Benzimidazole derivatives useful as SIK modulators

Abstract

The invention relates to a compound of formula (I), wherein L, R1, R2 and R3 are as defined in the description and in the claims. The compounds of formula (I) are useful as medicaments. # imgabs0 #

Description

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

[0002] The present invention particularly relates to a compound of formula (I),

[0003]

[0004] in

[0005] R 1 is optionally selected individually from R 4 substituted with 1, 2 or 3 substituents;

[0006] R 2 is hydrogen, alkoxy, halogen, dialkylaminoalkoxy, heteroarylamino or heterocycloalkyloxy; wherein heteroarylamino and heterocycloalkyloxy are optionally independently selected from R 5 substituted with 1, 2 or 3 substituents; R 3 is hydrogen, alkyl, dialkylaminoalkyl, heterocycloalkyl or heteroaryl; wherein heteroaryl and heterocycloalkyl are optionally independently selected from R 6 substituted with 1, 2 or 3 substituents;

[0007] R 4 Each instance of is independently selected from cyano, alkyl, alkoxy, halogen, haloalkoxy, and haloalkyl; R 5 Each instance of is independently selected from alkyl and dialkylaminocarbonyl;

[0008] R 6 Each instance of is independently selected from alkyl, heterocycloalkyl, (heterocycloalkyl)heterocycloalkyloxy, (alkoxy)heterocycloalkylalkyl, and dialkylaminocarbonyl; and L is absent, -O-, or -NH-;

[0009] or a pharmaceutically acceptable salt thereof.

[0010] Salt-inducible kinases (SIKs) belong to the AMP-activated protein kinase (AMPK) subfamily, known as AMPK-related kinases. There are three members, named SIK1, SIK2, and SIK3, and their expression range is wide. Their main biological role is to modify gene expression by controlling the phosphorylation and subcellular localization of two key transcriptional regulatory factors: CRTC (cAMP-regulated transcriptional coactivators) and class IIa HDACs (histone deacetylases). In fact, in the basal state, both CRTC and HDAC are phosphorylated by SIK kinases and sequestered in the cytoplasm by interacting with their cytoplasmic partner 14-3-3. In response to extracellular signals that usually increase intracellular cAMP levels, the activity of SIK kinases is inhibited, CRTC and HDAC are no longer phosphorylated, and are therefore released from 14-3-3. Therefore, they can translocate to the nucleus and regulate gene expression (reviewed by Wein et al., Trends Endocrinol Metab. 2018 Oct; 29(10): 723-735).

[0011] In macrophages, inhibition of SIK kinases results in 1) shuttling of CRTC3 to the nucleus and increased transcription of IL-10; 2) translocation of HDAC4 / 5 into the nucleus and subsequent deacetylation of NF-κB, leading to decreased transcription of proinflammatory cytokines (Clark et al., Proc Natl Acad Sci US A. 2012 Oct 16;109(42):16986-91.).

[0012] Macrophages are crucial for maintaining tissue homeostasis, mediating inflammation, and promoting its resolution. To achieve this functional diversity, macrophages have the ability to undergo distinct "polarizations" in response to environmental cues. The two extreme phenotypes along their activation state continuum are "M1," or "pro-inflammatory macrophages," and "M2," or "pro-resolving macrophages."

[0013] Strikingly, inhibition of intracellular SIK kinases overrides these extracellular macrophage polarization signals and pushes them toward a pro-resolving phenotype. This is accompanied by an increase in IL-10 (via interference with the SIK-CRTC3 pathway) and a concomitant decrease in TNF-α, IL-12, and IL-6 (via interference with the SIK-HDAC4 / 5 and NF-κB pathways). High levels of IL-10 and low levels of pro-inflammatory cytokines following SIK inhibition promote resolution of inflammation. Exploration of the SIK pathway was initially described in macrophages (Clark et al., Proc Natl Acad Sci US A. 2012 Oct 16;109(42):16986-91) and dendritic cells (Sundberg et al., Proc Natl Acad Sci US A. 2014 Aug 26;111(34):12468-73), and the therapeutic potential of pan-SIK inhibitors has been demonstrated in mouse LPS (lipopolysaccharide) challenge models (Sundberg et al., ACS Chem Biol. 2016 Aug 19;11(8):2105-11) and colitis models (Fu et al., Inflamm Bowel Dis. 2021 Oct 20;27(11):1821-1831). Since then, SIK has 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 does not affect SIK1, thereby limiting potential SIK1-related toxicity.

[0014] SIK inhibitors have high therapeutic potential in the following diseases: 1) diseases characterized by the influx of proinflammatory macrophages into tissues and impaired tissue homeostasis and healing function, or 2) diseases that benefit (partially or completely) from anti-TNF therapy or in which IL10 levels are insufficient. Diseases with inflammatory macrophage characteristics are, 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.

[0015] IBD is a disease that has been shown to be associated with IL-10 and TNF-α. Genetic alterations that reduce IL-10 function (such as SNPs in IL-10 or its receptor) are associated with an increased risk of IBD in humans. Furthermore, anti-TNF therapy is successful, but only a small fraction of IBD patients respond, and most of this limited response disappears over time. The dual action of the described SIK inhibitors (increasing IL-10 and reducing TNF-α) makes them particularly suitable for the treatment of IBD.

[0016] All three SIK kinase isoforms are widely expressed in human tissues, with the highest expression of SIK1 observed in skin and adipose tissue, SIK2 in adipose tissue, and SIK3 in testis and brain. Similar to their roles in macrophages, SIKs in these cells phosphorylate CRTCs and class II HDACs in response to extracellular signals, subsequently altering the expression of several cytokines.

[0017] In addition to its physiological role, there are reports that dysregulated SIK expression is associated with some diseases. For example, SIK2 has been described as a risk site for primary sclerosing cholangitis, a fibrotic disease often associated with IBD. In addition, SIK2 and SIK3 are highly expressed in ovarian and prostate cancers and are associated 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).

[0018] To date, many diseases caused by innate immune system disorders lack effective treatments, and there is an unmet medical need for new therapies. 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 may also have potential relevance in cancer, metabolic diseases, bone density disorders, pigmentation-related diseases or cosmetic, fibrotic diseases, and depression.

[0019] In this specification, the term "alkyl" refers, alone or in combination, 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 and more particularly a straight or branched chain alkyl group having 1 to 4 carbon atoms. Examples of straight and branched C1-C8 alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, isomeric amyls, isomeric hexyls, isomeric heptyls and isomeric octyl groups, particularly methyl, ethyl, propyl, butyl and amyl. The specific example of an alkyl group is methyl, ethyl, propyl, isopropyl, butyl and isobutyl. Methyl, ethyl, propyl and butyl, such as isobutyl, are further specific examples of "alkyl" in compounds of formula (I).

[0020] The term "heterocycloalkyl" refers to a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system having 4 to 12 ring atoms, either alone or in combination, comprising 1, 2 or 3 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon. Bicyclic means forming two rings with one or two common ring atoms."heterocycloalkyl" can include a carbonyl group, wherein carbon is a part for a ring system. The ring system can be connected to the remaining compound by an atom selected from C, N, S and O, particularly by an N atom ("N-heterocycloalkyl").Examples of “heterocycloalkyl” include, but are not limited to, morpholino, morpholin-4-yl, pyrrolidinyl, pyrrolidin-1-yl, pyrrolidin-3-yl, piperidinyl, 1-piperidinyl, 4-piperidinyl, 2-oxopyrrolidin-1-yl, piperazinyl, piperazin-1-yl, azetidinyl, azetidin-1-yl, [3-oxo-piperazin-1-yl], (1,1-dioxo-1,2-thiazolidin-2-yl), (4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl), (3-oxo-1,5,6,8-tetrahydrooxazolo[3,4-a]pyrazin-7-yl), [rac-(3aR,6aS)-2, 3,3a,5,6,6a-hexahydro-1H-pyrrolo[3,2-b]pyrrol-4-yl], [rac-(3aS,6aR)-2,3,3a,5,6,6a-hexahydro-1H-pyrrolo[3,2-b]pyrrol-4-yl], (4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-3-yl), (6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl), (4,7-diazaspiro[2.5]octan-7-yl), (2-oxa-5,8-diazaspiro[3.5]nonan-8-yl), 3-azabicyclo[3.2.0]heptan-3-yl ), (5-azaspiro[2.4]heptane-5-yl), (2-azabicyclo[2.2.1]heptane-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-piperidinyl), (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-piperidinyl), 2-oxo-4-piperidinyl, 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 piperidinyl and oxetanyl, more particularly 4-piperidinyl and oxetan-3-yl. In a particular embodiment, the heterocycloalkyl is "N-heterocycloalkyl."

[0021] The term "heterocycloalkyloxy" alone or in combination represents an "oxy" group attached to a "heterocycloalkyl" group.

[0022] The term "heterocycloalkylalkyl", alone or in combination, signifies an "alkyl" group in which at least one of the hydrogen atoms of the alkyl group has been replaced by a "heterocycloalkyl" group.

[0023] The term "heteroaryl", alone or in combination, means an aromatic monocyclic or bicyclic ring system having 5 to 12 ring atoms, which contains 1, 2, 3 or 4 heteroatoms each independently selected from N, O and S, the remaining ring atoms being carbon. The ring system may be linked to the rest of the compound via an atom selected from C, N, S and O, in particular via a N atom ("N-heteroaryl"). Examples of heteroaryl groups include, but are not limited to, pyrazolyl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyridinyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 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, furanyl, 2-furanyl, 3-furanyl, [6-oxo]- [4,5-b][1,4]oxazin-8-yl], pyrazol-1-yl, pyrazol-2-yl, 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-pyridinyl) and (2,3-dihydropyridazino[4,5-b][1,4]oxazin-8-yl). Specific examples of "heteroaryl" are pyrazolyl and pyridazinyl, more particularly pyrazol-1-yl, pyrazol-4-yl and pyridazin-3-yl. In a specific embodiment, heteroaryl is "N-heteroaryl".

[0024] The term "heteroarylamino" alone or in combination signifies an "amino" group in which one of the hydrogen atoms of the amino group is replaced by a "heteroaryl" group.

[0025] The term "alkoxy" or "alkyloxy", alone or in combination, refers to a radical of the formula "alkyl-O-", wherein the term "alkyl" has the meaning given previously, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. Specific examples of "alkoxy" are methoxy and ethoxy.

[0026] The term "oxy" alone or in combination refers to an -O- group.

[0027] The term "cyano" alone or in combination refers to a carbon atom connected via a triple bond to a nitrogen atom; this group is also known as a nitrile group.

[0028] The term "halogen" or "halo" alone or in combination denotes fluorine, chlorine, bromine or iodine and is particularly fluorine, chlorine or bromine, more particularly fluorine. The term "halo" in combination with another group denotes that the group is substituted with at least one halogen, particularly with one to five halogens, in particular one to four halogens, i.e. one, two, three or four halogens.

[0029] The term "haloalkyl", alone or in combination, means an alkyl group substituted with at least one halogen, particularly one to five halogens, especially one to three halogens, more especially two to three halogens. Specific "haloalkyl" groups are fluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl, difluoromethyl, difluoroethyl, trifluoromethyl and trifluoroethyl. More specific "haloalkyl" groups are difluoromethyl and trifluoroethyl.

[0030] The term "haloalkoxy", alone or in combination, means an alkoxy group substituted with at least one halogen, particularly with one to five halogens, especially one to three halogens. Particular "haloalkoxy" is difluoromethoxy.

[0031] The term "hydroxyl" or "hydroxyl", alone or in combination, refers to a -OH group.

[0032] The term "carbonyl," alone or in combination, refers to a -C(O)- group.

[0033] The term "amino" alone or in combination means a primary amino group (-NH2), a secondary amino group (-NH-) or a tertiary amino group (-N-).

[0034] The term "alkylamino" is an alkyl group attached to an -NH- group. The term "dialkylamino" refers to two alkyl groups attached to an -N- atom. Examples of "dialkylamino" groups are, for example, dimethylamino, diethylamino, and (methyl)(ethyl)amino.

[0035] The term "dialkylaminocarbonyl" alone or in combination represents a "carbonyl" group attached to a "dialkylamino" group.

[0036] The term "dialkylaminoalkoxy", alone or in combination, signifies an "alkoxy" group in which at least one of the hydrogen atoms of the alkoxy group has been replaced by a "dialkylamino" group.

[0037] The term "dialkylaminoalkyl", alone or in combination, signifies an "alkyl" group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a "dialkylamino" group.

[0038] The term "pharmaceutically acceptable salt" means a salt that is not biologically or otherwise undesirable. "Pharmaceutically acceptable salt" includes both acid addition salts and base addition salts. "Pharmaceutically acceptable acid addition salts" refers to those formed with inorganic acids and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, etc., and the organic acid can be selected from aliphatic, alicyclic, aromatic, aromatic aliphatic, heterocyclic, carboxylic and sulfonic organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, pamoic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid, etc. The term "pharmaceutically acceptable base addition salt" refers to those formed with organic or inorganic bases. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese and aluminum salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines and basic ion exchange resins (such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine and polyamine resins). Specific pharmaceutically acceptable salts of the compounds of the present invention are salts formed with formic acid.

[0039] The term "one or more compounds of the present invention" refers to compounds of formula (I) and stereoisomers, tautomers, solvates, and salts (eg, pharmaceutically acceptable salts) thereof.

[0040] Tautomeric forms, ie structural isomers which are interconvertible with the compounds of formula (I), may exist under certain circumstances, in particular in solution, and are to be understood as being included in the present invention.

[0041] If one of the starting materials or compounds of formula (I) contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups may be introduced before the key steps using methods known in the art (as described, for example, in "Protective Groups in Organic Chemistry" by TW Greene and PGM Wuts, 3rd edition, 1999, Wiley, New York). 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-butyloxycarbonyl (Boc), 9-fluorenylmethylcarbamate (Fmoc), 2-trimethylsilylethylcarbamate (Teoc), benzyloxycarbonyl (Cbz) and p-methoxybenzyloxycarbonyl (Moz).

[0042] The compounds of formula (I) may contain several asymmetric centers and may exist in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates.

[0043] The term "asymmetric carbon atom" means a carbon atom having four different substituents. According to the Cahn-Ingold-Prelog sequence rules, an asymmetric carbon atom can be in the "R" or "S" configuration.

[0044] Furthermore, the present invention includes all optical isomers of the compounds of formula (I) where applicable, ie diastereomers, diastereomeric mixtures, racemic mixtures, all corresponding enantiomers and / or tautomers thereof and solvates thereof.

[0045] If desired, the racemic mixture of the compounds of the invention can be separated to isolate the individual enantiomers. Separation can be performed by methods well known in the art, such as coupling the racemic mixture of the compound to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods such as fractional crystallization or chromatography.

[0046] In some embodiments providing optically pure enantiomers, optically pure enantiomers mean that the compound contains >90% by weight of the desired isomer, particularly >95% by weight of the desired isomer, or more particularly >99% by weight of the desired isomer, the weight percentages being based on the total weight of the isomers of the compound. Chirally pure compounds or chirally enriched compounds can be prepared by chiral selective synthesis or by separation of enantiomers. Separation of enantiomers can be performed on the final product or, alternatively, on a suitable intermediate.

[0047] The structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Specific examples of radioactive isotopes are 2 H. 3 H. 13 C. 14 C and 18 F. For example, one or more hydrogen atoms are replaced by deuterium or tritium, or one or more carbon atoms are enriched 13 C or 14 Structures in which the carbon of C is replaced are within the scope of the present invention.

[0048] Therefore, the present invention relates to:

[0049] According to the compound of the present invention, wherein R 1 is selected from pyrazolyl and pyridinyl, wherein pyrazolyl and pyridinyl are optionally independently selected from R 4 substituted with 1, 2 or 3 substituents;

[0050] According to the compound of the present invention, wherein R 1 is optionally selected individually from R 4 pyrazolyl substituted with 1, 2 or 3 substituents;

[0051] According to the compound of the present invention, wherein R 2 is hydrogen, alkoxy, halogen, dialkylaminoalkoxy, pyridazinylamino or oxetanyloxy; wherein pyridazinylamino and oxetanyloxy are optionally independently selected from R 5 substituted with 1, 2 or 3 substituents;

[0052] According to the compound of the present invention, wherein R 2 is hydrogen, methoxy, fluorine, dimethylaminoethoxy, pyridazinylamino or oxetanyloxy, wherein pyridazinylamino and oxetanyloxy are optionally independently selected from R 5 substituted with 1, 2 or 3 substituents;

[0053] According to the compound of the present invention, wherein R 3 is hydrogen, alkyl, dialkylaminoalkyl, piperidinyl, oxetanyl or pyridazinyl; wherein piperidinyl, oxetanyl and pyridazinyl are optionally independently selected from R 6 substituted with 1, 2 or 3 substituents;

[0054] According to the compound of the present invention, wherein R 3 is hydrogen, methyl, dimethylaminoethyl, piperidinyl, oxetanyl or pyridazinyl; wherein piperidinyl, oxetanyl and pyridazinyl are optionally selected from R 6 substituted with 1, 2 or 3 substituents;

[0055] According to the compound of the present invention, wherein R 4 is independently selected in each instance from cyano, alkyl, haloalkoxy, and haloalkyl;

[0056] According to the compound of the present invention, wherein R 4 independently selected in each instance from cyano, methyl, difluoromethoxy, difluoromethyl, and trifluoroethyl;

[0057] According to the compound of the present invention, wherein R 5 independently selected in each instance from methyl and dimethylaminocarbonyl;

[0058] According to the compound of the present invention, wherein R 6 In each instance, independently selected from alkyl, oxetanyl, (oxetanyl)piperidinyloxy, (methoxy)azetidinylethyl and dialkylaminocarbonyl; according to the compound of the present invention, wherein R 6 In each instance, independently selected from methyl, oxetanyl, (oxetanyl)piperidinyloxy, (methoxy)azetidinylethyl and dimethylaminocarbonyl; According to the compound of the present invention, wherein L is -NH-;

[0059] The compound according to the present invention, wherein L is absent;

[0060] According to the compound of the present invention, wherein L is -O-;

[0061] The compound according to the present invention, wherein the compound of formula (I) exists in the form of a free base; and

[0062] A pharmaceutically acceptable salt of a compound according to formula (I) as described herein.

[0063] The present invention further relates to a compound of formula (I) selected from 2-(3-cyano-5-methyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile;

[0064] 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile;

[0065] 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile;

[0066] 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[2-(dimethylamino)ethoxy]-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile;

[0067] 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[2-(dimethylamino)ethoxy]-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile;

[0068] 6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile;

[0069] 6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile;

[0070] 3-[[3-[5-Cyano-6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-2-pyridinyl]benzimidazol-5-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide;

[0071] 3-[[1-[5-Cyano-6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-2-pyridinyl]benzimidazol-5-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide;

[0072] 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile;

[0073] 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]-5-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile;

[0074] 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-fluoro-5-[[6-[[1-(oxetan-3-yl)-4-piperidinyl]oxy]pyridazin-3-yl]amino]benzimidazol-1-yl]pyridine-3-carbonitrile;

[0075] 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-fluoro-5-[[6-[2-(3-methoxyazetidin-1-yl)ethyl]pyridazin-3-yl]amino]benzimidazol-1-yl]pyridine-3-carbonitrile;

[0076] 2-[3-(Difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]-5-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile;

[0077] 2-[3-(Difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile;

[0078] 2-[3-(Difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile;

[0079] 2-[3-(Difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[5-methoxy-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile;

[0080] 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-(3-methyloxetan-3-yl)oxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile;

[0081] 2-[2-(difluoromethoxy)-5-methyl-4-pyridinyl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile;

[0082] 2-[3-(Difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[5-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile; and

[0083] 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[[1-(oxetan-3-yl)-4-piperidinyl]amino]benzimidazol-1-yl]pyridine-3-carbonitrile;

[0084] or a pharmaceutically acceptable salt thereof.

