New pyrazolopyridine derivatives

Abstract

The application relates to a compound of formula (I) or (II) wherein L, R1, R2, R3 and R4 are as defined in the claims. The compound of formula (I) or (II) can be used as a medicament that modulates SIK activity in autoimmune, inflammatory and other conditions.

Description

[0001] New Pyrazolopyridine Derivatives

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

[0003] The invention relates in particular to a compound of formula (I) or (II) wherein

[0004] L is -O-, -NH-, -S- or absent;

[0005] R1is haloalkyl, hydroxyalkyl, hydroxycycloalkyl, cyano, alkoxyalkyl, R5-carbonyl, or heterocycloalkyl; wherein heterocycloalkyl is optionally substituted with cyano;

[0006] R2is aryl or heteroaryl; wherein each instance of aryl and heteroaryl is optionally substituted with one, two, three or four substituents independently selected from R6;

[0007] R3is hydrogen or alkoxy;

[0008] R4is hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkylalkyl, heteroaryl or heterocycloalkyl; wherein each instance of cycloalkyl, aryl, heterocycloalkylalkyl, heteroaryl and heterocycloalkyl is optionally substituted with one or two substituents independently selected from R7;

[0009] R5is hydrogen, alkyl, alkoxy, alkoxyalkyl or haloalkyl; R6is at each instance independently selected from alkyl, cyano, haloalkyl, halogen, cycloalkyl, aminocarbonyl and alkoxyalkyl; and

[0010] R7is at each instance independently selected from alkyl, cyano, cycloalkyl, haloalkyl, halogen, heterocycloalkyl, heterocycloalkylalkyl, dialkylaminocarbonyl, amino and alkoxy; wherein heterocycloalkyl and heterocycloalkylalkyl are optionally substituted with one or two substituents independently selected from alkyl, alkoxy, halogen and heterocycloalkyl; or a pharmaceutically acceptable salt thereof.

[0011] Salt-inducible kinases (SIK) belong to a subfamily of AMP-activated protein kinases (AMPK) called AMPK -related kinases. There are three members, named SIK1, SIK2 and SIK3, that are broadly expressed. Their major biological role is to modify gene expression by controlling the phosphorylation and subcellular localization of two key classes of transcriptional regulatory factors: CRTCs (cAMP-regulated transcriptional coactivators) and class Ila HDACs (Histone deacetylases). Indeed, in basal state, both CRTCs and HDACs are phosphorylated by SIK kinases, and sequestered in the cytoplasm through interactions with their cytoplasmic chaperones 14-3-3. In response to extracellular cues that usually increase intracellular levels of cAMP, the SIK kinases’ activity is inhibited, CRTCs and HDACs are no longer phosphorylated and are hence released from 14-3-3. They can therefore translocate into the nucleus and regulate gene expression (reviewed in Wein et al., Trends Endocrinol Metab. 2018 Oct;29(10):723-735).

[0012] In macrophages, the inhibition of SIK kinases leads to 1) CRTC3 shuttling to the nucleus and increasing the transcription of IL-10,; and 2) translocation of HDAC4 / 5 to the nucleus and subsequent deacetylation of NF-KB resulting in decreased transcription of pro-inflammatory cytokines (Clark et al., Proc Natl Acad Sci U S A. 2012 Oct 16; 109(42): 16986-91.).

[0013] Macrophages are critical to maintaining tissue homeostasis, mediating inflammation, and promoting the resolution of inflammation. To achieve this diversity of function, macrophages have the ability to “polarize” differently in response to environment cues. The two extreme phenotypes along their activation state continuum are the “Ml” or “pro-inflammatory macrophages” and the “M2” or “pro-resolution macrophages”. Strikingly, the inhibition of intracellular SIK kinases overrides these extracellular macrophage polarization signals and pushes them toward a pro-resolution phenotype. This comes with an increase in IL-10 (by interfering with the SIK-CRTC3 pathway) and a concomitant decrease in TNF-a, IL-12 and IL-6 (by interfering with the SIK-HDAC4 / 5 and NF-KB pathway). The high levels of IL- 10 and low levels of pro-inflammatory cytokines upon SIK inhibition will promote resolution of inflammation. The exploration of the SIK pathway has initially been described in macrophages (Clark et al., Proc Natl Acad Sci U S A. 2012 Oct 16; 109(42): 16986- 91) and dendritic cells (Sundberg et al., Proc Natl Acad Sci U S A. 2014 Aug 26; 111(34): 12468- 73) and the therapeutic potential of pan-SIK inhibitors has been confirmed in a mouse LPS (lipopolysaccharide) challenge model (Sundberg et al., ACS Chem Biol. 2016 Aug 19; 1 l(8):2105-l 1) and in colitis models (Fu et al., Inflamm Bowel Dis. 2021 Oct 20;27(l l): 1821-1831). SIKs have since been shown to be important players in the functions of several immune cells, including mast cells (Darling et al., J Biol Chem. 2021 Jan-

[0014] Jun;296: 100428). Importantly, SIK1 is poorly expressed in macrophages and one embodiment of the invention are SIK2 / 3 inhibitors sparing SIK1, thus limiting potential SIKl-related toxicities.

[0015] SIK inhibitors have a high therapeutic potential in diseases that are 1) characterized by pro- inflammatory macrophage influx in the tissues and impaired tissue homeostasis and healing, or 2) where anti-TNF therapies are beneficial (partially or fully) or with insufficient levels of the IL10. Diseases with an inflammatory macrophage signature are e.g. rheumatoid arthritis, juvenile rheumatoid arthritis, NASH, primary sclerosing cholangitis, giant cell vasculitis and inflammatory bowel diseases (“IBD”), atherosclerosis, type 2 diabetes and glomerulonephritis.

[0016] Diseases with a proven link to IL-10 and TNF-a are IBD. Genetic alterations that reduce the function of IL- 10 (such as SNPs in IL- 10 or its receptor) are associated with an increased risk for IBD in humans. In addition, anti-TNF therapies are successful but only a subset of IBD patients are responsive and much of this limited responsiveness is lost over time. The described dual effect of SIK inhibitors (increased IL- 10 and decreased TNF-a) make them particularly pertinent for the treatment of IBD.

[0017] All three SIK kinase isoforms are expressed broadly in human tissues with the highest expression observed in skin and adipose tissues for SIK1, adipose tissue for SIK2 and testis and brain for SIK3. Similarly to their role in macrophages, SIKs in these cells phosphorylate CRTCs and class II HDACs in response to extracellular signals, which subsequently change the expression of several cellular factors.

[0018] In addition to their physiological roles, reports have linked dysregulation of SIK expression to a few diseases. For example, SIK2 has been described as a risk locus for primary sclerosing cholangitis, a fibrotic disease regularly associated with IBD. In addition, SIK2 and SIK3 expression is higher in ovarian and prostate cancers and correlated with poor survival (Miranda et al., Cancer Cell. 2016 Aug 8;30(2):273-289; Bon et al., Mol Cancer Res. 2015 Apr; 13 (4): 620- 635).

[0019] As of today many diseases caused by dysregulation of the innate immune system lack efficient therapies and there is a high unmet medical need for new therapies. The present invention relates to a novel compounds that are highly active SIK inhibitors for the treatment of inflammatory, allergic and autoimmune diseases. In addition to inflammation, allergic and autoimmune diseases, SIK inhibitors can thus also be of potential relevance in cancer, metabolic diseases, bone density dysregulation diseases, pigmentation-related diseases or cosmetology, fibrotic diseases and depressive disorders.

[0020] In the present description the term “alkyl”, alone or in combination, signifies a straightchain or branched-chain alkyl group with 1 to 8 carbon atoms, particularly a straight or branched- chain alkyl group with 1 to 6 carbon atoms and more particularly a straight or branched-chain alkyl group with 1 to 4 carbon atoms. Examples of straight-chain and branched-chain C1-C8 alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.- butyl, the isomeric pentyls, the isomeric hexyls, the isomeric heptyls and the isomeric octyls, particularly methyl, ethyl, propyl, butyl and pentyl. Particular examples of alkyl are methyl, ethyl, propyl, isopropyl, butyl and isobutyl. Methyl and ethyl are further particular examples of “alkyl” in the compound of formula (I) or (II).

[0021] The term “cycloalkyl”, alone or in combination, signifies a cycloalkyl ring with 3 to 8 carbon atoms and particularly a cycloalkyl ring with 3 to 6 carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. A particular example of “cycloalkyl” is cyclopropyl. The term “cyano”, alone or in combination, signifies a -CN group, wherein the carbon and the nitrogen atom are connected via a triple bond.

