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

Abstract

The present invention relates to a compound of formula (I) as a SIK modulator for treating or preventing rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell arteritis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis TIFF2025523524000103.tif67161 Preferred compounds are, for example, imidazo[4,5-b]pyridine derivatives or pyrazolo[1,5-a]pyrimidine derivatives.

Description

Technical Field

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

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

Chemical Formula

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

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

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

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

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

[0008] The disease that has been proven to be associated with IL-10 and TNF-α is IBD. Genetic changes that reduce the function of IL-10 (e.g., SNPs in IL-10 or its receptor) are associated with an increased risk of IBD in humans. Furthermore, although anti-TNF therapy is successful, only a subset of IBD patients are responsive, and much of this limited responsiveness is lost over time. The described dual effects of SIK inhibitors (increase in IL-10 and decrease in TNF-α) make them particularly suitable for the treatment of IBD.

[0009] All three SIK kinase isoforms are widely expressed in human tissues, with the highest expression of SIK1 observed in skin and adipose tissue, SIK2 in adipose tissue, and SIK3 in testis and brain. Similar to their roles in macrophages, SIKs in these cells phosphorylate CRTC and class II HDACs in response to extracellular signals, and then alter the expression of several cytokines.

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

[0011] Today, many diseases caused by dysregulation of the innate immune system lack effective treatment methods, and there is a high unmet medical need for new treatment methods. The present invention relates to novel compounds that are highly active SIK inhibitors for the treatment of inflammatory, allergic, and autoimmune diseases. Accordingly, in addition to inflammatory, allergic, and autoimmune diseases, SIK inhibitors may also potentially be associated with cancer, metabolic diseases, bone density dysregulation diseases, pigment-related diseases or aesthetics, fibrotic diseases, and depressive disorders.

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

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

[0014] The term "alkoxy" or "alkyloxy", alone or in combination, means a group of the formula alkyl-O-, and the term "alkyl" has the meaning given above, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. Specific examples of "alkoxy" are methoxy and ethoxy.

[0015] The term "oxy", alone or in combination, means an -O- group.

[0016] The term "halogen" or "halo", alone or in combination, means fluorine, chlorine, bromine, or iodine, and in particular, fluorine, chlorine, or bromine, more specifically fluorine. The term "halo", in combination with another group, means substitution of the group with at least one halogen, in particular 1 to 5 halogens, especially 1 to 4 halogens, i.e., 1, 2, 3, or 4 halogen substitutions.

[0017] The term "haloalkyl", alone or in combination, means an alkyl group substituted with at least one halogen, in particular 1 to 5 halogens, especially 1 to 3 halogens, more specifically 2 to 3 halogens. Specific "haloalkyls" are fluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl, difluoromethyl, difluoroethyl, trifluoromethyl and trifluoroethyl.

[0018] The term "haloalkoxy", alone or in combination, denotes an alkoxy group substituted with at least one halogen, in particular 1 to 5 halogens, especially 1 to 3 halogens. Specific "haloalkoxys" are fluoromethoxy, fluoroethoxy and fluoropropyloxy.

[0019] The terms "hydroxyl" and "hydroxy", alone or in combination, mean an -OH group.

[0020] The term "carbonyl", alone or in combination, means a -C(O)- group.

[0021] The term "amino", alone or in combination, means a primary amino group (-NH2), a secondary amino group (-NH-), or a tertiary amino group (-N-).

[0022] The term "alkylamino" is an alkyl group bonded to an -NH- group. The term "dialkylamino" means two alkyl groups bonded to an -N- atom.

[0023] The term "alkylcarbonyl" is an alkyl group bonded to a -C(O)- group. Specific "alkylcarbonyls" are methylcarbonyl (also known as acetyl) and ethylcarbonyl.

[0024] The term "sulfonyl", alone or in combination, means a -SO2- group.

[0025] The term "pharmaceutically acceptable salt" means a salt that is not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid addition salts and base addition salts. The term "pharmaceutically acceptable acid addition salt" refers to a pharmaceutically acceptable salt formed with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and an organic acid selected from aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. The term "pharmaceutically acceptable base addition salt" refers to a pharmaceutically acceptable salt formed with an organic base or an inorganic base. Examples of acceptable inorganic bases include sodium salts, potassium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, and aluminum salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperizine, piperidine, N-ethylpiperidine, and salts of polyamine resins.

[0026] The terms "compound of the present invention" and "compounds of the present invention" refer to compounds of formula (I) and their stereoisomers, tautomers, solvates and salts (e.g., pharmaceutically acceptable salts).

[0027] Tautomers, i.e., structural isomers that interconvert with the compounds of formula (I), especially in solution, may be present in some cases and are to be understood as being included in the present invention.

[0028] If one of the starting materials of the present invention or the compounds of formula (I) contains one or more functional groups that are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups (e.g., those described in <1} “Protective Groups in Organic Chemistry” by T.W. Greene and P.G.M. Wuts, 3 rd Ed., 1999, Wiley, New York) can be introduced before an important step of applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature. Examples of protecting groups are tert-butoxycarbonyl (Boc), 9-fluorenylmethyl carbamate (Fmoc), 2-trimethylsilylethyl carbamate (Teoc), benzyloxycarbonyl (Cbz), and p-methoxybenzyloxycarbonyl (Moz).

[0029] The compounds of formula (I) may contain several asymmetric centers and may exist as optically pure enantiomers, mixtures of enantiomers such as racemates, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.

[0030] 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 have the “R” or “S” configuration.

[0031] Furthermore, the present invention includes, where applicable, all optical isomers of the compounds of formula (I), i.e., diastereomers, mixtures of diastereomers, racemic mixtures, all corresponding enantiomers and / or tautomers thereof, and solvates thereof.