[0085] The present invention further specifically relates to a compound of formula (I) selected from 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile;

[0086] 6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile;

[0087] 6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile;

[0088] 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile;

[0089] 2-[3-(Difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile;

[0090] 2-[3-(Difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; and

[0091] 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-(3-methyloxetan-3-yl)oxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile;

[0092] or a pharmaceutically acceptable salt thereof.

[0093] One embodiment of the present invention relates to a compound according to the present invention, wherein the compound is a compound of formula (IIa)

[0094]

[0095] Among them, L, R 2 and R 3 As described in this article; R 4 is selected from cyano, haloalkyl and haloalkoxy, in particular selected from cyano, difluoromethoxy, difluoromethyl and trifluoroethyl.

[0096] One embodiment of the present invention relates to a compound according to the present invention, wherein the compound is of formula (IIb)

[0097]

[0098] Among them, L, R 2 and R 3 As described in this article; R 4 is selected from cyano, haloalkyl and haloalkoxy, in particular selected from cyano, difluoromethoxy, difluoromethyl and trifluoroethyl.

[0099] One embodiment of the present invention relates to a compound according to the present invention, wherein the compound is of formula (IIc)

[0100]

[0101] Among them, L, R 2 and R 3 As described in this article; R 4 is selected from cyano, haloalkyl and haloalkoxy, in particular selected from cyano, difluoromethoxy, difluoromethyl and trifluoroethyl.

[0102] One embodiment of the present invention relates to a compound according to the present invention, wherein the compound is of formula (III)

[0103]

[0104] Among them, L, R 1 、R 2 、R 4 and R 5 As described herein; and R 6 and independently in each instance selected from methyl, oxetanyl, (oxetanyl)piperidinyloxy, (methoxy)azetidinylethyl, and dimethylaminocarbonyl.

[0105] General synthetic scheme

[0106] The synthesis of compounds of formula (I) can be accomplished, for example, according to the non-exhaustive procedures in general schemes 1 to 4 described below. In some cases, the order of the reaction steps can be changed and the individual steps of the different schemes can be combined in different ways as disclosed herein and according to common general knowledge. In general, the reaction conditions and reaction conditions provided below can in some cases be further modified according to the procedures described herein and according to common general knowledge.

[0107] Solution 1

[0108] In Scheme 1, the synthesis of compounds of formula (Ia) or (I-a') is described. Compounds of formula (Ia) are compounds of formula (I) wherein R2 is hydrogen, alkoxy, halogen, dialkylaminoalkoxy, heteroarylamino or heterocycloalkyloxy; wherein heteroarylamino and heterocycloalkyloxy are optionally independently selected from R as described herein 5 substituted with 1, 2 or 3 substituents; R 1 The pyrazole R 4 and R 4 'substituted, where R 4 and R 4 'Independently selected from cyano, alkyl, haloalkoxy and haloalkyl; L is -NH-; R3 is pyridazinyl, wherein the pyridazinyl is optionally substituted by one, two or three R 6 Group substitution, where R 5 is independently selected in each instance from alkyl, heterocycloalkyl, (heterocycloalkyl)heterocycloalkyloxy, (alkoxy)heterocycloalkylalkyl and dialkylaminocarbonyl. The compound of formula (Ia') is a compound of formula (I) wherein R 3 is hydrogen, alkoxy, halogen, dialkylaminoalkoxy, heteroarylamino or heterocycloalkyloxy; wherein heteroarylamino and heterocycloalkyloxy are optionally independently selected from R as described herein 5 substituted with 1, 2 or 3 substituents; R 1 The pyrazole R 4 and R 4 'substituted, where R 4 and R 4 ' is independently selected from cyano, alkyl, haloalkoxy and haloalkyl; R 2 is a pyridazinyl group, wherein R 2 The pyridazinyl group is optionally substituted by one, two or three R 5 Group substitution, where R 5 In each instance, R2 / R3 are independently selected from alkyl, heterocycloalkyl, (heterocycloalkyl)heterocycloalkyloxy, (alkoxy)heterocycloalkylalkyl, and dialkylaminocarbonyl. In the following schemes, R2 / R3 are hydrogen, alkoxy, halogen, dialkylaminoalkoxy, heteroarylamino, or heterocycloalkyloxy. In the following schemes, R5 / R6 are independently selected from alkyl, heterocycloalkyl, (heterocycloalkyl)heterocycloalkyloxy, (alkoxy)heterocycloalkylalkyl, and dialkylaminocarbonyl.

[0109]

[0110] Step A: 6-Chloro-2-fluoro-pyridine-3-carbonitrile 1 can be reacted with a substituted pyrazole 2 in the presence of a suitable organic or mineral base such as, for example, DIPEA, DBU, K2CO3, Cs2CO3 or NaH in a suitable polar solvent such as DMF, DMA, NMP, DMSO or THF, MeTHF at a temperature ranging from about -10°C to about 120°C to give intermediate 3.

[0111] Step B: Intermediates 3 and 4 can be reacted in the presence of a suitable organic or mineral base such as, for example, DIPEA, DBU, K2CO3, Cs2CO3 or NaH in a suitable polar solvent such as, for example, DMF, DMA, NMP, DMSO or THF, MeTHF at a temperature ranging from about -10°C to about 120°C to give regioisomeric compounds Ia and I-a' which can be separated by flash column chromatography or preparative HPLC or preparative TLC.

[0112] Alternatively, intermediates 3 and 4 can be reacted under Buchwald-Hartwig coupling conditions using a suitable base (such as, for example, Cs2CO3, K2CO3, or K3PO4) and a suitable palladium catalyst (such as, for example, t-Buxphos-Pd-G3 or [tBuBrettPhosPd(allyl)]OTf) in a suitable solvent (such as, for example, t-pentanol) at between about 80°C and about 90°C to give regioisomeric compounds Ia and I-a', which can be separated by flash column chromatography or preparative HPLC or preparative TLC.

[0113] Option 2

[0114] In Scheme 2, the synthesis of compounds of formula (8) is described, wherein A is selected from alkyl, dialkylaminoalkyl, heteroaryl and heterocycloalkyl; wherein heteroaryl and heterocycloalkyl are optionally selected individually from R as described herein. 5 substituted with 1, 2 or 3 substituents.

[0115]

[0116] Step A: (4-Bromo-5-fluoro-2-nitro-phenyl)amine 5 and alcohol 6 can be reacted in the presence of a suitable organic or mineral base such as, for example, NaH, Cs2CO3 or DBU in a suitable solvent such as THF, MeTHF or dioxane at a temperature ranging from about -10°C to about 120°C to give intermediate 7.

[0117] Step B: The nitro group of intermediate 7 can be reduced in the presence of a metal reducing agent (such as, for example, Zn or Fe), an acid (such as, for example, AcOH or HCl), in a suitable polar protic solvent (such as, for example, MeOH or EtOH) at a temperature ranging from about -50°C to about 120°C to give the diamino intermediate 8.

[0118] Alternatively, the nitro group of intermediate 7 can be reduced in the presence of hydrogen in the presence of a catalyst such as, for example, Pd on charcoal in a suitable polar protic solvent such as, for example, MeOH or EtOH at a temperature ranging from about -10°C to about 65°C to give the diamino intermediate 8.

[0119] Step C: The diamino intermediate 8 is cyclized in the presence of an orthoformate such as trimethyl orthoformate, for example triethyl orthoformate, which can be used as a reaction solvent to give the benzimidazole intermediate 9.

[0120] Option 3

[0121] In Scheme 3, the synthesis of compounds of formula (4) is described, wherein R 2 is selected from hydrogen, alkoxy, halogen, dialkylaminoalkoxy, heteroarylamino and heterocycloalkyloxy; wherein heteroarylamino and heterocycloalkyloxy are optionally independently selected from R as described herein 5 1, 2 or 3 substituents of substituted; pyridazinyl is optionally substituted by one, two or three R 6 Group substitution, where R 6 and (alkoxy)heterocycloalkylalkyl, (alkoxy)heterocycloalkyloxy, and dialkylaminocarbonyl.

[0122]

[0123] Step A: Intermediate 10 and SEM-Cl can be reacted in the presence of a suitable organic or mineral base such as, for example, NaH, Cs2CO3, or DBU in a suitable polar solvent such as, for example, DMF, DMA, or NMP at a temperature ranging from about -50°C to about 120°C to give regioisomeric intermediates 11-a and 11-b.

[0124] Step B: Introduction of aminopyridazine 12 can be carried out via Buchwald-Hartwig coupling using a suitable base (such as, for example, Cs2CO3 K2CO3 or K3PO4) and a suitable palladium catalyst (such as, for example, t-Buxphos-Pd-G3 or [tBuBrettPhosPd(allyl)]OTf) in a suitable solvent (such as, for example, 1,4-dioxane) at between about 80°C and about 90°C to provide intermediates 13-a and 13-b.

[0125] Step C: The regioisomeric mixture of intermediates 13-a and 13-b can be combined with a strong acid (such as, for example, TFA) with or without a suitable solvent (such as, for example, DCM) to give intermediate 4.

[0126] Option 4

[0127] In Scheme 4, the synthesis of compounds of formula (Ib) or (I-b') is described. Compounds of formula (Ib) or (I-b') are compounds of formula (I) wherein R 1 is optionally selected individually from R 4 substituted heteroaryl with 1, 2 or 3 substituents; R 2 is hydrogen, alkoxy, halogen, dialkylaminoalkoxy, heteroarylamino or heterocycloalkyloxy; wherein heteroarylamino and heterocycloalkyloxy are optionally independently selected from R 5 substituted with 1, 2 or 3 substituents; R 3 is hydrogen, alkyl, dialkylaminoalkyl, heterocycloalkyl or heteroaryl; wherein heteroaryl and heterocycloalkyl are optionally independently selected from R 6 substituted with 1, 2 or 3 substituents; L is absent, -O- or -NH-.

[0128]

[0129] Step A: 2,6-Dichloronicotinonitrile 14 and intermediate 15 can be reacted in the presence of a suitable organic or mineral base (such as, for example, DIPEA, DBU, K2CO3, Cs2CO3, or NaH) in a suitable polar solvent (such as, for example, DMF, DMA, NMP, DMSO, or THF, MeTHF) at a temperature ranging from about -10°C to about 120°C to give regioisomeric intermediates 16-a and 16-b.

[0130] Step B: Palladium-catalyzed cross-coupling reaction (Suzuki-Miyaura) between intermediate (16-a) and / or (16-b) with the corresponding arylboronic acid R1B(OH)2 or arylpinacolborane R1Bpin, over a palladium catalyst (such as, for example, P(Ph3)4 or Pd(dppf)Cl2.CH2Cl2 or other suitable Pd catalyst) and a suitable base (K3PO4, Cs2CO3, K2CO3, Na2CO3), in a suitable solvent (such as, for example, a mixture of 1,4-dioxane and water) upon heating (e.g., at a temperature between about 80°C and about 110°C or via microwave irradiation at a temperature between about 80°C and about 120°C) affords a regioisomeric mixture of compounds of formula (Ia) and (Ib') which can be separated by flash column chromatography or preparative HPLC or preparative TLC.

[0131] Option 5

[0132] In Scheme 5, the synthesis of compounds of formula (Ic) or (I-c') is described. Compounds of formula (Ic) or (I-c') are compounds of formula (I) wherein R 1 is optionally selected individually from R as described herein 4 substituted heteroaryl with 1, 2 or 3 substituents; R 2 is hydrogen, alkoxy, halogen, dialkylaminoalkoxy, heteroarylamino or heterocycloalkyloxy; wherein heteroarylamino and heterocycloalkyloxy are optionally independently selected from R as described herein 5 substituted with 1, 2 or 3 substituents; R 3 is hydrogen, alkyl, dialkylaminoalkyl, heterocycloalkyl or heteroaryl; wherein heteroaryl and heterocycloalkyl are optionally independently selected from R 6 1, 2 or 3 substituents of substituted; pyridazinyl is optionally substituted by one, two or three R 6 Group substitution, where R 6 and (alkoxy)heterocycloalkylalkyl, (alkoxy)heterocycloalkyloxy, and dialkylaminocarbonyl.

[0133]

[0134] Step A: Introduction of aminopyridazines 12 onto intermediates 17-a and 17-b (as single compounds or as regioisomeric mixtures of two compounds) can be carried out via Buchwald-Hartwig coupling using a suitable base such as, for example, Cs2CO3, K2CO3 or K3PO4 and a suitable palladium catalyst such as, for example, t-Buxphos-Pd-G3 or [tBuBrettPhosPd(allyl)]OTf in a suitable solvent such as, for example, 1,4-dioxane at between about 80°C and about 90°C to afford compounds of formula (Ic) and (I-c') or regioisomeric mixtures thereof, which can be separated by flash column chromatography or preparative HPLC or preparative TLC.

[0135] Therefore, the present invention also relates to a process for preparing a compound according to the invention, which comprises one of the following steps:

[0136] (a) making a compound of formula (A1)

[0137]

[0138] With the compound of formula (A2)

[0139]

[0140] reacting in the presence of a suitable solvent and in the presence of a suitable base;

[0141] (b) making the compound of formula (B1)

[0142]

[0143] With the compound of formula (B2)

[0144] R1B(OH)2,

[0145] R1Bpin or R1BF3K, neopentyl glycol (B2)

[0146] in the presence of a suitable solvent and a suitable catalyst, or

[0147] (c) making a compound of formula (C1) or (C2)

[0148]

[0149] With the compound of formula (C3)

[0150]

[0151] reacting in the presence of a suitable solvent, a suitable base and a suitable catalyst,

[0152] wherein X1 is halogen, OMs or OTs, especially halogen; X2 is halogen, especially chlorine; L, R 1 、R 2 、R 3 and R 6 As mentioned in this article;

[0153] In step (a), the solvent may be, for example, a polar solvent, particularly DMF, DMA, NMP, DMSO or THF, more particularly DMSO;

[0154] In step (a), the base may be, for example, an organic or mineral base, in particular DIPEA, DBU, K 2 CO 3 , Cs 2 CO 3 or NaH, more in particular K 2 CO 3 ;

[0155] Conveniently, the reaction of step (a) is carried out at a temperature of about 0°C to about 120°C, in particular at about 50°C to about 80°C;

[0156] Conveniently, the reaction of step (a) is carried out over a period of about 1 hour to about 48 hours, particularly between about 2 hours and about 24 hours, more particularly between about 2 hours and about 16 hours;

[0157] Conveniently, the reaction of step (a) is carried out in the presence of DMSO and in the presence of K2CO3 at a temperature of about 50°C to about 80°C for a period of about 2 hours to about 24 hours;

[0158] In step (b), the solvent may be, for example, water, 1,4-dioxane or a mixture thereof, in particular a mixture of water and 1,4-dioxane;

[0159] In step (b), the base may be, for example, K3PO4, Cs2CO3, K2CO3, Na2CO3, in particular K2CO3;

[0160] In step (b), the catalyst can be, for example, a Pd catalyst, particularly Pd(PPh3)2Cl2, Pd(PPh3)4, Pd(dppf)Cl2·CH2Cl2; or Pd(Oac)2 or Pd2(dba)3 and a phosphine ligand; more particularly Pd(PPh3)4, Pd(dppf)Cl2·CH2Cl2;

[0161] Conveniently, the reaction of step (b) is carried out at a temperature of about 60°C to about 120°C, particularly about 80°C to about 110°C;

[0162] Conveniently, the reaction of step (b) is carried out over a period of about 1 hour to about 48 hours, particularly between about 2 hours and about 24 hours, more particularly between about 4 hours and about 16 hours;

[0163] Conveniently, the reaction of step (b) is carried out in the presence of a mixture of water and 1,4-dioxane in the presence of K2CO3 at a temperature of about 80°C to about 120°C for a period of about 2 hours to about 48 hours.

[0164] In step (c), the solvent may be, for example, water, 1,4-dioxane or a mixture thereof, in particular 1,4-dioxane or a mixture of water and 1,4-dioxane;

[0165] In step (c), the base may be, for example, K2CO3, Cs2CO3 or K3PO4, in particular K2CO3;

[0166] In step (c), the catalyst may be, for example, a Pd catalyst, in particular t-Buxphos-Pd-G3 or [tBuBrettPhos Pd(allyl)]OTf);

[0167] Conveniently, the reaction of step (c) is carried out at a temperature of about 60°C to about 120°C, in particular about 80°C to about 100°C;

[0168] Conveniently, the reaction of step (c) is carried out over a period of about 1 hour to about 48 hours, particularly between about 2 hours and about 24 hours, more particularly between about 4 hours and about 16 hours;

[0169] Conveniently, the reaction of step (c) is carried out in the presence of a mixture of water and 1,4-dioxane in the presence of K2CO3 at a temperature of about 80°C to about 120°C for a period of about 2 hours to about 48 hours.

[0170] The present invention also relates to compounds according to the invention when manufactured by a process as described herein.

[0171] The present invention also particularly relates to:

[0172] A compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, for use as a therapeutically active substance;

[0173] A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, and a therapeutically inert carrier;

[0174] Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein 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, in particular inflammatory bowel disease (IBD);

[0175] Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein for preparing 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, in particular inflammatory bowel disease (IBD);

[0176] A compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, 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, in particular inflammatory bowel disease (IBD); and

[0177] A method for treating or preventing rheumatoid arthritis, juvenile rheumatoid arthritis, nonalcoholic 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 described herein or a pharmaceutically acceptable salt thereof.

[0178] Pharmaceutical composition

[0179] Another embodiment of the present invention provides a kind of pharmaceutical composition or medicine containing the compounds of this invention and treatment inert carrier, diluent or excipient, and uses the compounds of this invention to prepare the method for such composition and medicine.In one example, formula (I) compound can be by being mixed with physiologically acceptable carrier (i.e. carrier that is nontoxic to recipient under used dosage and concentration) at ambient temperature under suitable pH and desired purity and be formulated as Galenic (galenical) administration form.The pH of preparation depends mainly on the specific use and concentration of compound, but is preferably in the range of about 3 to about 8.In one example, formula (I) compound is prepared in the acetate buffer of pH 5.In another embodiment, formula (I) compound is sterile.Compound can be, for example, as solid or amorphous composition, as lyophilized preparation or as aqueous solution storage.

[0180] The compositions are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the timing of administration, and other factors known to practitioners.

[0181] The compounds of the present invention can 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 local treatment is required, intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.

[0182] The compounds of the present invention can be administered in any convenient administration form, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain conventional components of pharmaceutical preparations, for example, diluents, carriers, pH adjusters, sweeteners, fillers and other active agents.

[0183] Typical formulations are prepared by mixing the compound of the invention with a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel, Howard C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams and Wilkins, 2004; Gennaro, Alfonso R. et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams and Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulation may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, flavorings, flavorings, diluents and other known additives to provide an aesthetically pleasing presentation of the drug (e.g., a compound of the present invention or a pharmaceutical composition thereof) or to facilitate the preparation of a pharmaceutical product (e.g., a medicament).

[0184] The invention will now be illustrated by the following examples, which are non-limiting.