[0022] The term “hydroxycycloalkyl”, alone or in combination, signifies a “hydroxyl” group linked to a “cycloalkyl” group. Examples of “hydroxycycloalkyl” include, but are not limited to, 1 -hydroxy cyclopropyl, 2 -hydroxy cyclopropyl, 1 -hydroxy cyclobutyl, 2 -hydroxy cyclobutyl and 3- hydroxy cyclobutyl. A particular example of “hydroxycycloalkyl” is 1 -hydroxycyclopropyl, also referred to as cyclopropan-l-ol.

[0023] The term “heterocycloalkyl”, alone or in combination, denotes a monovalent saturated or partly unsaturated mono- or bicyclic ring system of 4 to 12 ring atoms, comprising 1, 2, or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Bicyclic means consisting of two cycles having one or two ring atoms in common. “Hetercycloylkyl” may comprise a carbonyl group, wherein the carbon is part of the ring system. The ring system can be attached to the remaining compound via an atom selected from C, N, S and O, in particular via a N atom (“N-heterocycloalkyl). Examples of “heterocycloalkyl” include, but are not limited to, morpholino, morpholin-4-yl, pyrrolidinyl, pyrrolidin-l-yl, pyrrolidin-3-yl, piperidinyl, piperidin- 4-yl, piperidin-4-yl, 2-oxopyrrolidin-l-yl, piperazinyl, piperazin- 1-yl, azetidinyl, azetidin-l-yl, tetrahydrofuran-2-yl, [3-oxo-piperazin-l-yl], (l,l-dioxo-l,2-thiazolidin-2-yl), (4, 5,6,7- tetrahydropyrazolo[4,3-c]pyridin-l-yl), (3-oxo-l,5,6,8-tetrahydrooxazolo[3,4-a]pyrazin-7-yl), [rac-(3aR,6aS)-2,3,3a,5,6,6a-hexahydro-lH-pyrrolo[3,2-b]pyrrol-4-yl], [rac-(3aS,6aR)-

[0024] 2,3,3a,5,6,6a-hexahydro-lH-pyrrolo[3,2-b]pyrrol-4-yl], (4-oxo-6,7-dihydro-5H-pyrazolo[l,5- a]pyrazin-3-yl), (6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-l-yl), (4,7-diazaspiro[2.5]octan-7-yl), (2- oxa-5,8-diazaspiro[3.5]nonan-8-yl), 3-azabicyclo[3.2.0]heptan-3-yl), (5-azaspiro[2.4]heptan-5- yl), (2-azabicyclo[2.2.1]heptan-2-yl), 4-oxa-7-azaspiro[2.5]octan-7-yl, (3-azabicyclo[3.1.0]hexan- 3-yl), (6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-l-yl), 2-oxa-7-azaspiro[3.4]octan-7-yl, 2-oxa-6- azaspiro[3.3]heptan-6-yl, (2-oxo-l -piperidyl), (2,3-dihydropyridazino[4,5-b][l,4]oxazin-8-yl), pyrrolidin-l-yl, 2-oxo-pyrimidin-4-yl, 2-oxa-5-azaspiro[3.4]octan-5-yl, oxetan-3-yl, (2-oxo-l- piperidyl), 2-oxo-4-piperidyl, 5-oxo-pyrrolidin-3-yl, 2-oxa-5-azaspiro[3.4]octan-5-yl, (7,8- dihydro-5H-pyrano[4,3-c]pyridazin-3-yl), [rac-(4aS,7aR)-4-methyl-2,3,4a,5,7,7a- hexahydropyrrolo[3,4-b][l,4]oxazin-6-yl], 6,7-dihydro-5H-cyclopenta[c]pyridazin-3-yl, 5,6- dihydropyrrolo[2,3-c]pyridazin-7-yl, 7-oxo-5H-pyrrolo[3,4-b]pyridin-2-yl, 5,6-dihydro-4H- pyrazolo[4,3-c]pyridin-l-yl, 6-azaspiro[3.4]octan-6-yl and [rac-(3aS,6aS)-6-oxo-2,3,3a,4,5,6a- hexahydropyrrolo[2,3-c]pyrrol-l-yl]. Particular examples of “heterocycloalkyl” are tetrahydrofuran-2-yl, oxetan-3-yl, morpholin-4-yl, piperazin- 1-yl; azepan-4-yl, pyrrolidin-l-yl and piperidin-4-yl. In one particular embodiment, heterocycloalkyl is “N-heterocycloalkyl”.

[0025] The term “heteroaryl”, alone or in combination, signifies an aromatic mono- or bicyclic ring system with 5 to 12 ring atoms, comprising 1, 2, 3 or 4 heteroatoms each independently selected from N, O and S, the remaining ring atoms being carbon. The ring system can be attached to the remaining compound via an atom selected from C, N, S and O, in particular via a N atom (“N- heteroaryl”). Examples of heteroaryl include, but are not limited to, pyrazolyl, pyrazol-l-yl, pyrazol-3-yl, pyrazol-4-yl, pyridinyl, 2-pyridyl, 3 -pyridyl, 4-pyridyl, pyridazinyl, pyridazin-3-yl, pyridazin-4-yl, pyrazinyl, pyrazin-2-yl, isoxazolyl, isoxazol-3-yl, isoxazol-4-yl, oxazolyl, 2- oxazol-5-yl, 2-oxo-3-imidazol-l-yl, pyrimidinyl, pyrimidin-5-yl, benzotriazolyl, IH-benzotriazol- 4-yl, furanyl, furyl, 2-furyl, 3-furyl, [6-oxo-lH-pyridazin-5-yl], triazolyl, triazol-l-yl, triazol-2-yl, triazol-3-yl, triazol-4-yl, pyridin-2-one, 2-oxo-4-pyridyl. pyrimidin-2-yl, pyrimidin-5-yl, (1,3,4- oxadiazol-2-yl), (l,3,4-thiadiazol-2-yl), (l,2,4-triazin-3-yl), 2-oxo-pyrimidin-4-yl, (l-methyl-2- oxo-3 -pyridyl), 5-methyl-6-oxo-4H-pyrrolo[3,4-c]pyrazol-2-yl, and (2,3-dihydropyridazino[4,5- b][l,4]oxazin-8-yl). Particular examples of “heteroaryl” are pyrazol-l-yl, pyrazol-4-yl, pyridazin- 3-yl, pyridin-2-one, triazol-4-yl and 5-methyl-6-oxo-4H-pyrrolo[3,4-c]pyrazol-2-yl, a more particular example is pyridazin-3-yl. In one particular embodiment, heteroaryl is “N-heteroaryl”.

[0026] The term “aryl”, alone or in combination, denotes a monovalent aromatic carbocyclic mono- or bicyclic ring system comprising 6 to 10 carbon ring atoms. Examples of aryl moi eties include phenyl and naphthyl. A particular example of aryl is phenyl.

[0027] The term “heterocycloalkylalkyl”, alone or in combination, denotes a “heterocycloalkyl” group linked to an “alkyl” group, wherein the alkyl is further linked to the relevant compound. Particular examples of’ heterocycloalkylalkyl” are 2-morpholin-4-ylethyl and 2-morpholin-4- ylmethyl, more particular 2-morpholin-4-yl ethyl.

[0028] The term “alkoxy” or “alkyloxy”, alone or in combination, signifies a group of the formula alkyl-O- in which the term "alkyl" has the previously given significance, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert.-butoxy. Particular examples of “alkoxy” are methoxy and ethoxy.

[0029] The term “alkoxyalkyl” or “alkyloxyalkyl”, alone or in combination, signifies a group of the formula alkyl-O-alkyl in which the term "alkyl" has the previously given significance, such as for instance methoxymethyl, methoxyethyl, ethoxymethyl, n-propoxym ethyl, isopropoxymethyl, n-butoxymethyl, isobutoxymethyl, sec-butoxym ethyl and tert.-butoxym ethyl. Particular example of “alkoxyalkyl” are methoxy ethyl and methoxymethyl.

[0030] The term “oxy”, alone or in combination, signifies the -O- group.

[0031] The terms “halogen” or “halo”, alone or in combination, signifies fluorine, chlorine, bromine or iodine and particularly fluorine or chlorine, more particularly fluorine. The term “halo”, in combination with another group, denotes the substitution of said group with at least one halogen, particularly substituted with one to five halogens, particularly one to four halogens, i.e. one, two, three or four halogens.

[0032] The term “haloalkyl”, alone or in combination, denotes an alkyl group substituted with at least one halogen, particularly substituted with one to five halogens, particularly one to three halogens, more particularly two to three halogens. Examples of “haloalkyl” include, but are not limited to, fluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl, difluoromethyl, difluoroethyl, trifluoromethyl and trifluoroethyl. Particular “haloalkyl” are difluoromethyl, trifluoromethyl and tri fluoroethyl.

[0033] The term “haloalkoxy”, alone or in combination, denotes an alkoxy group substituted with at least one halogen, particularly substituted with one to five halogens, particularly one to three halogens. Particular “haloalkoxy” are fluoromethoxy, fluoroethoxy and fluoropropyloxy.

