Imidazo[4,5-c]pyridine derivatives as SIK modulators for the treatment of rheumatoid arthritis

Abstract

The present invention relates to imidazo[4,5-c]pyridine derivatives of formula (I) as SIK modulators for treating or preventing rheumatoid arthritis, juvenile idiopathic arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell arteritis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis. TIFF2025521780000065.tif58161

Description

Technical Field

[0001] The present invention relates to organic compounds useful for treatment and / or prophylaxis in mammals, particularly compounds that regulate SIK activity.

Background Art

[0002] The present invention particularly relates to compounds of formula (I)

Chemical formula

[0003] Salt-inducible kinase (SIK) belongs to a subfamily of AMP-activated protein kinase (AMPK), called AMPK-related kinases. There are three members, called SIK1, SIK2, and SIK3, which are widely expressed. Their major biological role is to modify gene expression by controlling the phosphorylation and intracellular localization of two important classes of transcriptional regulators, CRTC (cAMP-regulated transcriptional coactivator) and class IIa HDAC (histone deacetylase). Indeed, in the basal state, both CRTC and HDAC are phosphorylated by SIK kinases and sequestered in the cytoplasm through their interaction with the cytoplasmic chaperone 14-3-3. In response to extracellular cues that normally increase the intracellular level of cAMP, the activity of SIK kinases is inhibited, and CRTC and HDAC are no longer phosphorylated and are thus released from 14-3-3. Therefore, they can translocate into the nucleus and regulate gene expression (reviewed in Wein et al., Trends Endocrinol Metab. 2018 Oct;29(10):723-735).

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

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

[0006] Surprisingly, inhibition of intracellular SIK kinase abrogates these extracellular macrophage polarization signals and drives them towards a resolution-promoting phenotype. This is accompanied by an increase in IL-10 (by interfering with the SIK-CRTC3 pathway) and concomitant decreases in TNF-α, IL-12, and IL-6 (by interfering with the SIK-HDAC4 / 5 and NF-κB pathways). The high levels of IL-10 and low levels of pro-inflammatory cytokines upon SIK inhibition promote the resolution of inflammation. Exploration of the SIK pathway was first reported in macrophages (Clark et al., Proc Natl Acad Sci USA. 2012 Oct 16;109(42):16986-91) and dendritic cells (Sundberg et al., Proc Natl Acad Sci USA. 2014 Aug 26;111(34):12468-73), and the therapeutic potential of pan-SIK inhibitors has been confirmed in mouse LPS (lipopolysaccharide) challenge models (Sundberg et al., ACS Chem Biol. 2016 Aug 19;11(8):2105-11) and colitis models (Fu et al., Inflamm Bowel Dis. 2021 Oct 20;27(11):1821-1831). SIK has since been shown to play important roles in the functions of several immune cells, including mast cells (Darling et al., J Biol Chem. 2021 Jan-Jun;296:100428). Importantly, SIK1 is not highly expressed in macrophages, and one embodiment of the present invention is a SIK2 / 3 inhibitor that spares SIK1, thus limiting potential SIK1-related toxicity.

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

[0008] A disease in which the association with IL-10 and TNF-α has been demonstrated is IBD. Genetic changes that reduce the function of IL-10 (e.g., 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 subset of IBD patients are responsive, and much of this limited responsiveness is lost over time. The described dual effects of SIK inhibitors (increase in IL-10 and decrease in TNF-α) make them particularly suitable for the treatment of IBD.

[0009] 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 CRTC and class II HDACs in response to extracellular signals and then alter the expression of several cytokines.

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

[0011] Today, many diseases caused by dysregulation of the innate immune system lack effective treatment methods, and there is a high unmet medical need for new treatment methods. 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 potentially be related to cancer, metabolic diseases, bone density dysregulation diseases, pigment-related diseases or cosmetology, fibrotic diseases, and depressive disorders.

Summary of the Invention

[0012] As used herein, the term "alkyl" alone or in combination means a straight-chain or branched-chain alkyl group having 1 to 8 carbon atoms, particularly a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, more specifically a straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms. Examples of straight-chain and branched-chain C1-C8 alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, isomeric pentyl, isomeric hexyl, isomeric heptyl, and isomeric octyl, particularly methyl, ethyl, propyl, butyl, and pentyl. Specific examples of alkyl are methyl, ethyl, propyl, isopropyl, butyl, and isobutyl. Methyl, ethyl, propyl, and butyl, for example, isobutyl, are further specific examples of "alkyl" in the compounds of formula (I).

[0013] The term "cycloalkyl", alone or in combination, means a cycloalkyl ring having 3 to 8 carbon atoms, particularly a cycloalkyl ring having 3 to 6 carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Specific examples of "cycloalkyl" are cyclopropyl and cyclobutyl.

[0014] The term "heterocycloalkyl", alone or in combination, means a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system consisting of 4 to 12 ring atoms, containing 1, 2, or 3 ring heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. Bicyclic means consisting of two rings having one or two ring atoms in common. "Heterocycloylalkyl" may contain a carbonyl group, and the carbon is part of the ring system. The ring system can be bonded to the remaining compound via an atom selected from C, N, S, and O, particularly via an N atom ("N - heterocycloalkyl"). Examples of "heterocycloalkyl" include morpholino, morpholin - 4 - yl, pyrrolidinyl, pyrrolidin - 1 - yl, pyrrolidin - 3 - yl, piperidinyl, 1 - piperidyl, 4 - piperidyl, 2 - oxopyrrolidin - 1 - yl, piperazinyl, piperazin - 1 - yl, azetidinyl, azetidin - 1 - yl, [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]heptan - 5 - yl), (2 - azabicyclo[2.2.1]heptan - 2 - yl), 4 - oxa - 7 - azaspiro[2.5]octan - 7 - yl, (3 - azabicyclo[3.1.0]hexan - 3 - yl, (6,7 - dihydro - 4H - pyrazolo[4,3 - c]pyridin - 1 - yl), 2 - oxa - 7 - azaspiro[3.4] octan-7-yl, (2-oxo-1-piperidyl), (2,3-dihydropyridazino[4,5-b][1,4]oxazin-8-yl), pyrrolidin-1-yl, 2-oxo-pyrimidin-4-yl, morpholinoethyl, 2-oxa-5-azaspiro[3.4]octan-5-yl, oxetan-3-yl, (2-oxo-1-piperidyl), 2-oxo-4-piperidyl, 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], 3,4-dihydro-2H-1,4-oxazinyl, and [rac-(3aS,6aS)-6-oxo-2,3,3a,4,5,6a-hexahydropyrrolo[2,3-c]pyrrol-1-yl] are included, but not limited thereto. A specific example of "heterocycloalkyl" is 3,4-dihydro-2H-1,4-oxazine.