[0185] Examples

[0186] abbreviation

[0187] [tBuBrettPhos Pd(allyl)]OTf Allyl(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II) trifluoromethanesulfonate (CAS No. 1798782-15-6)

[0188] ACN acetonitrile

[0189] ATP adenosine triphosphate

[0190] aq. water-based

[0191] Boc tert-butyloxycarbonyl

[0192] CAS Chemical Abstracts Service

[0193] dba dibenzylideneacetone

[0194] DCM dichloromethane

[0195] DIPEA N,N-Diisopropylethylamine

[0196] DMF N,N-dimethylformamide

[0197] DMSO dimethyl sulfoxide

[0198] dppf 1,1'-ferrocenediyl-bis(diphenylphosphine)

[0199] eq. equivalent

[0200] ESI electrospray ionization

[0201] EtOAc

[0202] EtOH

[0203] FA Formic acid

[0204] HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0205] HPLC High-pressure liquid chromatography

[0206] iPrOH isopropyl alcohol

[0207] LCMS high performance liquid chromatography-mass spectrometry

[0208] MeOH methanol

[0209] Ms mesylate

[0210] NMR Nuclear Magnetic Resonance

[0211] NPLC normal phase liquid chromatography

[0212] PE petroleum ether

[0213] psi pounds per square inch

[0214] QToF Quadrupole Time of Flight

[0215] Rf retention factor

[0216] RT Room temperature

[0217] sat. saturated

[0218] tBuXPhosPdG3 [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]methanesulfonate palladium(II) (CAS No. 1447963-75-8)

[0219] Tf trifluoromethanesulfonyl

[0220] TFA trifluoroacetic acid

[0221] THF Tetrahydrofuran

[0222] TLC thin layer chromatography

[0223] Ts tosylate

[0224] TsOH Toluenesulfonic acid

[0225] UV

[0226] XantPhos (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine)

[0227] Example 1

[0228] 2-(3-cyano-5-methyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile

[0229]

[0230] Step 1: 6-Chloro-2-(3-cyano-5-methyl-pyrazol-1-yl)nicotinonitrile

[0231]

[0232] To a stirred solution of 6-chloro-2-fluoro-nicotinonitrile (250 mg, 1.60 mmol, 1.0 eq.) in N,N-dimethylformamide (4 mL) was added 5-methyl-1H-pyrazole-3-carbonitrile (205 mg, 1.92 mmol, 1.2 eq.) and KCO (221 mg, 1.60 mmol, 1.0 eq.) at room temperature under an argon atmosphere. Stirring was continued at room temperature for 2 hours and 30 minutes. The mixture was diluted with H2O (16 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with H2O (20 mL) and brine (20 mL), dried (MgSO4), filtered, and concentrated. The crude product was purified by flash chromatography (silica gel (20 g), 50% EtOAc in n-heptane) to give 6-chloro-2-(3-cyano-5-methyl-pyrazol-1-yl)nicotinonitrile (84 mg, 0.346 mmol, 22% yield) as a white solid. ESIpos[M+H] + 244.0

[0233] Step 2: 1H-Benzimidazol-5-yl-(6-methylpyridazin-3-yl)amine

[0234]

[0235] A mixture of 1H-benzimidazol-5-ylamine (2 g, 15.02 mmol, 1.0 eq.) and 3-chloro-6-methyl-pyridazine (2.32 g, 18.02 mmol, 1.2 eq.) in iPrOH (120 mL) was heated to 120 ° C. (oil bath temperature) under an argon atmosphere. Reflux stirring was continued for 3 x 9 hours (the reaction was stopped at the end of the day rather than left overnight. Some iPrOH was added the next day because some solvent was discharged from the flask during strong reflux. The mixture was cooled to room temperature and the solid was collected by filtration, washed with iPrOH and dried to give 1H-benzimidazol-5-yl-(6-methylpyridazin-3-yl)amine (2.516 g, 11.18 mmol, 74% yield) as a light brown solid. ESI pos[M+H] + 226.1

[0236] Step 3: 2-(3-cyano-5-methyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile

[0237]

[0238] To a stirred solution of 6-chloro-2-(3-cyano-5-methyl-pyrazol-1-yl)nicotinonitrile (79 mg, 0.324 mmol, 1.0 eq.) in dimethyl sulfoxide (3 mL) at room temperature under an argon atmosphere were added 1H-benzimidazol-5-yl-(6-methylpyridazin-3-yl)amine (81 mg, 0.324 mmol, 1.0 eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (74 mg, 73 uL, 0.486 mmol, 1.5 eq.). The mixture was heated to 85°C and stirred at this temperature for 1 hour and 30 minutes. The mixture was cooled to room temperature, diluted with EtOAc (15 mL), and washed with H2O (15 mL). The aqueous phase was extracted with EtOAc (3 x 15 mL). By the organic layer H that merges o (30mL) and salt solution (30mL) washing, dry (MgSO ), filter, and concentrate.Residual yellow solid is passed through to flash chromatography (silica gel, 0% to 15% MeOH in 20g, DCM) purifying, to obtain the light yellow solid of the mixture containing two kinds of regioisomers.This mixture is further purified to obtain 2- (3- cyano -5- methyl- pyrazoles -1- bases) -6- [5- [(6- methyl pyridazine -3- bases) amino] benzimidazolyl -1- bases] pyridine -3- carbonitrile (13mg, 0.030mmol, 9% yield) by preparation HPLC (Gemini NX, 12nm, 5 μm, 100x30mm, ACN / water+0.1% TEA) in light yellow solid.ESI pos[M+H] + 433.2

[0239] Example 2

[0240] 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile

[0241]

[0242] Step 1: 6-Chloro-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile

[0243]

[0244] To a solution of 6-chloro-2-fluoro-pyridine-3-carbonitrile (1.0 g, 6.39 mmol, 1.0 eq.) in DMSO (10 mL) was added 3-(difluoromethyl)-5-methyl-1H-pyrazole (844 mg, 6.39 mmol, 1.0 eq.) and K CO (2.477 mg, 19.16 mmol, 3.0 eq.) and stirred at 25 ° C for 1 hour. The reaction mixture was diluted with H O (20 mL) and extracted with EtOAc (3x10 mL). The combined organic phases were washed with salt water, dried (Na SO ), filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, 20 g, 30% EtOAc in petroleum ether) to give 6-chloro-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (800 mg, 2.98 mmol, 42% yield) as a white solid. ESI pos[M+H] + 268.9

[0245] 1 H NMR (400MHz, CDCl3) δ = 8.13 (d, J = 8.2Hz, 1H), 7.45 (d, J = 8.2Hz, 1H), 6.75 (t, J = 54.6Hz, 1H), 6.52 (s, 1H), 2.65 (s, 3H).

[0246] Step 2: 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; formic acid

[0247]

[0248] A mixture of 6-chloro-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (180 mg, 0.67 mmol, 1.0 eq.), N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine (151 mg, 0.67 mmol, 1.0 eq.), and KCO (278 mg, 2.01 mmol, 3.0 eq.) in DMSO (1 mL) was stirred at 50° C. for 2 hours. The reaction mixture was diluted with H O (10 mL) and extracted with ethyl acetate (3×5 mL). The combined organic layers were dried (Na SO ) and concentrated. The crude product was purified by preparative NPLC (ACSWH-PREP-NPLC-A, hexane-EtOH) to give two batches: crude 1 and crude 2.

[0249] The crude product 1 was further purified by preparative HPLC (ACS-WH-GX-F), ACN / water + 0.1% FA) to give 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; formic acid (27 mg, 0.06 mmol, 9% yield) as a yellow solid. ESI pos[M+H] + 457.9

[0250] 1 H NMR (400MHz, CD3OD) δ = 8.94 (br s,1H),8.56(d,J=8.6Hz,1H),8.26(s,1H),8.13(d,J=8.9Hz,1H),8.08(d,J=8.6Hz,1H),7.63(dd,J=2.0,9.0Hz, 1H), 7.36 (d, J = 9.2Hz, 1H), 7.12 (d, J = 9.2Hz, 1H), 6.83 (t, J = 54.5Hz, 1H), 6.64 (s, 1H), 2.62 (s, 3H), 2.53 (s, 3H).

[0251] Example 3

[0252] 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile

[0253]

[0254] The crude product 2 from Example 2, Step 2 was further purified by preparative HPLC (ACS-WH-GX-F), water / FA-ACN) to give 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; formic acid (25 mg, 0.06 mmol, 8% yield) as a yellow solid. ESI pos[M+H] + 457.9

[0255] 1H NMR (400MHz, CD3OD) δ=8.93(d,J=1.7Hz,1H),8.86(s,1H),8.63(d,J=8.4Hz,1H),8.10(d,J=8.6Hz,1H),7.71(d,J=8.7Hz,1H),7.49 (dd,J=2.1,8.8Hz,1H),7.37(d,J=9.2Hz,1H),7.15(d,J=9.2Hz,1H),6.83(t,J=54.5Hz,1H),6.60(s,1H),2.62(s,3H),2.55(s,3H).

[0256] Example 4

[0257] 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[2-(dimethylamino)ethoxy]-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile

[0258]

[0259] Step 1: 2-(5-Amino-2-bromo-4-nitro-phenoxy)ethyl-dimethyl-amine

[0260]

[0261] To a solution of 2-(dimethylamino)ethanol (2.21 g, 2.5 mL, 24.82 mmol, 1.8 eq.) in dry THF (50 mL) was added NaH (993 mg, 24.82 mmol, 1.8 eq.) at 0 ° C. The ice bath was removed and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled to 0 ° C. and (4-bromo-5-fluoro-2-nitro-phenyl)amine (3.24 g, 13.79 mmol, 1.0 eq.) was added, and the mixture was warmed to room temperature and stirred for 12 hours. The reaction was cooled to 0 ° C. and quenched with a saturated solution of NH4Cl (50 mL) and extracted with DCM (3x50 mL). The combined organic layer was dried (MgSO4), filtered, and concentrated. The crude product was purified by flash chromatography (SiNH2, 50 g, 0% to 10% MeOH in DCM) to give 2-(5-amino-2-bromo-4-nitro-phenoxy)ethyl-dimethyl-amine (4.068 g, 13.38 mmol, 97% yield). ESI pos[M+H] + 306.1

[0262] Step 2: 2-(4,5-Diamino-2-bromo-phenoxy)ethyl-dimethyl-amine

[0263]

[0264] Under Ar, 2-(5-amino-2-bromo-4-nitro-phenoxy)ethyl-dimethyl-amine (4.52 g, 13.38 mmol, 1.000 eq.) was dissolved in ethanol (189.4 mL). Active zinc (suspended in 1 M HCl, stirred for 30 minutes, filtered, washed with EtOH, and dried under vacuum) (8.74 g, 133.75 mmol, 10.0 eq.) was added, and the reaction mixture was cooled to 0°C. A solution of acetic acid (5.62 g, 5.36 mL, 93.63 mmol, 7.0 eq.) in ethanol (50 mL) was added dropwise while maintaining the temperature below 5°C. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was filtered, the filter cake washed with EtOH, and the solution evaporated to dryness. The crude product was quenched with 2N Na2CO3 solution (50 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine, dried (MgSO ), filtered and concentrated. The crude product was purified by flash chromatography (SiNH , 50 g, 0% to 10% MeOH in DCM) to give 2-(4,5-diamino-2-bromo-phenoxy)ethyl-dimethyl-amine (3.24 g, 11.82 mmol, 84% yield). ESI pos[M+H] + 274.2

[0265] Step 3: 2-[(6-Bromo-3H-benzimidazol-5-yl)oxy]ethyl-dimethyl-amine

[0266]

[0267] A solution of 2-(4,5-diamino-2-bromo-phenoxy)ethyl-dimethyl-amine (3.24 g, 11.82 mmol, 1.0 eq.) in trimethyl orthoformate (93.56 g, 96.45 mL, 881.62 mmol, 74.6 eq.) was stirred at 120 ° C for 3 hours. The reaction mixture was evaporated to dryness. The residue was dissolved in DCM (50 mL) and H2O (30 mL) was added. The organic layer was washed with brine (20 mL), dried (MgSO4), filtered and concentrated. The crude product was purified by flash chromatography (SiNH2, 50 g, 0% to 30% MeOH in DCM) to give 2-[(6-bromo-3H-benzimidazol-5-yl)oxy]ethyl-dimethyl-amine (984 mg, 3.464 mmol, 29% yield). ESI pos[M+H] + 284.2

[0268] Step 4: 2-[6-Bromo-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxyethyl-dimethyl-amine

[0269]

[0270] To a solution of 2-[(6-bromo-3H-benzimidazol-5-yl)oxy]ethyl-dimethyl-amine (805 mg, 2.69 mmol, 1.0 eq.) in DMF (6 mL) was added NaH (96.89 mg, 4.04 mmol, 1.500 eq.) in portions at 0°C. The resulting mixture was stirred at 0°C for 15 minutes. 2-(Trimethylsilyl)ethoxymethyl chloride (747 mg, 796 uL, 4.04 mmol, 1.5 eq.) was added dropwise and the temperature was maintained below 5°C. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was cooled to 0°C, quenched with saturated NaHCO solution (10 mL) and extracted with DCM (30 mL). The organic layer was washed with water (10 mL), brine (10 mL), dried (MgSO4), filtered and concentrated to give a mixture of 2-[6-bromo-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxyethyl-dimethyl-amine and 2-[6-bromo-1-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-N,N-dimethyl-ethylamine (455 mg, 1.10 mmol, 41% yield) which was used without further purification. ESI pos[M+H] + 416.3

[0271] Step 5: 6-[2-(Dimethylamino)ethoxy]-N-(6-methylpyridazin-3-yl)-1-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine

[0272]

[0273] Ar was bubbled through a suspension of a mixture of 2-[6-bromo-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxyethyl-dimethyl-amine and 2-[6-bromo-1-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-N,N-dimethyl-ethylamine (401 mg, 0.968 mmol, 1.0 eq.), (6-methylpyridazin-3-yl)amine (211 mg, 1.94 mmol, 2.0 eq.), and CsCO (946 mg, 2.9 mmol, 3.0 eq.) in dry 1,4-dioxane (14 mL) at room temperature for 5 minutes. [tBuBrettPhosPd(allyl)]OTf (151 mg, 0.194 mmol, 0.2 eq.) was then added, the vial was capped, and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was cooled, concentrated and purified by flash chromatography (silica gel, 12 g, 0% to 10% MeOH in DCM) to give a mixture of 6-[2-(dimethylamino)ethoxy]-N-(6-methylpyridazin-3-yl)-1-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine and 6-[2-(dimethylamino)ethoxy]-N-(6-methylpyridazin-3-yl)-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine (330 mg, 0.746 mmol, 77% yield). ESI pos [M+H] + 443.5

[0274] Step 6: Dimethyl-[2-[[6-[(6-methylpyridazin-3-yl)amino]-3H-benzimidazol-5-yl]oxy]ethyl]amine

[0275]

[0276] By 6-[2-(dimethylamino) ethoxy]-N-(6-methylpyridazine-3-yl)-1-(2-trimethylsilylethoxymethyl) benzimidazole-5-amine and 6-[2-(dimethylamino) ethoxy]-N-(6-methylpyridazine-3-yl)-3-(2-trimethylsilylethoxymethyl) benzimidazole-5-amine mixture (330mg, 0.746mmol, 1.0eq.) in TFA (4.88g, 3.3mL, 42.83mmol, 57eq.) solution in room temperature stirred 1 hour.Reaction mixture is concentrated to dryness, dissolved in DCM (30mL) and washed with 2N NaCO solution (10mL).Organic layer is washed with salt water (10mL), dried (MgSO4), filtered and concentrated. The crude product was purified by flash chromatography (SiNH2, 20 g, 0% to 10% MeOH in DCM) to give dimethyl-[2-[[6-[(6-methylpyridazin-3-yl)amino]-3H-benzimidazol-5-yl]oxy]ethyl]amine (160 mg, 0.513 mmol, 69% yield). ESI pos[M+H] + 313.3

[0277] Step 7: 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[2-(dimethylamino)ethoxy]-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile

[0278]

[0279] To a solution of 6-chloro-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]nicotinonitrile (50 mg, 0.186 mmol, 1.0 eq.) and dimethyl-[2-[[6-[(6-methylpyridazin-3-yl)amino]-3H-benzimidazol-5-yl]oxy]ethyl]amine (61 mg, 0.195 mmol, 1.05 eq.) in DMSO (1.5 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (31 mg, 31 uL, 0.205 mmol, 1.1 eq.) and the solution was stirred at 80° C. for 3 hours. The reaction was cooled to room temperature and diluted with DCM (10 mL) and H O (10 mL). The organic layer was washed with brine (5 mL), dried over MgSO , filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, 4 g, 0% to 10% MeOH in DCM) to give a mixture of 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[2-(dimethylamino)ethoxy]-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile and 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[2-(dimethylamino)ethoxy]-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile. The isomers were separated by preparative HPLC (YMC-Triart C18, 12 nm, 5 μm, 100×30 mm, ACN / water + 0.1% FA) to give 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[2-(dimethylamino)ethoxy]-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile as a yellow solid; formic acid (18 mg, 0.033 mmol, 18% yield). ESIpos [M+H] + 545.2. 1 H NMR (600MHz, DMSO-d6) δ = 9.04 (s, 1H), 8.79 (s, 1H), 8.80 (d, J = 7.9Hz, 1H), 8.56 (br s,1H),8.29(d,J=8.7Hz,1H),7.92(s,1H),7.36(d,J=9.1Hz,1H),7.19-7.30(m,1H),7.01-7.22(m,2H),6.76(s,1H),4.19(br s,2H),2.64-2.94(m,2H),2.60(s,3H),2.49-2.49(m,3H),2.29(br s,3H).

[0280] Example 5

[0281] 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[2-(dimethylamino)ethoxy]-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile

[0282]

[0283] Separation of the isomers from Example 5, Step 7 afforded 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[2-(dimethylamino)ethoxy]-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile and formic acid (13 mg, 0.024 mmol, 13% yield) as a yellow solid. ESI pos[M+H] + 545.2

[0284] 1 H NMR (600MHz, DMSO-d6) δ=9.20(s,1H),9.06(s,1H),8.81(d,J=8.7Hz,1H),8.60(s,1H),8.25(d,J=8.7Hz,1H),7.55(s,1H),7.32(d,J=9.1H z,1H),7.17(d,J=9.1Hz,1H),7.01-7.22(m,1H),6.68(s,1H),4.27(t,J=5.6Hz,2H),2.67-2.81(m,2H),2.58(s,3H),2.50(s,3H),2.31(br s,5H).

[0285] Example 6

[0286] 6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile

[0287]

[0288] Step 1: 4-Bromo-3-methyl-1-(2,2,2-trifluoroethyl)pyrazole

[0289]

[0290] A mixture of 4-bromo-3-methylpyrazole (15.0 g, 93.17 mmol, 1.0 eq.), 2,2,2-trifluoroethyl trifluoromethanesulfonate (22.71 g, 97.83 mmol, 1.05 eq.) and CsCO (25.33 g, 186.34 mmol, 2.0 eq.) in DMF (150 mL) was stirred at 100 ° C for 12 hours. The reaction mixture was filtered, and the filtrate was diluted with H O (250 mL) and extracted with EtOAc (3 x 250 mL). The combined organic layers were washed with brine (3 x 250 mL), dried over anhydrous Na SO , filtered and concentrated. The residue was purified by column chromatography (silica gel, 0% to 20% EtOAc in petroleum ether) to give a mixture of 4-bromo-3-methyl-1-(2,2,2-trifluoroethyl)pyrazole and 4-bromo-5-methyl-1-(2,2,2-trifluoroethyl)pyrazole (2:1 ratio) as a colorless oil (19.5 g, 80.24 mmol, 86% yield). ESI pos[M+H] + 242.9

[0291] 1 H NMR (400MHz, DMSO-d6) δ = 8.00 (s, 1H), 5.09-4.99 (m, 2H), 2.14 (s, 3H).