[0034] The terms “hydroxyl” and “hydroxy”, alone or in combination, signify the -OH group.

[0035] The terms “hydroxylalkyl” and “hydroxyalkyl”, alone or in combination, signify that the - OH group is linked to an alkyl group. Particular “hydroxyalkyl” are hydroxymethyl, hydroxyethyl and hydroxypropyl, more particularly 1 -hydroxy ethyl.

[0036] The term “carbonyl”, alone or in combination, signifies the -C(O)- group. The term “amino”, alone or in combination, signifies the primary amino group (-NH2), the secondary amino group (-NH-), or the tertiary amino group (-N-).

[0037] The term “alkylamino” is an alkyl group linked to a -NH- group, such as for instance methylamino, wherein the amino is further linked to the relevant compound. The term “dialkylamino” denotes two alkyl groups linked to a -N- atom, such as for instance dimethylamino, wherein the amino is further linked to the relevant compound.

[0038] The term “alkylcarbonyl”, is an alkyl group linked to a -C(O)- group, wherein the carbonyl is further linked to the relevant compound. Particular “alkylcarbonyl” are methylcarbonyl (also known as acetyl) and ethylcarbonyl.

[0039] The term “aminocarbonyl”, alone or in combination, denotes an “amino” group linked to a “carbonyl” group, wherein the carbonyl is further linked to the relevant compound.

[0040] The term “dialkylaminocarbonyl”, alone or in combination, denotes a “dialkylamino” group linked to a “carbonyl” group, wherein the carbonyl is further linked to the relevant compound.

[0041] The term “sulfonyl”, alone or in combination, signifies the -SO2- group.

[0042] The term “pharmaceutically acceptable salts” denotes salts which are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid and base addition salts. The term “pharmaceutically acceptable acid addition salt” denotes those pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and organic acids selected from aliphatic, cycloaliphatic, aromatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicyclic acid. The term “pharmaceutically acceptable base addition salt” denotes those pharmaceutically acceptable salts formed with an organic or inorganic base. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, and polyamine resins.

[0043] The term “compound(s) of this invention” and “compound(s) of the present invention” refers to compounds of formula (I) or (II) and stereoisomers, tautomers, solvates, and salts (e.g., pharmaceutically acceptable salts) thereof.

[0044] Tautomeric forms, i.e. structural isomers which interconvert with the compound of formula (I) or (II), in particular in solution, may in some instances exist and are to be understood as being included in the invention.

[0045] If one of the starting materials or compounds of formula (I) or (II) contain one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups (as described e.g. in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wuts, 3rdEd., 1999, Wiley, New York) can be introduced before the critical step applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature. Examples of protecting groups are tert-butoxy carbonyl (Boc), 9-fluorenylmethyl carbamate (Fmoc), 2-trimethylsilylethyl carbamate (Teoc), carbobenzyl oxy (Cbz) and p- methoxybenzyloxycarbonyl (Moz).

[0046] The compound of formula (I) or (II) can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.

[0047] The term “asymmetric carbon atom” means a carbon atom with four different substituents. According to the Cahn-Ingold-Prelog Convention an asymmetric carbon atom can be of the “R” or “S” configuration. Furthermore, the invention includes all optical isomers, i.e. diastereoisomers, diastereomeric mixtures, racemic mixtures, all their corresponding enantiomers and / or tautomers as well as their solvates, wherever applicable, of the compound of formula (I) or (II).

[0048] If desired, racemic mixtures of the compound of the invention may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.

[0049] In the embodiments, where an optically pure enantiomer is provided, optically pure enantiomer means that the compound contains > 90 % of the desired isomer by weight, particularly > 95 % of the desired isomer by weight, or more particularly > 99 % of the desired isomer by weight, said weight percent based upon the total weight of the isomer of the compound. A chirally pure or chirally enriched compound may be prepared by chirally selective synthesis or by separation of enantiomers. The separation of enantiomers may be carried out on the final product or alternatively on a suitable intermediate.

[0050] Structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Particular examples of radioisotopes are2H,3H,13C,14C and18F. For example the structures wherein one or more hydrogen atoms are replaced by deuterium or tritium, or one or more carbon atoms are replaced by a13C- or14C- enriched carbon are within the scope of this invention.

[0051] The invention thus relates to:

[0052] A compound according to the invention, wherein R1is difluoromethyl, hydroxymethyl, 1- hydroxyethyl, 1 -hydroxy cyclopropyl, cyano, methoxymethyl, R5-carbonyl, or heterocycloalkyl, wherein heterocycloalkyl is optionally substituted with cyano; a particular heterocycloalkyl is tetrahy drofuran-2 -yl ;

[0053] A compound according to the invention, wherein R2is phenyl or heteroaryl selected from pyrazol-l-yl, pyrazol-4-yl, pyridin-2-one, triazol-4-yl and 5-methyl-6-oxo-4H-pyrrolo[3,4- c]pyrazol-2-yl; wherein each instance of phenyl and heteroaryl is optionally substituted with one or two substituents independently selected from R6;

[0054] A compound according to the invention, wherein R3is methoxy or hydrogen, in particular hydrogen;

[0055] A compound according to the invention, wherein R4is hydrogen, methyl, 2-morpholino-4- ethyl, pyridazin-3-yl or heterocycloalkyl selected from azepan-4-yl, piperazin- 1-yl, pyrrolidin-1- yl, 7,8-dihydro-5H-pyrano[4,3-c]pyridazin-3-yl and piperidin-4-yl; wherein each instance of 2- morpholino-4-ethyl, pyridazin-3-yl and heterocycloalkyl is optionally substituted with one or two substituents independently selected from R7;

[0056] A compound according to the invention, wherein R4is pyridazin-3-yl optionally substituted with one or two substituents independently selected from R7;

[0057] A compound according to the invention, wherein R4is pyridazin-3-yl substituted with alkyl, in particular methyl;

[0058] A compound according to the invention, wherein R5is hydrogen, methyl or ethyl;

[0059] A compound according to the invention, wherein R6is at each instance independently selected from methyl, cyano, trifluoroethyl, trifluoromethyl, difluoromethyl, fluoro, chloro, cychlopropyl, aminocarbonyl and methoxyethyl;

[0060] A compound according to the invention, wherein R7is at each instance independently selected from methyl, cyclopropyl, difluoromethyl, trifluoroethyl, fluoro, chloro, dimethylaminocarbonyl, heterocycloalkyl and heterocycloalkyl alkyl; wherein heterocycloalkyl of R7is selected from oxetan-3-yl, morpholin-4-yl and piperazin- 1-yl; wherein heterocycloalkyl alkyl of R7is selected from (azetidin-l-yl)methyl, 2-oxa-6-azaspiro[3.3]heptan- 6-ylmethyl, morpholin-4-ylmethyl, morpholin-4-ylethyl, azetidin-l-ylmethyl and piperazin-1- ylmethyl; and wherein heterocycloalkyl and heterocycloalkylalkyl of R7are optionally substituted with one or two substituents independently selected from alkoxy, halogen and heterocycloalkyl; and

[0061] A compound according to the invention, wherein L is -O-. In one embodiment, the compound of the invention is a compound is of formula (I) wherein the substituents are as described herein.

[0062] In one embodiment, the compound of the invention is a compound is of formula (II) wherein the substituents are as described herein.

[0063] In one embodiment, the compound of the invention is a compound is of formula (I) wherein

[0064] L is -O-, -NH-, -S- or absent;

[0065] R1is haloalkyl, hydroxyalkyl, hydroxycycloalkyl, cyano, alkoxyalkyl, R5-carbonyl, or tetrahydrofuran-2-yl; wherein tetrahydrofuran-2-yl is optionally substituted with cyano;

[0066] R2is aryl or heteroaryl; wherein each instance of aryl and heteroaryl is optionally substituted with one, two, three or four substituents independently selected from R6; R3is hydrogen or alkoxy;

[0067] R4is hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkylalkyl, heteroaryl or heterocycloalkyl; wherein each instance of cycloalkyl, aryl, heterocycloalkylalkyl, heteroaryl and heterocycloalkyl is optionally substituted with one or two substituents independently selected from R7;

[0068] R5is hydrogen, alkyl, alkoxy, alkoxyalkyl or haloalkyl;

[0069] R6is at each instance independently selected from alkyl, cyano, haloalkyl, halogen, cycloalkyl, aminocarbonyl and alkoxyalkyl; and

[0070] R7is at each instance independently selected from alkyl, cyano, cycloalkyl, haloalkyl, halogen, heterocycloalkyl, heterocycloalkylalkyl, dialkylaminocarbonyl, amino and alkoxy; wherein heterocycloalkyl and heterocycloalkylalkyl are optionally substituted with one or two substituents independently selected from alkoxy, halogen and heterocycloalkyl; or a pharmaceutically acceptable salt thereof.

