New benzimidazole pyridine derivatives

Abstract

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

Description

[0001] New Benzimidazole Pyridine Derivatives

[0002] The present invention relates to organic compounds useful for therapy and / or prophylaxis in a mammal, and in particular to prodrugs of metabolites that modulate SIK activity. The invention further relates to their manufacture, pharmaceutical compositions containing them and their use as therapeutically active substances.

[0003] The invention relates in particular to a compound of formula (la) wherein one of Ri and R2 is a prodrug moiety, or wherein one of Ri and R2 together with the oxygen or nitrogen to which they are attached forms a prodrug moiety; and the other one of Ri and R2 is hydrogen; or a pharmaceutically acceptable salt thereof.

[0004] Salt-inducible kinases (SIK) belong to a subfamily of AMP-activated protein kinases (AMPK) called AMPK -related kinases. There are three members, named SIK1, SIK2 and SIK3, that are broadly expressed. Their major biological role is to modify gene expression by controlling the phosphorylation and subcellular localization of two key classes of transcriptional regulatory factors: CRTCs (cAMP-regulated transcriptional coactivators) and class Ila HDACs (Histone deacetylases). Indeed, in basal state, both CRTCs and HDACs are phosphorylated by SIK kinases, and sequestered in the cytoplasm through interactions with their cytoplasmic chaperones 14-3-3. In response to extracellular cues that usually increase intracellular levels of cAMP, the SIK kinases’ activity is inhibited, CRTCs and HDACs are no longer phosphorylated and are hence released from 14-3-3. They can therefore translocate into the nucleus and regulate gene expression (reviewed in Wein et al., Trends Endocrinol Metab. 2018 Oct;29(10):723-735).

[0005] In macrophages, the inhibition of SIK kinases leads to 1) CRTC3 shuttling to the nucleus and increasing the transcription of IL-10,; and 2) translocation of HDAC4 / 5 to the nucleus and subsequent deacetylation of NF-KB resulting in decreased transcription of pro-inflammatory cytokines (Clark et al., Proc Natl Acad Sci U S A. 2012 Oct 16; 109(42): 16986-91.).

[0006] Macrophages are critical to maintaining tissue homeostasis, mediating inflammation, and promoting the resolution of inflammation. To achieve this diversity of function, macrophages have the ability to “polarize” differently in response to environment cues. The two extreme phenotypes along their activation state continuum are the “Ml” or “pro-inflammatory macrophages” and the “M2” or “pro-resolution macrophages”.

[0007] Strikingly, the inhibition of intracellular SIK kinases overrides these extracellular macrophage polarization signals and pushes them toward a pro-resolution phenotype. This comes with an increase in IL-10 (by interfering with the SIK-CRTC3 pathway) and a concomitant decrease in TNF-a, IL-12 and IL-6 (by interfering with the SIK-HDAC4 / 5 and NF-KB pathway). The high levels of IL- 10 and low levels of pro-inflammatory cytokines upon SIK inhibition will promote resolution of inflammation. The exploration of the SIK pathway has initially been described in macrophages (Clark et al., Proc Natl Acad Sci U S A. 2012 Oct 16; 109(42): 16986- 91) and dendritic cells (Sundberg et al., Proc Natl Acad Sci U S A. 2014 Aug 26; 111(34): 12468- 73) and the therapeutic potential of pan-SIK inhibitors has been confirmed in a mouse LPS (lipopolysaccharide) challenge model (Sundberg et al., ACS Chem Biol. 2016 Aug 19; 1 l(8):2105-l 1) and in colitis models (Fu et al., Inflamm Bowel Dis. 2021 Oct 20;27(l l): 1821-1831). SIKs have since been shown to be important players in the functions of several immune cells, including mast cells (Darling et al., J Biol Chem. 2021 Jan- Jun;296: 100428). Importantly, SIK1 is poorly expressed in macrophages and one embodiment of the invention are SIK2 / 3 inhibitors sparing SIK1, thus limiting potential SIKl-related toxicities. SIK inhibitors have a high therapeutic potential in diseases that are 1) characterized by pro- inflammatory macrophage influx in the tissues and impaired tissue homeostasis and healing, or 2) where anti-TNF therapies are beneficial (partially or fully) or with insufficient levels of the IL10. Diseases with an inflammatory macrophage signature are e.g. rheumatoid arthritis, juvenile rheumatoid arthritis, NASH, primary sclerosing cholangitis, giant cell vasculitis and inflammatory bowel diseases (“IBD”), atherosclerosis, type 2 diabetes and glomerulonephritis.

[0008] Diseases with a proven link to IL-10 and TNF-a are IBD. Genetic alterations that reduce the function of IL-10 (such as SNPs in IL-10 or its receptor) are associated with an increased risk for IBD in humans. In addition, anti-TNF therapies are successful but only a subset of IBD patients are responsive and much of this limited responsiveness is lost over time. The described dual effect of SIK inhibitors (increased IL- 10 and decreased TNF-a) make them particularly pertinent for the treatment of IBD.

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

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

[0011] As of today many diseases caused by dysregulation of the innate immune system lack efficient therapies and there is a high unmet medical need for new therapies. The present invention relates to a novel compounds that are highly active SIK inhibitors for the treatment of inflammatory, allergic and autoimmune diseases. In addition to inflammation, allergic and autoimmune diseases, SIK inhibitors can thus also be of potential relevance in cancer, metabolic diseases, bone density dysregulation diseases, pigmentation-related diseases or cosmetology, fibrotic diseases and depressive disorders.

[0012] The present invention relates to a compound of formula (la), which is metabolized in vivo into the active metabolite of formula (I). The prodrugs of the present invention present improved physicochemical properties when compared to the metabolite, such as for instance permeability, which then also provides for an enhanced oral bioavailability and can further provide for favourable pharmacokinetics.

[0013] In the present description the term “alkyl”, alone or in combination, signifies a straightchain or branched-chain alkyl group with 1 to 8 carbon atoms, particularly a straight or branched- chain alkyl group with 1 to 6 carbon atoms and more particularly a straight or branched-chain alkyl group with 1 to 4 carbon atoms. Examples of straight-chain and branched-chain C1-C8 alkyl groups include, but are not limited to, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, the isomeric pentyls, the isomeric hexyls, the isomeric heptyls and the isomeric octyls, particularly methyl, ethyl, propyl, butyl and pentyl. Particular examples of alkyl are methyl, ethyl, propyl, iso-propyl, butyl and tert-butyl. Methyl, iso-propyl and tert-butyl are further particular examples of “alkyl” in the compound of formula (I) or (la).

[0014] The term “alkoxy” or “alkyloxy”, alone or in combination, signifies a group of the formula alkyl-O- in which the term "alkyl" has the previously given significance, such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. Particular examples of “alkoxy” are methoxy, iso-propoxy and tert-butoxy.

[0015] The term “oxy”, alone or in combination, signifies the -O- group.

[0016] The term “carbonyl”, alone or in combination, signifies the -C(O)- group.

[0017] The term “amino”, alone or in combination, signifies the primary amino group (-NH2), the secondary amino group (-NH-), or the tertiary amino group (-N-).

[0018] The term “alkylamino” is an alkyl group linked to a -NH- group, such as for instance methylamino, wherein the amino is further linked to the relevant compound. The term “dialkylamino” denotes two alkyl groups linked to a -N- atom, such as for instance dimethylamino, wherein the amino is further linked to the relevant compound.

[0019] The term “alkyl carbonyl”, is an alkyl group linked to a -C(O)- group, wherein the carbonyl is further linked to the relevant compound. Particular “alkylcarbonyl” are for instance methylcarbonyl (also known as acetyl), ethyl carbonyl, iso-propylcarbonyl and tert-butyl carbonyl.

[0020] The term “alkoxy carbonyl”, is an alkoxy group linked to a -C(O)- group, wherein the carbonyl is further linked to the relevant compound. Particular “alkoxycarbonyl” are for instance methoxycarbonyl, iso-propoxycarbonyl and tert-butoxycarbonyl.

[0021] The term “aminocarbonyl”, alone or in combination, denotes an “amino” group linked to a “carbonyl” group, wherein the carbonyl is further linked to the relevant compound.

[0022] The term “alkylaminocarbonyl”, alone or in combination, denotes an “alkylamino” group linked to a “carbonyl” group, wherein the carbonyl is further linked to the relevant compound. A particular example of “alkylaminocarbonyl” is for instance methylaminocarbonyl.

[0023] The term “dialkylaminocarbonyl”, alone or in combination, denotes a “dialkylamino” group linked to a “carbonyl” group, wherein the carbonyl is further linked to the relevant compound. A particular example of “dialkylaminocarbonyl” is for instance dimethylaminocarbonyl.

[0024] The term “alkylcarbonyloxyalkyl”, alone or in combination, denotes an “alkylcarbonyl” group linked to an “oxy” group, wherein the “oxy” group is further linked to the relevant compound via an “alkyl” group. Particular “alkylcarbonyloxyalkyl” are for instance methylcarbonyl oxymethyl .

