Imidazo [4, 5-b] pyridine and pyrazolo [1, 5-a] pyrimidine derivatives as SIK modulators for treatment of rheumatoid arthritis

Abstract

The present invention relates to compounds of formula (I) # imgabs0 # for use as SIK modulators 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. Preferred compounds are, for example, imidazo [4, 5-b] pyridine derivatives or pyrazolo [1, 5-a] pyrimidine derivatives.

Description

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

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

[0003]

[0004] in

[0005] A 1 is -C- or -N-;

[0006] A 2 is -C- or -N-; if A 1 is -C-, then A 2 is -N-; and the condition is that if A 1 If -N-, then A 2 for -C-;

[0007] R 1 is cyano, hydroxyalkyl, alkylcarbonyl, haloalkoxy, hydroxy, alkoxy, halogen, haloalkyl, alkyl or cycloalkyl;

[0008] R 2 is cyano, hydroxyalkyl, haloalkoxy, hydroxy, alkoxy, halogen, haloalkyl or alkyl;

[0009] R 3 is alkoxy, alkyl, haloalkyl, haloalkoxy, halogen or hydrogen;

[0010] R 4 is hydrogen, alkyl, alkoxy, haloalkyl, alkylaminocarbonyl or dialkylaminocarbonyl; R 5 is hydrogen, alkyl, halogen, haloalkyl or alkoxy; and

[0011] L is -O- or -NH-;

[0012] or a pharmaceutically acceptable salt thereof.

[0013] 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 into the nucleus and regulate gene expression (Wein et al. Review, Trends Endocrinol Metab.2018Oct; 29(10):723-735).

[0014] 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.).

[0015] 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."

[0016] 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.

[0017] 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.

[0018] 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.

[0019] 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 CRTCs and class II HDACs in response to extracellular signals, subsequently altering the expression of several cytokines.

[0020] 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).

[0021] To date, many diseases caused by innate immune system disorders lack effective treatments, 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.

[0022] 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).

[0023] 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.

[0024] 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.

[0025] The term "oxy" alone or in combination refers to an -O- group.

[0026] 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.

[0027] The term "haloalkyl" alone or in combination means an alkyl group substituted with at least one halogen, particularly one to five halogens, particularly one to three halogens, more particularly two to three halogens. Specific "haloalkyl" is fluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl, difluoromethyl, difluoroethyl, trifluoromethyl and trifluoroethyl.

[0028] 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.

[0029] The term "hydroxyl" or "hydroxy", alone or in combination, refers to a -OH group.

[0030] The term "carbonyl" alone or in combination refers to a -C(O)- group.

[0031] The term "amino", alone or in combination, means a primary amino group (-NH2), a secondary amino group (-NH-) or a tertiary amino group (-N-).

[0032] The term "alkylamino" is an alkyl group attached to a -NH- group. The term "dialkylamino" denotes two alkyl groups attached to an -N- atom.

[0033] The term "alkylcarbonyl" is an alkyl group attached to a -C(O)- group. Specific "alkylcarbonyl" groups are methylcarbonyl (also known as acetyl) and ethylcarbonyl.

[0034] The term "sulfonyl", alone or in combination, represents a -SO2- group.

[0035] 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, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine and polyamine resins).

[0036] The term "one or more compounds of the present invention" refers to compounds of formula (I) and stereoisomers, tautomers, solvates and salts (eg, pharmaceutically acceptable salts) thereof.

[0037] 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.

[0038] 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).

[0039] 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 racemates, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates.

[0040] 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.

[0041] 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.

[0042] 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.

[0043] In some embodiments providing optically pure enantiomers, optically pure enantiomers mean that the compound contains >90% by weight of the desired isomer, specifically >95% by weight of the desired isomer, or more specifically >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.

[0044] 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.

[0045] Therefore, the present invention relates to:

[0046] According to the compound of the present invention, wherein R 1 is cyano or hydroxyalkyl;

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

[0048] According to the compound of the present invention, wherein R 2 is cyano, haloalkyl or haloalkoxy;

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

[0050] According to the compound of the present invention, wherein R 3 is hydrogen or alkoxy;

[0051] According to the compound of the present invention, wherein R 3 is hydrogen or methoxy;

[0052] According to the compound of the present invention, wherein R 4 is hydrogen or dialkylaminocarbonyl;

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

[0054] According to the compound of the present invention, wherein R5 is hydrogen or alkyl;

[0055] According to the compound of the present invention, wherein R 5 is hydrogen or methyl;

[0056] According to the compound of the present invention, wherein A 1 is -C- and A 2 for -N-;

[0057] According to the compound of the present invention, wherein A 1 is-N- and A 2 for -C-;

[0058] According to the compound of the present invention, wherein L is -N-; and

[0059] According to the compound of the present invention, wherein L is -O-;

[0060] The present invention further relates to a compound of formula (I) selected from

[0061] 1-[2-(1-hydroxyethyl)-5-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-b]pyridin-3-yl]phenyl]-5-methyl-pyrazole-3-carbonitrile;

[0062] 1-[2-(1-Hydroxyethyl)-5-[6-[(6-methylpyridazin-3-yl)amino]pyrazolo[1,5-a]pyrimidin-3-yl]phenyl]-5-methyl-pyrazole-3-carbonitrile;

[0063] 1-[2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-4-[6-(pyridazin-3-ylamino)imidazo[4,5-b]pyridin-3-yl]phenyl]ethanol;

[0064] 3-[[3-[4-cyano-3-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]phenyl]-5-methoxy-imidazo[4,5-b]pyridin-6-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide;

[0065] 1-[2-(1-hydroxyethyl)-5-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyrimidin-3-yl]phenyl]-5-methylpyrazole-3-carbonitrile;

[0066] 3-[[3-[4-cyano-3-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]phenyl]imidazo[4,5-b]pyridin-6-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide;

[0067] 1-[3-Fluoro-2-(1-hydroxyethyl)-5-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-b]pyridin-3-yl]phenyl]-5-methyl-pyrazole-3-carbonitrile; and

[0068] 1-[2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-4-[6-[(6-methylpyridazin-3-yl)amino]pyrazolo[1,5-a]pyrimidin-3-yl]phenyl]ethanol;

[0069] or a pharmaceutically acceptable salt thereof.

[0070] The present invention further specifically relates to a compound of formula (I) selected from

[0071] 1-[2-(1-hydroxyethyl)-5-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-b]pyridin-3-yl]phenyl]-5-methyl-pyrazole-3-carbonitrile;

[0072] 1-[2-(1-hydroxyethyl)-5-[6-[(6-methylpyridazin-3-yl)amino]pyrazolo[1,5-a]pyrimidin-3-yl]phenyl]-5-methyl-pyrazole-3-carbonitrile; and

[0073] 1-[3-Fluoro-2-(1-hydroxyethyl)-5-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-b]pyridin-3-yl]phenyl]-5-methyl-pyrazole-3-carbonitrile;

[0074] or a pharmaceutically acceptable salt thereof.

[0075] One embodiment of the invention relates to compounds according to the invention, wherein the compound is of formula (II)

[0076]

[0077] Among them, L, R 1 , R 2 , R 3 , R 4 and R 5 As described herein.

[0078] One embodiment of the invention relates to compounds according to the invention, wherein the compound is of formula (III)

[0079]

[0080] Among them, L, R 1 , R 2 , R 3 , R 4 and R 5As described herein.

[0081] The synthesis of compounds of formula (I) can be accomplished, for example, according to the non-exhaustive procedures described below in general schemes 1 to 11 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.

[0082] Solution 1

[0083] In Scheme 1, the synthesis of compounds of formula (Ia) is described. In the following scheme, L, A 1 , A 2 , 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 hydroxyethyl.

[0084]

[0085] Step A: Intermediate 1 can be converted to compounds of formula (Ia) using a reducing agent such as NaBH4 in MeOH with a co-solvent such as THF, 1,4-dioxane, EtOH or dichloromethane at temperatures between -40°C and room temperature.

[0086] Solution 2

[0087] In Scheme 2, the synthesis of compounds of formula (Ia) is described. In the following scheme, A 1 is -C- and A 2 -N-; L, R 2 , R 3 , R 4 and R 5 As defined above. A compound of formula (Ib) is a compound of formula (I) as described herein, wherein R 1 A is hydroxyethyl 1 is -C- and A 2 For -N-.

[0088]

[0089] Step A: Intermediate 2 can be converted to compounds of formula (Ib) by Grignard reaction with methylmagnesium bromide in a solvent such as THF at a temperature between about -70°C to about 0°C.

[0090] Solution 3

[0091] In Scheme 3, the synthesis of compounds of formula (Ic) is described. In the following scheme, A1 -N-, A 2 is -C- and L is -NH-; R 1 , R 2 , R 3 , R 4 and R 5 As defined above. A compound of formula (Ic) is a compound of formula (I) as described herein, wherein A 1 is-N- and A 2 For -C-.

[0092]

[0093] Step A: Intermediate 3 can be converted to the corresponding bromo intermediate 4 by Sandmeyer reaction with a bromide source such as copper(I) dibromide, a nitrite source such as isoamyl nitrite in a solvent such as acetonitrile at temperatures between 60°C and 80°C.

[0094] Step B: Compounds of formula (Ic) can be obtained via Buchwald-Hartwig coupling of intermediate 4 with an aminopyridazine reactant using a suitable base such as Cs2CO3, K2CO3 or K3PO4 and a suitable palladium catalyst such as, for example, t-BuXPhos-Pd-G3 or [t-BuBrettPhosPd(allyl)]OTf in a solvent such as 1,4-dioxane at temperatures between 80°C and 100°C.

[0095] Solution 4

[0096] In Scheme 4, the synthesis of compounds of formula (Id) is described. In the following scheme, A 1 For -C-, A 2 is -N-, L is -NH- and R 1 is cyano, alkylcarbonyl or halogenated alkyl; R 1 , R 2 , R 3 , R 4 and R 5 As defined above. A compound of formula (Id) is a compound of formula (I) as described herein, wherein A 1 for -C- and A 2 For -N-.

[0097]

[0098] Step A: Compounds of formula (Id) can be obtained via Buchwald-Hartwig coupling of intermediate 4 with an aminopyridazine reactant using a suitable base such as Cs2CO3, K2CO3 or K3PO4 and a suitable palladium catalyst such as, for example, t-BuXPhos-Pd-G3 or [t-BuBrettPhosPd(allyl)]OTf in a solvent such as 1,4-dioxane at temperatures between 80°C and 90°C.

[0099] Solution 5

[0100] In the following scenario, A 1 -N-, A 2 for -C- and R 1 is cyano, alkylcarbonyl or halogenated alkyl; R 2 , R 3 , R 4 and R 5 As defined above.

[0101]

[0102] Step A: Intermediate 7 can be obtained by reacting aniline 5 with fluoro- or chloro-pyridine 6 in a solvent such as methanol, THF, acetonitrile, DMF, NMP or DMSO at a temperature between about 0°C and about 70°C.

[0103] Step B: Aromatic amine intermediates 8 can be obtained by reducing the corresponding nitro precursor 7 using a reducing agent such as Fe in a solvent such as EtOH or water in the presence of ammonium chloride or alternatively acetic acid at a temperature of 50° C. Alternatively, the reduction can be achieved using Raney nickel or Pd / C as a catalyst.

[0104] Step C: Intermediate 3 can be obtained from aniline intermediate 8 by condensation with trimethoxymethane in the presence of TsOH in a solvent such as EtOH or MeOH at a temperature between about 80°C and about 120°C.

[0105] Step D: Aniline intermediate 3 can be converted to the corresponding bromo intermediate 4 by Sandmeyer reaction with a bromide source such as copper(II) dibromide, a nitrite source such as isoamyl nitrite in a solvent such as acetonitrile at a temperature between about 60°C and about 80°C.

[0106] Solution 6

[0107] In the following scenario, A 1 -N-, A 2 for -C- and R 1 is cyano, alkylcarbonyl or halogenated alkyl; R 2 , R 3 , R4 and R 5 As defined above.

[0108]

[0109] Step A: Intermediate 10 can be obtained by reacting aniline 5 with fluoro- or chloro-pyridine 9 in a solvent such as MeOH, THF, acetonitrile, DMF or DMSO at a temperature between about 0° C. and about 70° C. Deprotonation of the aniline may be required, such as using a base such as lithium bis(trimethylsilyl)amide in a suitable aprotic solvent.

[0110] Step B: Aniline intermediate 11 can be obtained by reducing the corresponding nitro precursor 10 using a reducing agent such as Fe in a solvent such as EtOH or water in the presence of ammonium chloride at a temperature of about 50°C.

[0111] Step C: Aniline intermediate 4 can be obtained by condensation of intermediate 11 with trimethoxymethane in the presence of TsOH in a solvent such as MeOH at a temperature between about 80°C and about 120°C.

[0112] Solution 7

[0113] In the following scenario, A 1 -N-, A 2 for -C- and R 1 is cyano, alkylcarbonyl or halogenated alkyl; R 2 , R 3 , R 4 and R 5 As defined above.