[0015] The term "heteroaryl", alone or in combination, means an aromatic monocyclic or bicyclic ring system having 5 to 12 ring atoms, containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S respectively, with 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 an N atom ("N-heteroaryl"). Examples of heteroaryl include pyrazolyl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyridinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridazinyl, pyridazin-3-yl, pyridazin-4-yl, pyrazinyl, pyrazin-2-yl, isoxazolyl, isoxazol-3-yl, isoxazol-4-yl, pyrimidinyl, pyrimidin-5-yl, benzotriazolyl, 1H-benzotriazol-4-yl, furanyl, furyl, 2-furyl, 3-furyl, [6-oxo-1H-pyridazin-5-yl], triazolyl, triazol-1-yl, triazol-2-yl, 2-oxo-4-pyridyl, pyrimidin-2-yl, pyrimidin-5-yl, (1,3,4-oxadiazol-2-yl), (1,3,4-thiadiazol-2-yl), (1,2,4-triazin-3-yl), 2-oxo-pyrimidin-4-yl, (1-methyl-2-oxo-3-pyridyl), and (2,3-dihydropyridazino[4,5-b][1,4]oxazin-8-yl), but are not limited thereto. Specific examples of "heteroaryl" are pyrazol-1-yl, pyrazol-4-yl, pyridazin-3-yl, pyrimidin-5-yl.

[0016] The term "alkoxy" or "alkyloxy", alone or in combination, means a group of the formula alkyl-O-, and the term "alkyl" has the meaning given above, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. Specific examples of "alkoxy" are methoxy and ethoxy.

[0017] The term "oxy", alone or in combination, means an -O- group.

[0018] The term "oxo", alone or in combination, means the =O group.

[0019] The term "halogen" or "halo", alone or in combination, means fluorine, chlorine, bromine, or iodine, and in particular, fluorine, chlorine, or bromine, more specifically fluorine. The term "halo", in combination with another group, means substitution of the group with at least one halogen, in particular 1 to 5 halogens, specifically 1 to 4 halogens, i.e., substitution with 1, 2, 3, or 4 halogens.

[0020] The term "haloalkyl", alone or in combination, means an alkyl group substituted with at least one halogen, in particular 1 to 5 halogens, specifically 1 to 3 halogens, more specifically substituted with 2 to 3 halogens. Specific "haloalkyls" are fluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl, difluoromethyl, difluoroethyl, trifluoromethyl and trifluoroethyl.

[0021] The term "haloalkoxy", alone or in combination, denotes an alkoxy group substituted with at least one halogen, in particular 1 to 5 halogens, specifically 1 to 3 halogens. Specific "haloalkoxys" are fluoromethoxy, fluoroethoxy and fluoropropyloxy.

[0022] The terms "hydroxyl" and "hydroxy", alone or in combination, mean the -OH group.

[0023] The term "carbonyl", alone or in combination, means the -C(O)- group.

[0024] The term "amino", alone or in combination, means a primary amino group (-NH2), a secondary amino group (-NH-), or a tertiary amino group (-N-).

[0025] The term "alkylamino" refers to an alkyl group bonded to an -NH- group. The term "dialkylamino" means two alkyl groups bonded to an -N- atom.

[0026] The term "sulfonyl", alone or in combination, means an -SO2- group.

[0027] The term "pharmaceutically acceptable salt" means a salt that is not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid addition salts and base addition salts. The term "pharmaceutically acceptable acid addition salt" refers to a pharmaceutically acceptable salt formed with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and an organic acid selected from aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic acids, and sulfonic 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, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. The term "pharmaceutically acceptable base addition salt" refers to a pharmaceutically acceptable salt formed with an organic base or an inorganic base. Examples of acceptable inorganic bases include sodium salts, potassium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, 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, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperizine, piperidine, N-ethylpiperidine, and salts of polyamine resins. A specific pharmaceutically acceptable salt of the compound of formula (I) is, for example, its formate salt.

[0028] The terms "compound(s) of this invention" and "compound(s) of the present invention" refer to the compounds of formula (I) and their stereoisomers, tautomers, solvates, and salts (e.g., pharmaceutically acceptable salts).

[0029] Tautomers, i.e., structural isomers that interconvert, particularly in solution, with the compounds of formula (I) may be present in some cases and are to be understood as being included in the present invention.

[0030] If one of the starting materials of the present invention or the compounds of formula (I) contains one or more functional groups that are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups (e.g., as described in "Protective Groups in Organic Chemistry" by T.W. Greene and P.G.M. Wuts, 3rd Ed., 1999, Wiley, New York) can be introduced before the important steps of applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature. Examples of protecting groups are tert-butoxycarbonyl (Boc), 9-fluorenylmethyl carbamate (Fmoc), 2-trimethylsilylethyl carbamate (Teoc), benzyloxycarbonyl (Cbz), and p-methoxybenzyloxycarbonyl (Moz).

[0031] The compounds of formula (I) can contain several asymmetric centers and can exist as optically pure enantiomers, mixtures of enantiomers such as racemates, mixtures of diastereoisomers, diastereoisomer racemates or mixtures of diastereoisomer racemates.

[0032] 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 of the "R" or "S" configuration.

[0033] Furthermore, the present invention includes, where applicable, all optical isomers of the compounds of formula (I), i.e., diastereomers, mixtures of diastereomers, racemic mixtures, all corresponding enantiomers and / or tautomers thereof, and solvates thereof.

[0034] If desired, the racemic mixtures of the compounds of the present invention can be separated to isolate the individual enantiomers. The separation can be carried out by methods known in the art, such as coupling the racemic mixture of the compound to a enantiomerically pure compound to form a mixture of diastereomers, followed by separating the individual diastereomers by standard methods such as fractional recrystallization or chromatography.

[0035] In embodiments, when an optically pure enantiomer is provided, an optically pure enantiomer means that the compound contains more than 90% by weight of the desired isomer, particularly more than 95% by weight of the desired isomer, or more specifically more than 99% by weight of the desired isomer, and the weight percentages are based on the total weight of the isomers of the compound. Chiral pure or chiral enriched compounds can be prepared by chiral selective synthesis or by separation of enantiomers. The separation of enantiomers can be carried out on the final product or on a suitable intermediate.

[0036] The structures shown herein also mean including compounds that differ only in that one or more isotope-enriched atoms are present. Specific examples of radioactive isotopes are 2 H, 3 H, 13 C, 14 C and 18 F. For example, structures in which one or more hydrogen atoms are replaced by deuterium or tritium, or one or more carbon atoms are replaced by 13 C or 14 C enriched carbon are within the scope of the present invention.