[0025] The term “aminoalkylcarbonyl”, alone or in combination, denotes an “amino” group linked to an “alkylcarbonyl” group, wherein the “alkylcarbonyl” group is further linked to the relevant compound. A particular example of “aminoalkylcarbonyl” is for instance methylaminocarbonyl.

[0026] The term “alkoxycarbonyloxyalkyl”, alone or in combination, denotes an “alkoxycarbonyl” group linked to an “oxy” group, wherein the “oxy” group is further linked to the relevant compound via an alkyl group. Particular “alkoxycarbonyloxyalkyl” are for instance methoxycarbonyl oxymethyl . The term “alkoxycarbonyl(alkylamino)alkyl”, alone or in combination, denotes an “alkoxycarbonyl” group linked to an “alkylamino” group, wherein the “alkylamino” group is further linked to the relevant compound via an “alkyl” group. Particular examples of “alkoxycarbonyl(alkylamino)alkyl” are for instance methoxycarbonyl(methylamino)methyl and methoxycarbonyl(methylamino)ethyl.

[0027] The term “heteroaryl”, alone or in combination, signifies an aromatic mono- or bicyclic ring system with 5 to 12 ring atoms, comprising 1, 2, 3 or 4 heteroatoms each independently selected from N, O and S, the remaining ring atoms being carbon. The ring system can be attached to the remaining compound via an atom selected from C, N, S and O, in particular via a N atom (“N- heteroaryl”). The ring system can be partially or fully aromatic. Examples of heteroaryl include, but are not limited to, pyrazolyl, pyrazol-l-yl, pyrazol-3-yl, pyrazol-4-yl, pyridinyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, pyridazinyl, pyridazin-3-yl, pyridazin-4-yl, pyrazinyl, pyrazin-2-yl, isoxazolyl, isoxazol-3-yl, isoxazol-4-yl, oxazolyl, 2-oxazol-5-yl, 2-oxo-3-imidazol-l-yl, pyrimidinyl, pyrimidin-5-yl, benzotriazolyl, lH-benzotriazol-4-yl, furanyl, furyl, 2-furyl, 3-furyl, [6-oxo-lH- pyridazin-5-yl], triazolyl, triazol-l-yl, triazol-2-yl, triazol-3-yl, triazol-4-yl, pyridin-2-one, 2-oxo- 4-pyridyl. pyrimidin-2-yl, pyrimidin-5-yl, (l,3,4-oxadiazol-2-yl), (l,3,4-thiadiazol-2-yl), (1,2,4- triazin-3-yl), 2-oxo-pyrimidin-4-yl, (1 -methyl -2-oxo-3 -pyridyl), 5-methyl-6-oxo-4H-pyrrolo[3,4- c]pyrazol-2-yl, (2,3-dihydropyridazino[4,5-b][l,4]oxazin-8-yl) and 1, 3 -di ox ol -2-one. A particular example of “heteroaryl” is for instance l,3-dioxol-2-one.

[0028] The term “heteroarylalkyl”, alone or in combination, denotes a “heteroaryl” group linked to the relevant compound via an alkyl group. Particular examples of “heteroarylalkyl” are for instance l,3-dioxol-2-one-4-methyl and 4-methyl-l,3-dioxol-2-one-5-methyl

[0029] The term “ dihydrogen phosphate alkyl alone or in combination, denotes a dihydrogen phosphate group linked to the relevant compound via an “alkyl” group.

[0030] The term “pharmaceutically acceptable salts” denotes salts which are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid and base addition salts. The term “pharmaceutically acceptable acid addition salt” denotes those pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and organic acids selected from aliphatic, cycloaliphatic, aromatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicyclic acid. The term “pharmaceutically acceptable base addition salt” denotes those pharmaceutically acceptable salts formed with an organic or inorganic base. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, and polyamine resins.

[0031] The term “prodrug” denotes a form or derivative of a compound which is metabolized in vivo, e.g., by biological fluids or enzymes by a subject after administration, into a pharmacologically active form of the compound in order to produce the desired pharmacological effect. Various sites in the human body allow for metabolizing a prodrug into a pharmaceutically active form, such as for instance the liver, gut and plasma. Prodrugs are described e.g. in “The Organic Chemistry of Drug Design and Drug Action”, by Richard B. Silverman, Academic Press, San Diego, 2004, Chapter 8 Prodrugs and Drug Delivery Systems, pp. 497-558.

[0032] The term “prodrug moiety” denotes a chemical moiety that can be metabolized in vivo , e.g., by biological fluids or enzymes by a subject after administration, to yield a pharmacologically active form of the compound in order to produce the desired pharmacological effect. The compound of formula (I) as described herein is an active metabolite of the compound of formula (la), wherein the prodrug moiety is metabolized in vivo into the active form. Examples of “prodrug moi eties” are for instance dialkylaminocarbonyl, alkylaminocarbonyl, aminocarbonyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxyalkyl, aminoalkylcarbonyl, alkoxycarbonyloxyalkyl, alkoxycarbonyl(alkylamino)alkyl , heteroarylalkyl , dihydrogen phosphate methyl and -PO3H2. In particular, the following groups are examples of suitable prodrug moieties that can be metabolized into a hydroxyl moiety: carbonates, esters, carbamates, phosphate and phosphonooxymethylethers.

[0033] The term “compound(s) of this invention” and “compound(s) of the present invention” refers to compounds of formula (I) and / or formula(Ia) as applicable, as well as stereoisomers, tautomers, solvates, and salts (e.g., pharmaceutically acceptable salts) thereof.

[0034] Tautomeric forms, i.e. structural isomers which interconvert with the compound of formula (I) or (la) as applicable, in particular in solution, may in some instances exist and are to be understood as being included in the invention.

[0035] If one of the starting materials or compounds of formula (I) and / or (la) as applicable, contain one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups (as described e.g. in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wuts, 3rdEd., 1999, Wiley, New York) can be introduced before the critical step applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature. Examples of protecting groups are tert-butoxy carbonyl (Boc), 9-fluorenylmethyl carbamate (Fmoc), 2 -trimethyl silyl ethyl carbamate (Teoc), carbobenzyl oxy (Cbz) and p-methoxybenzyloxycarbonyl (Moz).

[0036] The compound of formula (I) and / or (la) as applicable, can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.

[0037] The term “asymmetric carbon atom” means a carbon atom with four different substituents. According to the Cahn-Ingold-Prelog Convention an asymmetric carbon atom can be of the “R” or “S” configuration.

[0038] Furthermore, the invention includes all optical isomers, i.e. diastereoisomers, diastereomeric mixtures, racemic mixtures, all their corresponding enantiomers and / or tautomers as well as their solvates, wherever applicable, of the compound of formula (I) and / or (la) as applicable.

[0039] If desired, racemic mixtures of the compound of the invention may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.

[0040] In the embodiments, where an optically pure enantiomer is provided, optically pure enantiomer means that the compound contains > 90 % of the desired isomer by weight, particularly > 95 % of the desired isomer by weight, or more particularly > 99 % of the desired isomer by weight, said weight percent based upon the total weight of the isomer of the compound. A chirally pure or chirally enriched compound may be prepared by chirally selective synthesis or by separation of enantiomers. The separation of enantiomers may be carried out on the final product or alternatively on a suitable intermediate.

[0041] Structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Particular examples of such isotopes are2H,3H,13C,14C and18F. For example the structures wherein one or more hydrogen atoms are replaced by deuterium or tritium, or one or more carbon atoms are replaced by a13C- or14C- enriched carbon are within the scope of this invention.

[0042] The invention thus also relates to:

[0043] A prodrug that is metabolized in vivo into the compound of formula (I) or a pharmaceutically acceptable salt thereof; A compound according to the invention, wherein one of Ri and R2 is dialkylaminocarbonyl, alkylaminocarbonyl, aminocarbonyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxyalkyl, aminoalkylcarbonyl, alkoxycarbonyloxyalkyl, alkoxycarbonyl(alkylamino)alkyl, heteroarylalkyl, dihydrogen phosphate alkyl or -PO3H2; and the other one is hydrogen; or a pharmaceutically acceptable salt thereof;

[0044] A compound according to the invention, wherein one of Ri and R2 is dialkylaminocarbonyl, alkylcarbonyl or alkoxycarbonyl, and the other one is hydrogen;

[0045] A compound according to the invention, wherein Ri is dimethylaminocarbonyl, methylcarbonyl, iso-propylcarbonyl, iso-propoxycarbonyl, tert-butoxy carbonyl or methoxycarbonyl; and wherein R2 is hydrogen; and

[0046] A compound according to the invention, wherein Ri is hydrogen; and wherein R2 is dimethylaminocarbonyl, methylcarbonyl, tert-butyl carbonyl or methoxycarbonyl.