[0032] Optionally, the racemic mixtures of the compounds of the invention can be separated to isolate the individual enantiomers. The separation can be carried out by methods known in the art, such as coupling the racemic mixture of the compound to a diastereomerically pure compound to form a mixture of diastereomers, followed by separating the individual diastereomers by standard methods such as fractional recrystallization or chromatography.

[0033] In embodiments where an optically pure enantiomer is provided, an optically pure enantiomer means that the compound contains more than 90% by weight of the desired isomer, particularly more than 95% by weight of the desired isomer, or more specifically more than 99% by weight of the desired isomer, and the weight percentages are based on the total weight of the isomers of the compound. Chiral pure or chiral enriched compounds can be prepared by chiral selective synthesis or by separation of enantiomers. The separation of enantiomers can be carried out on the final product or on a suitable intermediate.

[0034] The structures shown herein also mean that they include compounds that differ only in that one or more isotopically enriched atoms are present. Specific examples of radioisotopes are 2 H, 3 H, 13 C, 14 C and 18 F. For example, structures in which one or more hydrogen atoms are replaced by deuterium or tritium, or structures in which one or more carbon atoms are replaced by 13 C or 14 C enriched carbon are within the scope of the invention.

[0035] Accordingly, the present invention relates particularly to the following: R 1 is cyano or hydroxyalkyl, a compound according to the invention; R 1 is cyano or hydroxyethyl, a compound according to the invention; R 2 is cyano, haloalkyl or haloalkoxy, a compound according to the invention; R 2 is cyano, difluoromethyl or difluoromethoxy, a compound according to the invention; R 3 is hydrogen or alkoxy, a compound according to the invention; R 3 is hydrogen or methoxy, a compound according to the invention; R 4 is hydrogen or dialkylaminocarbonyl, a compound according to the invention; R 4 is hydrogen or dimethylaminocarbonyl, a compound according to the invention; R 5 is hydrogen or alkyl, a compound according to the invention; R 5 is hydrogen or methyl, a compound according to the invention; A 1 is -C-, A 2 is -N-, a compound according to the invention; A 1 is -N-, A 2 is -C-, a compound according to the invention; a compound according to the invention wherein L is -N-; and a compound according to the invention wherein L is -O-.

[0036] The present invention further provides 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; Relates to a compound of formula (I) selected from, or a pharmaceutically acceptable salt thereof.

[0037] The present invention further particularly 1-[2-(1-Hydroxyethyl)-5-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-b]pyridin-3-yl]phenyl]-5-methylpyrazole-3-carbonitrile; 1-[2-(1-Hydroxyethyl)-5-[6-[(6-methylpyridazin-3-yl)amino]pyrazolo[1,5-a]pyrimidin-3-yl]phenyl]-5-methylpyrazole-3-carbonitrile; and 1-[3-Fluoro-2-(1-hydroxyethyl)-5-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-b]pyridin-3-yl]phenyl]-5-methylpyrazole-3-carbonitrile; relates to a compound of formula (I) selected from, or a pharmaceutically acceptable salt thereof.

[0038] One embodiment of the present invention is a compound according to the present invention, of formula (II)

Chemical formula

[0039] One embodiment of the present invention is a compound according to the present invention, of formula (III)

Chemical formula

[0040] The synthesis of the compounds of formula (I) can be achieved, for example, according to the non-exhaustive procedures described below in General Schemes 1-11, or according to methods known to those skilled in the art. In some examples, the order of the reaction steps can be changed and the individual steps of different schemes can be combined in different ways as disclosed herein.

[0041] Scheme 1 Scheme 1 describes the synthesis of a compound of formula (I-a). In the following schemes, L, A 1 , A 2 , R 2 , R 3 , R 4 and R 5 are as defined above. The compound of formula (I-a) is R 1It is a compound of formula (I) described herein, wherein it is hydroxyethyl.

Chemical formula

[0042] Step A: Intermediate 1 can be converted to a compound of formula (I-a) using a reducing agent such as NaBH4 in MeOH containing a co-solvent such as THF, 1,4-dioxane, EtOH or dichloromethane at a temperature of -40 °C to room temperature.

[0043] Scheme 2 Scheme 2 describes the synthesis of the compound of formula (I-a). In the following scheme, A 1 is -C-, and A 2 is -N-; L, R 2 、R 3 、R 4 and R 5 are as defined above. The compound of formula (I-b) is a compound of formula (I) described herein, wherein R 1 is hydroxyethyl, A 1 is -C-, and A 2 is -N-.

Chemical formula

[0044] Step A: Intermediate 2 can be converted to a compound of formula (I-b) by a Grignard reaction with methylmagnesium bromide in a solvent such as THF at a temperature of about -70 °C to about 0 °C.

[0045] Scheme 3 Scheme 3 describes the synthesis of the compound of formula (I-c). In the following scheme, A 1 is -N-, A 2 is -C-, L is -NH-; R 1 、R 2 、R 3 、R 4 and R 5is as defined above. The compound of formula (I-c) is A 1 is -N-, and A 2 is -C-, which is a compound of formula (I) described herein.

Chemical formula

[0046] Step A: Intermediate 3 can be converted to the corresponding bromine intermediate 4 by a Sandmeyer reaction with a bromide source such as copper(I) dibromide and a nitrite source such as isoamyl nitrite in a solvent such as acetonitrile at a temperature of 60 °C to 80 °C.

[0047] Step B: The compound of formula (I-c) can be obtained by Buchwald-Hartwig coupling of intermediate 4 with an aminopyridazine reactant using an appropriate base such as Cs2CO3, K2CO3 or K3PO4 and an appropriate palladium catalyst such as t-BuXPhos-Pd-G3 or [t-BuBrettPhosPd(allyl)]OTf in a solvent such as 1,4-dioxane at a temperature of 80 °C to 100 °C.