[0037] Accordingly, the present invention R 1The compound according to the invention, wherein it is hydroxyalkyl or alkylcarbonyl, R 1 The compound according to the invention, wherein it is hydroxyethyl or methylcarbonyl, R 2 The compound according to the invention, wherein it is cyano, haloalkyl or haloalkoxy, R 2 The compound according to the invention, wherein it is cyano, difluoromethyl or difluoromethoxy, R 3 is hydrogen or methyl, and R 4 is hydrogen, or R 3 is R 4 and together with the atoms to which they are attached form a 5- to 7-membered heterocycloalkyl or heteroaryl ring, the compound according to the invention, R 3 is hydrogen or methyl, and R 4 is hydrogen, or R 3 is R 4 and together with the atoms to which they are attached form 3,4-dihydro-2H-1,4-oxazine, the compound according to the invention, R 3 is hydrogen or alkyl, and R 4 is hydrogen, the compound according to the invention, R 3 is R 4 and together with the atoms to which they are attached form a 5- to 7-membered heterocycloalkyl or heteroaryl ring, the compound according to the invention. R 3 is R 4 and together with the atoms to which they are attached form 3,4-dihydro-2H-1,4-oxazine

Chemical formula

[0038] The present invention further provides 1-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile, 1-[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile, 1-[3-(1-hydroxyethyl)-6-[6-[(6-methyl-3-pyridyl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile, 1-[6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanol, 1-[3-acetyl-6-[6-[methyl-(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile, 1-[3-acetyl-6-[6-(3-methyl-6,7-dihydropyridazino[4,3-b][1,4]oxazin-8-yl)imidazo[4,5-c]pyridin-3-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile, and 1-[2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-3-pyridyl]ethanol, relates to a compound of formula (I) selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

[0039] The present invention further relates to 1-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile, 1-[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile, and 1-[6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanol, relates to a compound of formula (I) selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

[0040] The synthesis of the compounds of formula (I) can be achieved, for example, according to the non-exhaustive procedures described below in General Schemes 1-6, or according to methods known to those skilled in the art. In some cases, the order of the reaction steps can be changed, and the individual steps of different schemes can be combined as disclosed herein.

[0041] Scheme 1 Scheme 1 describes the synthesis of a compound of formula (I-b) starting from a compound of formula (I-a). In the following Scheme A 1 wherein R 2 , R 3 , R 4 and R 5 are as described above. The compound of formula (I-a) is R 1is methylcarbonyl, a compound of formula (I) described herein. The compound of formula (I-b) has R 1 is hydroxyethyl, a compound of formula (I) described herein.

Chemical formula

[0042] Step A: The compound of formula (I-a) can be converted to the compound of formula (I-b) by using a reducing agent such as NaBH4 in MeOH at a temperature between about -40 °C and room temperature, together with a co-solvent such as THF, 1,4-dioxane, EtOH, MeOH, DCM.

[0043] Scheme 2 The following Scheme A 1 wherein R 2 , R 3 , R 4 and R 5 are as described above. The compound of formula (I-a) is a compound of formula (I) described herein where R 1 is methylcarbonyl.

Chemical formula

[0044] Step A: Intermediate 1 can be converted to the compound of formula (I-a) by a backward Hartwig coupling of Intermediate 3 with an aminopyridazine reactant at a temperature between about 80 °C and about 100 °C in a suitable solvent such as 1,4-dioxane, optionally with water as a co-solvent, using a suitable base such as Cs2CO3, K2CO3, or K3PO4, and a suitable palladium catalyst such as t-BuXPhos-Pd-G3 or [tBuBrettPhos Pd(allyl)]OTf.

[0045] Scheme 3 In the following scheme, R 2 is as described herein.

Chemical formula

[0046] Process A: Intermediate 2 and Intermediate 3 can be reacted in a suitable solvent, such as 1,4-dioxane or DMSO, in the presence of a suitable base, such as DBU, K2CO3 or Cs2CO3, at a temperature of about 80 °C to obtain Intermediate 1.

[0047] Scheme 4 The following Scheme A 1 in which, R 2 , R 3 , R 4 and R 5 are as described above. The compound of formula (I-a) is the compound of formula (I) described herein, wherein R 1 is methylcarbonyl.

Chemical Structure

[0048] Process A: Intermediate 2 and Intermediate 4 can be reacted at a temperature between about 50 °C and about 80 °C in a suitable solvent, such as 1,4-dioxane, DMF, NMP, DMA or DMSO, optionally together with water as a co-solvent, in the presence of a suitable base, such as DBU, K2CO3 or Cs2CO3, to obtain the compound of formula (I-a).

[0049] Scheme 5 In the following scheme, R 2 is as described herein.

Chemical Structure

[0050] Process A: Intermediate 7 can be obtained by reacting aniline 5 and fluoro- or chloro-pyridine 6 in a solvent such as DMF, NMP or DMA in the presence of a deprotonating agent such as NaH at a temperature between about -10 °C and room temperature.

[0051] Process B: Aniline intermediate 8 can be obtained by reducing the corresponding nitro precursor 7 using a reducing agent such as activated Zn in a solvent such as EtOH or water in the presence of HOAc at a temperature of about 50 °C.

[0052] Process C: Intermediate 1 of aniline intermediate 8 can be obtained by condensing with trimethoxymethane at a temperature of about 80 °C to about 120 °C in a solvent such as MeOH, optionally in the presence of TsOH.

[0053] Scheme 6 Scheme 6 describes the synthesis of intermediate 5a. The compound of formula 5a is a compound of formula 5, wherein R 2 is a substituent R selected from carbonitrile, alkyl or haloalkyl a , or methyl-pyrazolyl optionally substituted with a substituent R selected from hydrogen, alkyl and haloalkyl b .

Chemical formula

[0054] Process A: Intermediate 10a can be obtained by reacting component 9a with a suitable pyrazole component at a temperature of about 80 °C in a suitable solvent such as 1,4-dioxane, THF, DMF, DMA, NMP or DMSO in the presence of a suitable base such as DBU.

[0055] Process A’: Intermediate 10b can be obtained by reacting starting material 9b with a suitable pyrazole boronic acid ester at a temperature of about 80 °C in a solvent such as 1,4-dioxane, optionally together with water as a co-solvent, in the presence of a suitable base such as K2CO3 and a suitable catalyst such as Pd(dppf)Cl2·CH2Cl2.

[0056] Process B: Intermediate 11 can be obtained by reacting Intermediate 10 with (2,4-dimethoxybenzyl)amine in a suitable solvent such as 1,4-dioxane, THF, DMF, DMA, NMP or DMSO in the presence of a suitable base such as DIPEA at a temperature from room temperature to about 80 °C.

