New benzimidazole pyridine derivatives

Abstract

The present invention relates to a compound represented by formula (I) TIFF2025503006000162.tif48169 (In the formula, A1, R 1 , R 2 , R 3 , R 4 and R 5 as defined in the specification and claims. The compounds of formula (I) can be used as medicines.

Description

[Technical field]

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

[0002] The present invention relates in particular to a compound of formula (I) [ka] (In the formula, R 1 is hydrogen or alkoxy, R 2 is hydrogen, alkyl, amino, alkylamino, dialkylamino, haloalkyl, haloalkylamino, cycloalkylamino, hydroxy, alkoxy, cycloalkyl, cycloalkyloxy or haloalkoxy; A1 is -O-, -NR 6 - or a bond, R 6 is hydrogen or alkyl, R 3 is alkyl, haloalkyl, hydroxyalkyl, heterocycloalkyl, heteroaryl, phenyl, heteroarylalkyl, phenylalkyl, cycloalkyl, cycloalkylalkyl, (amino)(phenyl)alkyl, (amino)(halophenyl)alkyl or (amino)(heteroaryl)alkyl, and heterocycloalkyl, heteroaryl, phenyl, heteroarylalkyl, phenylalkyl, cycloalkyl and cycloalkylalkyl are R 7 and optionally substituted with 1, 2 or 3 substituents independently selected from Each R 7is independently selected from alkoxy, alkylamino, alkyl, aminocarbonyl, amino, cyano, cycloalkylamino, haloalkyl, halocycloalkyl, halogen, heteroaryl, hydroxycarbonylamino, alkoxyalkyl, alkylaminocarbonyl, alkylsulfonyl, aminocarbonyl, hydroxy, cycloalkylalkyl, haloalkoxy, heterocycloalkyl, and cycloalkyl; R 4 is hydrogen, alkyl, halogen, cyano, haloalkyl, alkoxy, alkoxyalkyl, dialkylaminoalkyl, dialkylamino, alkylamino, alkylaminoalkyl, cycloalkyl, cycloalkylamino, cycloalkyloxy, cycloalkylalkyl, heteroarylalkyl, heteroarylamino, heteroaryloxy, heterocycloalkyl, heterocycloalkylamino, heterocycloalkyloxy or heterocycloalkylalkyl; and cycloalkyl, cycloalkylamino, cycloalkyloxy, cycloalkylalkyl, heteroarylalkyl, heteroarylamino, heteroaryloxy, heterocycloalkyl, heterocycloalkylamino, heterocycloalkyloxy and heterocycloalkylalkyl are each independently selected from R 8 and optionally substituted with 1, 2 or 3 substituents independently selected from Each R 8 is independently selected from alkyl, halogen, cyano, alkylsulfonyl, alkylaminocarbonyl, heterocycloalkyl, and alkoxyheterocycloalkylalkyl; R 5is hydrogen, alkyl, halogen, cyano, haloalkyl, alkoxy, alkoxyalkyl, dialkylaminoalkyl, dialkylamino, alkylamino, alkylaminoalkyl, alkylsulfonyl, cycloalkyl, cycloalkylamino, cycloalkyloxy, cycloalkylalkyl, heteroarylalkyl, heteroarylamino, heteroaryloxy, heterocycloalkyl, heterocycloalkylamino, heterocycloalkyloxy or heterocycloalkylalkyl; and cycloalkyl, cycloalkylamino, cycloalkyloxy, cycloalkylalkyl, heteroarylalkyl, heteroarylamino, heteroaryloxy, heterocycloalkyl, heterocycloalkylamino, heterocycloalkyloxy and heterocycloalkylalkyl are each independently selected from R 9 and optionally substituted with 1, 2 or 3 substituents independently selected from or R 4 and R 5 together with the carbons to which they are attached form a 5- to 7-membered heterocyclic ring optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, cyano, halogen, haloalkyl, alkoxy, heteroaryl, and alkylheteroaryl; Each R 9 is independently selected from alkoxy, halogen, dialkylaminocarbonyl, alkyl, alkoxyalkoxy, alkoxyheterocycloalkylalkyl, alkoxyheterocycloalkylcarbonyl, haloalkyl, haloalkoxy, heterocycloalkylalkoxy, heterocycloalkyl, heterocycloalkyloxy, hydroxy, alkylheterocycloalkyl, alkylheterocycloalkylalkyl, heterocycloalkylalkyl, alkylsulfonyl, (alkyl)heterocycloalkyl, alkylheterocycloalkyloxy, heterocycloalkylheterocycloalkyl, (heterocycloalkyl)heterocycloalkyl, CH3-O-(CH2-CH2-O)7-, alkylaminocarbonyl, and cyano). or a pharma- ceutically acceptable salt thereof.

[0003] Salt-inducible kinases (SIKs) belong to a subfamily of AMP-activated protein kinases (AMPKs) called AMPK-related kinases. Roughly speaking, there are three members, designated SIK1, SIK2, and SIK3. Their primary biological role is to modify gene expression by controlling the phosphorylation and subcellular localization of two important classes of transcriptional regulators: CRTCs (cAMP-regulated transcriptional coactivators) and class IIa HDACs (histone deacetylases). Indeed, under basal conditions, both CRTCs and HDACs are phosphorylated by SIK kinases and sequestered in the cytoplasm via their interaction with the cytoplasmic chaperone 14-3-3. In response to extracellular cues that normally increase intracellular levels of cAMP, the activity of SIK kinases is inhibited and CRTCs and HDACs are no longer phosphorylated and thus released from 14-3-3. Thus, they can translocate into the nucleus and regulate gene expression (reviewed in Wein et al., Trends Endocrinol Metab. 2018 Oct;29(10):723-735).

[0004] In macrophages, inhibition of SIK kinase reduces the transcription of pro-inflammatory cytokines by 1) shuttling CRTC3 to the nucleus and increasing transcription of IL-10, and 2) translocation of HDAC4 / 5 to the nucleus and subsequent deacetylation of NF-κB (Clark et al., Proc Natl Acad Sci USA. 2012 Oct 16;109(42):16986-91.).

[0005] Macrophages are important for maintaining tissue homeostasis, mediating inflammation, and promoting the resolution of inflammation. To achieve this functional diversity, macrophages have the ability to "polarize" differently in response to environmental cues. The two extreme phenotypes along their activation state continuum are "M1" or "pro-inflammatory macrophages" and "M2" or "pro-resolution macrophages."

[0006] Surprisingly, inhibition of intracellular SIK kinase abolishes these extracellular macrophage polarizing signals and pushes them towards a pro-restorative phenotype. This is accompanied by an increase in IL-10 (by disrupting the SIK-CRTC3 pathway) and a concomitant decrease in TNF-α, IL-12 and IL-6 (by disrupting the SIK-HDAC4 / 5 and NF-κB pathways). High levels of IL-10 and low levels of pro-inflammatory cytokines upon SIK inhibition promote the resolution of inflammation. Exploration of the SIK pathway was first described in macrophages (Clark et al., Proc Natl Acad Sci USA. 2012 Oct 16; 109(42): 16986-91) and dendritic cells (Sundberg et al., Proc Natl Acad Sci USA. 2014 Aug 26; 111(34): 12468-73), and the therapeutic potential of pan-SIK inhibitors has been confirmed in mouse LPS (lipopolysaccharide) challenge models (Sundberg et al., ACS Chem Biol. 2016 Aug 19; 11(8): 2105-11) and in colitis models (Fu et al., Inflamm Bowel Dis. 2021 Oct 20; 27(11): 1821-1831). SIK has since been shown to play an important role in the function of several immune cells, including mast cells (Darling et al., J Biol Chem. 2021 Jan-Jun;296:100428). Importantly, SIK1 is poorly expressed in macrophages, and one embodiment of the present invention is a SIK2 / 3 inhibitor that spares SIK1, thus limiting potential SIK1-associated toxicity.

[0007] SIK inhibitors have high therapeutic potential in 1) diseases characterized by the influx of proinflammatory macrophages into tissues and impaired tissue homeostasis and healing, or 2) diseases in which anti-TNF therapy is (partially or completely) beneficial or where IL10 levels are insufficient.Diseases with inflammatory macrophage signatures include, for example, rheumatoid arthritis, juvenile rheumatoid arthritis, NASH, primary sclerosing cholangitis, giant cell vasculitis and inflammatory bowel disease ("IBD"), atherosclerosis, type 2 diabetes, and glomerulonephritis.

[0008] A disease with a proven association with IL-10 and TNF-α is IBD. Genetic alterations that reduce the function of IL-10 (such as SNPs in IL-10 or its receptor) are associated with an increased risk of IBD in humans. Furthermore, although anti-TNF therapy has been successful, 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 (increasing IL-10 and decreasing TNF-α) makes them particularly suitable for the treatment of IBD.

[0009] All three SIK kinase isoforms are widely expressed in human tissues, with highest expression observed in skin and adipose tissue for SIK1, in adipose tissue for SIK2, and in testis and brain for SIK3. Similar to their role in macrophages, SIKs in these cells phosphorylate CRTCs and class II HDCAs in response to extracellular signals, which subsequently alter the expression of several cellular factors.

[0010] In addition to their physiological roles, reports have linked dysregulation of SIK expression to several diseases. For example, SIK2 has been described as a risk locus for primary sclerosing cholangitis, a fibrotic disease commonly associated with IBD. Furthermore, SIK2 and SIK3 expression is higher in ovarian and prostate cancer and correlates with poor survival (Miranda et al., Cancer Cell. 2016 Aug 8; 30(2): 273-289; Bon et al., Mol Cancer Res. 2015 Apr; 13(4): 620-635).

[0011] Today, many diseases caused by dysregulation of the innate immune system lack efficient treatments and there is a high unmet medical need for new therapeutics. Summary of the Invention

[0012] The present invention relates to novel compounds that are highly active SIK inhibitors for the treatment of inflammatory, allergic and autoimmune diseases.Therefore, in addition to inflammatory, allergic and autoimmune diseases, SIK inhibitors can also potentially be related to cancer, metabolic disease, bone density dysregulation disease, pigmentation-related disease or cosmetology, fibrotic disease and depressive disorder.

[0013] As used herein, the term "alkyl", alone or in combination, refers to a straight or branched chain alkyl group having 1 to 8 carbon atoms, particularly a straight or branched chain alkyl group having 1 to 6 carbon atoms, more particularly a straight or branched chain alkyl group having 1 to 4 carbon atoms. Examples of straight and branched chain C1-C8 alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, the isomeric pentyls, isomeric hexyls, isomeric heptyls and isomeric octyls, in particular methyl, ethyl, propyl, butyl and pentyl. Particular examples of alkyl are methyl, ethyl, propyl, isopropyl, butyl and isobutyl. Methyl, ethyl, propyl and butyl, such as isobutyl, are further particular examples of "alkyl" in compounds of formula (I).

[0014] The term "cycloalkyl", alone or in combination, refers to a cycloalkyl ring having 3 to 8 carbon atoms, particularly a cycloalkyl ring having 3 to 6 carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Particular examples of "cycloalkyl" are cyclopropyl and cyclobutyl.

[0015] The term "heterocycloalkyl", alone or in combination, means a monovalent saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system of 4 to 12 ring atoms containing one, two or three ring heteroatoms selected from N, O and S, with the remaining ring atoms being carbon. Bicyclic means consisting of two rings having one or two ring atoms in common. A "heterocycloylalkyl" may contain a carbonyl group, where the carbon of the carbonyl group is part of the ring system. The ring system may be attached to the rest of the compound through an atom selected from C, N, S and O, particularly through an N atom ("N-heterocycloalkyl"). Examples of "heterocycloalkyl" include morpholino, morpholin-4-yl, pyrrolidinyl, pyrrolidin-1-yl, pyrrolidin-3-yl, piperidinyl, 1-piperidyl, 4-piperidyl, 2-oxopyrrolidin-1-yl, piperazinyl, piperazin-1-yl, azetidinyl, azetidin-1-yl, [(1S,5R,7R)-4-oxo-3-oxa-9-azatricyclo[5 30.01, 5]decane-9-yl], [3-oxo-piperazin-1-yl], (1,1-dioxo-1,2-thiazolidine-2-yl), (4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl), (3-oxo-1,5,6,8-tetrahydrooxazolo[3,4-a]pyrazin-7-yl), [rac-(3aR,6aS)-2,3,3a,5,6,6 a-Hexahydro-1H-pyrrolo[3,2-b]pyrrol-4-yl], [rac-(3aS,6aR)-2,3,3a,5,6,6a-Hexahydro-1H-pyrrolo[3,2-b]pyrrol-4-yl], (4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-3-yl), (6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl), (4,7 -diazaspiro[2.5]octan-7-yl), (2-oxa-5,8-diazaspiro[3.5]nonan-8-yl), 3-azabicyclo[3.2.0]heptan-3-yl), (5-azaspiro[2.4]heptan-5-yl), (2-azabicyclo[2.2.1]heptan-2-yl), 4-oxa-7-azaspiro[2.5]octan-7-yl, (3-azabicyclo[3.1.0]Hexan-3-yl, (6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl), 2-oxa-7-azaspiro[3.4]octan-7-yl, (2-oxo-1-piperidyl), (2,3-dihydropyridazino[4,5-b][1,4]oxazin-8-yl), pyrrolidin-1-yl, 2-oxo-pyrimidin-4-yl, morpholinoethyl, 2-oxa-5-azaspiro[3.4]octan-5-yl, oxetan-3-yl, (2-oxo-1-piperidyl), 2-oxo-4-piperidyl These include, but are not limited to, pyrrolidinyl, 5-oxo-pyrrolidin-3-yl, 2-oxa-5-azaspiro[3.4]octan-5-yl, (7,8-dihydro-5H-pyrano[4,3-c]pyridazin-3-yl), [rac-(4aS,7aR)-4-methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-6-yl], and [rac-(3aS,6aS)-6-oxo-2,3,3a,4,5,6a-hexahydropyrrolo[2,3-c]pyrrol-1-yl]. Particular examples of "heterocycloalkyl" are pyrrolidin-1-yl and pyrrolidin-3-yl. In one particular embodiment, heterocycloalkyl is "N-heterocycloalkyl". .

[0016] The term "heteroaryl," alone or in combination, means an aromatic monocyclic or bicyclic ring system having 5 to 12 ring atoms containing 1, 2, 3 or 4 heteroatoms each independently selected from N, O and S, with the remaining ring atoms being carbon. The ring system can be attached to the rest of the compound through an atom selected from C, N, S and O, particularly through an N atom ("N-heteroaryl"). Examples of heteroaryl include pyrazolyl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyridinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridazinyl, pyridazin-3-yl, pyridazin-4-yl, pyrazinyl, pyrazin-2-yl, isoxazolyl, isoxazol-3-yl, isoxazol-4-yl, pyrimidinyl, pyrimidin-5-yl, benzotriazolyl, 1H-benzotriazol-4-yl, furanyl, furyl, 2-furyl, 3-furyl, [6-oxo-1H -pyridazin-5-yl], triazolyl, triazol-1-yl, triazol-2-yl, 2-oxo-4-pyridyl, pyrimidin-2-yl, pyrimidin-5-yl, (1,3,4-oxadiazol-2-yl), (1,3,4-thiadiazol-2-yl), (1,2,4-triazin-3-yl), 2-oxo-pyrimidin-4-yl, (1-methyl-2-oxo-3-pyridyl), and (2,3-dihydropyridazino[4,5-b][1,4]oxazin-8-yl). Particular examples of "heteroaryl" are pyrazol-1-yl, pyrazol-4-yl, pyridazin-3-yl, and pyrimidin-5-yl. In one particular embodiment, heteroaryl is "N-heteroaryl".

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

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

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

[0020] The terms "halogen" or "halo", alone or in combination, mean fluorine, chlorine, bromine or iodine, particularly fluorine, chlorine or bromine, more particularly fluorine. The term "halo", in combination with another group, means substitution of said group with at least one halogen, particularly 1 to 5 halogens, particularly 1 to 4 halogens, i.e. 1, 2, 3 or 4 halogens.

[0021] The term "haloalkyl", alone or in combination, means an alkyl group substituted with at least one halogen, particularly substituted with 1 to 5 halogens, particularly substituted with 1 to 3 halogens, more particularly substituted with 2 to 3 halogens. Particular "haloalkyl" groups are fluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl, difluoromethyl, difluoroethyl, trifluoromethyl, and trifluoroethyl.

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

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

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

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

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

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

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

[0029] R 5When is optionally substituted (pyridazin-3-yl)amino, the compounds of formula (Ia) can exist as tautomers (Ia'), i.e. structural isomers which interconvert with compounds of formula (I), particularly in solution. [ka]

[0030] Other tautomeric forms of compounds of formula (I) may also exist and the corresponding tautomeric forms are intended to be considered as encompassed by compounds of formula (I).

[0031] R 2 Compounds of formula (I), where is hydrogen, alkyl, cycloalkyl or haloalkyl, have a hydrate form (I"), which can be represented as follows: [ka]

[0032] If one of the starting materials or compounds of formula (I) of the present invention contains one or more functional groups that are not stable or are reactive under the reaction conditions of one or more reaction steps, suitable protecting groups (e.g., those described in "Protective Groups in Organic Chemistry" by TW Greene and PG M Huts, 3 rd Protective groups (such as those described in E. Ed., 1999, Wiley, New York) may be introduced before key steps applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature. Examples of protecting groups are tert-butoxycarbonyl (Boc), 9-fluorenylmethylcarbamate (Fmoc), 2-trimethylsilylethylcarbamate (Teoc), carbobenzyloxy (Cbz), and p-methoxybenzyloxycarbonyl (Moz).

[0033] The compounds of formula (I) may contain several asymmetric centers and may exist as optically pure enantiomers, mixtures of enantiomers, e.g. racemates, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.

[0034] The term "asymmetric carbon atom" means a carbon atom that has four different substituents. According to the Cahn-Ingold-Prelog rules, the asymmetric carbon atom can be of the "R" or "S" configuration.

[0035] Furthermore, the present invention includes, where applicable, all optical isomers of the compounds of formula (I), i.e. diastereomers, diastereomeric mixtures, racemic mixtures, all corresponding enantiomers and / or tautomers thereof, and solvates thereof.

[0036] If desired, racemic mixtures of the compounds of the present invention can be separated to isolate the individual enantiomers. Separation can be carried out by methods known in the art, such as coupling a racemic mixture of a compound to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional recrystallization or chromatography.

[0037] In embodiments, when optically pure enantiomers are provided, optically pure enantiomers means that the compound contains more than 90% by weight of the desired isomer, particularly more than 95% by weight of the desired isomer, or more particularly more than 99% by weight of the desired isomer, the weight percentage being based on the total weight of the isomers of the compound. Chirally pure or chirally enriched compounds can be prepared by chiral selective synthesis or by separation of enantiomers. Separation of enantiomers can be carried out on the final product or on a suitable intermediate.

[0038] Additionally, the present invention includes all substituents of the compounds of formula (I) in their corresponding deuterated forms, where applicable.

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

[0040] Certain embodiments of the present invention relate to compounds of formula (I) as described herein, or pharma- ceutically acceptable salts thereof, in which at least one substituent comprises at least one radioisotope. Particular examples of radioisotopes include: 2 H, 3 H, 13 C. 14 C and 18 It's F.

[0041] General synthesis scheme Synthesis of compounds of formula (I) can be accomplished, for example, according to Schemes 1-6 and methods known to those skilled in the art.

[0042] Scheme 1 Scheme 1 describes the synthesis of compounds of formula (Ia). a is alkyl, R a A compound of formula (Ia) is a compound of formula (I) wherein A1 is a bond and R 1 is hydrogen, and R 2 is amino or aminoalkyl, R 3 is R 7 and R is phenyl optionally substituted with 1, 2 or 3 substituents independently selected from 4 is alkoxy, R 5 is alkoxy, and each R 7 is independently selected from alkoxy and halogen.

[0043] Scheme 1 describes the synthesis of compounds of formula (Ib). b is R 7 Compounds of formula (Ib) are compounds of formula (I) wherein A1 is -O- and R 1 is hydrogen, and R 2 is amino and R 3 is R7 and R is phenyl optionally substituted with 1, 2 or 3 substituents independently selected from 4 is alkoxy, R 5 is alkoxy, and each R 7 is independently selected from alkoxy and halogen.

[0044] Scheme 1 describes the synthesis of compounds of formula (Ic). c is R 7 Compounds of formula (Ic) are compounds of formula (I) wherein A1 is -NH- and R 1 is hydrogen, and R 2 is amino and R 3 is R 7 and R is phenyl optionally substituted with 1, 2 or 3 substituents independently selected from 4 is alkoxy, R 5 is alkoxy, and each R 7 is independently selected from alkoxy and halogen. [ka]

[0045] Step A: Ethyl 2,6-dichloronicotinate 1 can be subjected to aromatic nucleophilic substitution with 5,6-dialkoxy-1H-benzo[d]imidazole using a suitable base such as, for example, NaH or DABCO and a suitable solvent such as, for example, DMF at about 0° C. to give intermediate 2.

[0046] Step B: Intermediate 2 can be further converted to 3 using a substituted phenol in a suitable solvent such as DMF in the presence of a suitable base such as Cs2CO3 at about 50°C.

[0047] Step C: The primary amide can then be introduced to give compound Ib by saponification with a suitable base, e.g. KOH, in a suitable solvent (THF, CHCN, MeOH, HO or mixtures thereof), followed by amide coupling with oxalyl chloride and DMF in a suitable solvent, e.g. DCM, and a suitable amine source, e.g. NHOH.

[0048] Step B': Similarly, primary amide 4 can be obtained by saponification with a suitable base, e.g., KOH, in a mixture of solvents (THF, CHCN, MeOH, HO), followed by amide coupling with oxalyl chloride and DMF in a suitable solvent, e.g., DCM, and a suitable amine source, e.g., NHOH.

[0049] Step C': Subsequent coupling of 4 with aniline in ethylene glycol at 160° C. gives compound Ic.