[0071] In one embodiment, the compound of formula (II) is a compound of formula (Il-a) wherein

[0072] L is -0-, -NH-, -S- or absent;

[0073] R1is hydrogen, alkyl, alkoxy, alkoxyalkyl or haloalkyl; R2is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl; wherein each instance of cycloalkyl, aryl, heteroaryl and heterocycloalkyl is optionally substituted with one, two or three substituents independently selected from R5;

[0074] R3is hydrogen, alkoxy, alkyl, haloalkyl, or haloalkoxy;

[0075] R4is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl or heterocycloalkyl alkyl; wherein each instance of cycloalkyl, aryl, heteroaryl, heterocycloalkyl and heterocycloalkylalkyl is optionally substituted with one or two substituents independently selected from R6;

[0076] R5is alkyl, cyano, haloalkyl, halogen, cycloalkyl, alkoxy or aminocarbonyl; and

[0077] R6is at each instance independently selected from alkyl, cyano, haloalkyl, halogen, alkoxy, alkoxyheterocycloalkylalkyl, alkylheterocycloalkyl, haloalkyl, heterocycloalkyl, heterocycloalkylalkyl, haloheterocycloalkylalkyl, alkoxyheterocycloalkylalkyl or amino; or a pharmaceutically acceptable salt thereof.

[0078] In one embodiment, the compound of formula (II) is a compound of formula (Il-a) wherein

[0079] L is -O-, or absent;

[0080] R1is alkyl;

[0081] R2is heteroaryl optionally substituted with one or two substituents independently selected from R5; R3is hydrogen;

[0082] R4is hydrogen, alkyl, heteroaryl, heterocycloalkyl or heterocycloalkylalkyl; wherein each instance of heteroaryl, heterocycloalkyl and heterocycloalkylalkyl is optionally substituted with R6;

[0083] R5is haloalkyl, halogen or cycloalkyl; and

[0084] R6is alkyl or heterocycloalkyl; or a pharmaceutically acceptable salt thereof.

[0085] The invention also relates to a compound according to the invention selected from l-[3-(l-hydroxyethyl)-6-[6-[4-(oxetan-3-yl)piperazin-l-yl]pyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile;

[0086] 1 -[3 -( 1 -hydroxy ethyl)-6-[6-[rac-(3R,4R)-3 -amino-4-fluoropyrrolidin- 1 -yl]pyrazolo[ 1,5- a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[3-(l-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]pyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[3-[(lS)-l-hydroxyethyl]-6-[6-[(6-methylpyridazin-3-yl)amino]pyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[3-[(lR)-l-hydroxyethyl]-6-[6-[(6-methylpyridazin-3-yl)amino]pyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[3-(l-hydroxyethyl)-6-[6-[[6-[(3-methoxyazetidin-l-yl)methyl]pyridazin-3- yl]amino]pyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[6-[6-[[6-[(3-fluoroazetidin-l-yl)methyl]pyridazin-3-yl]amino]pyrazolo[l,5-a]pyridin-3- yl]-3-(l-hydroxyethyl)pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[6-[6-[[6-[(3,3-difluoroazetidin-l-yl)methyl]pyridazin-3-yl]amino]pyrazolo[l,5- a]pyridin-3-yl]-3-(l-hydroxyethyl)pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[3-[(lS)-l-hydroxyethyl]-6-[6-[[6-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)pyridazin-3- yl]amino]pyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[3-[(lR)-l-hydroxyethyl]-6-[6-[[6-[(3-methoxyazetidin-l-yl)methyl]pyridazin-3- yl]amino]pyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[3-[(lS)-l-hydroxyethyl]-6-[6-[[6-[(3-methoxyazetidin-l-yl)methyl]pyridazin-3- yl]amino]pyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[3-[(lS)-l-hydroxyethyl]-6-[5-methoxy-6-[(6-methylpyridazin-3-yl)amino]pyrazolo[l,5- a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile;

[0087] 3-[3-(l -hydroxyethyl)-6-[6-(2-morpholin-4-yl ethoxy )pyrazolo[l,5-a]pyri din-3-yl]pyri din-

[0088] 2-yl]benzonitrile; l-[3-(l-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[3-[(lS)-l-hydroxyethyl]-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[3-[(lR)-l-hydroxyethyl]-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile;

[0089] 3-fluoro-4-[3-(l-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-l-(2,2,2-trifluoroethyl)pyridin-2-one;

[0090] (lS)-l-[2-[3-(difluoromethyl)-5-methylpyrazol-l-yl]-6-[6-(6-methylpyridazin-3- yl )oxypyrazol o [ 1 , 5 -a] pyri din-3 -yl ] pyri din-3 -yl ] ethanol ;

[0091] (lR)-l-[2-[3-(difluoromethyl)-5-methylpyrazol-l-yl]-6-[6-(6-methylpyridazin-3- yl )oxypyrazol o [ 1 , 5 -a] pyri din-3 -yl ] pyri din-3 -yl ] ethanol ; l-[3-(hydroxymethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; 5-(difluoromethyl)-l-[3-(l-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5- a]pyridin-3-yl]pyridin-2-yl]pyrazole-3-carbonitrile;

[0092] 5 -(difluoromethyl)- 1 - [3 -[( 1 S)- 1 -hydroxy ethyl] -6- [6-(6-methylpyridazin-3 - yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]pyrazole-3-carbonitrile;

[0093] 5-(difluoromethyl)-l-[3-[(lR)-l-hydroxyethyl]-6-[6-(6-methylpyridazin-3- yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]pyrazole-3-carbonitrile; l-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyri din-3-yl]-2-[3-methyl- 1 -(2,2,2- trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]ethanol;

[0094] 1-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyri din-3-yl]-2-[5-methyl-l -(2,2,2- trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]ethanol;

[0095] 5-chloro-2-[3-(l -hydroxy ethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyri din-3 - yl]pyridin-2-yl]pyrazole-3-carbonitrile;

[0096] 5-cyclopropyl-l-[3-(l-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5- a]pyridin-3-yl]pyridin-2-yl]pyrazole-3-carbonitrile;

[0097] 5-cyclopropyl-2-[3-(l-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5- a]pyridin-3-yl]pyridin-2-yl]pyrazole-3-carbonitrile;

[0098] 5-(difluoromethyl)-l-[3-(l-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5- a]pyri din-3 -yl]pyridin-2-yl]pyrazole-3 -carboxamide;

[0099] 2-[3-(l-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-3-carbonitrile;

[0100] 1-[6-[6-(6-chloropyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-3-(l- hydroxyethyl)pyridin-2-yl]-5-methylpyrazole-3-carbonitrile;

[0101] 2-[3-(l-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3- yl]pyri din-2 -yl]-3,5-dimethyl-4H-pyrrolo[3,4-c]pyrazol-6-one; l-[2-[3-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]-6-[6-(6-morpholin-4-ylpyridazin-3- yl )oxypyrazol o [ 1 , 5 -a] pyri din-3 -yl ] pyri din-3 -yl ] ethanol ; l-[2-[3-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]-6-[6-[6-(morpholin-4- ylmethyl)pyridazin-3-yl]oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-3-yl]ethanol; l-[2-[5-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]-6-[6-(6-morpholin-4-ylpyridazin-3- yl )oxypyrazol o [ 1 , 5 -a] pyri din-3 -yl ] pyri din-3 -yl ] ethanol ; l-[6-[6-[6-(difluoromethyl)pyridazin-3-yl]oxypyrazolo[l,5-a]pyridin-3-yl]-3-[(lS)-l- hydroxyethyl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[6-[6-[6-(4-methylpiperazin-l-yl)pyridazin-3-yl]oxypyrazolo[l,5-a]pyridin-3-yl]-2-[3- methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]ethanol; l-[2-[3-(difluoromethyl)-5-methylpyrazol-l-yl]-6-[6-[6-[(3-methoxyazetidin-l- yl)methyl]pyridazin-3-yl]oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-3-yl]ethanol; l-[3-(l-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)sulfanylpyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[3-(l-hydroxyethyl)-6-pyrazolo[l,5-a]pyridin-3-ylpyridin-2-yl]-5-methylpyrazole-3- carbonitrile;

[0102] 1 -[2-[6-[4-(ox etan-3 -yl)piperazin- 1 -yl]pyrazolo[ 1 , 5-a]pyri din-3 -yl]-4-[ 1 -(2,2,2- trifluoroethyl)pyrazol-4-yl]-l,3-thiazol-5-yl]ethanol;

[0103] 1 -cyclopropyl-4-[5-( 1 -hydroxy ethyl)-2-(6-methoxypyrazolo[ 1 ,5 -a]pyri din-3 -yl)- 1,3- thiazol-4-yl]pyridin-2-one;

[0104] 4-[5-(l -hydroxyethyl)-2-[6-(2-morpholin-4-yl ethoxy )pyrazolo[l,5-a]pyri din-3 -yl]- 1,3- thiazol-4-yl]-l-(2,2,2-trifluoroethyl)pyridin-2-one;

