl.

6. The compound according to any one of claims 1 to 5, wherein R³ is hydrogen, cyclopropylcarbonyl, piperidinylcarbonyl, diazaspiroheptanyl, piperidyl, dihydro-5H- pyrano[4,3-c]pyridazinyl, l-methyl-6-oxo-pyridazinyl, dihydropyridazino[4,5-b][l,4]oxazinyl, 6-oxo-pyrrolo[2,3-c]pyridazinyl, 5,7-dihydropyrrolo[3,4-c]pyridazinyl, pyridazinyl or 5,6- dihy dropyrrol o [2, 3 -c] pyri dazinyl ; wherein piperidinylcarbonyl, diazaspiroheptanyl, piperidyl, dihydro-5H-pyrano[4,3- c]pyridazinyl, l-methyl-6-oxo-pyridazinyl, dihydropyridazino[4,5-b][l,4]oxazinyl, 6-oxo- pyrrolo[2,3-c]pyridazinyl, 5,7-dihydropyrrolo[3,4-c]pyridazinyl, pyridazinyl and 5,6- dihydropyrrolo[2,3-c]pyridazinyl are optionally substituted with 1, 2 or 3 substituents individually selected from R⁵.

7. The compound according to any one of claims 1 to 6, wherein R³ is hydrogen, cyclopropylcarbonyl, piperidinylcarbonyl, 2,6-diazaspiro[3.3]heptanyl, 4-piperidyl, 7,8-dihydro- 5H-pyrano[4,3-c]pyridazin-3-yl, l-methyl-6-oxo-pyridazin-3-yl, 2,3-dihydropyridazino[4,5- b][l,4]oxazin-8-yl, 6-oxo-pyrrolo[2,3-c]pyridazin-3-yl, 5,7-dihydropyrrolo[3,4-c]pyridazin-3-yl, pyridazin-3-yl or 5,6-dihydropyrrolo[2,3-c]pyridazin-7-yl; wherein piperidinylcarbonyl, 2,6-diazaspiro[3.3]heptanyl, 4-piperidyl, 7,8-dihydro-5H- pyrano[4,3-c]pyridazin-3-yl, l-methyl-6-oxo-pyridazin-3-yl, 2,3-dihydropyridazino[4,5- b][l,4]oxazin-8-yl, 6-oxo-pyrrolo[2,3-c]pyridazin-3-yl, 5,7-dihydropyrrolo[3,4-c]pyridazin-3-yl, pyridazin-3-yl and 5,6-dihydropyrrolo[2,3-c]pyridazin-7-yl are optionally substituted with 1, 2 or 3 substituents individually selected from R⁵.

8. The compound according to any one of claims 1 to 7, wherein R⁴ is at each instance independently selected from cyano, methyl, amino, methylsulfonyl, fluoro, methoxyethyl, cyclopropylmethyl, dimethylaminocarbonyl, difluoromethoxy, (lR)-2,2-difluoro-l -methylethoxy, difluoromethyl, trifluoromethyl and trifluoroethyl.

9. The compound according to any one of claims 1 to 8, wherein R⁵ is at each instance independently selected from tert-butyloxycarbonyl, methyl, ethyl, tetrahydrofuranyl, oxetanyl, 4- hydroxy-3-methyl-tetrahydrofuranyl, dimethylaminocarbonyl, 5-[rac-(l S,5R)-3-oxa-6- azabicyclo[3.1.1]heptanyl, l-methyl-5-oxo-pyrrolidinyl, 2-morpholinoethoxy, (l-methyl-4- piperidyl)oxy, (3R)-l-methyl-2-oxo-pyrrolidinyl, (3S)-l-methyl-2-oxo-pyrrolidinyl, l-(oxetan- 3-yl)-4-piperidyl]oxy, dimethylaminocarbonylmethyl, 5-(benzyloxycarbonylamino)-l,3-dioxan-

2-yl, methyl(2,2,2-trifluoroethyl)carbamoyl and 1-methylazeti din-3 -yl.