[0048] Scheme 4 Scheme 4 describes the synthesis of the compound of formula (I-d). In the following scheme, A 1 is -C-, A 2 is -N-, L is -NH-, and R 1 is cyano, alkylcarbonyl or haloalkyl; R 1 , R 2 , R 3 , R 4 and R 5 are as defined above. The compound of formula (I-d) is A 1 is -C-, and A 2 is -N-, which is a compound of formula (I) described herein.

Chemical formula

[0049] Process A: The compound of formula (I-d) can be obtained by Buchwald-Hartwig coupling of Intermediate 4 with an aminopyridazine reactant using an appropriate base such as Cs2CO3, K2CO3 or K3PO4 and an appropriate palladium catalyst such as t-BuXPhos-Pd-G3 or [t-BuBrettPhosPd(allyl)]OTf in a solvent such as 1,4-dioxane at a temperature of 80 °C to 90 °C.

[0050] Scheme 5 In the following scheme, A 1 is -N-, and A 2 is -C-, and R 1 is cyano, alkylcarbonyl or haloalkyl; R 2 , R 3 , R 4 and R 5 are as defined above.

Chemical formula

[0051] Process A: Intermediate 7 can be obtained by reacting aniline 5 with a fluoro or chloro pyridine 6 in a solvent such as methanol, THF, acetonitrile, DMF, NMP or DMSO at a temperature of about 0 °C to about 70 °C.

[0052] Process B: The aromatic amine intermediate 8 can be obtained by reducing the corresponding nitro precursor 7 using a reduction 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.

[0053] Process C: Intermediate 3 can be obtained from aniline intermediate 8 by condensing with trimethoxymethane in a solvent such as EtOH or MeOH in the presence of TsOH at a temperature of about 80 °C to about 120 °C.

[0054] Process D: Aniline intermediate 3 can be converted to the corresponding bromine intermediate 4 by a Sandmeyer reaction with a bromide source such as copper(II) dibromide and a nitrite source such as isoamyl nitrite in a solvent such as acetonitrile at a temperature of about 60 °C to about 80 °C.

[0055] Scheme 6 In the following scheme, A 1 is -N-, and A 2 is -C-, and R 1 is cyano, alkylcarbonyl or haloalkyl; R 2 , R 3 , R 4 and R 5 are as defined above.

Chemical formula

[0056] Process A: Intermediate 10 can be obtained by reacting aniline 5 with fluoro or chloropyridine 9 in a solvent such as MeOH, THF, acetonitrile, DMF or DMSO at a temperature of about 0 °C to about 70 °C. Deprotonation of aniline may be required, for example, using a base such as lithium bis(trimethylsilyl)amide in a suitable aprotic solvent.

[0057] Process B: Aniline intermediate 11 can be obtained by reducing the corresponding nitro precursor 10 using a reduction such as Fe in a solvent such as EtOH or water in the presence of ammonium chloride at a temperature of about 50 °C.

[0058] Process C: Intermediate 4 can be obtained from aniline intermediate 11 by condensing with trimethoxymethane in a solvent such as MeOH in the presence of TsOH at a temperature of about 80 °C to about 120 °C.

[0059] Scheme 7 In the following scheme, A 1 is -N-, and A 2 is -C-, and R1 is cyano, alkylcarbonyl or haloalkyl; R 2 , R 3 , R 4 and R 5 are as defined above.

Chemical formula

[0060] Step A: Intermediate 4 can be obtained by Chan-Lam coupling of boronic acid intermediate 12 and azabenzimidazole intermediate 13 in a solvent such as MeOH, EtOH, dichloromethane or acetonitrile in the presence of Cu(OAc)2 under an oxygen atmosphere at a temperature of about 50 °C to about 100 °C.

[0061] Scheme 8 In the following scheme, A 1 is -C-, A 2 is -N-, R 1 is cyano, alkylcarbonyl or haloalkyl; R 2 , R 3 , R 4 and R 5 are as defined above.

Chemical formula

[0062] Step A: Intermediate 4 can be obtained by Suzuki coupling between boronic acid ester 14 and iodo precursor 15 in a solvent such as 1,4-dioxane, THF, DMF, DMA, NMP, toluene, H2O or a mixture thereof in the presence of a catalyst such as Pd(dppf)Cl2·CH2Cl2 complex and a base such as K2CO3 or Cs2CO3 at a temperature of about 50 °C to about 80 °C.

[0063] Scheme 9 In the following scheme, A 1 is -C-, A 2 is -N-, R 1is cyano, alkylcarbonyl or haloalkyl; L, R 2 R 3 R 4 and R 5 are as defined above. In the following scheme, X is halogen, preferably bromine. The compound of formula (I-e) is a compound of formula (I) described herein where A 1 is -C-, A 2 is -N-, and L is -NH-. The compound of formula (I-f) is a compound of formula (I) described herein where A 1 is -C-, A 2 is -N-, and L is -O-. [Chemical formula]

[0064] Step A: The compound of formula (I-e) or (I-f) can be obtained by Suzuki coupling of boronic acid 16 and halo precursor 17 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 in the presence of a catalyst such as Pd(dppf)Cl2·CH2Cl2 complex and a base such as K2CO3 or Cs2CO3.

[0065] Scheme 10 In the following scheme, L, R 2 R 3 R 4 and R 5 are as defined above. [Chemical formula]

[0066] Process A: Intermediate 2 can be obtained by the Suzuki coupling of boronic ester 18 and halo precursor 17 in a solvent such as 1,4-dioxane, THF, DMF, DMA, NMP, toluene, H2O, or a mixture thereof, in the presence of a catalyst such as Pd(dppf)Cl2·CH2Cl2 complex and a base such as K2CO3 or Cs2CO3 at a temperature of about 50 °C to about 80 °C.

[0067] Scheme 11 In the following scheme, R 1 is cyano, alkylcarbonyl or haloalkyl; R 2 is as defined above.