[0114]

[0115] Step A: Intermediate 4 can be obtained by Chan-Lam coupling of boronic acid intermediate 12 with azabenzimidazole intermediate 13 in the presence of Cu(OAc)2 in a solvent such as MeOH, EtOH, dichloromethane or acetonitrile under oxygen atmosphere at temperatures between about 50°C and about 100°C.

[0116] Solution 8

[0117] In the following scenario, A 1 For -C-, A 2 for-N- and R 1 is cyano, alkylcarbonyl or halogenated alkyl; R 2 , R 3 , R 4 and R 5 As defined above.

[0118]

[0119] Step A: Intermediate 4 can be obtained by Suzuki coupling of boronate ester 14 with iodine precursor 15 in the presence of a catalyst such as Pd(dppf)Cl2.CH2Cl2 complex and a base such as K2CO3 or Cs2CO3 in a solvent such as 1,4-dioxane, THF, DMF, DMA, NMP, toluene, H2O or a mixture thereof at a temperature between about 50°C and about 80°C.

[0120] Solution 9

[0121] In the following scenario, A 1 For -C-, A 2 for-N- and R 1 is cyano, alkylcarbonyl or halogenated alkyl; L, R 2 , R 3 , R 4 and R 5 As defined above. In the following schemes, X is halogen, preferably bromine. The compound of formula (Ie) is a compound of formula (I) as described herein, wherein A 1 For -C-, A 2 is -N- and L is -NH-. The compound of formula (If) is a compound of formula (I) as described herein, wherein A 1 For -C-, A 2 is -N- and L is -O-.

[0122]

[0123] Step A: Compounds of formula (Ie) or (If) can be obtained by Suzuki coupling of boronic acid 16 with halogenated precursor 17 in the presence of a catalyst such as Pd(dppf)Cl2.CH2Cl2 complex and a base such as K2CO3 or Cs2CO3 in a solvent such as 1,4-dioxane, THF, DMF, DMA, NMP, toluene, H2O or a mixture thereof at a temperature between about 50°C and about 80°C.

[0124] Solution 10

[0125] In the following scheme, L, R 2 , R 3 , R 4 and R 5 As defined herein.

[0126]

[0127] Step A: Intermediate 2 can be obtained by Suzuki coupling of boronate ester 18 with halogenated precursor 17 in the presence of a catalyst such as Pd(dppf)Cl2.CH2Cl2 complex and a base such as K2CO3 or Cs2CO3 in a solvent such as 1,4-dioxane, THF, DMF, DMA, NMP, toluene, H2O or a mixture thereof at a temperature of about 50°C to about 80°C.

[0128] Solution 11

[0129] In the following scheme, R 1 is cyano, alkylcarbonyl or halogenated alkyl; R 2 As defined above.

[0130]

[0131] Step A: Intermediates 20 can be obtained by reacting the corresponding fluoro or chloro precursor 19 with a suitable pyrazole building block in the presence of a base such as DIPEA, NaHCO3, K2CO3, Cs2CO3 or DBU in a solvent such as DMSO, DMF at a temperature of about 50°C to about 100°C.

[0132] Step B: Aniline intermediate 5 can be obtained by reducing the corresponding nitro precursor 20 using a reducing agent such as Fe in the presence of ammonium chloride in a solvent such as EtOH or water.

[0133] Step C: Aniline intermediate 5 can be converted to the corresponding bromo intermediate 21 by Sandmeyer reaction with a bromine source such as copper(II) dibromide, a nitrite source such as isoamyl nitrite in a solvent such as acetonitrile at a temperature between about 60°C and about 80°C.

[0134] Step D: Boronate intermediate 16 can be obtained by reaction of bromo intermediate 21 with bis(pinacolato)diboron in the presence of a catalyst such as Pd(dppf)Cl2 and a base such as K2CO3 or KOAc in a solvent such as DMSO or 1,4-dioxane at a temperature of about 90°C.

[0135] Step E: Boronic acid intermediate 12 can be obtained by reaction of bromo intermediate 21 with bis(pinacolato)diboron in the presence of a catalyst such as Pd(dppf)Cl2 and a base such as K2CO3 or KOAc in a solvent such as DMSO, 1,4-dioxane at a temperature of about 90°C.

[0136] Solution 12

[0137]

[0138] Step A: Alkoxyvinyl intermediate 23 can be obtained by Stille coupling of precursor 22 with a tributyl(1-alkoxyvinyl)tin reagent in the presence of a palladium catalyst such as bis(triphenylphosphine)palladium(II) chloride in a solvent such as toluene, DMF or THF at a temperature between about 80°C and about 110°C.

[0139] Step B: Acetyl intermediate 24 can be obtained by acidic hydrolysis of intermediate 23 using, for example, 1 N aqueous HCl at room temperature in a suitable solvent such as, for example, THF.

[0140] Solution 13

[0141] In the following scheme, R 2 As defined above.

[0142]

[0143] Step A: Intermediate 26 can be obtained by reacting the corresponding cyano precursor 25 with DIBAL-H in a solvent such as toluene, THF, dichloromethane, hexane, n-heptane or mixtures thereof at a temperature between about -70°C and about 0°C.

[0144] Step B: Boronate intermediate 18 can be obtained by reaction of bromo intermediate 26 with bis(pinacolato)diboron in the presence of a catalyst such as Pd(dppf)Cl2 and a base such as K2CO3 or KOAc in a solvent such as DMSO, 1,4-dioxane at a temperature of about 90°C.

[0145] 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:

[0146] (a) making a compound of formula (B1)

[0147]

[0148] reacting with a suitable reducing agent in the presence of a suitable solvent,

[0149] (b) making the compound of formula (B2)

[0150]

[0151] reacting with a suitable Grignard reagent in the presence of a suitable solvent,

[0152] (c) making the compound of formula (B3)

[0153]

[0154] With the compound of formula (B4)

[0155]

[0156] In the presence of a suitable base, a suitable catalyst and a suitable solvent, or (d) reacting a compound of formula (B5) or (B5')

[0157]

[0158] With the compound of formula (B6)

[0159]

[0160] The reaction is carried out in the presence of a suitable solvent.

[0161] In the above method, R a is an alkyl group, R b and R b ' is independently selected from hydrogen and alkyl, or R b and R b 'Together with the oxygen atom to which they are attached, they form a five- to six-membered ring, the remaining ring members being carbon atoms optionally substituted with one or two alkyl substituents. X is halogen, in particular bromine; L, A 1 , A 2 , R 1 , R 2 , R 3 , R 4 and R 5 As described in this article.

[0162] In the reaction of step (a), the reducing agent may be, for example, LiBH4 or NaBH4, optionally in the presence of LiCl.

[0163] 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, 1,4-dioxane, EtOH or dichloromethane or a mixture thereof.

[0164] Suitable conditions for step (a) may be between about -60°C and about room temperature, particularly between about -40°C and room temperature.

[0165] Suitably, the conditions used for step (a) are NaH4 as reducing agent, MeOH as solvent with a suitable co-solvent and a reaction temperature between about -40°C and room temperature.

[0166] In the reaction of step (b), the Grignard reagent may be, for example, methylmagnesium bromide, methylmagnesium chloride, ethylmagnesium bromide or ethylmagnesium chloride.

[0167] In the reaction of step (b), the solvent may be, for example, THF or diethyl ether, optionally with toluene as a co-solvent.

[0168] Suitable conditions for step (b) may be between about -90°C and -50°C, particularly between about -80°C and about -60°C, more particularly at about -70°C.

[0169] Suitably, the conditions of step (b) are methylmagnesium bromide as reducing agent, THF as solvent and a reaction temperature of about -70°C.

[0170] In the reaction of step (c), the base may be, for example, Cs2CO3, K2CO3 or K3PO4.

[0171] In the reaction of step (c), the catalyst may be, for example, a suitable Pd catalyst, in particular t-BuXPhos-Pd-G3 or [t-BuBrettPhos Pd(allyl)]OTf.

[0172] In the reaction of step (c), the solvent may be, for example, 1,4-dioxane, THF, DMA, DMF, NMP, toluene, xylene, water or a mixture thereof.

[0173] Suitable conditions for step (c) may be between about 50°C and 120°C, particularly between about 70°C and about 100°C, more particularly between about 80°C and about 90°C.

[0174] Suitably, the conditions for step (c) are Cs2CO3 or K2CO3 as base, t-BuXPhos-Pd-G3 or [t-BuBrettPhos Pd(allyl)]OTf as catalyst, and 1,4-dioxane as solvent, at a reaction temperature between about 80°C and about 90°C.

[0175] In the reaction of step (d), the base may be, for example, Cs2CO3 or K2CO3.

[0176] In the reaction of step (d), the palladium catalyst may be, for example, Pd(dppf)Cl2.CH2Cl2.

[0177] In the reaction of step (d), the solvent may be, for example, 1,4-dioxane, THF, DMF, DMA, NMP, toluene, H2O or a mixture thereof.

[0178] Suitable conditions for step (d) may be between about 30°C and 100°C, particularly between about 40°C and about 90°C, more particularly between about 50°C and about 80°C.

[0179] Suitably, the conditions for step (d) are Cs2CO3 or K2CO3 as base, t-BuXPhos-Pd-G3 or [t-BuBrettPhosPd(allyl)]OTf as catalyst, and 1,4-dioxane as solvent, at a reaction temperature between about 80°C and about 90°C.

[0180] The present invention also relates to a compound according to the invention produced by a process according to the invention.

[0181] The present invention also specifically relates to:

[0182] A compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, for use as a therapeutically active substance;

[0183] A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, and a therapeutically inert carrier;

[0184] Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein 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, in particular inflammatory bowel disease (IBD);

[0185] Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein for preparing a medicament 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, in particular inflammatory bowel disease (IBD);

[0186] A compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, for use in the treatment or prevention of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis, in particular inflammatory bowel disease (IBD); and

[0187] 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) as described herein or a pharmaceutically acceptable salt thereof.

[0188] Pharmaceutical composition

[0189] 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 a method 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.

[0190] 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.

[0191] 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.

[0192] The compounds of the present invention can be administered in any convenient administration form, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain conventional components of pharmaceutical preparations, for example, diluents, carriers, pH adjusters, sweeteners, fillers and other active agents.

[0193] 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).

[0194] The invention will now be illustrated by the following examples, which are not limiting.

[0195] Examples

[0196] abbreviation

[0197] [t-BuBrettPhos 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)

[0198] ATP Adenosine triphosphate

[0199] aq. water-based

[0200] Boc tert-Butyloxycarbonyl

[0201] CAS Chemical Abstracts Service

[0202] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCM Dichloromethane

[0203] DIBAL-H Diisobutylaluminum hydride

[0204] DIPEA N,N-Diisopropylethylamine

[0205] DMF N,N-Dimethylformamide

[0206] DMSO Dimethyl sulfoxide

[0207] dppf 1,1'-ferrocenyldiyl-bis(diphenylphosphine)

[0208] equiv. Equivalent

[0209] ESI Electrospray ionization

[0210] Et Ethyl

[0211] EtOAc Ethyl acetate

[0212] EtOH

[0213] FA Formic acid

[0214] HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0215] HPLC High Pressure Liquid Chromatography

[0216] LC-MS High performance liquid chromatography-mass spectrometry

[0217] Me Methyl

[0218] MeOH Methanol

[0219] NIS N-iodosuccinimide

[0220] NMP N-Methyl-2-pyrrolidone

[0221] NMR Nuclear Magnetic Resonance

[0222] PE Petroleum Ether

[0223] psi pounds per square inch

[0224] QToF Quadrupole Time of Flight

[0225] RT Room temperature

[0226] sat. saturated

[0227] 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#1447963-75-8)

[0228] TEA Triethylamine

[0229] Tf trifluoromethanesulfonyl

[0230] TFA Trifluoroacetic acid

[0231] THF Tetrahydrofuran

[0232] TLC Thin layer chromatography

[0233] TsOH Toluenesulfonic acid

[0234] Example 1

[0235] 1-[2-(1-Hydroxyethyl)-5-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-b]pyridin-3-yl]phenyl]-5-methyl-pyrazole-3-carbonitrile

[0236]

[0237] Step 1: 1-(2-Fluoro-4-nitro-phenyl)ethanone

[0238]

[0239] To a brown turbid solution of 4-bromo-3-fluoronitrobenzene (CAS185331-69-5; 10.0 g, 45.45 mmol, 1.0 equiv) in toluene (200 mL) was added tributyl(1-ethoxyvinyl)tin (CAS 20420-43-3; 24.6 g, 68.2 mmol, 1.5 equiv), bis(triphenylphosphine)palladium(II) chloride (CAS13965-03-2; 2.39 g, 3.41 mmol, 0.08 equiv) The reaction mixture was stirred at 110°C for 16 hours under nitrogen atmosphere and the mixture became a black solution. The mixture was cooled to room temperature, quenched with saturated aqueous potassium fluoride solution (300 ml) and stirred at room temperature for 16 hours. The aqueous phase was extracted with EtOAc. The two-phase mixture was filtered, the organic phase filtrate was separated, washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product is purified by silica gel chromatography using petroleum ether / ethyl acetate gradient as eluent, to obtain the mixture of title compound and 1-(1-ethoxy vinyl)-2-fluoro-4-nitro-benzene, it is a light brown oil, is dissolved in THF (90mL) and the 1N HCl aqueous solution (90mL).The mixture is stirred at room temperature for 6 hours, then poured into saturated NaHCO in the aqueous solution, so that the pH value reaches about 8.The aqueous solution is extracted with EtOAc.By the organic salt water washing merged, through Na sO dry, filter, and concentrate.The crude product is purified by silica gel chromatography using petroleum ether / ethyl acetate gradient as eluent, to provide title compound (6.4g, 34.95mmol, 77% yield), it is a yellow solid.

