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

Abstract

# imgabs0. The present invention relates to imidazo [4, 5-c] pyridine derivatives of formula (I) as SIK modulators 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.

Description

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

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

[0003]

[0004] in

[0005] R 1 is hydroxyalkyl, alkylcarbonyl, cyclopropyl, haloalkyl or cyano;

[0006] R 2 is heteroaryl optionally substituted with one, two or three substituents independently selected from alkyl, haloalkyl, halogen, cyano, haloalkoxy and alkoxy;

[0007] R 3 is hydrogen or alkyl;

[0008] R 4 is hydrogen or alkyl; or R 3 With R 4 and the atoms to which they are attached together form a five- to seven-membered heterocycloalkyl or heteroaryl ring;

[0009] R 5 is alkyl or haloalkyl; and

[0010] A 1 is -CH- or -N-;

[0011] or a pharmaceutically acceptable salt thereof.

[0012] Salt-induced kinase (SIK) belongs to the AMP-activated protein kinase (AMPK) subfamily, known as AMPK-related kinase. There are three members, named SIK1, SIK2 and SIK3, and their expression range is wide. Their main biological role is to modify gene expression by controlling the phosphorylation and subcellular localization of two key transcriptional regulatory factors: CRTC (cAMP-regulated transcriptional coactivator) and class IIa HDAC (histone deacetylase). In fact, in the basal state, CRTC and HDAC are both phosphorylated by SIK kinase and isolated in the cytoplasm by interacting with their cytoplasmic partner 14-3-3. In response to extracellular signals that usually increase intracellular cAMP levels, the activity of SIK kinase is inhibited, CRTC and HDAC are no longer phosphorylated, and are therefore released from 14-3-3. Therefore, they can translocate to the nucleus and regulate gene expression (Wein et al., Trends Endocrinol Metab. 2018 Oct; 29 (10): 723-735).

[0013] In macrophages, inhibition of SIK kinases results in 1) shuttling of CRTC3 to the nucleus and increased transcription of IL-10; 2) translocation of HDAC4 / 5 into the nucleus and subsequent deacetylation of NF-κB, leading to decreased transcription of proinflammatory cytokines (Clark et al., Proc Natl Acad Sci US A. 2012 Oct 16;109(42):16986-91.).

[0014] Macrophages are essential for maintaining tissue homeostasis, mediating inflammation, and promoting the resolution of inflammation. To achieve this diversity of functions, macrophages have the ability to undergo different "polarizations" in response to environmental cues. The two extreme phenotypes along their activation state continuum are "M1" or "pro-inflammatory macrophages" and "M2" or "pro-resolving macrophages."

[0015] Strikingly, inhibition of intracellular SIK kinases overrides these extracellular macrophage polarization signals and pushes them toward a pro-resolving phenotype. This is accompanied by an increase in IL-10 (via interference with the SIK-CRTC3 pathway) and a concomitant decrease in TNF-α, IL-12, and IL-6 (via interference with the SIK-HDAC4 / 5 and NF-κB pathways). High levels of IL-10 and low levels of pro-inflammatory cytokines following SIK inhibition will promote resolution of inflammation. Exploration of the SIK pathway was initially described in macrophages (Clark et al., Proc Natl Acad Sci US A. 2012 Oct 16;109(42):16986-91) and dendritic cells (Sundberg et al., Proc Natl Acad Sci US A. 2014 Aug 26;111(34):12468-73), and the therapeutic potential of pan-SIK inhibitors has been demonstrated in mouse LPS (lipopolysaccharide) challenge models (Sundberg et al., ACS Chem Biol. 2016 Aug 19;11(8):2105-11) and colitis models (Fu et al., Inflamm Bowel Dis. 2021 Oct 20;27(11):1821-1831). Since then, SIK has been shown to play an important role in the function of several immune cells, including mast cells (Darling et al., J Biol Chem. 2021 Jan-Jun;296:100428). Importantly, SIK1 is poorly expressed in macrophages, and one embodiment of the present invention is a SIK2 / 3 inhibitor that does not affect SIK1, thereby limiting potential SIK1-related toxicity.

[0016] SIK inhibitors have high therapeutic potential in diseases that are 1) characterized by an influx of proinflammatory macrophages into tissues and impaired tissue homeostasis and healing, or 2) in which anti-TNF therapy is beneficial (partially or completely) or in which IL10 levels are insufficient. Diseases characterized by inflammatory macrophages are, for example, rheumatoid arthritis, juvenile rheumatoid arthritis, NASH, primary sclerosing cholangitis, giant cell vasculitis and inflammatory bowel disease ("IBD"), atherosclerosis, type 2 diabetes, and glomerulonephritis.

[0017] A disease that has been shown to be associated with IL-10 and TNF-α is IBD. Genetic changes that reduce IL-10 function (such as SNPs in IL-10 or its receptor) are associated with an increased risk of IBD in humans. In addition, anti-TNF therapy is successful, but only a small fraction of IBD patients respond, and most of this limited response disappears over time. The dual action of the described SIK inhibitors (increasing IL-10 and reducing TNF-α) makes them particularly suitable for the treatment of IBD.

[0018] 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 role in macrophages, SIKs in these cells phosphorylate CRTC and class II HDCA in response to extracellular signals, subsequently altering the expression of several cytokines.

[0019] In addition to its physiological role, there are reports that dysregulated SIK expression is associated with some diseases. For example, SIK2 has been described as a risk site for primary sclerosing cholangitis, a fibrotic disease often associated with IBD. In addition, SIK2 and SIK3 are highly expressed in ovarian and prostate cancers and are associated with poor survival (Miranda et al., Cancer Cell. 2016 Aug 8; 30(2): 273-289; Bon et al., Mol Cancer Res. 2015 Apr; 13(4): 620-635).

[0020] To date, many diseases caused by innate immune system disorders lack effective therapies, and the medical needs for new therapies have not been met. The present invention relates to a novel compound that is a highly active SIK inhibitor for the treatment of inflammatory, allergic and autoimmune diseases. Therefore, in addition to inflammatory, allergic and autoimmune diseases, SIK inhibitors may also have potential relevance to cancer, metabolic diseases, bone density disorders, pigmentation-related diseases or beauty, fibrotic diseases and depression.

[0021] In this specification, the term "alkyl" refers to a straight or branched alkyl group having 1 to 8 carbon atoms, particularly a straight or branched alkyl group having 1 to 6 carbon atoms and more particularly a straight or branched alkyl group having 1 to 4 carbon atoms, either alone or in combination. Examples of straight and branched C1-C8 alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, isomeric amyl, isomeric hexyl, isomeric heptyl and isomeric octyl, particularly methyl, ethyl, propyl, butyl and amyl. Specific examples of alkyl are methyl, ethyl, propyl, isopropyl, butyl and isobutyl. Methyl, ethyl, propyl and butyl, such as isobutyl, are further specific examples of "alkyl" in compounds of formula (I).

[0022] The term "cycloalkyl" alone or in combination refers to a cycloalkyl ring having 3 to 8 carbon atoms, particularly a cycloalkyl ring having 3 to 6 carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Specific examples of "cycloalkyl" are cyclopropyl and cyclobutyl.

[0023] The term "heterocycloalkyl" refers to a monovalent saturated or partially unsaturated monocyclic or bicyclic system having 4 to 12 ring atoms, either alone or in combination, comprising 1, 2 or 3 heteroatoms selected from N, O and S, and the remaining ring atoms are carbon. Bicyclic means consisting of two rings with one or two common ring atoms."heterocycloalkyl" may include a carbonyl group, wherein carbon is a part of a ring system. The ring system may be connected to the remaining compound by an atom selected from C, N, S and O, particularly by an N atom ("N-heterocycloalkyl").Examples of “heterocycloalkyl” include, but are not limited to, morpholino, morpholin-4-yl, pyrrolidinyl, pyrrolidin-1-yl, pyrrolidin-3-yl, piperidinyl, 1-piperidinyl, 4-piperidinyl, 2-oxopyrrolidin-1-yl, piperazinyl, piperazin-1-yl, azetidinyl, azetidin-1-yl, [3-oxo-piperazin-1-yl], (1,1-dioxo-1,2-thiazolidin-2-yl), (4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl), (3-oxo-1,5,6,8-tetrahydrooxazolo[3,4-a]pyrazin-7-yl), [rac-(3aR,6aS)-2,3,3a, 5,6,6a-hexahydro-1H-pyrrolo[3,2-b]pyrrol-4-yl], [rac-(3aS,6aR)-2,3,3a,5,6,6a-hexahydro-1H-pyrrolo[3,2-b]pyrrol-4-yl], (4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-3-yl), (6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl), (4,7-diazaspiro[2.5]octan-7-yl), (2-oxa-5,8-diazaspiro[3.5]nonan-8-yl), 3-azabicyclo[3.2.0]heptane-3-yl), (5-azaspiro[ 2.4]heptane-5-yl), (2-azabicyclo[2.2.1]heptane-2-yl), 4-oxa-7-azaspiro[2.5]octan-7-yl, (3-azabicyclo[3.1.0]hexan-3-yl), (6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl), 2-oxa-7-azaspiro[3.4]octan-7-yl, (2-oxo-1-piperidinyl), (2,3-dihydropyridazino[4,5-b][1,4]oxazin-8-yl), pyrrolidin-1-yl, 2-oxo-pyrimidin-4-yl, morpholinoethyl, 2-oxa-5-azaspiro[3.4]octan-5-yl, oxetane , (2-oxo-1-piperidinyl), 2-oxo-4-piperidinyl, 5-oxo-pyrrolidin-3-yl, 2-oxa-5-azaspiro[3.4]octan-5-yl, (7,8-dihydro-5H-pyrano[4,3-c]pyridazin-3-yl), [rac-(4aS,7aR)-4-methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-6-yl], 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]. A specific example of "heterocycloalkyl" is 3,4-dihydro-2H-1,4-oxazine.