Chemical formula

[0068] Process A: Intermediate 20 can be obtained by reacting the corresponding fluoro or chloro precursor 19 with an appropriate pyrazole component in a solvent such as DMSO, DMF, etc. in the presence of a base such as DIPEA, NaHCO3, K2CO3, Cs2CO3 or DBU at a temperature of about 50 °C to about 100 °C.

[0069] Process B: Aniline intermediate 5 can be obtained by reducing the corresponding nitro precursor 20 using a reduction such as Fe in a solvent such as EtOH or water in the presence of ammonium chloride.

[0070] Process C: Aniline intermediate 5 can be converted to the corresponding bromine intermediate 21 by a Sandmeyer reaction with a bromine source such as copper(II) dibromide and a nitrite source such as isoamyl nitrite in a solvent such as acetonitrile at a temperature of about 60 °C to about 80 °C.

[0071] Step D: Boronic acid ester intermediate 16 can be obtained by reacting bromo intermediate 21 with bis(pinacolato)diboron in a solvent such as DMSO or 1,4-dioxane at a temperature of about 90 °C in the presence of a catalyst such as Pd(dppf)Cl2 and a base such as K2CO3 or KOAc.

[0072] Step E: Boronic acid intermediate 12 can be obtained by reacting bromo intermediate 21 with bis(pinacolato)diboron in a solvent such as DMSO or 1,4-dioxane at a temperature of about 90 °C in the presence of a catalyst such as Pd(dppf)Cl2 and a base such as K2CO3 or KOAc.

[0073] Scheme 12

Chem.

[0074] Step B: The acetyl intermediate 24 can be obtained by acid hydrolysis of the intermediate 23 using 1N aqueous HCl solution in a suitable solvent such as THF at room temperature.

[0075] Scheme 13 In the following scheme, R 2 is as defined above.

Chem.

[0076] 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 a mixture thereof at a temperature in the range of about -70 °C to about 0 °C.

[0077] Process B: Boronate intermediate 18 can be obtained by reacting bromo intermediate 26 with bis(pinacolato)diboron in a solvent such as DMSO or 1,4-dioxane at a temperature of about 90 °C in the presence of a catalyst such as Pd(dppf)Cl2 and a base such as K2CO3 or KOAc.

[0078] Accordingly, the present invention also relates to the following process: (a) Reacting a compound of formula (B1)

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0079] In the above method, R a is alkyl, R b and R b ’ are independently selected from hydrogen and alkyl, or R b and R b ’ together with the oxygen atom to which they are attached form a 5- to 6-membered ring, and the remaining ring members are carbon atoms which may be substituted with one or two alkyl substituents. X is halo, especially bromo; L, A 1 , A 2 , R 1 , R 2 , R 3 , R 4 and R 5 are as described herein.

[0080] In the reaction of step (a), the reducing agent is, for example, LiBH4 or NaBH4 and may be used in the presence of LiCl, if appropriate.

[0081] In the reaction of step (a), the solvent may be, for example, MeOH which may contain a suitable co-solvent, if appropriate. The co-solvent may be, for example, THF, 1,4-dioxane, EtOH, dichloromethane or a mixture thereof.

[0082] Convenient conditions for step (a) may be from about -60 °C to near room temperature, especially from about -40 °C to room temperature.

[0083] Conveniently, the conditions for step (a) are NaH4 as reducing agent, MeOH as solvent containing a suitable co-solvent, and a reaction temperature of from about -40 °C to room temperature.

[0084] In the reaction of step (b), the Grignard reagent may be, for example, methylmagnesium bromide, methylmagnesium chloride, ethylmagnesium bromide or ethylmagnesium chloride.

[0085] In the reaction of step (b), the solvent can be, for example, THF or diethyl ether optionally containing toluene as a co-solvent.

[0086] The favorable conditions for step (b) can be about -90°C to -50°C, particularly about -80°C to about -60°C, more specifically about -70°C.

[0087] Advantageously, the conditions for step (b) are methylmagnesium bromide as a reducing agent, THF as a solvent, and a reaction temperature of about -70°C.

[0088] In the reaction of step (c), the base can be, for example, Cs2CO3, K2CO3 or K3PO4.

[0089] In the reaction of step (c), the catalyst can be, for example, a suitable Pd catalyst, particularly t-BuXPhos-Pd-G3 or [t-BuBrettPhosPd(allyl)]OTf.

[0090] In the reaction of step (c), the solvent can be, for example, 1,4-dioxane, THF, DMA, DMF, NMP, toluene, xylene, water or a mixture thereof.

[0091] The favorable conditions for step (c) can be about 50°C to 120°C, particularly about 70°C to about 100°C, more specifically about 80°C to about 90°C.

[0092] Advantageously, the conditions for step (c) are a reaction temperature of about 80°C to about 90°C, Cs2CO3 or K2CO3 as a base, t-BuXPhos-Pd-G3 or [t-BuBrettPhosPd(allyl)]OTf as a catalyst, and 1,4-dioxane as a solvent.

[0093] In the reaction of step (d), the base can be, for example, Cs2CO3 or K2CO3.

[0094] In the reaction of step (d), the catalyst can be, for example, Pd(dppf)Cl2·CH2Cl2.

[0095] In the reaction of step (d), the solvent can be, for example, 1,4-dioxane, THF, DMF, DMA, NMP, toluene, H2O or a mixture thereof.

[0096] Convenient conditions for step (d) can be from about 30 °C to 100 °C, particularly from about 40 °C to about 90 °C, more specifically from about 50 °C to about 80 °C.

[0097] Conveniently, the conditions for step (d) are a reaction temperature of from about 80 °C to about 90 °C, Cs2CO3 or K2CO3 as the base, t-BuXPhos-Pd-G3 or [t-BuBrettPhosPd(allyl)]OTf as the catalyst, and 1,4-dioxane as the solvent.