[0057] Process C: Intermediate 5a can be obtained by deprotecting Intermediate 11 with a strong acid such as TFA in a suitable solvent such as DCM at room temperature.

[0058] Accordingly, the present invention also relates to a process for preparing a compound according to the invention, the following steps: (a) reaction of a compound of formula (B1)

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0059] In the above process, X is halogen, A 1 , R 2 , R3 , R 4 and R 5 are as described in this specification.

[0060] In the reaction of step (a), the reducing agent can be, for example, LiBH4 or NaBH4.

[0061] In the reaction of step (a), the solvent can be, for example, MeOH optionally containing a suitable co-solvent. The co-solvent can be, for example, THF, dioxane, EtOH, dichloromethane or a mixture thereof.

[0062] Convenient conditions for step (a) are from about -60 °C to near room temperature, particularly from about -40 °C to room temperature.

[0063] Conveniently, the conditions for step (a) are NaBH4 as the reducing agent, MeOH as the solvent containing a suitable co-solvent, and a reaction temperature of from about -40 °C to room temperature.

[0064] In the reaction of step (b), the base can be, for example, Cs2CO3, K2CO3 or K3PO4.

[0065] In the reaction of step (b), the catalyst can be, for example, a suitable Pd catalyst, particularly t-BuXPhos-Pd-G3 or [tBuBrettPhos Pd(allyl)]OTf.

[0066] In the reaction of step (b), the solvent can be, for example, 1,4-dioxane, THF, DMA, DMF, NMP, toluene, xylene, water or a mixture thereof.

[0067] Convenient conditions for step (b) can be from about 60 °C to 120 °C, particularly from about 70 °C to about 110 °C, more specifically from about 80 °C to about 100 °C.

[0068] Conveniently, the conditions for step (b) are a reaction temperature of about 80 °C to about 100 °C, Cs2CO3 or K2CO3 as the base, t-BuXPhos-Pd-G3 or [tBuBrettPhos Pd(allyl)]OTf as the catalyst, and 1,4-dioxane as the solvent.

[0069] In the reaction of step (c), the base can be, for example, DBU, K2CO3 or Cs2CO3.

[0070] In the reaction of step (c), the solvent can be, for example, 1,4-dioxane, DMF, NMP, DMA or DMSO.

[0071] Convenient conditions for step (c) can be from about 30 °C to 120 °C, particularly from about 40 °C to about 100 °C, more specifically from about 50 °C to about 80 °C.

[0072] Conveniently, the conditions for step (c) are a reaction temperature of about 80 °C to about 100 °C, Cs2CO3 or K2CO3 as the base, t-BuXPhos-Pd-G3 or [tBuBrettPhos Pd(allyl)]OTf as the catalyst, and 1,4-dioxane as the solvent.

[0073] The present invention also relates to the compounds according to the invention when produced according to the method of the invention.

[0074] The present invention also particularly relates to the following. The compound of formula (I) described herein or a pharmaceutically acceptable salt thereof for use as a therapeutic active substance, A pharmaceutical composition comprising the compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier, Use of the compound of formula (I) described herein or a pharmaceutically acceptable salt thereof for treating or preventing rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell arteritis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis. Use of a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical for treating or preventing rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell arteritis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis, A compound of formula (I) described herein or a pharmaceutically acceptable salt thereof for use in treating or preventing rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell arteritis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis, and A method for treating or preventing rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell arteritis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis, comprising administering a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0075] Pharmaceutical composition Other embodiments of the invention provide a pharmaceutical composition or medicament containing a compound of the invention and a therapeutically inert carrier, diluent or excipient, and a method of using a compound of the invention for preparing such a composition and medicament. In one example, the compound of formula (I) may be formulated by mixing it with a physiologically acceptable carrier, i.e., a carrier that is not toxic to the recipient at the dosages and concentrations used in the dosage forms of the crude drug, at an appropriate pH and desired purity at ambient temperature. The pH of the formulation mainly depends on the specific application and the concentration of the compound, but is preferably in the range of about 3 to about 8. In one example, the compound of formula (I) is formulated in an acetate buffer at pH 5. In other embodiments, the compound of formula (I) is sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0076] The composition is formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered in this regard include the specific disorder being treated, the specific mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of drug delivery, the method of administration, the dosing schedule, and other factors known to the medical practitioner.

[0077] 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, intralung, intradermal, intrathecal, epidural, and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0078] The compounds of the present invention can be administered in any convenient dosage form, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions can contain conventional ingredients in pharmaceutical preparations, for example, diluents, carriers, pH adjusters, sweeteners, bulking agents, and additional active agents.

[0079] Typical formulations are prepared by mixing the compounds of the present invention with carriers or additives. 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 & 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, stabilizers, surfactants, wetting agents, smoothing agents, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, flow promoters, processing aids, colorants, sweeteners, flavors, fragrances, diluents, and other known additives for presenting the drug (i.e., the compound of the present invention or its pharmaceutical composition) well or for assisting in the manufacture of pharmaceutical products (i.e., pharmaceuticals).

[0080] Hereinafter, the present invention will be described by the following examples without limiting features.

Examples

[0081] Abbreviations [tBuBrettPhos Pd(allyl)]OTf Allyl(2-di-tert-butylphosphino-3,6-dimethoxy-2’,4’,6’-triisopropyl-1,1’-biphenyl)palladium(II) triflate (CAS No. 1798782-15-6) ATP Adenosine triphosphate aq. Aqueous solution BINAP (2,2’-Bis(diphenylphosphino)-1,1’-binaphthyl) Boc tert-Butyloxycarbonyl DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DIPEA N,N-Diisopropylethylamine DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide dppf 1,1'-Ferrocenediyl-bis(diphenylphosphine) dtbpy 4,4'-Di-tert-butyl-2,2'-dipyridyl equiv. Equivalent ESI Electrospray ionization Et Ethyl EtOAc Ethyl acetate EtOH Ethanol FA Formic acid HPLC High performance liquid chromatography LC-MS Liquid chromatography - mass spectrometry Me Methyl MeOH Methanol Ms Methanesulfonyl NMR Nuclear magnetic resonance PE Petroleum ether psi Pound per square inch RT Room temperature sat. Saturated SFC Supercritical fluid chromatography sol. Solution TBD Triazabicyclodecene TBDMS tert-Butyldimethylsilyl [tBuBrettPhos Pd(allyl)]OTf Trifluoromethanesulfonate allyl[(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) (CAS#1798782-15-6) t-BuXphos-Pd-G3 [(2-di-tert-butylphosphino-2’,4’,6’-triisopropyl-1,1’-biphenyl)-2-(2’-amino-1,1’-biphenyl)] palladium(II) methanesulfonate (CAS No. 1447963-75-8) TEA Triethylamine Tf Triflyl TFA Trifluoroacetic acid TFAA Trifluoroacetic anhydride THF Tetrahydrofuran