[0105] 1 -[2-[6-(2-morpholin-4-yl ethoxy )pyrazolo[ 1 , 5-a]pyri din-3 -yl]-4-[ 1 -(2,2,2- trifluoroethyl)pyrazol-4-yl]-l,3-thiazol-5-yl]ethanol; 1 -[2-[6-(6-methylpyridazin-3 -yl)oxypyrazolo[ 1 , 5-a]pyri din-3 -yl ] -4- [ 1 -(2,2,2- trifluoroethyl)pyrazol-4-yl]-l,3-thiazol-5-yl]ethanol;

[0106] 3-fluoro-4-[5-(l-hydroxyethyl)-2-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3- yl]- 1 ,3 -thi azol -4-yl]- 1 -(2,2,2-trifluoroethyl)pyridin-2-one; l-[2-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-4-[2-(2,2,2- tri fluoroethyl )tri azol -4-yl ] - 1 , 3 -thi azol - 5 -yl ] ethanol ; l-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5- methylpyrazole-3 -carbonitrile;

[0107] 1-[3-formyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5- methylpyrazole-3 -carbonitrile;

[0108] 2-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5- (trifluoromethyl)pyrazole-3-carbonitrile;

[0109] 1-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5- cyclopropylpyrazole-3-carbonitrile;

[0110] 2-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5- cyclopropylpyrazole-3-carbonitrile; l-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5- (difluoromethyl)pyrazole-3-carbonitrile;

[0111] 1 -[6-[6-(6-methylpyridazin-3 -yl)oxypyrazolo[ 1 , 5-a]pyri din-3 -yl]-2-[ 1 -(2,2,2- trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]propan-l-one; l-[3-(difluoromethyl)-6-[5-methoxy-6-[(6-methylpyridazin-3-yl)amino]pyrazolo[l,5- a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[3-(difluoromethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; 3-[5-(difluoromethyl)-6-[3-methyl- 1 -(2,2, 2 -trifluoroethyl )pyrazol-4-yl]pyri din-2 -yl]-6-(6- methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridine;

[0112] 3-[5-(difluoromethyl)-6-[5-methyl- 1 -(2,2, 2-trifluoroethyl)pyrazol-4-yl]pyri din-2 -yl]-6-(6- methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridine; l-[3-(methoxymethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyri din-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile;

[0113] 5-methyl-l-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-3-[trans-4- cyanooxolan-2-yl]pyridin-2-yl]pyrazole-3-carbonitrile;

[0114] 5-methyl-l-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-3-[cis-4- cyanooxolan-2-yl]pyridin-2-yl]pyrazole-3-carbonitrile;

[0115] 1-[3-(l-hydroxyethyl)-6-[6-[l-(oxetan-3-yl)piperidin-4-yl]oxypyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile;

[0116] 3-[3-[6-(3-cyano-5-methylpyrazol-l-yl)-5-(l-hydroxyethyl)pyridin-2-yl]pyrazolo[l,5- a]pyridin-6-yl]oxy-N,N,6-trimethylpyridazine-4-carboxamide;

[0117] 3-[5-(difluoromethyl)-6-[3-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-2-yl]-6-[6- [[4-(oxetan-3-yl)piperazin-l-yl]methyl]pyridazin-3-yl]oxypyrazolo[l,5-a]pyridine;

[0118] 3-[5-(difluoromethyl)-6-[5-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-2-yl]-6-[6- [[4-(oxetan-3-yl)piperazin-l-yl]methyl]pyridazin-3-yl]oxypyrazolo[l,5-a]pyridine;

[0119] 4-[[6-[3-[5-(difluoromethyl)-6-[3-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyri din-2- yl]pyrazolo[l,5-a]pyridin-6-yl]oxypyridazin-3-yl]methyl]morpholine;

[0120] 2-[3-(difluoromethyl)-5-methylpyrazol-l-yl]-6-[5-methoxy-6-[(6-methylpyridazin-3- yl)amino]pyrazolo[l,5-a]pyridin-3-yl]pyridine-3-carbonitrile;

[0121] (lS)-l-[2-[3,5-bis(difluoromethyl)pyrazol-l-yl]-6-[6-(7,8-dihydro-5H-pyrano[4,3- c]pyridazin-3-yloxy)pyrazolo[l,5-a]pyridin-3-yl]pyridin-3-yl]ethanol; 5-methyl-l-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-3- propanoylpyridin-2-yl]pyrazole-3-carbonitrile; l-[3-(l-hydroxyethyl)-6-[6-[l-(oxetan-3-yl)azepan-4-yl]oxypyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[3-(difluoromethyl)-6-[6-[[l-(oxetan-3-yl)piperidin-4-yl]amino]pyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile;

[0122] 1 -[6-[6-(6-methylpyridazin-3 -yl)oxypyrazolo[ 1 , 5-a]pyri din-3 -yl ] -2- [ 1 -(2,2,2- trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]cyclopropan-l-ol;

[0123] (1 S)-l-[2-[3-(2 -methoxy ethyl)-5-methylpyrazol-l-yl]-6-[6-(6-methylpyridazin-3- yl )oxypyrazol o [ 1 , 5 -a] pyri din-3 -yl ] pyri din-3 -yl ] ethanol ;

[0124] 1 - [3 -( 1 -hydroxyethyl)-6-[6-[ 1 -(2,2,2-trifluoroethyl)piperidin-4-yl]oxypyrazolo[ 1,5- a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; and

[0125] 1 -[6-[6-(l -cyclopropylpiperidin-4-yl)oxypyrazolo[ 1 ,5 -a]pyri din-3 -yl ] -3 -[( 1 S)- 1 - hydroxyethyl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; or a pharmaceutically acceptable salt thereof.

[0126] The invention further in particular relates to a compound according to the invention selected from l-[3-(l-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]pyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[3-[(lS)-l-hydroxyethyl]-6-[6-[(6-methylpyridazin-3-yl)amino]pyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[3-[(lS)-l-hydroxyethyl]-6-[5-methoxy-6-[(6-methylpyridazin-3-yl)amino]pyrazolo[l,5- a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[3-(l-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; and l-[3-[(lS)-l-hydroxyethyl]-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; or a pharmaceutically acceptable salt thereof.

[0127] The invention also relates to a process for the preparation of a compound according to the invention, comprising at least one of the following steps:

[0128] (a) the reaction of a compound of formula (Al) with a compound of formula (A2)

[0129] R4-L-H (A2), in presence of a suitable catalyst, a suitable solvent and a suitable base;

[0130] (b) the reaction of a compound of formula (Bl) with a suitable reduction agent, in presence of a suitable solvent; or

[0131] (c) the reaction of a compound of formula (Cl) with a compound of formula (C2)

[0132] R2-(B(OH)2(C2) in presence of a suitable catalyst, a suitable solvent and a suitable base; wherein L, R1, R2, R3and R4are as described herein;

[0133] In step (a) of the above process, the catalyst can be a suitable Pd catalyst, such as for instance chloro(crotyl)[l,2,3,4,5-pentaphenyl-r-(di-tert-butylphosphino)ferrocene]palladium(II);

[0134] In step (a) of the above process, the solvent can be an aprotic and non-polar organic solvent, such as for instance 1,4-di oxane;

[0135] In step (a) of the above process, the base can be a suitable inorganic base, such as for instance CS2CO3;

[0136] In step (b) of the above process, the reduction agent can be for instance NaBH4;

[0137] In step (b) of the above process, the solvent can be a suitable organic solvent, such as for instance MeOH, THF or a mixture thereof;

[0138] In step (c) of the above process, the catalyst can be a suitable Pd catalyst, such as for instance l,l'-bis(diphenylphosphino)ferrocene-palladium(II)di chloride;

[0139] In step (c) of the above process, the solvent can be for instance DMF, THF, 1,4-di oxane, water or a mixture thereof; preferably the solvent is a mixture of DMF and water;

[0140] In step (c) of the above process, the base can be a suitable inorganic base, such as for instance K2CO3, Na2COs or CS2CO3; The invention also relates to a compound according to the invention when manufactured according to a process as described herein.

[0141] The invention further also relates to:

[0142] A compound according to the invention, for use as therapeutically active substance;

[0143] A pharmaceutical composition comprising a compound according the invention and a therapeutically inert carrier;

[0144] The use of a compound according to the invention, for the treatment or prophylaxis of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel diseases (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis;

[0145] The use of a compound according to the invention, for the preparation of a medicament for the treatment or prophylaxis rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel diseases (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis;

[0146] A compound according to the invention, for use in the treatment or prophylaxis of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel diseases (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis; and

[0147] A method for the treatment or prophylaxis of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel diseases (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis, which method comprises administering an effective amount of a compound according to the invention, to a patient in need thereof.