[0098] The present invention also relates to the compounds according to the invention when produced according to the method of the invention. The present invention also particularly relates to the following. A compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof for use as a therapeutic active substance; A pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier; Use of a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof for treating or preventing rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell arteritis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis, particularly inflammatory bowel disease (IBD); Use of a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating or preventing rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell arteritis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis, particularly inflammatory bowel disease (IBD); The compound of formula (I) described herein or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis, particularly inflammatory bowel disease (IBD); 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, particularly inflammatory bowel disease (IBD), comprising administering an effective amount of the compound of formula (I) described herein or a pharmaceutically acceptable salt thereof.

[0099] Pharmaceutical composition Another embodiment of the present invention provides a pharmaceutical composition or medicament containing a compound of the present invention and a therapeutically inert carrier, diluent or excipient, and a method of using a compound of the present invention for preparing such a composition and medicament. In one example, the compound of formula (I) may be formulated by mixing with a physiologically acceptable carrier, i.e., a carrier that is not toxic to the recipient at the dosages and concentrations used in the dosage form of the crude drug, at an appropriate pH and desired purity at ambient temperature. The pH of the formulation mainly depends on the particular use and the concentration of the compound, but is preferably in the range of about 3 to about 8. In one example, the compound of formula (I) is formulated in an acetate buffer at pH 5. In other embodiments, the compound of formula (I) is sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0100] The composition is formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered in this regard 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 drug delivery, the method of administration, the dosing schedule, and other factors known to the medical practitioner.

[0101] The compounds of the present invention can be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intralung, intradermal, intrathecal, epidural and intranasal, and, if desired for local treatment, intralesional administration. Parenteral injection includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0102] The compounds of the present invention may be administered in any convenient dosage form, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain conventional components in pharmaceuticals, for example, diluents, carriers, pH adjusters, sweeteners, fillers, and additional active agents.

[0103] Typical formulations are prepared by mixing the compounds of the present invention with carriers or excipients. Suitable carriers and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel, Howard C. et al., "Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems", Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R. et al., "Remington: The Science and Practice of Pharmacy", Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C., "Handbook of Pharmaceutical Excipients", Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, stabilizers, surfactants, wetting agents, smoothing agents, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, flow promoters, processing aids, colorants, sweeteners, flavors, fragrances, diluents and other known additives to provide an aesthetically pleasing appearance of the drug (i.e., the compound of the present invention or its pharmaceutical composition) or to assist in the manufacture of pharmaceutical products (i.e., pharmaceuticals).

[0104] Hereinafter, the present invention will be described by the following examples which have no limiting features.

Examples

[0105] Abbreviations [t-BuBrettPhos Pd(allyl)]OTf Allyl(2-di-tert-butylphosphino-3,6-dimethoxy-2’,4’,6’-triisopropyl- 1,1’-biphenyl)palladium(II) triflate (CAS No. 1798782-15-6) ATP Adenosine triphosphate aq. Aqueous solution Boc tert-Butyloxycarbonyl CAS Chemical Abstracts Service DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCM Dichloromethane DIBAL-H Diisobutylaluminum hydride DIPEA N,N-Diisopropylethylamine DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide dppf 1,1’-Ferrocenediyl-bis(diphenylphosphine) equiv. Equivalent ESI Electrospray ionization Et Ethyl EtOAc Ethyl acetate EtOH Ethanol FA Formic acid HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazol[4,5-b]pyridinium 3-oxide hexafluorophosphate HPLC High-performance liquid chromatography LC-MS Liquid chromatography-mass spectrometry Me Methyl MeOH Methanol NIS N-Iodosuccinimide NMP N-Methyl-2-pyrrolidone NMR Nuclear magnetic resonance PE Petroleum ether psi Pound per square inch QToF Quadrupole time-of-flight RT Room temperature sat. Saturated t-BuXPhos-Pd-G3 [(2-Di-tert-butylphosphino-2’,4’,6’-triisopropyl-1,1’-biphenyl)-2-(2’-amino-1,1’-biphenyl)]palladium(II) methanesulfonate (CAS No. 1447963-75-8) TEA Triethylamine Tf Triflyl TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin layer chromatography TsOH p-Toluenesulfonic acid

[0106] Example 1 1-[2-(1-Hydroxyethyl)-5-[6-[(6-Methylpyridazin-3-yl)amino]imidazo[4,5-b]pyridin-3-yl]phenyl]-5-methyl-pyrazole-3-carbonitrile

Chem.

Chem.

[0107] Step 2: 1-(2-Acetyl-5-nitro-phenyl)-5-methyl-pyrazole-3-carbonitrile

Chemical Structure

[0108] Step 3: 1-(2-Acetyl-5-amino-phenyl)-5-methyl-pyrazole-3-carbonitrile

Chemical Structure

[0109] Step 4: 1-[2-acetyl-5-[(3,5-dinitro-2-pyridyl)amino]phenyl]-5-methyl-pyrazole-3-carbonitrile

Chemical formula

[0110] Step 5: 1-[2-Acetyl-5-[(3,5-diamino-2-pyridyl)amino]phenyl]-5-methyl-pyrazole-3-carbonitrile

Chemical Structure

[0111] Step 6: 1-[2-Acetyl-5-(6-aminoimidazo[4,5-b]pyridin-3-yl)phenyl]-5-methyl-pyrazole-3-carbonitrile

Chemical Structure

[0112] Step 7: 1-[2-Acetyl-5-(6-bromoimidazo[4,5-b]pyridin-3-yl)phenyl]-5-methyl-pyrazole-3-carbonitrile

Chemical Structure

[0113] 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

Chemical Structure

[0114] 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

Chem.