[0047] The invention further also relates to a compound according to the invention, selected from

[0048] 1-[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-[(15)-l-hydroxyethyl]-2-pyridyl]benzimidazol-

[0049] 5 -yl] -3 , 3 -dimethyl- 1 -(6-methylpyridazin-3 -yl)urea;

[0050] [(15)-l-[2-(3-cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-pyridyl]ethyl] A,A-dimethylcarbamate;

[0051] A-[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-[(15)-l-hydroxyethyl]-2-pyridyl]benzimidazol- 5-yl]-A-(6-methylpyridazin-3-yl)acetamide;

[0052] A-[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-[(15)-l-hydroxyethyl]-2-pyridyl]benzimidazol- 5-yl]-2,2-dimethyl-A-(6-methylpyridazin-3-yl)propanamide;

[0053] 2-methylpropionic acid [(15)-l-[2-(3-cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-pyridyl]ethyl] ester;

[0054] [(15)-l-[2-(3-cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-pyridyl]ethyl] isopropyl carbonate; tert-butyl [(15)-l-[2-(3-cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-pyridyl]ethyl] carbonate;

[0055] [(15)-l-[2-(3-cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-pyridyl]ethyl] methyl carbonate; and [(15)-l-[2-(3-cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-pyridyl]ethyl] acetate; or a pharmaceutically acceptable salt thereof.

[0056] The invention further also relates to a compound according to the invention, selected from

[0057] [(15)-l-[2-(3-cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-pyridyl]ethyl] methyl carbonate;

[0058] [(15)-l-[2-(3-cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-pyridyl]ethyl] isopropyl carbonate;

[0059] [(15)-l-[2-(3-cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-pyridyl]ethyl] acetate; and

[0060] 2-methylpropionic acid [(15)-l-[2-(3-cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-pyridyl]ethyl] ester; or a pharmaceutically acceptable salt thereof.

[0061] General Synthetic Schemes

[0062] The synthesis of the compound of formula (I) and / or (la) as applicable, can, for example, be accomplished according to the non-exhaustive procedures described below in general schemes 1- 4 or according to methods known to those skilled in the art. In some instances, the sequence of the reaction steps can be modified and the individual steps of the different schemes can be combined in different ways as disclosed herein.

[0063] Scheme 1 In scheme 1, Ri is as described herein; the compound of formula (la-1) is a compound according to formula (la), wherein R2 is hydrogen; X is a suitable leaving group; the base can be for instance DMAP.

[0064] Scheme 2

[0065] In scheme 2, Ri is as described herein; the compound of formula (la-1) is a compound according to formula (la), wherein R2 is hydrogen; X is a suitable leaving group.

[0066] Scheme 3 In scheme 3, R2 is as described herein; the compound of formula (la-2) is a compound according to formula (la), wherein Ri is hydrogen; PG is a suitable protection group, in particular a silyl ether protection group; X is a suitable leaving group, in particular chloro; the base in step 1 can be for instance imidazole; the base in step 2 can be for instance 4-dimethylaminopyridine.

[0067] Scheme 4

[0068] In scheme 4, Ri is as described herein; the compound of formula (la-3) is a compound according to formula (la), wherein R2 is hydrogen; R’ is a suitable alkyl group; the solvent can be for instance di chloromethane or tetrahydrofuran and the reaction can for instance be run at ambient temperature or at elevated temperatures (e.g. 50 °C).

[0069] The invention thus also relates to a process for the preparation of a compound according to the invention, comprising one of the following steps:

[0070] A process for the preparation of a compound according to the invention, comprising at least one of the following steps:

[0071] (a) the reaction of a compound of formula (I)

[0072] with a compound of formula Ri-X or R2-X; in presence of a suitable solvent and a suitable base;

[0073] (b) the reaction of a compound of formula (A2) with a suitable deprotection reagent and in presence of a suitable solvent;

[0074] (c) the reaction of a compound of formula (A3) with a compound of formula (A4) in presence of a suitable base and a suitable solvent; wherein X is a suitable leaving group; wherein PG is a suitable protection group; and wherein Ri and R2 are as described herein. In step (a) of the above process, X is preferentially halogen, in particular chloro; the solvent is preferentially THF or DCM; and the base is preferentially 4- dimethylaminopyridine or NaH;

[0075] In step (b) of the above process, PG is preferentially a suitable silyl ether moiety; PG is preferentially TBAF; and the solvent is preferentially THF; and

[0076] In step (c) of the above process, the base is preferentially K2CO3; and the solvent is preferentially DMSO.

[0077] The invention also relates in particular to:

[0078] A compound of formula (la) as described herein or a pharmaceutically acceptable salt thereof, for use as therapeutically active substance;

[0079] A pharmaceutical composition comprising a compound of formula (la) as described herein or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier;

[0080] The use of a compound of formula (la) as described herein or a pharmaceutically acceptable salt thereof, for the treatment or prophylaxis of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel diseases (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis, in particular inflammatory bowel diseases (IBD);

[0081] The use of a compound of formula (la) as described herein or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prophylaxis rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel diseases (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis, in particular inflammatory bowel diseases (IBD);

[0082] A compound of formula (la) as described herein or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel diseases (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis, in particular inflammatory bowel diseases (IBD); and A method for the treatment or prophylaxis of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel diseases (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis, which method comprises administering an effective amount of a compound of formula (la) as described herein or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

[0083] Pharmaceutical Compositions

[0084] Another embodiment of the invention provides a pharmaceutical composition or medicament containing a compound of the invention and a therapeutically inert carrier, diluent or excipient, as well as a method of using the compounds of the invention to prepare such composition and medicament. In one example, the compound of formula (la) may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form. The pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8. In one example, a compound according to the invention is formulated in an acetate buffer, at pH 5. In another embodiment, the compound according the invention is sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.

[0085] Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.

[0086] The compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, epidural and intranasal, and if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. The compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.

[0087] A typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).

[0088] The invention will now be illustrated by the following examples which have no limiting character.

[0089] Examples

[0090] Abbreviations

[0091] AcCl = actyl chloride; ACN = acetonitrile; CAS = chemical abstract service; CDI = 1,1'- Carbonyldiimidazole; DCM = dichloromethane; DIPEA = N,N-Diisopropylethylamine; DMAP = 4-dimethylaminopyridine; ESI = electrospray ionization; EtOAc = ethyl acetate; EtOH = ethanol; FA = formic acid; HPLC = high-performance liquid chromatography; ‘PrOH = iso-propanol; LC- MS= liquid chromatography-MS; MeOH = methanol; MS = mass spectrometry; NPLC = normalphase liquid chromatography; NMR = nuclear magnetic resonance; Rf = retention factor; RT = room temperature; SFC = supercritical fluid chromatography; TBAF = Tetra-n-butylammonium fluoride; TBSC1 = tert-Butyldimethylsilyl chloride; THF = tetrahydrofuran; TLC = thin layer chromatography.

[0092] Compound of formula (I) 5-Methyl-l-[6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-[(lS)-l- hydroxy ethyl] -2-pyridyl] pyrazole-3-carbonitrile

[0093] Intermediate 1: N-( 6-methylpyridazin-3-yl)-lH-benzimidazol-5-amine

[0094] A mixture of 5 -aminobenzimidazole (8.0 g, 60.1 mmol, 1.0 equiv.) and 3-chloro-6- methylpyridazine (7.34 g, 57.08 mmol, 0.950 equiv.) in 'PrOH (120 mL) was stirred at 120 °C for 72 hours. The dark brown suspension was concentrated in vacuo and the residue was triturated in MeOH (60 mL). The solid was collected by filtration and it was triturated in DCM (40 mL). The product was collected by filtration, washed with DCM and dried. The title compound (10 g, 71.3% yield) was obtained as brown solid. LC-MS: m / z = 226.0 [M+H]+, ESI pos.JH NMR (400 MHz, DMSO-t / 6): 5 = 9.60 (br s, 1H), 8.72 (s, 1H), 8.52 (d, J = 1.7 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.44 (dd, J = 2.0, 8.8 Hz, 1H), 7.39 (d, J = 9.2 Hz, 1H), 7.21 (d, J = 9.2 Hz, 1H), 5.04 - 4.15 (m, 1H), 2.49 (s, 3H).

[0095] Step 1: l-(3-acetyl-6-chloro-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile (intermediate 2)

[0096] A solution of l-(6-chloro-2-fluoro-3-pyridyl)ethanone (CAS# 1260663-13-5, 5 g, 28.81 mmol, 1 equiv.), 5-methyl-lH-pyrazole-3-carbonitrile (2.93 g, 27.37 mmol, 0.950 equiv.) and DIPEA (14.3 mL, 86.42 mmol, 3 equiv.) in DMSO (50 mL) was stirred at 80 °C for 4 hours. The reaction mixture was cooled to RT, poured into H2O (250 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (3 x 300mL) and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0% to 35% EtOAc in petroleum ether). The title compound (5.3 g, 70.6% yield) was obtained as yellow oil. LC-MS: m / z = 261.1 [M+H]+, ESI pos.