[0148] A method for the treatment tof rheumatoid arthritis, juvenile rheumatoid arthritis, nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel diseases (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis, which method comprises administering an effective amount of a compound according to the invention, to a patient in need thereof.

[0149] General Synthetic Schemes

[0150] The synthesis of the compound of formula (I) or (II) can, for example, be accomplished according to the non-exhaustive procedures described below in general Schemes 1-4. In some instances, the sequence of the reaction steps can be altered and the individual steps of the different schemes can be combined in different ways as disclosed herein and according to common general knowledge. In general, the reaction conditions provided below and the reaction conditions can in some instances be further modified according to the procedures described herein and according to common general knowledge.

[0151] Scheme 1

[0152] In Scheme 1, the synthesis of a compound of formula (I-a), (I-a’), (5-I-a’) or R-I-a’) is described. The compound of formula (I-a), (I-a’), (S-I-a’) or (7?-I-a’) is a compound of formula (I), wherein R2is heteroaryl; L, R3and R4are as described herein. In the compound of formula (I- a), R1is as described herein. In the compound of formula (I-a’), (S-I-a’) or (7?-I-a’), R1is hydroxy ethyl.

[0153]

[0154] Step A: l-(6-Chloro-2-fluoropyri din-3 -yl)ethanone 1 can be reacted with a heteroaryl 2 in the presence of a base such as for instance DIPEA in a solvent such as for instance DMSO while heating (e.g. 80 °C) to yield intermediate 3.

[0155] Step B: Intermediate 5 can be obtained from intermediate 6-bromopyrazolo[l,5-a]pyridine 3 through a sequence of (1) iodination with a suitable agent such as for instance NIS in a suitable solvent such as for instance acetonitrile at a suitable temperature such as for instance room temperature, and (2) metalation with a suitable agent such as for instance isopropylmagnesium chloride in presence of a suitable reagent such as for instance isopropoxy-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane in a suitable solvent such as THF.

[0156] Step C: Intermediate 6 can be obtained from intermediates 3 and 5 by a cross-coupling reaction (Suzuki -Miyaura) with a suitable catalyst such as for instance 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride and a suitable base such as for instance K2CO3 in a suitable solvent such as for instance DMF (DME) while heating (e.g. 45 °C - 120 °C).

[0157] Step D: Compounds of formula (I-a) can be obtained from intermediate 6 through a crosscoupling reaction with a suitable 7 with a suitable catalyst such as for instance chloro(crotyl)[l,2,3,4,5-pentaphenyl-r-(di-tert-butylphosphino)ferrocene]palladium(II) and a suitable base such as for instance CS2CO3 in a suitable solvent such as for instance 1,4-di oxane while heating (e.g. 85 °C).

[0158] Step E: Provided that R1is acetyl, then compounds of formula (I-a’) can be obtained from compounds of formula (I-a) by reduction with a suitable agent such as for instance NaBF in a solvent such as MeOH.

[0159] Step F: Compounds of formulat fS'-I-a’) and ( / M-a’) can be obtained by chiral separation of racemic compounds of formulat (I-a) by suitable separartion technique such as for instance chiral SFC.

[0160] Scheme 2

[0161] In Scheme 2, an alternative synthesis of a compound of formula (I-a) is described. The compound of formula (I-a) is a compound of formula (I), wherein R2is heteroaryl; L, R1, R3and R4are as described herein.

[0162]

[0163] Step A: Intermediate 3 can be obtained through a sequence of (1) reacting starting material 1 with a heteroaryl 2 in the presence of a base such as for instance DIPEA in a solvent such as for instance DMSO while heating (e.g. 50 °C), (2) borylation with a suitable agent such as for instance bis(pinacolato)diboron and a suitable catalyst such as for instance bis(triphenylphosphine)palladium(II) chloride and dry potassium acetate in a suitable solvent such as 1,4-di oxane while heating (e.g. 100 °C) to yield intermediate 3.

[0164] Step B: Intermediate 5 can be obtained from starting material 4 by iodination with suitable agent such as for instance NIS in a suitable solvent such as for instance acetonitrile at a suitable temperature (e.g. room temperature).

[0165] Step C: Intermediate 4 can be obtained from intermediates 3 and 5 by a cross-coupling reaction (Suzuki -Miyaura) with a suitable catalyst such as for instance 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride and a suitable base such as for instance CS2CO3 in a suitable solvent such as for instance a mixture of THF and water while heating (e.g. 65 °C).

[0166] Step D: Compounds of formula (I-a) can be obtained from intermediate 6 through a crosscoupling reaction with a suitable 7 with a suitable catalyst such as for instance chloro(crotyl)[l,2,3,4,5-pentaphenyl-r-(di-tert-butylphosphino)ferrocene]palladium(II) and a suitable base such as for instance CS2CO3 in a suitable solvent such as for instance 1,4-di oxane while heating (e.g. 85 °C). Scheme 3

[0167] In Scheme 3, an alternative synthesis of a compound of formula (I-a) is described. In the below scheme, the compound of formula (I-a) is a compound of formula (I).

[0168] Step A . Intermediate 3 can be obtained by reacting 1 with a suitable electrophile 2 (X being a leaving group such as for instance a halide) in presence of a base such as for instance CS2CO3 in a solvent such as for instance DMF while heating (e.g. 120 °C).

[0169] Step B Intermediate 4 can be obtained through a sequence of (1) bromination of 3 with a suitable agent such as NBS or bromine in a solvent such as for instance acetic acid or acetonitrile, (2) borylation with a suitable agent such as for instance B2pin2 (bis(pinacolato)diboron) and a suitable catalyst such as for instance bis(triphenylphosphine)palladium(II) chloride and dry potassium acetate in a suitable solvent such as 1,4-di oxane while heating (e.g. 100 °C).

[0170] Step C. Intermediate 6 can be obtained from intermediates 4 and 5 by a cross-coupling reaction (Suzuki -Miyaura) with a suitable catalyst such as for instance 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride and a suitable base such as for instance CS2CO3 in a suitable solvent such as for instance a mixture of DMF and water while heating (e.g. 100 °C).

[0171] Step D A compound of formular (I-a) can be obtained from intermediates 6 and a suitable boronic acid 7 by a cross-coupling reaction (Suzuki-Miyaura) with a suitable catalyst such as for instance l,l'-bis(diphenylphosphino)ferrocene-palladium(II)di chloride and a suitable base such as for instance K2CO3 in a suitable solvent such as for instance a mixture of DMF and water while heating (e.g. 90 °C).

[0172] Scheme 4

[0173] In Scheme 4, the synthesis of a compound of formula (Il-a) or (II-a’). The compound of formula (II-a) or (II-a’) is a compound of formula (II), wherein R1is hydroxyethyl; L, R2, R3and R4are as described herein.

[0174] Step A : Intermediate 2 can be obtained from 2-amino-4-chloro-thiazole-5-carbaldehyde 1 through a sequence of (1) protection with a suitable agent such as di -tert-butyl dicarbonate in a solvent such as for example 1,4-di oxane and a base such as 4-dimethylaminopyridine, (2) addition of an agent such as for instance methyl magnesium bromide in a solvent such as THF, (3) oxidation with an agent such as manganese dioxide in a suitable solvent such as for instance di chi oromethane .

[0175] Step B. Intermediate 4 can be obtained from intermediates 2 and 3 by a cross-coupling reaction (Suzuki -Miyaura) with a suitable catalyst such as for instance 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride and a suitable base such as for instance Na2CC>3 in a suitable solvent such as for instance a mixture of DMF and water while heating (e.g. 100 °C). Deprotection might occur in the same step or might have to be run separaterly with an agent such as for instance trifluoroacetic acid.

[0176] Step C. Intermadiate 5 can be obtained from 4 by reacting it with a suitable reagent such as for instance isoamyl nitrite and copper(II)chloride in a solvent such as acetonitrile while heating (e.g. 65 °C).

[0177] Step D. Compounds of formula (Il-a) can be obtained from intermediates 5 and 6 by a cross-coupling reaction (Suzuki -Miyaura) with a suitable catalyst such as for instance 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride and a suitable base such as for instance Na2CC>3 in a suitable solvent such as for instance a mixture of DMF and water while heating (e.g. 100 °C).

[0178] Step E: Compounds of formula (II-a’) can be obtained from compounds (Il-a) by reduction with a suitable agent such as for instance NaBFLj in a solvent such as MeOH.