[0050] Step B: Palladium-catalyzed cross-coupling reaction (Suzuki-Miyaura) of 2 with the corresponding arylboronic acid or arylpinacolborane catalyst Pd(PPh3)4pr PdCl2(dppf)CH2Cl2 and a suitable base (e.g., Na2CO3) in a suitable solvent (e.g., DME, 1,4-dioxane and HO) with heating (e.g., MW at 120 °C or 90 °C) provides intermediate 5.

[0051] Step C: Saponification of 5 with a suitable base, for example LiOH, in a suitable solvent, for example THF / MeOH, gives the free carboxylic acid 6.

[0052] Step D: 6 can be coupled with a primary amide in the presence of HATU to give the secondary amide Ia, which upon reaction with thionyl chloride and DMF, followed by conversion with ammonia, gives the corresponding primary amide I-a'.

[0053] Scheme 2 Scheme 2 describes the synthesis of compounds of formula (Id). Compounds of formula (Id) are compounds of formula (I) where A1 is -NH- and R 1 is hydrogen, and R 2 is amino and R 3 is R 7 and R is an arylalkyl or aryl optionally substituted with 1, 2 or 3 substituents independently selected from 4 is alkoxy, R 5 is alkoxy, and each R 7 is independently selected from alkoxy and halogen. [ka]

[0054] Step A: 2,6-dichloronicotinate 7 can be reacted with an alkylamine or benzylamine (?) in a suitable solvent such as, for example, 2-methoxyethanol in the presence of a base such as, for example, TEA at about 80° C. to give intermediate 8.

[0055] Step B: Intermediate 8 can be subjected to aromatic nucleophilic substitution with 5,6-dimethoxy-1H-benzo[d]imidazole 9 in a suitable solvent such as DMSO using a suitable base such as NaHCO3 at about 130°C to give 10.

[0056] Step C: Saponification of the ester group of 10 with a suitable base, for example KOH, in a suitable solvent, for example an EtOH / H2O mixture, gives acid 11.

[0057] Step D: Acid 9 can be converted to the corresponding amide of formula (Id) using, for example, EDCI and HOBt in a suitable solvent, such as DMF at about 50°C.

[0058] Scheme 3 Scheme 3 describes the synthesis of compounds of formula (Ie). Compounds of formula (Ie) are compounds of formula (I) where A1 is a bond and R 1is hydrogen, and R 2 is alkoxy, R 3 is N-heterocycloalkyl, R 4 is alkoxy, R 5 is an alkoxy. [ka]

[0059] Step A: Chlorpyridine derivative 12 can be substituted with saturated N-heterocycle 13 in the presence of a strong base (such as NaH or Cs2CO3 or other carbonates) in a polar solvent (such as DMF, DMA, NMP or DMSO) to give compounds of formula (Ie).

[0060] Scheme 4 Scheme 4 describes the synthesis of a compound of formula (If). Compounds of formula (If) are compounds of formula (I), where A1 is a bond and R 1 is hydrogen, and R 2 is alkoxy, R 3 is N-heterocycloalkyl, R 4 is alkoxy, R 5 is an alkoxy. [ka]

[0061] Step A: Alkyl 2,6-dichloronicotinate 14 can be reacted with cyclic amide 15 in a suitable solvent such as DMF in the presence of a suitable base such as NaH at about 0° C. to provide intermediate 16.

[0062] Step B: Intermediate 16 can be further substituted with 5,6-disubstituted benzimidazole in the presence of a strong base such as NaH in a polar solvent (eg, DMF or DMSO) at about 0° C. to give the intermediate compound of formula (If).

[0063] Scheme 5 Scheme 5 describes the synthesis of a compound of formula (Ig) and its regioisomer (I-g'). A compound of formula (Ig) is a compound of formula (I), where A1 is a bond and R 1 is hydrogen, and R 2 is alkyl or alkoxy, R 3 is R 7 and R is pyrazol-1-yl, optionally substituted with 1, 2 or 3 substituents independently selected from 4 is hydrogen, and R 5 is R 9 (pyridazin-3-yl)amino optionally substituted with 7 is independently selected from alkyl, cyano, haloalkyl, alkoxy, alkylaminocarbonyl, and alkylsulfonyl; R 9 is alkyl. Compounds of formula (I-g') are compounds of formula (I) wherein A1 is a bond and R 1 is hydrogen, and R 2 is alkyl or alkoxy, R 3 is R 7 and R is pyrazol-1-yl, optionally substituted with 1, 2 or 3 substituents independently selected from 4 is R 8 (pyridazin-3-yl)amino optionally substituted with R 5 is hydrogen, and each R 7 is independently selected from alkyl, cyano, haloalkyl, alkoxy, alkylaminocarbonyl, and alkylsulfonyl; R 8 is alkyl. [ka]

[0064] Step A: 1-(6-chloro-2-fluoro-3-pyridyl)alkanone (or a suitable derivative thereof) 17 can be reacted with a substituted pyrazole in the presence of a suitable organic or mineral base (e.g., DIPEA, DBU, K2CO3, Cs2CO3, or NaH) in a polar solvent (e.g., DMF, DMSO, or THF) to give intermediate 18.

[0065] Step B: Intermediate 21 can be obtained by reaction of 5-aminobenzimidazole 19 with 3-chloro-alkylpyridazinyl 20 in a suitable solvent such as iPrOH with heating at reflux.

[0066] Step C: Intermediates 18 and 21 can be combined in a suitable polar solvent (e.g., DMF, DMSO or THF) in the presence of a suitable organic or inorganic base (DIPEA, DBU, K2CO3, Cs2CO3, or NaH) to give regioisomeric compounds of formula (Ig) and (I-g'), which can be separated by flash column chromatography.

[0067] Scheme 6 Scheme 6 describes the synthesis of a compound of formula (Ih) and its regioisomer (I-h'). A compound of formula (Ih) is a compound of formula (I), where A1 is a bond and R 1 is hydrogen, and R 2 is alkyl, R 3 is pyrazol-1-yl optionally substituted with 1, 2 or 3 substituents independently selected from R; 4 is hydrogen, and R 5 is R 9 and each R 7 is independently selected from alkyl, cyano, haloalkyl, alkoxy, alkylaminocarbonyl, and alkylsulfonyl; R 9 is alkyl. Compounds of formula (I-h') are compounds of formula (I) where A1 is a bond and R 1 is hydrogen, and R 2is alkyl or alkoxy, R 3 is R 7 and R is pyrazol-1-yl, optionally substituted with 1, 2 or 3 substituents independently selected from 4 is R 8 R is a heteroarylamino optionally substituted with 5 is hydrogen, and each R 7 is independently selected from alkyl, cyano, haloalkyl, alkoxy, alkylaminocarbonyl, and alkylsulfonyl; R 8 is alkyl. [ka]

[0068] Step A: Regioisomeric intermediates 23 and 24 can be obtained similarly as described in Scheme 10 using intermediate 18 (from Scheme 5) and 5-bromobenzimidazole 22 as the second reagent.

[0069] Step B: The introduction of a heteroarylamino group to obtain compounds of formula (Ih) and regioisomers (I-h') can be carried out via Buchwald-Hartwig coupling. The reaction can be carried out at about 90° C. using a suitable base, such as Cs2CO3 as a palladium catalyst and t-Buxphos-Pd-G3, or at about 80° C. using Cs2CO3 as a base and [tBuBrettPhos Pd(allyl)]OTf as a catalyst. The corresponding regioisomers Ih and I-h' can be separated by either flash chromatography or preparative high pressure liquid chromatography.

[0070] The present invention therefore also relates to a process for the preparation of a compound according to the invention, comprising one of the following steps: (a) reacting a compound represented by formula (B1) or (B2) in the presence of a palladium catalyst and a base: [ka] with an amine, (b) in the presence of a base, [ka] and a compound of formula (C2) [ka] Reaction with compounds of (c) in the presence of a base, [ka] with an amine, or (d) reacting a compound of formula (D1) with a compound of formula (D2) in the presence of a base and a palladium catalyst; reacting with a compound (D2), wherein D2 is selected from (i) an optionally substituted aryl boronic acid or ester, and (ii) an optionally substituted heteroaryl boronic acid or ester; A1, A2, A3, R 1 , R 2 , R 3 , R 4 and R 5 is as defined above, and R a is alkyl or cycloalkyl, R b is hydrogen or alkyl, R c is alkyl or cycloalkyl and X is halogen.

[0071] The amine in step (a) can be an arylamine, heteroarylamine, alkylamine, cycloalkylamine, or heterocycloalkylamine.

[0072] Advantageously, the palladium catalyst in step (a) can be selected from QPhosPd(crotyl)Cl, t-BuXphos-Pd-G3, RuPhos-Pd-G3, [tBuBrettPhos Pd(allyl)]OTf and Pd2(dba)3. Advantageously, the palladium catalyst is t-BuXphos-Pd-G3.

[0073] Advantageously, the base in step (a) may be selected from K3PO4, Na2CO3, K2CO3, Cs2CO3 and KOAc. Advantageously, the base is Cs2CO3.

[0074] Advantageously, the solvent of step (a) may be selected from DMF, DME, DMA, toluene, 1,4-dioxane and H2O, or a mixture thereof. Advantageously, the solvent is 1,4-dioxane.

[0075] Convenient conditions for step (a) are from about 20° C. to about 280° C., particularly from about 40° C. to about 230° C., more particularly from about 60° C. to about 180° C., for 1 to 24 hours, advantageously from 1 to 12 hours.

[0076] In step (a), X is conveniently chloro or bromo, especially bromo.

[0077] Advantageously, the base in step (b) may be selected from DBU, DIPEA, TEA, K3PO4, Na2CO3, NaHCO3, K2CO3, Cs2CO3 and KOAc. Advantageously, the base is NaHCO3 or K2CO3.

[0078] Advantageously, the solvent of step (b) may be selected from DMF, DMSO, IPA, THF, DME, DMA, toluene, 1,4-dioxane and H2O, or mixtures thereof. Advantageously, the solvent is DMSO.

[0079] Advantageously, in step (b), a palladium catalyst can be used together with a suitable base selected from K3PO4, Na2CO3, K2CO3, Cs2CO3 and KOAc. Advantageously, the palladium catalyst can be selected from QPhosPd(crotyl)Cl, t-BuXphos-Pd-G3, RuPhos-Pd-G3, [tBuBrettPhos Pd(allyl)]OTf and Pd2(dba)3.

[0080] Convenient conditions for step (b) are from about -40°C to about 220°C, particularly from about -30°C to about 200°C, more particularly from about -20°C to about 180°C for 1 to 24 hours, advantageously from 1 to 12 hours.

[0081] In step (b), X is conveniently chloro or bromo, especially bromo.

[0082] The amine in step (c) can be an optionally substituted heteroaryl selected from pyrrole, pyrazole and triazole.

[0083] Conveniently, the base in step (c) may be selected from DBU, DIPEA, TEA, K3PO4, Na2CO3, K2CO3, Cs2CO3 and KOAc.

[0084] Conveniently, the solvent in step (c) may be selected from DMF, DMSO, IPA, THF or a mixture thereof.

[0085] Convenient conditions for step (c) are from about -40°C to about 200°C, particularly from about -20°C to about 160°C, more particularly from about 0°C to about 120°C for 1 to 24 hours, advantageously from 1 to 12 hours.

[0086] In step (c), X is conveniently bromo or chloro, especially bromo.

[0087] Conveniently, the base in step (d) may be selected from K3PO4, Na2CO3, K2CO3, Cs2CO3 and KOAc.

[0088] Advantageously, the palladium catalyst in step (d) can be selected from Pd(PPh3)4, Pd2(dba)3, PdCl2(dppf).CH2Cl2 and Pd(OAc)2. Advantageously, the palladium catalyst is Pd(PPh3)4 or PdCl2(dppf).CH2Cl2.

[0089] Conveniently, the solvent in step (d) may be selected from DMF, DME, DMA, toluene, 1,4-dioxane and H2O, or a mixture thereof.

[0090] Convenient conditions for step (d) are from about -20°C to about 220°C, particularly from about 40°C to about 200°C, more particularly from about 60°C to about 180°C for 1 to 24 hours, advantageously from 1 to 12 hours.

[0091] In step (d), X is conveniently chloro and bromo, especially chloro.

[0092] In step (d), the benzene and heteroaryl are preferentially substituted with one, two or three substituents independently selected from halogen, amino, cyano, haloalkyl, halophenyl and heteroaryl.

[0093] The present invention also relates to the compounds according to the invention when produced according to the process of the invention.

[0094] Pharmaceutical Compositions Another embodiment of the present invention provides pharmaceutical compositions or medicaments containing the compounds of the present invention and therapeutically inert carriers, diluents or excipients, as well as methods of using the compounds of the present invention to prepare such compositions and medicaments. In one example, the compounds of formula (I) may be formulated by mixing at ambient temperature with a physiologically acceptable carrier, i.e., a carrier that is not toxic to the recipient at the doses and concentrations used in galenical dosage forms, at an appropriate pH and desired purity. The pH of the formulation will depend primarily on the particular application and the concentration of the compound, but is preferably in the range of about 3 to about 8. In one example, the compounds of formula (I) are formulated in acetate buffer at pH 5. In another embodiment, the compounds of formula (I) are sterile. The compounds may be stored, for example, as solid or amorphous compositions, as lyophilized formulations, or as aqueous solutions.

[0095] The compositions are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to consider in this regard include the particular disorder to be treated, the particular mammal to be treated, the clinical condition of the individual patient, the cause of the disorder, the site of drug delivery, the method of administration, the administration schedule, and other factors known to medical practitioners.

[0096] The compounds of the present invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, epidural and intranasal, and, if desired for localized treatment, intralesional administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.

[0097] The compounds of the present invention may be administered in any convenient dosage form, such as tablets, powders, capsules, liquids, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain conventional ingredients in pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, fillers and additional active agents.

[0098] Typical preparation is prepared by mixing the compound of the present invention with carrier or excipient.Suitable carrier and excipient are well known to those skilled in the art and are described in detail in, for example, Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems.Philadelphia: Lippincott, Williams&Wilkins,2004;Gennaro, Alfonso R., et al.Remington: The Science and Practice of Pharmacy.Philadelphia: Lippincott, Williams&Wilkins,2000;and Rowe, Raymond C.Handbook of Pharmaceutical Excipients.Chicago, Pharmaceutical Press,2005. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricating agents, emulsifying agents, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, flavors, flavorings, diluents, and other known additives to present the drug (i.e., a compound of the invention or a pharmaceutical composition thereof) aesthetically or to aid in the manufacture of a pharmaceutical product (i.e., a drug product).

[0099] Example A Film-coated tablets containing the following ingredients can be manufactured in a conventional manner. [Table 1]

[0100] The active ingredient is sieved and mixed with microcrystalline cellulose, and the mixture is granulated with an aqueous solution of polyvinylpyrrolidone.The granules are then mixed with sodium starch glycolate and magnesium stearate and compressed to obtain kernels of 120 or 350 mg, respectively.The kernels are lacquered with an aqueous solution / suspension of the above film coat.

[0101] Example B Capsules containing the following ingredients may be prepared in a conventional manner. [Table 2]

[0102] The ingredients are sieved, mixed and filled into size 2 capsules.

[0103] Example C The injection solution may have the following composition: [Table 3]

[0104] Dissolve the active ingredient in a mixture of polyethylene glycol 400 and water for injection (parts). Adjust the pH to 5.0 by adding acetic acid. Adjust the volume to 1.0 ml with the remaining amount of water. Filter the solution, fill into vials with appropriate overages and sterilize.

[0105] Experimental procedure Abbreviation: [tBuBrettPhos Pd(allyl)]OTf allyl(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl- 1,1'-biphenyl)palladium(II) triflate (CAS number 1798782-15-6) 2-Me-THF 2-Methyltetrahydrofuran aq.Aqueous solution Boc tert-Butyloxycarbonyl CDI Carbonyldiimidazole DABCO 1,8-diazabicyclo[5.4.0]undec-7-ene DAST Diethylaminosulfur trifluoride dba Dibenzylideneacetone DCM Dichloromethane DIAD Diisopropyl azodicarboxylate DIBAL-H Diisobutylaluminum hydride DIPEA N,N-Diisopropylethylamine DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide dppf 1,1'-ferrocenediyl-bis(diphenylphosphine) dtbbpy 4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine dtbpy 4,4'-di-tert-butyl-2,2'-dipyridyl EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide equivalent (equiv.) equivalent ESI Electrospray Ionization Et Ethyl Et2O Diethyl ether EtOAc Ethyl acetate EtOH Ethanol FA Formic Acid HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazole[4,5-b]pyridinium 3-oxide hexafluorophosphate HMDS Bis(trimethylsilyl)amine HOBt Hydroxybenzotriazole HPLC High Pressure Liquid Chromatography IPA Isopropyl Alcohol Ir[dF(CF3)ppy]2(dtbpy)(PF6) [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate LCMS High Performance Liquid Chromatography LDA Lithium diisopropylamide mCPBA metachloroperoxybenzoic acid Me Methyl MeOH Methanol Ms Methanesulfonyl NPLC Normal Phase Liquid Chromatography PE Petroleum Ether ppy 2-phenylpyridine psi pounds per square inch PTSA Paratoluenesulfonic acid Qphos 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene RT room temperature RuPhos-Pd-G3 (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)] palladium(II) methanesulfonate (CAS number 1445085-77-7) sat. saturation SFC Supercritical Fluid Chromatography sol.solution TBD Triazabicyclodecene TBDMS tert-Butyldimethylsilyl t-BuXphos-Pd-G3 [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (CAS number 1447963-75-8) TEA Triethylamine Tf Trifle TFA Trifluoroacetic acid TFAA Trifluoroacetic anhydride THF Tetrahydrofuran TLC Thin Layer Chromatography

[0106] Example 1 2-(2-Chlorophenoxy)-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide [ka] Step 1: Ethyl 2-chloro-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)nicotinate [ka] To a stirred solution of 5,6-dimethoxy-1H-benzo[d]imidazole (1 g, 5.6 mmol, 1.0 equiv) in DMF (20 mL) at 0° C. was added NaH (60% dispersion in mineral oil) (224 mg, 5.6 mmol, 1.0 equiv), followed by DABCO (628 mg, 5.6 mmol, 1.0 equiv). After stirring at 0° C. for 15 min, ethyl 2,6-dichloronicotinate (1.226 g, 5.6 mmol, 1.0 equiv) was added. Stirring at 0° C. was continued for 2 h. The mixture was poured into ice-cold H2O (100 mL). The precipitated solid was collected by filtration, washed with H2O, and dried at 60° C. for 16 h. The crude title compound (1.46 g, 72% yield) was obtained as a yellow solid. LC-MS: m / z=362 [M+H] + ,ESI pos.

[0107] Step 2: Ethyl 2-(2-chlorophenoxy)-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylate [ka] A stirred mixture of ethyl 2-chloro-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)nicotinate (100 mg, 0.28 mmol, 1.0 equiv), 2-chlorophenol (44 mg, 0.34 mmol, 1.2 equiv) and Cs2CO3 (182 mg, 0.56 mmol, 2.0 equiv) in DMF (2 mL) was heated at 50° C. for 2 h. The reaction mixture was cooled to room temperature, poured into H2O and extracted with EtOAc (3 times). The combined organic layers were washed with H2O (3×) and brine, dried over MgSO4, filtered and concentrated to dryness. The crude title compound (141 mg, quantitative yield) was obtained, which was used in the next step without further purification.

[0108] Step 3: 2-(2-chlorophenoxy)-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide [ka] A mixture of crude ethyl 2-(2-chlorophenoxy)-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylate (141 mg, 0.28 mmol, 1.0 equiv) and KOH (56 mg, 1 mmol, 3.6 equiv) in a mixture of THF / CH3CN / MeOH / H2O 1:1:1:1 (4 mL) was stirred at room temperature for 1 h. AcOH (0.5 mL) was added to the mixture, which was then concentrated in vacuo. The residue was triturated in a mixture of EtOAc and Et2O. The solid was collected by filtration, dried, and suspended in CHCl2 (10 mL). To the reaction mixture was added oxalyl chloride (250 μL) and one drop of DMF. After stirring at room temperature for 1 h, the mixture was cooled to 0° C. and concentrated NH4OH (2 mL) was added dropwise. The mixture was stirred at 0° C. for 30 min and then at room temperature for 1 h. The mixture was filtered and the layers were separated. The aqueous phase was extracted with CH2Cl2 (2x). All the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (SiO2, 5% MeOH in CH2Cl2). The title compound (34 mg, 28.6% yield) was obtained as a white solid. LC-MS: m / z=425 [M+H] + ,ESI pos.

[0109] Example 2 6-(5,6-dimethoxy-benzimidazol-1-yl)-2-phenylamino-nicotinamide [ka] Step 1: 2-Chloro-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide [ka] A mixture of ethyl 2-chloro-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)nicotinate (obtained as in step 1 of Example 1) (250 mg, 0.69 mmol, 1.0 equiv.) and KOH (100 mg, 1.78 mmol, 2.6 equiv.) in a mixture of THF / CH3CN / MeOH / H2O 1:1:1:1 (4 mL) was stirred at RT for 2 h. The reaction mixture was concentrated in vacuo. The residual solid was taken up in CHCl (10 mL). Thionyl chloride (1 mL) and DMF (0.5 mL) were added and the mixture was stirred at reflux for 3 h. The mixture was cooled to RT and concentrated to dryness. The residual solid was suspended in CHCl (10 mL) and concentrated NHOH (1 mL) was added dropwise at 0 °C. After stirring at 0 °C for 1 h, the cooling bath was removed and the mixture was stirred at RT overnight. The mixture was partitioned between EtOAc (25 mL) and H2O (25 mL). The insoluble material was filtered off. The layers in the filtrate were separated. The aqueous phase was extracted with EtOAc (3x). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated in a mixture of EtOAc / hexanes to give a suspension. The solid was collected by filtration and dried to give the crude title compound which was used without further purification.

[0110] Step 2: 2-Anilino-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide [ka] A mixture of crude 2-chloro-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide (75 mg, 0.23 mmol, 1.0 equiv.) and aniline (93 mg, 1 mmol, 1.0 equiv.) in ethylene glycol (1 mL) was stirred at 160° C. for 8 h. The reaction mixture was poured into H2O and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residual dark oil was purified by flash chromatography (SiO2, 10% MeOH in CH2Cl2). The title compound (20 mg, 21.7% yield) was obtained as an orange foam. LC-MS: m / z=390 [M+H] + ,ESI pos.