[0240] 1 H NMR (400MHz, CDCl3-d) δ = 8.12-8.08 (m, 1H), 8.07-8.02 (m, 2H), 2.71 (d, J = 4.6Hz, 3H).

[0241] Step 2: 1-(2-Acetyl-5-nitro-phenyl)-5-methyl-pyrazole-3-carbonitrile

[0242]

[0243] To a light brown clear solution of 5-methyl-1H-pyrazole-3-carbonitrile (CAS 38693-82-2; 4.12 g, 38.4 mmol, 1.1 eq.) in DMSO (20 mL) was added 1-(2-fluoro-4-nitro-phenyl)ethanone (6.4 g, 34.95 mmol, 1.0 eq.) and NaHCO (5.87 g, 69.9 mmol, 2.0 eq.). The brown suspension was stirred at 60 ° C under N for 16 hours. The reaction was then poured into water. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered and concentrated under vacuum. The crude product was purified by preparative HPLC using heptane / 0.1% NH3 in EtOH as eluent to provide the title compound (4.0 g, 14.8 mmol, 42% yield) as a brown solid and the isomer 2-(2-acetyl-5-nitro-phenyl)-5-methyl-pyrazole-3-carbonitrile (800 mg, 2.96 mmol, 8% yield) as a brown solid. LC-MS: m / z=271.0 [M+H] + ,ESI pos.

[0244] 1 H NMR (400MHz, CDCl3-d) δ = 8.47 (dd, J = 2.1, 8.5Hz, 1H), 8.26 (d, J = 2.1Hz, 1H), 7.90 (d, J = 8.6Hz, 1H), 6.67 (s, 1H), 2.31 (s, 3H), 2.27 (s, 3H).

[0245] Step 3: 1-(2-Acetyl-5-amino-phenyl)-5-methyl-pyrazole-3-carbonitrile

[0246]

[0247] To a solution of 1-(2-acetyl-5-nitro-phenyl)-5-methyl-pyrazole-3-carbonitrile (4.0 g, 14.8 mmol, 1.0 equiv) in EtOH (30 mL) was added Fe (4.13 g, 74.0 mmol, 5.0 equiv), NH4Cl (8.0 g, 149.6 mmol, 10.1 equiv) and water (10 mL). The reaction mixture was stirred at 50 ° C for 16 hours under a nitrogen atmosphere. The color of the mixture changed from yellow to brown. The suspension was filtered through a silica gel pad, and the filter cake was washed with EtOH. The combined filtrate was concentrated. The crude product was purified by silica gel chromatography to obtain the title compound (3.5 g, 14.7 mmol, 98% yield) as a yellow solid. LC-MS: m / z=241.2[M+H] + ,ESI pos.

[0248] 1 H NMR (400MHz, MeOH-d4) δ = 7.82 (d, J = 8.7Hz, 1H), 6.81 (dd, J = 2.3, 8.7Hz, 1H), 6.71 (d, J = 0.6Hz, 1H), 6.52 (d, J = 2.3Hz, 1H), 2.19 (s, 3H), 2.14 (s, 3H).

[0249] Step 4: 1-[2-Acetyl-5[(3,5-dinitro-2-pyridinyl)amino]phenyl]-5-methyl-pyrazole-3-carbonitrile

[0250]

[0251] A solution of 2-chloro-3,5-dinitropyridine (CAS2578-45-2; 2.91 g, 14.3 mmol, 0.98 equiv) and 1-(2-acetyl-5-amino-phenyl)-5-methyl-pyrazole-3-carbonitrile (3.5 g, 14.57 mmol, 1.0 equiv) in MeOH (60 mL) was stirred at 50 ° C for 16 hours. The resulting yellow suspension was 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 as a yellow solid. It was ground with MeOH (20 mL) at 25 ° C for 30 minutes. The suspension was filtered. The solid was washed with EtOAc. The combined filtrate was concentrated to dryness to give the title compound (4.2 g, 10.3 mmol, 70% yield) as a yellow solid. LC-MS: m / z=408.1[M+H] + ESI pos

[0252] 1 H NMR (400MHz, CDCl3-d) δ = 10.79 (s, 1H), 9.39 (s, 2H), 7.99 (d, J = 2.0Hz, 1H), 7 .94-7.91(m,1H),7.89-7.86(m,1H),6.66(s,1H),2.27(s,3H),2.20(s,3H).

[0253] Step 5: 1-[2-Acetyl-5[(3,5-diamino-2-pyridinyl)amino]phenyl]-5-methyl-pyrazole-3-carbonitrile

[0254]

[0255] To a solution of 1-[2-acetyl-5-[(3,5-dinitro-2-pyridyl)amino]phenyl]-5-methyl-pyrazole-3-carbonitrile (4.2g, 10.31mmol, 1.0 equivalent) in EtOH (30mL) was added Fe (2.88g, 51.6mmol, 5.0 equivalent), NH4Cl (5.52g, 103.1mmol, 10.0 equivalent) and water (10mL). The reaction mixture was stirred at 50 ° C for 16 hours under a nitrogen atmosphere. The resulting suspension was filtered through a silica gel pad, and the residue was washed with EtOH. The combined filtrate was concentrated. The remaining solid was washed with water and extracted with EtOAc, followed by extraction with DCM / MeOH (10: 1). The combined organic layer was dried over Na2SO4, filtered and concentrated to obtain the title compound (3.5g, 10.1mmol, 98% yield) as a dark green solid. LC-MS: m / z=348.1[M+H] + ESI pos

[0256] 1 H NMR (400MHz, MeOH-d4) δ = 7.88 (d, J = 8.8Hz, 1H), 7.24 (d, J = 2.5Hz, 1H), 7.01 (dd, J = 2 .4,8.8Hz,1H),6.71-6.70(m,2H),6.60(d,J=2.5Hz,1H),2.20(s,3H),2.16(s,3H).

[0257] Step 6: 1-[2-Acetyl-5-(6-aminoimidazo[4,5-b]pyridin-3-yl)phenyl]-5-methyl-pyrazole-3-carbonitrile

[0258]

[0259] The mixture of 1-[2-acetyl-5-[(3,5-diamino-2-pyridyl)amino]phenyl]-5-methyl-pyrazole-3-carbonitrile (3.5g, 10.1mmol, 1.0 equivalent) in EtOH (100mL) was treated with trimethoxymethane (11.0mL, 100.4mmol, 10.0 equivalent) and TsOH (155.0mg, 1.01mmol, 0.1 equivalent) and heated at 120°C for 4 hours. The reaction mixture was concentrated. The residue was dissolved in THF (60mL) and 1N HCl (60mL) and stirred at room temperature for 4 hours. The reaction mixture was diluted with NaHCO solution and extracted with EtOAc. The combined organic layer was dried over NaSO, filtered and concentrated. The residue was ground with MeOH and EtOAc at room temperature for 30 minutes. The mixture was filtered. The solid was washed with petroleum ether and dried to give the title compound (2.8 g, 7.84 mmol, 81% yield) as a brown solid. LC-MS: m / z=358.1 [M+H] + ESI pos.

[0260] 1 H NMR (400MHz, DMSO-d6) δ=8.92(s,1H),8.52(dd,J=2.2,8.6Hz,1H),8.34(d,J=2.1Hz,1H),8.15(d,J=8.5Hz,1H ), 7.91 (d, J = 2.4Hz, 1H), 7.30 (d, J = 2.4Hz, 1H), 7.03 (d, J = 0.8Hz, 1H), 5.27 (s, 2H), 2.29 (s, 3H), 2.23 (s, 3H).

[0261] Step 7: 1-[2-Acetyl-5-(6-bromoimidazo[4,5-b]pyridin-3-yl)phenyl]-5-methyl-pyrazole-3-carbonitrile

[0262]

[0263] Isoamyl nitrite (1.63 g, 13.9 mmol, 2.0 equivalents) was added to a suspension of copper (I) dibromide (2.43 g, 10.9 mmol, 1.6 equivalents) in acetonitrile (30 mL). The green-brown suspension was heated to 65 ° C under a nitrogen atmosphere. A suspension of 1-[2-acetyl-5-(6-aminoimidazo[4,5-b]pyridin-3-yl)phenyl]-5-methyl-pyrazole-3-carbonitrile in acetonitrile (30 mL) (2.7 g, 6.8 mmol, 1.0 equivalents) was added to the reaction mixture, and the mixture became black. The reaction was stirred for 10 minutes, then quenched with water, and extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was ground with MeOH (10 mL), petroleum ether (30 mL) and DCM (5 mL) at 25 ° C for 30 minutes. The mixture was filtered. The solid was dried to give the first batch of the title compound (853.8 mg, 2.03 mmol, 28% yield) as a brown solid. The filtrate was concentrated and purified by silica gel chromatography using a hexane / EtOH+0.1% formic acid gradient to give the second batch of the title compound (596 mg, 1.4 mmol, 19% yield) as a light brown solid. LC-MS: m / z=421.0 [M+H] + ,ESI pos.

[0264] Step 8: 1-[2-Acetyl-5-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-b]pyridin-3-yl]phenyl]-5-methyl-pyrazole-3-carbonitrile

[0265]

[0266] A suspension of 1-[2-acetyl-5-(6-bromoimidazo[4,5-b]pyridin-3-yl)phenyl]-5-methyl-pyrazole-3-carbonitrile (50 mg, 0.12 mmol, 1.0 equiv), (6-methylpyridazin-3-yl)amine (CAS 18591-82-7; 25.9 mg, 0.237 mmol, 2.0 equiv) and Cs2CO3 (116.0 mg, 0.356 mmol, 3.0 equiv) in 1,4-dioxane at room temperature (ultra dry (1.67 mL)) was flushed with argon for 5 minutes. [t-BuBrettPhos Pd(allyl)]OTf (9.27 mg, 0.012 mmol, 0.1 equiv) was then added, the vial was locked, and the mixture was then heated to 80°C and stirring was continued for 2 hours. The reaction mixture was cooled to room temperature. The crude product was purified by silica gel chromatography using a dichloromethane / MeOH gradient as eluent to provide the title compound (55 mg, 82% yield) as an off-white solid. LC-MS: m / z=449.2 [M+H]+ ,ESI pos.

[0267] Step 9: 1-[2-(1-hydroxyethyl)-5-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-b]pyridin-3-yl]phenyl]-5-methyl-pyrazole-3-carbonitrile

[0268]

[0269] To a mixture of 1-[2-acetyl-5-[6-[(6-methylpyridazine-3-yl)amino]imidazo[4,5-b]pyridin-3-yl]phenyl]-5-methyl-pyrazole-3-carbonitrile (54.7 mg, 0.122 mmol, 1.0 equiv) in methanol (1.0 mL) and anhydrous tetrahydrofuran (1.0 mL) was added NaBH4 (6.91 mg, 0.18 mmol, 1.5 equiv) at 0 ° C. The mixture was stirred at 0 ° C for 15 minutes, then warmed to room temperature and stirred for 2 hours. The mixture was diluted with dry DMF (0.52 mL), cooled to 0 ° C and treated with NaBH4 (6.91 mg, 0.183 mmol, 1.5 equiv). The mixture was stirred at 0 ° C for 30 minutes, then quenched with saturated NH4Cl solution, and extracted with DCM. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel chromatography using a DCM / MeOH gradient as eluent to afford the title compound (29 mg, 51% yield) as a light yellow solid. LC-MS: m / z=452.4 [M+H] + ,ESI pos.

[0270] Example 2

[0271] 1-[2-(1-Hydroxyethyl)-5-[6-[(6-methylpyridazin-3-yl)amino]pyrazolo[1,5-a]pyrimidin-3-yl]phenyl]-5-methyl-pyrazole-3-carbonitrile

[0272]

[0273] Step 1: 1-(2-Acetyl-5-bromo-phenyl)-5-methyl-pyrazole-3-carbonitrile

[0274]

[0275] A solution of 1-(4-bromo-2-fluoro-phenyl)ethanone (CAS 625446-22-2; 1 g, 4.61 mmol, 1.0 eq) in DMF (15.9 mL) was treated with K2CO3 (955 mg, 6.9 mmol, 1.5 eq) and 5-methyl-1H-pyrazole-3-carbonitrile (592 mg, 5.53 mmol, 1.2 eq). The reaction mixture was stirred at 100 °C overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layers were washed with brine, combined, dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel chromatography to provide the title compound (812 mg, 57% yield) as a light brown solid. LC-MS: m / z=304.4[M+H] + ,ESI pos.