[0024] The term "heteroaryl", alone or in combination, means an aromatic monocyclic or bicyclic ring system having 5 to 12 ring atoms, which contains 1, 2, 3 or 4 heteroatoms each independently selected from N, O and S, the remaining ring atoms being carbon. The ring system may be linked to the remaining compound via an atom selected from C, N, S and O, in particular via a N atom ("N-heteroaryl"). Examples of heteroaryl include, but are not limited to, pyrazolyl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyridinyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, pyridazinyl, pyridazin-3-yl, pyridazin-4-yl, pyrazinyl, pyrazin-2-yl, isoxazolyl, isoxazol-3-yl, isoxazol-4-yl, pyrimidinyl, pyrimidin-5-yl, benzotriazolyl, 1H-benzotriazol-4-yl, furanyl, furanyl, 2-furanyl, 3-furanyl, [6-oxo]

[0063] "heteroaryl" includes, but is not limited to, pyrazol-1-yl, pyrazol-2-yl, pyrimidin-5-yl, (1,3,4-oxadiazol-2-yl), (1,3,4-thiadiazol-2-yl), (1,2,4-triazin-3-yl), 2-oxo-pyrimidin-4-yl, (1-methyl-2-oxo-3-pyridinyl), and (2,3-dihydropyridazino[4,5-b][1,4]oxazin-8-yl). Specific examples of "heteroaryl" are pyrazol-1-yl, pyrazol-4-yl, pyridazin-3-yl, and pyrimidin-5-yl.

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

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

[0027] The term "oxo", alone or in combination, represents a =0 group.

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

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

[0030] The term "haloalkoxy", alone or in combination, denotes an alkoxy group substituted with at least one halogen, particularly with one to five halogens, especially one to three halogens. Specific "haloalkoxy" are fluoromethoxy, fluoroethoxy and fluoropropoxy.

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

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

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

[0034] The term "alkylamino" is an alkyl group attached to a -NH- group. The term "dialkylamino" denotes two alkyl groups attached to an -N- atom.

[0035] The term "sulfonyl", alone or in combination, represents a -SO2- group.

[0036] The term "pharmaceutically acceptable salt" means a salt that is not biologically or otherwise undesirable. "Pharmaceutically acceptable salt" includes both acid addition salts and base addition salts. "Pharmaceutically acceptable acid addition salts" refers to those pharmaceutically acceptable salts formed with inorganic acids and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, etc., and the organic acid can be selected from aliphatic, alicyclic, aromatic, aromatic aliphatic, heterocyclic, carboxylic acid and sulfonic acid organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, pamoic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid, etc. The term "pharmaceutically acceptable base addition salt" means those pharmaceutically acceptable salts formed with organic or inorganic bases. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese and aluminum salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines and basic ion exchange resins (such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine and polyamine resins). Specific pharmaceutically acceptable salts of compounds of formula (I) are for example formates thereof.

[0037] The term "one or more compounds of the invention" refers to compounds of formula (I) and stereoisomers, tautomers, solvates and salts (eg, pharmaceutically acceptable salts) thereof.

[0038] Tautomeric forms, ie structural isomers which are interconvertible with the compounds of formula (I), may exist under certain circumstances, especially in solution, and are to be understood as being included in the present invention.

[0039] If one of the starting materials or compounds of formula (I) contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups may be introduced before the key steps using methods known in the art (such as described in "Protective Groups in Organic Chemistry" by TW Greene and PGM Wuts, 3rd edition, 1999, Wiley, New York). Such protecting groups may be removed at a later stage of the synthesis using standard methods described in the literature. Examples of protecting groups are tert-butyloxycarbonyl (Boc), 9-fluorenylmethylcarbamate (Fmoc), 2-trimethylsilylethylcarbamate (Teoc), benzyloxycarbonyl (Cbz) and p-methoxybenzyloxycarbonyl (Moz).

[0040] The compounds of formula (I) may contain several asymmetric centers and may exist in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates.

[0041] The term "asymmetric carbon atom" means a carbon atom having four different substituents. According to the Cahn-Ingold-Prelog sequence rules, an asymmetric carbon atom can be in the "R" or "S" configuration.

[0042] Furthermore, the present invention includes all optical isomers of the compounds of formula (I) where applicable, ie diastereomers, diastereomeric mixtures, racemic mixtures, all corresponding enantiomers and / or tautomers thereof and solvates thereof.

[0043] If desired, the racemic mixture of the compounds of the invention can be separated to isolate the individual enantiomers. Separation can be carried out by methods well known in the art, such as coupling the racemic mixture of the compound to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods such as fractional crystallization or chromatography.

[0044] In some embodiments providing an optically pure enantiomer, an optically pure enantiomer means that the compound contains >90% by weight of the desired isomer, particularly >95% by weight of the desired isomer, or more particularly >99% by weight of the desired isomer, the weight percentages being based on the total weight of the isomers of the compound. Chirally pure compounds or chirally enriched compounds can be prepared by chiral selective synthesis or by separation of enantiomers. Separation of enantiomers can be performed on the final product, or alternatively on a suitable intermediate.

[0045] The structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Specific examples of radioactive isotopes are 2 H. 3 H. 13 C. 14 C and 18 F. For example, one or more hydrogen atoms are replaced by deuterium or tritium, or one or more carbon atoms are enriched 13 C or 14 Structures substituted with the carbon of C are within the scope of the present invention.

[0046] Therefore, the present invention relates to:

[0047] According to the compound of the present invention, wherein R 1 is hydroxyalkyl or alkylcarbonyl;

[0048] According to the compound of the present invention, wherein R 1 is hydroxyethyl or methylcarbonyl;

[0049] According to the compound of the present invention, wherein R 2 is cyano, haloalkyl or haloalkoxy;

[0050] According to the compound of the present invention, wherein R 2 is cyano, difluoromethyl or difluoromethoxy;

[0051] According to the compound of the present invention, wherein R 3 is hydrogen or methyl, and R 4 is hydrogen; or R 3 With R 4 and the atoms to which they are attached together form a five- to seven-membered heterocycloalkyl or heteroaryl ring;

[0052] According to the compound of the present invention, wherein R 3 is hydrogen or methyl, and R 4 is hydrogen; or R 3 With R 4 and the atoms to which they are attached together form 3,4-dihydro-2H-1,4-oxazine;

[0053] According to the compound of the present invention, wherein R 3 is hydrogen or alkyl, and R 4 is hydrogen;

[0054] According to the compound of the present invention, wherein R 3 With R 4 and the atoms to which they are attached together form a five- to seven-membered heterocycloalkyl or heteroaryl ring;

[0055] According to the compound of the present invention, wherein R 3 With R 4 and the atoms to which they are attached together form 3,4-dihydro-2H-1,4-oxazine

[0056] and wherein the double bond of 3,4-dihydro-2H-1,4-oxazine is part of the aromatic system of the pyridazine of the compound of formula (I);

[0057] According to the compound of the present invention, wherein R 5 is methyl or difluoromethyl;

[0058] According to the compound of the present invention, wherein R 5 is an alkyl group;

[0059] According to the compound of the present invention, wherein R 5 is methyl;

[0060] According to the compound of the present invention, wherein A 1 is -N-; and

[0061] According to the compound of the present invention, wherein A 1 It is -CH-.

[0062] The present invention further relates to a compound of formula (I) selected from

[0063] 1-[3-Acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridinyl]-5-methyl-pyrazole-3-carbonitrile;

[0064] 1-[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridinyl]-5-methyl-pyrazole-3-carbonitrile;

[0065] 1-[3-(1-hydroxyethyl)-6-[6-[(6-methyl-3-pyridinyl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridinyl]-5-methyl-pyrazole-3-carbonitrile;

[0066] 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-pyridinyl]ethanol;

[0067] 1-[3-Acetyl-6-[6-[methyl-(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridinyl]-5-methyl-pyrazole-3-carbonitrile;

[0068] 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-pyridinyl]-5-methyl-pyrazole-3-carbonitrile; and

[0069] 1-[2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-3-pyridinyl]ethanol;

[0070] or a pharmaceutically acceptable salt thereof.

[0071] The present invention further relates to a compound of formula (I) selected from

[0072] 1-[3-Acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridinyl]-5-methyl-pyrazole-3-carbonitrile;

[0073] 1-[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridinyl]-5-methyl-pyrazole-3-carbonitrile; and

[0074] 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-pyridinyl]ethanol;

[0075] or a pharmaceutically acceptable salt thereof.

[0076] The synthesis of compounds of formula (I) can be accomplished, for example, according to the non-exhaustive procedures in general Schemes 1 to 6 described below or according to methods known to those skilled in the art. In some cases, the order of the reaction steps can be modified and the individual steps of the different schemes can be combined in different ways as disclosed herein.

[0077] Solution 1

[0078] In Scheme 1, the synthesis of compounds of formula (Ib) starting from compounds of formula (Ia) is described. In the following scheme, A 1 , R 2 , R 3 , R 4 and R 5 As defined above. A compound of formula (Ia) is a compound of formula (I) as described herein, wherein R 1 The compound of formula (Ib) is a compound of formula (I) as described herein, wherein R 1 It is hydroxyethyl.