[0111] Example 3 2-(Benzylamino)-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide [ka] Step 1: Ethyl 2-(benzylamino)-6-chloro-pyridine-3-carboxylate [ka] To a solution of ethyl 2,6-dichloronicotinate (3.3 g, 15 mmol, 1.0 equiv) and NEt3 (1.82 g, 18 mmol, 1.2 equiv) in 2-methoxyethanol (30 mL) was added benzylamine (1.93 g, 18 mmol, 1.2 equiv). The reaction mixture was heated to 80° C. and stirred for 15 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in EtOAc and washed with H2O. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 1% EtOAc in petroleum ether) to give the title compound (3 g, 69% yield). 1H NMR(CDCl3,300MHz):δ 8.43(br s,1H),8.05(d,1H,J=7.8Hz),7.39-7.26(m,5H),6.54(d,1H,J=8.1Hz),4.73(d,2H,J=5.7Hz),4.31(q,2H,J=7.1Hz),1.37(q,3H,J=7.1Hz).

[0112] Step 2: Ethyl 2-(benzylamino)-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylate [ka] To a mixture of ethyl 2-(benzylamino)-6-chloro-pyridine-3-carboxylate (1 g, 3.45 mmol, 1.0 equiv.) and NaHCO3 (0.35 g, 4.14 mmol, 1.2 equiv.) in DMSO (15 mL) was added 5,6-dimethoxy-1H-benzo[d]imidazole (0.74 g, 4.14 mmol, 1.2 equiv.). The reaction mixture was heated to 130° C. and stirring was continued for 20 h. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was diluted with H2O and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (SiO2, 1% MeOH in CH2Cl2) to give the title compound (0.83 g, 55% yield). LC-MS: m / z=433 [M+H] + ,ESI pos.

[0113] Step 3: 2-(benzylamino)-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylic acid [ka]

[0114] Starting from ethyl 2-(benzylamino)-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylate (0.11 g, 0.25 mmol, 1.0 equiv.) and following the procedure described in Step 3 of Example 6, the title compound was obtained (50 mg, 50% yield). Step 4: 2-(benzylamino)-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide [ka] A mixture of 2-(benzylamino)-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylic acid (0.15 g, 0.37 mmol, 1.0 equiv), EDCI (77 mg, 0.41 mmol, 1.1 equiv) and HOBt (55 mg, 0.41 mmol, 1.1 equiv) in DMF (6 mL) was heated to 50° C. and stirred for 1 h. The reaction mixture was cooled to room temperature. Concentrated NH4OH (1 mL) was added and the resulting solution was stirred at room temperature for 3 h. The mixture was poured into H2O to give a suspension. The precipitated solid was collected by filtration, washed with H2O and dried. The title compound (105 mg, 70% yield) was obtained as an off-white solid. LC-MS: m / z=404 [M+H] + ,ESI pos.

[0115] Example 4 2-[[3-amino-1-(3-thienyl)propyl]amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide hydrochloride [ka] Step 1: Ethyl 2-[[3-(tert-butoxycarbonylamino)-1-(3-thienyl)propyl]amino]-6-chloro-pyridine-3-carboxylate [ka] Starting with tert-butyl N-[3-amino-3-(thiophen-3-yl)propyl]carbamate (prepared according to the procedure described on page 30 of WO 2012 / 098068) (1.23 g, 4.8 mmol, 1.2 eq.), the title compound (0.75 g, 43% yield) was obtained according to the procedure described in step 1 of example 3. LC-MS: m / z=440 [M+H] + ,ESI pos.

[0116] Step 2: Ethyl 2-[[3-(tert-butoxycarbonylamino)-1-(3-thienyl)propyl]amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylate [ka] Starting from ethyl 2-[[3-(tert-butoxycarbonylamino)-1-(3-thienyl)propyl]amino]-6-chloro-pyridine-3-carboxylate (0.15 g, 0.34 mmol, 1.0 eq.), the procedure described in step 2 of example 3 was followed to give the title compound (0.16 g, 97.6% yield). LC-MS: m / z=482 [M+H] + ,ESI pos.

[0117] Step 3: 2-[[3-amino-1-(3-thienyl)propyl]amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylic acid hydrochloride [ka] Starting from ethyl 2-[[3-(tert-butoxycarbonylamino)-1-(3-thienyl)propyl]amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylate (0.11 g, 0.23 mmol, 1.0 eq.), the procedure described in step 3 of example 3 was followed to give the title compound (70 mg, 63% yield). LC-MS: m / z=454 [M+H] + ,ESI pos.

[0118] Step 4: 2-[[3-amino-1-(3-thienyl)propyl]amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide hydrochloride [ka] Starting from 2-[[3-amino-1-(3-thienyl)propyl]amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylic acid hydrochloride (70 mg, 0.14 mmol, 1.0 eq.), the procedure described in step 4 of example 3 was followed to give the title compound (30 mg, 44% yield) as a white solid. LC-MS: m / z=453 [M+H] + ,ESI pos.

[0119] Example 5 2-[(3-amino-1-phenyl-propyl)amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide hydrochloride [ka] Step 1: Ethyl 2-[[3-(tert-butoxycarbonylamino)-1-phenyl-propyl]amino]-6-chloro-pyridine-3-carboxylate [ka] Starting with tert-butyl N-(3-amino-3-phenylpropyl)carbamate (prepared according to the procedure described on page 22 of WO 2012 / 098068) (0.9 g, 3.6 mmol, 1.2 eq.), the procedure described in step 1 of example 3 was followed to give the title compound (0.27 g, 21% yield). LC-MS: m / z=434 [M+H] + ,ESI pos.

[0120] Step 2: Ethyl 2-[(3-amino-1-phenyl-propyl)amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylate hydrochloride [ka] Starting from ethyl 2-[[3-(tert-butoxycarbonylamino)-1-phenyl-propyl]amino]-6-chloro-pyridine-3-carboxylate (40 mg, 0.092 mmol, 1.0 eq.), the procedure described in step 2 of example 3 was followed to give the title compound (35 mg, 74% yield). LC-MS: m / z=476 [M+H] + ,ESI pos.

[0121] Step 3: 2-[(3-amino-1-phenyl-propyl)amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylic acid [ka] Starting from ethyl 2-[(3-amino-1-phenyl-propyl)amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylate hydrochloride (190 mg, 0.37 mmol, 1.0 eq.), the title compound (80 mg, 48.3% yield) was obtained according to the procedure described in step 2 of example 17. LC-MS: m / z=448 [M+H] + ,ESI pos.

[0122] Step 4: 2-[(3-amino-1-phenyl-propyl)amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide hydrochloride [ka] Starting from 2-[(3-amino-1-phenyl-propyl)amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylic acid (80 mg, 0.179 mmol, 1.0 eq.), the procedure described in step 4 of example 3 was followed to give the title compound (30 mg, 34.7% yield) as a white solid. LC-MS: m / z=447[M+H] + ,ESI pos.

[0123] Example 6 6-(5,6-dimethoxybenzimidazol-1-yl)-2-(2-phenylethylamino)pyridine-3-carboxamide [ka] Step 1: Ethyl 6-chloro-2-(2-phenylethylamino)pyridine-3-carboxylate [ka] Starting from phenethylamine (0.58 g, 4.8 mmol, 1.2 eq.), the procedure described in step 1 of example 3 was followed to give the title compound (0.9 g, 74% yield). LC-MS: m / z=305 [M+H] + ,ESI pos.

[0124] Step 2: Ethyl 6-(5,6-dimethoxybenzimidazol-1-yl)-2-(2-phenylethylamino)pyridine-3-carboxylate [ka] Starting from ethyl 6-chloro-2-(2-phenylethylamino)pyridine-3-carboxylate (0.85 g, 2.8 mmol, 1.0 eq.), the procedure described in step 2 of example 3 was followed to give the title compound (0.68 g, 54% yield). LC-MS: m / z=447 [M+H] + ,ESI pos.

[0125] Step 3: 6-(5,6-dimethoxybenzimidazol-1-yl)-2-(2-phenylethylamino)pyridine-3-carboxylic acid [ka] To a solution of a mixture of ethyl 6-(5,6-dimethoxybenzimidazol-1-yl)-2-(2-phenylethylamino)pyridine-3-carboxylate (0.22 g, 0.5 mmol, 1.0 equiv.) in EtOH (10 mL) and H2O (1 mL) was added KOH (0.7 g, 12.5 mmol, 25 equiv.). The reaction mixture was heated to reflux and stirred for 30 min. The mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in H2O and the aqueous phase was washed with CHCl. ​​The pH of the aqueous layer was adjusted to about 4-5 with concentrated HCl to give a suspension. The solid was collected by filtration and dried. The title compound (0.15 g, 72% yield) was obtained. LC-MS: m / z=419 [M+H] + ,ESI pos.

[0126] Step 4: 6-(5,6-dimethoxybenzimidazol-1-yl)-2-(2-phenylethylamino)pyridine-3-carboxamide [ka] Starting from 6-(5,6-dimethoxybenzimidazol-1-yl)-2-(2-phenylethylamino)pyridine-3-carboxylic acid (70 mg, 0.167 mmol, 1.0 eq.), the procedure described in step 4 of example 3 was followed to give the title compound (38 mg, 54% yield) as an off-white solid. LC-MS: m / z=418 [M+H] + ,ESI pos.

[0127] Example 7 6-(5,6-dimethoxybenzimidazol-1-yl)-2-(2-thienylmethylamino)pyridine-3-carboxamide [ka] Step 1: Ethyl 6-chloro-2-(2-thienylmethylamino)pyridine-3-carboxylate [ka] Starting from 2-thiophenemethylamine (0.54 g, 4.8 mmol, 1.2 eq.), the procedure described in step 1 of example 3 was followed to give the title compound (0.84 g, 71% yield). LC-MS: m / z=297 [M+H] + ,ESI pos.

[0128] Step 2: Ethyl 6-(5,6-dimethoxybenzimidazol-1-yl)-2-(2-thienylmethylamino)pyridine-3-carboxylate [ka] Starting from ethyl 6-chloro-2-(2-thienylmethylamino)pyridine-3-carboxylate (0.8 g, 2.7 mmol, 1.0 eq.), the procedure described in step 2 of example 3 was followed to give the title compound (0.71 g, 58% yield). LC-MS: m / z=439 [M+H] + ,ESI pos.

[0129] Step 3: 6-(5,6-dimethoxybenzimidazol-1-yl)-2-(2-thienylmethylamino)pyridine-3-carboxylic acid [ka] Starting with ethyl 6-(5,6-dimethoxybenzimidazol-1-yl)-2-(2-thienylmethylamino)pyridine-3-carboxylate (0.35 g, 0.8 mmol, 1.0 eq.), the procedure described in step 3 of example 3 was followed to give the title compound (275 mg, 84% yield). LC-MS: m / z=411 [M+H] + ,ESI pos.

[0130] Step 4: 6-(5,6-dimethoxybenzimidazol-1-yl)-2-(2-thienylmethylamino)pyridine-3-carboxamide [ka] Starting from 6-(5,6-dimethoxybenzimidazol-1-yl)-2-(2-thienylmethylamino)pyridine-3-carboxylic acid (150 mg, 0.36 mmol, 1.0 equiv.), the procedure described in step 4 of example 3 was followed to give the title compound (135 mg, 90% yield) as a white solid. LC-MS: m / z=410 [M+H] + ,ESI pos.

[0131] Example 8 2-[(4-chlorophenyl)methylamino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide [ka] Step 1: Ethyl 6-chloro-2-[(4-chlorophenyl)methylamino]pyridine-3-carboxylate [ka] Starting from 4-chlorobenzylamine (0.68 g, 4.8 mmol, 1.2 eq.), the procedure described in step 1 of example 3 was followed to give the title compound (0.83 g, 64% yield). LC-MS: m / z=325 [M+H] + ,ESI pos.

[0132] Step 2: Ethyl 2-[(4-chlorophenyl)methylamino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylate [ka] Starting from ethyl 6-chloro-2-[(4-chlorophenyl)methylamino]pyridine-3-carboxylate (0.8 g, 2.47 mmol, 1.0 eq.), the procedure described in step 2 of example 3 was followed to give the title compound (0.53 g, 46% yield). LC-MS: m / z=467 [M+H] + ,ESI pos.

[0133] Step 3: 2-[(4-chlorophenyl)methylamino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylic acid [ka] Starting from ethyl 2-[(4-chlorophenyl)methylamino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylate (0.2 g, 0.43 mmol, 1.0 eq.), the procedure described in step 3 of example 3 was followed to give the title compound (155 mg, 82% yield). LC-MS: m / z=439 [M+H] + ,ESI pos.

[0134] Step 4: 2-[(4-chlorophenyl)methylamino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide [ka] Starting from 6-(5,6-dimethoxybenzimidazol-1-yl)-2-(2-thienylmethylamino)pyridine-3-carboxylic acid (100 mg, 0.23 mmol, 1.0 eq.), the procedure described in step 4 of example 3 was followed to give the title compound (65 mg, 65% yield) as a white solid. LC-MS: m / z=438 [M+H] + ,ESI pos.

[0135] Example 9 2-[2-(3-chlorophenyl)ethylamino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide [ka] Step 1: Ethyl 6-chloro-2-[2-(3-chlorophenyl)ethylamino]pyridine-3-carboxylate [ka] Starting from 2-(3-chlorophenyl)ethylamine (0.75 g, 4.8 mmol, 1.2 equiv.) and following the procedure described in Step 1 of Example 3, the title compound (1.1 g, 68% yield) was obtained. 1 H NMR(CDCl3,300MHz):δ 8.14(br s,1H),8.01(d,1H,J=8.1Hz),7.25-7.12(m,4H),6.51(d,1H,J=8.1Hz),4.33-4 .26(m,2H),3.75(q,2H,J=6.7Hz),2.92(t,2H,J=7.0Hz),1.36(t,3H,J=7.1Hz).

[0136] Step 2: Ethyl 2-[2-(3-chlorophenyl)ethylamino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylate [ka] Starting from ethyl 6-chloro-2-[2-(3-chlorophenyl)ethylamino]pyridine-3-carboxylate (1 g, 2.95 mmol, 1.0 eq.), the procedure described in step 2 of example 3 was followed to give the title compound (0.78 g, 50% yield). LC-MS: m / z=481 [M+H] + ,ESI pos.

[0137] Step 3: 2-[2-(3-chlorophenyl)ethylamino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylic acid [ka] Starting from ethyl 2-[2-(3-chlorophenyl)ethylamino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylate (0.2 g, 0.42 mmol, 1.0 eq.), the procedure described in step 3 of example 3 was followed to give the title compound (160 mg, 84% yield). LC-MS: m / z=453 [M+H] + ,ESI pos.

[0138] Step 4: 2-[2-(3-chlorophenyl)ethylamino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide [ka] Starting from 6-(5,6-dimethoxybenzimidazol-1-yl)-2-(2-thienylmethylamino)pyridine-3-carboxylic acid (120 mg, 0.265 mmol, 1.0 equiv.), the procedure described in step 4 of example 3 was followed to give the title compound (105 mg, 87.5% yield) as a white solid. LC-MS: m / z=452 [M+H] + ,ESI pos.

[0139] Example 10 2-[[2-amino-1-(3-chlorophenyl)ethyl]amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide hydrochloride [ka] Step 1: Ethyl 2-[[2-(tert-butoxycarbonylamino)-1-(3-chlorophenyl)ethyl]amino]-6-chloro-pyridine-3-carboxylate [ka] Starting from tert-butyl N-[2-amino-2-(3-chlorophenyl)ethyl]carbamate (1.3 g, 4.8 mmol, 1.2 equiv.), the procedure described in Step 1 of Example 3 was followed to give the title compound (0.68 g, 37.6% yield). 1 H NMR(CDCl3,300MHz):δ 8.64(d,1H,J=7.8Hz),8.03(d,1H,J=8.1Hz),7.36-7.23(m,4H),6.54(d,1H,J=7.8Hz),5.45- 5.38(m,1H),4.78-4.76(m,1H),4.34(q,2H,J=7.0Hz),3.64-3.51(m,2H),1.44-1.36(m,12H).

[0140] Step 2: Ethyl 2-[[2-amino-1-(3-chlorophenyl)ethyl]amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylate hydrochloride [ka] Starting from ethyl 2-[[2-(tert-butoxycarbonylamino)-1-(3-chlorophenyl)ethyl]amino]-6-chloro-pyridine-3-carboxylate (35 mg, 0.077 mmol, 1.0 eq.), the procedure described in step 2 of example 3 was followed to give the title compound (25 mg, 61% yield). LC-MS: m / z=496 [M+H] + ,ESI pos.

[0141] Step 3: 2-[[2-amino-1-(3-chlorophenyl)ethyl]amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylic acid hydrochloride [ka] Starting from ethyl 2-[[2-amino-1-(3-chlorophenyl)ethyl]amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylate hydrochloride (35 mg, 0.066 mmol, 1.0 equiv.), the procedure described in step 3 of example 3 was followed to give the crude title compound (43 mg). LC-MS: m / z=468 [M+H] + ,ESI pos.

[0142] Step 4: 2-[[2-amino-1-(3-chlorophenyl)ethyl]amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide hydrochloride [ka]

[0143] Starting from crude 2-[[2-amino-1-(3-chlorophenyl)ethyl]amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylic acid hydrochloride (43 mg, 0.086 mmol, 1.0 equiv.) and following the procedure described in step 4 of example 3, the title compound (30 mg, 69% yield) was obtained as an off-white solid. LC-MS: m / z=467 [M+H] + ,ESI pos.

[0144] Example 11 2-[[3-amino-1-(3-chlorophenyl)propyl]amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide hydrochloride [ka] Step 1: Ethyl 2-[[3-(tert-butoxycarbonylamino)-1-(3-chlorophenyl)propyl]amino]-6-chloro-pyridine-3-carboxylate [ka] Starting with tert-butyl N-[3-amino-3-(3-chlorophenyl)propyl]carbamate (prepared according to the procedure described on page 24 of WO 2012 / 098068) (1.71 g, 6 mmol, 1.2 eq.), the procedure described in step 1 of example 3 was followed to give the title compound (0.72 g, 31% yield). LC-MS: m / z=468 [M+H] + ,ESI pos.

[0145] Step 2: Ethyl 2-[[3-amino-1-(3-chlorophenyl)propyl]amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylate [ka] Starting from ethyl 2-[[3-(tert-butoxycarbonylamino)-1-(3-chlorophenyl)propyl]amino]-6-chloro-pyridine-3-carboxylate (80 mg, 0.17 mmol, 1.0 eq.), the procedure described in step 2 of example 3 was followed to give the title compound (52 mg, 59.6% yield). LC-MS: m / z=510 [M+H] + ,ESI pos.

[0146] Step 3: 2-[[3-amino-1-(3-chlorophenyl)propyl]amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylic acid hydrochloride [ka] Starting from ethyl 2-[[3-amino-1-(3-chlorophenyl)propyl]amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylate (0.13 g, 0.25 mmol, 1.0 eq.), the procedure described in step 3 of example 3 was followed to give the crude title compound (130 mg, quantitative yield). LC-MS: m / z=482 [M+H] + ,ESI pos.

[0147] Step 4: 2-[[3-amino-1-(3-chlorophenyl)propyl]amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide hydrochloride [ka] Starting from crude 2-[[3-amino-1-(3-chlorophenyl)propyl]amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylic acid hydrochloride (130 mg, 0.25 mmol, 1.0 equiv.), the procedure described in step 4 of example 3 was followed to give the title compound (62 mg, 48% yield). LC-MS: m / z=481 [M+H] + ,ESI pos.

[0148] Example 12 2-[[2-Amino-1-(3-thienyl)ethyl]amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide hydrochloride [ka] Step 1: Ethyl 2-[[2-(tert-butoxycarbonylamino)-1-(3-thienyl)ethyl]amino]-6-chloro-pyridine-3-carboxylate [ka] Starting with tert-butyl N-[2-amino-2-(thiophen-3-yl)ethyl]carbamate (prepared according to the procedure described on page 32 of WO 2012 / 098068) (1.16 g, 4.8 mmol, 1.2 equiv.), the procedure described in step 1 of example 3 was followed to give the title compound (405 mg, 24% yield). 1H NMR(CDCl3,300MHz):δ 8.554(d,1H,J=8.4Hz),8.04(d,1H,J=8.1Hz),7.33-7.30(m,1H),7.25(br s,1H),7.13-7.12(m,1H),6.54(d,1H,J=8.1Hz),5.62-5.56(m,1H),4.86- 4.85(m,1H),4.32(q,2H,J=7.0Hz),3.67-3.57(m,2H),1.39-1.34(m,12H).

[0149] Step 2: Ethyl 2-[[2-amino-1-(3-thienyl)ethyl]amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylate hydrochloride [ka] Starting from ethyl 2-[[2-(tert-butoxycarbonylamino)-1-(3-thienyl)ethyl]amino]-6-chloro-pyridine-3-carboxylate (35 mg, 0.082 mmol, 1.0 eq.), the procedure described in step 2 of example 3 was followed to give the title compound (40 mg, 97% yield). LC-MS: m / z=468 [M+H] + ,ESI pos.

[0150] Step 3: 2-[[2-amino-1-(3-thienyl)ethyl]amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylic acid hydrochloride [ka] Starting from ethyl 2-[[2-amino-1-(3-thienyl)ethyl]amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylate hydrochloride (0.048 g, 0.095 mmol, 1.0 eq.), the procedure described in step 3 of example 3 was followed to give the crude title compound (0.053 g, quantitative yield). LC-MS: m / z=440 [M+H] + ,ESI pos.

[0151] Step 4: 2-[[2-amino-1-(3-thienyl)ethyl]amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide hydrochloride [ka] Starting from crude 2-[[2-amino-1-(3-thienyl)ethyl]amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylic acid hydrochloride (53 mg, 1.11 mmol, 1.0 equiv.) and following the procedure described in step 4 of example 3, the title compound (35 mg, 66.5% yield) was obtained as a white solid. LC-MS: m / z=439 [M+H] + ,ESI pos.