[0276] Step 2: 1-[2-Acetyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-methyl-pyrazole-3-carbonitrile

[0277]

[0278] To a light yellow solution of 1-(2-acetyl-5-bromo-phenyl)-5-methyl-pyrazole-3-carbonitrile (785 mg, 2.58 mmol, 1 eq.) in DMSO (10 mL) was added bis(pinacol)diboron (CAS 73183-34-3; 786 mg, 3.1 mmol, 1.2 eq.) and potassium acetate (760 mg, 7.7 mmol, 3 eq.) followed by Pd(dppf)Cl2 (189 mg, 0.26 mmol, 0.1 eq.). The reaction mixture was stirred at 90°C for 2 hours. The reaction mixture was poured into water and extracted twice with ethyl acetate. The organic layer was back extracted with saturated NaCl, dried over MgSO4 and concentrated. The crude material was purified by silica gel chromatography to give the title compound (908 mg, eq.) as a light brown solid. LC-MS: m / z=270.1 [M-pinacol+H] + ,ESIpos.

[0279] Step 3: 1-[2-Acetyl-5-(6-bromopyrazolo[1,5-a]pyrimidin-3-yl)phenyl]-5-methyl-pyrazole-3-carbonitrile

[0280]

[0281] A solution of 1-[2-acetyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-methyl-pyrazole-3-carbonitrile (900 mg, 2.6 mmol, 1.0 equiv) in 1,4-dioxane (12 mL) was treated with 6-bromo-3-iodo-pyrazolo[1,5-a]pyrimidine (CAS 1109284-33-4; 996 mg, 3.1 mmol, 1.2 equiv), K2CO3 (885 mg, 6.4 mmol, 2.5 equiv) in water (3 mL) and Pd(dppf)Cl2.CH2Cl2 complex (424 mg, 0.51 mmol, 0.2 equiv). The reaction mixture was stirred at 50° C. for 90 minutes, then poured into water and extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel chromatography using a heptane / ethyl acetate gradient as eluent to provide the title compound (711 mg, 60% purity, 39% yield) as a yellow solid. LC-MS: m / z=423.1 [M+H] + ,ESI pos.

[0282] Step 4: 1-[2-Acetyl-5-[6-[(6-methylpyridazin-3-yl)amino]pyrazolo[1,5-a]pyrimidin-3-yl]phenyl]-5-methyl-pyrazole-3-carbonitrile

[0283]

[0284] A solution of 1-[2-acetyl-5-(6-bromopyrazolo[1,5-a]pyrimidin-3-yl)phenyl]-5-methyl-pyrazole-3-carbonitrile (100 mg, 0.24 mmol, 1.0 equiv) in 1,4-dioxane (2 mL) was treated with (6-methylpyridazin-3-yl)amine (51.8 mg, 0.48 mmol, 2.0 equiv) and Cs2CO3 (232 mg, 0.71 mmol, 3.0 equiv) at room temperature. The reaction mixture was degassed and flushed with argon, then [t-BuBrettPhosPd(allyl)]OTf (18.6 mg, 0.024 mmol, 0.1 equiv) was added. The mixture was stirred at 80 °C for 2 hours, then diluted with water and extracted twice with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography using a DCM / methanol gradient as eluent to provide the title compound (28.7 mg, 24% yield) as a yellow solid. LC-MS: m / z=450.3 [M+H] + ,ESI pos.

[0285] Step 5: 1-[2-(1-Hydroxyethyl)-5-[6-[(6-methylpyridazin-3-yl)amino]pyrazolo[1,5-a]pyrimidin-3-yl]phenyl]-5-methyl-pyrazole-3-carbonitrile

[0286]

[0287] A solution of 1-[2-acetyl-5-[6-[(6-methylpyridazine-3-yl)amino]pyrazolo[1,5-a]pyrimidin-3-yl]phenyl]-5-methyl-pyrazole-3-carbonitrile (28.7 mg, 0.06 mmol, 1.0 equiv) in isopropanol (1.5 mL) and THF (1.5 mL) was treated with NaBH4 (4.8 mg, 0.13 mmol, 2.0 equiv) and then stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography using a DCM / MeOH gradient to give the title compound (10.5 mg, 36% yield) as a yellow solid. LC-MS: m / z=452.3[M+H] + ,ESI pos.

[0288] Example 3

[0289] 1-[2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-4-[6-(pyridazin-3-ylamino)imidazo[4,5-b]pyridin-3-yl]phenyl]ethanol

[0290]

[0291] Step 1: 1-(2-Fluoro-4-nitro-phenyl)ethanone

[0292]

[0293] Tributyl(1-ethoxyvinyl)tin (24.62 g, 68.2 mmol, 1.5 equiv) and bis(triphenylphosphine)palladium(II) chloride (2.39 g, 3.4 mmol, 0.08 equiv) were added to a brown turbid solution of 4-bromo-3-fluoronitrobenzene (10.0 g, 45.5 mmol, 1.0 equiv) in toluene (200 mL). The reaction was stirred at 110 °C for 16 hours under a nitrogen atmosphere and the reaction became a black solution. The mixture reaction was cooled to room temperature, quenched with saturated potassium fluoride aqueous solution (300 ml), stirred at room temperature for 16 hours and extracted with ethyl acetate. The mixture was filtered. The organic phase of the filtrate was separated, washed with brine, dried over sodium sulfate, filtered and concentrated. The residue is purified by silica gel chromatography using petroleum ether / ethyl acetate gradient, to obtain a mixture (10g) of 1-(1-ethoxy vinyl)-2-fluoro-4-nitro-benzene and required product 1-(2-fluoro-4-nitro-phenyl) ethyl ketone, it is a light brown oil. The mixture is dissolved in 90mL THF and 90mL 1N HCl aqueous solution and stirred at 30 ℃ (room temperature) for 2 hours. The mixture is poured into saturated NaHCO the aqueous solution (300mL, aqueous phase pH value is about 8). The aqueous solution is extracted with EtOAc. The organic matter merged is washed with salt water, through Na sO dried, filtered, and concentrated. The crude product is purified by silica gel chromatography using petroleum ether / ethyl acetate gradient as eluent, to obtain title compound (5.0g, 27.3mmol, 60% yield), it is a yellow oil.

[0294] 1 H NMR (400MHz, CDCl3-d) δ = 8.13-8.10 (m, 1H), 8.09-8.04 (m, 2H), 2.73 (d, J = 4.8Hz, 3H).

[0295] Step 2: 1-(2-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)-4-nitrophenyl)ethan-1-one

[0296]

[0297] To a solution of 1-(2-fluoro-4-nitro-phenyl)ethanone (CAS 866579-96-6; 2.0 g, 10.9 mmol, 1 eq.) in DMSO (30 mL) was added 3-(difluoromethyl)-5-methyl-1H-pyrazole (CAS 934759-09-8; 1.44 g, 10.9 mmol, 1 eq.) followed by NaHCO (1.83 g, 21.8 mmol, 2 eq.). The reaction mixture was stirred at 80° C. for 12 h, then diluted with H O and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous Na SO, filtered and concentrated. The crude product was purified by silica gel chromatography using an ethyl acetate / petroleum ether gradient as eluent and a second time by preparative HPLC using a 0.225% aqueous formic acid / acetonitrile gradient as eluent to afford the title compound (in a mixture with its isomers) (400 mg, 12% yield; mixture with isomer 1-(2-(5-(difluoromethyl)-3-methyl-1H-pyrazol-1-yl)-4-nitrophenyl)ethan-1-one) as a red solid. LC-MS: m / z=296.1 [M+H] + ESI pos.

[0298] Step 3: 1-(4-amino-2-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)phenyl)ethan-1-one

[0299]

[0300] To a solution of 1-[2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-4-nitro-phenyl]ethanone (650 mg, 2.2 mmol, 1 eq; a mixture with isomer 1-(2-(5-(difluoromethyl)-3-methyl-1H-pyrazol-1-yl)-4-nitrophenyl)ethan-1-one in a solution of ethanol (9 mL) and water (3 mL) was added Fe (616 mg, 11.0 mmol, 5 eq) and NH4Cl (1.17 g, 22.0 mmol, 10 eq). The reaction mixture was stirred at 50°C for 3 h. The reaction was filtered and the filtrate was concentrated to give the title compound (a mixture with isomer 1-(4-amino-2-(5-(difluoromethyl)-3-methyl-1H-pyrazol-1-yl)phenyl)ethan-1-one)) as a crude product which was used in the next step without further purification.

[0301] Step 4: 1-(4-bromo-2-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)phenyl)ethan-1-one

[0302]

[0303] A mixture of copper (I) bromide (240.6 mg, 1.7 mmol, 1 eq.) and isoamyl nitrite (397.5 mg, 3.39 mmol, 2 eq.) in acetonitrile (10 mL) was stirred at 65 ° C for 30 minutes until the mixture turned black. Then, 1-[4-amino-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]phenyl]ethanone (450 mg, 1.7 mmol, 1 eq.; a mixture of two isomers) was added. The reaction mixture was stirred at 65 ° C for 30 minutes. The crude product was purified by preparative TLC using petroleum ether / ethyl acetate 3:1 as eluent to obtain the title compound (250 mg, 0.76 mmol, 45% yield; a mixture of isomers 1-[4-bromo-2-[5-(difluoromethyl)-3-methyl-pyrazol-1-yl]phenyl]ethanone) as a white solid. LC-MS: m / z = 328.9 [M+H] + ESI pos.

[0304] 1 H NMR (400MHz, CDCl3-d) δ = 7.67-7.61 (m, 1H), 7.59-7.53 (m, 1H), 7.48 (d, J = 1.7Hz, 1H), 6.73-6.43 (m, 1H), 6.40 (s, 1H), 2.16 (s, 3H), 1.88 (s, 3H).

[0305] Step 5: (4-Acetyl-3-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)phenyl)boronic acid

[0306]

[0307] To a solution of 1-[4-bromo-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]phenyl]ethanone (250 mg, 0.76 mmol, 1 eq; and isomer 1-[4-bromo-2-[5-(difluoromethyl)-3-methyl-pyrazol-1-yl]phenyl]ethanone) in 1,4-dioxane (5 mL) was added bis(pinacolato)diboron (289 mg, 1.14 mmol, 1.5 eq), Pd(dppf)Cl2.CH2Cl2 (53.5 mg, 0.08 mmol, 0.1 eq) and KOAc (223.3 mg, 2.28 mmol, 3 eq). The mixture was stirred at 90° C. for 3 h under nitrogen atmosphere and then concentrated. The crude product was purified by preparative HPLC using a 0.225% aqueous formic acid / acetonitrile gradient as eluent to give the title compound (80 mg, 0.27 mmol, 36% yield) as a white solid. LC-MS: m / z=295.0 [M+H] + ,ESI pos.

[0308] Step 6: 1-(4-(6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)-2-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)phenyl)ethan-1-one

[0309]

[0310] To a solution of 6-bromo-3H-imidazo[4,5-b]pyridine (CAS28279-49-4; 45 mg, 0.23 mmol, 1 eq) in MeOH (2 mL) was added [4-acetyl-3-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]phenyl]boronic acid (73.5 mg, 0.25 mmol, 1.1 eq) and Cu(OAc)2 (8.22 mg, 0.05 mmol, 0.2 eq). The reaction mixture was stirred at 50 °C for 12 h under an O2 atmosphere. The crude product was purified to give the title compound (40 mg, 0.09 mmol, 36% yield) as a white solid. LC-MS: m / z=448.0[M+H] + ESI pos.; 446.0[M+H] + ESI pos.

[0311] Step 7: 1-(2-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)-4-(6-(pyridazin-3-ylamino)-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)ethan-1-one

[0312]

[0313] To a solution of 1-[4-(6-bromoimidazo[4,5-b]pyridin-3-yl)-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]phenyl]ethanone solution (30.0 mg, 0.07 mmol, 1 eq) in 1,4-dioxane (2 mL) was added 3-aminopyridazine (12.8 mg, 0.130 mmol, 2 eq) followed by [t-BuBrettPhos Pd(allyl)]OTf (5.25 mg, 0.01 mmol, 0.1 eq) CsCO (65.7 mg, 0.2 mmol, 3 eq). The reaction mixture was stirred at 90 °C under nitrogen atmosphere for 4 hours, then diluted with ethyl acetate and filtered. The filtrate was concentrated. The crude product was purified by TLC using dichloromethane / MeOH (10:1) as eluent to give the title compound (20 mg, 0.04 mmol, 65% yield) as a yellow solid. LC-MS: m / z=461.2 [M+H] + ,ESI pos.