[0082] Example 1 1-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [Chemical formula]

[0083] Step 1: 1-[3-acetyl-6-(6-chloroimidazo[4,5-c]pyridin-3-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile [Chemical formula]

[0084] Under an argon atmosphere, 6-chloro-3H-imidazo[4,5-c]pyridine (CAS 2589-11-9, 100 mg, 0.65 mmol, 1 equiv) was dissolved in dimethyl sulfoxide (5 mL). Then, 1-(3-acetyl-6-chloro-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile (Example 3, Step 1; 254 mg, 0.98 mmol, 1.5 equiv) and 1,8-diazabicyclo[5.4.0]undec-7-ene (CAS 6674-22-2; 109.0 mg, 108 uL, 0.72 mmol, 1.1 equiv) were added. The reaction mixture was stirred at room temperature overnight. Further, 1,8-diazabicyclo[5.4.0]undec-7-ene (109 mg, 108 uL, 0.72 mmol, 1.1 equiv) was added. The reaction mixture was stirred at 80 °C for 1 hour and then cooled to room temperature. This was partitioned between water and EtOAc and extracted. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by reverse-phase chromatography using water / acetonitrile as the eluent to give a mixture of two positional isomers (219 mg). The positional isomers were separated by SFC chromatography using 35% MeOH to give the title compound (39 mg, 16%) as a brown solid. LC-MS: m / z = 378.1 [M+H] + , ESI pos.

[0085] Step 2: 1-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile, formic acid

Chem.

[0086] In a sealed tube, 1-[3-acetyl-6-(6-chloroimidazo[4,5-c]pyridin-3-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (41 mg, 0.11 mmol, 1 equiv) was dissolved in 1,4-dioxane (4 mL). (6-Methylpyridazin-3-yl)amine (23.7 mg, 0.22 mmol, 2 equiv), Cs2CO3 (70.7 mg, 0.22 mmol, 2 equiv) and water (29.3 mg, 29.3 uL, 1.63 mmol, 15 equiv) were added. The reaction mixture was flushed with argon and then t-BuXPhos-Pd-G3 (17.2 mg, 0.022 mmol, 0.2 equiv) was added. The reaction mixture was stirred at 90 °C. After 2.5 h, t-BuXPhos-Pd-G3 (17.24 mg, 0.022 mmol, 0.20 equiv) was added again and stirring was continued at 90 °C for 1 h. The reaction mixture was cooled to room temperature. The metal scavenger SiliaMetS™ thiol was added. The reaction mixture was stirred at room temperature for 30 min, filtered, and the residue on the filter was washed with MeOH / DCM / FA (90 / 10 / 0.05). The filtrate was concentrated. The crude product was purified by silica gel chromatography using a DCM / MeOH gradient as the eluent and then by reverse phase chromatography using a gradient of 1% aqueous formic acid / acetonitrile as the eluent to obtain the title compound (4.5 mg, 8%) as a pale yellow lyophilized powder. LC-MS: m / z = 453.3 [M+H] + , ESI pos.

[0087] Example 2 1-[3-(1-Hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

Chem.

[0088] Under an argon atmosphere, 1-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (Example 1; 234 mg, 0.14 mmol, 1 equivalent) was dissolved in methanol (3.5 mL). NaBH4 (15.9 mg, 0.42 mmol, 3 equivalents) was added, and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water. The crude product was purified by reverse-phase chromatography using a 0.1% aqueous trimethylamine / acetonitrile gradient as the eluent to obtain the title compound (15 mg, 23%) as a lyophilized powder. LC-MS: m / z = 453.3 [M+H] + , ESI pos.

[0089] Example 3 1-[3-(1-Hydroxyethyl)-6-[6-[(6-methyl-3-pyridyl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

Chemical formula

[0090] Step 1: 1-(3-Acetyl-6-chloro-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile

Chemical formula

[0091] Step 2: 1-[3-acetyl-6-[(2,4-dimethoxybenzyl)amino]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

Chem.

[0092] Step 3: 1-(3-acetyl-6-amino-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile

Chem.

[0093] Step 4: 2-bromo-5-fluoro-1-oxidopyridin-1-ium

Chem.

[0094] Dynamic DSC scan (30 - 500 °C, 10 °C / min): onset temperature of pyrolysis 110 °C, enthalpy: 490 J / g.

[0095] Step 5: 2 - Bromo - 5 - fluoro - 4 - nitro - pyridine

Chem.

[0096] After cooling to room temperature, the reaction mixture was poured into ice - cold water, adjusted to pH 6 with 4M NaOH, and extracted with DCM. The combined organic extracts were dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography using a heptane / ethyl acetate gradient as the eluent and a second silica gel chromatography using a DCM / MeOH gradient as the eluent to obtain the title compound (1.33 g, 33%) as a yellow oil.

[0097] Dynamic DSC scan (30 - 400 °C, 10 °C / min): Tm = 148 °C: onset of temperature for pyrolysis: ca. 173 °C, enthalpy: 1594 J / g. Destruction by high energy!

[0098] Step 6: 1 - [3 - Acetyl - 6 - [(6 - bromo - 4 - nitro - 3 - pyridyl)amino] - 2 - pyridyl] - 5 - methyl - pyrazole - 3 - carbonitrile

Chem.

[0099] Step 7: 1-[3-acetyl-6-[(4-amino-6-bromo-3-pyridyl)amino]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

Chemical Structure

[0100] Step 8: 1-[3-acetyl-6-(6-bromoimidazo[4,5-c]pyridin-3-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

Chemical formula

[0101] Step 9: 1-[3-Acetyl-6-[6-[(6-methyl-3-pyridyl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

Chem.

[0102] Step 10: 1-[3-(1-Hydroxyethyl)-6-[6-[(6-methyl-3-pyridyl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile, formic acid

Chem.