[0079]

[0080] Step A: Compounds of formula (Ia) can be converted to compounds of formula (Ib) using a reducing agent such as NaBH4 in MeOH and a co-solvent such as THF, 1,4-dioxane, EtOH, MeOH, DCM at temperatures between about -40°C and RT.

[0081] Solution 2

[0082] In the following scenario, A 1 , R 2 , R 3 , R 4 and R 5 As defined above. A compound of formula (Ia) is a compound of formula (I) as described herein, wherein R 1 It is methylcarbonyl.

[0083]

[0084] Step A: Intermediate 1 can be converted to a compound of formula (Ia) via Buchwald-Hartwig coupling of intermediate 3 with an aminopyridazine reactant using a suitable base such as, for example, Cs2CO3, K2CO3 or K3PO4 and a suitable palladium catalyst such as, for example, t-BuXPhos-Pd-G3 or [tBuBrettPhos Pd(allyl)]OTf in a suitable solvent such as 1,4-dioxane, optionally with water as a co-solvent, at a temperature between about 80°C and about 100°C.

[0085] Solution 3

[0086] In the following scheme, R 2 As described in this article.

[0087]

[0088] Step A: Intermediates 2 and 3 can be reacted in the presence of a suitable base such as, for example, DBU, K2CO3 or Cs2CO3 in a suitable solvent such as, for example, 1,4-dioxane or DMSO at a temperature of about 80°C to give intermediate 1.

[0089] Solution 4

[0090] In the following scenario, A 1 , R 2 , R 3 , R 4 and R 5 As defined above. A compound of formula (Ia) is a compound of formula (I) as described herein, wherein R 1 It is methylcarbonyl.

[0091]

[0092] Step A: Intermediates 2 and 4 can be reacted in the presence of a suitable base such as, for example, DBU, K2CO3 or Cs2CO3 in a suitable solvent such as, for example, 1,4-dioxane, DMF, NMP, DMA or DMSO, optionally with water as a co-solvent, at a temperature between about 50°C and about 80°C to give compounds of formula (Ia).

[0093] Solution 5

[0094] In the following scheme, R 2 As described in this article.

[0095]

[0096] Step A: Intermediates 7 can be obtained by reacting anilines 5 and fluoro or chloro pyridines 6 in a solvent such as DMF, NMP or DMA in the presence of a deprotonating agent such as, for example, NaH at temperatures between about -10 °C and RT.

[0097] Step 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.

[0098] Step C: Intermediate 1 can be obtained by condensation of aniline intermediate 8 with trimethoxymethane, optionally in the presence of TsOH, in a solvent such as MeOH at a temperature between about 80°C and about 120°C.

[0099] Solution 6

[0100] In Scheme 6, the synthesis of intermediate 5a is described. The compound of formula 5a is a compound of formula 5, wherein R 2 is optionally substituted by a substituent R selected from carbonitrile, alkyl or haloalkyla or a substituent R selected from hydrogen, alkyl and haloalkyl b Substituted methyl-pyrazolyl.

[0101]

[0102] Step A: Intermediate 10a can be obtained by reacting building block 9a with a suitable pyrazole building block 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 at a temperature of about 80°C.

[0103] Step A': Intermediate 10b can be obtained by reacting starting material 9b with a suitable pyrazole borate in the presence of a suitable base such as K2CO3 and a suitable catalyst such as Pd(dppf)Cl2.CH2Cl2 in a solvent such as 1,4-dioxane, optionally with water as a co-solvent, at a temperature of about 80°C.

[0104] Step B: Intermediate 11 can be obtained by reacting intermediate 10 with (2,4-dimethoxybenzyl)amine in a suitable solvent such as for example 1,4-dioxane, THF, DMF, DMA, NMP or DMSO in the presence of a suitable base such as for example DIPEA at a temperature between RT and about 80°C.

[0105] Step C: Intermediate 5a can be obtained by deprotection of intermediate 11 with a strong acid such as for example TFA in a suitable solvent such as for example DCM at RT.

[0106] Therefore, the present invention also relates to a process for preparing a compound according to the invention, which process comprises one of the following steps:

[0107] (a) making a compound of formula (B1)

[0108]

[0109] reacting with a suitable reducing agent in the presence of a suitable solvent,

[0110] (b) making the compound of formula (B2)

[0111]

[0112] With the compound of formula (B3)

[0113]

[0114] In the presence of a suitable base, a suitable catalyst and a suitable solvent, or

[0115] (c) making the compound of formula (B4)

[0116]

[0117] With the compound of formula (B5)

[0118]

[0119] The reaction is carried out in the presence of a suitable base.

[0120] In the above method, X is halogen; A 1 , R 2 , R 3 , R 4 and R 5 As described in this article.

[0121] In the reaction of step (a), the reducing agent may be, for example, LiBH4 or NaBH4.

[0122] In the reaction of step (a), the solvent may be, for example, MeOH optionally with a suitable co-solvent. The co-solvent may be, for example, THF, dioxane, EtOH, dichloromethane or a mixture thereof.

[0123] Convenient conditions for step (a) are between about -60°C and about room temperature, especially between about -40°C and room temperature.

[0124] Conveniently, the conditions of step (a) are NaBH4 as reducing agent, MeOH as solvent with a suitable co-solvent and a reaction temperature between about -40°C and room temperature.

[0125] In the reaction of step (b), the base may be, for example, Cs2CO3, K2CO3 or K3PO4.

[0126] In the reaction of step (b), the catalyst may be, for example, a suitable Pd catalyst, in particular t-BuXPhos-Pd-G3 or [tBuBrettPhosPd(allyl)]OTf.

[0127] In the reaction of step (b), the solvent may be, for example, 1,4-dioxane, THF, DMA, DMF, NMP, toluene, xylene, water or a mixture thereof.

[0128] Convenient conditions for step (b) may be between about 60°C and 120°C, particularly between about 70°C and about 110°C, more particularly between about 80°C and about 100°C.

[0129] Conveniently, the conditions for step (b) are Cs2CO3 or K2CO3 as base, t-BuXPhos-Pd-G3 or [tBuBrettPhosPd(allyl)]OTf as catalyst and 1,4-dioxane as solvent at a reaction temperature between about 80°C and about 100°C.

[0130] In the reaction of step (c), the base may be, for example, DBU, K2CO3 or Cs2CO3.

[0131] In the reaction of step (c), the solvent may be, for example, 1,4-dioxane, DMF, NMP, DMA or DMSO.

[0132] Convenient conditions for step (c) may be between about 30°C and 120°C, particularly between about 40°C and about 100°C, more particularly between about 50°C and about 80°C.

[0133] Conveniently, the conditions for step (c) are Cs2CO3 or K2CO3 as base, t-BuXPhos-Pd-G3 or [tBuBrettPhosPd(allyl)]OTf as catalyst and 1,4-dioxane as solvent at a reaction temperature between about 80°C and about 100°C.

[0134] The present invention also relates to a compound according to the invention produced by a process according to the invention.

[0135] The present invention also particularly relates to:

[0136] A compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, for use as a therapeutically active substance;

[0137] A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, and a therapeutically inert carrier;

[0138] Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein for the treatment or prevention of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis, in particular inflammatory bowel disease (IBD);

[0139] Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein for preparing a medicament for the treatment or prevention of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis, in particular inflammatory bowel disease (IBD);

[0140] A compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, for use in the treatment or prevention of rheumatoid arthritis, juvenile rheumatoid arthritis, nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis, in particular inflammatory bowel disease (IBD); and

[0141] A method for treating or preventing rheumatoid arthritis, juvenile rheumatoid arthritis, nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis, comprising administering to a patient in need thereof an effective amount of a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof.

[0142] Pharmaceutical composition

[0143] Another embodiment of the present invention provides a pharmaceutical composition or medicine containing the compounds of this invention and a therapeutic inert carrier, diluent or excipient, and methods for preparing such compositions and medicines using the compounds of this invention. In one example, the compound of formula (I) can be formulated as a galenical administration form by mixing with a physiologically acceptable carrier (i.e., a carrier that is nontoxic to the recipient at the dosage and concentration used) at ambient temperature under appropriate pH and desired purity. The pH of the formulation depends primarily on the specific use and 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 another embodiment, 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.

[0144] The compositions are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the timing of administration, and other factors known to practitioners.

[0145] The compounds of the present invention can be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, epidural and intranasal, and if local treatment is required, intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.

[0146] The compounds of the present invention can be administered in any convenient administration form, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain conventional components in pharmaceutical preparations, for example, diluents, carriers, pH adjusters, sweeteners, fillers and other active agents.

[0147] The usual formulations are prepared by mixing the compounds of the invention and carriers or excipients. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, for example, Ansel, Howard C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams and Wilkins, 2004; Gennaro, Alfonso R. et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams and Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulation may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavoring agents, flavoring agents, diluents and other known additives to provide an aesthetically pleasing display of the drug (e.g., a compound of the invention or a pharmaceutical composition thereof) or to aid in the preparation of a pharmaceutical product (e.g., a drug).

[0148] The invention will now be illustrated by the following examples, which are not limiting.