[0115] Example 2 1-[2-(1-Hydroxyethyl)-5-[6-[(6-methylpyridazin-3-yl)amino]pyrazolo[1,5-a]pyrimidin-3-yl]phenyl]-5-methyl-pyrazole-3-carbonitrile

Chemical formula

Chemical formula

[0116] Step 2: 1-[2-Acetyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-methyl-pyrazole-3-carbonitrile

Chemical Structure

[0117] Step 3: 1-[2-Acetyl-5-(6-bromopyrazolo[1,5-a]pyrimidin-3-yl)phenyl]-5-methyl-pyrazole-3-carbonitrile [Chemical Structure] 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 eq) 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 eq), a solution of K2CO3 (885 mg, 6.4 mmol, 2.5 eq) dissolved in water (3 mL), and Pd(dppf)Cl2·CH2Cl2 complex (424 mg, 0.51 mmol, 0.2 eq). 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 gradient of heptane / ethyl acetate as the eluent to obtain the title compound (711 mg, purity 60%, yield 39%) as a brown solid. LC-MS: m / z = 423.1 [M+H] + , ESI pos.

[0118] 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 [Chemical Structure] 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 eq) in 1,4-dioxane (2 mL) was treated with (6-methylpyridin-3-yl)amine (51.8 mg, 0.48 mmol, 2.0 eq) and Cs2CO3 (232 mg, 0.71 mmol, 3.0 eq) at room temperature. The reaction mixture was degassed and flushed with argon, then [t-BuBrettPhos Pd(allyl)]OTf (18.6 mg, 0.024 mmol, 0.1 eq) was added. The mixture was stirred at 80 °C for 2 h, 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 gradient of DCM / methanol as the eluent to give the title compound (28.7 mg, 24% yield) as a yellow solid. LC-MS: m / z = 450.3 [M+H] + , ESI pos.

[0119] Step 5: 1-[2-(1-Hydroxyethyl)-5-[6-[(6-methylpyridin-3-yl)amino]pyrazolo[1,5-a]pyrimidin-3-yl]phenyl]-5-methyl-pyrazole-3-carbonitrile

Chemical formula

[0120] Example 3 1-[2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]-4-[6-(pyridazin-3-ylamino)imidazo[4,5-b]pyridin-3-yl]phenyl]ethanol

Chemical Structure

Chemical Structure

[0121] Step 2: 1-(2-(3-(Difluoromethyl)-5-methyl-1H-pyrazol-1-yl)-4-nitrophenyl)ethan-1-one

Chemical Structure

[0122] Step 3: 1-(4-Amino-2-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)phenyl)ethan-1-one

Chemical formula

[0123] Step 4: 1-(4-Bromo-2-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)phenyl)ethan-1-one

Chemical formula

[0124] Step 5: (4-Acetyl-3-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)phenyl)boronic acid

Chem.

[0125] 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

Chem.

[0126] 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

Chem.

[0127] 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

Chem.

[0128] Example 4 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

Chem.

Chem.

[0129] Step 2: tert-Butyl 3-(difluoromethoxy)-5-methyl-pyrazole-1-carboxylate

Chem.

[0130] Step 3: 3-(Difluoromethoxy)-5-methyl-1H-pyrazole hydrochloride

Chem.

[0131] Step 4: 2-[3-(Difluoromethoxy)-5-methyl-pyrazol-1-yl]-4-nitro-benzonitrile

Chemical Structure

[0132] Step 5: 4-Amino-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]benzonitrile

Chem.

[0133] Step 6: 4-[(5-Bromo-6-methoxy-3-nitro-2-pyridyl)amino]-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]benzonitrile

Chem.

[0134] Step 7: 4-[(3-Amino-5-bromo-6-methoxy-2-pyridyl)amino]-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]benzonitrile

Chem.

[0135] Step 8: 4-(6-Bromo-5-methoxy-imidazo[4,5-b]pyridin-3-yl)-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]benzonitrile

Chemical Structure

[0136] Step 9: Ethyl 3-(benzhydrylideneamino)-6-methyl-pyridazine-4-carboxylate

Chemical Structure

[0137] Step 10: 3-(Benzhydrylideneamino)-6-methyl-pyridazine-4-carboxylic acid

Chemical Structure

[0138] Step 11: 3-(Benzhydrylideneamino)-N,N,6-trimethyl-pyridazine-4-carboxamide

Chem.

[0139] Step 12: 3-Amino-N,N,6-trimethyl-pyridazine-4-carboxamide

Chem.

[0140] Project 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 [Chemical formula] 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 equivalent) and 3-amino-N,N,6-trimethyl-pyridazine-4-carboxamide (3 mg, 0.13 mmol, 2 equivalents) in 1,4-dioxane (2 mL), [t-BuBrettPhosPd(allyl)]OTf (10 mg, 0.01 mmol, 0.2 equivalent) and Cs2CO3 (61.7 mg, 0.19 mmol, 3 equivalents) were added. The reaction mixture was flushed with nitrogen, stirred at 80 °C for 2 hours, then cooled to room temperature, 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 preparative HPLC using a gradient of 0.1% formic acid / acetonitrile as the eluent, followed by preparative TLC using DCM / MeOH as the eluent, to obtain the title compound (5.1 mg, 0.01 mmol, 14% yield) as a white solid by lyophilization. LC-MS: m / z = 575.2 [M+H] + ,ESI pos. 1 H NMR (400 MHz, MeOH-d4) δ = 9.08 (s, 1H), 8.76 (s, 1H), 8.53 (s, 1H), 8.46 (br d, J = 9.5 Hz, 1H), 8.16 (d, J = 8.4 Hz, 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).