[0152] Example 13 Methyl 2-(3-chlorophenyl)-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)nicotinate [ka] Step 1: Methyl 2-chloro-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)nicotinate [ka] In a 200 mL four-neck flask, a 60% dispersion of NaH in mineral oil (637 mg, 15.9 mmol, 2 equiv.) was combined with DMF (30 mL) to give a grey suspension. The mixture was cooled to 0° C. and 5,6-dimethoxy-1H-benzo[d]imidazole (1.42 g, 7.97 mmol, 1.0 equiv.) was added. The reaction mixture was stirred for 15 min. A solution of methyl 2,6-dichloronicotinate (1.64 g, 7.97 mmol, 1.0 equiv.) in DMF (10 mL) was added dropwise to the reaction mixture and stirring was continued for 15 min. The reaction mixture was quenched with 30 mL of 1 M HCl and a precipitate formed. The suspension was collected by filtration, washed with H2O, and dried under high vacuum. The title compound (1.414 g, 46.9% yield) was obtained as a light brown solid. LC-MS: m / z=348.1 [M+H] + ,ESI pos.

[0153] Step 2: Methyl 2-(3-chlorophenyl)-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)nicotinate [ka] In a microwave vial was added methyl 2-chloro-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)nicotinate (1 g, 2.88 mmol, 1.0 equiv), 2M Na2CO3 (5 mL, 10.1 mmol, 3.5 equiv), 1,2-dimethoxyethane (15 mL), (3-chlorophenyl)boronic acid (674 mg, 4.31 mmol, 1.5 equiv) and Pd(PPh3)4 (332 mg, 288 μmol, 0.1.0 equiv). The vial was capped and heated in a microwave at 120° C. for 20 min. The reaction mixture was cooled to room temperature and diluted with 25 mL of H2O and 25 mL of ethyl acetate. The aqueous phase was back extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 80 g, 0% to 5% MeOH in DCM). The chromatographic product was triturated in acetone, collected by filtration, washed with acetone and dried. The title compound (353 mg, 27.2% yield) was obtained as a light brown solid. LC-MS: m / z=424.2 [M+H] + ,ESI pos.

[0154] Example 14 Methyl 6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(2-oxopiperidin-1-yl)nicotinate [ka] Step 1: Methyl 6-chloro-2-(2-oxopiperidin-1-yl)nicotinate [ka] To a suspension of NaH 60% mineral oil dispersion (208 mg, 5.2 mmol, 1.0 equiv) in dry DMF (31 mL) was added piperidin-2-one (515 mg, 5.2 mmol, 1.0 equiv) and the reaction mixture was stirred at 23° C. for 30 min. The reaction mixture was cooled to 0° C. and methyl 6-chloro-2-fluoronicotinate (986 mg, 5.2 mmol, 1.0 equiv) was added. The cooling bath was removed and the solution was allowed to warm to 23° C. Stirring was continued for 1 h. The reaction mixture was added to ice-cold saturated aqueous NH4Cl (100 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to leave a pale yellow liquid. The crude material was purified by flash chromatography (silica gel, 20 g, 0-80% heptane in EtOAc). The title compound (791 mg, 53.8% yield) was obtained as a pale yellow solid. LC-MS: m / z=269.1[M+H] + ,ESI pos.

[0155] Step 2: Methyl 6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(2-oxopiperidin-1-yl)nicotinate [ka] A suspension of sodium hydride (60% dispersion in mineral oil) (20 mg, 0.5 mmol, 1.0 equiv) in dry DMF (1.9 ml) was cooled to 0° C., 5,6-dimethoxy-1H-benzo[d]imidazole (89.1 mg, 0.5 mmol, 1.0 equiv) was added and the reaction mixture was stirred for 15 min. Methyl 6-chloro-2-(2-oxopiperidin-1-yl)nicotinate (134 mg, 0.5 mmol, 1.0 equiv) was dissolved in dry DMF (600 μl) and the solution was added dropwise. Stirring was continued at 0° C. for 15 min and then allowed to warm to room temperature overnight. The reaction mixture was cooled, diluted with cold saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (silica gel, 0-10% MeOH in DCM) to give the title compound (62.5 mg, 28.9% yield) as an off-white solid. LC-MS: m / z=411.2 [M+H] + ,ESI pos.

[0156] Example 15 Methyl 6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(2-oxopyrrolidin-1-yl)nicotinate [ka] Step 1: Methyl 6-chloro-2-(2-oxopyrrolidin-1-yl)nicotinate [ka] Following the procedure described in step 1 of example 14 using pyrrolidin-2-one (443 mg, 5.2 mmol, 1.0 equiv.), the title compound (744 mg, 53.4% ​​yield) was obtained as an orange liquid. LC-MS: m / z=255.1 [M+H] + ,ESI pos.

[0157] Step 2: Methyl 6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(2-oxopyrrolidin-1-yl)nicotinate [ka] Following the procedure described in Step 2 of Example 14 (reaction time 21 hours at room temperature), the title compound (236 mg, 56.6% yield) was obtained as an off-white solid. LC-MS: m / z=397.2 [M+H] + ,ESI pos.

[0158] Example 16 6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(piperidin-1-yl)nicotinic acid [ka] To a stirred solution of methyl 6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(2-oxopiperidin-1-yl)nicotinate (obtained as in step 2 of Example 14) (62 mg, 0.15 mmol, 1.0 equiv.) in a mixture of dry THF (560 μL) and ethanol (560 μL), calcium chloride (58 mg, 525 μmol, 3.5 equiv.) was added. The reaction mixture was cooled to 0° C. NaBH4 (25 mg, 675 μmol, 4.5 equiv.) was added in one portion and the mixture was stirred for 10 min. The cooling bath was removed and stirring at room temperature was continued for 2 h. The mixture was poured into ice-cold saturated aqueous NH4Cl solution (50 mL), which was extracted with DCM. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to dryness. The crude product was purified by preparative HPLC. The title compound (9.3 mg, 15.4% yield) was obtained as a white solid. LC-MS: m / z=381.2 [MH] - ,ESI neg.

[0159] Example 17 2-(3-cyanophenyl)-6-(5,6-dimethoxybenzimidazol-1-yl)-N-ethyl-pyridine-3-carboxamide; [ka] Step 1: Methyl 2-(3-cyanophenyl)-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylate [ka] Methyl 2-chloro-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylate (obtained similarly to step 1 of Example 1) (2.2 g, 6.33 mmol, 1.0 equiv.), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (1.59 g, 6.96 mmol, 1.1 equiv.), PdCl2(dppf)·CHCl2 (517 mg, 0.630 mmol, 0.1 equiv.) and Na2CO3 (1.34 g, 12.65 mmol, 2 equiv.) were added to a mixture of 1,4-dioxane (20 mL) and H2O (5 mL). The reaction mixture was heated to 80 °C and stirred for 12 h. The mixture was cooled to room temperature, diluted with H2O (100 mL) and EtOAc (100 mL) and stirred for 30 min. The insoluble material was filtered off and the filter cake was washed with 100 mL of EtOAc. The organic layer from the filtrate was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to leave the crude title compound (2.2 g, 83.9% yield) as a dark brown solid. LC-MS: m / z=415.3 [M+H] + ,ESI pos.

[0160] Step 2: 2-(3-cyanophenyl)-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylic acid [ka] To a solution of a mixture of methyl 2-(3-cyanophenyl)-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylate (2.2 g, 5.31 mmol, 1.0 equiv.) in THF (31 mL) and methanol (21 mL) was added 0.5 M lithium hydroxide hydrate in H2O (21.2 mL, 10.62 mmol, 2 equiv.). The mixture was stirred at 20° C. for 12 h and then at 30° C. for 4 h. The pH of the dark reaction mixture was adjusted to 7 by the addition of 1N HCl. The organic solvent was removed under reduced pressure and the remaining aqueous solution was lyophilized to give the title compound (1.75 g, 72.4% yield) as a black solid. LC-MS: m / z=401.0 [M+H] + ,ESI pos.

[0161] Step 3: 2-(3-cyanophenyl)-6-(5,6-dimethoxybenzimidazol-1-yl)-N-ethyl-pyridine-3-carboxamide [ka] To a solution of 2-(3-cyanophenyl)-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylic acid (100 mg, 0.250 mmol, 1 equiv.) in DMF (2 mL) was added ethylamine (0.02 mL, 0.370 mmol, 1.5 equiv.), N,N-diisopropylethylamine (0.130 mL, 0.750 mmol, 3 equiv.) and HATU (140 mg, 0.370 mmol, 1.5 equiv.). The reaction mixture was stirred at 30° C. for 3 h. The reaction mixture was filtered. The filtrate was purified by preparative HPLC (Waters Xbridge C18 (150 mm x 50 mm x 10 μm)). Flow rate: 60 mL / min gradient: 35% to 85% CH3CN in (10 mM NH4HCO3 in water), then 100% CH3CN (4 min)) to give the title compound (25.5 mg, 0.060 mmol, 23.9% yield) as a white solid. LC-MS:m / z=428.2[M+H]+,ESI pos.1H NMR(400MHz,CDCl3)δ=8.45(s,1H),8.20(s,1H),8.16(d,J=8.4Hz,1H),8.07(d,J=8.1Hz,1H),7.93(s,1H),7.80(d,J=7.7Hz,1 H),7.66-7.58(m,2H),7.33(s,1H),5.61(s,1H),3.97(d,J=12.3Hz,6H),3.44-3.35(m,2H),2.02(s,1H),1.09(t,J=7.3Hz,3H).

[0162] Example 18 2-(3-Cyanophenyl)-6-(5,6-dimethoxybenzimidazol-1-yl)-N-methyl-pyridine-3-carboxamide; Formic acid [ka] To a stirred solution of 2-(3-cyanophenyl)-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylic acid (obtained as in step 2 of Example 17) (100 mg, 0.250 mmol, 1.0 equiv.) in DMF (2 mL) was added methylamine hydrochloride (0.04 mL, 0.5 mmol, 2 equiv.), N,N-diisopropylethylamine (0.13 mL, 0.75 mmol, 3.0 equiv.) and HATU (0.14 g, 0.37 mmol, 1.5 equiv.). The reaction mixture was stirred at 30° C. for 12 h. The reaction mixture was purified by preparative HPLC: column Phenomenex Synergi C18 150 mm×25 mm×10 μm). Flow rate 25 mL / min. Direct purification was performed using a gradient: 21% to 41% CH3CN (10 min) in (HO containing 0.225% formic acid v / v), then 100% CH3CN (2 min). The title compound (6.9 mg, 6.3% yield) was obtained as a white lyophilized solid. LC-MS: m / z=414.3 [M+H] + ,ESI pos. 1 H NMR(DMSO-d6,400MHz):δ 9.00(s,1H),8.51(br d,1H,J=4.5Hz),8.39(s,1H),8.26(s,1H),8.1-8.2(m,3H),8.03(d,1H,J=8.2Hz),7.97(d,1H ,J=7.8Hz),7.73(t,1H,J=7.8Hz),7.34(s,1H),3.84(d,6H,J=6.5Hz),2.70(d,3H,J=4.5Hz).

[0163] Example 19 2-(3-Cyanophenyl)-N-cyclopropyl-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide [ka] Starting from 2-(3-cyanophenyl)-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylic acid (obtained as in step 2 of Example 17) (100 mg, 0.25 mmol, 1.0 equiv.) with cyclopropylamine (0.03 mL, 0.37 mmol, 1.5 equiv.), the procedure described in Example 18 was followed to obtain the title compound (20 mg, 7.9% yield) as a white lyophilized solid after purification by preparative HPLC: (column Waters Xbridge (150 mm×25 mm×5 μm) flow rate 25 mL / min gradient: 20% to 50% CH3CN (10 min) then 100% CH3CN (2 min) in H2O with 0.05% ammonium hydroxide v / v). LC-MS: m / z=440.3 [M+H] + ,ESI pos. 1 H NMR(400MHz,DMSO-d6):δ=9.00(s,1H),8.60(d,1H,J=3.9Hz),8.20(s,1H),8.1-8.2(m,1H),8.0-8.1(m,3H),7.98(d,1H,J= 7.6Hz),7.7-7.8(m,1H),7.34(s,1H),3.84(d,6H,J=3.9Hz),2.73(dt,1H,J=3.7,7.3Hz),0.6-0.7(m,2H),0.3-0.4(m,2H).

[0164] Example 20 2-(3-cyanophenyl)-6-(5,6-dimethoxybenzimidazol-1-yl)-N-(2,2,2-trifluoroethyl)pyridine-3-carboxamide [ka] Starting from 2-(3-cyanophenyl)-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylic acid (obtained as in step 2 of example 17) (100 mg, 0.25 mmol, 1.0 equiv.) with 2,2,2-trifluoroethylamine (0.06 mL, 0.5 mmol, 2 equiv.), the procedure described in example 18 (reaction temperature 50° C.) was followed to obtain the title compound (36.5 mg, 28.6% yield) as a white solid after purification by preparative HPLC: column Waters Xbridge (150 mm×25 mm×5 μm), flow rate 25 mL / min gradient: 27% to 57% CH3CN (9.5 min) in H2O with 0.05% ammonium hydroxide v / v, then 100% CH3CN (2 min). LC-MS: m / z=482.2 [M+H] + ,ESI pos. 1 H NMR (400MHz, DMSO-d6): δ=9.28(t,1H,J=6.1Hz),9.02(s,1H),8.1-8.2(m,4H),8.05 (d,1H,J=7.9Hz),7.97(d,1H,J=7.9Hz),7.71(t,1H,J=7.9Hz),7.34(s,1H),4.04(br dd,2H,J=6.6,9.4Hz),3.84(d,6H,J=2.0Hz).

[0165] Example 21 2-(3-cyanophenyl)-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide [ka] Step 1: 2-(3-cyanophenyl)-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carbonyl chloride [ka] A mixture of 2-(3-cyanophenyl)-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxylic acid (obtained as in step 2 of Example 17) (400 mg, 1 mmol, 1.0 equiv.) and thionyl chloride (20 mL) was stirred at 80° C. for 2 h. The yellow suspension was concentrated to dryness to give the crude title compound (400 mg, 76.5% yield) as a yellow solid, which was used in the next step without purification. LC-MS: m / z=415.2 [M+H] + ,ESI pos.

[0166] Step 2: 2-(3-cyanophenyl)-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide [ka] 2-(3-Cyanophenyl)-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carbonyl chloride (100 mg, 0.24 mmol, 1.0 equiv) was added to a stirred, cooled (0° C.) solution of NH3 (41 mg, 2.39 mmol, 10 equiv) in THF (2 mL). The cooling bath was removed and the reaction mixture was stirred at 30° C. for 3 h. The reaction mixture was concentrated to dryness and the residue was purified by preparative HPLC. Column Waters Xbridge (150 mm×25 mm×5 μm). Flow rate 25 mL / min gradient: 15% to 45% CH3CN (10 min) then 100% CH3CN (2 min) in H2O containing 0.05% ammonium hydroxide v / v. The title compound (5.2 mg, 5.2% yield) was obtained as a white lyophilized solid. LC-MS: m / z=400.2 [M+H] + ,ESI pos. 1 H NMR(400MHz,DMSO-d6):δ=9.00(s,1H),8.28(t,1H,J=1.5Hz),8.1-8.2(m,1H),8.1-8.1( m,4H),7.97(td,1H,J=1.3,7.9Hz),7.7-7.8(m,2H),7.33(s,1H),3.84(d,6H,J=5.6Hz).

[0167] Example 22 2-(3-cyano-5-methyl-pyrazol-1-yl)-6-[5-(2-morpholinoethoxy)benzimidazol-1-yl]pyridine-3-carboxamide [ka] Step 1: 4-[2-(4-nitrophenoxy)ethyl]morpholine [ka] To a stirred solution of 4-nitrophenol (5.0 g, 35.94 mmol, 1.0 equiv), 2-morpholinoethanol (5.89 g, 35.94 mmol, 1.0 equiv) and triphenylphosphine (10.37 g, 39.54 mmol, 1.1 equiv) in THF (80 mL) was added dropwise a solution of DEAD (6.89 g, 39.54 mmol, 1.1 equiv) in THF (20 mL) at 0° C. under nitrogen atmosphere. The mixture was then stirred at 30° C. for 16 h. The reaction mixture was poured into H2O (200 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 10% MeOH in EtOAc). The title compound (3.6 g, 39.7% yield) was obtained as an off-white solid. LC-MS: m / z=253.0[M+H] + ,ESI pos. 1 H NMR(400MHz,CD3OD):δ=8.25-8.18(m,2H),7.14-7.08(m,2H),4.27(t,J=5.4Hz,2H),3.75-3.68(m,4H),2.85(t,J=5.5Hz,2H),2.64-2.56(m,4H).

[0168] Step 2: 4-(2-morpholin-4-ylethoxy)aniline [ka] To a solution of 4-[2-(4-nitrophenoxy)ethyl]morpholine (3.5 g, 13.87 mmol, 1.0 equiv) in MeOH (40 mL) was added 10% Pd / C (0.67 g, 0.630 mmol, 0.050 equiv). The mixture was stirred under H2 (15 psi) at 25°C for 16 h. The mixture was filtered and the filtrate was concentrated in vacuo to give the crude title compound (2.7 g, 87.5% yield) as a pale yellow solid. LC-MS: m / z=223.1 [M+H] + ,ESI pos.

[0169] Step 3: N-[4-(2-morpholinoethoxy)phenyl]acetamide [ka] To a stirred solution of 4-(2-morpholin-4-ylethoxy)aniline (2.7 g, 12.15 mmol, 1.0 equiv.) and triethylamine (5.1 mL, 36.44 mmol, 3.0 equiv.) in DCM (30 mL) was added acetic anhydride (1.49 g, 14.58 mmol, 1.2 equiv.) at 0° C. The mixture was then stirred at 25° C. under nitrogen atmosphere for 16 h. The mixture was then poured into H2 (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 50% to 100% EtOAc in petroleum ether). The title compound (2.2 g, 74% yield) was obtained as a white solid. LC-MS: m / z=265.1 [M+H] + ,ESI pos. 1 H NMR(400MHz,CDCl3):δ=7.41-7.36(m,2H),7.17(br s,1H),6.90-6.83(m,2H),4.10(t,J=5.7Hz,2H),3.77-3.73(m,4H),2.81(t,J=5.7Hz,2H),2.62-2.57(m,4H),2.16(s,3H).

[0170] Step 4: N-[4-(2-morpholinoethoxy)-2-nitro-phenyl]acetamide [ka] To a stirred solution of N-[4-(2-morpholinoethoxy)phenyl]acetamide (1.8 g, 6.81 mmol, 1.0 equiv) in acetic anhydride (20 mL, 180.35 mmol, 26.48 equiv) was added nitric acid (2.6 mL, 37.88 mmol, 5.56 equiv) dropwise at 0 °C. The cooling bath was removed and the mixture was stirred at 20 °C for an additional 1 h. The mixture was quenched by careful addition of ice-cold H2O (150 mL). The mixture was then basified by adding 1 N NaOH until pH 9 was reached. It was extracted with EtOAc (4 x 50 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude title compound (1.8 g, 85.4% yield) as a red oil. LC-MS: m / z = 310.1 [M+H] + ,ESI pos.

[0171] Step 5: 4-(2-morpholinoethoxy)-2-nitro-aniline [ka] To a stirred solution of N-[4-(2-morpholinoethoxy)-2-nitro-phenyl]acetamide (1.8 g, 3.23 mmol, 1.0 equiv) in a mixture of EtOH (15 mL) and H2O (5 mL) was added potassium hydroxide (1.63 g, 29.1 mmol, 5 equiv). The mixture was stirred at 80° C. for 4 h. The reaction mixture was cooled to room temperature and poured into H2O (100 mL). It was extracted with EtOAc (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude title compound (1.2 g, 77.1% yield) as a red oil. LC-MS: m / z=268.2 [M+H] + ,ESI pos. 1H NMR (400MHz, CDCl3): δ=7.58(d,J=2.9Hz,1H),7.12-7.07(m,1H),6.76(d,J=9.0Hz,1H ),4.09(t,J=5.6Hz,2H),3.77-3.74(m,4H),2.80(t,J=5.6Hz,2H),2.61-2.57(m,4H).

[0172] Step 6: Methyl 2-chloro-6-[4-(2-morpholinoethoxy)-2-nitro-anilino]pyridine-3-carboxylate [ka] To a solution of methyl 2,6-dichloronicotinate (400 mg, 1.94 mmol, 1.0 equiv) and 4-(2-morpholinoethoxy)-2-nitro-aniline (519 mg, 1.94 mmol, 1.0 equiv) in 1,4-dioxane (10 mL) was added Cs2CO3 (1.9 g, 5.82 mmol, 3.0 equiv) and t-BuXphos-Pd-G3 (CAS number 1447963-75-8) (154 mg, 0.19 mmol, 0.1.0 equiv). The reaction mixture was sparged with N2 and then heated to 100 °C and stirring was continued for 2 h. The mixture was cooled to room temperature, poured into H2O (15 mL) and extracted with EtOAc (3 x 15 ml). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was divided into two equal parts. The first half of the crude material was purified by preparative TLC (silica gel, 10% MeOH in DCM, UV detection) to give the title compound (88 mg, 10.4% yield) as a red solid. The other half of the crude material was purified by preparative HPLC: column Waters Xbridge C18 (150 mm x 50 mm x 10 μm). Flow rate: 60 mL / min gradient: 35% to 85% CH3CN in (10 mM NH4HCO3 in H2O), then 100% CH3CN (4 min). More title compound (78 mg, 9.2% yield) was obtained as a red solid. LC-MS: m / z=437.0 [M+H] + ,ESI pos.