10. The compound according to any one of claims 1 to 9, wherein R⁵ is at each instance independently selected from tert-butyl oxycarbonyl, methyl, ethyl, 6-tetrahydrofuran-3-yl, oxetan-3-yl, 4-hydroxy-3 -methyl -tetrahydrofuran-3-yl, dimethylaminocarbonyl, 5-[rac-(lS,5R)-

3-oxa-6-azabicyclo[3.1.1]heptan-6-yl, l-methyl-5-oxo-pyrrolidin-2-yl, 2-morpholinoethoxy, (1- methyl-4-piperidyl)oxy, (3R)-1 -methyl -2-oxo-pyrrolidin-3-yl, (3S)-l-methyl-2-oxo-pyrrolidin- 3-yl, l-(oxetan-3-yl)-4-piperidyl]oxy, dimethylaminocarbonylmethyl, 5-

(benzyl oxycarbonylamino)- 1,3 -di oxan-2-yl, methyl(2,2,2-trifluoroethyl)carbamoyl and 1- methylazetidin-3-yl.

11. The compound according to any one of claims 1 to 10, wherein A¹ is -CH-.

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

13. The compound of formula (I) according to any one of claims 1 to 12, selected from l-[3-(difluoromethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]- 5-methyl-pyrazole-3-carbonitrile; l-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]- 5-methyl-pyrazole-3-carbonitrile; l-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-2-pyridyl]-N-(6- methylpyridazin-3-yl)-6-(2 -morpholinoethoxy )benzimidazol-5-amine; l-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(ox etan-3- yloxy)benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[5-(difluoromethyl)-6-[3-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-N-(6- methylpyridazin-3-yl)benzimidazol-5-amine;

N-[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2-pyridyl]benzimidazol-5- yl]cyclopropanecarboxamide;

1-[6-[l-(cyclopropylmethyl)-3 -methyl -pyrazol-4-yl]-5-(difluoromethyl)-2-pyridyl]-6- methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine;

3-(difluoromethoxy)-l-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-6,7-dihydropyrazolo[4,3-c]pyridin-4- one;

2-[3-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2-pyridyl]-6-[(6- methylpyridazin-3-yl)amino]benzimidazol-5-yl]oxy-N,N-dimethyl-acetamide; l-[5-(difluoromethyl)-6-[l-(2-methoxyethyl)-3-methyl-pyrazol-4-yl]-2-pyridyl]-6- methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; l-[5-(difluoromethyl)-6-[l-(2-methoxyethyl)-5-methyl-pyrazol-4-yl]-2-pyridyl]-6- methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; l-[5-(difluoromethyl)-6-[3-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridyl]-6- methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; l-[6-[l-(cyclopropylmethyl)-3-methyl-pyrazol-4-yl]-5-(difluoromethyl)-2-pyridyl]-6- fluoro-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; l-[3-(difluoromethyl)-6-[6-fluoro-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[3-(difluoromethyl)-6-[6-methoxy-5-[[5-[(lS)-3-oxa-6-azabicyclo[3.1.1]heptan-6- yl]pyridazin-3-yl]amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile;

2-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3- yloxy)benzimidazol-l-yl]-2-pyridyl]-3,5-dimethyl-4H-pyrrolo[3,4-c]pyrazol-6-one;

1-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-(l-methyl-5-oxo-pyrrolidin-2-yl)pyridazin-3- yl]amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile;

2-[6-[[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy- benzimidazol-5-yl]amino]pyridazin-3-yl]-N,N-dimethyl-acetamide; l-[3-(difluoromethyl)-6-[6-methoxy-5-(3-methyl-5-methylol-5,6-dihydropyrrolo[2,3- c]pyridazin-7-yl)benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[5-(difluoromethyl)-6-[2-methyl-5-(2,2,2-trifluoroethyl)-l,2,4-triazol-3-yl]-2-pyridyl]-6- methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; l-[3-(difluoromethyl)-6-(6-methoxybenzimidazol-l-yl)-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile; l-[5-(difluoromethyl)-6-[l-methyl-5-(2,2,2-trifluoroethyl)-l,2,4-triazol-3-yl]-2-pyridyl]-6- methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; l-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-[(3R)-l-methyl-2-oxo-pyrrolidin-3- yl]pyridazin-3-yl]amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[3-(difluoromethyl)-6-[6-methoxy-5-[[6-[(3S)-l -methyl -2-oxo-pyrrolidin-3-yl]pyridazin- 3-yl]amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; benzyl N-[2-[6-[[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2- pyridyl]benzimidazol-5-yl]amino]pyridazin-3-yl]-l,3-dioxan-5-yl]carbamate; l-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl]-2-pyridyl]-4,6-dihydrofuro[3,4-c]pyrazole-3-carbonitrile; l-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-2-pyridyl]-6-methoxy- N-[6-methyl-5-(l-methylazetidin-3-yl)pyridazin-3-yl]benzimidazol-5-amine; l-[3-(difluoromethyl)-6-[5-[(6-ethyl-5,7-dihydropyrrolo[3,4-c]pyridazin-3-yl)amino]-6- methoxy-benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile;