[0141] Example 5 1-[2-(1-Hydroxyethyl)-5-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyrimidin-3-yl]phenyl]-5-methylpyrazole-3-carbonitrile

Chemical formula

Chemical formula

[0142] Step 2: 3-Bromo-6-(6-methylpyridazin-3-yl)oxy-pyrazolo[1,5-a]pyrimidine

Chemical formula

[0143] Step 3: 1-[2-Acetyl-5-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyrimidin-3-yl]phenyl]-5-methyl-pyrazole-3-carbonitrile

Chemical Structure

[0144] Step 4: 1-[2-(1-Hydroxyethyl)-5-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyrimidin-3-yl]phenyl]-5-methylpyrazole-3-carbonitrile

Chemical formula

[0145] Example 6 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

Chemical formula

Chemical formula

[0146] Step 2: 4-[(3,5-diamino-2-pyridyl)amino]-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]benzonitrile

Chemical formula

[0147] Step 3: 4-(6-Aminoimidazo[4,5-b]pyridin-3-yl)-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]benzonitrile

Chemical Structure

[0148] Step 4: 4-(6-Bromoimidazo[4,5-b]pyridin-3-yl)-2-[3-(difluoromethoxy)-5-methyl-pyrazol-1-yl]benzonitrile

Chemical Structure

[0149] 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

Chemical Structure

[0150] Example 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

Chemical Structure

Chem.

[0151] Project 2: 1-(2,6-Difluoro-4-nitro-phenyl)ethanone

Chem.

[0152] Step 3: 1-(2-Acetyl-3-fluoro-5-nitro-phenyl)-5-methyl-pyrazole-3-carbonitrile

Chemical Structure

[0153] Step 4: 1-(2-Acetyl-5-amino-3-fluoro-phenyl)-5-methyl-pyrazole-3-carbonitrile

Chem.

[0154] Step 5: 1-[2-Acetyl-5-[(3,5-dinitro-2-pyridyl)amino]-3-fluorophenyl]-5-methyl-pyrazole-3-carbonitrile

Chem.

[0155] 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

Chemical formula

[0156] 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 [Chemical Structure] To a brown suspension of 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 (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 h. This was treated again with NaBH4 (32.4 mg, 0.86 mmol, 5.0 equiv) and stirred at 30 °C for 1 h. The reaction mixture was treated with saturated aqueous NH4Cl 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 gradient of 0.225% aqueous formic acid / acetonitrile as the 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 11H NMR (400 MHz, DMSO-d6) δ = 9.46 (s, 1H), 9.01 (s, 1H), 8.89 - 8.86 (m, 1H), 8.60 (t, J = 1.8 Hz, 1H), 8.36 (dd, J = 2.1, 12.2 Hz, 1H), 8.05 (s, 1H), 7.39 (d, J = 9.2 Hz, 1H), 7.12 (d, J = 9.0 Hz, 1H), 7.04 (s, 1H), 5.37 (br s, 1H), 4.61 - 4.00 (m, 1H), 2.53 (d, J = 2.0 Hz, 3H), 2.27 (s, 3H), 1.43 (br d, J = 6.5 Hz, 3H).

[0157] Example 8 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

Chemical Structure

Chemical Structure

[0158] Step 2: 4-Bromo-2-[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]benzaldehyde

Chem.

[0159] Step 3: 2-[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde

Chem.

[0160] Step 4: N-(6-Methylpyridazin-3-yl)pyrazolo[1,5-a]pyrimidin-6-amine

Chemical Structure

[0161] Step 5: 3-Iodo-N-(6-methylpyridazin-3-yl)pyrazolo[1,5-a]pyrimidin-6-amine

Chemical formula

[0162] 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

Chem.

[0163] 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

Chem.

[0164] Example 9 - Phosphorylation assay SIK1-3: In the presence of SIK2 (either SIK1 or SIK3) and ATP, the CHK peptide (KKKVSRSGLYRSPSMPENLNRPR with a C-terminal arginine amide modification) was phosphorylated at one of the four appropriate serines. Only one phosphorylation was observed under the assay conditions. 60 nl of each compound dilution series (12 points; dilution factor 3, generally 30 μM to 170 pM) in DMSO was transferred to the assay plate by acoustic dispensing and pre-incubated for 30 minutes (ambient temperature) after the addition of 5 μl of SIK1 (5 nM) or 5 μl of SIK2 (0.5 nM) or 7 μl of SIK3 (1.5 nM) each in assay buffer (12.5 mM HEPES (pH 7.0), 10 mM magnesium acetate, 0.005% BSA). 10 μM CHK-peptide solution in assay buffer and 5 μl of 100 μM ATP for SIK1 and SIK2, 3 μl for SIK3 were added and incubated for 45 minutes in the ambient environment. The reaction was quenched by adding 40 μl of 0.125% aqueous formic acid. RapidFire (RF) mass spectrometry was utilized for data generation as described below. Multiple charged species (3 - 5 charges) of phosphorylated and non-phosphorylated forms measured by MRM (Multiple Reaction Monitoring; API5000 or 6500+) or EIC (Extracted Ion Current; QToF) were summed and the ratio was calculated for data evaluation (sum of phosphorylated species / sum of all species). Normalization was performed by Genedata software based on the non-inhibitory control DMSO and the commercially available SIK inhibitor (R) 1 μM YKL-05-099 (CAS number 1936529-65-5). The results of the assay are represented by the maximum half-maximal inhibitory concentration (IC50) and summarized in Table 1 below.

[0165] RapidFire Setup: The sample was aspirated by vacuum for a maximum of 600 ms and loaded onto a C4 cartridge (Agilent; #G9203A) with 0.1% formic acid in water at 1.5 ml / min for 3000 ms. Subsequently, the sample was transferred to an API 5000 (API 6500+) or QToF mass spectrometer with 90% acetonitrile; 10% water; 0.007% TFA; 0.093% formic acid at 1.25 ml / min for 4000 ms. The cartridge was reconditioned with 0.1% aqueous formic acid for an additional 500 ms.

[0166] MS-Setup Sciex API5000 / API6500+: For all MS analyses using the following MS settings in MRM mode: Electrospray positive; Ion spray voltage: 4000 V; Temperature: 550 °C; Collision gas: 5; Curtain gas: 15; Gas 1: 40; Gas 2: 42; EP 10. DP = declustering potential; CE = collision energy; CXP = cell exit potential.