[0173] Step 7: Methyl 6-[2-amino-4-(2-morpholinoethoxy)anilino]-2-chloro-pyridine-3-carboxylate [ka] To a solution of methyl 2-chloro-6-[4-(2-morpholinoethoxy)-2-nitro-anilino]pyridine-3-carboxylate (78.0 mg, 0.180 mmol, 1.0 equiv) in EtOH (1.5 mL) was added Fe (49.85 mg, 0.89 mmol, 5.0 equiv), NH4Cl (95.5 mg, 1.8 mmol, 10 equiv) and water (0.3 mL). The reaction mixture was stirred at 60° C. under nitrogen atmosphere for 12 h. The reaction mixture was concentrated to dryness and 5 mL of 10% MeOH in DCM was added to the residue. The resulting suspension was stirred at 50° C. for 30 min. The mixture was cooled to room temperature and filtered. The filtrate was concentrated to leave the crude material, which was purified by preparative TLC (silica gel, 10% MeOH in DCM, UV detection). The title compound (35 mg, 48.2% yield) was obtained as a yellow oil. LC-MS: m / z=407.0 [M+H] + ,ESI pos.

[0174] Step 8: Methyl 2-chloro-6-[5-(2-morpholinoethoxy)benzimidazol-1-yl]pyridine-3-carboxylate [ka] A solution of methyl 6-[2-amino-4-(2-morpholinoethoxy)anilino]-2-chloro-pyridine-3-carboxylate (50 mg, 0.12 mmol, 1.0 equiv.) in trimethyl orthoformate (260 mg, 2.46 mmol, 20 equiv.) was stirred at 120° C. for 20 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by preparative TLC (silica gel, 80% EtOAc in petroleum ether, UV detection, Rf 0.5). The title compound (20 mg, 39% yield) was obtained as a light brown solid. LC-MS: m / z=407.1 [M+H] + ,ESI pos.

[0175] Step 9: Methyl 2-(3-cyano-5-methyl-pyrazol-1-yl)-6-[5-(2-morpholinoethoxy)benzimidazol-1-yl]pyridine-3-carboxylate [ka] To a solution of methyl 2-chloro-6-[5-(2-morpholinoethoxy)benzimidazol-1-yl]pyridine-3-carboxylate (15 mg, 0.04 mmol, 1.0 equiv.) in DMSO (1.5 mL), 5-methyl-1H-pyrazole-3-carbonitrile (4 mg, 0.04 mmol, 1.0 equiv.) and K2CO3 (10 mg, 0.07 mmol, 2 equiv.) were added. The reaction mixture was stirred at 50 °C for 2 h. The mixture was directly purified by preparative HPLC: column Phenomenex Gemini-NX C18 (75 mm × 30 mm × 3 μm). Flow rate: 25 mL / min. Gradient: 23% to 53% CH3CN in (0.05% NH4OH in H2O v / v) (7 min), then 100% CH3CN (2 min). The title compound (10 mg, 57% yield) was isolated as a colorless oil. LC-MS: m / z=488.1 [M+H] + ,ESI pos. 1 H NMR(400MHz,CDCl3):δ ppm2.46-2.55(m,3H)3.00-3.20(m,2H)3.46-3.59(m,2H)3.60-3.71(m,2H)3.84(s,3H)3.97-4.09(m,2H)4.27-4.41(m,2H)4.65-4 .77(m,2H)6.69(s,1H)7.05-7.15(m,1H)7.36-7.45(m,1H)7.86-7.96(m,1H)8.00-8.09(m,1H)8.49-8.58(m,1H)8.90-9.01(m,1H).

[0176] Step 10: 2-(3-cyano-5-methyl-pyrazol-1-yl)-N-[(2,4-dimethoxyphenyl)methyl]-6-[5-(2-morpholinoethoxy)benzimidazol-1-yl]pyridine-3-carboxamide [ka] To a solution of methyl 2-(3-cyano-5-methyl-pyrazol-1-yl)-6-[5-(2-morpholinoethoxy)benzimidazol-1-yl]pyridine-3-carboxylate (20 mg, 0.04 mmol, 1.0 equiv.) and 2,4-dimethoxybenzylamine (0.01 mL, 0.08 mmol, 2 equiv.) in toluene (2 mL) was added TBD (9 mg, 0.06 mmol, 1.5 equiv.). The mixture was stirred at 100° C. for 16 h. The mixture was cooled to room temperature and concentrated. The residue was purified by preparative TLC (silica gel, 10% MeOH in DCM, Rf 0.45, UV detection). The title compound (9 mg, 35.2% yield) was obtained as a colorless oil. LC-MS: m / z=623.2 [M+H] + ,ESI pos.

[0177] Step 11: 2-(3-cyano-5-methyl-pyrazol-1-yl)-6-[5-(2-morpholinoethoxy)benzimidazol-1-yl]pyridine-3-carboxamide [ka] To a solution of 2-(3-cyano-5-methyl-pyrazol-1-yl)-N-[(2,4-dimethoxyphenyl)methyl]-6-[5-(2-morpholinoethoxy)benzimidazol-1-yl]pyridine-3-carboxamide (9 mg, 0.014 mmol, 1.0 equiv.) in DCM (1 mL) was added TFA (1.0 mL) at 0 °C. The cooling bath was removed and stirring at room temperature was continued for 24 h. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC: column Waters Xbridge C18 (150 mm x 25 mm x 5 μm). Flow rate: 25 mL / min gradient: 16% to 46% CH3CN (9 min) in (10 mM NH4HCO3 in H2O), then 100% CH3CN (0.5 min). The title compound (1.5 mg, 18.7% yield) was obtained as a white lyophilized solid. LC-MS: m / z=473.2 [M+H] + ,ESI pos.1 H NMR(400MHz,METHANOL-d4):δ ppm2.54(s,3H)3.16-3.24(m,2H)3.84-4.00(m,4H)4.44(br s,2H)4.53-4.73(m,4H)6.83(d,J=0.75Hz,1H)7.14-7.22(m,1H)7.41(d,J=2.50Hz, 1H)8.13(d,J=8.38Hz,1H)8.21(d,J=9.01Hz,1H)8.42(d,J=8.38Hz,1H)9.00(s,1H).

[0178] Example 23 2-(2,2-Difluoro-1-methyl-ethoxy)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carboxamide [ka] Step 1: Methyl 6-chloro-2-(2,2-difluoro-1-methyl-ethoxy)pyridine-3-carboxylate [ka] To a solution of 1,1-difluoropropan-2-ol (2.027 g, 15.83 mmol, 1.2 equiv.) in THF (100 mL) was added Cs2CO3 (8.59 g, 26.38 mmol, 2 equiv.) and methyl 6-chloro-2-fluoro-pyridine-3-carboxylate (2.5 g, 13.19 mmol, 1.0 equiv.). The reaction mixture was stirred at 30° C. for 21 h and then concentrated under reduced pressure. H2O (100 mL) was added to the residue, which was extracted with EtOAc (3×100 mL). The combined organic layers were concentrated and the residue was purified by flash chromatography (silica gel, 20% EtOAc in petroleum ether). The title compound (3.75 g, quantitative yield) was obtained as a pale yellow oil. LC-MS: m / z=266.0 [M+H] + ,ESI pos.

[0179] Step 2: 6-Chloro-2-(2,2-difluoro-1-methyl-ethoxy)-N-[(2,4-dimethoxyphenyl)methyl]pyridine-3-carboxamide [ka] To a solution of methyl 6-chloro-2-(2,2-difluoro-1-methyl-ethoxy)pyridine-3-carboxylate (3.4 g, 12.8 mmol, 1.0 equiv.) and 2,4-dimethoxybenzylamine (2.9 mL, 19.2 mmol, 1.5 equiv.) in THF (50 mL) was added TBD (2.14 g, 15.36 mmol, 1.2 equiv.). The reaction mixture was stirred at 30° C. for 16 h and then concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 20% EtOAc in petroleum ether). The title compound (4.136 g, 67.7% yield) was obtained as a white solid. LC-MS: m / z=401.1 [M+H] + ,ESI pos.

[0180] Step 3: 2-(2,2-difluoro-1-methyl-ethoxy)-N-[(2,4-dimethoxyphenyl)methyl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carboxamide and 2-(2,2-difluoro-1-methyl-ethoxy)-N-[(2,4-dimethoxyphenyl)methyl]-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carboxamide [ka]

[0181] Following the procedure described in step 2 of Example 27, the first title compound 2-(2,2-difluoro-1-methyl-ethoxy)-N-[(2,4-dimethoxyphenyl)methyl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carboxamide (77 mg, 24.3% yield) was obtained as a grey solid at 90° C. for 18 hours reaction time. LC-MS: m / z=590.2[M+H] + ,ESI pos.

[0182] 1 H NMR (400MHz, CDCl3): δ=8.80(d,J=8.1Hz,1H),8.57(s,1H),8.06(br t,J=5.4Hz,1H),7.95(d,J=8.8Hz,1H),7.80(d,J=1.9Hz,1H),7.48(dd,J=1.9,8.8Hz,1 H),7.39-7.30(m,2H),7.27-7.23(m,1H),7.19-7.08(m,2H),6.54-6.46(m,2H),6.00(br t,J=55.1Hz,1H),5.75-5.64(m,1H),4.62(d,J=5.6Hz,2H),3.95-3.87(m,3H),3.83(s,3H),2.62(s,3H),1.84(br s,3H),1.56(d,J=6.5Hz,3H).

[0183] Purification by preparative HPLC: column Waters Xbridge (150 mm x 25 mm x 5 μm). Flow rate: 25 mL / min. Gradient: 35% to 60% CH3CN (10 min) in (0.05% ammonium hydroxide in H2O v / v), then purification by 100% CH3CN (2 min).

[0184] The second title compound 2-(2,2-difluoro-1-methyl-ethoxy)-N-[(2,4-dimethoxyphenyl)methyl]-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridazine-3-carboxamide (80 mg, 23.4% yield) was also obtained as a grey solid. LC-MS: m / z=590.2 [M+H] + ,ESI pos.

[0185] 1 H NMR (400MHz, CDCl3): δ=8.68(d,J=8.3Hz,1H),8.65(d,J=1.4Hz,1H),8.38(s,1H),8.04(br t,J=5.4Hz,1H),7.70(d,J=8.6Hz,1H),7.28-7.14(m,3H),7.12-7.01(m,3H),6.89(d,J=9.0Hz,1H),6.44-6.36(m,2H),6.06(br t,J=55.0Hz,1H),5.81-5.69(m,1H),4.53(d,J=5.6Hz,2H),3.79(s,3H),3.74(s,3H),2.52(s,3H),1.40(d,J=6.5Hz,3H).

[0186] Step 4: 2-(2,2-difluoro-1-methyl-ethoxy)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carboxamide [ka] A mixture of TFA (1.0 mL, 13.46 mmol, 103.08 equiv) and 2-(2,2-difluoro-1-methyl-ethoxy)-N-[(2,4-dimethoxyphenyl)methyl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carboxamide (77 mg, 0.13 mmol, 1.0 equiv) was stirred at 50° C. for 2 h.

[0187] The reaction was cooled to room temperature, concentrated under reduced pressure and the residue was purified by preparative HPLC: column Phenomenex Luna C18 (150 mm x 25 mm x 10 μm). Flow rate: 25 mL / min gradient: 6% to 36% CH3CN (10 min) in (0.225% formic acid in H2O v / v), then 100% CH3CN (2 min). The title compound (44.5 mg, 77.5% yield) was obtained as an orange lyophilized solid. LC-MS: m / z=440.1 [M+H] + ,ESI pos. 1H NMR(400MHz,CD3OD):δ=8.90(s,1H),8.60(d,J=8.2Hz,1H),8.20(d,J=1.7Hz,1H),8.13(d,J=8.9Hz,1H),7.66-7.59(m,2H) ),7.49(d,J=9.2Hz,1H),7.27(d,J=9.2Hz,1H),6.41-6.09(m,1H),5.86-5.73(m,1H),2.57(s,3H),1.60(d,J=6.6Hz,3H).

[0188] Example 24 2-(2,2-Difluoro-1-methyl-ethoxy)-N-[(2,4-dimethoxyphenyl)methyl]-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carboxamide [ka] Starting from 2-(2,2-difluoro-1-methyl-ethoxy)-N-[(2,4-dimethoxyphenyl)methyl]-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carboxylate (80 mg, 0.14 mmol, 1.0 equiv.) and following the procedure described in step 4 of Example 23, the title compound (25.3 mg, 40.3% yield) was obtained after purification by preparative HPLC: column Phenomenex Luna C18 (150 mm×25 mm×10 μm). Flow rate: 25 mL / min gradient: 6% to 36% CH3CN (10 min) in (0.225% formic acid in H2O v / v), then 100% CH3CN (2 min) as an orange lyophilized solid. LC-MS: m / z=440.1 [M+H] + ,ESI pos. 1H NMR(400MHz,METHANOL-d4):δ=9.18(d,J=1.9Hz,1H),8.79(s,1H),8.62(d,J=8.1Hz,1H),7.63(dd,J=8.4,16.3Hz,2H),7.37(d,J=9.1Hz,1H), 7.25(dd,J=1.9,8.7Hz,1H),7.13(d,J=9.1Hz,1H),6.45-6.13(m,1H),5.89(ddt,J=2.0,6.4,12.3Hz,1H),2.54(s,3H),1.48(d,J=6.5Hz,3H).

[0189] Example 25 2-(3-cyano-5-methyl-pyrazol-1-yl)-6-[5-[[(3S,4R)-4-fluoropyrrolidin-3-yl]amino]benzimidazol-1-yl]pyridine-3-carboxamide; Formic acid [ka] Step 1: Methyl 6-chloro-2-(3-cyano-5-methyl-pyrazol-1-yl)pyridine-3-carboxylate [ka] A solution of methyl 6-chloro-2-fluoro-pyridine-3-carboxylate (1.0 g, 5.28 mmol, 1.0 equiv), 5-methyl-1H-pyrazole-3-carbonitrile (509 mg, 4.75 mmol, 0.9 equiv) and DIPEA (2.6 mL, 15.83 mmol, 3.0 equiv) in DMSO (15 mL) was stirred at 30° C. for 16 h. The reaction mixture was concentrated under vacuum. The residue was purified by preparative HPLC: column Waters Xbridge (150 mm×25 mm×5 μm). Flow rate: 25 mL / min gradient: 41% to 71% CH3CN in (0.05% NH4OH in H2O v / v) (10 min), then 100% CH3CN (2 min). The title compound (700 mg, 48% yield) was obtained as a white solid. LC-MS: m / z=276.9[M+H] + ,ESI pos. 1H NMR (400MHz, CDCl3): δ=8.20(d,J=8.1Hz,1H),7.54(d,J=8.1Hz,1H),6.60(s,1H),3.79(s,3H),2.51(s,3H).

[0190] Step 2: Methyl 6-(5-bromobenzimidazol-1-yl)-2-(3-cyano-5-methyl-pyrazol-1-yl)pyridine-3-carboxylate [ka] To a solution of methyl 6-chloro-2-(3-cyano-5-methyl-pyrazol-1-yl)pyridine-3-carboxylate (700 mg, 2.53 mmol, 1.0 equiv.) in DMSO (7 mL) was added 5-bromo-1H-benzimidazole (499 mg, 2.53 mmol, 1.0 equiv.) and K2CO3 (699 mg, 5.06 mmol, 2 equiv.). The reaction mixture was stirred at 30 °C for 2 h and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC: column Phenomenex Luna C18 (150 mm x 25 mm x 10 μm). Flow rate: 25 mL / min Gradient: 53% to 83% CH3CN (10 min) in (0.225% formic acid in H2O v / v), then 100% CH3CN (2 min). The title compound (200 mg, 18.1% yield) was obtained as a white lyophilized solid. LC-MS: m / z=439.0 [M+H] + ,ESI pos.

[0191] 1 H NMR (400MHz, CDCl3): δ=9.17(br s,1H),8.56(d,J=8.2Hz,1H),8.10(d,J=1.5Hz,1H),8.03(d,J=8.8Hz,1H),7.98(br d,J=8.4Hz,1H),7.59(dd,J=1.7,8.8Hz,1H),6.68(s,1H),3.83(s,3H),2.51(s,3H).

[0192] Step 3: Methyl 2-(3-cyano-5-methyl-pyrazol-1-yl)-6-[5-[[(3S,4R)-1-tert-butoxycarbonyl-4-fluoro-pyrrolidin-3-yl]amino]benzimidazol-1-yl]pyridine-3-carboxylate [ka] To a solution of methyl 6-(5-bromobenzimidazol-1-yl)-2-(3-cyano-5-methyl-pyrazol-1-yl)pyridine-3-carboxylate (190.0 mg, 0.430 mmol, 1.0 equiv.) in 1,4-dioxane (6 mL) was added tert-butyl (3S,4R)-3-amino-4-fluoropyrrolidine-1-carboxylate (106 mg, 0.52 mmol, 1.2 equiv.), Cs2CO3 (424.7 mg, 1.3 mmol, 3.0 equiv.) and t-Buxphos-Pd-G3 (34.5 mg, 0.040 mmol, 0.10 equiv.). The grey suspension was then stirred at 100° C. under a nitrogen atmosphere for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. After purification by preparative TLC (silica gel, 10% MeOH in DCM, UV detection), the title compound (70 mg, 28.8% yield) was obtained as a yellow oil. LC-MS: m / z=561.3 [M+H] + ,ESI pos.

[0193] Step 4: tert-Butyl (3S,4R)-3-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-[(2,4-dimethoxyphenyl)methylcarbamoyl]-2-pyridyl]benzimidazol-5-yl]amino]-4-fluoro-pyrrolidine-1-carboxylate [ka] Following the procedure described in step 2 of Example 23, using a reaction time of 12 h at 50° C., the title compound (40 mg, 64.5% yield) was obtained as a yellow oil after purification by preparative TLC (silica gel, 10% MeOH in DCM, UV detection). LC-MS: m / z=696.3 [M+H]+ ,ESI pos.

[0194] Step 5: 2-(3-cyano-5-methyl-pyrazol-1-yl)-6-[5-[[(3S,4R)-4-fluoropyrrolidin-3-yl]amino]benzimidazol-1-yl]pyridine-3-carboxamide; formic acid [ka] A solution of tert-butyl (3S,4R)-3-[[1-[6-(3-cyano-5-methyl-pyrazol-1-yl)-5-[(2,4-dimethoxyphenyl)methylcarbamoyl]-2-pyridyl]benzimidazol-5-yl]amino]-4-fluoro-pyrrolidine-1-carboxylate (30 mg, 0.04 mmol, 1.0 equiv.) in TFA (0.5 mL) was stirred at 70 °C for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC: column Phenomenex Luna C18 (150 mm × 25 mm × 10 μm). Flow rate: 25 mL / min Gradient: 1% to 30% CH3CN (10 min) in (0.225% formic acid in H2O v / v), then 100% CH3CN (2 min). The title compound (15.6 mg, 69.4% yield) was obtained as a white lyophilized solid. LC-MS: m / z=446.1 [M+H] + ,ESI pos.

[0195] 1 H NMR(400MHz,METHANOL-d4):δ=8.88(s,1H),8.49(br s,1H),8.37(d,J=8.5Hz,1H),8.07(br d,J=8.4Hz,1H),8.05(br d,J=9.0Hz,1H),7.09(d,J=2.3Hz,1H),6.95(dd,J=2.3,9.0Hz,1H),6.81(s,1H),5.28(br s,1H),4.48-4.30(m,1H),3.75-3.69(m,1H),3.66(s,1H),3.59(br d,J=5.9Hz,1H),3.15(t,J=11.0Hz,1H),2.52(s,3H).

[0196] Example 26 Methyl 2-(3-methoxy-5-methyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carboxylate [ka] Step 1: Methyl 6-chloro-2-(3-methoxy-5-methyl-pyrazol-1-yl)pyridine-3-carboxylate [ka] Prepared as in Example 27, step 1 using methyl 6-chloro-2-fluoro-pyridine-3-carboxylate (1.0 g, 5.28 mmol, 1.0 equiv) and 3-methoxy-5-methyl-1H-pyrazole (600.0 mg, 5.35 mmol, 1.0 equiv) to give methyl 6-chloro-2-(3-methoxy-5-methyl-pyrazol-1-yl)pyridine-3-carboxylate (1.4 g, 4.97 mmol, 94.2% yield) as a white solid. LC-MS: m / z=282.2 [M+H] + ,ESI pos.

[0197] Step 2: Methyl 2-(3-methoxy-5-methyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carboxylate and Methyl 2-(3-methoxy-5-methyl-pyrazol-1-yl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carboxylate [ka] Prepared similarly to Example 27, step 2, using N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine (0.92 g, 4.07 mmol, 1.04 equiv., prepared in Example 27, intermediate 1), methyl 6-chloro-2-(3-methoxy-5-methyl-pyrazol-1-yl)pyridine-3-carboxylate (1.1 g, 3.91 mmol, 1.0 equiv.) and KCO (1.65 g, 11.94 mmol, 3.1.0 equiv.). Methyl 2-(3-methoxy-5-methyl-pyrazol-1-yl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carboxylate (370 mg, 0.79 mmol, 20.1% yield) and methyl 2-(3-methoxy-5-methyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carboxylate (350 mg, 0.74 mmol, 18.1% yield) were obtained as pale yellow solids. LC-MS: m / z=471.1 [M+H] + ,ESI pos.

[0198] Example 27 1-[3-Acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Intermediate 1: N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine [ka] iA mixture of 5-aminobenzimidazole (8.0 g, 60.1 mmol, 1.0 equiv) and 3-chloro-6-methylpyridazine (7.34 g, 57.08 mmol, 0.950 equiv) in PrOH (120 mL) was stirred at 120° C. for 72 h. The dark brown suspension was concentrated in vacuo and the residue was triturated in MeOH (60 mL). The solid was collected by filtration and triturated in DCM (40 mL). The product was collected by filtration, washed with DCM and dried. The title compound (10 g, 71.3% yield) was obtained as a brown solid. LC-MS: m / z=226.0 [M+H] + ,ESI pos. 1 H NMR(400MHz,DMSO-d6):δ=9.60(br s,1H),8.72(s,1H),8.52(d,J=1.7Hz,1H),7.63(d,J=8.8Hz,1H),7.44(dd,J=2.0,8.8 Hz,1H),7.39(d,J=9.2Hz,1H),7.21(d,J=9.2Hz,1H),5.04-4.15(m,1H),2.49(s,3H).