[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]- [2-(trifluoromethyl)azetidin-l-yl]methanone; l-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-2-pyridyl]-N-(6- methylpyridazin-3-yl)-6-pyrrolidin-3-yloxy-benzimidazol-5-amine; l-[3-(difluoromethyl)-6-[3-(6-methylpyridazin-3-yl)-2-oxo-lH-imidazo[4,5- f]benzimidazol-7-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[3-(difluoromethyl)-6-[l-(6-methylpyridazin-3-yl)-2-oxo-3H-imidazo[4,5- f]benzimidazol-7-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 6-[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-(difluoromethyl)-2-pyridyl]-6-methoxy- benzimidazol-5-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester; l-[6-[5-(2,6-diazaspiro[3.3]heptan-2-yl)-6-methoxy-benzimidazol-l-yl]-3- (difluoromethyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[5-(difluoromethyl)-6-[l-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]-2-pyridyl]-6-methoxy-N- (6-methylpyridazin-3-yl)benzimidazol-5-amine; l-[3-(difluoromethyl)-6-[5-[[l-[(3R,4R)-4-hydroxy-3-methyl-tetrahydrofuran-3-yl]-4- piperidyl]amino]-6-methoxy-benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile; l-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl]pyrazin-2-yl]-5-methyl-pyrazole-3-carbonitrile; or a pharmaceutically acceptable salt thereof.

14. The compound of formula (I) according to any one of claims 1 to 13, selected from l-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]- 5-methyl-pyrazole-3-carbonitrile; l-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[3-(difluoromethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(ox etan-3- yloxy)benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[3-(difluoromethyl)-6-[5-(7,8-dihydro-5H-pyrano[4,3-c]pyridazin-3-ylamino)-6- methoxy-benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; l-[6-[l-(cyclopropylmethyl)-3 -methyl -pyrazol-4-yl]-5-(difluoromethyl)-2-pyridyl]-6- methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine;

1 -[5-(difluoromethyl)-6-[3-methyl-l -(2, 2, 2-tri fluoroethyl )pyrazol-4-yl]-2-pyridyl]-6- methoxy-N-(6-methylpyridazin-3-yl)benzimidazol-5-amine; l-[5-(difluoromethyl)-6-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-2-pyridyl]-6-methoxy- N-[6-methyl-5-(l-methylazetidin-3-yl)pyridazin-3-yl]benzimidazol-5-amine;

1-[3-(difluoromethyl)-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l- yl]pyrazin-2-yl]-5-methyl-pyrazole-3-carbonitrile;

15. A process for the preparation of a compound according to any one of claims 1 to 14, comprising one of the following steps:

(c) the reaction of a compound of formula (DI) with a compound of formula (D2) in presence of a suitable solvent and in presence of a suitable base; wherein X is halogen, OMs or OTs, in particular halogen; L, R¹, R², R³ R⁴ and R⁵ are as defined in any one of claims 1 to 12.

16. A compound according to any one of claims 1 to 14 when manufactured according to a process of claim 15.

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

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

19. The use of a compound of formula (I) according to any one of claims 1 to 14 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.

20. The use of a compound of formula (I) according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or 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.

21. A compound of formula (I) according to any one of claims 1 to 14 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 .

22. 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 14 or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

23. The invention as hereinbefore described.