Table 1

[0167] MS-Setup Agilent QToF 6545 For all MS analyses using the following MS settings in MS mode: Dual AJS electrospray positive; VCap: 3000 V; Drying and sheath gas: 340 °C, 8 l / min; Nebulizer: 60 psig; Nozzle voltage: 2000 V; Fragmentor: 130 V; Skimmer: 35 V; Oct1 RF Vpp: 700 V; Reference mass at 5 spectra / s

[0168]

Table 2

[0169]

Table 3

[0170] Example A Film-coated tablets containing the following ingredients can be manufactured in a conventional manner:

Table 4

[0171] The active ingredient is sieved, mixed with microcrystalline cellulose, and the mixture is granulated with an aqueous solution of polyvinylpyrrolidone. The granules are then mixed with sodium starch glycolate and magnesium stearate and compressed to obtain kernels of 120 or 350 mg each. The kernels are lacquered with the above aqueous film coating solution / suspension.

[0172] Example B Capsules containing the following ingredients can be manufactured in a conventional manner:

Table 5

[0173] The ingredients are sieved, mixed, and filled into size 2 capsules.

[0174] Example C The injection solution can have the following composition:

Table 6

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

Claims

1. Equation (I) 【Chemistry 1】 (In the formula, A １ is -C- or -N-; A ２ is -C- or -N-; however, A １ If A is -C-, ２ is -N-; A １ If A is -N-, ２ is -C-; R １ These are cyano, hydroxyalkyl, alkylcarbonyl, haloalkoxy, hydroxy, alkoxy, halogen, haloalkyl, alkyl, or cycloalkyl; R ２ These are 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; (L is either -O- or -NH-) Compounds of or pharmaceutically acceptable salts thereof.

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

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

4. R ２ The compound according to claim 1, wherein the compound is cyano, haloalkyl, or haloalkoxy.

5. R ２ The compound according to claim 1, wherein the compound is cyano, difluoromethyl, or difluoromethoxy.

6. R ３ The compound according to claim 1, wherein the compound is hydrogen or an alkoxy.

7. R ３ The compound according to claim 1, wherein the compound is hydrogen or methoxy.

8. R ４ The compound according to claim 1, wherein the compound is hydrogen or a dialkylaminocarbonyl.

9. R ４ The compound according to claim 1, wherein the compound is hydrogen or dimethylaminocarbonyl.

10. R ５ The compound according to claim 1, wherein the compound is hydrogen or alkyl.

11. R ５ The compound according to claim 1, wherein the compound is hydrogen or methyl.

12. A １ is -C-, A ２ The compound according to claim 1, wherein the element is -N-.

13. A １ is -N-, A ２ The compound according to claim 1, wherein the compound is -C-.

14. The compound according to claim 1, wherein L is -NH-.

15. below, 1-[2-(1-hydroxyethyl)-5-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-b]pyridine-3-yl]phenyl]-5-methylpyrazole-3-carbonitrile; 1-[2-(1-hydroxyethyl)-5-[6-[(6-methylpyridazin-3-yl)amino]pyrazolo[1,5-a]pyrimidine-3-yl]phenyl]-5-methylpyrazole-3-carbonitrile; 1-[2-[3-(difluoromethyl)-5-methylpyrazole-1-yl]-4-[6-(pyridazine-3-ylamino)imidazo[4,5-b]pyridine-3-yl]phenyl]ethanol; 3-[[3-[4-cyano-3-[3-(difluoromethoxy)-5-methylpyrazole-1-yl]phenyl]-5-methoxyimidazo[4,5-b]pyridine-6-yl]amino]-N,N,6-trimethylpyridazine-4-carboxamide; 1-[2-(1-hydroxyethyl)-5-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyrimidine-3-yl]phenyl]-5-methylpyrazole-3-carbonitrile; 3-[[3-[4-cyano-3-[3-(difluoromethoxy)-5-methylpyrazole-1-yl]phenyl]imidazo[4,5-b]pyridine-6-yl]amino]-N,N,6-trimethylpyridazine-4-carboxamide; 1-[3-fluoro-2-(1-hydroxyethyl)-5-[6-[(6-methylpyridazin-3-yl)amino]imidazo[4,5-b]pyridine-3-yl]phenyl]-5-methylpyrazole-3-carbonitrile; and 1-[2-[3-(difluoromethyl)-5-methylpyrazole-1-yl]-4-[6-[(6-methylpyridazine-3-yl)amino]pyrazolo[1,5-a]pyrimidine-3-yl]phenyl]ethanol; A compound, or a pharmaceutically acceptable salt thereof, selected from the above.

16. A method for preparing the compound according to any one of claims 1 to 14, comprising the following steps: (a) Formula (B1) 【Chemistry 2】 A step of reacting the compound with a suitable reducing agent in the presence of a suitable solvent, (b) Formula (B2) 【Transformation 3】 The process involves reacting the compound with a suitable Grignard reagent in the presence of a suitable solvent. (c) Formula (B3) 【Chemistry 4】 The compound is given by formula (B4) 【Transformation 5】 A step of reacting the compound with a suitable base, a suitable catalyst and a suitable solvent, or (d) Formula (B5) or (B5') 【Transformation 6】 The compound is given by formula (B6) 【Transformation 7】 The process involves reacting the compound with a suitable solvent. (In the formula, L, A １ A ２ , R １ , R ２ , R ３ , R ４ and R ５ is as defined in any one of claims 1 to 14; X is a halogen; R ａ is alkyl, R ｂ and R ｂ’ is independently selected from hydrogen and alkyl, or R ｂ and R ｂ’ These atoms, together with the oxygen atoms to which they are bonded, form a 5-6 membered ring, and the remaining ring members are carbon atoms which may be substituted with one or two alkyl substituents. A method that includes one of the following.

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

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

19. The pharmaceutical composition according to claim 18 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 mellitus, or glomerulonephritis.

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

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

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