[0097] Step 2: l-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl- pyrazole-3-carbonitrile and l-[ 3-acetyl-6-[ 6-[ ( 6-methylpyridazin-3-yl )amino]benzimidazol-l-yl / - 2-pyridyl]-5-methyl-pyrazole-3-carbonitrile A mixture of l-(3-acetyl-6-chloro-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile (5.3 g, 20.33 mmol, 1 equiv.), N-(6-methylpyridazin-3-yl)-lH-benzimidazol-5-amine (intermediate 1) (4.58 g, 20.33 mmol, 1 equiv.) and K2CO3 (5.62 g, 40.66 mmol, 2 equiv.) in DMSO (50 mL) was stirred at 50 °C for 12 hours. The mixture was cooled to RT and poured into H2O (500 mL). A solid precipitated out. This was extracted with EtOAc (3 x 400 mL). The combined organic layers were concentrated. The residue was purified by preparative HPLC: column Phenomenex Luna C18 (250mm x 70 mm x 15pm. Flow rate 140 mL / min. Gradient: 20% to 50% CH3CN in (H2O with 0.225% formic acid v / v) (35 min) then 100% CH3CN (1 min). A mixture of the two title compounds was obtained. This mixture was purified by preparative NPLC: column Welch Ultimate XB-SiOH (250mm x 70mm x lOum). Flow rate 140 mL / min. Gradient: 20% to 60% EtOH in hexane (20 min) then 100% EtOH (3 min) to yield l-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile (1.1 g, 12% yield) as a light brown solid and l-[3-acetyl- 6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile (600 mg, 6.6% yield) as light brown solid. Regioisomer 1 : LC-MS: m / z = 450.1 [M+H]+, ESI pos. 'H NMR (400 MHz, DMSO-t / 6) 5 = 9.31 (s, 1H), 9.01 (s, 1H), 8.98 (d, J= 2.0 Hz, 1H), 8.55 (d, J= 8.4 Hz, 1H), 8.27 (d, J= 8.4 Hz, 1H), 7.70 (d, J= 8.7 Hz, 1H), 7.46 (dd, J= 2.0, 8.7 Hz, 1H), 7.30 (d, J= 9.0 Hz, 1H), 7.09 - 7.04 (m, 2H), 2.55 (s, 3H), 2.50 (br s, 3H), 2.19 (s, 3H). Regioisomer 2: LC-MS: m / z = 450.1 [M+H]+, ESI pos. 'HNMR (400 MHz, DMSO-t / 6) 8 = 9.30 (s, 1H), 9.11 (s, 1H), 8.54 (d, J= 8.4 Hz, 1H), 8.47 (d, J= 1.7 Hz, 1H), 8.30 (d, J= 8.6 Hz, 1H), 8.14 (d, .7= 8.9 Hz, 1H), 7.53 (dd, J= 1.9, 8.9 Hz, 1H), 7.34 (d, J= 9.0 Hz, 1H), 7.14 (s, 1H), 7.10 (d, J= 9.0 Hz, 1H), 2.54 (s, 3H), 2.48 (br s, 3H), 2.20 (s, 3H).

[0098] Step 3: l-[3-(l-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0099] To a solution of l-[3-acetyl-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]- 5-methyl-pyrazole-3-carbonitrile (600 mg, 1.33 mmol, 1 equiv.) in a mixture of MeOH (10 mL) and THF (10 mL) was added NaBIH (151 mg, 3.99 mmol, 2.99 equiv.) at 0 °C. Stirring at 0 °C was continued for 1 hour. DMF (5 mL) was added to the mixture which was stirred at 20 °C for 2 hours. The mixture was cooled again to 0 °C and NaBLL (76 mg, 2 mmol, 1.5 equiv.) was added. The cooling bath was removed and stirring at RT was continued for 2 hours. The reaction mixture was quenched by the slow addition of H2O (50 mL) and then extracted with DCM (2 x 50 mL). The combined organic extracts were concentrated under vacuum. The residue was purified by preparative HPLC: column Waters Xbridge (150mm x 25mm x 5pm). Flow rate 60 mL / min. Gradient: 19% to 49% CH3CN in (10 mM NH4HCO3 in H2O) (11 min) then 100 % CH3CN (2 min). The title compound (400 mg, 65% yield) was obtained as a white liophilized solid. LC-MS: m / z = 452.2 [M+H]+, ESI pos.

[0100] Step 4: 5-Methyl-l-[ 6-[5-[ ( 6-methylpyridazin-3-yl )amino ]benzimidazol-l-yl ]-3-[ (1S)-1- hydroxyethyl / -2 -pyridyl ]pyrazole-3-carbonitrile l-[3-(l-hydroxyethyl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5- methyl-pyrazole-3 -carbonitrile (obtained as in step 3 of example 64) (400 mg, 0.89 mmol, 1 equiv.) was purified by chiral SFC (Daicel Chiralpak AY-H (250mm x 30mm x 10pm). Flow rate: 70 mL / min. 60% (0.1% NH4OH in isopropanol). The title compound (157.5 mg, 39.4% yield) was obtained as a white solid. LC-MS: m / z = 452.2 [M+H]+, ESI pos.JH NMR (400 MHz, CD3OD): 5 = 8.89 (s, 1H), 8.50 (d, J= 8.5 Hz, 1H), 8.22 (d, J= 1.9 Hz, 1H), 8.13 (dd, J= 8.7, 15.2 Hz, 2H), 7.60 (dd, J= 2.1, 8.9 Hz, 1H), 7.35 (d, J= 9.1 Hz, 1H), 7.12 (d, J= 9.1 Hz, 1H), 6.87 (d, J= 0.6 Hz, 1H), 4.78 - 4.74 (m, 1H), 2.53 (s, 3H), 2.41 (s, 3H), 1.41 (d, J= 6.5 Hz, 3H).

[0101] Assignment of the absolute configuration of the stereogenic carbon was performed by Mosher ester analysis: 3.6 mg (8.0 pmol) of alcohol were dissolved in CDCI3 and 2.9 pl of pyridine (36.3 pmol, 7 equiv.), were added followed by of (A -Mosher chloride ((A)-a-Methoxy-a- trifluoromethylphenylacetyl chloride, 7.6 pl, 40.2 umol, 5.0 equiv.) for the formation of the corresponding (S -Mosher ester. Comparison by overlay with the ’H-NMR spectrum (COSY) of its enantiomer shows an upfield shift of the C2-methyl group hence indicating an (^-configuration of the alcohol.

[0102] Example 1

[0103] [(15)-l-[2-(3-cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-pyridyl]ethyl] methyl carbonate

[0104] Step 1 : [(lS)-l-[2-( 3-cyano-5-methyl-pyrazol-l-yl)-6-[ 5-[( 6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl ]-3-pyridyl] ethyl ] imidazole- 1 -carboxylate

[0105] To a suspension of l-[3-[(15)-l-hydroxyethyl]-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (5.10 g, 11.3 mmol, 1.00 eq.) in di chloromethane (200 mL) and tetrahydrofuran (400 mL) was added CDI (14.1 g, 87.0 mmol, 7.70 eq.) in 7 portions every 30 minutes over 7 hours while stirring at 45 °C. The reaction mixture was cooled down and used in the following step. Step 2: [(lS)-l-[2-(3-cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-pyr idyl] ethyl] methyl carbonate

[0106] To the reaction mixture obtained in Step 1 was added MeOH (95.3 g, 120 mL, 2.97 mol, 263 eq.) and the mixture was stirred 30 minutes at RT. 4-dimethylaminopyridine (207 mg, 1.69 mmol, 0.15 eq.) was added and the mixture was stirred for 30 minutes at RT. 4-dimethylaminopyridine (1.38 g, 11.29 mmol, 1.00 eq.) was added and the reaction mixture was stirred for 30 minutes at RT. The reaction mixture was heated to 50 °C and stirred for 15 minutes. The reaction mixture was concentrated and the residue was dissolved in MeOH (50 mL) and stirred for 10 minutes at 50 °C. The reaction mixtue was concentrated under reduced pressure and the residue was pourred into 500ml water and the mixture was stirred for 10 minutes at RT. The mixture was extracted with EtOAc (3 x 100 mL) and the combined organic layers were washed with water (3 x 50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated. The crude was purrified by SiO? chromatography (ISCO: 120 g from 0% to 5% MeOH in CH2Q2). The product was recrystalized from CH2CI2 / EtOAC (1 : 1) and the solid was filtered and dried to give [(15)-l-[2-(3-cyano-5- methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-pyridyl]ethyl] methyl carbonate (5.18 g, 10.2 mmol, 90% yield over 2 steps) as a white solid. LC-MS: m / z = 510.2 [M+H]+, ESI pos. 'H NMR (600 MHz, CDCI3) 8 ppm 8.61 (s, 1 H), 8.28 (d, J = 8.5 Hz, 1 H), 8.03 (d, J= 8.8 Hz, 1 H), 7.80 (dd, J= 5.0, 3.4 Hz, 2 H), 7.40 - 7.44 (m, 1 H), 7.14 - 7.20 (m, 1 H), 7.09 (d, J= 9.1 Hz, 1 H), 7.00 (br s, 1 H), 6.72 (q, J= 0.8 Hz, 1 H), 5.49 (q, J= 6.6 Hz, 1 H), 3.72 (s, 3 H), 2.63 (s, 3 H), 2.51 (d, J = 0.9 Hz, 3 H), 1.78 (d, J = 6.6 Hz, 3 H). 99.8% ee (chiral SFC, Daicel Chiralpak AY, 150x4.6mm, 5pm, co-solvents: MeOH + 0.1% diethylamine, 6 min gradient: 20% to 40%, oven temperature: 40 °C, BPR 2000 PSI) Example 2 [(15)-l-[2-(3-cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-pyridyl]ethyl] isopropyl carbonate