[0179] The invention also relates in particular to:

[0180] A compound of formula (I) or (II) as described herein or a pharmaceutically acceptable salt thereof, for use as therapeutically active substance;

[0181] A pharmaceutical composition comprising a compound of formula (I) or (II) as described herein or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier;

[0182] The use of a compound of formula (I) or (II) as described herein or a pharmaceutically acceptable salt thereof, for the treatment or prophylaxis of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel diseases (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis, in particular inflammatory bowel diseases (IBD);

[0183] The use of a compound of formula (I) or (II) as described herein or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prophylaxis rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel diseases (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis, in particular inflammatory bowel diseases (IBD);

[0184] A compound of formula (I) or (II) as described herein or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel diseases (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis, in particular inflammatory bowel diseases (IBD); and

[0185] A method for the treatment or prophylaxis of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel diseases (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis, which method comprises administering an effective amount of a compound of formula (I) or (II) as described herein or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

[0186] Pharmaceutical Compositions

[0187] Another embodiment of the invention provides a pharmaceutical composition or medicament containing a compound of the invention and a therapeutically inert carrier, diluent or excipient, as well as a method of using the compounds of the invention to prepare such composition and medicament. In one example, the compound of formula (I) or (II) may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non -toxic to recipients at the dosages and concentrations employed into a galenical administration form. The pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8. In one example, a compound of formula (I) or (II) is formulated in an acetate buffer, at pH 5. In another embodiment, the compound of formula (I) or (II) is sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.

[0188] Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.

[0189] The compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, epidural and intranasal, and if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0190] The compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.

[0191] A typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament). The invention will now be illustrated by the following examples which have no limiting character.

[0192] Examples

[0193] Abbreviations:

[0194] [tBuBrettPhos Pd(allyl)]OTf trifluoromethanesulfonate allyl[(2-Di-tert-butylphosphino- 3,6-dimethoxy-2',4',6'-triisopropyl-l,r-biphenyl)-2-(2'- amino- 1 , 1 '-biphenyl)] palladium(II)

[0195] 2-Me-THF 2-methyl tetrahydrofuran

[0196] ACN acetonitrile aq. aqueous

[0197] BINAP 2,2 " -Bi s(diphenylphosphino)- 1,1" -binaphthalene

[0198] Boc tert-butyl oxy carb onyl

[0199] CAS chemical abstract service

[0200] CDI carbonyldiimidazole

[0201] CS2CO3 caesium carbonate

[0202] DABCO l,8-diazabicyclo[5.4.0]undec-7-ene

[0203] DAST diethylaminosulfur trifluoride dba dib enzyli deneacetone

[0204] DCM dichloromethane

[0205] DIAD diisopropyl azodicarboxylate

[0206] DIBAL-H diisobutylaluminium hydride

[0207] DIPEA N,N-diisopropylethylamine

[0208] DMF N,N-dimethylformamide DMSO dimethyl sulfoxide dppf 1, l’-ferrocenediyl-bis(diphenylphosphine) dtbbpy 4,4 ’ -bi s( 1 , 1 -dimethyl ethyl)-2,2 ’ -bipyridine dtbpy 4,4’-di-tert-butyl-2,2’-dipyridyl

[0209] Diglyme 2-methoxyethyl ether

[0210] EDCI l-ethyl-3-(3-dimethylaminopropyl)carbodiimide equiv. or eq equivalents

[0211] ESI electrospray ionization

[0212] ESP positive electrospray ionization

[0213] ESN positive electrospray ionization

[0214] Et ethyl

[0215] Et2O diethyl ether

[0216] EtOAc ethyl acetate

[0217] EtOH ethanol

[0218] FA formic acid

[0219] HATU l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- b]pyridinium 3 -oxide hexafluorophosphate

[0220] HMDS bis(trimethylsilyl)amine

[0221] HOBt hydoxybenzotri azole

[0222] HPLC reverse phase high pressure liquid chromatography

[0223] IPA isopropyl alcohol Ir [dF (CF3)ppy]2(dtbpy)(PF6) [4, 4'-bisfl -dimethyl ethyl )-2,2'-bipyri dine-N I ,N I ']bis[3, 5- difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl- C]Iridium(III) hexafluorophosphate

[0224] K2CO3potassium carbonate KHCO3 potassium bicarbonate LCMS high-performance liquid chromatography LDA lithium diisopropylamide mCPBA meta-chloroperoxybenzoic acid m / z mass-to-charge ratio Me methyl MeOH methanol MgSO4Magnesium sulfate Ms methanesulfonyl MS mass spectrometry Na2SO4sodium sulfate NaCl sodium chloride NBS N-bromosuccinimide NIS N-iodosuccinimide NPLC normal phase liquid chromatography Pd(OAc)2palladium(II)acetate

[0225] Pd / C palladium on carbon PE petroleum ether ppy 2-phenylpyridine psi pounds per square inch

[0226] PTSA para toluene sulfonic acid

[0227] Qphos l,2,3,4,5-Pentaphenyl-r-(di-tert-butylphosphino)ferrocene QPhosPd(crotyl)Cl chloro(crotyl)(2-dicyclohexylphosphino-2',4',6'- triisopropyl- 1 , 1 '-biphenyl) palladium(II) rt or RT room temperature RuPhos-Pd-G3 (2-Dicyclohexylphosphino-2 6 '-dii sopropoxy- 1,1'- biphenyl)[2-(2 '-amino- 1, 1 '-biphenyl)]palladium(II) methanesulfonate sat. saturated

[0228] SFC supercritical fluid chromatography sol. solution

[0229] TBD triazabicyclodecene

[0230] TBDMS tert-butyldimethylsilyl

[0231] TBME tert.-butyl-methyl ether t-BuXphos-Pd-G3 [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-l,l '- biphenyl)-2-(2 '-amino- 1, 1 '-biphenyl)] palladium(II) methanesulfonate

[0232] TEA triethylamine

[0233] Tf triflyl TFA trifluoroacetic acid

[0234] TFAA trifluoroacetic acid anhydride

[0235] THF tetrahydrofuran

[0236] TLC thin layer chromatography

[0237] Xphos dicyclohexyl[2',4',6'-tris(propan-2-yl)[l,l'-biphenyl]-2- yl]phosphane

[0238] XPhosPd G2 chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'- biphenyl)[2-(2 '-amino- 1, 1 '-biphenyl)]palladium(II)

[0239] Example 1 l-[3-(l-hydroxyethyl)-6-[6-[4-(oxetan-3-yl)piperazin-l-yl]pyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile

[0240] Step 1 : l-(3-acetyl-6-chloropyridin-2-yl)-5-methylpyrazole-3-carbonitrile Under Argon, l-(6-Chloro-2-fluoropyri din-3 -yl)ethanone (10g, 57.6 mmol, Eq: 1; CAS [1260663-13-5]) was dissolved in dry DMSO (70 mL), at RT, 5-methyl-lH-pyrazole-3- carbonitrile (5.9 g, 54.7 mmol; CAS [38693-82-2]) and DIPEA (28.6 mL, 172.8 mmol) was added. The mixture was stirred for 4 hours at 80 °C. Water was added and the resulting solution was extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuum. The residue was purified by flash chromatography on Silica gel eluting with 0 % to 35 % EtOAc in petoleum ether to give the title compound as a light yellow solid (14 g, 79% yield). SFC separation gave the title compound as a white solid (7.78 g, 76.4% yield). MS (ESP) m / z = 261.1 [M+H]+

[0241] Step 2: 6-bromo-3-iodopyrazolo[l,5-a]pyridine

[0242] Under Argon, 6-bromopyrazolo[l,5-a]pyridine (3.5 g, 17.8 mmol, Eq: 1; CAS [1264193-11-4]) was dissolved in acetonitrile (35 mL) at RT and N-iodosuccinimide (4.4 g, 19.5 mmol, 1.1 eq; CAS [516-12-1]) was added portionwise and stirred for 1 hour at RT. Water was added and the resulting solution was extracted with TBME. The organic layer was dried over Na2SO4 and concentrated in vacuum. The residue was purified by flash chromatography on Silica gel eluting with 0 % to 20 % EtOAc in heptane to give the title compound as an off-white solid (7.7 g, 99% yield). MS (ESP) m / z = 322.8 [M+H]+

[0243] Step 3: 6-bromo-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine

[0244] Under Argon, 6-bromo-3-iodopyrazolo[l,5-a]pyridine (2.0 g, 6.19 mmol, Eq 1) was dissolved in dry THF (40 mL). At 0 °C isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.9 mL, 9.3 mmol; CAS[61676-62-8]) was added, followed by dropwise addition of 1.3M isopropylmagnesium chloride in THF (4.76 mL, 6.19 mmol) and the mixture was stirred 1 hour at 0 °C. Further isopropoxy -4,4,5, 5-tetramethyl-l, 3, 2-dioxaborolane (1.9 mL, 9.3 mmol) and 1.3M isopropylmagnesium chloride in THF (4.76 mL, 6.19 mmol) was added and the mixture was stirred 1 hour at RT. The mixture was poured on water and the resulting solution was extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuum. The residue was purified by flash chromatography on Silica gel eluting with 0 % to 20 % EtOAc in heptane to give the title compound as a colorless oil (1.66 g, 75% yield). MS (ESP) m / z = 323.0 [M+H]+