[0149] Examples

[0150] Abbreviation [tBuBrettPhos Pd(allyl)]OTf Allyl(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)trifluoromethanesulfonate palladium(II) (CAS No. 1798782-15-6)

[0151] ATP Adenosine triphosphate

[0152] aq. water-based

[0153] BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl)

[0154] Boc tert-Butyloxycarbonyl

[0155] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0156] DIPEA N,N-Diisopropylethylamine

[0157] DMF N,N-Dimethylformamide

[0158] DMSO Dimethyl sulfoxide

[0159] dppf 1,1'-ferrocenyldiyl-bis(diphenylphosphine)

[0160] dtbpy 4,4'-di-tert-butyl-2,2'-bipyridine

[0161] equiv. Equivalent

[0162] ESI Electrospray ionization

[0163] Et Ethyl

[0164] EtOAc Ethyl acetate

[0165] EtOH

[0166] FA Formic acid

[0167] HPLC High Pressure Liquid Chromatography

[0168] LC-MS High Performance Liquid Chromatography

[0169] Me Methyl

[0170] MeOH Methanol

[0171] Ms Methanesulfonyl

[0172] NMR Nuclear Magnetic Resonance

[0173] PE Petroleum Ether

[0174] psi pounds per square inch

[0175] RT Room temperature

[0176] sat. saturated

[0177] SFC Supercritical Fluid Chromatography

[0178] sol. solution

[0179] TBD Triazabicyclodecene

[0180] TBDMS tert-Butyldimethylsilyl [tBuBrettPhos Pd(allyl)]OTf Allyl[(2-di-tert-butylphosphino-3,6-dimethoxy-2', 4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) trifluoromethanesulfonate (CAS No. 1798782-15-6)

[0181] t-BuXPhos-Pd-G3 [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]methanesulfonate palladium(II) (CAS No. 1447963-75-8)

[0182] TEA Triethylamine

[0183] Tf trifluoromethanesulfonyl

[0184] TFA Trifluoroacetic acid

[0185] TFAA Trifluoroacetic anhydride

[0186] THF Tetrahydrofuran

[0187] Example 1

[0188] 1-[3-Acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridinyl]-5-methyl-pyrazole-3-carbonitrile

[0189]

[0190] Step 1: 1-[3-Acetyl-6-(6-chloroimidazo[4,5-c]pyridin-3-yl)-2-pyridinyl]-5-methyl-pyrazole-3-carbonitrile

[0191]

[0192] Under 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 RT overnight. More 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 RT. It was distributed 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 eluent to obtain a mixture of two regioisomers (219 mg): the regioisomers were separated by SFC chromatography using 35% MeOH to obtain the title compound (39 mg, 16%) as a brown solid. LC-MS: m / z=378.1[M+H] + ,ESI pos.

[0193] Step 2: 1-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridinyl]-5-methyl-pyrazole-3-carbonitrile, formic acid

[0194]

[0195] In a sealed tube, 1-[3-acetyl-6-(6-chloroimidazo[4,5-c]pyridin-3-yl)-2-pyridinyl]-5-methyl-pyrazole-3-carbonitrile (41 mg, 0.11 mmol, 1 eq) was dissolved in 1,4-dioxane (4 mL). (6-Methylpyridazin-3-yl)amine (23.7 mg, 0.22 mmol, 2 eq), Cs2CO3 (70.7 mg, 0.22 mmol, 2 eq) and water (29.3 mg, 29.3 uL, 1.63 mmol, 15 eq) were added. The reaction mixture was flushed with argon and then t-BuXPhos-Pd-G3 (17.2 mg, 0.022 mmol, 0.2 eq) was added. The reaction mixture was stirred at 90 °C. After 2.5 hours, 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 hour. The reaction mixture was cooled to RT. A spatula of metal scavenger was added. Thiol. The reaction mixture was stirred at RT for 30 minutes and 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 eluent, and then by reverse phase chromatography using a 1% formic acid aqueous solution / acetonitrile gradient as eluent to give the title compound (4.5 mg, 8%) as a light yellow lyophilized powder. LC-MS: m / z=453.3 [M+H] + ,ESI pos.

[0196] Example 2

[0197] 1-[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridinyl]-5-methyl-pyrazole-3-carbonitrile

[0198]

[0199] Under argon atmosphere, 1-[3-acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridinyl]-5-methyl-pyrazole-3-carbonitrile (Example 1; 234 mg, 0.14 mmol, 1 eq) was dissolved in methanol (3.5 mL). NaBH4 (15.9 mg, 0.42 mmol, 3 eq) was added and the reaction mixture was stirred at RT 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 solution / acetonitrile gradient as eluent to give the title compound (15 mg, 23%) as a lyophilized powder. LC-MS: m / z=453.3[M+H]+ ,ESI pos.

[0200] Example 3

[0201] 1-[3-(1-hydroxyethyl)-6-[6-[(6-methyl-3-pyridinyl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridinyl]-5-methyl-pyrazole-3-carbonitrile

[0202]

[0203] Step 1: 1-(3-Acetyl-6-chloro-2-pyridinyl)-5-methyl-pyrazole-3-carbonitrile

[0204]

[0205] A solution of 1-(6-chloro-2-fluoro-3-pyridyl)ethanone (CAS#1260663-13-5; 5 g, 28.81 mmol, 1 eq.), 5-methyl-1H-pyrazole-3-carbonitrile (2.93 g, 27.4 mmol, 0.95 eq.) and DIPEA (14.3 mL, 86.42 mmol, 3 eq.) in DMSO (50 mL) was stirred at 80 ° C for 4 hours. The reaction mixture was cooled to RT, poured into H2O and extracted with EtOAc. The combined organic layers were washed with brine and concentrated. The crude product was purified by flash chromatography using a petroleum ether / EtOAc gradient as eluent to give the title compound (5.3 g, 71% yield) as a yellow oil. LC-MS: m / z=261.1[M+H] + ,ESI pos.

[0206] Step 2: 1-[3-Acetyl-6-[(2,4-dimethoxybenzyl)amino]-2-pyridinyl]-5-methyl-pyrazole-3-carbonitrile

[0207]

[0208] Under argon atmosphere, 1-(3-acetyl-6-chloro-2-pyridinyl)-5-methyl-pyrazole-3-carbonitrile (1.14 g, 4.37 mmol, 1 eq) was dissolved in DMSO (8.6 mL). DIPEA (1.9 mL, 10.9 mmol, 2.5 eq) and (2,4-dimethoxybenzyl)amine (803 mg, 723 uL, 4.8 mmol, 1.1 eq) were added. The reaction mixture was stirred overnight at RT. More (2,4-dimethoxybenzyl)amine (802.9 mg, 723 uL, 4.8 mmol, 1.1 eq) was added and the reaction mixture was stirred again overnight at RT. It was then partitioned between water and EtOAc. The organic layer was dried over MgSO4; then filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography using a heptane / ethyl acetate gradient as eluent to give the title compound as a yellow oil (1.85 g, quantitative). LC-MS: m / z=392.2 [M+H] + ,ESI pos.

[0209] Step 3: 1-(3-Acetyl-6-amino-2-pyridinyl)-5-methyl-pyrazole-3-carbonitrile

[0210]

[0211] Under argon atmosphere, 1-[3-acetyl-6-[(2,4-dimethoxybenzyl)amino]-2-pyridinyl]-5-methyl-pyrazole-3-carbonitrile (1.95 g, 4.73 mmol, 1 eq) was dissolved in DCM, extra dry (14.25 mL). TFA (10.25 g, 6.93 mL, 89.92 mmol, 19 eq) was added, and the reaction mixture was stirred at RT for 30 minutes, turning into a dark red solution. It was then neutralized with triethylamine and concentrated. The residue was triturated in MeOH overnight and then filtered. The filtrate was concentrated. The crude product was purified by reverse phase chromatography using NH3 to give the title compound (830 mg, 72%) as a light brown powder. LC-MS: m / z=242.1[M+H] + ,ESI pos.

[0212] Step 4: 2-Bromo-5-fluoro-1-oxido-pyridin-1-ium

[0213]

[0214] Under argon atmosphere, 2-bromo-5-fluoro-pyridine (CAS 41404-58-4; 4.12 g, 22.9 mmol, 1 eq) was dissolved in DCM (41.2 mL). At 0 ° C, TFAA (14.5 g, 9.7 mL, 68.8 mmol, 3 eq) was added, followed by dropwise addition of H2O2 (2.68 g, 2.4 mL, 27.5 mmol, 1.2 eq) over 30 minutes: very exothermic! The reaction mixture was stirred overnight at RT and then carefully poured into ice-cold water. The aqueous layer was extracted several times with DCM. The combined organic layers were dried over MgSO4 and concentrated in vacuo at RT. The compound began to solidify under heat formation and was therefore cooled in an ice bath for 30 minutes. The crude product was used in the next step without any further purification. Dynamic DSC scanning (30-500°C, 10°C / min): onset temperature of exothermic decomposition 110°C, enthalpy: 490 J / g.

[0215] Step 5: 2-Bromo-5-fluoro-4-nitro-pyridine

[0216]

[0217] Under argon atmosphere, 2-bromo-5-fluoro-1-oxidation-pyridin-1-ium (4.4 g, 18.33 mmol, 1 eq) was dissolved in concentrated H2SO4 (28.2 g, 15.3 mL, 287 mmol, 15.6 eq) to give a pink solution. At 0°C, fuming HNO3 (10.8 g, 7.65 mL, 171.2 mmol, 9.3 eq) was slowly added (exothermic: <10°C) to produce a light yellow solution. The reaction mixture was heated to 120°C for 12 hours. The nitrogen oxide fumes produced were captured in a cooled aqueous NaOH solution.