[0103] Example 4 1-[6-[6-[(6-Methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanol [Chemistry]

[0104] Process 1: 4-Bromo-3-methyl-1-(2,2,2-trifluoroethyl)pyrazole [Chemistry] To DMF (150 mL), a mixture of 4-bromo-3-methylpyrazole (a 3:1 mixture with positional isomers; 15.0 g, 93.2 mmol, 1.0 equiv), 2,2,2-trifluoroethyl trifluoromethanesulfonate (22.71 g, 97.8 mmol, 1.05 equiv), and Cs2CO3 (25.33 g, 186.3 mmol, 2.0 equiv) was stirred at 100 °C for 12 h. The reaction mixture was then filtered. The filtrate was diluted with H2O and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by silica gel chromatography to obtain a 2:1 mixture of the title compound and its positional isomer 4-bromo-3-methyl-1-(2,2,2-trifluoroethyl)pyrazole (19.5 g, 80.2 mmol, 86%) as an off-white oil. LC-MS: m / z = 242.9 [M+H] + , ESI pos. 1 1H NMR (400 MHz, DMSO-d6) δ = 8.00 (s, 1H), 5.09 - 4.99 (m, 2H), 2.14 (s, 3H).

[0105] Process 2: 3-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)pyrazole [Chemistry] To a mixture of 1,4-dioxane (200 mL), bis(pinacolato)diboron (17.24 g, 67.9 mmol, 1.5 equiv), and 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 equiv), Pd(dppf)Cl2·CH2Cl2 (3.7 g, 4.53 mmol, 0.1 equiv) and potassium acetate (5.66 mL, 90.53 mmol, 2.0 equiv) were added. The reaction mixture was stirred at 100 °C for 16 h under a nitrogen atmosphere and then concentrated. The crude product was purified by flash chromatography on silica gel using a petroleum ether / ethyl acetate gradient (0%-20%) as the eluent and by preparative HPLC using a hexane / ethyl acetate gradient as the eluent to give the first product of the title compound (a 3:1 mixture of isomers; 6.0 g, 20.7 mmol, 33% yield) as an off-white oil and the second product of the title compound (a 2:1 mixture of isomers; 2.0 g, 6.9 mmol, 11%) as a yellow oil. LC-MS: m / z = 291.1 [M+H] + , ESI pos.

[0106] Step 3: 1-[6-Chloro-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanone

Chemical formula

[0107] Step 4a: N-(6-methylpyridazin-3-yl)-3-(2-trimethylsilylethoxymethyl)imidazo[4,5-c]pyridin-6-amine [Chemical formula] To a solution of 6-chloro-3H-imidazo[4,5-c]pyridine (880.0 mg, 5.73 mmol, 1.0 equiv) dissolved in DMF (10 mL), 2-(trimethylsilyl)ethoxymethyl chloride (2.03 mL, 11.5 mmol, 2.0 equiv) and TEA (1.59 mL, 11.46 mmol, 2.0 equiv) were added. The mixture was stirred at 20 °C for 2 h. Then, water was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with NaCl solution and then concentrated under reduced pressure to obtain a residue. The crude product was purified by silica column using a petroleum ether / ethyl acetate gradient as the eluent to give the title compound (1.1 g, 54%) as a yellow oil. LC-MS: m / z = 284.0, [M+H] + , ESI pos.

[0108] Step 5: N-(6-Methylpyridazin-3-yl)-3-(2-trimethylsilylethoxymethyl)imidazo[4,5-c]pyridin-6-amine

Chem.

[0109] Step 5: N-(6-Methylpyridazin-3-yl)-3H-imidazo[4,5-c]pyridin-6-amine

Chem.

[0110] Project 6: 1-[6-[6-[(6-Methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanone

Chem.

[0111] The mixture of four isomers was purified by SFC (0.1% NH3H2O in isopropyl alcohol) to obtain two mixtures of two isomers each. 1-[6-[6-[(6-Methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanone and 1-[6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanone (70 mg). 1-[6-[6-[(6-Methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-1-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanone and 1-[6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-1-yl]-2-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanone (50 mg). LC-MS: m / z = 508.3 [M+H] + , ESI pos.

[0112] A mixture of 1-[6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanone and 1-[6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanone (70.0 mg) was separated by SFC (0.1% NH3H2O in isopropyl alcohol) to give the title compound 1-[6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanone (25 mg) as a yellow solid. LC-MS: m / z = 508.2, [M+H] + , ESI pos. 11H NMR (400 MHz, DMSO-d6) δ = 9.94 (s, 1H), 9.32 (d, J = 0.8 Hz, 1H), 9.29 (s, 1H), 8.36 (d, J = 0.6 Hz, 1H), 8.29 (d, J = 8.6 Hz, 1H), 8.09 (s, 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.72 (d, J = 9.1 Hz, 1H), 7.40 (d, J = 9.1 Hz, 1H), 5.21 - 5.10 (m, 2H), 2.51 (brs, 3H), 2.36 (s, 3H), 2.30 (s, 3H) Also, 1-[6-[6-[(6-Methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanone (12 mg) was obtained as a white solid. LC-MS: m / z = 508.2, [M + H] + , ESI pos. 1 1H NMR (400 MHz, DMSO-d6) δ = 10.04 (s, 1H), 9.01 (s, 1H), 8.81 (s, 1H), 8.77 (s, 1H), 8.35 (d, J = 8.5 Hz, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.90 (s, 1H), 7.74 (d, J = 9.1 Hz, 1H), 7.41 (d, J = 9.1 Hz, 1H), 5.26 - 5.14 (m, 2H), 2.52 (brs, 3H), 2.41 (s, 3H), 2.41 (s, 3H)

[0113] A mixture of 1-[6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-1-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanone and 1-[6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-1-yl]-2-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanone (50 mg) was purified by SFC (0.1% NH3H2O in isopropyl alcohol) to 1-[6-[6-[(6-Methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-1-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanone (35 mg) was obtained as a white solid. LC-MS: m / z = 508.2, [M+H] + , ESI pos. 1 H NMR (400 MHz, DMSO-d6) δ = 10.03 (s, 1H), 9.08 (s, 1H), 9.02 (s, 1H), 8.78 (s, 1H), 8.54 (s, 1H), 8.37 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 9.1 Hz, 1H), 7.45 (d, J = 9.1 Hz, 1H), 5.24 - 5.13 (m, 2H), 2.54 (s, 3H), 2.44 (s, 3H), 2.14 (s, 3H) Also, 1-[6-[6-[(6-Methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-1-yl]-2-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanone (18 mg) was obtained as a yellow solid. LC-MS: m / z = 508.2, [M+H] + , ESI pos. 1 H NMR (400 MHz, DMSO-d6) δ = 9.94 (s, 1H), 9.33 (s, 1H), 9.31 (s, 1H), 8.38 (s, 1H), 8.34 (d, J = 8.5 Hz, 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.75 (s, 1H), 7.70 (d, J = 9.1 Hz, 1H), 7.40 (d, J = 9.1 Hz, 1H), 5.28 - 5.18 (m, 2H), 2.53 - 2.51 (m, 3H), 2.41 (s, 3H), 2.40 (s, 3H).