[0199] Step 1: 1-(3-acetyl-6-chloro-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile [ka] A solution of 1-(6-chloro-2-fluoro-3-pyridyl)ethanone (5 g, 28.81 mmol, 1.0 equiv), 5-methyl-1H-pyrazole-3-carbonitrile (2.93 g, 27.37 mmol, 0.950 equiv) and DIPEA (14.3 mL, 86.42 mmol, 3 equiv) in DMSO (50 mL) was stirred at 80 °C for 4 h. The reaction mixture was cooled to room temperature, poured into H2O (250 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (3 x 300 mL) and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0% to 35% EtOAc in petroleum ether). The title compound (5.3 g, 70.6% yield) was obtained as a yellow oil. LC-MS: m / z = 261.1 [M + H] +,ESI pos.

[0200] Step 2: 1-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile and 1-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] A mixture of 1-(3-acetyl-6-chloro-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile (5.3 g, 20.33 mmol, 1.0 equiv), N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine (Intermediate 1) (4.58 g, 20.33 mmol, 1.0 equiv) and K2CO3 (5.62 g, 40.66 mmol, 2 equiv) in DMSO (50 mL) was stirred at 50 °C for 12 h. The mixture was cooled to room temperature and poured into H2O (500 mL). A white solid precipitated out. It was extracted with EtOAc (3 x 400 mL). The combined organic layers were concentrated. The residue was purified by preparative HPLC: column Phenomenex Luna C18 (250 mm x 70 mm x 15 μm. Flow rate 140 mL / min gradient: 20% to 50% CH3CN (35 min) in (HO containing 0.225% formic acid v / v), then 100% CH3CN (1 min). A mixture of the two title compounds was obtained. This mixture was purified by preparative NPLC: column Welch Ultimate XB-SiOH (250 mm x 70 mm x 10 um). Flow rate 140 mL / min gradient: 20% to 60% EtOH in hexane (20 min), then 100% EtOH (3 min).

[0201] The first title compound 1-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (1100 mg, 12% yield) was obtained as a light brown solid. LC-MS: m / z=450.1[M+H]+ ,ESI pos. 1 H NMR(400MHz,DMSO-d6)δ=9.31(s,1H),9.01(s,1H),8.98(d,J=2.0Hz,1H),8.55(d,J=8.4Hz,1H),8.27(d,J=8.4Hz,1H ),7.70(d,J=8.7Hz,1H),7.46(dd,J=2.0,8.7Hz,1H),7.30(d,J=9.0Hz,1H),7.09-7.04(m,2H),2.55(s,3H),2.50(br s,3H),2.19(s,3H).

[0202] The second title compound 1-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (600 mg, 6.6% yield) was obtained as a light brown solid. LC-MS: m / z=450.1 [M+H] + ,ESI pos. 1 H NMR(400MHz,DMSO-d6)δ=9.30(s,1H),9.11(s,1H),8.54(d,J=8.4Hz,1H),8.47(d,J=1.7Hz,1H),8.30(d,J=8.6Hz,1H),8.14( d,J=8.9Hz,1H),7.53(dd,J=1.9,8.9Hz,1H),7.34(d,J=9.0Hz,1H),7.14(s,1H),7.10(d,J=9.0Hz,1H),2.54(s,3H),2.48(br s,3H),2.20(s,3H).

[0203] Example 28 1-[3-Acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] 1-[3-Acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile was obtained in Example 27, step 2. LC-MS: m / z=450.2 [M+H] + ,ESI pos.

[0204] Example 29 1-[2,4-Dimethoxy-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone [ka] 1-[2,4-Dimethoxy-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone was prepared according to the methods described herein and known to those skilled in the art. LC-MS: m / z=405.2 [M+H] + ,ESI pos.

[0205] Example 30 1-[3-Acetyl-6-(6,7-dihydro-5H-pyrrolo[3,2-f]benzimidazol-3-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] 1-[3-Acetyl-6-(6,7-dihydro-5H-pyrrolo[3,2-f]benzimidazol-3-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile was synthesized according to the method described herein using intermediate 18 and 3,5,6,7-tetrahydropyrrolo[3,2-f]benzimidazole (CAS: 28996-22-7). LC-MS: m / z=384.2=[M+H]+, ESI pos.

[0206] Example 31 1-[3-Acetyl-6-(6,7-dihydro-5H-pyrrolo[2,3-f]benzimidazol-1-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] 1-[3-Acetyl-6-(6,7-dihydro-5H-pyrrolo[3,2-f]benzimidazol-3-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile was synthesized according to the method described herein using intermediate 18 and 3,5,6,7-tetrahydropyrrolo[3,2-f]benzimidazole (CAS: 28996-22-7). LC-MS: m / z=384.2=[M+H]+, ESI pos.

[0207] Example 32 (3R,5S)-1-[3-formyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrrolidine-3-carbonitrile [ka] Step 1: tert-Butyl (2S,4S)-2-methyl-4-methylsulfonyloxy-pyrrolidine-1-carboxylate [ka] To a solution of tert-butyl (2R,4R)-4-hydroxy-2-methyl-pyrrolidine-1-carboxylate (1.0 g, 4.97 mmol, 1.0 equiv.) and TEA (2.5 g, 24.9 mmol, 5.0 equiv.) in DCM (10 mL) was added MsCl (0.78 mL, 9.95 mmol, 2.0 equiv.) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 3 h. TLC (PE / EA=1 / 1, ninhydrin) showed that tert-butyl (2R,4R)-4-hydroxy-2-methyl-pyrrolidine-1-carboxylate was completely consumed and a new spot was formed. The mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4 and the volatiles were evaporated. The residue was purified by flash column chromatography (10-50% EtOAc in PE) to give tert-butyl rac-(2R,4R)-2-methyl-4-methylsulfonyloxy-pyrrolidine-1-carboxylate (1410 mg, 5.05 mmol, 96.5% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ=5.21-5.15(m,1H),4.06-3.71(m,2H),3.56(br d,J=10.4Hz,1H),3.03(s,3H),2.45(br d,J=1.6Hz,1H),1.90-1.81(m,1H),1.47(s,9H),1.30-1.26(m,3H).

[0208] Step 2: tert-Butyl (2S,4R)-4-cyano-2-methyl-pyrrolidine-1-carboxylate [ka] To a mixture of tert-butyl (2S,4S)-2-methyl-4-methylsulfonyloxy-pyrrolidine-1-carboxylate (1.4 g, 5.0 mmol, 1.0 equiv.) in DMSO (15 mL) was added sodium cyanide (0.98 g, 20.0 mmol, 4.0 equiv.). The mixture was stirred at 80 °C for 16 h. The mixture was poured into aqueous solution. Saturated NaHCO3 was added and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and the volatiles were evaporated. The residue was purified by column chromatography (10-50% EtOAc in PE) to give tert-butyl (2S,4R)-4-cyano-2-methyl-pyrrolidine-1-carboxylate (805 mg, 3.83 mmol, 72.6% yield) as a colorless oil. LC-MS: m / z=155.1 [M-56+H] + ESI pos. 1 H NMR(400MHz,CDCl3)δ=5.21-5.15(m,1H),4.06-3.71(m,2H),3.56(br d,J=10.4Hz,1H),3.03(s,3H),2.45(br d,J=1.7Hz,1H),1.90-1.81(m,1H),1.47(s,9H),1.30-1.26(m,3H).

[0209] (NaCN post-treatment: KOH aqueous solution (1M) was added to the combined aqueous phase until the pH was about 12. The mixture was then poured into NaClO aqueous solution (5%, 1500 mL), left overnight, and detected by the analytical department, recycled by a special recycling bucket.)

[0210] Step 3: (3R,5S)-5-Methylpyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid [ka] To a solution of tert-butyl (2S,4R)-4-cyano-2-methyl-pyrrolidine-1-carboxylate (1.5 g, 7.13 mmol, 1.0 equiv) in DCM (10 mL) was added TFA (10.0 mL, 123.25 mmol, 17.3 equiv). The mixture was stirred at 25° C. for 2 h. The mixture was concentrated in vacuo to give (3R,5S)-5-methylpyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid as a light brown oil. The crude product was used in the next step without further purification. 1 H NMR(400MHz,DMSO-d6)δ=3.63-3.43(m,4H),2.60-2.52(m,1H),1.86-1.76(m,1H),1.32(d,J=6.5Hz,3H).

[0211] Step 4: (3R,5S)-1-(6-chloro-3-formyl-2-pyridyl)-5-methyl-pyrrolidine-3-carbonitrile [ka] A solution of (3R,5S)-5-methylpyrrolidine-3-carbonitrile; 2,2,2-trifluoroacetic acid (used as crude product from previous step) and DIPEA (6.18 mL, 37.37 mmol, 5.59 equiv.) in DMSO (20 mL) was stirred at room temperature for 5 min. Then, 6-chloro-2-fluoro-pyridine-3-carbaldehyde (CAS number 1093880-37-5, 7.05 mmol, 1.05 equiv.) was added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-25% EtOAc in PE) to give (3R,5S)-1-(6-chloro-3-formyl-2-pyridyl)-5-methyl-pyrrolidine-3-carbonitrile.

[0212] Step 5: Mixture of (3R,5S)-1-[3-formyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrrolidine-3-carbonitrile and (3R,5S)-1-[3-formyl-6-[-5[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrrolidine-3-carbonitrile [ka] A mixture of (3R,5S)-1-(6-chloro-3-formyl-2-pyridyl)-5-methyl-pyrrolidine-3-carbonitrile (1.0 equiv.), N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine (Intermediate 1) (1.0 equiv.) and K2CO3 (2 equiv.) in DMSO (50 mL) was stirred at 50° C. for 12 h. The mixture was cooled to room temperature and poured into H2O (500 mL). A solid precipitated out. It was extracted with EtOAc (3×400 mL). The combined organic layers were concentrated. Purification by preparative HPLC (Phenomenex Luna C18 250 mm x 50 mm x 10 μm, gradient 5-40% CH3CN (with 0.1% TFA) in H2O, 20 min, then 100% CH3CN (2 min), flow rate 100 mL / min) gives (3R,5S)-1-[3-formyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrrolidine-3-carbonitrile and (3R,5S)-1-[3-formyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrrolidine-3-carbonitrile. LC-MS: m / z=439.2[M+H]+ESI pos.

[0213] Example 33 (3R,5S)-1-[3-formyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrrolidine-3-carbonitrile [ka] (3R,5S)-1-[3-formyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrrolidine-3-carbonitrile was synthesized according to the procedure described for Example 32. LC-MS: m / z=439.2[M+H]+ESI pos.

[0214] Example 34 5-Methyl-1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-(2,2,2-trifluoroacetyl)-2-pyridyl]pyrazole-3-carbonitrile [ka] Step 1: 1-(6-chloro-2-fluoro-3-pyridyl)-2,2,2-trifluoro-ethanone [ka] LDA (4.56 mL, 9.12 mmol, 1.2 equiv) in THF (20 mL) was added dropwise to a solution of 2-chloro-6-fluoropyridine (1.0 g, 7.6 mmol, 1.0 equiv) at -70 °C. A yellow suspension formed. The mixture was stirred at -70 °C for 1 h, then N-methoxy-N-methyltrifluoroacetamide (1.26 g, 7.99 mmol, 1.05 equiv) was added dropwise. After addition, the clear yellow solution was stirred at -70 °C for 1 h. The mixture was quenched with 100 mL of saturated aqueous NH4Cl, extracted with EtOAc, and the organic layer was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 25% EtOAc in PE) to give 1-(6-chloro-2-fluoro-3-pyridyl)-2,2,2-trifluoro-ethanone (600 mg, 2.64 mmol, 34.7% yield) as a light brown oil. LC-MS: m / z=246.1 [M+H2O+H] + ,ESI pos.

[0215] Step 2: 1-[6-chloro-3-(2,2,2-trifluoroacetyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] To a mixture of 1-(6-chloro-2-fluoro-3-pyridyl)-2,2,2-trifluoro-ethanone (6.2 g, 27.25 mmol, 1.0 equiv) and 5-methyl-1H-pyrazole-3-carbonitrile (2.91 g, 27.21 mmol, 1.0 equiv) in DMSO (50 mL) was added DIPEA (7.9 mL, 54.5 mmol, 2.0 equiv) dropwise at 0° C. After addition, the mixture was stirred at 20° C. for 3 h. The mixture was quenched with 100 mL water, extracted with 100 mL EtOAc, and the organic layer was concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (Waters Xbridge BEH C18 150 mm x 50 mm x 10 μm, gradient 30-50% CH3CN (containing 10 mM NH4HCO3) in H2O over 22 min, then 100% CH3CN (5 min), flow rate 140 mL / min) to give 1-[6-chloro-3-(2,2,2-trifluoroacetyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (3.2 g, 10.17 mmol, 37.3% yield) as a pink solid. LC-MS: m / z=315.1 [M+H] + ,333.1[M+H2O+H] + ESI pos.

[0216] Step 3: 5-Methyl-1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-(2,2,2-trifluoroacetyl)-2-pyridyl]pyrazole-3-carbonitrile; formic acid and 5-methyl-1-[6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-(2,2,2-trifluoroacetyl)-2-pyridyl]pyrazole-3-carbonitrile; formic acid [ka] A mixture of 1-[6-chloro-3-(2,2,2-trifluoroacetyl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (0.4 g, 1.27 mmol, 1.0 equiv), N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine (301.0 mg, 1.34 mmol, 1.05 equiv) and DIPEA (0.45 mL, 2.54 mmol, 2.0 equiv) in DMF (10 mL) was stirred at 100 °C for 16 h. The mixture was purified by preparative HPLC (Shim-pack C18 150 mm x 25 mm x 10 μm, gradient 1-30% CH3CN in HO (with 0.225% formic acid) over 10 min, then 100% CH3CN (2 min), flow rate 25 mL / min, single injection) to give 5-methyl-1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-(2,2,2-trifluoroacetyl)-2-pyridyl]pyrazole-3-carbonitrile; formic acid (170 mg, 26.6% yield) as a dark brown solid (LC-MS: m / z=504.1 [M+H]). + ,ESI pos.), 5-methyl-1-[6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-(2,2,2-trifluoroacetyl)-2-pyridyl]pyrazole-3-carbonitrile; formic acid (120 mg, 18.8% yield) was obtained as a dark brown solid (LC-MS: m / z=504.1[M+H] + ,ESI pos.).

[0217] Example 35 1-[3-Acetyl-6-[6-keto-7,7-dimethyl-5-(6-methylpyridazin-3-yl)pyrrolo[2,3-f]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] 1-[3-Acetyl-6-[6-keto-7,7-dimethyl-5-(6-methylpyridazin-3-yl)pyrrolo[2,3-f]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile was prepared according to the methods described herein and known to those skilled in the art. LC-MS: m / z=518.2[M+H]+,ESI pos.

[0218] Example 36 1-[3-formyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] 1-[3-formyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile was synthesized in the same manner as in Example 27 using 1-(6-chloro-3-formyl-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile. LC-MS: m / z=436.3[M+H]+, ESI pos.

[0219] Example 37 1-[3-Acetyl-6-[5-[(2-keto-1-methyl-3-pyridyl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] 1-[3-Acetyl-6-[5-[(2-keto-1-methyl-3-pyridyl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile was synthesized according to the method described herein using the appropriate intermediates 18, 19 and 3-chloro-1-methyl-pyridin-2-one (CAS: 123062-64-6). LC-MS: m / z=465.4[M+H]+, ESI pos.

[0220] Example 38 1-[3-Acetyl-6-[5-(3-methoxy-1-methyl-pyrazol-4-yl)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] 1-[3-Acetyl-6-[5-(3-methoxy-1-methyl-pyrazol-4-yl)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile was synthesized according to the methods described herein and known to those skilled in the art. LC-MS: m / z=453.4[M+H]+,ESI pos.

[0221] Example 39 1-[3-Acetyl-6-[5-[(6-pyrrolidin-2-ylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] Step 1: tert-Butyl 2-(6-aminopyridazin-3-yl)pyrrolidine-1-carboxylate An oven-dried 15 mL vial equipped with a magnetic stir bar was charged with 6-iodopyridazin-3-amine (1.00 g, 4.52 mmol, 1.0 equiv), 1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.27 g, 5.88 mmol, 1.3 equiv), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (51 mg, 0.05 mmol, 0.01 equiv), NiCl2.dtbbpy (90 mg, 0.23 mmol, 0.05 equiv), Cs2CO3 (2.21 g, 6.79 mmol, 1.5 equiv) in DMA (40 mL). The reaction mixture was bubbled with N2 for 10 min and then irradiated with two 34 W blue LED lamps (approximately 7 cm away from the light source to maintain the reaction temperature at 25 °C) for 12 h. The reaction mixture was poured into H2O (150 mL) and extracted with EtOAc (3 x 40 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (Waters Xbridge 150 mm x 25 mm x 5 μm, water (10 mM NH4HCO3)-ACN) to give tert-butyl 2-(6-aminopyridazin-3-yl)pyrrolidine-1-carboxylate (120 mg, 0.45 mmol, 10% yield) as a white solid. LC-MS: m / z = 265.1 [M + H] +, ESI pos.

[0222] Step 2: tert-Butyl 2-[6-[[1-[5-acetyl-6-(3-cyano-5-methyl-pyrazol-1-yl)-2-pyridyl]benzimidazol-5-yl]amino]pyridazin-3-yl]pyrrolidine-1-carboxylate To a solution of tert-butyl 2-(6-aminopyridazin-3-yl)pyrrolidine-1-carboxylate (69 mg, 0.26 mmol, 1.1 equiv.) and 1-[3-acetyl-6-(5-bromobenzimidazol-1-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (100 mg, 0.24 mmol, 1.0 equiv., prepared in Example 65, step 1) in 1,4-dioxane (8 mL) was added Cs2CO3 (232 mg, 0.71 mmol, 3.0 equiv.). The mixture was bubbled with N2 for 10 min and [tBuBrettPhos Pd(allyl)]OTf (19 mg, 0.02 mmol, 0.1 equiv.) was added. The reaction mixture was stirred at 80° C. for 2 h. The mixture was cooled to room temperature, poured into H2O (20 mL) and extracted with EtOAc (3 x 20 ml). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (DCM:MeOH 10:1) to give tert-butyl 2-[6-[[1-[5-acetyl-6-(3-cyano-5-methyl-pyrazol-1-yl)-2-pyridyl]benzimidazol-5-yl]amino]pyridazin-3-yl]pyrrolidine-1-carboxylate (110 mg, 0.18 mmol, 77% yield) as a light brown solid. LC-MS: m / z=605.2[M+H]+,ESI pos.

[0223] Step 3: 1-[3-acetyl-6-[5-[(6-pyrrolidin-2-ylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile To a solution of tert-butyl 2-[6-[[1-[5-acetyl-6-(3-cyano-5-methyl-pyrazol-1-yl)-2-pyridyl]benzimidazol-5-yl]amino]pyridazin-3-yl]pyrrolidine-1-carboxylate (30 mg, 0.05 mmol, 1.0 equiv.) in DCM (1.5 mL) was added HCl (4 M in dioxane) (0.8 mL). The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated. The residue was purified by preparative HPLC (Phenomenex Synergi C18 150 mm x 25 mm x 10 μm, water with FA-ACN) to give 1--[3-acetyl-6-[5-[(6-pyrrolidin-2-ylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (20 mg, 0.04 mmol, 78% yield) as an off-white solid. LC-MS: m / z=505.2[M+H]+, ESI pos.

[0224] Example 40 1-[3-Formyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [ka] 1-[3-formyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile was synthesized in the same manner as in Example 27 using 1-(6-chloro-3-formyl-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile. LC-MS: m / z=436.3[M+H]+, ESI pos.

[0225] Enzyme activity assay: Assay Description SIK1-3, RapidFire: In the presence of SIK2 (SIK1 or SIK3, respectively) and ATP, the CHK peptide (KKKVSRSGLYRSPSMPENLNRPR with a C-terminal arginine amide modification) was phosphorylated at one of four viable serines. Only one phosphorylation is observed under the assay conditions. 60 nl of each compound dilution series (12 points; dilution factor 3, typically 30 μM to 170 pM) in DMSO was transferred to the assay plate by acoustic dispensing and pre-incubated for 30 min (ambient temperature) after the addition of 5 μl of SIK1 (5 nM) or 5 μl of SIK2 (0.5 nM) or 7 μl of SIK3 (1.5 nM), respectively, in assay buffer (12.5 mM HEPES (pH 7.0), 10 mM magnesium acetate, 0.005% BSA). 10 μM CHK-peptide solutions in assay buffer and 5 μl 100 μM ATP for SIK1 and SIK2, 3 μl for SIK3 were added and incubated for 45 min at ambient temperature. The reaction was quenched by adding 40 μl 0.125% formic acid in water. RapidFire (RF) mass spectrometry was utilized for data generation as described below. Phosphorylated and non-phosphorylated multiple charged species (3-5 charges) measured by MRM (multiple reaction monitoring; API5000 or 6500+) or EIC (extracted ion current; QToF) were summed and ratios were calculated for data evaluation (total phosphorylated species / total total species). Normalization was performed by Genedata software based on the non-inhibited control DMSO and a commercially available SIK inhibitor (1 μM YKL-05-099 (CAS number 1936529-65-5)). The results of the assay are expressed as half-maximal inhibitory concentrations (IC50) and are summarized in Table 1 below.