[0292] Step 2: 3-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)pyrazole

[0293]

[0294] A 2:1 mixture of 4-bromo-3-methyl-1-(2,2,2-trifluoroethyl)pyrazole and 4-bromo-5-methyl-1-(2,2,2-trifluoroethyl)pyrazole (11.0 g, 45.26 mmol, 1.0 eq.) was dissolved in 1,4-dioxane (200 mL). Potassium acetate (5.66 mL, 90.53 mmol, 2.0 eq.) and bis(pinacolato)diboron (13.79 g, 54.32 mmol, 1.2 eq., CAS: 73183-34-3) were added, followed by Pd(dppf)Cl2.CH2Cl2 (3.7 g, 4.53 mmol, 0.1 eq.). The mixture was stirred at 100°C under a N2 atmosphere for 16 hours. The mixture was cooled to room temperature and concentrated. The residue was purified by flash chromatography (silica gel, 0% to 20% EtOAc in petroleum ether) to give a mixture of 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)pyrazole and 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)pyrazole, which was analyzed by preparative HPLC (Welch Ultimate XB-SiOH 10 μm, 250*70 mm, hexane-EtOH) was further purified to give a mixture of 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)pyrazole and 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)pyrazole (3:1 ratio) (6.0 g, 20.68 mmol, 46% yield). ESI pos[M+H] + 291.1

[0295] Step 3: 2-Chloro-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile

[0296]

[0297] To a solution of 2,6-dichloronicotinonitrile (100 mg, 0.58 mmol, 1.0 eq.) and N-(6-methylpyridazine-3-yl)-1H-benzimidazol-5-amine (130 mg, 0.58 mmol, 1.0 eq.) in DMSO (2 mL) was added diisopropylethylamine (0.2 mL, 1.16 mmol, 2.0 eq.). The mixture was stirred at 130°C for 12 hours. The mixture was cooled to room temperature and H2O (20 mL) was added. The mixture was extracted with DCM (2 x 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0% to 10% MeOH in DCM) and further purified by preparative HPLC (Welch Ultimate XB-SiOH 10 μm, 250×70 mm, hexanes-EtOH) to give 2-chloro-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile (90 mg, 0.25 mmol, 34% yield) as a yellow solid. ESI pos[M+H] + 362.1

[0298] 1 H NMR (400MHz, DMSO-d6) δ = 9.43 (s, 1H), 9.12 (s, 1H), 8.66 (d, J = 8.5Hz, 1H), 8.52 (d, J = 1.9Hz, 1H), 8.28 (d, J=8.9Hz,1H),8.21(d,J=8.6Hz,1H),7.58(dd,J=2.2,8.9Hz,1H),7.34(s,1H),7.13(s,1H),2.54(s,3H).

[0299] Step 4: 6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile; formic acid

[0300]

[0301] To a mixture of 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)pyrazole and 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)pyrazole (3:1 ratio) (221 mg, 0.76 mmol, 1.1 eq.) in 1,4-dioxane (5 mL) and water (0.5 mL) was added 1% ethanol (221 mg, 0.76 mmol, 1.1 eq.). L) were added 2-chloro-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile (250 mg, 0.69 mmol, 1.0 eq.), potassium carbonate (191 mg, 1.38 mmol, 2.0 eq.) and Pd(dppf)Cl2.CH2Cl2 (56 mg, 0.07 mmol, 0.1 eq.), and the mixture was stirred at 100°C under N2 atmosphere for 12 hours. The mixture was concentrated and the residue was purified by reverse phase flash chromatography (0% to 30% ACN in water + 0.1 FA) to give a mixture of 6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile and 6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile as an off-white solid (147 mg, 0.30 mmol, 43% yield). The isomers were separated by preparative SFC (column: Phenomenex Luna C18, 10 μm, 150×25 mm) to give 6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile (25 mg, 0.050 mmol, 7% yield) as a yellow solid. ESI pos [M+H] + 489.9.

[0302] 1 H NMR (400MHz, DMSO-d6) δ = 9.25 (s, 1H), 9.06 (s, 1H), 8.60-8.54 (m, 2H), 8.46 (d, J = 1.6Hz, 1H), 8.21 (d, J = 8.8Hz, 1H) ,8.04(d,J=8.7Hz,1H),7.59-7.49(m,1H),7.34(d,J=9.0Hz,1H),7.09(d,J=9.0Hz,1H),5.30-5.20(m,2H),2.48(br s,3H),2.46(s,3H).

[0303] Example 7

[0304] 6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile

[0305]

[0306] Separation of the isomers from Example 6, Step 4, afforded 6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile and formic acid (4 mg, 0.001 mmol, 1% yield) as a yellow solid. ESI pos[M+H] + 490.0. 1 H NMR (400MHz, DMSO-d6) δ=9.25(s,1H),9.09(s,1H),8.58(d,J=8.6Hz,1H),8.42(d,J=2.0Hz,1H),8.23(d,J=9.0Hz,1H),8.18(s,1H ),8.06(d,J=8.8Hz,1H),7.59-7.53(m,1H),7.34(d,J=9.0Hz,1H),7.08(d,J=9.1Hz,1H),5.33-5.23(m,2H),2.59(s,3H),2.48(br s,3H).

[0307] Example 8

[0308] 3-[[3-[5-cyano-6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-2-pyridinyl]benzimidazol-5-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide

[0309]

[0310] Step 1: tert-Butyl 3-hydroxy-5-methyl-pyrazole-1-carboxylate

[0311]

[0312] To a solution of 5- methyl -1H- pyrazole -3- alcohol (5.0g, 50.97mmol, 1.0eq.) in DCM (50mL), di-tert-butyl dicarbonate (11.72mL, 50.97mmol, 1.0eq.) and triethylamine (7.81mL, 56.07mmol, 1.1eq.) are added, and the reaction is stirred at room temperature for 18 hours. The reaction solution is poured into water (150mL) and extracted with DCM (2x100mL). The combined organic layer is washed with salt water (3x150mL), through Na2SO4, filtered, and concentrated. The residue is purified by flash chromatography (silica gel, 0% to 10% MeOH in DCM) to obtain 3- hydroxy -5- methyl - pyrazole -1- tert-butyl formate (9.8g, 49.44mmol, 90% yield) as a yellow solid. ESI pos[M-C4H8+H] + 143.0.

[0313] 1 H NMR (400MHz, DMSO-d6) δ = 10.68 (d, J = 3.5Hz, 1H), 5.70 (d, J = 0.9Hz, 1H), 2.37 (d, J = 0.6Hz, 3H), 1.52 (s, 9H).

[0314] Step 2: tert-Butyl 3-(difluoromethoxy)-5-methyl-pyrazole-1-carboxylate

[0315]

[0316] To a solution of tert-butyl 3-hydroxy-5-methyl-pyrazole-1-carboxylate (17.0 g, 85.76 mmol, 1.0 eq.) in acetonitrile (250 mL) was added sodium (14.38 g, 94.34 mmol, 1.1 eq.) and CsCO (55.89 g, 171.53 mmol, 2.0 eq.). The reaction was stirred at 80 ° C for 12 hours. The mixture was filtered and the filter cake was rinsed with acetonitrile (4x50 mL). The filtrate was concentrated and the residue was purified by flash chromatography (silica gel, 10% EtOAc in petroleum ether) to obtain tert-butyl 3-(difluoromethoxy)-5-methyl-pyrazole-1-carboxylate (14.0 g, 56.4 mmol, 66% yield) as a colorless oil. ESI pos[M-C4H8+H] + 193.0

[0317] 1H NMR (400MHz, CD3OD) δ = 7.38-6.84 (m, 1H), 5.97 (s, 1H), 2.46 (d, J = 0.7Hz, 3H), 1.59 (s, 9H).

[0318] Step 3: 3-(Difluoromethoxy)-5-methyl-1H-pyrazole

[0319]

[0320] To a solution of tert-butyl 3-(difluoromethoxy)-5-methyl-pyrazole-1-carboxylate (12.5 g, 50.36 mmol, 1.0 eq.) in DCM (30 mL) was added 4 M HCl in dioxane (31.25 mL, 125.0 mmol, 2.48 eq.), and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated to give 3-(difluoromethoxy)-5-methyl-1H-pyrazole (7.4 g, 49.96 mmol, 95% yield) as a yellow oil. ESI pos[M-C4H8+H] + 149.1. 1 H NMR (400MHz, CDCl3) δ = 13.40 (s, 1H), 6.68 (t, J = 72.1Hz, 1H), 5.85 (s, 1H), 2.41 (s, 3H).

[0321] Step 4: 6-Chloro-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile

[0322]

[0323] A mixture of 6-chloro-2-fluoropyridine-3-carbonitrile (280 mg, 1.79 mmol, 1.0 eq.), 3-(difluoromethoxy)-5-methyl-1H-pyrazole (265 mg, 1.79 mmol, 1.0 eq.) and potassium carbonate (742 mg, 5.37 mmol, 3.0 eq.) in DMSO (6 mL) was stirred at 25 ° C for 2.5 hours. LCMS showed that a small amount of starting material remained and 67% of the required mass was detected. The mixture was poured into water (40 mL) and extracted with EtOAc (3x40 mL). The combined organic layer was washed with salt water (3x80 mL), dried over anhydrous Na SO dried, filtered and concentrated. The crude product was purified by column chromatography (silica gel, 0% to 50% EtAOc in petroleum ether) to give 6-chloro-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (270 mg, 0.95 mmol, 53% yield) as a white solid. ESI pos[M+H] + 285.0.1 H NMR (400MHz, CDCl3) δ = 8.05 (d, J = 8.2Hz, 1H), 7.31 (d, J = 8.2Hz, 1H), 7.34-6.98 (t, 1H), 5.95 (s, 1H), 2.65 (s, 3H).

[0324] Step 5: 6-(6-Bromobenzimidazol-1-yl)-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile

[0325]

[0326] A mixture of 6-chloro-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (310 mg, 1.09 mmol, 1.0 eq.), 5-bromo-1H-benzimidazole (215 mg, 1.09 mmol, 1.0 eq.) and potassium carbonate (452 ​​mg, 3.27 mmol, 3.0 eq.) in DMSO (6 mL) was stirred at 25° C. for 1 hour. The mixture was poured into water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (3×80 mL), dried over anhydrous Na SO , filtered and concentrated. The residue was purified by column chromatography (silica gel, 10% to 40% EtOAc in petroleum ether) to give 6-(5-bromobenzimidazol-1-yl)-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (135.0 mg, 0.3 mmol, 27.84% yield) as a white solid: ESI pos [M+H] + 445.1. 1 H NMR (400 MHz, DMSO-d6) δ = 9.18 (s, 1H), 8.77 (d, J = 8.6 Hz, 1H), 8.18 (dd, J = 3.4, 8.6 Hz, 2H), 8.04 (d, J = 1.7 Hz, 1H), 7.61 (dd, J = 1.8, 8.7 Hz, 1H), 7.36 (t, J = 72.8 Hz, 1H), 6.35 (s, 1H), 2.53 (s, 3H) and 6-(6-bromobenzimidazol-1-yl)-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (125.0 mg, 0.28 mmol, 25.78% yield) as a white solid. ESI pos [M+H] + 445.1. 1H NMR (400MHz, DMSO-d6) δ = 9.17 (s, 1H), 8.77 (d, J = 8.4Hz, 1H), 8.46 (d, J = 1.7Hz, 1H), 8.20 (d, J = 8. 6Hz, 1H), 7.78 (d, J = 8.6Hz, 1H), 7.58-7.54 (m, 1H), 7.54-7.16 (m, 1H), 6.38 (s, 1H), 2.57 (s, 3H).

[0327] Step 6: 3-(Benzhydrylamino)-6-methyl-pyridazine-4-carboxylic acid ethyl ester

[0328]

[0329] To 3-chloro-6-methyl-pyridazine-4-ethyl formate (50mg, 0.25mmol, 1.0eq.) and benzophenone imine (0.06mL, 0.37mmol, 1.5eq.) in 1,4-dioxane (1mL) add CsCO (244mg, 0.75mmol, 3.0eq.) and Xantphos Pd G (21mg, 0.02mmol, 0.1eq.). The mixture is bubbled with N and stirred at 100°C for 16 hours under N. The reaction mixture is poured into water (10mL) and extracted with EtOAc (3x10mL). The organic layer combined is through NaSODry, filtered and concentrated. The crude product was purified by preparative TLC (EtOAc) to give 3-(benzylideneamino)-6-methyl-pyridazine-4-carboxylic acid ethyl ester (60 mg, 0.17 mmol, 70% yield) as a yellow oil. ESI pos[M+H] + 346.1. 1 H NMR (400MHz, CDCl3) δ = 7.93-7.10 (m, 8H), 4.30 (q, J = 7.2Hz, 2H), 2.68 (s, 3H), 1.30-1.27 (m, 3H).

[0330] Step 7: 3-(Benzhydrylamino)-6-methyl-pyridazine-4-carboxylic acid

[0331]

[0332] To a mixture of ethyl 3-(benzylideneamino)-6-methyl-pyridazine-4-carboxylate (1.4 g, 4.05 mmol, 1.0 eq.) in a mixture of THF (5 mL) / methanol (5 mL) / H O (2.5 mL) was added LiOH (243 mg, 10.14 mmol, 2.5 eq.). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated to give 3-(benzylideneamino)-6-methyl-pyridazine-4-carboxylic acid (1.2 g, 3.78 mmol, 93% yield) as a yellow solid. The crude product was used directly in the next step without further purification. ESI pos[M+H] + 318.0.

[0333] Step 8: 3-(Benzhydrylamino)-N,N,6-trimethyl-pyridazine-4-carboxamide

[0334]

[0335] To a solution of 3-(benzylideneamino)-6-methyl-pyridazine-4-carboxylic acid (1.00 g, 3.15 mmol, 1.0 eq.) in DMF (15 mL) was added DIPEA (1.65 mL, 9.45 mmol, 3.0 eq.), HATU (2.22 g, 9.45 mmol, 3.0 eq.) and dimethylamine hydrochloride (514 mg, 6.3 mmol, 2.0 eq.). The reaction mixture was stirred at 30° C. for 16 hours. The reaction mixture was poured into water (60 mL) and extracted with EtOAc (3×40 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give 3-(benzylideneamino)-N,N,6-trimethyl-pyridazine-4-carboxamide (1.09 mg, 3.15 mmol, quantitative yield), which was used in the next step without further purification. ESI pos[M+H] + 345.1.

[0336] Step 9: 3-Amino-N,N,6-trimethyl-pyridazine-4-carboxamide

[0337]

[0338] To a solution of 3-(benzhydrylamino)-N, N, 6-trimethyl-pyridazine-4-carboxamide (400 mg, 1.16 mmol, 1.0 eq.) in methanol (20 mL) was added hydroxylamine hydrochloride (161 mg, 2.32 mmol, 2.0 eq.), sodium acetate (0.22 mL, 2.9 mmol, 2.5 eq.), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated. The residue was dissolved in EtOAc (30 mL) and washed with H2O (20 mL). The aqueous layer was extracted with EtOAc (3x10 mL). The combined organic phases were washed with brine (3x10 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (EtOAc) to obtain 3-amino-N, N, 6-trimethyl-pyridazine-4-carboxamide (199 mg, 1.10 mmol, 95% yield) as a brown solid. ESIpos[M+H] + 181.1. 1 H NMR (400MHz, CDCl3) δ = 6.92 (s, 1H), 5.42 (br s, 2H), 3.04 (br s, 3H), 2.94 (br s, 3H), 2.50 (s, 3H).

[0339] Step 10: 3-[[3-[5-cyano-6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-2-pyridinyl]benzimidazol-5-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide; formic acid

[0340]

[0341] A mixture of 3-amino-N,N,6-trimethyl-pyridazine-4-carboxamide (41 mg, 0.22 mmol, 2.0 eq.), 6-(6-bromobenzimidazol-1-yl)-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (50 mg, 0.11 mmol, 1.0 eq.), and cesium carbonate (110 mg, 0.34 mmol, 3.0 eq.) in 1,4-dioxane (2 mL) was sparged with N for 3 minutes. [tBuBrettPhosPd(allyl)]OTf (18 mg, 0.02 mmol, 0.2 eq.) was added, and the mixture was stirred at 80° C. for 2 hours. The solution was filtered and the filtrate was concentrated and the residue was purified by preparative HPLC (Phenomenex luna C18 10 μm, 150 mm x 25 mm, water + 0.1% FA-ACN) to give 3-[[3-[5-cyano-6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-2-pyridinyl]benzimidazol-5-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide; formic acid (23 mg, 0.04 mmol, 37% yield) as a yellow solid. ESI pos[M+H] + 545.2.

[0342] 1 H NMR (400MHz, DMSO-d6) δ=9.02(s,1H),8.75(d,J=8.6Hz,1H),8.64(d,J=1.8Hz,1H),8.56(s,1H),8.13(d,J=8.7Hz,1H),7.71(d,J=8.7 Hz,1H),7.59(dd,J=2.0,8.8Hz,1H),7.33(s,1H),7.53-7.17(t,1H),6.27(s,1H),2.97(s,3H),2.87(s,3H),2.54(s,3H),2.52(s,3H).

[0343] Example 9

[0344] 3-[[1-[5-cyano-6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-2-pyridinyl]benzimidazol-5-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide

[0345]

[0346] A mixture of 3-amino-N,N,6-trimethyl-pyridazine-4-carboxamide (40 mg, 0.22 mmol, 2.0 eq.), 6-(5-bromobenzimidazol-1-yl)-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (50 mg, 0.11 mmol, 1.0 eq.), and cesium carbonate (110 mg, 0.34 mmol, 3.0 eq.) in 1,4-dioxane (2 mL) was sparged with N for 10 minutes. [tBuBrettPhosPd(allyl)]OTf (18 mg, 0.02 mmol, 0.2 eq.) was added, and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated. The residue was purified by preparative HPLC (Phenomenex luna C18 10 μm, 150 mm x 25 mm, water + 0.1% FA-ACN) to give 3-[[1-[5-cyano-6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-2-pyridinyl]benzimidazol-5-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide; formic acid (33 mg, 0.06 mmol, 53% yield) as a yellow solid. ESI pos[M+H] + 545.2.

[0347] 1 H NMR (400MHz, DMSO-d6) δ = 9.10 (s, 1H), 8.74 (d, J = 8.6Hz, 1H), 8.44 (s, 1H), 8.24 (d, J = 1.8Hz, 1H), 8.16 (dd, J = 8.8, 12.6Hz, 2H), 7.58(dd,J=2.0,8.9Hz,1H),7.34(s,1H),7.55-7.19(t,1H),6.35(s,1H),2.99(s,3H),2.90(s,3H),2.58(s,3H),2.52(s,3H).

[0348] Example 10

[0349] 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetane

[0350] -3-aminobenzoyloxy)benzimidazol-1-yl]pyridine-3-carbonitrile

[0351]

[0352] Step 1: 6-[5-Bromo-6-(oxetan-3-yloxy)benzimidazol-1-yl]-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile

[0353]

[0354] To a solution of 6-chloro-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (200 mg, 0.74 mmol, 1.0 eq., prepared in Example 2, step 1) in DMSO (3 mL) was added 5-bromo-6-(oxetanes-3-yloxy)-1H-benzimidazole (200 mg, 0.74 mmol, 1.0 eq.; prepared in Example 14, step 3), K CO (308.68 mg, 2.23 mmol, 3.0 eq.), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (3x5 mL). The combined organic phases were washed with brine (3x5 mL), dried over anhydrous Na SO, filtered, and concentrated. The residue was purified by preparative TLC (DCM / MeOH 10:1) to give: 6-[5-bromo-6-(oxetan-3-yloxy)benzimidazol-1-yl]-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (70 mg, 0.14 mmol, 18% yield) as a white solid; ESI pos [M+H] + 502.7; 1 H NMR (400MHz, CDCl3) δ = 8.47 (s, 1H), 8.40 (d, J = 8.4Hz, 1H), 8.12 (s, 1H), 7.65 (d, J = 8.4Hz, 1H), 7.33 (s, 1H), 6.8 3(t,J=54.6Hz,1H),6.64(s,1H),5.22(quin,J=5.7Hz,1H),4.94-4.90(m,2H),4.89-4.84(m,2H),2.60(s,3H);

[0355] as well as

[0356] 6-[6-Bromo-5-(oxetan-3-yloxy)benzimidazol-1-yl]-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (80 mg, 0.16 mmol, 20% yield); ESI pos[M+H] + 502.7. 1H NMR (400MHz, CDCl3) δ = 8.59 (s, 1H), 8.41 (d, J = 8.4Hz, 1H), 8.35 (s, 1H), 7.66 (d, J = 8.4Hz, 1H), 6.96 (s, 1H), 6.80 (br t,J=54.6Hz,1H),6.62(s,1H),5.38-5.31(m,1H),5.09(br t,J=6.7Hz,2H),4.93-4.89(m,2H),2.69(s,3H).