[0314] 1 H NMR (400MHz, MeOH-d4) δ = 8.91 (s, 1H), 8.77 (d, J = 2.3Hz, 1H), 8.68 (d, J = 2.3Hz, 1H), 8.63 (d, J = 3.9Hz, 1H), 8.36-8.29 (m, 2H), 8.04 ( d,J=8.4Hz,1H),7.49(dd,J=4.6,9.1Hz,1H),7.20(dd,J=1.1,9.0Hz,1H),6.88-6.60(t,1H),6.58(s,1H),2.40(s,3H),2.08(s,3H).

[0315] Step 8: 1-(2-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)-4-(6-(pyridazin-3-ylamino)-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)ethan-1-ol

[0316]

[0317] A solution of 1-[2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-4-[6-(pyridazine-3-ylamino)-imidazo[4,5-b]pyridin-3-yl]phenyl]ethanone (20.0 mg, 0.04 mmol, 1 eq.) in methanol (1 mL) and DCM (1 mL) was cooled to -10 ° C. A precipitate was formed, so DMF (1 mL) was added. The reaction mixture became a colorless solution and was then treated with NaBH4 (4.93 mg, 0.130 mmol, 3 eq.) at -10 ° C. The reaction mixture was stirred at -10 ° C for 30 minutes, then quenched with saturated NH4Cl, and extracted with DCM. The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC using a 0.225% formic acid aqueous solution / acetonitrile gradient as eluent. The product-containing fractions were concentrated and freeze-dried to give the title compound (8.9 mg, 0.020 mmol, 43% yield) as a white solid. LC-MS: m / z = 463.1 [M+H] + ESI pos.

[0318] 1H NMR (400MHz, MeOH-d4) δ = 8.82 (s, 1H), 8.77 (d, J = 2.2Hz, 1H), 8.70-8.63 (m, 2H), 8.21 (dd, J = 1.9, 8.5Hz, 1H), 8.06-8.01 (m, 2H), 7.51 (dd ,J=4.6,8.9Hz,1H),7.22(dd,J=1.2,9.2Hz,1H),6.95-6.62(m,1H),6.56(s,1H),4.65-4.51(m,1H),2.33(s,3H),1.37(d,J=6.4Hz,3H).

[0319] Example 4

[0320] 3-[[3-[4-cyano-3-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]phenyl]-5-methoxy-imidazo[4,5-b]pyridin-6-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide

[0321]

[0322] Step 1: tert-Butyl 3-hydroxy-5-methyl-pyrazole-1-carboxylate

[0323]

[0324] To a solution of 5-methyl-1H-pyrazole-3-ol (10.0 g, 101.9 mmol, 1.0 equiv) in dichloromethane (100 mL) was added di-tert-butyl dicarbonate (23.44 mL, 101.9 mmol, 1.0 equiv) and triethylamine (15.6 mL, 112.1 mmol, 1.1 equiv). The reaction mixture was stirred at 25 ° C for 18 hours, then poured into water and extracted with dichloromethane. The organic layer was washed with brine and dried over Na2SO4, then concentrated. The crude product was ground with petroleum ether (50 mL), filtered and dried to give the title compound (10.0 g, 50.5 mmol, 49% yield) as a white solid. LC-MS: m / z=143.0[M+H-C4H8] + ESI pos.

[0325] 1 H NMR (400MHz, CDCl3-d) δ = 12.35-12.01 (m, 1H), 5.68 (d, J = 0.7Hz, 1H), 2.48 (d, J = 0.6Hz, 3H), 1.64 (s, 9H).

[0326] Step 2: 3-(Difluoromethoxy)-5-methyl-pyrazole-1-carboxylic acid tert-butyl ester

[0327]

[0328] Cs2CO3 (49.3 g, 151.35 mmol, 2.0 equiv) was added to a white suspension of sodium difluorochloroacetate (12.7 g, 83.2 mmol, 1.1 equiv) and tert-butyl 3-hydroxy-5-methyl-pyrazole-1-carboxylate (15.0 g, 75.67 mmol, 1.0 equiv) in acetonitrile (250 mL). The reaction mixture was stirred at 80 ° C for 12 hours, then cooled to room temperature and filtered. The filtrate was concentrated. The crude product was purified by silica gel chromatography using a petroleum ether / ethyl acetate gradient to give the title compound (10.0 g, 40.3 mmol, 53% yield) as a colorless oil. LC-MS: m / z=193.1 [M+H-C4H8] + ESI pos.

[0329] 1 H NMR (400MHz, CDCl3-d) δ = 7.06 (t, J = 72.6Hz, 1H), 5.85 (s, 1H), 2.51 (s, 3H), 1.65 (s, 10H).

[0330] Step 3: 3-(Difluoromethoxy)-5-methyl-1H-pyrazole hydrochloride

[0331]

[0332] To a solution of tert-butyl 3-(difluoromethoxy)-5-methyl-pyrazole-1-carboxylate (10.0 g, 40.3 mmol, 1.0 equiv) in DCM (30 mL) was added a solution of HCl in dioxane (30.0 mL, 120.0 mmol, 3.0 equiv). The reaction mixture was stirred at 25 °C for 4 hours. The solution was concentrated and the crude product was used directly in the next step without purification. LC-MS: m / z=149.0 [M+H] + ESI pos.

[0333] 1 H NMR (400MHz, CDCl3-d) δ = 12.92 (br s, 2H), 6.71 (t, J = 71.2Hz, 1H), 5.94 (s, 1H), 2.47 (s, 3H).

[0334] Step 4: 2-[3-(Difluoromethoxy)-5-methyl-pyrazol-1-yl]-4-nitro-benzonitrile

[0335]

[0336] To a light colorless transparent solution of 2-fluoro-4-nitrobenzonitrile (3.1 g, 18.6 mmol, 1.2 eq.) and 3-(difluoromethoxy)-5-methyl-1H-pyrazole (2.3 g, 15.5 mmol, 1.0 eq.) in DMSO (100 mL) was added K2CO3 (4.3 g, 31.1 mmol, 2.0 eq.). The yellow suspension was then stirred at 50 ° C for 16 hours. After the mixture had cooled to room temperature, it was poured into water and extracted with ethyl acetate. The combined organics were washed with brine, dried over NaSO4, filtered and concentrated. The crude product was purified by silica gel chromatography using a petroleum ether / ethyl acetate gradient to give the title compound (3.3 g, 11.2 mmol, 72% yield) as a white solid. LC-MS: m / z=295.1[M+H] + ,ESI pos.

[0337] 1 H NMR (400MHz, CDCl3-d) δ = 8.44-8.31 (m, 2H), 8.04 (d, J = 8.4Hz, 1H), 6.98 (t, J = 72.7Hz, 1H), 6.03 (s, 1H), 2.39 (s, 3H).

[0338] Step 5: 4-amino-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]benzonitrile

[0339]

[0340] To a solution of 2-[3-(difluoromethoxy)-5-methyl-pyrazole-1-yl]-4-nitro-benzonitrile (3.3g, 11.2mmol, 1.0 equivalent) in EtOH (100mL) was added Fe (3.13g, 56.1mmol, 5.0 equivalent), NH4Cl (6.0g, 112.2mmol, 10.0 equivalent) and water (50mL). The reaction mixture was stirred at 50 ° C for 16 hours under a nitrogen atmosphere. Then, the mixture was filtered through a diatomaceous earth pad while hot. The filtrate was concentrated. Water (50mL) was added to the crude product. Water was extracted with ethyl acetate. The combined organic matter was 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 to obtain the title compound (2.05g, 69% yield) as a white solid. LC-MS: m / z = 265.0 [M+H] + ,ESI pos.

[0341] 1H NMR (400MHz, DMSO-d6) δ = 7.55 (d, J = 8.6Hz, 1H), 7.29 (t, J = 73.2Hz, 1H), 6.71 (dd, J=2.2,8.6Hz,1H),6.62(d,J=2.2Hz,1H),6.53(s,2H),6.10(s,1H),2.20(s,3H).

[0342] Step 6: 4-[(5-bromo-6-methoxy-3-nitro-2-pyridinyl)amino]-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]benzonitrile

[0343]

[0344] To the orange solution of 4-amino-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]benzonitrile (1.0g, 3.78mmol, 1 equivalent) and 5-bromo-2-fluoro-6-methoxy-3-nitro-pyridine (1.04g, 4.16mmol, 1.1 equivalents) in THF (30mL) was added dropwise bis(trimethylsilyl) lithium amide (11.35mL, 11.35mmol, 3 equivalents) at 0°C under a nitrogen atmosphere. The mixture was stirred for 1 hour at 0°C. The red reaction mixture was poured into water. The aqueous solution was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by preparative TLC using petroleum ether / ethyl acetate 3:1 to obtain the title compound (1.8g, 3.63mmol, 96% yield) as a brown solid. LC-MS: m / z=494.8 / 496.8[M+H] + ,ESI pos.

[0345] 1 H NMR (400MHz, CDCl3-d) δ = 10.71 (s, 1H), 8.63 (s, 1H), 8.13 (d, J = 2.0Hz, 1H), 7.69 (d, J = 8.6Hz, 1 H), 7.58 (dd, J = 1.8, 8.6 Hz, 1H), 6.81 (t, J = 73.0 Hz, 1H), 5.86 (s, 1H), 4.02 (s, 3H), 2.25 (s, 3H).

[0346] Step 7: 4-[(3-amino-5-bromo-6-methoxy-2-pyridinyl)amino]-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]benzonitrile

[0347]

[0348] To a yellow solution of 4-[(5-bromo-6-methoxy-3-nitro-2-pyridinyl)amino]-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]benzonitrile (1.5 g, 3.03 mmol, 1 eq.) in ethanol (25 mL) was added iron (845.7 mg, 15.1 mmol, 5 eq.), NH4Cl (1.62 g, 30.3 mmol, 10 eq.) and water (12.5 mL). The yellow suspension was stirred at 50 ° C for 16 hours under a nitrogen atmosphere. Then, MeOH (50 mL) was added to the mixture and stirred continuously at 50 ° C for 2 hours. The mixture was filtered while hot. The filtrate was concentrated. The crude product was dissolved in ethyl acetate and washed with H2O. The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel chromatography using an ethyl acetate / petroleum ether gradient as eluent to afford the title compound (0.917 g, 2.36 mmol, 65% yield) as a brown solid. LC-MS: m / z=465.0 / 467.0 [M+H] + ,ESI pos.

[0349] 1 H NMR (400MHz, CDCl3-d) δ = 7.89 (s, 1H), 7.68-7.62 (m, 1H), 7.61-7.55 (m, 1H), 7. 46-7.37(m,2H),6.93(t,J=73.2Hz,1H),5.92(s,1H),3.94(s,3H),2.32(s,3H).

[0350] Step 8: 4-(6-Bromo-5-methoxy-imidazo[4,5-b]pyridin-3-yl)-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]benzonitrile

[0351]

[0352] To a yellow solution of 4-[(3-amino-5-bromo-6-methoxy-2-pyridinyl)amino]-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]benzonitrile (1.1 g, 2.36 mmol, 1 eq.) and trimethyl orthoformate (2.51 g, 23.64 mmol, 10 eq.) in ethanol (40 mL) was added TsOH (40.7 mg, 0.240 mmol, 0.1 eq.). The resulting suspension was stirred at 80 ° C for 2 hours. The solid slowly dissolved during this process. The reaction mixture was poured into water and extracted with ethyl acetate. 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 provide the title compound (850 mg, 1.79 mmol, 76% yield) as a brown solid. LC-MS: m / z=475.0 / 477.0[M+H] + ,ESI pos.

[0353] 1 H NMR (400MHz, CDCl3-d) δ = 8.35 (s, 1H), 8.32 (s, 1H), 8.22 (d, J = 2.0Hz, 1H), 8.12-8.07 (m ,1H),8.03-7.98(m,1H),6.96(t,J=72.9Hz,1H),6.01(s,1H),4.09(s,3H),2.41(s,3H).

[0354] Step 9: 3-(Benzhydrylamino)-6-methyl-pyridazine-4-carboxylic acid ethyl ester

[0355]

[0356] To 3-chloro-6-methyl-pyridazine-4-ethyl formate (2.0g, 9.97mmol, 1 equivalent) and α-phenylbenzylamine (2.5mL, 14.9mmol, 1.5 equivalents) in 1,4-dioxane (25mL) solution CsCO (9.74g, 29.9mmol, 3 equivalents) and Xantphos Pd G4 (0.96g, 1mmol, 0.1 equivalents) are added. The mixture is stirred at 100 ° C for 16 hours under a nitrogen atmosphere. The reaction mixture is poured into water and extracted with EtOAc. Organic matter is dried over sodium sulfate, filtered and concentrated. The crude product is purified by silica gel chromatography to obtain the title compound (1.4g, 4.1mmol, 41% yield), which is a yellow solid. The aqueous phase is freeze-dried. The residue is treated with ethyl acetate / methanol 10:1 and stirred for 30 minutes. The mixture was filtered and the mother liquor was concentrated to give another batch of the title compound (800 mg, 2.52 mmol, 25% yield) as a yellow solid. LC-MS: 346.1 [M+H] + , ESI pos.