[0114] Step 7: 1-[6-[6-[(6-Methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanol, formic acid

Chem.

[0115] Example 5 1-[3-Acetyl-6-[6-[methyl-(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

Chemical Structure

[0116] Step 1: 1-[3-Acetyl-6-(6-chloroimidazo[4,5-c]pyridin-3-yl)-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile (corresponding to Step 1 of Example 1)

Chem.

[0117] Step 2: 1-[3-acetyl-6-[6-[methyl-(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

Chem.

[0118] Example 6 1-[3-acetyl-6-[6-(3-methyl-6,7-dihydropyridazino[4,3-b][1,4]oxazin-8-yl)imidazo[4,5-c]pyridin-3-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

Chem.

[0119] Step 1: 3,6-dichloro-4-(2-iodoethoxy)pyridazine

Chem.

[0120] Step 2: 2-(3,6-Dichloropyridazin-4-yl)oxy-N-[(2,4-dimethoxyphenyl)methyl]ethanamine

Chemical formula

[0121] Step 3: 3-Chloro-8-[(2,4-dimethoxyphenyl)methyl]-6,7-dihydropyridazino[4,3-b][1,4]oxazine [Chem.] To a solution of Cs2CO3 (2.55 g, 7.82 mmol, 2 equiv) and 2-(3,6-dichloropyridazin-4-yl)oxy-N-[(2,4-dimethoxyphenyl)methyl]ethanamine (1.4 g, 3.91 mmol, 1 equiv) dissolved in toluene (40 mL), BINAP (340.7 mg, 0.55 mmol, 0.14 equiv) was added. The mixture was stirred at 110 °C for 2 h, then diluted with DCM and filtered through a celite pad. The filtrate was washed with brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica column chromatography using a petroleum ether / ethyl acetate gradient (900 mg, 2.8 mmol, 72% yield). LC-MS: m / z = 322.1 [M+H] + , ESI pos. 1 H NMR (400 MHz, CDCl3-d) δ = 7.03 (d, J = 8.3 Hz, 1H), 6.65 (s, 1H), 6.53 - 6.43 (m, 2H), 4.40 (s, 2H), 4.39 - 4.35 (m, 2H), 3.82 (s, 6H), 3.49 - 3.44 (m, 2H).

[0122] Step 4: 8-[(2,4-Dimethoxyphenyl)methyl]-3-methyl-6,7-dihydropyridazino[4,3-b][1,4]oxazine [Chem.] To a solution of trimethylboroxin (971.4 mg, 3.87 mmol, 1.5 eq) and 3-chloro-8-[(2,4-dimethoxyphenyl)methyl]-6,7-dihydropyridazino[4,3-b][1,4]oxazine (830.0 mg, 2.58 mmol, 1 eq) in 1,4-dioxane (15 mL) were added Pd(dppf)Cl2 (189 mg, 0.26 mmol, 0.1 eq) and K2CO3 (713 mg, 5.16 mmol, 2 eq) under a nitrogen atmosphere. The mixture was stirred at 100 °C for 12 h and then diluted with DMF (10 mL) and MeOH (40 mL). Thiourea on resin was added and stirring was continued for 3 h. The mixture was filtered and concentrated. The crude product was purified by preparative HPLC using a gradient of 0.1% aqueous formic acid / acetonitrile as the eluent. The product-containing fractions were lyophilized to give the title compound (600 mg, 1.99 mmol, 77% yield) as a yellow rubber. LC-MS: m / z = 302.1 [M+H] + , ESI pos.

[0123] Step 5: 3-Methyl-7,8-dihydro-6H-pyridazino[4,3-b][1,4]oxazine

Chemical Structure

[0124] Step 6: 1-[3-Acetyl-6-[6-(3-methyl-6,7-dihydropyridazino[4,3-b][1,4]oxazin-8-yl)imidazo[4,5-c]pyridin-3-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile

Chemical Structure

[0125] Example 7 1-[2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-3-pyridyl]ethanol

Chemical formula

[0126] Step 1: 1-[6-Chloro-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-3-pyridyl]ethanone

Chemical formula

[0127] Step 2: 1-[2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-3-pyridyl]ethanone

Chemical formula

[0128] This mixture was separated by SFC using acetonitrile / MeOH + 0.1% NH3 as the eluent to give the title compound 1-[2-[3-(difluoromethyl)-5-methylpyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-3-pyridyl]ethanone (10 mg, 32% yield) as a yellow solid. LC / MS: m / z = 476.1, [M+H] + , ESI pos. 11H NMR (400 MHz, DMSO-d6) δ = 9.99 (s, 1H), 9.33 (s, 1H), 9.22 (d, J = 0.7 Hz, 1H), 8.44 (d, J = 8.4 Hz, 1H), 8.34 (s, 1H), 8.29 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 9.3 Hz, 1H), 7.41 (d, J = 9.2 Hz, 1H), 7.22 - 6.90 (m, 1H), 6.76 (s, 1H), 2.59 (s, 3H), 2.54 (brs, 3H), 2.03 (s, 3H).

[0129] Furthermore, the positional isomer 1-[2-[3-(difluoromethyl)-5-methylpyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-1-yl]-3-pyridyl]ethanone (2 mg, 0.02 mmol, yield 7%) was obtained as a yellow solid. LC-MS: m / z = 476.1, [M + H] + , ESI pos.

[0130] Step 3: 1-[2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-3-pyridyl]ethanol

Chemical Structure

[0131] The crude product was purified by reverse-phase chromatography using an acetonitrile / 0.1% aqueous formic acid gradient as the eluent to obtain the title compound (1.2 mg, 14% yield) as a freeze-dried white solid. LC-MS: m / z = 478.2, [M+H] + , ESI pos. 1 H NMR (400 MHz, MeOH-d4) δ = 9.43 (s, 1H), 9.27 (s, 1H), 8.52 (d, J = 8.5 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H), 7.85 (s, 1H), 7.77 (s, 2H), 6.98 - 6.65 (m, 1H), 6.61 (s, 1H), 4.80 - 4.80 (m, 1H), 2.61 (s, 3H), 2.42 (s, 3H), 1.39 (d, J = 6.4 Hz, 3H).