[0226] RapidFire Configuration: The samples were aspirated by vacuum for up to 600 ms and loaded onto a C4 cartridge (Agilent; number G9203A) at 1.5 ml / min for 3000 ms with 0.1% formic acid in water. The samples were then transferred to an API5000 (API6500+) or QToF mass spectrometer at 1.25 ml / min for 4000 ms with 90% acetonitrile; 10% water; 0.007% TFA; 0.093 formic acid. The cartridge was reconditioned with 0.1% formic acid in water for another 500 ms. MS Settings Sciex API5000 / API6500+: All MS analyses were performed in MRM mode using the following MS settings: electrospray positive; ion spray voltage: 4000 V; temperature: 550 °C; collision gas: 5; curtain gas: 15; Gas 1: 40; Gas 2: 42; EP: 10 [Table 4]

[0227] MS-Setup Agilent QToF 6545 All MS analysis modes used the following MS settings on the MS: Dual AJS electrospray positive; VCap: 3000V; Drying and sheath gas: 340°C at 8 l / min; Nebulizer: 60 psig; Nozzle voltage: 2000V; Fragmenter: 130V; Skimmer: 35V; Oct1 RF Vpp: 700V; Reference mass at 5 spectra / s. [Table 5]

[0228] [Table 6] TIFF2025503006000150.tif250170 TIFF2025503006000151.tif186170

[0229] Specific Numbered Embodiments 1. Formula (I): [ka] (In the formula, R 1 is hydrogen or alkoxy, R 2 is hydrogen, alkyl, amino, alkylamino, dialkylamino, haloalkyl, haloalkylamino, cycloalkylamino, hydroxy, alkoxy, cycloalkyl, cycloalkyloxy or haloalkoxy; A1 is -O-, -NR 6 - or a bond, R 6 is hydrogen or alkyl, R 3 is alkyl, haloalkyl, hydroxyalkyl, heterocycloalkyl, heteroaryl, phenyl, heteroarylalkyl, phenylalkyl, cycloalkyl, cycloalkylalkyl, (amino)(phenyl)alkyl, (amino)(halophenyl)alkyl or (amino)(heteroaryl)alkyl, and heterocycloalkyl, heteroaryl, phenyl, heteroarylalkyl, phenylalkyl, cycloalkyl and cycloalkylalkyl are R 7 and optionally substituted with 1, 2 or 3 substituents independently selected from Each R 7 is independently selected from alkoxy, alkylamino, alkyl, aminocarbonyl, amino, cyano, cycloalkylamino, haloalkyl, halocycloalkyl, halogen, heteroaryl, hydroxycarbonylamino, alkoxyalkyl, alkylaminocarbonyl, alkylsulfonyl, aminocarbonyl, hydroxy, cycloalkylalkyl, haloalkoxy, heterocycloalkyl, and cycloalkyl; R 4is hydrogen, alkyl, halogen, cyano, haloalkyl, alkoxy, alkoxyalkyl, dialkylaminoalkyl, dialkylamino, alkylamino, alkylaminoalkyl, cycloalkyl, cycloalkylamino, cycloalkyloxy, cycloalkylalkyl, heteroarylalkyl, heteroarylamino, heteroaryloxy, heterocycloalkyl, heterocycloalkylamino, heterocycloalkyloxy or heterocycloalkylalkyl; and cycloalkyl, cycloalkylamino, cycloalkyloxy, cycloalkylalkyl, heteroarylalkyl, heteroarylamino, heteroaryloxy, heterocycloalkyl, heterocycloalkylamino, heterocycloalkyloxy and heterocycloalkylalkyl are each independently selected from R 8 and optionally substituted with 1, 2 or 3 substituents independently selected from Each R 8 is independently selected from alkyl, halogen, cyano, alkylsulfonyl, alkylaminocarbonyl, heterocycloalkyl, and alkoxyheterocycloalkylalkyl; R 5 is hydrogen, alkyl, halogen, cyano, haloalkyl, alkoxy, alkoxyalkyl, dialkylaminoalkyl, dialkylamino, alkylamino, alkylaminoalkyl, alkylsulfonyl, cycloalkyl, cycloalkylamino, cycloalkyloxy, cycloalkylalkyl, heteroarylalkyl, heteroarylamino, heteroaryloxy, heterocycloalkyl, heterocycloalkylamino, heterocycloalkyloxy or heterocycloalkylalkyl; and cycloalkyl, cycloalkylamino, cycloalkyloxy, cycloalkylalkyl, heteroarylalkyl, heteroarylamino, heteroaryloxy, heterocycloalkyl, heterocycloalkylamino, heterocycloalkyloxy and heterocycloalkylalkyl are each independently selected from R 9 and optionally substituted with 1, 2 or 3 substituents independently selected from or R 4 and R 5together with the carbons to which they are attached form a 5- to 7-membered heterocyclic ring optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, cyano, halogen, haloalkyl, alkoxy, heteroaryl, and alkylheteroaryl; Each R 9 is independently selected from alkoxy, halogen, dialkylaminocarbonyl, alkyl, alkoxyalkoxy, alkoxyheterocycloalkylalkyl, alkoxyheterocycloalkylcarbonyl, haloalkyl, haloalkoxy, heterocycloalkylalkoxy, heterocycloalkyl, heterocycloalkyloxy, hydroxy, alkylheterocycloalkyl, alkylheterocycloalkylalkyl, heterocycloalkylalkyl, alkylsulfonyl, (alkyl)heterocycloalkyl, alkylheterocycloalkyloxy, heterocycloalkylheterocycloalkyl, (heterocycloalkyl)heterocycloalkyl, CH3-O-(CH2-CH2-O)7-, alkylaminocarbonyl, and cyano). or a pharma- ceutically acceptable salt thereof.

[0230] 2.R 1 is hydrogen or methoxy.

[0231] 3.R 1 The compound of embodiment 1 or 2, wherein is hydrogen.

[0232] 4.R 1 The compound according to any one of embodiments 1 to 3, wherein is alkoxy, in particular methoxy.

[0233] 5.R 2 The compound of any one of embodiments 1-4, wherein is hydrogen, methyl, amino, methylamino, ethylamino, dimethylamino, trifluoromethyl, trifluoromethylamino, cyclopropylamino, hydroxy, or methoxy.

[0234] 6.R 2The compound of any one of embodiments 1-5, wherein is methyl, amino, methylamino, ethylamino, trifluoromethylamino, cyclopropylamino, hydroxy, or methoxy.

[0235] 7.R 2 The compound of any one of embodiments 1-5, wherein is hydrogen, dimethylamino, or trifluoromethyl.

[0236] 8.R 2 The compound of any one of embodiments 1-5, wherein is amino or alkyl.

[0237] 9.R 2 The compound of any one of embodiments 1-5, wherein is amino or methyl.

[0238] 10. A compound according to any one of embodiments 1-9, wherein A1 is -O- or a bond.

[0239] 11. The compound according to any one of embodiments 1-9, wherein A1 is -O-.

[0240] 12. The compound according to any one of embodiments 1-9, wherein A1 is a bond.

[0241] 13.A1 is -NR 6 -.

[0242] 14.R 6 The compound of any one of embodiments 1-13, wherein is hydrogen or methyl.

[0243] 15.R 5 The compound of any one of embodiments 1-14, wherein is hydrogen.

[0244] 16.R 6 The compound of any one of embodiments 1-14, wherein is alkyl.

[0245] 17.R 6 The compound of any one of embodiments 1-16, wherein is methyl. 18.R 3 is alkyl, haloalkyl, heterocycloalkyl, heteroaryl, phenyl, phenylalkyl, (amino)(phenyl)alkyl, (amino)(halophenyl)alkyl or (amino)(heteroaryl)alkyl; heterocycloalkyl, heteroaryl, phenyl, heteroarylalkyl and phenylalkyl are R 7 and optionally substituted with 1, 2 or 3 substituents independently selected from Each R 7 The compound of any one of embodiments 1-17, wherein is independently selected from halogen, alkyl, cyano, alkoxy, and haloalkyl.

[0246] 19.R 3 is methyldifluoropropyl, phenyl, phenylmethyl, phenylethyl, 2-amino-1-(3-chlorophenyl)ethyl, 3-amino-1-phenyl-propyl, 3-amino-1-(3-thienyl)propyl, 2-thienylmethyl, heterocycloalkyl or heteroaryl, and heterocycloalkyl, heteroaryl, phenyl, phenylmethyl and phenylethyl are R 7 and optionally substituted with 1, 2 or 3 substituents independently selected from Each R 7 19. The compound according to any one of claims 1 to 18, wherein is independently selected from chloro, methyl, cyano, methoxy and difluoromethyl.

[0247] 20. Substituent R 3Heterocycloalkyl is 2-morpholino, pyrrolidinyl, piperidyl, 2-oxopyrrolidinyl, (1,1-dioxo-1,2-thiazolidinyl), (4,5,6,7-tetrahydropyrazolo[4,3-c]pyridinyl), pyrrolidinyl, [rac-(3aR,6aS)-2,3,3a,5,6,6a-hexahydro-1H-pyrrolo[3,2-b]pyrrolyl] , [rac-(3aS,6aR)-2,3,3a,5,6,6a-hexahydro-1H-pyrrolo[3,2-b]pyrrolyl], [3-oxo-piperazinyl], (4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazinyl), (6,7-dihydro-4H-pyrazolo[4,3-c]pyridinyl), azetidinyl, pyrrolidinyl, (3-oxo-1, 5,6,8-Tetrahydrooxazolo[3,4-a]pyrazinyl), piperazinyl, 4,7-diazaspiro[2.5]octanyl, (2-oxa-5,8-diazaspiro[3.5]nonanyl), 3-azabicyclo[3.2.0]heptanyl), (5-azaspiro[2.4]heptanyl), (2-azabicyclo[2.2.1]heptanyl), morpholinyl, 4-o 1,5-dihydro-4H-pyrazolo[4,3-c]pyridinyl, 2-oxa-7-azaspiro[3.4]octanyl, and (1S,5R,7R)-4-oxo-3-oxa-9-azatricyclo[5.3.0.01,5]decan-9-yl; Substituent R 3 The compound according to any one of the preceding embodiments, wherein said heteroaryl is selected from 2-oxo-pyridyl, pyrazolyl, pyridyl, pyridazinyl, isoxazol-4-yl, pyrimidinyl, 1H-benzotriazolyl, furyl, [6-oxo-1H-pyridazinyl] and triazolyl.

[0248] 21. Substituent R 3 wherein said heterocycloalkyl is selected from 2-oxo-1-piperidyl, 2-oxopyrrolidin-1-yl, 1-piperidyl, pyrrolidin-1-yl, and [(1S,5R,7R)-4-oxo-3-oxa-9-azatricyclo[5.3.0.01,5]decan-9-yl]; R 3 The compound of any one of embodiments 1-20, wherein the heteroaryl substituent is pyrazol-1-yl.

[0249] 22. R 4 is hydrogen, halogen, cyano, haloalkyl, alkoxy, alkoxyalkyl, dialkylaminoalkyl, dialkylamino, alkylamino, alkylaminoalkyl, cycloalkyl, cycloalkylamino, cycloalkyloxy, cycloalkylalkyl, heteroarylalkyl, heteroarylamino, heteroaryloxy, heterocycloalkyl, heterocycloalkylamino, heterocycloalkyloxy or heterocycloalkylalkyl; and cycloalkyl, cycloalkylamino, cycloalkyloxy, cycloalkylalkyl, heteroarylalkyl, heteroarylamino, heteroaryloxy, heterocycloalkyl, heterocycloalkylamino, heterocycloalkyloxy and heterocycloalkylalkyl are each independently selected from R 8 and optionally substituted with 1, 2 or 3 substituents independently selected from Each R 8 is independently selected from alkyl, halogen, cyano, alkylsulfonyl, alkylaminocarbonyl, heterocycloalkyl, and alkoxyheterocycloalkylalkyl; R 5is hydrogen, halogen, cyano, haloalkyl, alkoxy, alkoxyalkyl, dialkylaminoalkyl, dialkylamino, alkylamino, alkylaminoalkyl, alkylsulfonyl, cycloalkyl, cycloalkylamino, cycloalkyloxy, cycloalkylalkyl, heteroarylalkyl, heteroarylamino, heteroaryloxy, heterocycloalkyl, heterocycloalkylamino, heterocycloalkyloxy or heterocycloalkylalkyl; and cycloalkyl, cycloalkylamino, cycloalkyloxy, cycloalkylalkyl, heteroarylalkyl, heteroarylamino, heteroaryloxy, heterocycloalkyl, heterocycloalkylamino, heterocycloalkyloxy and heterocycloalkylalkyl are each independently selected from R 9 and optionally substituted with 1, 2 or 3 substituents independently selected from or R 4 and R 5 together with the carbons to which they are attached form a 5- to 7-membered heterocyclic ring optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, cyano, halogen, haloalkyl, alkoxy, heteroaryl, and alkylheteroaryl; Each R 9 are independently selected from alkoxy, halogen, dialkylaminocarbonyl, alkyl, alkoxyalkoxy, alkoxyheterocycloalkylalkyl, alkoxyheterocycloalkylcarbonyl, haloalkyl, haloalkoxy, heterocycloalkylalkoxy, heterocycloalkyl, heterocycloalkyloxy, hydroxy, alkylheterocycloalkyl, alkylheterocycloalkylalkyl, heterocycloalkylalkyl, alkylsulfonyl, (alkyl)heterocycloalkyl, alkylheterocycloalkyloxy, heterocycloalkylheterocycloalkyl, (heterocycloalkyl)heterocycloalkyl, CH3-O-(CH2-CH2-O)7-, alkylaminocarbonyl, and cyano; However, R 4 and R 5The compound of any one of embodiments 1-21, with the proviso that only one of may be hydrogen.

[0250] 23. R 4 is hydrogen, fluoro, cyano, trifluoromethyl, methoxy, methoxyethyl, dimethylaminoethyl, cyclopropylcarbonyl, morpholinoethyl, (1,1-dioxo-1,2-thiazolidin-2-yl)methyl, (2-oxopyrrolidin-1-yl)methyl, (2-oxo-1-piperidyl)methyl, heteroaryl or heterocycloalkyl, and heteroaryl and heterocycloalkyl are R 8 and optionally substituted with 1, 2 or 3 substituents independently selected from Each R 8 is independently selected from methyl, fluoro, cyano, methylsulfonyl, oxetan-3-yl, and (3-methoxyazetidin-1-yl)methyl; R 5 is hydrogen, alkoxy, heterocycloalkylalkoxy, heterocycloalkylamino, heteroarylamino, heteroarylalkyl, or heteroaryl; and heterocycloalkylalkoxy, heterocycloalkylamino, heteroarylamino, heteroarylalkyl, and heteroaryl are R 9 and optionally substituted with 1, 2 or 3 substituents independently selected from or R 4 and R 5 together with the carbons to which they are attached form a 5- to 7-membered heterocycle which may be optionally substituted with 1, 2, or 3 substituents independently selected from alkyl and alkylheteroaryl; Each R 9 is independently selected from alkyl, alkoxy, halogen, haloalkyl, dialkylaminocarbonyl, heterocycloalkyl, and (heterocycloalkyl)heterocycloalkyl; However, R 4 and R 5 The compound of any one of embodiments 1-22, with the proviso that only one of may be hydrogen.

[0251] 24.R 4 is hydrogen, fluoro, cyano, trifluoromethyl, methoxy, methoxyethyl, dimethylaminoethyl, cyclopropylcarbonyl, morpholinoethyl, (1,1-dioxo-1,2-thiazolidin-2-yl)methyl, (2-oxopyrrolidin-1-yl)methyl, (2-oxo-1-piperidyl)methyl, heteroaryl or heterocycloalkyl, and heteroaryl and heterocycloalkyl are R 8 and optionally substituted with 1, 2 or 3 substituents independently selected from Each R 8 The compound of any one of embodiments 1-23, wherein is independently selected from methyl, fluoro, cyano, methylsulfonyl, oxetan-3-yl, and (3-methoxyazetidin-1-yl)methyl.

[0252] 25.R 4 is hydrogen, fluoro, alkoxy, heteroarylamino, or heteroarylalkyl, and heteroarylamino and heteroarylalkyl are R 8 and optionally substituted with 1, 2 or 3 substituents independently selected from Each R 8 The compound of any one of embodiments 1-24, wherein is independently selected from alkyl.

[0253] 26.R 4 is hydrogen, fluoro, alkoxy, (pyridazin-3-yl)amino or (pyridazin-3-yl)alkyl, and (pyridazin-3-yl)amino or (pyridazin-3-yl)alkyl is R 8 and optionally substituted with 1, 2 or 3 substituents independently selected from Each R 8 The compound of any one of embodiments 1-25, wherein is independently selected from alkyl.

[0254] 27.R 4The compound of any one of embodiments 1-26, wherein is hydrogen, fluoro, methoxy, (pyridazin-3-yl)amino, or (pyridazin-3-yl)alkyl, wherein (pyridazin-3-yl)amino and (pyridazin-3-yl)alkyl are optionally substituted with methyl.

[0255] 28. Substituent R 4 heterocycloalkyl is selected from piperidyl, piperazinyl, pyrrolidinyl, 2,3-dihydropyridazino[4,5-b][1,4]oxazinyl, pyrrolidinyl, 2-oxo-pyrimidinyl, 2-oxa-5-azaspiro[3.4]octanyl, and oxetanyl; Substituent R 4 The compound of any one of embodiments 1-27, wherein said heteroaryl is selected from pyridazinyl and pyridyl.

[0256] 29. Substituent R 4 wherein said heterocycloalkyl is selected from 4-piperidyl, piperazin-1-yl, pyrrolidin-3-yl, 2,3-dihydropyridazino[4,5-b][1,4]oxazin-8-yl, pyrrolidin-1-yl, 2-oxo-pyrimidin-4-yl, 2-oxa-5-azaspiro[3.4]octan-5-yl, and oxetan-3-yl; Substituent R 4 The compound of any one of embodiments 1-28, wherein said heteroaryl is selected from pyridazin-3-yl and 3-pyridyl.

[0257] 30.R 4 The compound of any one of embodiments 1-29, wherein is hydrogen.

[0258] 31.R 4 The compound of any one of embodiments 1-29, wherein is alkoxy.

[0259] 32.R 4 The compound of any one of embodiments 1-29, wherein is methoxy.

[0260] 33.R 5 is hydrogen, alkoxy, heterocycloalkylalkoxy, heterocycloalkylamino, heteroarylamino, heteroarylalkyl, or heteroaryl; and heterocycloalkylalkoxy, heterocycloalkylamino, heteroarylamino, heteroarylalkyl, and heteroaryl are R 9 and optionally substituted with 1, 2 or 3 substituents independently selected from Each R 9 The compound of any one of embodiments 1-32, wherein is independently selected from alkyl, alkoxy, halogen, haloalkyl, dialkylaminocarbonyl, heterocycloalkyl, and (heterocycloalkyl)heterocycloalkyl.

[0261] 34.R 5 is hydrogen, methoxy, 2-morpholinoethoxy, (pyridazin-3-yl)amino, (pyridazin-3-yl)alkyl, pyrazol-4-yl, (2-oxo-3-pyridyl)amino, and (pyridazin-3-yl)amino, (pyridazin-3-yl)alkyl, pyrazol-4-yl and (2-oxo-3-pyridyl)amino are R 9 and optionally substituted with 1, 2 or 3 substituents independently selected from Each R 9 The compound of any one of embodiments 1-32, wherein is independently selected from methyl, fluoro, halogen, dimethylaminocarbonyl, heterocycloalkyl, and (heterocycloalkyl)heterocycloalkyl.

[0262] 35.R 5 The compound according to any one of embodiments 1-34, wherein is (pyridazin-3-yl)amino optionally substituted with alkyl.

[0263] 36.R 4 and R 5are taken together with the carbons to which they are attached to form a 5-7 membered heterocycle, optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, halogen, haloalkyl, alkoxy, heteroaryl, and alkylheteroaryl.

[0264] 37.R 4 and R 5 are taken together with the carbons to which they are attached to form a 5-7 membered heterocycle, optionally substituted with 1, 2, or 3 substituents independently selected from alkyl and alkylheteroaryl.

[0265] 38.R 4 and R 5 The compound of any one of embodiments 1-36, with the proviso that only one of may be hydrogen.