[0357] 1 H NMR (400MHz, CDCl3-d) δ = 7.92-7.19 (m, 11H), 4.31 (q, J = 7.1Hz, 2H), 2.68 (s, 3H), 1.27 (t, J = 7.2Hz, 3H).

[0358] Step 10: 3-(Benzhydrylamino)-6-methyl-pyridazine-4-carboxylic acid

[0359]

[0360] To a mixture of ethyl 3-(benzhydrylamino)-6-methyl-pyridazine-4-carboxylate (1.4 g, 4.05 mmol, 1 eq.) in THF (5 mL), MeOH (5 mL), water (2.5 mL) was added LiOH (242.7 mg, 10.Mmol, 2.5 eq.). The mixture was stirred at 25 ° C for 1 h and then concentrated under reduced pressure to give the title compound (1.2 g, 3.8 mmol, 93% yield) as a yellow solid. The crude product was used directly in the next step without further purification. LC-MS: 318.0 [M + H] + , ESI pos.

[0361] Step 11: 3-(Benzhydrylamino)-N,N,6-trimethyl-pyridazine-4-carboxamide

[0362]

[0363] To a stirred solution of 3-(benzhydrylamino)-6-methyl-pyridazine-4-carboxylic acid (800.0 mg, 2.52 mmol, 1 eq) in DMF (12 mL) was added dimethylamine hydrochloride (411.1 mg, 5.04 mmol, 2 eq), DIPEA (1.3 mL, 7.56 mmol, 3 eq) and HATU (1.78 g, 7.56 mmol, 3 eq). The reaction mixture was stirred at 30 °C for 16 h. The mixture was used directly in the next step. LC-MS: 345.1 [M+H] + , ESI pos.

[0364] Step 12: 3-Amino-N,N,6-trimethyl-pyridazine-4-carboxamide

[0365]

[0366] HCl in 1,4-dioxane (10.0 mL, 40 mmol, 6.9 eq) was added to 3-(benzhydrylamino)-N,N,6-trimethyl-pyridazine-4-carboxamide (2.0 g, 5.81 mmol, 1 eq) at 0°C and stirred at 30°C for 1 hour. The mixture was purified by preparative HPLC using a 0.05% aqueous ammonium hydroxide / acetonitrile gradient as eluent, and then by a second preparative HPLC using a 10 mmol ammonium carbonate / acetonitrile gradient as eluent to give the title compound (500 mg, 2.77 mmol, 45% yield) as a white solid after lyophilization. LC-MS: 181.0 [M+H] + , ESI pos.

[0367] 1 H NMR (400MHz, MeOH-d4) δ = 7.28 (s, 1H), 3.12 (s, 3H), 2.99 (s, 3H), 2.52 (s, 3H).

[0368] Step 13: 3-[[3-[4-cyano-3-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]phenyl]-5-methoxy-imidazo[4,5-b]pyridin-6-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide

[0369]

[0370] To a colorless solution of 4-(6-bromo-5-methoxy-imidazo[4,5-b]pyridin-3-yl)-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]benzonitrile (30.0 mg, 0.06 mmol, 1 eq) and 3-amino-N,N,6-trimethyl-pyridazine-4-carboxamide (3 mg, 0.13 mmol, 2 eq) in 1,4-dioxane (2 mL) was added [t-BuBrettPhos Pd(allyl)]OTf (10 mg, 0.01 mmol, 0.2 eq) and CsCO (61.7 mg, 0.19 mmol, 3 eq). The reaction mixture was flushed with nitrogen, stirred at 80° C. for 2 h, then cooled to room temperature, poured into water and extracted with ethyl acetate. The combined organic layers were dried over NaSO, filtered and concentrated. The crude product was purified by preparative HPLC using a 0.1% formic acid / acetonitrile gradient as eluent, followed by preparative TLC using DCM / MeOH as eluent to afford the title compound (5.1 mg, 0.01 mmol, 14% yield) which was lyophilized to a white solid. LC-MS: m / z=575.2 [M+H] + ,ESI pos.

[0371] 1 H NMR(400MHz,MeOH-d4)δ=9.08(s,1H),8.76(s,1H),8.53(s,1H),8.46(br d,J=9.5Hz,1H),8.16(d,J=8.4Hz,1H),7.49(s,1H),7.30-6.89(m,1H),6.12(s,1H),4.13(s,3H),3.19(br s,3H),3.11(br s,3H),2.63(s,3H),2.41(s,3H).

[0372] Example 5

[0373] 1-[2-(1-Hydroxyethyl)-5-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyrimidin-3-yl]phenyl]-5-methylpyrazole-3-carbonitrile

[0374]

[0375] Step 1: 6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyrimidine

[0376]

[0377] The pyrazolo[1,5-a]pyrimidine-6-ol solution (CAS1580489-59-3; 1 g, 7.4 mmol, 1.0 equiv) was dissolved in DMF (50 mL) and treated with 3-chloro-6-methyl-pyridazine (1.14 g, 8.88 mmol, 1.2 equiv) and Cs2CO3 (4.82 g, 14.8 mmol, 2.0 equiv) at room temperature. The mixture was stirred at 100 ° C for 16 hours, then cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography using a DCM / MeOH gradient as an eluent to obtain the title compound (259 mg, 12% yield) as a light yellow solid. LC-MS: m / z=228.6[M+H] + ,ESI pos.

[0378] Step 2: 3-Bromo-6-(6-methylpyridazin-3-yl)oxy-pyrazolo[1,5-a]pyrimidine

[0379]

[0380] Br2 (246 mg, 79 uL, 1.54 mmol, 1.4 eq) was added dropwise to a solution of 6-(6-methylpyridazine-3-yl)oxypyrazolo[1,5-a]pyrimidine (250 mg, 1.1 mmol, 1.0 eq) in acetic acid (10 mL). The mixture was stirred at room temperature for 1 hour. More Br2 (246 mg, 79 uL, 1.54 mmol, 1.4 eq) was added and then stirred at room temperature for 1 hour. The mixture was poured onto water and extracted with DCM. 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 (121 mg, 34% yield) as a light brown liquid. LC-MS: m / z=307.9[M+H] + ,ESI pos.

[0381] Step 3: 1-[2-Acetyl-5-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyrimidin-3-yl]phenyl]-5-methyl-pyrazole-3-carbonitrile

[0382]

[0383] A solution of 1-[2-acetyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-methyl-pyrazole-3-carbonitrile (Example 2, Step 2; 60 mg, 0.17 mmol, 1.0 equiv) in 1,4-dioxane (2 mL) was treated with a solution of 3-bromo-6-(6-methylpyridazin-3-yl)oxy-pyrazolo[1,5-a]pyrimidine (52.3 mg, 0.17 mmol, 1.0 equiv), K2CO3 (59 mg, 0.43 mmol, 2.5 equiv) in water (0.5 mL), and then treated with Pd(dppf)Cl2.CH2Cl2 complex (28 mg, 0.034 mmol, 0.2 equiv). The reaction mixture was stirred at 50° C. for 90 minutes, then poured into water and extracted with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel chromatography using a heptane / ethyl acetate gradient as eluent to obtain the title compound (35 mg, 43% yield) as a yellow solid. LC-MS: m / z=451.2 [M+H] + ,ESI pos.

[0384] Step 4: 1-[2-(1-hydroxyethyl)-5-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyrimidin-3-yl]phenyl]-5-methylpyrazole-3-carbonitrile

[0385]

[0386] A suspension of 1-[2-acetyl-5-[6-(6-methylpyridazine-3-yl)oxypyrazolo[1,5-a]pyrimidin-3-yl]phenyl]-5-methyl-pyrazole-3-carbonitrile (35 mg, 0.08 mmol, 1.0 equiv) in isopropanol (2.3 mL) and THF (2.3 mL) was treated with NaBH4 (5.9 mg, 0.16 mmol, 2.0 equiv). The mixture was stirred at room temperature for 2 hours, then diluted with water and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography using a heptane / ethyl acetate gradient as eluent to obtain the title compound (14 mg, 40% yield) as a yellow powder. LC-MS: m / z=457.2[M+H] + ,ESI+

[0387] Example 6

[0388] 3-[[3-[4-cyano-3-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]phenyl]imidazo[4,5-b]pyridin-6-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide

[0389]

[0390] Step 1: 2-[3-(Difluoromethoxy)-5-methyl-pyrazol-1-yl]-4-[(3,5-dinitro-2-pyridinyl)amino]benzonitrile

[0391]

[0392] To a yellow solution of 4-amino-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]benzonitrile (Example 4, Step 5; 400 mg, 1.51 mmol, 1.0 equiv) in methanol (30 mL) was added 2-chloro-3,5-dinitropyridine (CAS2578-45-2; 308 mg, 1.51 mmol, 1.0 equiv) and stirred at 70 ° C for 2 hours. More 2-chloro-3,5-dinitropyridine (154 mg, 0.76 mmol, 0.5 equiv) was added to the mixture and stirring was continued at 70 ° C for 16 hours. The mixture was concentrated. The crude product was purified by silica gel chromatography using a petroleum ether / ethyl acetate gradient as eluent to give the title compound (530.0 mg, 1.23 mmol, 81% yield) as a yellow solid. LC-MS: m / z=432.1 [M+H] + ,ESI pos.

[0393] 1 H NMR (400MHz, CDCl3-d) δ = 10.82 (s, 1H), 9.42 (s, 2H), 8.12 (d, J = 1.1Hz, 1H), 7.92-7.79 (m, 2H), 6.97 (t, J = 72.9Hz, 1H), 6.00 (s, 1H), 2.39 (s, 3H).

[0394] Step 2: 4-[(3,5-diamino-2-pyridinyl)amino]-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]benzonitrile

[0395]

[0396] To a yellow solution of 2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]-4-[(3,5-dinitro-2-pyridyl)amino]benzonitrile (530.0 mg, 1.23 mmol, 1.0 equiv) in EtOH (20 mL) was added Fe (686 mg, 12.3 mmol, 10.0 equiv), NH4Cl (1.3 g, 24.6 mmol, 20.0 equiv) and water (10 mL). The yellow suspension was stirred at 50 ° C for 2 hours under a nitrogen atmosphere. Then, MeOH (50 mL) was added to the mixture and stirred continuously at 50 ° C for 30 minutes. The mixture was filtered while hot. The filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with saturated NaHCO3 solution. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column method using ethyl acetate / MeOH gradient as eluent to provide the title compound (330.0 mg, 0.89 mmol, 72% yield) as a dark green solid. LC-MS: m / z=372.0 [M+H] + ,ESI pos.

[0397] 1 H NMR (400MHz, CDCl3-d) δ = 7.54 (d, J = 9.2Hz, 1H), 7.41 (d, J = 2.4Hz, 1H), 7.11 (s, 1H), 6.93-6.88 ( m,2H),6.74(s,1H),6.48(d,J=2.6Hz,1H),6.20(s,1H),5.89(s,1H),3.51(s,4H),2.28(s,3H).

[0398] Step 3: 4-(6-aminoimidazo[4,5-b]pyridin-3-yl)-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]benzonitrile

[0399]

[0400] To a dark green solution of 4-[(3,5-diamino-2-pyridyl)amino]-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]benzonitrile (250.0 mg, 0.67 mmol, 1.0 equiv) in methanol (250 mL) was added trimethyl orthoformate (714 mg, 6.7 mmol, 10.0 equiv) and TsOH (11.6 mg, 0.07 mmol, 0.1 equiv). The green suspension was stirred at 80 ° C for 60 hours. The mixture was concentrated to remove most of the methanol. Then, the mixture was poured into NaHCO3 and extracted with ethyl acetate. The combined organics were dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC using a 0.1% formic acid / acetonitrile gradient as eluent to obtain the title compound (35.0 mg, 0.09 mmol, 14% yield) as a white solid. LC-MS: m / z=382.1[M+H] + ,ESI pos.

[0401] Step 4: 4-(6-bromoimidazo[4,5-b]pyridin-3-yl)-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]benzonitrile

[0402]

[0403] Isoamyl nitrite (18.4 mg, 0.16 mmol, 2.0 equiv) was added to a dark green suspension of copper (I) bromide (11.3 mg, 0.08 mmol, 1.0 equiv) in acetonitrile (6 mL) and stirred at 65 ° C for 15 minutes under an argon atmosphere. The reaction mixture was cooled to room temperature. More 4-(6-aminoimidazo [4,5-b] pyridine-3-yl) -2- [3- (difluoromethoxy) -5-methyl-pyrazole-1-yl] benzonitrile (30.0 mg, 0.08 mmol, 1.0 equiv) in acetonitrile (1 mL) was added to the reaction mixture, which was stirred at 65 ° C for 30 minutes and then poured into water. The aqueous solution was extracted with ethyl acetate. The combined organics were washed with brine, dried over Na2SO4, and concentrated. The crude product was purified by preparative TLC using ethyl acetate as eluent to give the title compound (30.0 mg, 0.07 mmol, 86% yield) as a white solid. LC-MS: m / z=445.0 / 447.0 [M+H] + ,ESI pos.