[0218] After cooling to RT, 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 eluent and by a second silica gel chromatography using a DCM / MeOH gradient as eluent to obtain the title compound (1.33 g, 33%) as a yellow oil.

[0219] Dynamic DSC scanning (30-400°C, 10°C / min): Tm = 148°C: Onset temperature of exothermic decomposition: about 173°C, enthalpy: 1594 J / g. High energy destruction!

[0220] Step 6: 1-[3-Acetyl-6-[(6-bromo-4-nitro-3-pyridinyl)amino]-2-pyridinyl]-5-methyl-pyrazole-3-carbonitrile

[0221]

[0222] Under argon atmosphere, 1-(3-acetyl-6-amino-2-pyridinyl)-5-methyl-pyrazole-3-carbonitrile (650 mg, 2.7 mmol, 1 eq) was dissolved in DMF, extra dry (10.8 mL). At -10°C, NaH (168.1 mg, 3.5 mmol, 1.3 eq) was added (gas evolution) followed by a solution containing 2-bromo-5-fluoro-4-nitro-pyridine (654.9 mg, 2.96 mmol, 1.1 eq) in DMF, extra dry (5.4 mL). The reaction mixture turned black and was stirred at -10°C for 30 minutes. A second portion of 2-bromo-5-fluoro-4-nitro-pyridine (178.6 mg, 0.81 mmol, 0.3 eq) was added and the reaction mixture was stirred at -10°C for 15 minutes. It was then partitioned between NH4Cl solution and EtOAc. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography using a DCM / MeOH gradient as eluent to give the title compound (520 mg, 43%) as an orange gum. LC-MS: m / z=442.1 [M+H] + ,ESI pos.

[0223] Step 7: 1-[3-Acetyl-6-[(4-amino-6-bromo-3-pyridinyl)amino]-2-pyridinyl]-5-methyl-pyrazole-3-carbonitrile

[0224]

[0225] Under an argon atmosphere and in a flask equipped with a mechanical stirrer, 1-[3-acetyl-6-[(6-bromo-4-nitro-3-pyridinyl)amino]-2-pyridinyl]-5-methyl-pyrazole-3-carbonitrile (0.92 g, 2.1 mmol, 1 eq) was suspended in ethanol (15.3 mL). Activated zinc (1.36 g, 20.8 mmol, 10 eq) was added, and the orange suspension was cooled to 0 ° C. A solution containing acetic acid (874 mg, 834 uL, 14.6 mmol, 7 eq) in ethanol (7.7 mL) was added dropwise while keeping the temperature below 5 ° C. The reaction mixture turned black and stirred at 0 ° C for 30 minutes, then stirred at RT for 1 hour. The reaction mixture was filtered and the filter cake was washed with EtOAc. The filtrate was concentrated to give a crude product, which was used in the next step without further purification. LC-MS: m / z=413.1[M+H]+, ESI pos

[0226] Step 8: 1-[3-Acetyl-6-(6-bromoimidazo[4,5-c]pyridin-3-yl)-2-pyridinyl]-5-methyl-pyrazole-3-carbonitrile

[0227]

[0228] Under an argon atmosphere, 1-[3-acetyl-6-[(4-amino-6-bromo-3-pyridinyl)amino]-2-pyridinyl]-5-methyl-pyrazole-3-carbonitrile (0.86 g, 2.1 mmol, 1 equiv) was dissolved in trimethoxymethane (14.47 g, 14.9 mL, 136.4 mmol, 65.5 equiv). The reaction mixture was stirred at 90 ° C for 4 hours. The volatiles were evaporated. The crude product was purified by silica gel chromatography using a DCM / MeOH gradient as eluent and a second silica gel chromatography using a heptane / ethyl acetate gradient as eluent to give the title compound (113 mg, 13%) as a red solid. LC-MS: m / z=424.1[M+H] + ,ESIpos.

[0229] Step 9: 1-[3-Acetyl-6-[6-[(6-methyl-3-pyridinyl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridinyl]-5-methyl-pyrazole-3-carbonitrile

[0230]

[0231] Analogously to the procedure described in Example 1, Step 2, using (6-methyl-3-pyridinyl)amine as the amine component, the title compound was obtained as a yellow oil. LC-MS: m / z=450.3 [M+H] + ,ESI pos.

[0232] Step 10: 1-[3-(1-hydroxyethyl)-6-[6-[(6-methyl-3-pyridinyl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridinyl]-5-methyl-pyrazole-3-carbonitrile, formic acid

[0233]

[0234] Under an argon atmosphere, 1-[3-acetyl-6-[6-[(6-methyl-3-pyridinyl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridinyl]-5-methyl-pyrazole-3-carbonitrile (3 mg, 0.007 mmol, 1 eq) was dissolved in MeOH (0.165 mL). NaBH4 (757 ug, 0.020 mmol, 3 eq) was added. The reaction mixture was stirred at RT for 30 minutes and then quenched by adding water. The reaction mixture was purified by reverse phase chromatography using 0.1% aqueous formic acid / acetonitrile as eluent to give the title compound (1 mg, 29%) as a white lyophilized powder. LC-MS: m / z=496.4[MH] - ,ESI neg.

[0235] Example 4

[0236] 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-pyridinyl]ethanol

[0237]

[0238] Step 1: 4-Bromo-3-methyl-1-(2,2,2-trifluoroethyl)pyrazole

[0239]

[0240] A mixture of 4-bromo-3-methylpyrazole (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) in DMF (150 mL) was stirred at 100 ° C for 12 hours. 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 NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography to give a 2:1 mixture of the title compound and its positional isomer 4-bromo-3-methyl-1-(2,2,2-trifluoroethyl)pyrazole as an off-white oil (19.5 g, 80.2 mmol, 86%) LC-MS: m / z = 242.9 [M+H] + ,ESI pos.

[0241] 1H NMR (400MHz, DMSO-d6) δ = 8.00 (s, 1H), 5.09-4.99 (m, 2H), 2.14 (s, 3H).

[0242] Step 2: 3-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)pyrazole

[0243]

[0244] To a mixture of bis(pinacolato)diboron (17.24 g, 67.9 mmol, 1.5 eq) 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 eq) in 1,4-dioxane (200 mL) was added Pd(dppf)Cl2.CH2Cl2 (3.7 g, 4.53 mmol, 0.1 eq) and potassium acetate (5.66 mL, 90.53 mmol, 2.0 eq). The reaction mixture was stirred at 100° C. for 16 h under nitrogen atmosphere and then concentrated. The crude product was purified by flash chromatography on silica gel using a petroleum ether / ethyl acetate gradient as eluent (0%-20%) and by a second chromatography on preparative HPLC using a hexane / ethyl acetate gradient as eluent to afford the first batch of the title compound as an off-white oil (3:1 mixture of isomers; 6.0 g, 20.7 mmol, 33% yield) and the second batch of the title compound as a yellow oil (2:1 mixture of isomers; 2.0 g, 6.9 mmol, 11%). LC-MS: m / z=291.1 [M+H] + ,ESI pos.

[0245] Step 3: 1-[6-Chloro-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridinyl]ethanone

[0246]

[0247] A mixture of 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-pyrazole (1.0 g, 3.45 mmol, 1.0 eq), 1-(2-bromo-6-chloro-3-pyridyl)ethanone (808 mg, 3.45 mmol, 1.0 eq), potassium carbonate (953 mg, 6.89 mmol, 2.0 eq) and Pd(dppf)Cl2.CH2Cl2 (281 mg, 0.34 mmol, 0.1 eq) in 1,4-dioxane (20 mL) and water (2 mL) was stirred at 80° C. for 12 hours under a nitrogen atmosphere. The reaction mixture was concentrated. The crude product was purified by silica gel column chromatography using a petroleum ether / ethyl acetate gradient as eluent to give the title compound (790.0 mg, 2.29 mmol, 72% yield) as a yellow oil. LC-MS: m / z=318.1, [M+H] + ,ESI pos.

[0248] Step 4a: N-(6-methylpyridazin-3-yl)-3-(2-trimethylsilylethoxymethyl)imidazo[4,5-c]pyridin-6-amine

[0249]

[0250] 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 to a solution of 6-chloro-3H-imidazo[4,5-c]pyridine (880.0 mg, 5.73 mmol, 1.0 equiv) in DMF (10 mL). The mixture was stirred at 20 ° C for 2 hours. Then, water was added and extracted with ethyl acetate. The combined organics were washed with NaCl solution and then concentrated under reduced pressure to obtain a residue. The crude product was purified by silica gel column chromatography using a petroleum ether / ethyl acetate gradient as eluent to obtain the title compound (1.1 g, 54%) as a yellow oil. LC-MS: m / z=284.0, [M+H] + ,ESI pos.

[0251] Step 5: N-(6-methylpyridazin-3-yl)-3-(2-trimethylsilylethoxymethyl)imidazo[4,5-c]pyridin-6-amine

[0252]

[0253] A mixture of 2-[(6-chloroimidazo[4,5-c]pyridin-3-yl)methoxy]ethyl-trimethyl-silane (900.0 mg, 3.17 mmol, 1.0 equiv), 3-amino-6-methylpyridazine (1.04 g, 9.51 mmol, 3.0 equiv), Cs2CO3 (2.06 g, 6.3 mmol, 2.0 equiv) and allyl(trifluoromethylsulfonyloxy)palladium di-tert-butyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphine (248 mg, 0.32 mmol, 0.1 equiv) in 1,4-dioxane (30 mL) was stirred at 100° C. under a nitrogen atmosphere for 12 hours. The mixture was filtered and concentrated. The crude product was purified by reverse phase flash chromatography using an acetonitrile / 0.1% aqueous formic acid gradient as eluent to give the title compound (670.0 mg, 1.88 mmol, 59% yield) as a yellow solid. LC-MS: m / z=357.0, [M+H] + ,ESI pos.