[0266] 39. Below 2-(2-chloro-phenoxy)-6-(5,6-dimethoxy-benzimidazol-1-yl)-nicotinamide; 6-(5,6-dimethoxy-benzimidazol-1-yl)-2-phenylamino-nicotinamide; 2-[[3-amino-1-(3-thienyl)propyl]amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide; 2-[(3-amino-1-phenyl-propyl)amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide; 6-(5,6-dimethoxybenzimidazol-1-yl)-2-(2-phenylethylamino)pyridine-3-carboxamide; 2-(benzylamino)-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide; 6-(5,6-dimethoxybenzimidazol-1-yl)-2-(2-thienylmethylamino)pyridine-3-carboxamide; 2-[(4-chlorophenyl)methylamino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide; 2-[2-(3-chlorophenyl)ethylamino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide; 2-[[2-amino-1-(3-chlorophenyl)ethyl]amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide; 2-[[3-amino-1-(3-chlorophenyl)propyl]amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide; 2-[[2-amino-1-(3-thienyl)ethyl]amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide; Methyl 2-(3-chlorophenyl)-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)nicotinate; Methyl 6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(2-oxopiperidin-1-yl)nicotinate; Methyl 6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(2-oxopyrrolidin-1-yl)nicotinate; 6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(piperidin-1-yl)nicotinic acid; 2-(3-cyanophenyl)-6-(5,6-dimethoxybenzimidazol-1-yl)-N-ethyl-pyridine-3-carboxamide; 2-(3-cyanophenyl)-6-(5,6-dimethoxybenzimidazol-1-yl)-N-methyl-pyridine-3-carboxamide; 2-(3-cyanophenyl)-N-cyclopropyl-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide; 2-(3-cyanophenyl)-6-(5,6-dimethoxybenzimidazol-1-yl)-N-(2,2,2-trifluoroethyl)pyridine-3-carboxamide; 2-(3-cyanophenyl)-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide; 2-(3-cyano-5-methyl-pyrazol-1-yl)-6-[5-(2-morpholinoethoxy)benzimidazol-1-yl]pyridine-3-carboxamide; 2-(2,2-difluoro-1-methyl-ethoxy)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carboxamide; 2-(2,2-difluoro-1-methyl-ethoxy)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carboxamide; 2-(3-cyano-5-methyl-pyrazol-1-yl)-6-[5-[[(3S,4R)-4-fluoropyrrolidin-3-yl]amino]benzimidazol-1-yl]pyridine-3-carboxamide; Methyl 2-(3-methoxy-5-methyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carboxylate; 1-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[2,4-dimethoxy-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone; 1-[3-acetyl-6-(6,7-dihydro-5H-pyrrolo[3,2-f]benzimidazol-3-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-acetyl-6-(6,7-dihydro-5H-pyrrolo[2,3-f]benzimidazol-1-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; (3R,5S)-1-[3-formyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrrolidine-3-carbonitrile; (3R,5S)-1-[3-formyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrrolidine-3-carbonitrile; 5-Methyl-1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-(2,2,2-trifluoroacetyl)-2-pyridyl]pyrazole-3-carbonitrile; 1-[3-acetyl-6-[6-keto-7,7-dimethyl-5-(6-methylpyridazin-3-yl)pyrrolo[2,3-f]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-formyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-acetyl-6-[5-[(2-keto-1-methyl-3-pyridyl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-acetyl-6-[5-(3-methoxy-1-methyl-pyrazol-4-yl)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-acetyl-6-[5-[(6-pyrrolidin-2-ylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; and 1-[3-formyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 39. The compound of formula (I) according to any one of embodiments 1 to 38, selected from:

[0267] 40. Below 2-(2-chloro-phenoxy)-6-(5,6-dimethoxy-benzimidazol-1-yl)-nicotinamide; 6-(5,6-dimethoxy-benzimidazol-1-yl)-2-phenylamino-nicotinamide; 2-[[3-amino-1-(3-thienyl)propyl]amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide; 2-[(3-amino-1-phenyl-propyl)amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide; 6-(5,6-dimethoxybenzimidazol-1-yl)-2-(2-phenylethylamino)pyridine-3-carboxamide; 2-(benzylamino)-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide; 6-(5,6-dimethoxybenzimidazol-1-yl)-2-(2-thienylmethylamino)pyridine-3-carboxamide; 2-[(4-chlorophenyl)methylamino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide; 2-[2-(3-chlorophenyl)ethylamino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide; 2-[[2-amino-1-(3-chlorophenyl)ethyl]amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide; 2-[[3-amino-1-(3-chlorophenyl)propyl]amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide; 2-[[2-amino-1-(3-thienyl)ethyl]amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide; Methyl 2-(3-chlorophenyl)-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)nicotinate; Methyl 6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(2-oxopiperidin-1-yl)nicotinate; Methyl 6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(2-oxopyrrolidin-1-yl)nicotinate; 6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(piperidin-1-yl)nicotinic acid; 2-(3-cyanophenyl)-6-(5,6-dimethoxybenzimidazol-1-yl)-N-ethyl-pyridine-3-carboxamide; 2-(3-cyanophenyl)-6-(5,6-dimethoxybenzimidazol-1-yl)-N-methyl-pyridine-3-carboxamide; 2-(3-cyanophenyl)-N-cyclopropyl-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide; 2-(3-cyanophenyl)-6-(5,6-dimethoxybenzimidazol-1-yl)-N-(2,2,2-trifluoroethyl)pyridine-3-carboxamide; 2-(3-cyanophenyl)-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide; 2-(3-cyano-5-methyl-pyrazol-1-yl)-6-[5-(2-morpholinoethoxy)benzimidazol-1-yl]pyridine-3-carboxamide; 2-(2,2-difluoro-1-methyl-ethoxy)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carboxamide; 2-(2,2-difluoro-1-methyl-ethoxy)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carboxamide; 2-(3-cyano-5-methyl-pyrazol-1-yl)-6-[5-[[(3S,4R)-4-fluoropyrrolidin-3-yl]amino]benzimidazol-1-yl]pyridine-3-carboxamide; Methyl 2-(3-methoxy-5-methyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carboxylate; 1-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; and 1-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 39. The compound of formula (I) according to any one of embodiments 1 to 38, selected from:

[0268] 41. Below 2-(2-chloro-phenoxy)-6-(5,6-dimethoxy-benzimidazol-1-yl)-nicotinamide; 6-(5,6-dimethoxy-benzimidazol-1-yl)-2-phenylamino-nicotinamide; 6-(5,6-dimethoxybenzimidazol-1-yl)-2-(2-phenylethylamino)pyridine-3-carboxamide; 2-[[2-amino-1-(3-chlorophenyl)ethyl]amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide; and 2-[[2-amino-1-(3-thienyl)ethyl]amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide; 39. The compound of formula (I) according to any one of embodiments 1 to 38, selected from:

[0269] 42. Below 2-(2,2-difluoro-1-methyl-ethoxy)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carboxamide; and 1-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 39. The compound of formula (I) according to any one of embodiments 1 to 38, selected from:

[0270] 43. Below 2-(2,2-difluoro-1-methyl-ethoxy)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carboxamide; 1-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; (3R,5S)-1-[3-formyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrrolidine-3-carbonitrile; 5-Methyl-1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-(2,2,2-trifluoroacetyl)-2-pyridyl]pyrazole-3-carbonitrile; and 1-[3-formyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 39. The compound of formula (I) according to any one of embodiments 1 to 38, selected from:

[0271] 44. The following: (a) reacting a compound represented by formula (B1) or (B2) in the presence of a palladium catalyst and a base: [ka] with an amine, (b) in the presence of a base, [ka] and a compound of formula (C2) [ka] with a compound of (c) in the presence of a base, [ka] with an amine, or (d) reacting a compound of formula (D1) with a compound of formula (D2) in the presence of a base and a palladium catalyst; reacting with a compound (D2), wherein D2 is selected from (i) an optionally substituted aryl boronic acid or ester, and (ii) an optionally substituted heteroaryl boronic acid or ester; A1, R 1 , R 2 , R 3 , R 4 and R 5 is as defined in any one of embodiments 1 to 43, and R a is alkyl or cycloalkyl, R b is hydrogen or alkyl, and R cA process for the preparation of a compound according to any one of embodiments 1 to 43, wherein is alkyl or cycloalkyl and X is halogen.

[0272] 45. The compound according to any one of embodiments 1 to 43, when produced according to the process of embodiment 44.

[0273] 46. ​​A compound of formula (I), or a pharma- ceutically acceptable salt thereof, as defined in any one of embodiments 1-43, for use as a therapeutically active substance.

[0274] 47. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of embodiments 1 to 43 or a pharma- ceutically acceptable salt thereof and a therapeutically inert carrier.

[0275] 48. The use of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, as defined in any one of embodiments 1 to 43, for the treatment or prevention of rheumatoid arthritis, juvenile rheumatoid arthritis, nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis.

[0276] 49. Use of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, as defined in any one of embodiments 1-43, for the preparation of a medicament for the treatment or prevention of rheumatoid arthritis, juvenile rheumatoid arthritis, nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis.

[0277] 50. A compound of formula (I), or a pharma- ceutically acceptable salt thereof, as defined in any one of embodiments 1-43, for use in the treatment or prophylaxis of rheumatoid arthritis, juvenile rheumatoid arthritis, nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis.

[0278] 51. A method for the treatment or prevention of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis, comprising administering to a patient in need thereof an effective amount of a compound of formula (I) as defined in any one of embodiments 1 to 43 or a pharma- ceutically acceptable salt thereof.

Claims

1. Formula (I) 【Chemistry 1】 (In the formula, R １ is hydrogen or alkoxy, R ２ is hydrogen, alkyl, amino, alkylamino, dialkylamino, haloalkyl, haloalkylamino, cycloalkylamino, hydroxy, alkoxy, cycloalkyl, cycloalkyloxy or haloalkoxy; A1 is —O—, —NR ６ - or a bond, R ６ is hydrogen or alkyl, R ３ is alkyl, haloalkyl, hydroxyalkyl, heterocycloalkyl, heteroaryl, phenyl, heteroarylalkyl, phenylalkyl, cycloalkyl, cycloalkylalkyl, (amino)(phenyl)alkyl, (amino)(halophenyl)alkyl or (amino)(heteroaryl)alkyl, and heterocycloalkyl, heteroaryl, phenyl, heteroarylalkyl, phenylalkyl, cycloalkyl and cycloalkylalkyl are each independently selected from R ７ and optionally substituted with 1, 2, or 3 substituents independently selected from Each R ７ is independently selected from alkoxy, alkylamino, alkyl, aminocarbonyl, amino, cyano, cycloalkylamino, haloalkyl, halocycloalkyl, halogen, heteroaryl, hydroxycarbonylamino, alkoxyalkyl, alkylaminocarbonyl, alkylsulfonyl, aminocarbonyl, hydroxy, cycloalkylalkyl, haloalkoxy, heterocycloalkyl, and cycloalkyl; R ４ is hydrogen, alkyl, halogen, cyano, haloalkyl, alkoxy, alkoxyalkyl, dialkylaminoalkyl, dialkylamino, alkylamino, alkylaminoalkyl, cycloalkyl, cycloalkylamino, cycloalkyloxy, cycloalkylalkyl, heteroarylalkyl, heteroarylamino, heteroaryloxy, heterocycloalkyl, heterocycloalkylamino, heterocycloalkyloxy or heterocycloalkylalkyl; and cycloalkyl, cycloalkylamino, cycloalkyloxy, cycloalkylalkyl, heteroarylalkyl, heteroarylamino, heteroaryloxy, heterocycloalkyl, heterocycloalkylamino, heterocycloalkyloxy and heterocycloalkylalkyl are each independently selected from R ８ and optionally substituted with 1, 2, or 3 substituents independently selected from Each R ８ is independently selected from alkyl, halogen, cyano, alkylsulfonyl, alkylaminocarbonyl, heterocycloalkyl, and alkoxyheterocycloalkylalkyl; R ５ is hydrogen, alkyl, halogen, cyano, haloalkyl, alkoxy, alkoxyalkyl, dialkylaminoalkyl, dialkylamino, alkylamino, alkylamino, alkylaminoalkyl, alkylsulfonyl, cycloalkyl, cycloalkylamino, cycloalkyloxy, cycloalkylalkyl, heteroarylalkyl, heteroarylamino, heteroaryloxy, heterocycloalkyl, heterocycloalkylamino, heterocycloalkyloxy or heterocycloalkylalkyl; and cycloalkyl, cycloalkylamino, cycloalkyloxy, cycloalkylalkyl, heteroarylalkyl, heteroarylamino, heteroaryloxy, heterocycloalkyl, heterocycloalkylamino, heterocycloalkyloxy and heterocycloalkylalkyl are each independently selected from R ９ and optionally substituted with 1, 2, or 3 substituents independently selected from or R ４ and R ５ together with the carbons to which they are attached form a 5- to 7-membered heterocyclic ring optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, cyano, halogen, haloalkyl, alkoxy, heteroaryl, and alkylheteroaryl; Each R ９ is alkoxy, halogen, dialkylaminocarbonyl, alkyl, alkoxyalkoxy, alkoxyheterocycloalkylalkyl, alkoxyheterocycloalkylcarbonyl, haloalkyl, haloalkoxy, heterocycloalkylalkoxy, heterocycloalkyl, heterocycloalkyloxy, hydroxy, alkylheterocycloalkyl, alkylheterocycloalkylalkyl, heterocycloalkylalkyl, alkylsulfonyl, (alkyl)heterocycloalkyl, alkylheterocycloalkyloxy, heterocycloalkylheterocycloalkyl, (heterocycloalkyl)heterocycloalkyl, CH ３ -O-(CH ２ -CH ２ -O) ７ -, alkylaminocarbonyl, and cyano. or a pharmaceutically acceptable salt thereof.

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

3. R ２ 3. The compound of claim 1 or 2, wherein is hydrogen, methyl, amino, methylamino, ethylamino, dimethylamino, trifluoromethyl, trifluoromethylamino, cyclopropylamino, hydroxy, or methoxy.

4. R ２ 3. The compound of claim 1 or 2, wherein is amino or alkyl.

5. The compound of claim 1 or 2, wherein A1 is —O— or a bond.

6. R ３ is alkyl, haloalkyl, heterocycloalkyl, heteroaryl, phenyl, phenylalkyl, (amino)(phenyl)alkyl, (amino)(halophenyl)alkyl or (amino)(heteroaryl)alkyl, and heterocycloalkyl, heteroaryl, phenyl, heteroarylalkyl and phenylalkyl are each independently selected from R ７ and optionally substituted with 1, 2, or 3 substituents independently selected from Each R ７ 3. The compound of claim 1 or 2, wherein is independently selected from halogen, alkyl, cyano, alkoxy, and haloalkyl.

7. R ３ is methyldifluoropropyl, phenyl, phenylmethyl, phenylethyl, 2-amino-1-(3-chlorophenyl)ethyl, 3-amino-1-phenyl-propyl, 3-amino-1-(3-thienyl)propyl, 2-thienylmethyl, heterocycloalkyl or heteroaryl, and heterocycloalkyl, heteroaryl, phenyl, phenylmethyl and phenylethyl are ７ and optionally substituted with 1, 2, or 3 substituents independently selected from Each R ７ 3. The compound of claim 1 or 2, wherein is independently selected from chloro, methyl, cyano, methoxy, and difluoromethyl.

8. R ４ is hydrogen, halogen, cyano, haloalkyl, alkoxy, alkoxyalkyl, dialkylaminoalkyl, dialkylamino, alkylamino, alkylaminoalkyl, cycloalkyl, cycloalkylamino, cycloalkyloxy, cycloalkylalkyl, heteroarylalkyl, heteroarylamino, heteroaryloxy, heterocycloalkyl, heterocycloalkylamino, heterocycloalkyloxy or heterocycloalkylalkyl; and cycloalkyl, cycloalkylamino, cycloalkyloxy, cycloalkylalkyl, heteroarylalkyl, heteroarylamino, heteroaryloxy, heterocycloalkyl, heterocycloalkylamino, heterocycloalkyloxy and heterocycloalkylalkyl are each independently selected from R ８ and optionally substituted with 1, 2, or 3 substituents independently selected from Each R ８ is independently selected from alkyl, halogen, cyano, alkylsulfonyl, alkylaminocarbonyl, heterocycloalkyl, and alkoxyheterocycloalkylalkyl; R ５ is hydrogen, halogen, cyano, haloalkyl, alkoxy, alkoxyalkyl, dialkylaminoalkyl, dialkylamino, alkylamino, alkylamino, alkylaminoalkyl, alkylsulfonyl, cycloalkyl, cycloalkylamino, cycloalkyloxy, cycloalkylalkyl, heteroarylalkyl, heteroarylamino, heteroaryloxy, heterocycloalkyl, heterocycloalkylamino, heterocycloalkyloxy or heterocycloalkylalkyl; and cycloalkyl, cycloalkylamino, cycloalkyloxy, cycloalkylalkyl, heteroarylalkyl, heteroarylamino, heteroaryloxy, heterocycloalkyl, heterocycloalkylamino, heterocycloalkyloxy and heterocycloalkylalkyl are each independently selected from R ９ and optionally substituted with 1, 2, or 3 substituents independently selected from or R ４ and R ５ together with the carbons to which they are attached form a 5- to 7-membered heterocyclic ring optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, cyano, halogen, haloalkyl, alkoxy, heteroaryl, and alkylheteroaryl; Each R ９ is alkoxy, halogen, dialkylaminocarbonyl, alkyl, alkoxyalkoxy, alkoxyheterocycloalkylalkyl, alkoxyheterocycloalkylcarbonyl, haloalkyl, haloalkoxy, heterocycloalkylalkoxy, heterocycloalkyl, heterocycloalkyloxy, hydroxy, alkylheterocycloalkyl, alkylheterocycloalkylalkyl, heterocycloalkylalkyl, alkylsulfonyl, (alkyl)heterocycloalkyl, alkylheterocycloalkyloxy, heterocycloalkylheterocycloalkyl, (heterocycloalkyl)heterocycloalkyl, CH ３ -O-(CH ２ -CH ２ -O) ７ independently selected from -, alkylaminocarbonyl, and cyano; However, R ４ and R ５ 3. A compound according to claim 1 or 2, with the proviso that only one of may be hydrogen.

9. R ４ is hydrogen, fluoro, cyano, trifluoromethyl, methoxy, methoxyethyl, dimethylaminoethyl, cyclopropylcarbonyl, morpholinoethyl, (1,1-dioxo-1,2-thiazolidin-2-yl)methyl, (2-oxopyrrolidin-1-yl)methyl, (2-oxo-1-piperidyl)methyl, heteroaryl, or heterocycloalkyl, and heteroaryl and heterocycloalkyl are each independently selected from R ８ and optionally substituted with 1, 2, or 3 substituents independently selected from Each R ８ is independently selected from methyl, fluoro, cyano, methylsulfonyl, oxetan-3-yl, and (3-methoxyazetidin-1-yl)methyl; R ５ is hydrogen, alkoxy, heterocycloalkylalkoxy, heterocycloalkylamino, heteroarylamino, heteroarylalkyl, or heteroaryl, and heterocycloalkylalkoxy, heterocycloalkylamino, heteroarylamino, heteroarylalkyl, and heteroaryl are each independently selected from R ９ and optionally substituted with 1, 2, or 3 substituents independently selected from or R ４ and R ５ together with the carbons to which they are attached form a 5- to 7-membered heterocyclic ring optionally substituted with 1, 2, or 3 substituents independently selected from alkyl and alkylheteroaryl; Each R ９ is independently selected from alkyl, alkoxy, halogen, haloalkyl, dialkylaminocarbonyl, heterocycloalkyl, and (heterocycloalkyl)heterocycloalkyl; However, R ４ and R ５ 3. A compound according to claim 1 or 2, with the proviso that only one of may be hydrogen.

10. R ４ 3. The compound of claim 1 or 2, wherein is hydrogen.

11. R ５ The compound of claim 1 or 2, wherein is pyridazin-3-yl optionally substituted with alkyl.

12. below: 2-(2-chloro-phenoxy)-6-(5,6-dimethoxy-benzimidazol-1-yl)-nicotinamide; 6-(5,6-dimethoxy-benzimidazol-1-yl)-2-phenylamino-nicotinamide; 2-[[3-amino-1-(3-thienyl)propyl]amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide; 2-[(3-amino-1-phenyl-propyl)amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide; 6-(5,6-dimethoxybenzimidazol-1-yl)-2-(2-phenylethylamino)pyridine-3-carboxamide; 2-(benzylamino)-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide; 6-(5,6-dimethoxybenzimidazol-1-yl)-2-(2-thienylmethylamino)pyridine-3-carboxamide; 2-[(4-chlorophenyl)methylamino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide; 2-[2-(3-chlorophenyl)ethylamino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide; 2-[[2-amino-1-(3-chlorophenyl)ethyl]amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide; 2-[[3-amino-1-(3-chlorophenyl)propyl]amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide; 2-[[2-amino-1-(3-thienyl)ethyl]amino]-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide; Methyl 2-(3-chlorophenyl)-6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)nicotinate; Methyl 6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(2-oxopiperidin-1-yl)nicotinate; Methyl 6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(2-oxopyrrolidin-1-yl)nicotinate; 6-(5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)-2-(piperidin-1-yl)nicotinic acid; 2-(3-cyanophenyl)-6-(5,6-dimethoxybenzimidazol-1-yl)-N-ethyl-pyridine-3-carboxamide; 2-(3-cyanophenyl)-6-(5,6-dimethoxybenzimidazol-1-yl)-N-methyl-pyridine-3-carboxamide; 2-(3-cyanophenyl)-N-cyclopropyl-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide; 2-(3-cyanophenyl)-6-(5,6-dimethoxybenzimidazol-1-yl)-N-(2,2,2-trifluoroethyl)pyridine-3-carboxamide; 2-(3-cyanophenyl)-6-(5,6-dimethoxybenzimidazol-1-yl)pyridine-3-carboxamide; 2-(3-cyano-5-methyl-pyrazol-1-yl)-6-[5-(2-morpholinoethoxy)benzimidazol-1-yl]pyridine-3-carboxamide; 2-(2,2-difluoro-1-methyl-ethoxy)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carboxamide; 2-(2,2-difluoro-1-methyl-ethoxy)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carboxamide; 2-(3-cyano-5-methyl-pyrazol-1-yl)-6-[5-[[(3S,4R)-4-fluoropyrrolidin-3-yl]amino]benzimidazol-1-yl]pyridine-3-carboxamide; Methyl 2-(3-methoxy-5-methyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carboxylate; 1-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[2,4-dimethoxy-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-pyridyl]ethanone; 1-[3-acetyl-6-(6,7-dihydro-5H-pyrrolo[3,2-f]benzimidazol-3-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-acetyl-6-(6,7-dihydro-5H-pyrrolo[2,3-f]benzimidazol-1-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; (3R,5S)-1-[3-formyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrrolidine-3-carbonitrile; (3R,5S)-1-[3-formyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrrolidine-3-carbonitrile; 5-methyl-1-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-3-(2,2,2-trifluoroacetyl)-2-pyridyl]pyrazole-3-carbonitrile; 1-[3-acetyl-6-[6-keto-7,7-dimethyl-5-(6-methylpyridazin-3-yl)pyrrolo[2,3-f]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-formyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-acetyl-6-[5-[(2-keto-1-methyl-3-pyridyl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-acetyl-6-[5-(3-methoxy-1-methyl-pyrazol-4-yl)benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-acetyl-6-[5-[(6-pyrrolidin-2-ylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; and 1-[3-formyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile; 3. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from:

13. A process for the preparation of a compound according to claim 1 or 2, comprising the steps of: (a) reacting a compound represented by formula (B1) or (B2) in the presence of a palladium catalyst and a base 【Chemistry 2】 with an amine, (b) in the presence of a base, a compound of formula (C1) 【Transformation 3】 and a compound of formula (C2) 【Chemistry 4】 Reaction with compounds of (c) reacting a compound represented by formula (D1) in the presence of a base 【Transformation 5】 with an amine, or (d) reacting a compound of formula (D1) with a compound (D2) in the presence of a base and a palladium catalyst, wherein D2 is selected from (i) an optionally substituted aryl boronic acid or ester, and (ii) an optionally substituted heteroaryl boronic acid or ester; A1, R １ , R ２ , R ３ , R ４ and R ５ is as defined in claim 1 or 2, and R ａ is alkyl or cycloalkyl, and R ｂ is hydrogen or alkyl, and R ｃ is alkyl or cycloalkyl and X is halogen.

14. 3. A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

15. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 or 2 or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier.

16. 16. The pharmaceutical composition of claim 15 for the treatment or prevention of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis.

17. 10. Use of a compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis.

18. 3. A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis.

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