[0404] Step 5: 3-[[3-[4-cyano-3-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]phenyl]imidazo[4,5-b]pyridin-6-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide

[0405]

[0406] To a yellow solution of 3-amino-N,N,6-trimethyl-pyridazine-4-carboxamide (Example 4, Step 12; 24.3 mg, 0.13 mmol, 2.0 equiv) in 1,4-dioxane (5 mL) was added 4-(6-bromoimidazo[4,5-b]pyridin-3-yl)-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]benzonitrile (30.0 mg, 0.07 mmol, 1.0 equiv), [t-BuBrettPhos Pd(allyl)]OTf (10.53 mg, 0.01 mmol, 0.2 equiv) and Cs2CO3 (65.9 mg, 0.2 mmol, 3.0 equiv). The reaction mixture was flushed with nitrogen. The yellow suspension was stirred at 80°C for 1 hour, then it was poured into water and extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by preparative TLC using dichloromethane / methanol 10:1, then by preparative HPLC using a 0.1% formic acid / acetonitrile gradient as eluent to give the title compound (4.7 mg, 0.01 mmol, 13% yield) as a white freeze-dried product. LC-MS: m / z=545.3 [M+H] + ,ESI pos.

[0407] 1 H NMR (400MHz, MeOH-d4) δ = 8.97 (s, 1H), 8.70 (d, J = 2.3Hz, 1H), 8.57 (dd, J = 2.2, 3.7Hz, 2H), 8.44 (dd, J = 2.2, 8.6Hz, 1H), 8.1 7(d,J=8.6Hz,1H),7.43(s,1H),7.10(t,J=73.2Hz,1H),6.13(s,1H),3.16(s,3H),3.08(s,3H),2.61(s,3H),2.43(s,3H).

[0408] Example 7

[0409] 1-[3-Fluoro-2-(1-hydroxyethyl)-5-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-b]pyridin-3-yl]phenyl]-5-methyl-pyrazole-3-carbonitrile

[0410]

[0411] Step 1: 2-(1-ethoxyvinyl)-1,3-difluoro-5-nitro-benzene

[0412]

[0413] To a toluene (100 mL) solution of 4-bromo-3,5-difluoronitrobenzene (CAS167415-27-2; 5.0 g, 21.01 mmol, 1.0 equivalent) was added bis(triphenylphosphine)palladium chloride (II) (1.47 g, 2.1 mmol, 0.1 equivalent) and tributyl(1-ethoxyvinyl)tin (11.38 g, 31.51 mmol, 1.5 equivalents). The mixture was flushed with nitrogen and stirred at 110 ° C for 14 hours. The reaction mixture was cooled to room temperature, quenched with saturated potassium fluoride and stirred at room temperature for 12 hours. The aqueous phase was extracted with ethyl acetate. The organic matter was washed with brine and dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography using a petroleum ether / ethyl acetate gradient as an eluent to provide the title compound (5.0 g, 21.8 mmol, 83% yield) as an orange liquid.

[0414] 1 H NMR (400MHz, CDCl3-d) δ = 7.86-7.78 (m, 2H), 4.68 (d, J = 3.1Hz, 1H), 4.45 (d, J = 2.9Hz, 1H), 3.97 (q, J = 7.0Hz, 2H), 1.43-1.39 (m, 3H).

[0415] Step 2: 1-(2,6-difluoro-4-nitro-phenyl)ethanone

[0416]

[0417] HCl (10.0 mL, 10.0 mmol, 0.46 equiv) was added to the orange solution of 2-(1-ethoxyvinyl)-1,3-difluoro-5-nitro-benzene (5.0 g, 21.8 mmol, 1.0 equiv) in THF (10 mL). The mixture was heated to 30 ° C and stirred for 2 days, then basified to pH 8 with saturated NaHCO3 aqueous solution. The resulting mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel chromatography using petroleum ether / ethyl acetate gradient as eluent to provide the title compound (2.8 g, 13.9 mmol, 61% yield), which was an orange liquid.

[0418] 1 H NMR (400MHz, CDCl3-d) δ = 7.91-7.85 (m, 2H), 2.67 (t, J = 1.3Hz, 3H).

[0419] Step 3: 1-(2-Acetyl-3-fluoro-5-nitro-phenyl)-5-methyl-pyrazole-3-carbonitrile

[0420]

[0421] To a yellow solution of 1-(2,6-difluoro-4-nitro-phenyl)ethanone (2.8 g, 13.92 mmol, 1.0 equiv), 5-methyl-1H-pyrazole-3-carbonitrile (1.19 g, 11.14 mmol, 0.8 equiv) in DMSO (20 mL) was added DIPEA (5.4 g, 41.8 mmol, 3.0 equiv). The mixture was stirred at 100 °C for 12 hours to give a brown solution, then quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel chromatography using a petroleum ether / ethyl acetate gradient as eluent to give the title compound (1.3 g, 4.51 mmol, 29% yield; containing 30% of the regioisomer 2-(2-acetyl-3-fluoro-5-nitro-phenyl)-5-methyl-pyrazole-3-carbonitrile) as a white solid. LC-MS: m / z = 289.1 [M+H] + ,ESI pos.

[0422] Step 4: 1-(2-Acetyl-5-amino-3-fluoro-phenyl)-5-methyl-pyrazole-3-carbonitrile

[0423]

[0424] To a colorless solution of 1-(2-acetyl-3-fluoro-5-nitro-phenyl)-5-methyl-pyrazole-3-carbonitrile (1.3 g, 4.51 mmol, 1.0 eq; containing 30% regioisomers) in EtOH (14 mL) was added NH4Cl (2.41 g, 45.1 mmol, 10.0 eq), water (7 mL) and Fe (1.26 mg, 22.6 mmol, 5.0 eq). The mixture was then heated to 50°C and stirred at 50°C for 2 hours to give a black suspension. The reaction mixture was filtered through a pad of celite at 50°C, the filter cake was washed with methanol (30 mL×5), and the filtrate was concentrated under vacuum. Water (50 mL) was added to the resulting mixture, and the product was extracted with ethyl acetate (20 mL×3). The organic phase was washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound 850.0 mg, 3.29 mmol, 66% yield; containing 30% of the regioisomer 2-(2-acetyl-5-amino-3-fluoro-phenyl)-5-methyl-pyrazole-3-carbonitrile) as a gray solid. LC-MS: 259.1 [M+H] + , ESI pos.

[0425] Step 5: 1-[2-Acetyl-5[(3,5-dinitro-2-pyridinyl)amino]-3-fluoro-phenyl]-5-methyl-pyrazole-3-carbonitrile

[0426]

[0427] A brown solution of 2-chloro-3,5-dinitropyridine (CAS 2578-45-2; 693.57 mg, 3.41 mmol, 1.0 equiv), 1-(2-acetyl-5-amino-3-fluoro-phenyl)-5-methyl-pyrazole-3-carbonitrile (880.0 mg, 3.41 mmol, 1.0 equiv; containing 30% regioisomer) in MeOH (10 mL) was heated to 70° C. and stirred at 70° C. overnight to give a brown suspension, which was then concentrated. The residue was taken up in water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography using a petroleum / ethyl acetate gradient as eluent to give the title compound (1.3 g, 3.1 mmol, 83% yield; containing 30% of the regioisomer 2-[2-acetyl-5-[(3,5-dinitro-2-pyridinyl)amino]-3-fluoro-phenyl]-5-methyl-pyrazole-3-carbonitrile) as an orange solid. LC-MS: 426.1 [M+H] + ,ESIpos.

[0428] Step 6: 1-[2-Acetyl-3-fluoro-5-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-b]pyridin-3-yl]phenyl]-5-methyl-pyrazole-3-carbonitrile

[0429]

[0430] Analogously to Example 6 (steps 7-10) and starting from 1-[2-acetyl-5-[(3,5-dinitro-2-pyridinyl)amino]-3-fluoro-phenyl]-5-methyl-pyrazole-3-carbonitrile (containing 30% of regioisomers), the title compound was obtained as a brown solid. After the last step, the desired positional isomer was separated from the undesired compound by crystallization from ethyl acetate / water during the work-up of the reaction mixture. LC-MS: 468.2 [M+H] + , ESI pos.

[0431] 1H NMR (400MHz, DMSO-d6) δ = 9.53 (br s, 1H), 9.10 (s, 1H), 8.89 (d, J = 1.9Hz, 1H), 8.65 (d, J = 1.5Hz, 1H), 8.55 (br d,J=11.4Hz,1H),8.37(s,1H),7.40(d,J=9.1Hz,1H),7.14(br d,J=9.0Hz,1H),7.07(s,1H),3.58(s,3H),2.41(s,3H),2.32(s,3H).

[0432] Step 7: 1-[3-Fluoro-2-(1-hydroxyethyl)-5-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-b]pyridin-3-yl]phenyl]-5-methyl-pyrazole-3-carbonitrile

[0433]

[0434] To a brown suspension of 1-[2-acetyl-3-fluoro-5-[6-[(6-methylpyridazine-3-yl)amino]imidazo[4,5-b]pyridin-3-yl]phenyl]-5-methyl-pyrazole-3-carbonitrile (80.0 mg, 0.17 mmol, 1.0 equiv) in DMSO (0.5 mL) and methanol (1 mL) was added NaBH4 (32.37 mg, 0.86 mmol, 5.0 equiv) at 20 °C. The reaction mixture was heated to 30 °C and stirred for 1 hour. It was treated again with NaBH4 (32.4 mg, 0.86 mmol, 5.0 equiv) and stirred at 30 °C for 1 hour. The reaction mixture was treated with saturated NH4Cl aqueous solution (1 mL) and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude residue was purified by preparative HPLC using a 0.225% aqueous formic acid / acetonitrile gradient as eluent to give the title compound (6.4 mg, 0.01 mmol, 7.9% yield) as a white solid. LC-MS: 470.2 [M+H] + , ESI pos

[0435] 1H NMR (400MHz, DMSO-d6) δ = 9.46 (s, 1H), 9.01 (s, 1H), 8.89-8.86 (m, 1H), 8.60 (t, J = 1.8Hz, 1H), 8.36 (dd ,J=2.1,12.2Hz,1H),8.05(s,1H),7.39(d,J=9.2Hz,1H),7.12(d,J=9.0Hz,1H),7.04(s,1H),5.37(br s,1H),4.61-4.00(m,1H),2.53(d,J=2.0Hz,3H),2.27(s,3H),1.43(br d,J=6.5Hz,3H).

[0436] Example 8

[0437] 1-[2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-4-[6-[(6-methylpyridazin-3-yl)amino]pyrazolo[1,5-a]pyrimidin-3-yl]phenyl]ethanol

[0438]

[0439] Step 1: 4-Bromo-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]benzonitrile

[0440]

[0441] 3-(Difluoromethyl)-5-methyl-1H-pyrazole (1.98 g, 15.0 mmol, 1.0 equiv) and potassium carbonate (6.22 g, 45.0 mmol, 3.0 equiv) were added to a colorless solution of 4-bromo-2-fluorobenzonitrile (CAS 105942-08-3; 3.0 g, 15.0 mmol, 1.0 equiv) in DMF (60 mL). The white suspension was stirred at 20 ° C for 16 hours. The mixture was poured into water and extracted with ethyl acetate. The combined organics 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 (4.0 g, 12.8 mmol, 85% yield) as a white solid. LC-MS: 312.0 / 314.0 [M+H] + ,ESI pos.

[0442] 1 H NMR (400MHz, CDCl3-d) δ = 7.80-7.68 (m, 3H), 6.72 (t, J = 54.9Hz, 1H), 6.52 (s, 1H), 2.37 (s, 3H).

[0443] Step 2: 4-Bromo-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]benzaldehyde

[0444]

[0445] To a colorless solution of 4-bromo-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]benzonitrile (3) (3.0 g, 9.6 mmol, 1.0 equiv) in THF (45 mL) was added a 1 M toluene solution of DIBAL-H (24.0 mL, 24.0 mmol, 2.5 equiv) dropwise at 0 °C under nitrogen. The yellow solution was stirred at 0 °C for 2 hours. The reaction mixture was quenched with 1N HCl and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (1.2 g, 3.8 mmol, 40% yield) using a petroleum ether / ethyl acetate gradient as eluent as a colorless oil. LC-MS: 314.8 / 316.8 [M+H] + ,ESI pos.

[0446] 1 H NMR (400MHz, CDCl3-d) δ = 9.58 (d, J = 0.6Hz, 1H), 7.96 (d, J = 8.3Hz, 1H), 7.86-7.7 3(m,1H),7.64(d,J=1.8Hz,1H),6.70(t,J=54.8Hz,1H),6.54(s,1H),2.31(s,3H)

[0447] Step 3: 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde

[0448]

[0449] To a colorless solution of 4-bromo-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]benzaldehyde (1.60 g, 5.1 mmol, 1.0 equiv) in 1,4-dioxane (40 mL) was added bis(pinacol)diboron (2.58 g, 10.2 mmol, 2.0 equiv), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride, toluene complex (417 mg, 0.51 mmol, 0.1 equiv) and potassium acetate (0.95 mL, 15.23 mmol, 3.0 equiv). The reaction mixture was flushed with nitrogen and stirred at 100 ° C for 2 hours, then poured into water and extracted with ethyl acetate. 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 eluent to afford the title compound (2.4 g, 6.63 mmol, 91% yield) as a yellow oil. LC-MS: 281.1 [M+H] + , ESI pos.