[0107] According to the procedures described in step 1 and step 2 of Example 1, with l-[3-[(15)-l- hydroxyethyl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl- pyrazole-3 -carbonitrile (150 mg, 0.332 mmol), the title compound [(15)-l-[2-(3-cyano-5-methyl- pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-pyridyl]ethyl] isopropyl carbonate (127 mg, 0.236 mmol, 71% yield over 2 steps) was obtained as a white solid. LC-MS: m / z = 538.3 [M+H]+, ESI pos. 'H NMR (600 MHz, CDC13) 8 ppm 8.59 (s, 1 H), 8.27 (d, J= 8.3 Hz, 1 H), 8.01 (d, .7= 8.8 Hz, 1 H), 7.77 - 7.80 (m, 1 H), 7.75 - 7.83 (m, 1 H), 7.40 (dd, J= 8.8, 2.1 Hz, 1 H), 7.12 - 7.16 (m, 1 H), 7.07 (d, J= 9.1 Hz, 1 H), 7.02 (br s, 1 H), 6.69 (d, = 0.9 Hz, 1 H), 5.45 (q, J= 6.6 Hz, 1 H), 4.74 (quin, J= 6.2 Hz, 1 H), 2.60 (s, 3 H), 2.48 (d, J= 0.8 Hz, 3 H), 1.74 (d, J= 6.6 Hz, 3 H), 1.17 - 1.32 (m, 6 H).

[0108] Example 3 tert-butyl [(15)-l-[2-(3-cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3- yl)amino] benzimidazol- 1-yl] -3-pyridyl] ethyl] carbonate To a solution of l-[3-[(15)-l-hydroxyethyl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol- l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (150 mg, 0.332 mmol, 1.00 eq.) in tetrahydrofuran (3.3 mL) were added (Boc)2O (83 mg, 89 pL, 382 umol, 1.15 eq.) and 4- dimethylaminopyridine (8 mg, 66 umol, 0.20 eq.). The reaction mixture was stirred at RT for 10 minutes. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (SiCL, 0% to 6% MeOH in DCM) to give N-[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-[(15)-l-hydroxyethyl]-2- pyridyl]benzimidazol-5-yl]-N-(6-methylpyridazin-3-yl)carbamic acid tert-butyl ester (157 mg, 0.286 mmol, 86%) as white solid. LC-MS: m / z = 552.3 [M+H]+, ESI pos. 'H NMR (600 MHz, CDC13) 8 ppm 8.59 (s, 1 H), 8.28 (d, J= 8.4 Hz, 1 H), 8.00 (d, J= 8.8 Hz, 1 H), 7.78 (dd, J= 5.3, 3.1 Hz, 2 H), 7.37 - 7.42 (m, 1 H), 7.13 (d, J = 9.1 Hz, 1 H), 7.06 - 7.09 (m, 1 H), 7.04 (s, 1 H), 6.69 (d, J= 0.9 Hz, 1 H), 5.38 - 5.46 (m, 1H), 2.60 (s, 3 H), 2.46 (d, J= 0.8 Hz, 3 H), 1.71 (d, J= 6.6 Hz, 3 H), 1.40 (s, 9 H).

[0109] Example 4 [(15)-l-[2-(3-cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3- yl)amino] benzimidazol- 1-yl] -3-pyridyl] ethyl] acetate

[0110] Step 1: l-[ 6-chloro-3-[(lS)-l-hydroxyethyl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

[0111] To a solution of l-(3-acetyl-6-chloro-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile (Compound I, Intermediate 2) (2.34 g, 8.98 mmol, 1.00 eq.) in methanol (72 mL) was added NaBTLj (374 mg, 9.87 mmol, 1.10 eq.) and the reaction mixture was stirred for 1 hour at RT. The reaction mixture was pourred into water (100 mL) and extracted with EtOAc (3 x 75 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered concentrated. The crude product (2.46 g, 9.365 mmol) was purified by chiral SFC (Daicel Chiralpak AY-H (250mm x 30mm x 10pm). Flow rate: 70 mL / min. 60% (0.1% NH4OH in isopropanol)) to give l-[6-chloro- 3-[(15)-l-hydroxyethyl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (1.10 g, 4.198 mmol, 45% yield) as a white solid. LC-MS: m / z = 307.1 [M+HCOO]', ESI neg.

[0112] Step 2: [(lS)-l-[6-chloro-2-(3-cyano-5-methyl-pyrazol-l-yl)-3-pyridyl]ethyl] ester

[0113] To a stirred solution of l-[6-chloro-3-[(15)-l-hydroxyethyl]-2-pyridyl]-5-methyl-pyrazole-3- carbonitrile (125 mg, 0.476 mmol, 1.00 eq.) in dry DCM (3 mL) was added EtsN (72 mg, 100 pL, 0.714 mmol, 1.50 eq.) followed by dropwise addition of AcCl (406 pL, 5.71 mmol, 12.00 eq.) over 2 hours. The reaction mixture was stirred for an additional 15 minutes. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (SiO2, 0% to 20% EtOAc in Heptane) to give [(1 S)-l-[6-chloro- 2-(3-cyano-5-methyl-pyrazol-l-yl)-3-pyridyl]ethyl] ester (147 mg, 0.471 mmol, 99%) as colorless oil. LC-MS: m / z = 305.2 [M+H]+, ESI pos. Step 3: [(lS)-l-[2-(3-cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3- yl)amino ]benzimidazol-l-yl / -3-pyridyl] ethyl / acetate

[0114] [(15)-l-[6-chloro-2-(3-cyano-5-methyl-pyrazol-l-yl)-3-pyridyl]ethyl] ester (147 mg, 0.482 mmol, 1.00 eq.), lH-benzimidazol-5-yl-(6-methylpyridazin-3-yl)amine (Compound I, Intermediate 1) (130 mg, 0.579 mmol, 1.20 eq.), tripotassium phosphate (307 mg, 1.45 mmol, 3.00 eq.) and tBuXPhosPdG3 (19 mg, 0.024 mmol, 0.05 eq.; CAS number 1447963-75-8)) were put in a flask under Argon. t-Amyl alcohol (2.41 mL) was added and the reaction mixture was stirred for at 80 °C for 1.5 hours. The reaction mixture was cooled to RT and concentrated. The residue was purified by flash chromatography (SiCh, 0% to 8% MeOH in DCM) to give [(15)-l-[2-(3-cyano-5-methyl- pyrazol-l-yl)-6-[6-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-pyridyl]ethyl] ester (36 mg, 14%) as a light yellow solid. LC-MS: m / z = 494.2 [M+H]+, ESI pos. 'H NMR (600 MHz, CDC13) 8 ppm 8.57 (s, 1 H), 8.20 (d, J= 8.4 Hz, 1 H), 7.99 (d, J= 8.3 Hz, 1 H), 7.75 - 7.78 (m, 1 H), 7.67 - 7.86 (m, 1 H), 7.38 (dd, J= 8.7, 2.1 Hz, 1 H), 7.12 - 7.22 (m, 2 H), 7.03 - 7.09 (m, 1 H), 6.68 (d, J= 0.8 Hz, 1 H), 5.47 (d, J= 6.6 Hz, 1 H), 2.60 (s, 3 H), 2.47 (d, J= 0.8 Hz, 3 H), 2.39 - 2.43 (m, 1 H), 1.95 - 1.97 (m, 1 H), 1.70 (d, J= 6.6 Hz, 3 H).