[0254] Step 5: N-(6-methylpyridazin-3-yl)-3H-imidazo[4,5-c]pyridin-6-amine

[0255]

[0256] A solution of N-(6-methylpyridazin-3-yl)-3-(2-trimethylsilylethoxymethyl)imidazo[4,5-c]pyridin-6-amine (670 mg, 1.88 mmol, 1.0 equiv) in TFA (7.0 mL) was stirred at 25 ° C for 2 hours. The mixture was concentrated. The crude product was purified by reverse phase flash chromatography using an acetonitrile / 0.1% aqueous formic acid gradient as eluent to give the title compound (580 mg, 2.56 mmol, 95% yield) as a yellow solid. LC-MS: m / z=227.2, [M+H] + ,ESIpos.

[0257] 1 H NMR (400MHz, DMSO-d6) δ = 11.59-11.31 (m, 1H), 8.89 (s, 1H), 8.55 (s, 1H), 7.84-7.74 (m, 3H), 2.57 (s, 3H).

[0258] Step 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-pyridinyl]ethanone

[0259]

[0260] To a solution of N-(6-methylpyridazine-3-yl)-3H-imidazo[4,5-c]pyridin-6-amine (200.0 mg, 0.62 mmol, 1.0 equiv) in DMSO (5 mL) was added 1-[6-chloro-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanone (197 mg, 0.62 mmol, 1.0 eq) and potassium carbonate (171 mg, 1.24 mmol, 2.0 eq). The mixture was stirred at 70 ° C for 12 hours, then quenched with water and filtered. The filtrate was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase flash chromatography using an acetonitrile / 0.1% aqueous formic acid gradient to give 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-pyridinyl]ethanone, 1-[6-[6-[(6-methyl-pyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridinyl]ethanone as yellow solids. A mixture of 1-[6-[6-[(6-methyl-pyridazin-3-yl)amino]imidazo[4,5-c]pyridin-1-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridinyl]ethanone and 1-[6-[6-[(6-methyl-pyridazin-3-yl)amino]imidazo[4,5-c]pyridin-1-yl]-2-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridinyl]ethanone (150.0 mg, 0.3 mmol, 48% yield). LC-MS: m / z=508.1, [M+H] + ,ESI pos.

[0261] The mixture of 4 isomers was purified by SFC (0.1% NH3H2O ​​in isopropanol) to give two mixtures of each of two isomers.

[0262] 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).

[0263] 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).

[0264] LC-MS: m / z = 508.3 [M+H] + ,ESI pos.

[0265] 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-pyridinyl]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-pyridinyl]ethanone (70.0 mg) was purified by SFC (0.1% 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) was isolated from NH3H2O ​​in isopropanol to give a yellow solid. LC-MS: m / z=508.2, [M+H] + ,ESI pos.

[0266] 1 H NMR (400MHz, DMSO-d6) δ=9.94(s,1H),9.32(d,J=0.8Hz,1H),9.29(s,1H),8.36(d,J=0.6Hz,1H),8.29(d,J=8.6Hz ,1H),8.09(s,1H),8.07(d,J=8.6Hz,1H),7.72(d,J=9.1Hz,1H),7.40(d,J=9.1Hz,1H),5.21-5.10(m,2H),2.51(br s,3H),2.36(s,3H),2.30(s,3H)

[0267] and

[0268] 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-pyridinyl]ethanone (12 mg) as a white solid. LC-MS: m / z=508.2, [M+H] + ,ESI pos.

[0269] 1 H NMR (400MHz, DMSO-d6) δ = 10.04 (s, 1H), 9.01 (s, 1H), 8.81 (s, 1H), 8.77 (s, 1H), 8.35 (d, J = 8.5Hz, 1H), 7.9 5(d,J=8.5Hz,1H),7.90(s,1H),7.74(d,J=9.1Hz,1H),7.41(d,J=9.1Hz,1H),5.26-5.14(m,2H),2.52(br s,3H),2.41(s,3H),2.41(s,3H)

[0270] 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-pyridinyl]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-pyridinyl]ethanone (50 mg) was purified by SFC (0.1% NH3H2O ​​in isopropanol) to give

[0271] 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-pyridinyl]ethanone (35 mg) as a white solid. LC-MS: m / z=508.2, [M+H] + ,ESI pos.

[0272] 1H NMR (400MHz, 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 = 8.4Hz, 1H), 7.97 (d,J=8.5Hz,1H),7.63(d,J=9.1Hz,1H),7.45(d,J=9.1Hz,1H),5.24-5.13(m,2H),2.54(s,3H),2.44(s,3H),2.14(s,3H)

[0273] and

[0274] 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-pyridinyl]ethanone (18 mg) as a yellow solid. LC-MS: m / z=508.2, [M+H] + ,ESI pos.

[0275] 1 H NMR (400MHz, DMSO-d6) δ = 9.94 (s, 1H), 9.33 (s, 1H), 9.31 (s, 1H), 8.38 (s, 1H), 8.34 (d, J = 8.5Hz, 1H), 8.07 (d, J = 8.6Hz, 1H), 7.75(s,1H),7.70(d,J=9.1Hz,1H),7.40(d,J=9.1Hz,1H),5.28-5.18(m,2H),2.53-2.51(m,3H),2.41(s,3H),2.40(s,3H).

[0276] 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-pyridinyl]ethanol, formic acid

[0277]

[0278] To a solution 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-pyridinyl]ethanone (23.0 mg, 0.05 mmol, 1.0 equiv) in methanol (2 mL) was added NaBH4 (8.57 mg, 0.23 mmol, 5.0 equiv) at -70 ° C. The mixture was stirred at -70 ° C for 0.5 hours. The reaction mixture was quenched at 20 ° C by adding NH4Cl aqueous solution. The crude product was purified by reverse phase HPLC using 0.1% formic acid aqueous solution / acetonitrile as eluent to give the title compound (11.0 mg, 0.02 mmol, 46% yield) as a yellow solid. LC-MS: m / z=510.3, [M+H] + ,ESI pos.

[0279] 1 H NMR (400MHz, MeOH-d4) δ=9.32(s,1H),9.07(s,1H),8.29(d,J=8.5Hz,1H),8.25(s,1H),8.13(s,1H),8.02(s,1H),7.89(d,J= 8.5Hz,1H),7.75(d,J=9.3Hz,1H),7.47(d,J=9.1Hz,1H),5.04-4.95(m,3H),2.56(s,3H),2.35(s,3H),1.46(d,J=6.4Hz,3H).

[0280] Example 5

[0281] 1-[3-Acetyl-6-[6-[methyl-(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridinyl]-5-methyl-pyrazole-3-carbonitrile

[0282]

[0283] Step 1: 1-[3-acetyl-6-(6-chloroimidazo[4,5-c]pyridin-3-yl)-2-pyridinyl]-5-methyl-pyrazole-3-carbonitrile (corresponding to Example 1, Step 1)

[0284]

[0285] A solution of 6-chloro-3H-imidazo[4,5-c]pyridine (520 mg, 3.381 mmol, 1.0 eq.), 1-(3-acetyl-6-chloro-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile (971 mg, 3.7 mmol, 1.1 eq.) in dimethyl sulfoxide (15.6 mL) was stirred with 1,8-diazabicyclo[5.4.0]undec-7-ene (567 mg, 561 uL, 3.72 mmol, 1.1 eq.) at 80° C. for 3 hours. 1,8-diazabicyclo[5.4.0]undec-7-ene (567 mg, 561 uL, 3.72 mmol, 1.1 eq.) was added again and stirring was continued at 80° C. for 6 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography using a DCM / MeOH gradient as eluent to give the title compound (456 mg, 36%) as a light brown solid.

[0286] Step 2: 1-[3-Acetyl-6-[6-[methyl-(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridinyl]-5-methyl-pyrazole-3-carbonitrile

[0287]

[0288] A suspension of 1-[3-acetyl-6-(6-chloroimidazo[4,5-c]pyridin-3-yl)-2-pyridinyl]-5-methyl-pyrazole-3-carbonitrile (125 mg, 0.288 mmol, 1.0 eq), methyl-(6-methylpyridazin-3-yl)amine (CAS 18591-82-7; 73.4 mg, 0.595 mmol, 2.0 eq) and Cs2CO3 (485.1 mg, 1.488 mmol, 5.0 eq) in 1,4-dioxane (8.2 mL) was flushed with argon for 5 minutes at RT. Then [tBuBrettPhos Pd(allyl)]OTf (23.3 mg, 0.03 mmol, 0.10 eq) was added. The vial was sealed. The reaction mixture was heated to 80° C. for 2 hours. [tBuBrettPhos Pd(allyl)]OTf (23.26 mg, 0.03 mmol, 0.10 equiv) was added again and stirring was continued at 80 °C for 2 hours. The reaction mixture was then concentrated. The crude product was purified by silica gel chromatography using a DCM / MeOH gradient and a second silica gel chromatography using an EtOAc / MeOH gradient as eluent to give the title compound (33 mg, 30%) as a white solid. LC-MS: m / z=242.1 [M+H] + ,ESI pos.