[0357] Step 2: 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile

[0358]

[0359] To a solution of 6-[5-bromo-6-(oxetan-3-yloxy)benzimidazol-1-yl]-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (70 mg, 0.14 mmol, 1.0 eq.) in 1,4-dioxane (3 mL) were added 3-amino-6-methylpyridazine (18 mg, 0.17 mmol, 1.2 eq.) and CsCO (136.49 mg, 0.42 mmol, 3.0 eq.), and the mixture was bubbled with N for 10 minutes. [tBuBrettPhosPd(allyl)]OTf (22 mg, 0.03 mmol, 0.2 eq.) was added, and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (10 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (ACS-WH-GX-F, water + 0.1% FA-ACN) to afford 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile as a white solid; formic acid (15 mg, 0.03 mmol, 20% yield). ESI pos[M+H] + 529.9.

[0360] 1H NMR (400MHz, DMSO-d6) δ = 9.05 (s, 1H), 8.87 (s, 1H), 8.81 (d, J = 8.6Hz, 1H), 8.38 (s, 1H), 8.29 (d, J = 8.7Hz, 1H), 7.42 (s, 1H), 7. 37(s,2H),7.15(t,J=54.2Hz,1H),6.82(s,1H),5.28(quin,J=5.4Hz,1H),4.79-4.75(m,2H),4.75-4.71(m,2H),2.55(s,6H).

[0361] Example 11

[0362] 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]-5-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile

[0363]

[0364] Analogously to Example 10, Step 2, 6-[6-bromo-5-(oxetan-3-yloxy)benzimidazol-1-yl]-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (Example 10, Step 1) (80 mg, 0.16 mmol, 1.0 eq.), 1,4-dioxane (3 mL), 3-amino-6-methylpyridazine (21 mg, 0.19 mmol, 1.2 eq.), Cs2CO3 (155.99 mg, 0.48 mmol, 3.0 eq.) and [tBuBrettPhos Pd(allyl)]OTf (25 mg, 0.03 mmol, 0.2 eq.) was used to prepare the title compound to give 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]-5-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile (19.5 mg, 0.04 mmol, 21.92% yield) as a white solid. ESI pos [M+H] + 529.9.

[0365] 1H NMR (400MHz, DMSO-d6) δ = 9.28 (s, 1H), 9.03 (s, 1H), 8.79 (d, J = 8.6Hz, 1H), 8.41 (s, 1H), 8.22 (d, J = 8.7Hz, 1H), 7.32 (s, 2H), 7.2 4-6.95(m,2H),6.66(s,1H),5.45(quin,J=5.3Hz,1H),5.02(t,J=6.7Hz,2H),4.72(dd,J=5.1,7.2Hz,2H),2.55(s,3H),2.48(br s,3H).

[0366] Example 12

[0367] 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-fluoro-5-[[6-[[1-(oxetan-3-yl)-4-piperidinyl]oxy]pyridazin-3-yl]amino]benzimidazol-1-yl]pyridine-3-carbonitrile

[0368]

[0369] Step 1: tert-Butyl 4-(6-chloropyridazin-3-yl)oxypiperidine-1-carboxylate

[0370]

[0371] To a solution of 1-Boc-4-hydroxypiperidine (1621 mg, 8.05 mmol, 1.2 eq.) in THF (15 mL) was added NaH (60% in oil) (537 mg, 13.43 mmol, 2.0 eq.) in portions at 0 ° C under N2. The reaction mixture was stirred at 0 ° C for 30 minutes. 3,6-dichloropyridazine (1.0 g, 6.71 mmol, 1.0 eq.) was added at 0 ° C, and the reaction mixture was allowed to reach room temperature and stirred for 2 hours. The reaction mixture was poured into a saturated NH4Cl aqueous solution (100 mL) and extracted with ethyl acetate (3x100 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 15% EtAOc in petroleum ether) to obtain tert-butyl 4- (6-chloropyridazine-3-yl) oxypiperidine-1-carboxylate (1.8 mg, 5.74 mmol, 85% yield) as a white solid. ESI pos[M+H] + 314.2.

[0372] 1H NMR (400MHz, CDCl3) δ = 7.38 (d, J = 9.2Hz, 1H), 6.94 (d, J = 9.2Hz, 1H), 5.44 (tt, J = 3.9, 8.1Hz, 1 H),3.90-3.75(m,2H),3.31-3.22(m,2H),2.12-2.04(m,2H),1.83-1.68(m,2H),1.48(s,9H).

[0373] Step 2: 3-Chloro-6-(4-piperidinyloxy)pyridazine; hydrochloride

[0374]

[0375] To a solution of tert-butyl 4-(6-chloropyridazin-3-yl)oxypiperidine-1-carboxylate (300 mg, 0.96 mmol, 1.0 eq.) in DCM (3 mL) was added 4M HCl in dioxane (1.0 mL, 4.0 mmol, 4.18 eq.). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to give 3-chloro-6-(4-piperidinyloxy)pyridazine; hydrochloride (200 mg, 0.8 mmol, 98% yield) as a white solid. ESI pos[M+H] + 214.2. 1 H NMR (400MHz, DMSO-d6) δ = 8.92 (br s, 2H), 7.83 (d, J = 9.3Hz, 1H), 7.36 (d, J = 9.3Hz, 1H), 5.40 (tt, J = 3.7, 7.8Hz, 1H), 3.24 (br s,2H),3.17-3.07(m,2H),2.20(ddd,J=3.3,6.9,10.2Hz,2H),2.01-1.90(m,2H).

[0376] Step 3: 3-Chloro-6-[[1-(oxetan-3-yl)-4-piperidinyl]oxy]pyridazine

[0377]

[0378] By 3- chloro- 6- (4- piperidyl oxy) pyridazine (150mg, 0.7mmol, 1.0eq.) and 3- oxetanes (152mg, 2.11mmol, 3.0eq.) solution in MeOH (3mL) is stirred at room temperature for 10 minutes. NaBH is added CN (88mg, 1.4mmol, 2.0eq.) and the mixture is stirred at room temperature for 1 hour. The reaction mixture is poured into water (10mL) and extracted with EtOAc (3x10mL). The combined organic layer is dried over NaSO, filtered and concentrated. The residue is purified by preparative TLC (DCM / MeOH 10: 1) to obtain 3- chloro- 6- [[1- (oxetanes -3- bases) -4- piperidyl] oxy] pyridazine (160mg, 0.59mmol, 84% yield) as a white solid. ESI pos[M+H] + 270.1.

[0379] 1 H NMR (400MHz, DMSO-d6) δ=7.78(d,J=9.3Hz,1H),7.31(d,J=9.3Hz,1H),5.16(td,J=4.3,8.3Hz,1H),4.53(t,J= 6.4Hz,2H),4.46-4.39(m,2H),3.42(t,J=6.4Hz,1H),2.61-2.54(m,2H),2.15-2.00(m,4H),1.78-1.67(m,2H).

[0380] Step 4: N-[6-[[1-(Oxetane-3-yl)-4-piperidinyl]oxy]pyridazin-3-yl]-1,1-diphenyl-formaniline

[0381]

[0382] To a solution of benzophenone imine (0.12 mL, 0.72 mmol, 1.5 eq.) and 3-chloro-6-[[1-(oxetanes-3-yl)-4-piperidinyl]oxy]pyridazine (130 mg, 0.48 mmol, 1.0 eq.) in 1,4-dioxane (4 mL) was added CsCO (314 mg, 0.96 mmol, 2.0 eq.) and Xantphos Pd G (23 mg, 0.02 mmol, 0.05 eq.). The mixture was sparged with N for 10 minutes and stirred at 100 ° C for 16 hours under N. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (3x30 mL). The combined organic phases were dried over NaSO, filtered, and concentrated. The residue was purified by preparative TLC (DCM / MeOH 10:1) to give N-[6-[[1-(oxetan-3-yl)-4-piperidinyl]oxy]pyridazin-3-yl]-1,1-diphenyl-formanimine (120 mg, 0.29 mmol, 60% yield) as a white solid. ESI pos[M+H] + 415.3.

[0383] 1 H NMR (400MHz, DMSO-d6) δ = 7.73-7.68 (m, 2H), 7.59 (d, J = 7.4Hz, 1H), 7.54- 7.47(m,2H),7.36-7.32(m,3H),7.17-7.13(m,2H),7.10(s,1H),7.11-7.0 7(m,1H),7.03-6.98(m,1H),5.07-4.97(m,1H),4.52(t,J=6.5Hz,2H),4. 44-4.38(m,2H),3.43-3.35(m,2H),2.08-1.96(m,4H),1.68-1.57(m,2H).

[0384] Step 5: 6-[[1-(Oxetane-3-yl)-4-piperidinyl]oxy]pyridazin-3-amine

[0385]

[0386] To a solution of N-[6-[[1-(oxetane-3-yl)-4-piperidinyl]oxy]pyridazin-3-yl]-1,1-diphenyl-formimine (400 mg, 0.97 mmol, 1.0 eq.) in MeOH (8 mL) was added sodium acetate (0.18 mL, 2.41 mmol, 2.5 eq.) and hydroxylamine hydrochloride (134 mg, 1.93 mmol, 2.0 eq.) and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated and the residue was purified by preparative TLC (DCM / MeOH 10: 1) to give 6-[[1-(oxetane-3-yl)-4-piperidinyl]oxy]pyridazin-3-amine (180 mg, 0.72 mmol, 75% yield) as a white solid. ESI pos[M+H] + 251.1.

[0387] 1 H NMR (400MHz, DMSO-d6) δ = 6.87-6.78 (m, 2H), 5.85 (s, 2H), 4.94 (tt, J = 4.1, 8.5Hz, 1H), 4.55 -4.50(m,2H),4.42(t,J=6.1Hz,2H),2.10-1.94(m,4H),1.64(dtd,J=3.5,9.1,12.5Hz,2H)

[0388] Step 6: 5-Bromo-6-fluoro-1H-benzimidazole

[0389]

[0390] A mixture of 4-bromo-5-fluoro-benzene-1,2-diamine (4.0 g, 19.51 mmol, 1.0 eq.) in formic acid (33 mL, 883.5 mmol, 45 eq.) was stirred at 100 ° C for 16 hours. The reaction mixture was concentrated and the resulting oil was partitioned between EtOAc (200 mL) and saturated aqueous NaHCO (500 mL). The aqueous layer was extracted with EtOAc (2x100 mL) and the combined organic layers were dried over Na SO, filtered and concentrated to give 5-bromo-6-fluoro-1H-benzimidazole (4.0 g, 18.6 mmol, 95% yield) as a brown solid, which was used without further purification. ESI pos[M+H] + 217.0.

[0391] Step 7: 6-(5-Bromo-6-fluoro-benzoimidazol-1-yl)-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile and 6-(6-Bromo-5-fluoro-benzoimidazol-1-yl)-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile

[0392]

[0393] To a solution of 6-chloro-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (Example 2, Step 1) (400 mg, 1.49 mmol, 1.0 eq.) in DMSO (5 mL) was added 5-bromo-6-fluoro-1H-benzimidazole (320 mg, 1.49 mmol, 1.0 eq.) and K CO (617 mg, 4.47 mmol, 3.0 eq.), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na SO , filtered and concentrated. The residue was purified by flash chromatography (silica gel, 20% EtOAc in petroleum ether) to give a mixture of 6-(5-bromo-6-fluoro-benzoimidazol-1-yl)-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile and 6-(6-bromo-5-fluoro-benzoimidazol-1-yl)-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile as a yellow solid (400 mg, 0.89 mmol, 42% yield). ESI pos [M+H] + 448.8.

[0394] Step 8: 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-fluoro-5-[[6-[[1-(oxetan-3-yl)-4-piperidinyl]oxy]pyridazin-3-yl]amino]benzimidazol-1-yl]pyridine-3-carbonitrile; formic acid

[0395]

[0396] To a suspension of 6-[[1-(oxetan-3-yl)-4-piperidinyl]oxy]pyridazin-3-amine (34 mg, 0.13 mmol, 1.2 eq.) in 1,4-dioxane (2 mL) was added a mixture of 6-(5-bromo-6-fluoro-benzimidazol-1-yl)-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile and 6-(6-bromo-5-fluoro-benzimidazol-1-yl)-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (50 mg, 0.11 mmol, 1.0 eq.), Cs2CO3 (109 mg, 0.34 mmol, 3.0 eq.) and [tBuBrettPhosPd(allyl)]OTf (17 mg, 0.02 mmol, 0.2 eq.). The mixture was bubbled with N for 10 minutes and stirred at 80 ° C for 2 hours. The reaction mixture was poured into H o (10 mL) and extracted with EtOAc (3x10 mL). The combined organic phase was dried over anhydrous Na sO , filtered and concentrated. The crude product was purified by preparative HPLC (ACS-WH-GX-F, water + 0.1% FA-ACN) to obtain 2- [3- (difluoromethyl) -5- methyl- pyrazol -1- bases] -6- [6- fluoro -5- [[6- [[1- (oxetanes -3- bases) -4- piperidinyl] oxy] pyridazine -3- bases] amino] benzimidazol -1- bases] pyridine -3- carbonitrile as a white solid; formic acid (28 mg, 0.05 mmol, 41% yield). ESIpos [M+H] + 617.3.

[0397] 1 H NMR (400MHz, DMSO-d6) δ = 9.16 (s, 1H), 8.88-8.79 (m, 3H), 8.30 (d, J = 8.6Hz, 1H), 8.09 (d, J = 11.7Hz, 1H), 7.45 (br d,J=9.4Hz,1H),7.28-6.98(m,2H),6.79(s,1H),5.17-5.00(m,1H),4.86-4.64(m,1H),4 .62-4.36(m,4H),3.51-3.34(m,2H),2.58(s,3H),2.16-1.98(m,4H),1.79-1.62(m,2H).

[0398] Example 13

[0399] 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-fluoro-5-[[6-[2-(3-methoxyazetidin-1-yl)ethyl]pyridazin-3-yl]amino]benzimidazol-1-yl]pyridine-3-carbonitrile

[0400]

[0401] Step 1: 3-Methoxyazetidine; hydrochloride

[0402]

[0403] To a solution of tert-butyl 3-methoxyazetidine-1-carboxylate (1.5 mg, 8.01 mmol, 1.0 eq.) in 1,4-dioxane (10 mL) was added 4M HCl (10 mL, 40.0 mmol, 5.0 eq.) in dioxane. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give 3-methoxyazetidine (600 mg, 6.89 mmol, 86% yield) as a light yellow oil, which was used in the next step without further purification.

[0404] Step 2: 3-Chloro-6-vinylpyridazine

[0405]

[0406] A solution of 3,6-dichloropyridazine (2.0 g, 13.42 mmol, 1.0 eq.) and vinylboronic acid pinacol ester (2.1 g, 13.42 mmol, 1.0 eq.) in a mixture of 1,4-dioxane (20 mL) and H₂O (8 mL) was bubbled with N₂ for 10 minutes. Pd(dppf)Cl₂·DCM (1.1 g, 1.34 mmol, 0.1 eq.) and K₂CO₃ (5.6 g, 40.27 mmol, 3.0 eq.) were added, and the suspension was stirred at 100°C under N₂ for 4 hours. 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 dried over Na₂SO₄, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 30% EtOAc in petroleum ether) to give 3-chloro-6-vinylpyridazine (1.0 g, 7.11 mmol, 53% yield) as a white solid. ESI pos[M+H] + 141.0

[0407] Step 3: tert-Butyl N-(6-vinylpyridazin-3-yl)carbamate

[0408]

[0409] A suspension of 3-chloro-6-vinyl-pyridazine (700 mg, 4.98 mmol, 1.0 eq.), tert-butyl carbamate (875 mg, 7.47 mmol, 1.5 eq.) and CsCO (3.2 g, 9.96 mmol, 2.0 eq.) in 1,4-dioxane (10 mL) was sparged with N for 10 minutes. Pd(dba) (456 mg, 0.5 mmol, 0.1 eq.) and Xantphos (577 mg, 1.0 mmol, 0.2 eq.) were added and the reaction mixture was stirred at 90° C. under N for 3 hours. The reaction mixture was cooled to room temperature, poured into saturated NHCl (200 mL) and extracted with EtAOAc (3×100 mL). The combined organic layers were dried over NaSO, filtered and concentrated. The residue was purified by column chromatography (silica gel, 0% to 60% EtOAc in petroleum ether) to give tert-butyl N-(6-vinylpyridazin-3-yl)carbamate (1.10 g, 4.97 mmol, 99% yield) as a light yellow gum. ESI pos[M+H] + 166.0.

[0410] 1 H NMR (400MHz, CDCl3) δ = 8.20 (d, J = 9.4Hz, 1H), 7.95 (br s, 1H), 7.59 (d, J = 9.3Hz, 1H), 6.99 (dd, J = 11.1, 17.8Hz, 1H), 6.10 (d, J = 17.9Hz, 1H), 5.58 (d, J = 11.1Hz, 1H), 1.55 (s, 9H).

[0411] Step 4: tert-Butyl N-[6-[2-(3-methoxyazetidin-1-yl)ethyl]pyridazin-3-yl]carbamate

[0412]

[0413] To a solution of tert-butyl N-(6-vinylpyridazin-3-yl)carbamate (1.10 g, 4.97 mmol, 1.0 eq.) and 3-methoxyazetidine hydrochloride (1.23 g, 9.94 mmol, 2.0 eq.) in MeOH (10 mL) was added acetic acid (940 μL, 14.91 mmol, 3.0 eq.). The mixture was stirred at 65 ° C for 16 hours under N2. The reaction mixture was concentrated and the residue was purified by preparative HPLC (Phenomenex luna C18 15 μm, 150 mm x 40 mm, water + 0.1% FA-ACN) to give tert-butyl N-[6-[2-(3-methoxyazetidine-1-yl)ethyl]pyridazin-3-yl]carbamate (840 mg, 2.72 mmol, 55% yield) as a colorless gum. ESI pos[M+H] + 309.1.

[0414] 1 H NMR (400MHz, CDCl3) δ = 8.43 (s, 1H), 8.17 (d, J = 9.3Hz, 1H), 7.88 (br d,J=1.4Hz,1H),7.37(d,J=9.3Hz,1H),4.23-4.16(m,1H),4.14-4.08(m,2H),3.38-3.31(m,4H),3.27(s,3H),3.16-3.10(m,2H),1.54(s,9H).

[0415] Step 5: 6-[2-(3-methoxyazetidin-1-yl)ethyl]pyridazin-3-amine

[0416]

[0417] To a solution of tert-butyl N-[6-[2-(3-methoxyazetidin-1-yl)ethyl]pyridazin-3-yl]carbamate (200 mg, 0.65 mmol, 1.0 eq.) in DCM (2 mL) was added TFA (2.0 mL, 25.92 mmol, 40 eq.), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was purified by preparative HPLC (Phenomenexluna C18 10 μm, 150 mm x 25 mm, water + 0.1% FA-ACN) to give 6-[2-(3-methoxyazetidin-1-yl)ethyl]pyridazin-3-amine (120.0 mg, 0.58 mmol, 89% yield) as a white solid. ESI pos[M+H] + 209.0.

[0418] 1H NMR (400MHz, CD3OD) δ=7.74(d,J=9.4Hz,1H),7.48(d,J=9.5Hz,1H),4.59-4.38(m,2H),4.31(quin,J=5.3Hz,1H),4.21-3.90(m,2H),3.68(br t,J=7.0Hz,2H),3.35(s,3H),3.13(t,J=7.0Hz,2H)

[0419] Step 6: 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-fluoro-5-[[6-[2-(3-methoxyazetidin-1-yl)ethyl]pyridazin-3-yl]amino]benzimidazol-1-yl]pyridine-3-carbonitrile

[0420]

[0421] To a solution of a mixture of 6-(5-bromo-6-fluoro-benzoimidazol-1-yl)-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile and 6-(6-bromo-5-fluoro-benzoimidazol-1-yl)-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (50 mg, 0.110 mmol, 1.0 eq., prepared in Example 12, Step 7) in 1,4-dioxane (2 mL) were added 6-[2-(3-methoxyazetidin-1-yl)ethyl]pyridazin-3-amine; 2,2,2-trifluoroacetic acid (72 mg, 0.220 mmol, 2.0 eq.) and Cs2CO3 (109 mg, 0.340 mmol, 3 eq.). The mixture was bubbled with N for 10 minutes, then [tBuBrettPhosPd(allyl)]OTf (9 mg, 0.010 mmol, 0.10 eq.) was added. The mixture was stirred at 80°C for 2 hours. The mixture was cooled to room temperature, poured into saturated aqueous NH4Cl solution (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (Phenomenex luna C18 10 μm, 150 mm x 25 mm, water + 0.1% FA-ACN) to give a mixture of 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-fluoro-5-[[6-[2-(3-methoxyazetidin-1-yl)ethyl]pyrazin-3-yl]amino]benzimidazol-1-yl]pyridine-3-carbonitrile and 2-[5-(difluoromethyl)-3-methyl-pyrazol-1-yl]-6-[5-fluoro-6-[[6-[2-(3-methoxyazetidin-1-yl)ethyl]pyrazin-3-yl]amino]benzimidazol-1-yl]pyridine-3-carbonitrile as a yellow solid. The mixture was purified by SFC (Daicel Chiral OD 10 μm 250 mm x 30 mm, 0.1% NH 4 OH in EtOH) and then by preparative HPLC (Waters Xbridge 5 μm 150x25 mm, water + 0.1% NH 4 HCO 3 -ACN) to give 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-fluoro-5-[[6-[2-(3-methoxyazetidin-1-yl)ethyl]pyridazin-3-yl]amino]benzimidazol-1-yl]pyridine-3-carbonitrile (7 mg, 0.01 mmol, 8% yield) as a yellow solid. ESI pos [M+H] + 217.0.