[0115] Example 5

[0116] 2-methylpropionic acid [(15)-l-[2-(3-cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-pyridyl]ethyl] ester

[0117] To a solution of 4-dimethylaminopyridine (65 mg, 532 umol, 4.00 eq.) and 2-methylpropionyl chloride (28 mg, 28 pL, 266 pmol, 2.00 eq.) in dry DCM (2 mL) was added l-[3-[(15)-l- hydroxyethyl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl- pyrazole-3 -carbonitrile (Compound I) (60 mg, 133 pmol, 1.00 eq.). The reaction mixture was stirred at RT for 15 minutes. MeOH (2 mL) was added and the mixture was stirred at RT for 30 minutes. The reaction mixture was concentrated and the residue was purified by flash chromatography (SiCh, 0% to 8% MeOH in DCM) to give 2-methylpropionic acid [(15)-l-[2-(3- cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3- pyridyl] ethyl] ester (58 mg, 112 pmol, 84%) as white solid. LC-MS: m / z = 522.3 [M+H]+, ESI pos.XH NMR (600 MHz, CDCh) 6 ppm 8.57 (s, 1 H), 8.17 (d, J= 8.2 Hz, 1 H), 8.00 (dd, J= 8.8, 0.6 Hz, 1 H), 7.70 - 7.83 (m, 2H), 7.39 (dd, J= 8.7, 2.0 Hz, 1 H), 7.11 - 7.19 (m, 1 H), 7.04 - 7.09 (m, 1 H), 7.02 (br s, 1 H), 6.68 (d, J= 0.8 Hz, 1 H), 5.45 (q, J= 6.6 Hz, 1 H), 2.60 (s, 3 H), 2.49 - 2.54 (m, 1 H), 2.48 (d, J= 0.8 Hz, 3 H), 1.71 (d, J= 6.6 Hz, 3 H), 1.12 (dd, J= 9.6, 7.0 Hz, 6 H).

[0118] Example 6 [(15)-l-[2-(3-cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-pyridyl]ethyl] N,N-dimethylcarbamate

[0119] To a solution of l-[3-[(15)-l-hydroxyethyl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol- l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (Compound I) (100 mg, 221 pmol, 1.00 eq.) in dry THF (1 mL) was added NaH (12 mg, 244 pmol, 1.10 eq.) and dimethylcarbamoyl chloride (22 pL, 244 pmol, 1.10 eq.). The reaction mixture was stirred at RT for 30 minutes. Methanol (1 mL) was added and the mixture was stirred at RT for 30 minutes. The volatile were evaporated and the residue was purified by reversed phase flash chromatography (0% to 50% ACN in water) to give [(lS)-l-[2-(3-cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol- l-yl]-3-pyridyl]ethyl] N,N-dimethylcarbamate (75 mg, 144 pmol, 65% yield) as yellow powder. LC-MS: m / z = 523.3 [M+H]+, ESI pos. 'H NMR (600 MHz, DMSO-d6) 5 ppm 9.63 (br s, 1 H), 9.06 (s, 1 H), 8.43 (d, J= 8.6 Hz, 1 H), 8.37 (d, J= 2.0 Hz, 1 H), 8.27 (d, J= 8.5 Hz, 1 H), 8.08 (d, J = 9.0 Hz, 1 H), 7.52 (d, J = 9.2 Hz, 1 H), 7.49 (dd, J= 8.9, 2.2 Hz, 1 H), 7.31 (d, J= 9.1 Hz, 1 H), 7.11 (d, J = 0.8 Hz, 1 H), 5.27 (q, J = 6.6 Hz, 1 H), 2.88 (s, 3 H), 2.72 (s, 3 H), 2.52 (s, 3 H), 2.38 (d, J= 0.8 Hz, 3 H), 1.57 (d, J= 6.6 Hz, 3 H).

[0120] Example 7 l-[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-[(lS)-l-hydroxyethyl]-2-pyridyl]benzimidazol-5- yl]-3,3-dimethyl-l-(6-methylpyridazin-3-yl)urea

[0121]

[0122] Step 1: 1 -[3-[(l S)-l-[tert-butyl(dimethyl)silyl] oxyethyl] -6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile l-[3-[(15)-l-hydroxyethyl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]- 5-methyl-pyrazole-3-carbonitrile (Compound I) (150 mg, 332 pmol, 1.00 eq.) was suspended in DCM (1.5 mL). Imidazole (68 mg, 997 pmol, 3.00 eq.) was added followed TBSC1 (110 mg, 731 pmol, 2.20 eq.) and the reaction mixture was stirred at 50 °C for 2 hours. The reaction mixture was cooled to RT and diluted with water (20 mL) and extracted with DCM (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (SiCh, 0% to 10% MeOH in DCM) to give l-[3- [(15)-l-[tert-butyl(dimethyl)silyl]oxyethyl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol- l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (175 mg, 310 pmol, 93% yield) as a light yellow solid. LC-MS: m / z = 566.5 [M+H]+, ESI pos.

[0123] Step 2: l-[ l-[5-[(l S)-l - [ter t-butyl(dimethyl) silyl] oxyethyl] -6-(3-cyano-5-methyl-pyrazol-l -yl)-2- pyridyl ]benzimidazol-5-yl -3, 3 -dimethyl- l-( 6-methylpyridazin-3-yl)urea

[0124] l-[3-[(15)-l-[tert-butyl(dimethyl)silyl]oxyethyl]-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (80 mg, 141 pmol, 1.00 eq.)was dissolved in DMF (800 pL). NaH (7.5 mg, 156 pmol, 1.10 eq.) was added and the reaction mixture was stirred at RT for 15 minutes. Dimethylcarbamoyl chloride (17 mg, 14 pL, 156 pmol, 1.10 eq.) was added and the reaction mixture was stirred for 2 hours at RT. Dimethyl carbamoyl chloride (17 mg, 14 pL, 156 pmol, 1.10 eq.) was added and the reaction mixture was stirred for 2 hours at RT. The reaction mixture was quenched by addition of saturated aqueous NH4CI (4 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chomratography (SiCL; 0% to 10% MeOH in DCM) to give l-[l-[5-[(15)-l-[tert- butyl(dimethyl)silyl]oxyethyl]-6-(3-cyano-5-methyl-pyrazol-l-yl)-2-pyridyl]benzimidazol-5-yl]- 3,3-dimethyl-l-(6-methylpyridazin-3-yl)urea (70 mg, 71% yield, 110 pmol, ) as a light yellow oil. LC-MS: m / z = 637.4 [M+H]+, ESI pos.

[0125] Step 3: l-[ l-[ 6-(3-cyano-5-methyl-pyrazol-l-yl)-5-[(lS)-l-hydroxyethyl]-2-pyridyl]benzimidazol- 5-yl -3, 3 -dimethyl- l-( 6-methylpyridazin-3-yl)urea l-[l-[5-[(15)-l-[tert-butyl(dimethyl)silyl]oxyethyl]-6-(3-cyano-5-methyl-pyrazol-l-yl)-2- pyridyl]benzimidazol-5-yl]-3,3-dimethyl-l-(6-methylpyridazin-3-yl)urea (70 mg, 56 pmol, 1.00 eq.) was dissolved in THF (0.5 mL). 1 M TBAF in THF (IM) (168 pL, 168 pmol, 3.00 eq.) was added and the reaction mixture was stirred for 1 hour at RT. Water (0.5 mL) was added and the mixture was stirred for 30 min at RT. The reaction mixture was concentrated and the residue was purified by reversed phase flash chromatography (0% to 50% ACN in water) to give l-[l-[6-(3- cyano-5-methyl-pyrazol-l-yl)-5-[(15)-l-hydroxyethyl]-2-pyridyl]benzimidazol-5-yl]-3,3- dimethyl-l-(6-methylpyridazin-3-yl)urea (10 mg, 19 pmol, 35% yield) as a white solid. LC-MS: m / z = 523.4 [M+H]+, ESI pos. 'H NMR (600 MHz, CDC13) 8 ppm 8.57 (s, 1 H), 8.36 (d, J= 8.4 Hz, 1 H), 7.96 (d, J= 8.8 Hz, 1 H), 7.71 (d, J= 8.4 Hz, 1H), 7.66 (d, J= 1.9 Hz, 1 H), 7.20 - 7.25 (m, 1 H), 7.20 (s, 1 H), 7.05 - 7.10 (m, 1 H), 6.66 - 6.71 (m, 1 H), 4.81 - 4.88 (m, 1 H), 3.46 - 3.76 (m, 1 H), 2.91 - 2.96 (m, 6 H), 2.93 (s, 6 H), 2.63 (s, 3 H), 2.45 (s, 3 H), 1.46 - 1.51 (m, 3 H).

[0126] Example 8 N-[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-[(15)-l-hydroxyethyl]-2-pyridyl]benzimidazol-5- yl]-N-(6-methylpyridazin-3-yl)acetamide

[0127] Step 1: N-[l-[5-[(lS)-l-[tert-butyl(dimethyl)silyl] oxyethyl] -6-(3-cyano-5-methyl-pyrazol-l -yl)-2- pyridyl ]benzimidazol-5-yl ]-N-( 6-methylpyridazin-3-yl )acetamide

[0128]

[0129] To a solution of 4-dimethylaminopyridine (26 mg, 0.21 mmol, 4.0 eq.) and acetyl chloride (5 pL mL, 0.06 mmol, 1.2 eq.) in dry DCM (3 mL) was added l-[3-[(15)-l-[tert- butyl(dimethyl)silyl]oxyethyl]-6-[5-[(6-methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile (step 1 in Example 7) (30 mg, 0.05 mmol, 1.0 eq.) and then the reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated and the residue was purified by preparative TLC (EtOAc / MeOH 9:1, Rf = 0.45) to give N-[l-[5- [(15)-l-[tert-butyl(dimethyl)silyl]oxyethyl]-6-(3-cyano-5-methyl-pyrazol-l-yl)-2- pyridyl]benzimidazol-5-yl]-N-(6-methylpyridazin-3-yl)acetamide (10 mg, 0.02 mmol, 31% yield) as off white solid. LC-MS: m / z = 608.1 [M+H]+, ESI pos.