[0289] Example 6

[0290] 1-[3-Acetyl-6-[6-(3-methyl-6,7-dihydropyridazin[4,3-b][1,4]oxazin-8-yl)imidazo[4,5-c]pyridin-3-yl]-2-pyridinyl]-5-methyl-pyrazole-3-carbonitrile

[0291]

[0292] Step 1: 3,6-Dichloro-4-(2-iodoethoxy)pyridazine

[0293]

[0294] 2-iodoethanol (4.43 g, 25.8 mmol, 1.05 equiv) was added to a solution of 3,4,6-trichloropyridazine (4.5 g, 24.5 mmol, 1 equiv) in THF (100 mL) at 0 ° C under a nitrogen atmosphere. The reaction mixture was stirred at 0 ° C for 30 minutes. Then, NaH (1.18 g, 29.44 mmol, 1.2 equiv) was added at 0 ° C. The reaction mixture was stirred at 50 ° C for 16 hours, then dissolved in a saturated NH4Cl aqueous solution and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography using a petroleum ether / ethyl acetate gradient as an eluent to obtain the title compound (3 g, 9.41 mmol, 38% yield) as a light yellow solid. LC-MS: m / z=318.9[M+H] + ,ESI pos.

[0295] Step 2: 2-(3,6-dichloropyridazin-4-yl)oxy-N-[(2,4-dimethoxyphenyl)methyl]ethylamine

[0296]

[0297] To a solution of 3,6-dichloro-4-(2-iodoethoxy)pyridazine (3.0 g, 9.41 mmol, 1 eq.) and 2,4-dimethoxybenzylamine (1.7 mL, 11.3 mmol, 1.2 eq.) in DMSO (30 mL) was added DIPEA (3.65 g, 28.2 mmol, 3 eq.). The mixture was stirred at 50 ° C for 12 hours, then poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel chromatography using a petroleum ether / ethyl acetate gradient as an eluent to give the title compound (1.25 g, 3.5 mmol, 37% yield) as a yellow solid. LC-MS: m / z=358.2[M+H] +,ESI pos.

[0298] Step 3: 3-Chloro-8-[(2,4-dimethoxyphenyl)methyl]-6,7-dihydropyridazino[4,3-b][1,4]oxazine

[0299]

[0300] To a solution of Cs2CO3 (2.55 g, 7.82 mmol, 2 eq.) and 2-(3,6-dichloropyridazin-4-yl)oxy-N-[(2,4-dimethoxyphenyl)methyl]ethylamine (1.4 g, 3.91 mmol, 1 eq.) in toluene (40 mL) was added BINAP (340.7 mg, 0.55 mmol, 0.14 eq.). The mixture was stirred at 110 °C for 2 hours, 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 (900 mg, 2.8 mmol, 72% yield) as a yellow solid was purified by silica gel column chromatography using a petroleum ether / ethyl acetate gradient. LC-MS: m / z=322.1[M+H] + ,ESI pos.

[0301] 1 H NMR (400MHz, CDCl3-d) δ = 7.03 (d, J = 8.3Hz, 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).

[0302] Step 4: 8-[(2,4-dimethoxyphenyl)methyl]-3-methyl-6,7-dihydropyridazino[4,3-b][1,4]oxazine

[0303]

[0304] To a solution of trimethylcyclotriboroxane (971.4 mg, 3.87 mmol, 1.5 eq) and 3-chloro-8-[(2,4-dimethoxyphenyl)methyl]-6,7-dihydropyridazine[4,3-b][1,4]oxazine (830.0 mg, 2.58 mmol, 1 eq) in 1,4-dioxane (15 mL) was added Pd(dppf)Cl2 (189 mg, 0.26 mmol, 0.1 eq) and K2CO3 (713 mg, 5.16 mmol, 2 eq) under 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 the 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 0.1% aqueous formic acid / acetonitrile gradient as eluent. The fractions containing the product were lyophilized to give the title compound as a yellow gum (600 mg, 1.99 mmol, 77% yield). LC-MS: m / z = 302.1 [M+H] + ,ESI pos.

[0305] Step 5: 3-Methyl-7,8-dihydro-6H-pyridazino[4,3-b][1,4]oxazine

[0306]

[0307] A solution of 3-chloro-8-[(2,4-dimethoxyphenyl)methyl]-6,7-dihydropyridazine[4,3-b][1,4]oxazine (550.0 mg, 1.71 mmol, 1 eq.) in TFA (5.0 mL, 67.3 mmol, 39.5 eq.) was stirred at 25 °C for 4 hours. The mixture was diluted with DCM and then basified by adding ammonia water to a pH of 8-9. The mixture was then extracted with water. The aqueous layer was concentrated in vacuo. The residue was purified by preparative HPLC using a 10 mM NH4CO3 aqueous solution / acetonitrile gradient as eluent. The fractions containing the product were lyophilized to give the title compound (88.8 mg, 0.59 mmol, 34% yield) as a white solid. LC-MS: m / z=152.0[M+H] + ,ESI pos.

[0308] 1 H NMR (400MHz, MeOH-d4) δ = 6.54 (s, 1H), 4.41-4.34 (m, 2H), 3.50-3.42 (m, 2H), 2.36 (s, 3H).

[0309] 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-pyridinyl]-5-methyl-pyrazole-3-carbonitrile

[0310]

[0311] A suspension of 1-[3-acetyl-6-(6-chloroimidazo[4,5-c]pyridin-3-yl)-2-pyridinyl]-5-methyl-pyrazole-3-carbonitrile (Example 1, Step 1; 100 mg, 0.24 mmol, 1.0 equiv), 3-methyl-7,8-dihydro-6H-pyridazino[4,3-b][1,4]oxazine (36.0 mg, 0.24 mmol, 1.0 equiv) and cesium carbonate (388.1 mg, 1.19 mmol, 5.0 equiv) in 1,4-dioxane (6.56 mL) was flushed with argon for 5 minutes at RT. [tBuBrettPhos Pd(allyl)]OTf (18.6 mg, 0.024 mmol, 0.10 equiv) was then added. The reaction vial was sealed and the mixture was heated to 80° C. for 2 hours. [tBuBrettPhos Pd (allyl)] OTf (18.61 mg, 0.024 mmol, 0.10 eq) was added again and heating to 80 ° C was continued for 2 hours. The reaction mixture was cooled to RT, flushed with argon again and treated with [tBuBrettPhos Pd (allyl)] OTf (18.61 mg, 0.024 mmol, 0.10 eq) and stirred at 80 ° C for 1 hour. The reaction mixture was concentrated. The crude product was purified by silica gel chromatography using a dichloromethane / MeOH gradient as eluent. The fractions containing the product were concentrated. The residue was ground with diethyl ether. The solid was filtered and dried to give the title compound (23 mg, 18%) as a light brown solid. LC-MS: m / z=493.2[M+H] + ,ESI pos.

[0312] Example 7

[0313] 1-[2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-3-pyridinyl]ethanol

[0314]

[0315] Step 1: 1-[6-Chloro-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-3-pyridinyl]ethanone

[0316]

[0317] A mixture of 1-(6-chloro-2-fluoro-3-pyridyl)ethanone (1.0 g, 5.76 mmol, 1.0 equiv), 3-(difluoromethyl)-5-methyl-1H-pyrazole (761.13 mg, 5.76 mmol, 1.0 equiv) and DIPEA (2.22 g, 17.3 mmol, 3.0 equiv) in DMSO (10 mL) was stirred at 100 ° C for 12 hours. The crude product was purified by reverse phase chromatography using an acetonitrile / 0.1% aqueous formic acid gradient as eluent and lyophilized to give the title compound (800 mg, 2.8 mmol, 49% yield) as a gray solid. LC-MS: m / z=286.1, [M+H] + ,ESI pos.

[0318] 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-pyridinyl]ethanone

[0319]

[0320] To a solution of N-(6-methylpyridazin-3-yl)-3H-imidazo[4,5-c]pyridin-6-amine (Example 4, Step 6; 230.0 mg, 0.71 mmol, 1.0 equiv) in DMSO (5 mL) was added 1-[6-chloro-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-3-pyridyl]ethanone (Example 1, Step 1; 203.3 mg, 0.71 mmol, 1.0 equiv) and K2CO3 (196.7 mg, 1.42 mmol, 2.0 equiv). The mixture was stirred at 70°C for 12 hours, then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified twice by silica gel chromatography using a hexane / ethyl acetate gradient as eluent to give a mixture of positional isomers 1-[2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-3-pyridinyl]ethanone and 1-[2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-1-yl]-3-pyridinyl]ethanone as a yellow solid (30.0 mg, 0.06 mmol, 9% yield). LC-MS: m / z=476.2, [M+H] + ,ESI pos.

[0321] The mixture was separated by SFC using acetonitrile / MeOH+0.1% NH3 as eluent to give the title compound 1-[2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-3-pyridinyl]ethanone (10 mg, 32% yield) as a yellow solid. LC / MS: m / z=476.1, [M+H] + ,ESI pos.

[0322] 1 H NMR (400MHz, DMSO-d6) δ = 9.99 (s, 1H), 9.33 (s, 1H), 9.22 (d, J = 0.7Hz, 1H), 8.44 (d, J = 8.4Hz, 1H), 8.34 (s, 1H), 8.29 ( d,J=8.4Hz,1H),7.76(d,J=9.3Hz,1H),7.41(d,J=9.2Hz,1H),7.22-6.90(m,1H),6.76(s,1H),2.59(s,3H),2.54(br s,3H),2.03(s,3H).