[0422] 1H NMR (400MHz, CDCl3) δ = 8.63 (d, J = 7.5Hz, 1H), 8.61 (s, 1H), 8.39 (d, J = 8.4Hz, 1H), 7 .90(d,J=10.9Hz,1H),7.67(d,J=8.4Hz,1H),7.36(d,J=9.0Hz,1H),7.05(d,J=9.0H z,1H),6.93(s,1H),6.79(s,1H),6.66(s,1H),6.60(s,1H),4.56-4.43(m,2H),4.3 9-4.32(m,1H),3.83-3.68(m,4H),3.36(t,J=7.4Hz,2H),3.32(s,3H),2.65(s,3H).

[0423] Example 14

[0424] 2-[3-(Difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]-5-(oxetane-3-oxy)benzimidazol-1-yl]pyridine-3-carbonitrile

[0425]

[0426] Step 1: 4-Bromo-2-nitro-5-(oxetan-3-yloxy)aniline

[0427]

[0428] Under N2, sodium hydride (60% in oil) (2.3g, 57.61mmol, 1.5eq.) was added portionwise to a solution of oxetane-3-ol (4.26g, 57.46mmol, 1.5eq.) in THF (90mL) cooled to 0°C and the mixture was stirred at 0°C for 30 minutes. 4-bromo-5-fluoro-2-nitro-aniline (9.0g, 38.3mmol, 1.0eq.) was added and the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 12 hours. The reaction was quenched with H2O (100mL), which formed a precipitate. The mixture was filtered and the filter cake was dried under reduced pressure to obtain 4-bromo-2-nitro-5-(oxetane-3-yloxy)aniline (4.0g, 13.84mmol, 36% yield). The filtrate was extracted with EtOAc (3x250mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was triturated in a mixture of gasoline ether / EtOAc (10:1, 30 mL) at room temperature for 30 minutes. The mixture was filtered and the filter cake was dried under reduced pressure to give 4-bromo-2-nitro-5-(oxetane-3-yloxy)aniline (7.0 g, 24.21 mmol, 63% yield) as a yellow solid. ESI pos[M+H] + 289.0.

[0429] 1 H NMR (400MHz, DMSO-d6) δ = 8.16 (s, 1H), 7.56 (s, 2H), 6.21 (s, 1H), 5.31 (q, J = 5.4Hz, 1H), 4.93 (t, J = 6.8Hz, 2H), 4.59 (dd, J = 5.2, 7.6Hz, 2H).

[0430] Step 2: 4-Bromo-5-(oxetan-3-yloxy)benzene-1,2-diamine

[0431]

[0432] Under N2, to a solution of 4-bromo-2-nitro-5-(oxetanes-3-yloxy)aniline (10.5g, 36.32mmol, 1.0eq.) in EtOH (120mL) was added Fe (10.14g, 181.61mmol, 5.0eq.), NHCl (19.43g, 363.22mmol, 10.0eq.) and H2O (40mL). The reaction mixture was stirred at 50°C for 12 hours under N2. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with H2O (100mL) and extracted with EtOAc (3x100mL). The combined organic layers were concentrated to give 4-bromo-5-(oxetanes-3-yloxy)benzene-1,2-diamine (9.4g, 36.28mmol, quantitative yield) as a black solid. ESI pos[M+H] + 259.0.

[0433] Step 3: 5-Bromo-6-(oxetan-3-yloxy)-1H-benzimidazole; formic acid

[0434]

[0435] By 4- bromo- 5- (oxetane -3- bases oxygen) benzene -1,2- diamine (9.0g, 34.74mmol, 1.0eq.) and formic acid (8.0mL, 41463.19mmol, 1193.68eq.) in triethyl orthoformate (80mL) stir at 80 DEG C for 12 hours.The reaction mixture is cooled to room temperature and concentrated.The residue is purified by preparative HPLC (Phenomenex luna C18 10 μm, 150mm x 40mm, water + 0.1% FA-ACN) to obtain 5- bromo- 6- (oxetane -3- bases oxygen) -1H- benzimidazole (8.6g, 31.96mmol, 91% yield) as a white solid.ESI pos[M+H] + 270.9.

[0436] 1 H NMR (400MHz, CDCl3) δ = 8.16 (s, 1H), 8.05 (s, 1H), 7.88 (s, 1H), 6.80 (s, 1H), 5.29 (td, J = 5.6, 11.2Hz, 1H), 5.04 (t, J = 6.8Hz, 2H), 4.95-4.84 (m, 2H).

[0437] Step 4: 6-[6-Bromo-5-(oxetan-3-yloxy)benzimidazol-1-yl]-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile and 6-[5-Bromo-6-(oxetan-3-yloxy)benzimidazol-1-yl]-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile

[0438]

[0439] To a colorless solution of 6-chloro-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (350 mg, 1.23 mmol, 1.0 eq.) in DMSO (10 mL) was added 5-bromo-6-(oxetane-3-yloxy)-1H-benzimidazole (331 mg, 1.23 mmol, 1.0 eq.), N,N-diisopropylethylamine (0.64 mL, 3.69 mmol, 3.0 eq.) and the mixture was stirred at 100 ° C for 12 hours. The reaction mixture was cooled to room temperature, poured into H O (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over Na SO , filtered, and concentrated. The residue was purified by preparative TLC (DCM / MeOH=9:1, Rf=0.60 / 0.65) to give 6-[5-bromo-6-(oxetan-3-yloxy)benzimidazol-1-yl]-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (70 mg, 0.14 mmol, 11% yield) as a light yellow solid; ESI pos[M+H] + 519.0. 1 H NMR (400MHz, DMSO-d6) δ = 9.07 (s, 1H), 8.79 (d, J = 8.4Hz, 1H), 8.18 (d, J = 8.6Hz, 1H), 8.11 (s, 1H), 7.57 -7.20(t,1H),7.48(s,1H),6.39(s,1H),5.32(quin,J=5.4Hz,1H),4.82(t,J=6.7Hz,2H),4.64(dd,J=5.0,7.2Hz,2H),3.33(s,3H);

[0440] and 6-[6-bromo-5-(oxetan-3-yloxy)benzimidazol-1-yl]-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (30 mg, 0.06 mmol, 5% yield) as a light yellow solid. ESI pos[M+H] + 519.0

[0441] Step 5: 2-[3-(Difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]-5-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile; formic acid

[0442]

[0443] A solution of 6-[6-bromo-5-(oxetan-3-yloxy)benzimidazol-1-yl]-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (30 mg, 0.06 mmol, 1.0 eq.) and 3-amino-6-methylpyridazine (13 mg, 0.12 mmol, 2.0 eq.) in 1,4-dioxane (10 mL) was sparged with N for 10 minutes. [tBuBrettPhosPd(allyl)]OTf (9 mg, 0.01 mmol, 0.2 eq.) and CsCO (57 mg, 0.17 mmol, 3.0 eq.) were added and the reaction mixture was stirred at 80° C. under N for 2 hours. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Phenomenex Synergi C18 10 μm, 150 mm x 25 mm, 0.1% FA-ACN in water) to give 2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazine-3-yl)amino]-5-(oxetanes-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile as an off-white solid; formic acid (11 mg, 0.02 mmol, 35% yield). ESI pos[M+H] + 546.2.

[0444] 1 H NMR (400MHz, DMSO-d6) δ=9.31-9.27(m,1H),9.00(s,1H),8.75(d,J=8.6Hz,1H),8.46-8.41(m,1H),8.11(d,J=8.6Hz,1H),7.54 -7.17(t,1H),7.37-7.33(m,2H),7.08(s,1H),6.25(s,1H),5.48-5.42(m,1H),5.02(t,J=6.5Hz,2H),4.74-4.70(m,2H),3.32(s,3H),2.55(br s,3H)

[0445] Example 15

[0446] 2-[3-(Difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetane-3-oxy)benzimidazol-1-yl]pyridine-3-carbonitrile

[0447]

[0448] A solution of 6-[5-bromo-6-(oxetan-3-yloxy)benzimidazol-1-yl]-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (50 mg, 0.1 mmol, 1.0 eq.) and 3-amino-6-methylpyridazine (21 mg, 0.19 mmol, 2.0 eq.) in 1,4-dioxane (10 mL) was sparged with N for 10 minutes. [tBuBrettPhosPd(allyl)]OTf (15 mg, 0.02 mmol, 0.2 eq.) and CsCO (94.48 mg, 0.29 mmol, 3.0 eq.) were added and the reaction mixture was stirred at 80° C. under N for 2 hours. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC (Phenomenex SynergiC18 10 μm, 150 mm x 25 mm, 0.1% FA-ACN in water) to give 2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetanes-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile as a light yellow solid; formic acid (22 mg, 0.04 mmol, 42% yield). ESI pos[M+H] + 546.2.

[0449] 1 H NMR (400MHz, DMSO-d6) δ = 9.00 (s, 1H), 8.89-8.86 (m, 1H), 8.76 (d, J = 8.6Hz, 1H), 8.39 (s, 1H), 8.20-8.17 (m, 1H), 7.58 -7.22(t,1H),7.42-7.37(m,3H),6.39(s,1H),5.32(quin,J=5.4Hz,1H),4.86-4.81(m,2H),4.78-4.73(m,2H),3.29-3.22(m,3H),2.54(br s,3H).

[0450] Example 16

[0451] 2-[3-(Difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile

[0452]

[0453] Step 1: 4-Bromo-5-methoxy-2-nitro-aniline

[0454]

[0455] To a solution of 5-methoxy-2-nitroaniline (10.0 g, 59.47 mmol, 1.0 eq.) in acetonitrile (150 mL) was added NBS (11.6 g, 65.42 mmol, 1.1 eq.) in batches at room temperature under N2, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into a saturated Na2SO3 solution (300 mL) under vigorous stirring and H2O (500 mL) was added. The resulting precipitate was filtered and the filter cake was dried to give 4-bromo-5-methoxy-2-nitro-aniline (13.0 g, 52.62 mmol, 88% yield) as a yellow solid. ESI pos[M+H] + 249.1.

[0456] 1 H NMR (400MHz, CDCl3) δ = 8.36 (s, 1H), 6.25 (br s, 2H), 6.18 (s, 1H), 3.92 (s, 3H)

[0457] Step 2: 4-Bromo-5-methoxy-benzene-1,2-diamine

[0458]

[0459] To a solution of 4- bromo- 5- methoxy -2- nitro - aniline (13.0 g, 52.6 mmol, 1.0 eq.) in a mixture of DCM (260 mL) and MeOH (260 mL) was added saturated NH4Cl (520 mL, 1052 mmol, 20.0 eq.) and the mixture was bubbled with N2 for 10 minutes at room temperature. Zn (34.4 g, 527 mmol, 10.0 eq.) was added in batches at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated. The residue was dissolved in DCM (600 mL) and washed with salt water (3x200 mL). The combined organic phase was concentrated to obtain 4- bromo- 5- methoxy - benzene -1,2- diamine (11.0 g, 50.68 mmol, 96% yield) as a black solid, which was used without further purification. ESI pos[M+H] + 217.0. 1 H NMR (400MHz, DMSO-d6) δ = 6.66 (s, 1H), 6.34 (s, 1H), 4.79-4.13 (m, 4H), 3.63 (s, 3H).

[0460] Step 3: 5-Bromo-6-methoxy-1H-benzimidazole

[0461]

[0462] To a solution of 4-bromo-5-methoxy-benzene-1,2-diamine (11.0 g, 50.7 mmol, 1.0 eq.) in trimethyl orthoformate (200 mL, 507 mmol, 10.0 eq.) was added formic acid (10.0 mL, 265 mmol, 5.2 eq.) and the mixture was stirred at 90 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (400 mL) and washed with saturated NaHCO (300 mL). The organic phase was then washed with brine (3x100 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (silica gel, EtOAc) to obtain 5-bromo-6-methoxy-1H-benzimidazole (9.6 g, 42.3 mmol, 83% yield) as a yellow solid. ESI pos[M+H] + 227.0. 1 H NMR (400MHz, DMSO-d6) δ = 12.53-12.20 (m, 1H), 8.14 (br s, 1H), 7.90-7.68 (m, 1H), 7.40-7.09 (m, 1H), 3.86 (s, 3H).

[0463] Step 4: 2-[(5-Bromo-6-methoxy-benzimidazol-1-yl)methoxy]ethyl-trimethyl-silane and 2-[(6-Bromo-6-methoxy-benzimidazol-1-yl)methoxy]ethyl-trimethyl-silane

[0464]

[0465] To a solution of 2-(trimethylsilyl)ethoxymethyl chloride (3.27 mL, 18.5 mmol, 1.4 eq.) in DMF (60 mL) was added sodium hydride (60% in oil) (635 mg, 15.9 mmol, 1.2 eq.) in portions at 0°C. After addition, the mixture was allowed to reach room temperature and stirred for 1 hour. The mixture was cooled to 0°C and 5-bromo-6-methoxy-1H-benzimidazole (3.0 g, 13.2 mmol, 1.0 eq.) was added. The mixture was allowed to warm to room temperature and stirred for 16 hours. The mixture was poured into a saturated aqueous NH4Cl solution (300 mL), extracted with EtOAc (3 x 100 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0% to 20% EtOAc in petroleum ether) to give a mixture of 2-[(5-bromo-6-methoxy-benzoimidazol-1-yl)methoxy]ethyl-trimethyl-silane and 2-[(6-bromo-5-methoxy-benzoimidazol-1-yl)methoxy]ethyl-trimethyl-silane as a yellow oil (2.8 g, 7.84 mmol, 59% yield). ESI pos[M+H] + 357.0.

[0466] Step 5: 6-methoxy-N-(6-methylpyridazin-3-yl)-1-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine and 6-methoxy-N-(6-methylpyridazin-3-yl)-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine

[0467]

[0468] A mixture of 2-[(5-bromo-6-methoxy-benzoimidazol-1-yl)methoxy]ethyl-trimethyl-silane and 2-[(6-bromo-5-methoxy-benzoimidazol-1-yl)methoxy]ethyl-trimethyl-silane (2.8 g, 7.84 mmol, 1.0 eq.), 3-amino-6-methylpyridazine (1.71 g, 15.7 mmol, 2.0 eq.) and Cs2CO3 (7.66 g, 23.5 mmol, 3.0 eq.) in 1,4-dioxane (50 mL) was sparged with N2 for 10 minutes. [tBuBrettPhosPd(allyl)]OTf (613 mg, 0.78 mmol, 0.1 eq.) was added and the mixture was stirred at 80° C. under N2 for 4 hours. The mixture is poured into saturated NH4Cl aqueous solution (300mL), extracted with EtOAc (3x100mL) and the combined organic layer is passed through Na2SO4, dried, filtered and concentrated. The residue is purified by flash chromatography (silica gel, 0% to 100% EtOAc in petroleum ether) to obtain a mixture of 6-methoxy-N-(6-methylpyridazine-3-yl)-1-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine and 6-methoxy-N-(6-methylpyridazine-3-yl)-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine (3.0g, 7.78mmol, 94% yield) as a yellow oil.ESI pos[M+H] + 386.1.

[0469] Step 6: 6-Methoxy-N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine

[0470]

[0471] A mixture of 6-methoxy-N-(6-methylpyridazin-3-yl)-1-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine and 6-methoxy-N-(6-methylpyridazin-3-yl)-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine (3.0 g, 7.39 mmol, 1.0 eq.) in trifluoroacetic acid (10 mL, 130 mmol, 18 eq.) was stirred at room temperature for 3 hours. The mixture was concentrated and the resulting gum was dissolved in MeOH (10 mL). Aqueous NH3 solution (10%) (10 mL) was carefully added until pH 7, and the resulting yellow precipitate was filtered. The filter cake was washed with PE (3x10 mL) and dried to give 6-methoxy-N-(6-methylpyridazine-3-yl)-1H-benzimidazol-5-amine (1.0 g, 3.92 mmol, 52% yield) as a yellow solid. The combined filtrate was concentrated and the resulting residue was purified by preparative HPLC (Kromasil Eternity XT 10 μm, 250 mm x 80 mm, 0.1% NH4HCO3-ACN in water) to give 6-methoxy-N-(6-methylpyridazine-3-yl)-1H-benzimidazol-5-amine (0.5 g, 1.96 mmol, 26% yield) as a yellow solid. ESI pos[M+H] + 256.1. 1 H NMR (400MHz, CD3OD) δ = 8.61 (s, 1H), 8.36 (s, 1H), 7.41 (d, J = 9.3Hz, 1H), 7.33-7.28 (m, 1H), 7.26 (s, 1H), 3.98 (s, 3H), 2.54 (s, 3H).

[0472] Step 7: 2-[3-(Difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; formic acid

[0473]

[0474] To a solution of 6-chloro-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (100 mg, 0.35 mmol, 1.0 eq.) and 6-methoxy-N-(6-methylpyridazin-3-yl)-1H-benzimidazol-5-amine (90 mg, 0.35 mmol, 1.0 eq.) in DMSO (2 mL) was added KCO (136 mg, 1.05 mmol, 3.0 eq.). The reaction mixture was then stirred at 50°C for 16 hours. The reaction mixture was cooled to room temperature and diluted with H0 (20 mL) and EtOAc (10 mL). The resulting mixture of regioisomers was filtered. The filter cake was dissolved in DMSO (2 mL) and purified by preparative HPLC (ACS-WH-GX-F, 0.1% FA-ACN in water) to give 2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; formic acid (18 mg, 0.04 mmol, 10% yield) as a white solid. ESI pos [M+H] + 504.2.

[0475] 1 H NMR (400MHz, DMSO-d6) δ=8.97(s,1H),8.87-8.83(m,1H),8.74(d,J=8.6Hz,1H),8.40(s,1H),8.19(d,J=8.7Hz,1H),7 .83(s,1H),7.55(s,1H),7.37(s,1H),7.36-7.32(m,2H),7.19(s,1H),6.35(s,1H),3.92(s,3H),2.62(s,3H),2.48(br s,3H).

[0476] Example 17

[0477] 2-[3-(Difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[5-methoxy-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile

[0478]

[0479] The aqueous layer from example 16, post-processing in step 7 is extracted with EtOAc (3x10mL). The combined organic layer is washed with brine (3x10mL), dried over Na2SO4, filtered, and concentrated. The residue is purified by preparative TLC (dichloromethane: methanol = 10: 1) to obtain 2- [3- (difluoromethoxy) -5- methyl - pyrazol -1- bases] -6- [5- methoxy -6- [(6- methyl pyridazine -3- bases) amino] benzimidazol -1- bases] pyridine -3- carbonitrile (9 mg, 0.02 mmol, 5% yield) as a yellow solid. ESI pos[M+H] + 504.2.