[0130] Step 2: N-[ l-[ 6-(3-cyano-5-methyl-pyrazol-l-yl)-5-[(lS)-l-hydroxyethyl]-2- pyridyl ]benzimidazol-5-yl ]-N-( 6-methylpyridazin-3-yl )acetamide

[0131] To a solution of N-[l-[5-[(15)-l-[tert-butyl(dimethyl)silyl]oxyethyl]-6-(3-cyano-5-methyl- pyrazol-l-yl)-2-pyridyl]benzimidazol-5-yl]-N-(6-methylpyridazin-3-yl)acetamide (10 mg, 0.02 mmol, 1.00 eq.) in THF (2 mL) was added TBAF (IM in THF) (0.05 mL, 0.05 mmol, 3.00 eq.) at RT. The resulting solution was stirred for 2 hours at RT. The reaction mixture was then partitioned between EtOAc (10 mL) and water (20 mL), and the aqueous phase was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over ISfeSCU, filtered and concentrated. The residue was purified by preparative TLC (DCM / MeOH 10: 1 Rabb= 0.45, UV) followed by preparative HPLC (Phenomenex Luna C18 150 mm x 25mm x 10 pm, 5% to 10 % water + 0.225% FA in ACN), 25 mL / min) to give N-[l-[6-(3-cyano-5-methyl-pyrazol-l- yl)-5-[(15)-l-hydroxyethyl]-2-pyridyl]benzimidazol-5-yl]-N-(6-methylpyridazin-3-yl)acetamide (4.5 mg, 0.01 mmol, 55% yield) as off white solid. LC-MS: m / z = 494.1 [M+H]+, ESI pos. 'H NMR (400 MHz, METHANOL-d4) 5 = 9.05 (s, 1H), 8.55 (d, J= 8.5 Hz, 1H), 8.29 (d, J= 8.8 Hz, 1H), 8.19 (d, J= 8.5 Hz, 1H), 7.95 (d, J = 9.0 Hz, 1H), 7.87 (d, J= 1.9 Hz, 1H), 7.69 (d, J= 8.9 Hz, 1H), 7.49 (dd, J = 2.0, 8.8 Hz, 1H), 6.88 (d, J= 0.6 Hz, 1H), 4.80 (s, 1H), 2.68 (s, 3H), 2.41 (s, 3H), 2.16 (s, 3H), 1.43 (d, J= 6.5 Hz, 3H).

[0132] Example 9 N-[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-[(15)-l-hydroxyethyl]-2-pyridyl]benzimidazol-5- yl]-2,2-dimethyl-N-(6-methylpyridazin-3-yl)propanamide

[0133] To a solution of 4-dimethylaminopyridine (54 mg, 443 pmol, 4.00 eq.) and pivaloyl chloride (16 pL, 133 pmol, 1.20 eq.) in dry DCM (6 mL) was added l-[3-[(15)-l-hydroxyethyl]-6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (Compound I) (50 mg, 111 pmol, 1.00 eq.). The reaction was stirred for 5 minutes at RT. MeOH (6 mL) was added and the reaction mixture was stirred at RT for 30 minutes. The reaction mixture was concentrated and the residue was purified by flash chromatography (SiCh, 0% to 8% MeOH in DCM) to give N-[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-[(15)-l-hydroxyethyl]-2- pyridyl]benzimidazol-5-yl]-2,2-dimethyl-N-(6-methylpyridazin-3-yl)propionamide (50 mg, 93 pmol, 84% yield) as white solid. LC-MS: m / z = 536.4 [M+H]+, ESI pos.JH NMR (600 MHz, CDC13) 8 ppm 8.86 - 9.04 (m, 1 H), 8.42 - 8.56 (m, 1 H), 8.01 - 8.18 (m, 1 H), 7.73 - 7.92 (m, 3 H), 7.39 - 7.69 (m, 2 H), 6.65 - 6.78 (m, 1 H), 4.94 (br d, J= 6.4 Hz, 1 H), 2.81 (br s, 3 H), 2.48 (s, 3 H), 1.54 (d, J = 6.3 Hz, 3 H), 1.19 (s, 8 H).

[0134] Example 10 Phosphorylation assay SIK1-3

[0135] In the presence of SIK2 (resp. SIK1 or SIK3) and ATP the CHK-peptide (KKKVSRSGLYRSPSMPENLNRPR with C-terminal arginine amide modification) were phosphorylated at one of the four feasible serine’s. Only one phosphorylation is observed under the assay conditions. 60 nl of each compound dilution series (12 point; dilution factor 3, generally 30 pM to 170 pM) in DMSO were transferred by acoustic dispensing to the assay plate and 30 minutes pre-incubated (ambient temperature) after the addition of 5 pl SIK1 (5 nM) resp. 5 pl SIK2 (0.5 nM) or 7 pl SIK3 (1.5 nM) in assay-buffer (12.5 mM HEPES (pH 7.0), 10 mM magnesium acetate, 0.005% BSA). 10 pM CHK-peptide solution and 5 pl of 100 pM ATP for SIK1 & SIK2 resp. 3 pl for SIK3 in assay-buffer were added and incubated ambient for 45 minutes. 40 pl of 0.125% formic acid in water were added to quench the reaction. RapidFire (RF) Mass Spectrometry was utilized for data generation as described below. The multiple charged species (3-5 charges) for the phosphorylated and non-phosphorylated form measured by MRM (Multiple Reaction Monitoring; API5000 or 6500+) or EIC (Extracted Ion Current; QToF) were summed up and the ratio calculated (sum phosphorylated species / sum all species) for data evaluation. Normalization was performed by Genedata software based on the non-inhibition control DMSO and the commercially available SIK inhibitor @ IpM YKL-05-099 (CAS number 1936529-65-5). The results of the assay are expressed in half-maximal inhibitory concentrations (IC50s) and are summarized below in Table 1. RapidFire Setup:

[0136] Samples were aspirated by vacuum for max. 600ms and loaded to C4-cartridge (Agilent;

[0137] #G9203A) for 3000ms@1.5ml / min with 0.1% formic acid in water. Afterwards samples were transferred to the API5000 (AP 16500+) or QToF mass spectrometer for 4000ms@1.25ml / min with 90% acetonitrile; 10% water; 0.007% TFA; 0.093 formic acid. The cartridge was reconditioned for additional 500ms with 0.1% formic acid in water.

[0138] MS-Setup Sciex API5000 / API6500+:

[0139] All MS analyses using the following MS-setup in MRM mode: Electrospray positive; Ion Spray Voltage: 4000V; Temperature: 550 °C; Collision Gas: 5; Curtain Gas: 15; Gas 1 : 40; Gas 2: 42; EP: 10. DP = declustering potential; CE = collision energy; CXP = cell exit potential.

[0140] MS-Setup Agilent QToF 6545

[0141] All MS analyses using the following MS-setup in Mode MS: Dual AJS Electrospray positive;

[0142] VCap: 3000V; Drying & Sheath gas: 340 °C@81 / min; Nebulizer: 60psig; Nozzle Voltage: 2000V; Fragmentor: 130V; Skimmer: 35V; Octi RF Vpp: 700V; Ref masses on@5spectra / s

[0143] Example 11

[0144] Human Whole Blood Assay, Alpha LISA

[0145] Human Whole Blood (ordered from the medical center, Roche Basel under Heparin-Lithium anti clog agent) is transferred into 384 well assay plates (Phenoplate-Perkin Elmer) and pre-incubated with the SIK inhibitors for 1 hour. The inhibitor compounds (serial diluted in DMSO) are tested on two different healthy blood donors, in 16 concentrations, ranging from 10 pM, down to 0.3 nM final in the assay plate, with a serial dilution factor of 2. The final DMSO concentration in the assay plate was 0.1%. Subsequently, cells are stimulated for 3 hours with lOOng / mL LPS. Plasma is collected after plate centrifugation (1300 rpm, 5min) and transferred into alphaLISA plate. The cytokines IL- 10 and TNFa are measured, by following the SOP provided by Perkin Elmer for beads and antibodies dilutions and addition.