[0323] In addition, the positional isomer 1-[2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-1-yl]-3-pyridyl]ethanone (2 mg, 0.02 mmol, 7% yield) was obtained as a yellow solid. LC-MS: m / z=476.1, [M+H] + ,ESI pos.

[0324] 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-pyridinyl]ethanol

[0325]

[0326] To a solution of 1-[2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-3-pyridinyl]ethanone (8.0 mg, 0.02 mmol, 1.0 equiv) in MeOH (2 mL) was added a solution of NaBH4 (3.18 mg, 0.08 mmol, 5.0 equiv) in MeOH (0.5 mL) at -70°C. The mixture was stirred at -70°C for 0.5 h. The reaction mixture was quenched by the addition of aqueous ammonium chloride at 20°C.

[0327] The crude product was purified by reverse phase chromatography using an acetonitrile / 0.1% aqueous formic acid gradient as eluent to give the title compound (1.2 mg, 14% yield) as a lyophilized white solid. LC-MS: m / z=478.2, [M+H] + ,ESI pos.

[0328] 1 H NMR (400MHz, MeOH-d4) δ = 9.43 (s, 1H), 9.27 (s, 1H), 8.52 (d, J = 8.5Hz, 1H), 8.20 (d, J = 8.5Hz, 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=6.4Hz,3H).

[0329] Example 8 - Phosphorylation Assay SIK1-3:

[0330] In the presence of SIK2 (SIK1 or SIK3, respectively) and ATP, the CHK peptide (KKKVSRSGLYRSPSMPENLNRPR with a C-terminal arginine amide modification) is phosphorylated at one of the four available serines. Only one phosphorylation was observed under the assay conditions. 60nl of each compound dilution series (12 points; dilution factor 3, typically 30μM to 170pM) in DMSO was transferred to the assay plate by acoustic dispensing and pre-incubated for 30 minutes (ambient temperature) after adding 5μl SIK1 (5nM), 5μl SIK2 (0.5nM) or 7μl SIK3 (1.5nM) in assay buffer (12.5mM HEPES (pH 7.0), 10mM magnesium acetate, 0.005% BSA), respectively. 10 μM CHK-peptide solution and 5 μl 100 μM ATP were added to SIK1 and SIK2, respectively, and 3 μl was added to SIK3 in the assay buffer, and incubated in the environment for 45 minutes. 40 μl 0.125% formic acid aqueous solution was added to quench the reaction. Data were generated using RapidFire (RF) mass spectrometry as described below. Multiple charged species (3-5 charges) of phosphorylated and non-phosphorylated forms measured by MRM (multiple reaction monitoring; API5000 or 6500+) or EIC (extracted ion current; QToF) were added and the ratio (total sum of phosphorylated species / total sum of all species) was calculated for data evaluation. A commercially available SIK inhibitor (CAS No. 1936529-65-5) based on non-inhibitory control DMSO and 1 μM YKL-05-099 was normalized by Genedata software. The results of the assay are expressed as half-maximal inhibitory concentration (IC50) and are summarized in Table 1 below.

[0331] RapidFire Settings:

[0332] The sample was vacuum-pumped for a maximum of 600 ms and loaded into a C4 cartridge (Agilent; No. G9203A) and treated with 0.1% formic acid in water for 3000 ms at 1.5 ml / min. The sample was then transferred to an API5000 (API6500+) or QToF mass spectrometer and treated with 90% acetonitrile; 10% water; 0.007% TFA; 0.093 formic acid for 4000 ms at 1.25 ml / min. The cartridge was treated with 0.1% formic acid in water for an additional 500 ms.

[0333] MS Settings Sciex API5000 / API6500+:

[0334] All MS analyses were performed in MRM mode using the following MS settings: electrospray positive ion; ion spray voltage: 4000 V; temperature: 550 °C; collision gas: 5; curtain gas: 15; gas 1: 40; gas 2: 42; EP: 10. DP = declustering potential; CE = collision energy; CXP = collision cell exit voltage.

[0335] name Q1(m / z) Q3(m / z) Time (ms) DP(V) CE(V) CXP(V) CHK(4+) 676.0 84.2 50 46 99 18 CHK(5+) 541.0 84.2 50 51 71 36 pCHK(4+) 696.0 84.2 50 66 105 18 pCHK(5+) 557.0 84.2 50 51 53 4

[0336] MS Setup Agilent QToF6545

[0337] All MS analyses were performed in MS mode using the following MS settings: Dual AJS electrospray positive ionization; VCap: 3000 V; Drying and sheath gas: 340 °C, 8 l / min; Nebulizer: 60 psig; Nozzle voltage: 2000 V; Fragmentor: 130 V; Skimmer: 35 V; Oct1 RF Vpp: 700 V; Reference mass at 5 spectra / s

[0338] name EIC(m / z) width CHK(3+) 900.8345 50ppm CHK(4+) 675.8789 50ppm CHK(5+) 540.9048 50ppm pCHK(3+) 927.4961 50ppm pCHK(4+) 695.8747 50ppm

[0339] Table 1: IC50 values ​​for inhibition of SIK1, SIK2 and SIK3:

[0340]

[0341]

[0342] Example A

[0343] Film-coated tablets containing the following ingredients can be manufactured in a conventional manner:

[0344] <![CDATA[ Element ]]> <![CDATA[ Each tablet ]]> Kernel: The compound of formula (I) or a pharmaceutically acceptable salt thereof 10.0mg 200.0mg Microcrystalline Cellulose 23.5mg 43.5mg Lactose Hydrous 60.0mg 70.0mg Povidone K30 12.5mg 15.0mg Sodium starch glycolate 12.5mg 17.0mg Magnesium Stearate 1.5mg 4.5mg (Core Weight) 120.0mg 350.0mg Film coating: Hydroxypropyl methylcellulose 3.5mg 7.0mg Polyethylene glycol 6000 0.8mg 1.6mg talc 1.3mg 2.6mg Iron oxide (yellow) 0.8mg 1.6mg Titanium Dioxide 0.8mg 1.6mg

[0345] The active ingredient is sieved and mixed with microcrystalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidone in water. The granules are then mixed with sodium starch glycolate and magnesium stearate and compressed to obtain kernels of 120 or 350 mg, respectively. The kernels are painted with an aqueous solution / suspension of the above film coating.

[0346] Example B

[0347] Capsules containing the following ingredients may be manufactured in a conventional manner:

[0348] <![CDATA[ Element ]]> <![CDATA[ Each capsule ]]> The compound of formula (I) or a pharmaceutically acceptable salt thereof 25.0mg lactose 150.0mg Corn starch 20.0mg talc 5.0mg

[0349] The ingredients are sieved and mixed and filled into size 2 capsules.

[0350] Example C

[0351] The injection solution can have the following composition:

[0352] The compound of formula (I) or a pharmaceutically acceptable salt thereof 3.0mg Polyethylene glycol 400 150.0mg Acetic acid Adjust pH to 5.0 Water for injection solution Add to 1.0ml

[0353] The active ingredient is dissolved in a mixture of polyethylene glycol 400 and water for injection (part). The pH is adjusted to 5.0 by adding acetic acid. The volume is adjusted to 1.0 ml by adding the balance of water. The solution is filtered, filled into a vial with an appropriate overage and sterilized.

Claims

1. A compound of formula (I), in 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 With R 4 and the atoms to which they are attached together form a five- to seven-membered heterocycloalkyl or heteroaryl ring; R 5 is alkyl or haloalkyl; and A 1 is -CH- or -N-; or a pharmaceutically acceptable salt thereof.

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

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

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

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

6. A compound according to any one of claims 1 to 5, wherein R 3 is hydrogen or methyl, and R 4 is hydrogen; or R 3 With R 4 Together with the atoms to which they are attached, they form a five- to seven-membered heterocycloalkyl or heteroaryl ring.

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

8. A compound according to any one of claims 1 to 7, wherein R 5 It is an alkyl group.

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

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

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

12. A compound of formula (I) according to any one of claims 1 to 11, selected from 1-[3-Acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridinyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridinyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[6-[(6-methyl-3-pyridinyl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridinyl]-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-pyridinyl]ethanol; 1-[3-Acetyl-6-[6-[methyl-(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridinyl]-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-pyridinyl]-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-pyridinyl]ethanol; or a pharmaceutically acceptable salt thereof.

13. A compound of formula (I) according to any one of claims 1 to 12, selected from 1-[3-Acetyl-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridinyl]-5-methyl-pyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-c]pyridin-3-yl]-2-pyridinyl]-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-pyridinyl]ethanol; 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) making a compound of formula (B1) reacting with a suitable reducing agent in the presence of a suitable solvent, (b) making the compound of formula (B2) With the compound of formula (B3) In the presence of a suitable base, a suitable catalyst and a suitable solvent, or (c) making the compound of formula (B4) With the compound of formula (B5) react in the presence of a suitable base, Wherein X is a halogen; A 1 , R 2 , R 3 , R 4 and R 5 As defined in any one of claims 1 to 9.

15. A compound according to any one of claims 1 to 13, prepared according to the process of claim 14.

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

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

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

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

20. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, 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, the method comprising administering to a patient in need thereof an effective amount of a compound of formula (I) according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.

22. The invention as herein described.

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