[0480] 1 H NMR (400MHz, DMSO-d6) δ = 9.26 (d, J = 8.1Hz, 1H), 8.97 (s, 1H), 8.73 (d, J = 8.6Hz, 1H), 8.42 (s, 1H), 8.10 (d, J = 8.6Hz, 1H), 7. 53(s,1H),7.44(s,1H),7.34(s,1H),7.31-7.28(m,2H),7.16(s,1H),6.24(s,1H),3.96(s,3H),2.55(s,3H),2.46(s,3H).

[0481] Example 18

[0482] 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-(3-methyloxetan-3-yl)oxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile

[0483]

[0484] Step 1: 4-Bromo-5-(3-methyloxetan-3-yl)oxy-2-nitro-aniline

[0485]

[0486] To a solution of 3-methyloxetane-3-ol (742 mg, 8.43 mmol, 1.1 eq.) in THF (80 mL) was added sodium hydride (60% in oil) (460 mg, 11.49 mmol, 1.5 eq.) in portions at room temperature under N2. The mixture was stirred at 70°C for 1 hour under N2. The reaction mixture was cooled to room temperature, and a solution of 4-bromo-5-fluoro-2-nitro-aniline (1.80 g, 7.66 mmol, 1.0 eq.) in THF (10 mL) was added dropwise to the reaction mixture. The mixture was stirred at 50°C for 16 hours under N2. The mixture was poured into water (100 mL) and extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, 0% to 75% EtOAc in petroleum ether) to give 4-bromo-5-(3-methyloxetan-3-yl)oxy-2-nitro-aniline (700 mg, 2.31 mmol, 30% yield) as a yellow solid. ESI pos [M+H] + 303.0.

[0487] 1 H NMR (400MHz, CDCl3) δ = 8.41 (s, 1H), 6.33-6.03 (m, 2H), 5.61 (s, 1H), 4.99 (d, J = 6.8Hz, 2H), 4.65 (d, J = 7.5Hz, 3H), 1.85 (s, 3H).

[0488] Step 2: 4-Bromo-5-(3-methyloxetan-3-yl)oxy-benzene-1,2-diamine

[0489]

[0490] To a solution of 4-bromo-5-(3-methyloxetane-3-yl)oxy-2-nitro-aniline (700 mg, 2.31 mmol, 1.0 eq.) in EtOH (40 mL) were added iron (645 mg, 11.55 mmol, 5.0 eq.), NHCl (1.24 g, 23.09 mmol, 10 eq.) and H2O (20 mL). The suspension was stirred at 50°C under N2 for 2 hours. MeOH (100 mL) was added and the mixture was stirred at 50°C for 30 minutes. The mixture was filtered hot and the filtrate was concentrated and diluted with H2O (50 ml) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with saturated NaHCO3 solution (3 x 50 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (SiO 2 , 20 g, EtOAc) to give 4-bromo-5-(3-methyloxetan-3-yl)oxy-benzene-1 ,2-diamine (370 mg, 1.35 mmol, 59% yield) as a dark green solid. ESI pos[M+H] + 272.9.

[0491] 1 H NMR (400MHz, CDCl3) δ = 6.94 (s, 1H), 6.08 (s, 1H), 4.97 (d, J = 6.5Hz, 2H), 4.50 (d, J = 7.1Hz, 2H), 3.92-2.91 (m, 4H), 1.72 (s, 3H).

[0492] Step 3: 5-Bromo-6-(3-methyloxetan-3-yl)oxy-1H-benzimidazole

[0493]

[0494] To a solution of 4-bromo-5-(3-methyloxetane-3-yl)oxy-benzene-1,2-diamine (370 mg, 1.35 mmol, 1.0 eq.) in EtOH (10 mL) was added trimethyl orthoformate (1.44 g, 13.55 mmol, 10 eq.) and TsOH (23 mg, 0.14 mmol, 0.1 eq.). The mixture was stirred at 80 ° C for 2 hours. The reaction mixture was cooled to room temperature and quenched with saturated NaHCO (10 mL) and extracted with ethyl acetate (3x30 mL). The combined organic layer was dried over Na SO, filtered and concentrated. The crude product was purified by flash chromatography (SiO , 20 g, 10% MeOH in EtOAc) to obtain 5-bromo-6-(3-methyloxetane-3-yl)oxy-1H-benzimidazole (300 mg, 1.06 mmol, 78% yield) as a brown solid. ESIpos[M+H] + 282.9

[0495] Step 4: 6-[5-Bromo-6-(3-methyloxetan-3-yl)oxy-benzimidazol-1-yl]-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile

[0496]

[0497] To a solution of 6-chloro-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (Example 2, Step 1) (237 mg, 0.88 mmol, 1.0 eq.) in DMSO (10 mL) was added 5-bromo-6-(3-methyloxetane-3-yl)oxy-1H-benzimidazole (250 mg, 0.88 mmol, 1.0 eq.) and K CO (366 mg, 2.65 mmol, 3.0 eq.), and the suspension was stirred at room temperature for 2 hours. The reaction mixture was poured into H O (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over Na SO, filtered, and concentrated. The crude product was purified by preparative NPLC (Welch Ultimate XB-SiOH 10 μm, 250 mm×70 mm, hexanes-EtOH) to give 6-[6-bromo-5-(3-methyloxetan-3-yl)oxy-benzoimidazol-1-yl]-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (100 mg, 0.19 mmol, 22% yield) as an off-white solid: ESI pos [M+H] + 515.1;

[0498] 1H NMR (400MHz, CDCl3) δ = 8.60 (br s,1H),8.41(d,J=8.4Hz,1H),8.35(s,1H),7.66(d,J=8.4Hz,1H),6.97-6.65(m,2H), 6.62(s,1H),5.06(d,J=6.7Hz,2H),4.69(d,J=7.1Hz,2H),2.70(s,3H),1.86(s,3H);

[0499] and 6-[5-bromo-6-(3-methyloxetan-3-yl)oxy-benzoimidazol-1-yl]-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (100 mg, 0.19 mmol, 22% yield) as a yellow oil. ESIpos[M+H] + 515.1;

[0500] 1 H NMR (400MHz, CDCl3) δ = 8.50 (s, 1H), 8.40 (d, J = 8.4Hz, 1H), 8.12 (s, 1H), 7.65 (d, J = 8.4Hz, 1H), 7.35 (s, 1H), 6.80(t,J=54.6Hz,1H),6.62(s,1H),4.97(d,J=6.6Hz,2H),4.47(d,J=7.1Hz,2H),2.58(s,3H),1.75(s,3H).

[0501] Step 5: 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-(3-methyloxetan-3-yl)oxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile

[0502]

[0503] To a solution of 3-amino-6-methylpyridazine (42 mg, 0.39 mmol, 2.0 eq.) in 1,4-dioxane (5 mL) was added 6-[5-bromo-6-(3-methyloxetan-3-yl)oxy-benzimidazol-1-yl]-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (100 mg, 0.19 mmol, 1.0 eq.) and CsCO (190 mg, 0.58 mmol, 3.0 eq.). The reaction mixture was bubbled with N for 10 minutes. [tBuBrettPhosPd(allyl)]OTf (15 mg, 0.02 mmol, 0.1 eq.) was added and the suspension was stirred at 80° C. under N for 1 hour. The mixture was poured into H O (30 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated. The residue was purified by preparative HPLC (Phenomenex C18 3 μm, 75 mm x 30 mm, 0.1% FA-ACN in water, followed by preparative TLC (DCM / MeOH 10:1, Rf=0.4) to afford 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-(3-methyloxetanes-3-yl)oxy-5-[(6-methylpyridazine-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile (24 mg, 0.04 mmol, 23% yield) as a yellow solid. ESI pos[M+H]+544.1.

[0504] 1 H NMR (400MHz, CDCl3) δ = 8.55 (s, 1H), 8.48 (s, 1H), 8.38 (d, J = 8.6Hz, 1H), 7.66 (d, J = 8.4Hz, 1H), 7.28 (br s,1H),7.25-7.21(m,1H),7.15-7.10(m,1H),6.96-6.66(m,1H),6.62(s,1H),4.9 6(d,J=6.6Hz,2H),4.48(d,J=7.0Hz,2H),2.66(s,3H),2.58(s,3H),1.74(s,3H).

[0505] Example 19

[0506] 2-[2-(difluoromethoxy)-5-methyl-4-pyridinyl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetane-3-oxy)benzimidazol-1-yl]pyridine-3-carbonitrile

[0507]

[0508] Step 1: 4-Bromo-5-methyl-pyridin-2-ol

[0509]

[0510] A mixture of 4-bromo-2-chloro-5-methylpyridine (4.0 g, 19.37 mmol, 1.0 eq.) and t-BuONa (11.17 g, 116.24 mmol, 6.0 eq.) in tert-butanol (80 mL) was stirred at 120 ° C for 24 hours. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (3x100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by reverse phase HPLC (Phenomenex Synergi C18 10 μm, 150 mm x 25 mm, 0.1% FA-ACN in water) to obtain 4-bromo-5-methyl-pyridin-2-ol (3.5 g, 18.62 mmol, 96% yield) as a yellow solid. ESI pos[M+H] + 188.1.

[0511] Step 2: 4-Bromo-2-(difluoromethoxy)-5-methyl-pyridine

[0512]

[0513] A mixture of (2-chloro-2,2-difluoro-acetyl)oxysodium (10.4 g, 31.9 mmol, 3.0 eq.), CsCO (13.9 g, 42.6 mmol, 4.0 eq.) and 4-bromo-5-methyl-pyridin-2-ol (2.0 g, 10.6 mmol, 1.0 eq.) in DMF (40 mL) was stirred at 100 ° C for 12 hours. The reaction mixture was filtered, and the filtrate was diluted with H2O (100 mL) and extracted with EtOAc (3x100 mL). The combined organic layers were washed with brine (3x100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, 20% EtOAc in petroleum ether) to give 4-bromo-2-(difluoromethoxy)-5-methyl-pyridine (450 mg, 1.89 mmol, 18% yield) as a colorless oil. ESI pos[M+H] + 237.7.

[0514] Step 3: 2-(Difluoromethoxy)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[0515]

[0516] A mixture of 4-bromo-2-(difluoromethoxy)-5-methyl-pyridine (400 mg, 1.68 mmol, 1.0 eq.), bis(pinacolato)diboron (1.71 mg, 6.72 mmol, 4.0 eq.), potassium acetate (330 mg, 3.36 mmol, 2.0 eq.), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (137 mg, 0.17 mmol, 0.1 eq.) in 1,4-dioxane (20 mL) was stirred at 80° C. under N for 2 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column (silica gel, 20% to 50% EtOAc in petroleum ether) to give 2-(difluoromethoxy)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (260 g, 0.912 mmol, 54% yield) as a yellow solid. ESI pos[M+H] + 286.1.

[0517] Step 4: 6-Chloro-2-[2-(difluoromethoxy)-5-methyl-4-pyridinyl]pyridine-3-carbonitrile

[0518]

[0519] To a solution of 2-bromo-6-chloro-pyridine-3-carbonitrile (100 mg, 0.460 mmol, 1.0 eq.) in a mixture of 1,4-dioxane (2 mL) and water (0.2 mL) was added 2-(difluoromethoxy)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.31 g, 4.60 mmol, 10 eq.), Na2CO3 (146.22 mg, 1.38 mmol, 3 eq.) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (38 mg, 0.050 mmol, 0.10 eq.). The mixture was sparged with nitrogen for 10 minutes and stirred at 60°C under N2 for 2 hours. The mixture was poured into saturated NH4Cl solution (50 mL) and extracted with EtOAc (3x30 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (Phenomenex luna C18 10 μm, 150 mm x 25 mm, 0.225% FA-ACN in water) to obtain 6-chloro-2-[2-(difluoromethoxy)-5-methyl-4-pyridyl]pyridine-3-carbonitrile (50 mg, 0.17 mmol, 37% yield) as a white solid. ESI pos[M+H] +296.2.

[0520] 1 H NMR (400MHz, CD3OD) δ = 8.33 (d, J = 8.4Hz, 1H), 8.26 (s, 1H), 7.76 (s, 1H), 7.74-7.39 (m, 1H), 7.08 (s, 1H), 2.21 (s, 3H).

[0521] Step 5: 2-[[5-Bromo-6-(oxetan-3-yloxy)benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane and 2-[[6-Bromo-5-(oxetan-3-yloxy)benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane

[0522]

[0523] To a solution of 5-bromo-6-(oxetanes-3-yloxy)-1H-benzimidazole (4.5 g, 16.7 mmol, 1.0 eq.) in DMF (80 mL) was added sodium hydride (60% in oil) (0.80 g, 20.1 mmol, 1.2 eq.) in portions at 0 ° C. The mixture was allowed to warm to room temperature and stirred at room temperature for 1 hour. The mixture was cooled to 0 ° C. and 2-(trimethylsilyl)ethoxymethyl chloride (4.44 mL, 25.1 mmol, 1.5 eq.) was added dropwise. The mixture was stirred at room temperature for 16 hours. The mixture was poured into a saturated NH4Cl aqueous solution (400 mL) and extracted with EtOAc (3x150 mL). The combined organic layers were washed with brine (3x100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0% to 10% MeOH in EtOAc) to give a mixture of 2-[[5-bromo-6-(oxetan-3-yloxy)benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane and 2-[[6-bromo-5-(oxetan-3-yloxy)benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane as a yellow oil (2.0 g, 5.01 mmol, 30% yield). ESI pos[M+H] + 401.0.

[0524] Step 6: N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)-1-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine and N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine

[0525]

[0526] To a yellow solution of a mixture of 2-[[5-bromo-6-(oxetan-3-yloxy)benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane and 2-[[6-bromo-5-(oxetan-3-yloxy)benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (2.0 mg, 5.01 mmol, 1.0 eq.) in 1,4-dioxane (40 mL) was added 3-amino-6-methylpyridazine (1.1 g, 10.02 mmol, 2.0 eq.) and Cs2CO3 (4.9 g, 15.02 mmol, 3.0 eq.). The reaction mixture was sparged with N2 for 10 minutes. [tBuBrettPhosPd(allyl)]OTf (783 mg, 1.0 mmol, 0.20 eq.) was added and the mixture was stirred at 80°C for 4 hours. The mixture is poured into saturated NH4Cl aqueous solution (200mL), extracted with EtOAc (3x100mL).The organic layer merged is through Na2SO4 drying, filtered and concentrated.Residue is passed through flash chromatography (silica gel, 0% to 15% MeOH in EtOAc) purifying to obtain N- (6- methylpyridazine -3- bases) -6- (oxetanes -3- bases oxygen base) -1- (2- trimethylsilylethoxymethyl) benzimidazole -5- amine and N- (6- methylpyridazine -3- bases) -6- (oxetanes -3- bases oxygen base) -3- (2- trimethylsilylethoxymethyl) benzimidazole -5- amine mixture (1.5g, 3.51mmol, 70% yield) as light yellow oil.ESI pos[M+H] + 428.1

[0527] Step 7: N-(6-methylpyridazin-3-yl)-6-(oxetane-3-oxy)-1H-benzimidazol-5-amine

[0528]

[0529] A mixture of N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)-1-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine and N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-amine (1.5 g, 3.51 mmol, 1.0 eq.) in trifluoroacetic acid (10 mL, 129.8 mmol, 37 eq.) was stirred at room temperature for 3 hours. The mixture was concentrated and the residue was dissolved in H O (30 mL) and acetonitrile (10 mL) at room temperature. The solution was lyophilized to give a yellow solid, which was purified by flash chromatography (silica gel, 0% to 105 MeOH in EtOAc) to give N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)-1H-benzimidazol-5-amine (1.0 g, 3.36 mmol, 96% yield) as a yellow solid. ESI pos[M+H] + 298.1.

[0530] 1 H NMR (400MHz, CD3OD) δ=8.97(br s,1H),8.64(br s,1H),7.79-7.69(m,2H),7.01(s,1H),5.49(br s,1H),5.13-5.05(m,2H),4.79(br d,J=3.5Hz,2H),2.66-2.61(m,3H).

[0531] Step 8: 2-[2-(difluoromethoxy)-5-methyl-4-pyridinyl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile; formic acid

[0532]

[0533] To a solution of N-(6-methylpyridazin-3-yl)-6-(oxetan-3-yloxy)-1H-benzimidazol-5-amine (60 mg, 0.2 mmol, 1.2 eq.) in tert-amyl alcohol (1.0 mL) was added 6-chloro-2-[2-(difluoromethoxy)-5-methyl-4-pyridyl]pyridine-3-carbonitrile (50 mg, 0.17 mmol, 1.0 eq.) and K PO (108 mg, 0.51 mmol, 3.0 eq.). The mixture was bubbled with N for 10 minutes. tBuXPhosPdG (13 mg, 0.02 mmol, 0.1 eq.) was added and the reaction mixture was stirred at 80° C. under N for 2 hours. The reaction mixture was cooled to room temperature, poured into a saturated NH Cl solution (30 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by preparative TLC (DCM / MeOH 10:1) to give a mixture of 2-[2-(difluoromethoxy)-5-methyl-4-pyridinyl]-6-[6-[(6-methylpyridazin-3-yl)amino]-5-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile and 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile (20 mg, 0.04 mmol, 21% yield). The mixture of regioisomers was analyzed by preparative HPLC (Phenomenex Luna C18 10 μm 150 mm x 25 mm, 0.225% in water). FA-ACN) to give 2-[2-(difluoromethoxy)-5-methyl-4-pyridinyl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile; formic acid (2.29 mg, 0.0 mmol, 2.25% yield) as a light yellow solid (LCMS: WUX002952-507-P1F2; HNMR: WUX002952-507-P1B). ESI pos [M+H] + 557.3.

[0534] 1H NMR (400MHz, DMSO-d6) δ=9.11(s,1H),8.87-8.84(m,1H),8.74(d,J=8.8Hz,1H),8.44(s,1H),8.36-8.30(m,2H),7.82(t,J=72.8Hz,1 H),7.51(s,1H),7.47(s,1H),7.37-7.34(m,2H),5.18-5.11(m,1H),4.67-4.62(m,2H),4.60-4.56(m,2H),2.54(s,3H),2.27(s,3H).

[0535] Example 20

[0536] 2-[3-(Difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[5-(oxetane-3-oxy)benzimidazol-1-yl]pyridine-3-carbonitrile

[0537]

[0538] To a solution of 6-chloro-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (Example 8, Step 4) (100 mg, 0.35 mmol, 1.0 eq.) and 5-(oxetane-3-oxy)-1H-benzimidazole (87 mg, 0.46 mmol, 1.3 eq.) in DMSO (3 mL) was added KCO (145.35 mg, 1.05 mmol, 3.0 eq.). The reaction was stirred at 80° C. for 16 hours. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Phenomenex Luna C18 10 μm 150 mm x 25 mm, 0.225% FA-ACN in water) followed by SFC (Daicel ChiralPak IG 10 μm 250 mm x 30 mm, 0.1% NH4OH-EtOH) to afford 2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[5-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile (5 mg, 0.01 mmol, 3% yield) as a yellow solid. ESI pos[M+H] + 439.1.

[0539] 1H NMR (400 MHz, methanol-d4) δ = 8.90 (s, 1H), 8.51 (d, J = 8.4 Hz, 1H), 8.20-8.05 (m, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.45-6.97 (m, 3H), 6.14 (s, 1H), 5.43-5.31 (m, 1H), 5.06 (t, J = 6.7 Hz, 2H), 4.73 (dd, J = 5.1, 7.2 Hz, 3H), 2.61 (s, 3H).