[0146] The alphaLisa plate are read on the FSX pherastar under 680 nM light excitation and 615 nm emission. Normalization was performed for each individual plate by Genedata software based on the non-inhibition control DMSO wells and a known SIK inhibitor (termed ‘417; lOpM final concentration; compound is known from WO2019105886) in positive controls wells. The results of the assay are expressed in half-maximal inhibitory (IC50s for TNF), and in half-maximal activity concentrations (EC50s for IL- 10).

[0147]

[0148] Structure of ‘417:

[0149] The principle of the AlphaLISA is further explained below: IL-10 and TNFa concentration in the cell supernatant is measured by aLISA, which allows the measurement in a sensitive, quantitative and reproducible manner. The assay is based on the binding of the cytokine to a biotinylated anti- analyte antibody (IL-10 or TNFa) to Streptavidin coated Donor beads, while another anti-analyte antibody is conjugated to the aLISA Acceptor beads. In presence of the analyte, the beads come to close proximity, and the excitation of the donor beads by a light wave length of 680nm trigger the release of singlet oxygen molecules inducing a cascade of energy transfer towards the acceptor beads, resulting in an emission of light at 615nM.

[0150] Material and Reagents for hWBA:

[0151]

[0152] The results of the assays described in Examples 10 and 11 indicate that the prodrugs of the present invention themselves have only reduced SIK inhibitory activity (see enzymatic data as described in Example 10), butthat they provide for an efficient prodrug upon metabolic processing (see TNFa activity as described in Example 11), which can be attributed to the activity of the metabolite in the hWBA. The results of the assays described in Examples 10 and 11 are summarized below in Table 1.

[0153] Table 1: IC50 values for inhibition of SIK1, SIK2, and SIK3 and TNFa hWBA EC50:

[0154] Example 12

[0155] Papp (passive permeability measurements) obtained as part of Unidirectional P-gp Screen

[0156] Experiment Description

[0157] The general assay uses transfected LLC-PK1 cells (porcine kidney epithelial cells) overexpressing human or mouse P-gp, cultured on 96 well semi-permeable filter membrane plates, where they form a polarized monolayer with tight junctions, and act as a barrier between the apical and basolateral compartment. P-gp is expressed in the apical-facing membrane of the monolayer.

[0158] The tightness of the cell monolayer and functional activity of P-gp are confirmed by addition of a cell-impermeable marker, Lucifer yellow, and a reference P-gp substrate, edoxaban, respectively.

[0159] The assay is fully automated on a Tecan liquid handling robot.

[0160] Data analysis and interpretation

[0161] For substrate testing the assay determines the unidirectional permeability (Papp A>B Equation 1) of a test compound by dosing to the apical (i.e. donor compartment) side of the cell monolayer, in the absence and presence of specific P-gp inhibitor, zosuquidar, and measuring the movement of the compound into the basolateral (i.e. receiver) compartment over a 3 hour incubation at 37°C. The effect of P-gp is measured by expressing the apical efflux ratio (AP-ER, Equation 2). The mean permeability (Papp) is determined in the absence of P-gp via the zosuquidar condition. The AP-ER and mean Pappare then used to categorize compound properties for degree of efflux and permeability (Table 2).

[0162] 1 dQ PaPP ~ cd ~di

[0163] Equation 1. Papp, A, CO, and dQ / dt represent the apparent permeability (Papp), the filter surface area (A), the initial concentration (Co), and the amount transported per time period (dQ / dt), respectively. Pappvalues are calculated on the basis of a single time point.

[0164] Equation 2. Calculation of the apical efflux ratio (AP-ER). Papp, inh (A>B) is the permeability in the apical to basolateral direction in the presence of the inhibitor, and Papp (A>B)the permeability value in the apical-to-basolateral direction in the absence of the inhibitor.

[0165] Results The compounds of the present invention exhibit an increased Pappcompared to the metabolite, while retaining the overall drug-like properties. Overall, the increased permeability indicates an improved oral bioavailability of the prodrugs when compared with the metabolite.

[0166] Table 2 - Papppermeability

[0167] Example A

[0168] Film coated tablets containing the following ingredients can be manufactured in a conventional manner:

[0169] The active ingredient is sieved and mixed with microcrystalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidone in water. The granulate is then mixed with sodium starch glycolate and magnesium stearate and compressed to yield kernels of 120 or 350 mg respectively. The kernels are lacquered with an aqueous solution / suspension of the above mentioned film coat.

[0170] Example B

[0171] Capsules containing the following ingredients can be manufactured in a conventional manner:

[0172] The components are sieved and mixed and filled into capsules of size 2.

[0173] Example C

[0174] Injection solutions can have the following composition:

[0175] The active ingredient is dissolved in a mixture of Polyethylene glycol 400 and water for injection (part). The pH is adjusted to 5.0 by addition of acetic acid. The volume is adjusted to 1.0 ml by addition of the residual amount of water. The solution is filtered, filled into vials using an appropriate overage and sterilized.

Claims

Claims1. A compound according to formula (la)wherein one of Ri and R2 is a prodrug moiety, or wherein one of Ri and R2 together with the oxygen or nitrogen to which they are attached forms a prodrug moiety; and the other one of Ri and R2 is hydrogen; or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, wherein one ofRi and R2 is dialkylaminocarbonyl, alkylaminocarbonyl, aminocarbonyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxyalkyl, aminoalkylcarbonyl, alkoxycarbonyloxyalkyl, alkoxycarbonyl(alkylamino)alkyl, heteroarylalkyl, dihydrogen phosphate alkyl or -PO3H2; and the other one is hydrogen; or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 or 2, wherein one of Ri and R2 is dialkylaminocarbonyl, alkylcarbonyl or alkoxycarbonyl, and the other one is hydrogen.

4. A compound according to any one of claims 1 to 3, wherein Ri is dimethylaminocarbonyl, methylcarbonyl, iso-propylcarbonyl, iso-propoxycarbonyl, tertbutoxycarbonyl or methoxycarbonyl; and wherein R2 is hydrogen.

5. A compound according to any one of claims 1 to 3, wherein Ri is hydrogen; and wherein R2 is dimethylaminocarbonyl, methylcarbonyl, tert-butyl carbonyl or methoxycarbonyl.

6. A compound according to any one of claims 1 to 5 selected from1-[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-[(15)-l-hydroxyethyl]-2-pyridyl]benzimidazol-5 -yl] -3 , 3 -dimethyl- 1 -(6-methylpyridazin-3 -yl)urea;[(15)-l-[2-(3-cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-pyridyl]ethyl] 7V,A-dimethylcarbamate; V-[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-[(15)-l-hydroxyethyl]-2-pyridyl]benzimidazol-5-yl]-A-(6-methylpyridazin-3-yl)acetamide; V-[l-[6-(3-cyano-5-methyl-pyrazol-l-yl)-5-[(15)-l-hydroxyethyl]-2-pyridyl]benzimidazol-5-yl]-2,2-dimethyl-7V-(6-methylpyridazin-3-yl)propanamide;2-methylpropionic acid [(15)-l-[2-(3-cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6- methylpyridazin-3-yl)amino]benzimidazol-l-yl]-3-pyridyl]ethyl] ester;[(15)-l-[2-(3-cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-pyridyl]ethyl] isopropyl carbonate; tert-butyl [(15)-l-[2-(3-cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-pyridyl]ethyl] carbonate;[(15)-l-[2-(3-cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-pyridyl]ethyl] methyl carbonate; and[(15)-l-[2-(3-cyano-5-methyl-pyrazol-l-yl)-6-[5-[(6-methylpyridazin-3- yl)amino]benzimidazol-l-yl]-3-pyridyl]ethyl] acetate; or a pharmaceutically acceptable salt thereof.

7. A process for the preparation of a compound according to any one of claims 1 to 6, comprising at least one of the following steps:(a) the reaction of a compound of formula (I)with a compound of formula Ri-X or R2-X; in presence of a suitable solvent and a suitable base;(b) the reaction of a compound of formula (A2)with a suitable deprotection reagent and in presence of a suitable solvent;(c) the reaction of a compound of formula (A3)with a compound of formula (A4)in presence of a suitable base and a suitable solvent; wherein X is a suitable leaving group; wherein PG is a suitable protection group; and wherein Ri and R2 are according to any one of the preceding claims.

8. A compound according to any one of claims 1 to 6 when manufactured according to a process of claim 7.

9. A compound according to any one of claims 1 to 6, for use as therapeutically active substance.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6, and a therapeutically inert carrier.

11. The use of a compound according to any one of claims 1 to 6, for the treatment or prophylaxis of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholicsteatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel diseases (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis.

12. The use of a compound according to any one of claims 1 to 6, for the preparation of a medicament for the treatment or prophylaxis rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel diseases (IBD), atherosclerosis, type 2 diabetes or glom erul onephriti s .

13. A compound according to any one of claims 1 to 6, for use in the treatment or prophylaxis of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel diseases (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis.

14. A method for the treatment or prophylaxis of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel diseases (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis, which method comprises administering an effective amount of a compound according to any one of claims 1 to 6, to a patient in need thereof.

15. The invention as hereinbefore described.***

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