[0132] Example 8 - Phosphorylation assay SIK1 - 3: In the presence of SIK2 (either SIK1 or SIK3) and ATP, the CHK peptide (KKKVSRSGLYRSPSMPENLNRPR, having a C-terminal arginine amide modification) was phosphorylated at one of the four serine residues that are capable of being phosphorylated. Only one phosphorylation was observed under these assay conditions. In DMSO, 60 nl of each compound dilution series (12 points; dilution factor 3, generally 30 μM to 170 pM) was transferred to the assay plate by acoustic dispensing and pre-incubated for 30 minutes (ambient temperature) after the addition of 5 μl of SIK1 (5 nM), 5 μl of SIK2 (0.5 nM) or 7 μl of SIK3 (1.5 nM) in 5 μl of assay buffer (12.5 mM HEPES (pH 7.0), 10 mM magnesium acetate, 0.005% BSA). 10 μM CHK-peptide solution in assay buffer and 5 μl of 100 μM ATP for SIK1 and SIK2, respectively, or 3 μl for SIK3 were added and incubated for 45 minutes at ambient temperature. The reaction was quenched by the addition of 40 μl of 0.125% formic acid in water. RapidFire (RF) mass spectrometry was utilized for data generation 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 summed and the ratio was calculated for data evaluation (sum of phosphorylated species / sum of all species). Normalization was performed by Genedata software based on the non-inhibitory control DMSO and the commercially available SIK inhibitor (R) 1 μM YKL-05-099 (CAS number 1936529-65-5). The results of the assay are represented as the maximum half-maximal inhibitory concentration (IC50) and summarized in Table 1 below.

[0133] RapidFire Setup: The sample was aspirated by vacuum for up to 600 ms and loaded onto a C4 cartridge (Agilent; #G9203A) with 0.1% formic acid in water at 3000 ms @ 1.5 ml / min. Subsequently, the sample was transferred to an API 5000 (API 6500+) or QToF mass spectrometer at 4000 ms @ 1.25 ml / min using 90% acetonitrile; 10% water; 0.007% TFA; 0.093 formic acid. The cartridge was reconditioned with 0.1% formic acid in water for an additional 500 ms.

[0134] MS settings Sciex API5000 / API6500+: For all MS analyses using the following MS settings in MRM mode: electrospray positive; 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 = cell exit potential.

Table 1

[0135] MS settings Agilent QToF 6545 For all MS analyses using the following MS settings in MS mode: dual AJS electrospray positive; VCap: 3000 V; drying and sheath gas: 340 °C, 8 l / min; nebulizer: 60 psig; nozzle voltage: 2000 V; fragmenter: 130 V; skimmer: 35 V; Oct1 RF Vpp: 700 V; reference mass at 5 spectra / s

Table 2

[0136]

Table 3

[0137] Example A Film-coated tablets containing the following components can be manufactured in a conventional manner.

Table 4

[0138] The active ingredient is sieved, mixed with microcrystalline cellulose, and the mixture is granulated with an aqueous solution of polyvinylpyrrolidone. Then, the granules are mixed with sodium starch glycolate and magnesium stearate and compressed to obtain nuclei of 120 or 350 mg each. The nuclei are lacquered with the above aqueous solution / suspension of the film coating.

[0139] Example B Capsules containing the following components can be manufactured in a conventional manner.

Table 5

[0140] Example C The injection solution can have the following composition:

Table 6

Claims

1. A compound of formula (I) 【Chemical 1】 (wherein R １ is hydroxyalkyl, alkylcarbonyl, cyclopropyl, haloalkyl or cyano, R ２ is heteroaryl optionally substituted with one, two or three substituents independently selected from alkyl, haloalkyl, halogen, cyano, haloalkoxy and alkoxy; R ３ is hydrogen or alkyl, R ４ is hydrogen or alkyl, or R ３ is R ４ together with the atoms to which they are attached forms a 5- to 7-membered heterocycloalkyl or heteroaryl ring, R ５ is alkyl or haloalkyl, A １ is -CH- or -N-) or a pharmaceutically acceptable salt thereof.

2. R １ The compound according to claim 1, wherein R is hydroxyalkyl or alkylcarbonyl.

3. R １ The compound according to claim 1 or 2, wherein R is hydroxyethyl or methylcarbonyl.

4. R ２ The compound according to any one of claims 1 to 3, wherein R is cyano, haloalkyl or haloalkoxy.

5. R ２ The compound according to any one of claims 1 to 4, wherein R is cyano, difluoromethyl or difluoromethoxy.

6. R ３ is hydrogen or methyl, and R ４ is hydrogen, or R ３ is such that R ４ and the atoms to which they are attached together form a 5- to 7-membered heterocycloalkyl or heteroaryl ring, a compound according to any one of claims 1 to 5.

7. R ３ is hydrogen or methyl, and R ４ is hydrogen, or R ３ is R ４ and together with the atom to which they are attached form 3,4-dihydro-2H-1,4-oxazine, a compound according to any one of claims 1 to 6.

8. R ５ The compound according to any one of claims 1 to 7, wherein R is alkyl.

9. R ５ The compound according to any one of claims 1 to 8, wherein R is methyl.

10. A １ The compound according to any one of claims 1 to 9, wherein A is -N-.

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

12. 1-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile, 1-[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile, 1-[3-(1-hydroxyethyl)-6-[6-[(6-methyl-3-pyridyl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile, 1-[6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanol, 1-[3-acetyl-6-[6-[methyl-(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile, 1-[3-acetyl-6-[6-(3-methyl-6,7-dihydropyridazino[4,3-b][1,4]oxazin-8-yl)imidazo[4,5-c]pyridin-3-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile, and 1-[2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-3-pyridyl]ethanol The compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof.

13. 1-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile, 1-[3-(1-Hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridyl]-5-methyl-pyrazole-3-carbonitrile, and 1-[6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanol A compound of formula (I) according to any one of claims 1 to 12, selected from the above, or a pharmaceutically acceptable salt thereof.

14. A method for preparing a compound according to any one of claims 1 to 13, comprising one of the following steps: (a) Reaction of a compound of formula (B1) ​ with a suitable reducing agent, in the presence of a suitable solvent, (b) Reaction of a compound of formula (B2) 【Chemical Formula 3】 with a compound of formula (B3) 【Chemical Formula 4】 in the presence of a suitable base, a suitable catalyst and a suitable solvent, or (c) Reaction of a compound of formula (B4) 【Chemical Formula 5】 with a compound of formula (B5) [Chemical Formula 6] in the presence of a suitable base (In these formulas, X is halogen, A １ , R ２ , R ３ , R ４ and R ５ are as defined in any one of claims 1 to 9).

15. A compound according to any one of claims 1 to 13, when produced according to the method of claim 14.

16. Use of a compound of formula (I) according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof for use as a therapeutic active substance.

17. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier.

18. Use of a compound of formula (I) according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof for treating or preventing rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell arteritis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis.

19. Use of a compound of formula (I) according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating or preventing rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell arteritis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis.

20. The compound of formula (I) according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis.

21. 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 the compound of formula (I) according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.

22. The invention as described previously in the specification.

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