[0540] Example 21

[0541] 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[[1-(oxetan-3-yl)-4-piperidinyl]amino]benzimidazol-1-yl]pyridine-3-carbonitrile

[0542]

[0543] Step 1: tert-Butyl N-[1-(oxetan-3-yl)-4-piperidinyl]carbamate

[0544]

[0545] To N-(4-piperidyl) carbamic acid tert-butyl ester (5.0g, 24.97mmol, 1.0eq.) in DCM (250mL) solution, add 3-oxetanes (5.4g, 74.94mmol, 3.0eq.) and acetic acid (1.05g, 17.48mmol, 0.7eq.) and the mixture was stirred at room temperature for 10 minutes.Sodium triacetoxyborohydride (15.9g, 75.02mmol, 3.0eq.) is added and the mixture was stirred at room temperature for 16 hours.Reactant mixture is diluted with saturated NaHCO the aqueous solution (200mL), and extracted with DCM (3x100mL).By the organic layer H merging o (100mL) and salt solution (3x50mL) washing, through Na sO dry, filter and concentrate. The crude product was purified by flash (silica gel, 0% to 10% MeOH in EtOAc) to give tert-butyl N-[1-(oxetan-3-yl)-4-piperidinyl]carbamate (5.4 g, 21.07 mmol, 84% yield) as a white solid. ESI pos[M+H] + 257.1.

[0546] 1H NMR (400MHz, CDCl3) δ=4.67-4.61(m,2H),4.60-4.55(m,2H),4.47(br s,1H),3.52-3.37(m,2H),2.66(br d,J=11.4Hz,2H),2.01-1.86(m,4H),1.44(s,11H).

[0547] Step 2: 1-(Oxetane-3-yl)piperidin-4-amine; dihydrochloride

[0548]

[0549] To a solution of tert-butyl N-[1-(oxetane-3-yl)-4-piperidinyl]carbamate (5.4 g, 21.1 mmol, 1.0 eq.) in DCM (40 mL) and MeOH (20 mL) was added 4 M HCl in dioxane (32 mL, 128 mmol, 6.1 eq.). The reaction mixture was stirred at room temperature for 4 hours to give a white suspension. The reaction mixture was concentrated to give 1-(oxetane-3-yl)piperidin-4-amine; dihydrochloride (4.8 g, 21.0 mmol, 99% yield) as a white solid, which was used without further purification. ESI pos[M+H] + 157.1.

[0550] Step 3: 4-nitro-N1-[1-(oxetan-3-yl)-4-piperidinyl]benzene-1,3-diamine

[0551]

[0552] To a suspension of 1-(oxetane-3-yl)piperidin-4-amine; dihydrochloride (3.24 g, 14.1 mmol, 1.1 eq.) in DMSO (20 mL) was added KCO (5.33 g, 38.6 mmol, 3.0 eq.) and stirred at room temperature for 5 minutes. 5-Fluoro-2-nitroaniline (2.0 g, 12.8 mmol, 1.0 eq.) was added and the mixture was stirred at 100 ° C for 16 hours. The reaction mixture was cooled to room temperature, poured into a saturated NH4Cl aqueous solution (300 mL) under vigorous stirring and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, 0% to 10% MeOH in EtOAc) to give 4-nitro-N1-[1-(oxetan-3-yl)-4-piperidinyl]benzene-1,3-diamine (1.4 g, 4.79 mmol, 37% yield) as a white solid. ESI pos[M+H]+ 293.0.

[0553] 1 H NMR (400MHz, DMSO-d6) δ = 7.71 (d, J = 9.5Hz, 1H), 7.28 (br s, 2H), 6.84 (br d,J=7.5Hz,1H),6.02(dd,J=2.0,9.5Hz,1H),5.88(d,J=1.8Hz,1H),4.57-4.47(m,2H),4.41(t,J=6.0Hz,2H),3.38(br t,J=6.4Hz,1H),3.25-3.15(m,1H),2.67(br d,J=11.1Hz,2H),1.94-1.83(m,4H),1.51-1.37(m,2H).

[0554] Step 4: N4-[1-(oxetan-3-yl)-4-piperidinyl]benzene-1,2,4-triamine

[0555]

[0556] To a solution of 4-nitro-N1-[1-(oxetanes-3-yl)-4-piperidinyl]benzene-1,3-diamine (100 mg, 0.34 mmol, 1.0 eq.) in MeOH (15 mL) was added Fe (191 mg, 3.42 mmol, 10 eq.), NHCl (366 mg, 6.84 mmol, 20 eq.) and H2O (5 mL), and the reaction mixture was stirred at 50 ° C for 2 hours under N2. The reaction was cooled to room temperature and diluted with MeOH (10 mL). NH3 aqueous solution (10%) (0.5 mL) was added, and the mixture was stirred at 30 ° C for 10 minutes. The mixture was filtered through a celite pad, and the filter cake was washed with MeOH (3x5 mL). The filtrate was dried over Na2SO4, filtered and concentrated to give N4-[1-(oxetan-3-yl)-4-piperidinyl]benzene-1,2,4-triamine (100 mg, 0.38 mmol, quantitative yield) as a dark brown solid, which was used without further purification.TLC: DCM / MeOH 10:1, Rf=0.20.

[0557] Step 5: N-[1-(Oxetane-3-yl)-4-piperidinyl]-1H-benzimidazol-5-amine

[0558]

[0559] To a solution of N4-[1-(oxetane-3-yl)-4-piperidinyl]benzene-1,2,4-triamine (100 mg, 0.38 mmol, 1.0 eq.) in EtOH (2 mL) was added TsOH (7 mg, 0.04 mmol, 0.1 eq.) and trimethoxymethane (417 μL, 3.81 mmol, 10 eq.), and the reaction mixture was stirred at 80 ° C. under N2 for 2 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by preparative HPLC (Phenomenex luna C18 15 μm 150 mm x 40 mm, 0.1% NH4OH-ACN in water) to give N-[1-(oxetane-3-yl)-4-piperidinyl]-1H-benzimidazol-5-amine (35 mg, 0.13 mmol, 34% yield) as a brown solid. ESI pos[M+H] + 273.1.

[0560] Step 6: 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[[1-(oxetan-3-yl)-4-piperidinyl]amino]benzimidazol-1-yl]pyridine-3-carbonitrile

[0561]

[0562] To a solution of 6-chloro-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]pyridine-3-carbonitrile (Example 2, Step 1) (48 mg, 0.18 mmol, 1.2 eq.) in tert-amyl alcohol (2.0 mL) was added N-[1-(oxetane-3-yl)-4-piperidinyl]-1H-benzimidazol-5-amine (40 mg, 0.15 mmol, 1.0 eq.) and K PO (94 mg, 0.44 mmol, 3.0 eq.). The reaction mixture was bubbled with N for 10 minutes. tBuXPhosPdG (23 mg, 0.03 mmol, 0.2 eq.) was added and the reaction mixture was stirred at 80° C. under N for 16 hours. The reaction mixture was cooled to room temperature, poured into saturated aqueous NH Cl (30 mL), and extracted with EtOAc (3×10 mL). The combined organic layers were dried over NaSO, filtered and concentrated. The residue was purified by preparative TLC (DCM / MeOH 10:1) to give a mixture of 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[[1-(oxetanes-3-yl)-4-piperidinyl]amino]benzimidazol-1-yl]pyridine-3-carbonitrile and 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[[1-(oxetanes-3-yl)-4-piperidinyl]amino]benzimidazol-1-yl]pyridine-3-carbonitrile (20 mg, 0.04 mmol, 27% yield) as a yellow oil. The mixture of isomers was purified by SFC (DAICEL CHIRALCEL OD 10 μm, 250 mm x 30 mm, 0.1% NH4OH-ACN in MeOH) to give 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[[1-(oxetan-3-yl)-4-piperidinyl]amino]benzimidazol-1-yl]pyridine-3-carbonitrile (6 mg, 0.01 mmol, 29% yield) as a yellow solid. ESI pos [M+H]+ 505.1.

[0563] 1H NMR (400MHz, DMSO-d6) δ=8.98(s,1H),8.72(d,J=8.6Hz,1H),8.19(d,J=8.6Hz,1H),7.93(br d,J=8.9Hz,1H),7.11(br t,J=54.0Hz,1H),6.87(s,1H),6.76(brs,2H),5.54(br d,J=8.0Hz,1H),4.53(br t,J=6.3Hz,2H),4.42(br t,J=6.0Hz,2H),3.39(br s,1H),2.67(br s,5H),2.55(s,3H),1.98-1.89(m,4H).

[0564] Example 22 - Phosphorylation Assay SIK1-3:

[0565] In the presence of SIK2 (SIK1 or SIK3, respectively) and ATP, the CHK peptide (KKKVSRSGLYRSPSMPENLNRPR with a C-terminal arginine amide modification) is phosphorylated at one of the four available serines. Only one phosphorylation was 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 minutes (ambient temperature) after addition of 5 μl SIK1 (5 nM), 5 μl SIK2 (0.5 nM), or 7 μl SIK3 (1.5 nM) in assay buffer (12.5 mM HEPES (pH 7.0), 10 mM magnesium acetate, 0.005% BSA). 10 μM CHK-peptide solution and 100 μM ATP solution (5 μl for SIK1 and SIK2, 3 μl for SIK3) in the assay buffer were added respectively and incubated for 45 minutes under ambient conditions. 40 μl of 0.125% formic acid aqueous solution was added to quench the reaction. Data were generated using RapidFire (RF) mass spectrometry as described below. Multiple charged species (3-5 charges) of phosphorylated and non-phosphorylated forms measured by MRM (multiple reaction monitoring; API5000 or 6500+) or EIC (extracted ion current; QToF) were added and the ratio (total sum of phosphorylated species / total sum of all species) was calculated for data evaluation. Based on a commercially available SIK inhibitor (CAS No. 1936529-65-5) of non-inhibitory control DMSO and 1 μM YKL-05-099, normalization was performed by Genedata software. The assay results are expressed as half-maximal inhibitory concentration (IC50) and are summarized in Table 1 below.

[0566] RapidFire Settings:

[0567] The sample was vacuum-pumped for a maximum of 600 ms and loaded into a C4 cartridge (Agilent; No. G9203A) and treated with 0.1% formic acid in water at 1.5 ml / min for 3000 ms. The sample was then transferred to an API 5000 (API 6500+) or QToF mass spectrometer and treated with 90% acetonitrile; 10% water; 0.007% TFA; 0.093% formic acid at 1.25 ml / min for 4000 ms. The cartridge was then treated with 0.1% formic acid in water for an additional 500 ms.

[0568] MS settings for Sciex API5000 / API6500+:

[0569] All MS analyses were performed in MRM mode using the following MS settings: electrospray positive ionization; ion spray voltage: 4000 V; temperature: 550°C; collision gas: 5; curtain gas: 15; gas 1: 40; gas 2: 42; EP: 10. DP = declustering potential; CE = collision energy; CXP = collision cell exit voltage.

[0570] name Q1(m / z) Q3(m / z) Time (ms) DP(V) CE(V) CXP(V) CHK(4+) 676.0 84.2 50 46 99 18 CHK(5+) 541.0 84.2 50 51 71 36 pCHK(4+) 696.0 84.2 50 66 105 18 pCHK(5+) 557.0 84.2 50 51 53 4

[0571] MS setup Agilent QToF 6545

[0572] All MS analyses were performed in MS mode using the following MS settings: Dual AJS electrospray positive ionization; VCap: 3000 V; drying and sheath gas: 340 °C, 8 l / min; nebulizer: 60 psig; nozzle voltage: 2000 V; fragmentor: 130 V; skimmer: 35 V; Oct1 RF Vpp: 700 V; reference mass at 5 spectra / s

[0573] name EIC(m / z) width CHK(3+) 900.8345 50ppm CHK(4+) 675.8789 50ppm CHK(5+) 540.9048 50ppm pCHK(3+) 927.4961 50ppm pCHK(4+) 695.8747 50ppm

[0574] Table 1: IC50 values ​​for inhibition of SIK1, SIK2, and SIK3:

[0575]

[0576]

[0577] Example A

[0578] Film-coated tablets containing the following ingredients can be manufactured in a conventional manner:

[0579] <![CDATA[ Element ]]> <![CDATA[ Each tablet ]]> Kernel: Compound of formula (I) or a pharmaceutically acceptable salt thereof 10.0mg 200.0mg microcrystalline cellulose 23.5mg 43.5mg Lactose hydrate 60.0mg 70.0mg Povidone K30 12.5mg 15.0mg Sodium starch glycolate 12.5mg 17.0mg magnesium stearate 1.5mg 4.5mg (Core Weight) 120.0mg 350.0mg Film coating: Hydroxypropyl methylcellulose 3.5mg 7.0mg Polyethylene glycol 6000 0.8mg 1.6mg talcum powder 1.3mg 2.6mg Iron oxide (yellow) 0.8mg 1.6mg Titanium dioxide 0.8mg 1.6mg

[0580] The active ingredient is sieved and mixed with microcrystalline cellulose, and the mixture is granulated with a solution of polyvinylpyrrolidone in water. The granules are then mixed with sodium starch glycolate and magnesium stearate and compressed to give kernels of 120 mg or 350 mg, respectively. The kernels are painted with an aqueous solution / suspension of the above-mentioned film coating.

[0581] Example B

[0582] Capsules containing the following ingredients can be manufactured in a conventional manner:

[0583] <![CDATA[ Element ]]> <![CDATA[ Each capsule <!-- 57 -->]]> Compound of formula (I) or a pharmaceutically acceptable salt thereof 25.0mg lactose 150.0mg corn starch 20.0mg talcum powder 5.0mg

[0584] The ingredients were sieved and mixed and filled into size 2 capsules.

[0585] Example C

[0586] The injection solution can have the following composition:

[0587] Compound of formula (I) or a pharmaceutically acceptable salt thereof 3.0mg polyethylene glycol 400 150.0mg Acetic acid Adjust pH to 5.0 Water for injection solution Add to 1.0ml

[0588] The active ingredient is dissolved in a mixture of polyethylene glycol 400 and water for injection (part). The pH is adjusted to 5.0 by adding acetic acid. The volume is adjusted to 1.0 ml by adding the remainder of water. The solution is filtered, filled into a vial using an appropriate overfill and sterilized.

Claims

1. A compound of formula (I) in R 1 is optionally selected individually from R 4 substituted with 1, 2 or 3 substituents; R 2 is hydrogen, alkoxy, halogen, dialkylaminoalkoxy, heteroarylamino or heterocycloalkyloxy; wherein heteroarylamino and heterocycloalkyloxy are optionally independently selected from R 5 substituted with 1, 2 or 3 substituents; R 3 is hydrogen, alkyl, dialkylaminoalkyl, heterocycloalkyl or heteroaryl; wherein heteroaryl and heterocycloalkyl are optionally independently selected from R 6 substituted with 1, 2 or 3 substituents; R 4 Each instance of is independently selected from cyano, alkyl, alkoxy, halogen, haloalkoxy, and haloalkyl; R 5 Each instance of is independently selected from alkyl and dialkylaminocarbonyl; R 6 Each instance of is independently selected from alkyl, heterocycloalkyl, (heterocycloalkyl)heterocycloalkyloxy, (alkoxy)heterocycloalkylalkyl, and dialkylaminocarbonyl; and L is absent, -O- or -NH-; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein R 1 is selected from pyrazolyl and pyridinyl, wherein pyrazolyl and pyridinyl are optionally independently selected from R 4 substituted with 1, 2 or 3 substituents.

3. The compound according to claim 1 or 2, wherein R 1 is optionally selected individually from R 4 1, 2 or 3 substituents of pyrazolyl.

4. The compound according to any one of claims 1 to 3, wherein R 2 is hydrogen, alkoxy, halogen, dialkylaminoalkoxy, pyridazinylamino or oxetanyloxy; wherein pyridazinylamino and oxetanyloxy are optionally independently selected from R 5 substituted with 1, 2 or 3 substituents.

5. The compound according to any one of claims 1 to 4, wherein R 2 is hydrogen, methoxy, fluorine, dimethylaminoethoxy, pyridazinylamino or oxetanyloxy; wherein pyridazinylamino and oxetanyloxy are optionally independently selected from R 5 substituted with 1, 2 or 3 substituents.

6. The compound according to any one of claims 1 to 5, wherein R 3 is hydrogen, alkyl, dialkylaminoalkyl, piperidinyl, oxetanyl or pyridazinyl; wherein piperidinyl, oxetanyl and pyridazinyl are optionally independently selected from R 6 substituted with 1, 2 or 3 substituents.

7. A compound according to any one of claims 1 to 6, wherein R 3 is hydrogen, methyl, dimethylaminoethyl, piperidinyl, oxetanyl or pyridazinyl; wherein piperidinyl, oxetanyl and pyridazinyl are optionally selected from R 6 substituted with 1, 2 or 3 substituents.

8. A compound according to any one of claims 1 to 7, wherein R 4 is in each instance individually selected from cyano, alkyl, haloalkoxy, and haloalkyl.

9. The compound according to any one of claims 1 to 8, wherein R 4 is independently selected in each instance from cyano, methyl, difluoromethoxy, difluoromethyl, and trifluoroethyl.

10. The compound according to any one of claims 1 to 9, wherein R 5 is independently selected at each instance from methyl and dimethylaminocarbonyl.

11. The compound according to any one of claims 1 to 10, wherein R 6 and wherein the alkyl radical is independently selected in each instance from the group consisting of alkyl, oxetanyl, (oxetanyl)piperidinyloxy, (methoxy)azetidinylethyl, and dialkylaminocarbonyl.

12. A compound according to any one of claims 1 to 11, wherein R 6 and independently in each instance selected from methyl, oxetanyl, (oxetanyl)piperidinyloxy, (methoxy)azetidinylethyl, and dimethylaminocarbonyl.

13. The compound according to any one of claims 1 to 12, wherein L is -NH-.

14. A compound of formula (I) according to any one of claims 1 to 13, selected from: 2-(3-cyano-5-methyl-pyrazol-1-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[2-(dimethylamino)ethoxy]-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[2-(dimethylamino)ethoxy]-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; 6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile; 6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile; 3-[[3-[5-Cyano-6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-2-pyridinyl]benzimidazol-5-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide; 3-[[1-[5-Cyano-6-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-2-pyridinyl]benzimidazol-5-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide; 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]-5-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-fluoro-5-[[6-[[1-(oxetan-3-yl)-4-piperidinyl]oxy]pyridazin-3-yl]amino]benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-fluoro-5-[[6-[2-(3-methoxyazetidin-1-yl)ethyl]pyridazin-3-yl]amino]benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(Difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]-5-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(Difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(Difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(Difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[5-methoxy-6-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-(3-methyloxetan-3-yl)oxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[2-(difluoromethoxy)-5-methyl-4-pyridinyl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(Difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[5-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile; and 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[[1-(oxetan-3-yl)-4-piperidinyl]amino]benzimidazol-1-yl]pyridine-3-carbonitrile; or a pharmaceutically acceptable salt thereof.

15. A compound of formula (I) according to any one of claims 1 to 14, selected from: 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; 6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile; 6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]-2-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridine-3-carbonitrile; 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(Difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[5-[(6-methylpyridazin-3-yl)amino]-6-(oxetan-3-yloxy)benzimidazol-1-yl]pyridine-3-carbonitrile; 2-[3-(Difluoromethoxy)-5-methyl-pyrazol-1-yl]-6-[6-methoxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; and 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-(3-methyloxetan-3-yl)oxy-5-[(6-methylpyridazin-3-yl)amino]benzimidazol-1-yl]pyridine-3-carbonitrile; or a pharmaceutically acceptable salt thereof.

16. A method for preparing a compound according to any one of claims 1 to 15, comprising one of the following steps: (a) making a compound of formula (A1) With the compound of formula (A2) reacting in the presence of a suitable solvent and in the presence of a suitable base; (b) making the compound of formula (B1) With the compound of formula (B2) in the presence of a suitable solvent and a suitable catalyst, or (c) making a compound of formula (C1) or (C2) With the compound of formula (C3) reacting in the presence of a suitable solvent, a suitable base and a suitable catalyst, wherein X1 is halogen, OMs or OTs, especially halogen; X2 is halogen, especially chlorine; L, R 1 、R 2 、R 3 and R 6 As defined in any one of claims 1 to 13.

17. The compound according to any one of claims 1 to 15, which is manufactured according to the method according to claim 16.

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

19. A pharmaceutical composition comprising: a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, and a therapeutically inert carrier.

20. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 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.

21. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15 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.

22. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, 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.

23. A method for treating or preventing rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis, comprising administering to a patient in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15.

24. The invention as hereinbefore described.

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