[0450] 1 H NMR (400MHz, CDCl3-d)δ=9.69-9.60(m,1H),8.06(s,2H),7.85(s,1H),6.85-6.55(m,1H),6.51(s,1H),2.26(s,3H),1.40-1.35(m,12H)

[0451] Step 4: N-(6-methylpyridazin-3-yl)pyrazolo[1,5-a]pyrimidin-6-amine

[0452]

[0453] 6-Bromopyrazolo[1,5-a]pyrimidine (2.0 g, 10.1 mmol, 1.0 equiv) and cesium carbonate (9.9 g, 30.3 mmol, 3.0 equiv) were added to a yellow solution of 3-amino-6-methylpyridazine (1.32 g, 12.1 mmol, 1.2 equiv) in 1,4-dioxane (20 mL). The air in the flask was replaced with nitrogen 3 times. Then, [t-BuBrettPhos Pd(allyl)]OTf (1.58 g, 2.02 mmol, 0.2 equiv) was added to the mixture, which was then stirred at 80 ° C for 2 hours. The mixture was poured into water, extracted with EtOAc and filtered to obtain an insoluble crude product as a brown solid. The solid was triturated with ethyl acetate / methanol 20 / 1 (30 mL) at 25°C for 30 minutes to give the title compound (1.3 g, 5.75 mmol, 57% yield) as a brown solid. LC-MS = 277.0 [M+H] + ,ESI pos.

[0454] Step 5: 3-iodo-N-(6-methylpyridazin-3-yl)pyrazolo[1,5-a]pyrimidin-6-amine

[0455]

[0456] NIS (1.29 g, 11.49 mmol, 2.0 eq) was added to a yellow solution of N-(6-methylpyridazine-3-yl)pyrazolo[1,5-a]pyrimidine-6-amine (1.3 g, 5.75 mmol, 1.0 eq) in DMF (15 mL). The reaction was stirred at 30 ° C for 16 hours. The reaction mixture was treated with NIS (325 mg, 2.9 mmol, 0.5 eq) again and continued to stir for another 4 hours at 30 ° C. The reaction mixture was concentrated. The crude product was ground with 10 mL of ethyl acetate at room temperature for 30 minutes. The mixture was filtered and the filter cake was concentrated to give the title compound (1.3 g, 3.7 mmol, 64% yield) as a brown solid. LC-MS=353.0[M+H] + ,ESI pos.

[0457] Step 6: 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-4-[6-[(6-methylpyridazin-3-yl)amino]pyrazolo[1,5-a]pyrimidin-3-yl]benzaldehyde

[0458]

[0459] To a colorless solution of 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (308.56 mg, 0.85 mmol, 1.2 eq) in 1,4-dioxane (12 mL) was added 3-iodo-N-(6-methylpyridazin-3-yl)pyrazolo[1,5-a]pyrimidin-6-amine (6) 250.0 mg, 0.71 mmol, 1.0 eq), Pd(dppf)2Cl2·DCM (116 mg, 0.14 mmol, 0.2 eq), Na2CO3 (225.7 mg, 2.1 mmol, 3.0 eq) and water (2.5 mL). The brown suspension was stirred at 80° C. for 2 h, then poured into water and extracted with ethyl acetate. The combined organic matter was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC using 10mmol NH4Cl solution / acetonitrile gradient as eluent to provide the title compound (20.0mg, 0.04mmol, 6% yield) (as a yellow solid) (30.0mg, 0.07mmol, 4% yield) (as a yellow solid). LC-MS: 461.2[M+H] + , ESI pos.

[0460] Step 7: 1-[2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-4-[6-[(6-methylpyridazin-3-yl)amino]pyrazolo[1,5-a]pyrimidin-3-yl]phenyl]ethanol

[0461]

[0462] To a yellow solution of 2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-4-[6-[(6-methylpyridazine-3-yl)amino]pyrazolo[1,5-a]pyrimidin-3-yl]benzaldehyde (20.0 mg, 0.04 mmol, 1.0 equiv) in THF (2 mL) was added methylmagnesium bromide (0.14 mL, 0.43 mmol, 10.0 equiv) at -70 ° C under a nitrogen atmosphere. The mixture was stirred at -70 ° C for 2 hours, then quenched with saturated NH4Cl solution and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by preparative HPLC using a 0.1% formic acid aqueous solution / acetonitrile gradient as an eluent to give the title compound (3.59 mg, 0.01 mmol, 17.36% yield) as a yellow solid after lyophilization. LC-MS:459.2[M+H-18] + ,ESI pos.

[0463] 1 H NMR (400MHz, MeOH-d4) δ = 9.97 (d, J = 2.3Hz, 1H), 8.63 (d, J = 2.4Hz, 1H), 8.50 ( s,1H),8.26(dd,J=1.4,8.3Hz,1H),8.10(d,J=1.6Hz,1H),7.81(d,J=8.2Hz,1 H),7.40(d,J=9.2Hz,1H),7.15(d,J=9.0Hz,1H),6.79(t,J=55.0Hz,1H),6.5 5(s,1H),4.53-4.42(m,1H),2.55(s,3H),2.28(s,3H),1.35(d,J=6.5Hz,3H).

[0464] Example 9-Phosphorylation assay SIK1-3:

[0465] In the presence of SIK2 (or SIK1 or SIK3) 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 addition of 5μl SIK1 (5nM) or 5μl SIK2 (0.5nM) or 7μl SIK3 (1.5nM) in assay buffer (12.5mM HEPES (pH 7.0), 10mM magnesium acetate, 0.005% BSA). 10 μM CHK-peptide solution and 5 μl of 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 of 0.125% formic acid aqueous solution was added to quench the reaction. Data were generated using RapidFire (RF) mass spectrometry as described below. Multiple charged species (3-5 charges) of phosphorylated and non-phosphorylated forms measured by MRM (multiple reaction monitoring; API5000 or 6500+) or EIC (extracted ion current; QToF) were added and the ratio (total sum of phosphorylated species / total sum of all species) was calculated for data evaluation. 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.

[0466] RapidFire Settings:

[0467] 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 another 500 ms.

[0468] MS Settings Sciex API5000 / API6500+:

[0469] 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 = cell exit potential.

[0470] 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

[0471] MS Setup Agilent QToF 6545

[0472] 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

[0473] 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

[0474] Table 1: IC50 values ​​for inhibition of SIK1, SIK2 and SIK3:

[0475]

[0476]

[0477] Example A

[0478] Film-coated tablets containing the following ingredients can be manufactured in a conventional manner:

[0479] <![CDATA[ Element ]]> <![CDATA[ Each tablet ]]> Kernel: The compound of formula (I) or a pharmaceutically acceptable salt thereof 10.0 mg 200.0 mg Microcrystalline Cellulose 23.5 mg 43.5 mg Lactose Hydrous 60.0 mg 70.0 mg Povidone K30 12.5 mg 15.0 mg Sodium starch glycolate 12.5 mg 17.0 mg Magnesium Stearate 1.5 mg 4.5 mg (Core Weight) 120.0 mg 350.0 mg Film coating: Hydroxypropyl methylcellulose 3.5 mg 7.0 mg Polyethylene glycol 6000 0.8 mg 1.6 mg talc 1.3 mg 2.6 mg Iron oxide (yellow) 0.8 mg 1.6 mg Titanium Dioxide 0.8 mg 1.6 mg

[0480] The active ingredient is sieved and mixed with microcrystalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidone in water. The granules are then mixed with sodium starch glycolate and magnesium stearate and compressed to give kernels of 120 or 350 mg, respectively. The kernels are painted with an aqueous solution / suspension of the above film coating.

[0481] Example B

[0482] Capsules containing the following ingredients may be manufactured in a conventional manner:

[0483] <![CDATA[ Element ]]> <![CDATA[ Each capsule ]]> The compound of formula (I) or a pharmaceutically acceptable salt thereof 25.0 mg lactose 150.0 mg Corn starch 20.0 mg talc 5.0 mg

[0484] The ingredients are sieved and mixed and filled into size 2 capsules.

[0485] Example C

[0486] The injection solution can have the following composition:

[0487] 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

[0488] The active ingredient is dissolved in a mixture of polyethylene glycol 400 and water for injection (part). The pH is adjusted to 5.0 by adding acetic acid. The volume is adjusted to 1.0 ml by adding the remainder of water. The solution is filtered, filled into a vial with an appropriate overage and sterilized.

Claims

1. A compound of formula (I), in A 1 is -C- or -N-; A 2 is -C- or -N-; provided that if A1 is -C-, then A2 is -N-; and provided that if A1 is -N-, then A2 is -C-; R 1 is cyano, hydroxyalkyl, alkylcarbonyl, haloalkoxy, hydroxy, alkoxy, halogen, haloalkyl, alkyl or cycloalkyl; R 2 is cyano, hydroxyalkyl, haloalkoxy, hydroxy, alkoxy, halogen, haloalkyl or alkyl; R 3 is alkoxy, alkyl, haloalkyl, haloalkoxy, halogen or hydrogen; R 4 is hydrogen, alkyl, alkoxy, haloalkyl, alkylaminocarbonyl or dialkylaminocarbonyl; R 5 is hydrogen, alkyl, halogen, haloalkyl or alkoxy; and L is -O- or -NH-; or a pharmaceutically acceptable salt thereof.

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

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

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 alkoxy.

7. A compound according to any one of claims 1 to 6, wherein R 3 It is hydrogen or methoxy.

8. A compound according to any one of claims 1 to 7, wherein R 4 is hydrogen or dialkylaminocarbonyl.

9. A compound according to any one of claims 1 to 8, wherein R 4 It is hydrogen or dimethylaminocarbonyl.

10. A compound according to any one of claims 1 to 9, wherein R 5 is hydrogen or alkyl.

11. A compound according to any one of claims 1 to 10, wherein R 5 It is hydrogen or methyl.

12. A compound according to any one of claims 1 to 11, wherein A 1 is -C- and A 2 For -N-.

13. A compound according to any one of claims 1 to 12, wherein A 1 is-N- and A 2 For -C-.

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

15. A compound of formula (I) according to any one of claims 1 to 14, selected from: 1-[2-(1-hydroxyethyl)-5-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-b]pyridin-3-yl]phenyl]-5-methyl-pyrazole-3-carbonitrile; 1-[2-(1-Hydroxyethyl)-5-[6-[(6-methylpyridazin-3-yl)amino]pyrazolo[1,5-a]pyrimidin-3-yl]phenyl]-5-methyl-pyrazole-3-carbonitrile; 1-[2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-4-[6-(pyridazin-3-ylamino)imidazo[4,5-b]pyridin-3-yl]phenyl]ethanol; 3-[[3-[4-cyano-3-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]phenyl]-5-methoxy-imidazo[4,5-b]pyridin-6-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide; 1-[2-(1-hydroxyethyl)-5-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyrimidin-3-yl]phenyl]-5-methylpyrazole-3-carbonitrile; 3-[[3-[4-cyano-3-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]phenyl]imidazo[4,5-b]pyridin-6-yl]amino]-N,N,6-trimethyl-pyridazine-4-carboxamide; 1-[3-Fluoro-2-(1-hydroxyethyl)-5-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-b]pyridin-3-yl]phenyl]-5-methyl-pyrazole-3-carbonitrile; and 1-[2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-4-[6-[(6-methylpyridazin-3-yl)amino]pyrazolo[1,5-a]pyrimidin-3-yl]phenyl]ethanol; or a pharmaceutically acceptable salt thereof.

16. A method for preparing a compound according to any one of claims 1 to 41, 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) reacting with a suitable Grignard reagent in the presence of a suitable solvent, (c) making the compound of formula (B3) With the compound of formula (B4) In the presence of a suitable base, a suitable catalyst and a suitable solvent, or (d) making a compound of formula (B5) or (B5) With the compound of formula (B6) react in the presence of a suitable solvent, Among them, L, A 1 , A 2 , R 1 , R 2 , R 3 , R 4 and R 5 As defined in any one of claims 1 to 14; X is halogen; R a is an alkyl group, R b and R b ' is independently selected from hydrogen and alkyl, or R b and R b Together with the oxygen atom to which they are attached, they form a five- to six-membered ring, the remaining ring members being carbon atoms optionally substituted with one or two alkyl substituents.

17. A compound according to any one of claims 1 to 15, prepared according to the process of claim 16.

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

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

20. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15 for the treatment or prevention of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis.

21. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15 for the preparation of a medicament for the treatment or prevention of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis.

22. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, for use in the treatment or prevention of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis.

23. A method for treating or preventing rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis, 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 15 or a pharmaceutically acceptable salt thereof.

24. The invention as herein described.

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