[0245] Step 4: l-[3-acetyl-6-(6-bromopyrazolo[l,5-a]pyridin-3-yl)pyridin-2-yl]-5-methylpyrazole-3- carbonitrile

[0246] Under Argon, 6-bromo-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine (110 mg, 0.307 mmol, 1 Eq.) was dissolved in DMF (2 mL) and water (1 mL). l-(3-acetyl-6- chloropyridin-2-yl)-5-methylpyrazole-3 -carbonitrile (96 mg, 0.368 mmol) and K2CO3 (127.1 mg, 0.92 mmol) was added. Argon was bubbled through the mixture for 5 minutes, then 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (25 mg, 31 mmol; CAS [95464-05-4]) was added and the mixture was stirred for 16 hours at 45 °C. The mixture was poured on water and the resulting solution was extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuum. The residue was purified by flash chromatography on silica gel eluting with 0 % to 40 % EtOAc in heptane to give the title compound as a colorless oil (81.8 mg, 63% yield). MS (ESP) m / z = 421.1 [M+H]+

[0247] Step 5: l-[3-acetyl-6-[6-[4-(oxetan-3-yl)piperazin-l-yl]pyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]- 5-methylpyrazole-3-carbonitrile

[0248]

[0249] Under Argon, l-[3-acetyl-6-(6-bromopyrazolo[l,5-a]pyridin-3-yl)pyridin-2-yl]-5- methylpyrazole-3 -carbonitrile (20 mg, 0.047 mmol, Eq. 1) in 1,4-dioxane (2 mL) was added l-(3- Oxetanyl)-piperazine (10.1 mg, 0.071 mmol; CAS [1254115-23-5]), followed by CS2CO3 (30.9 mg, 0.095 mmol) and water (8.5 ul, 0.470 mmol). Argon was bubbled through the mixture for 5 minutes. Chloro(crotyl)[l,2,3,4,5-pentaphenyl-r-(di-tert-butylphosphino)ferrocene]palladium(II) (3.45 mg, 0.004 mmol; CAS [1252598-33-6]) was added and the mixture stirred for 16 hours at 85 °C. The crude mixture was subjected to silica gel purification eluting with 0 % to 100 % EtOAc in heptane to give the title compound as a light brown solid (8.3 mg, 35% yield). MS (ESP) m / z = 483.2 [M+H]+

[0250] Step 6: l-[3-(l-hydroxyethyl)-6-[6-[4-(oxetan-3-yl)piperazin-l-yl]pyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile

[0251] Under Argon, l-[3-acetyl-6-[6-[4-(oxetan-3-yl)piperazin-l-yl]pyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile (25 mg, 0.05 mmol, Eq. 1) was suspended in methanol (10 mL), and sodium borohydride (13.3 mg, 0.352 mmol; CAS[16940-66-2]) was added portionwise and the mixture was stirred for 30 minutes at RT. Water was added and the resulting solution was extracted with DCM. The organic layer was dried over Na2SO4 and concentrated in vacuum. The residue was purified by flash chromatography on Silica gel eluting with 0 % to 12 % MeOH in DCM to give the title compound as a light yellow lyophilized powder (7.5 mg, 30.2% yield). MS (ESP) m / z = 485.2 [M+H]+

[0252] Example 2 l-[3-(l-hydroxyethyl)-6-[6-[rac-(31?,41?)-3-amino-4-fluoropyrrolidin-l-yl]pyrazolo[l,5- a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile

[0253] Step 1 : tert-butyl 7V-[(35',45 -l-[3-[5-acetyl-6-(3-cyano-5-methylpyrazol-l-yl)pyridin-2- yl]pyrazolo[l,5-a]pyridin-6-yl]-4-fluoropyrrolidin-3-yl]carbamate

[0254]

[0255] Under Argon, l-[3-acetyl-6-(6-bromopyrazolo[l,5-a]pyridin-3-yl)pyridin-2-yl]-5- methylpyrazole-3 -carbonitrile (100 mg, 0.237 mmol, Eq. 1) (for preparation see example 1, step 4) in 1,4-dioxane (6 mL) was added (35,45)-(4-Fluoro-pyrrolidin-3-yl)-carbamic acid tert-butyl ester hydrochloride (85.7 mg, 0.356 mmol; CAS[2097061-01-l]) followed by CS2CO3 (232 mg, 0.712 mmol) and water (42.8 ul, 2.37 mmol). Argon was bubbled through the mixture for 5 minutes. Chloro(crotyl)[l,2,3,4,5-pentaphenyl-r-(di-tert-butylphosphino)ferrocene]palladium(II) (21.55 mg, 0.024 mmol; CAS [1252598-33-6]) was added and the mixture stirred for 16 hours at 110 °C. The crude was coated on silica gel and purified by flash chromatography on eluting with 0 % to 80 % EtOAc in heptane to give the title compound as a yellow oil (77 mg, approximately 50% purity). This material was used as such as in the next step. MS (ESP) m / z = 545.3 [M+H]+

[0256] Step 2: tert-butyl A-[rac-(3A,4A)-l-[3-[6-(3-cyano-5-methylpyrazol-l-yl)-5-(l- hydroxyethyl)pyridin-2-yl]pyrazolo[l,5-a]pyridin-6-yl]-4-fluoropyrrolidin-3-yl]carbamate

[0257]

[0258] Under Argon, tert-butyl A-[(35,45)-l -[3-[5-acetyl-6-(3-cyano-5-methylpyrazol-l -yl)pyridin-2- yl]pyrazolo[l,5-a]pyridin-6-yl]-4-fluoropyrrolidin-3-yl]carbamate (77 mg, approx. 50% purity, 0.071 mmol, Eq. 1) was suspended in Methanol (18 m ) and sodium borohydride (18.7 mg, 0.495 mmol; CAS[16940-66-2]) was added and the mixture stirred for 30 minutes at RT. Water was added and the resulting solution was extracted with DCM. The organic layer was dried over Na2SO4 and concentrated in vacuum. The residue was purified by flash chromatography on Silica gel eluting with 0 % to 5 % MeOH in DCM to give the title compound as a light brown solid (14 mg, 34.4% yield) MS (ESP) m / z = 547.1 [M+H]+

[0259] Step 3 : 1 -[3 -( 1 -hydroxyethyl)-6-[6-[rac-(3A,4A)-3 -amino-4-fluoropyrrolidin- 1 -yl]pyrazolo[ 1,5- a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile Under Argon, tert-butyl A-[rac-(3A,4A)-l-[3-[6-(3-cyano-5-methylpyrazol-l-yl)-5-(l- hydroxyethyl)pyridin-2-yl]pyrazolo[l,5-a]pyridin-6-yl]-4-fluoropyrrolidin-3-yl]carbamate (14 mg, 0.024 mmol, Eq. 1) was stirred in 4M 1,4-dioxane (1 mL) at RT for one hour. The reaction mixture was evaporated and purified by preparative HPLC to give the title compound as a light yellow solid (2.8 mg, 23% yield). MS (ESP) m / z = 447.1 [M+H]+

[0260] Example 3 l-[3-(l-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]pyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile

[0261] This example was prepared in analogy to example 1 by using 3-Amino-6-methylpyridazine instead of l-(3-Oxetanyl)-piperazine and [tBuBrettPhos Pd(allyl)]OTf (CAS [1798782-17-8]) instead of Chloro(crotyl)[l, 2,3,4, 5-pentaphenyl-l'-(di-tert- butylphosphino)ferrocene]palladium(II) in step 5 to give the title compound as a light yellow solid. MS (ESP) m / z = 452.3 [M+H]+

[0262] Example 4 l-[3-[(15)-l-hydroxyethyl]-6-[6-[(6-methylpyridazin-3-yl)amino]pyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile

[0263] tert-butyl N-[rac-(37?,47?)-l-[3-[6-(3-cyano-5-methylpyrazol-l-yl)-5-(l-hydroxyethyl)pyri din-2- yl]pyrazolo[l,5-a]pyridin-6-yl]-4-fluoropyrrolidin-3-yl]carbamate (37 mg, 0.08 mmol) (see example 3) was separated by chiral SFC (first eluting isomer) to give the title compound as an off-white solid (16 mg, 43% yield). MS (ESP) m / z = 452.2 [M+H]+. The absolute configuration was assigned based on the corresponding Mosher’s ester (see J. Org. Chem. 1969, 34, 9, 2543- 2549).

[0264] Example 5

[0265] 1- [3- [(ll?)-l-hydroxyethyl]-6- [6- [(6-methylpyridazin-3-yl)amino] pyrazolo [1,5-a] pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile

[0266] This example was isolated in analogy to example 4 (second eluting isomer) to give the title compound as an off-white solid (14 mg, 37% yield). MS (ESP) m / z = 452.2 [M+H]+ Example 6

[0267] 1- [3-(l -hydroxy ethyl)-6- [6- [ [6- [(3-methoxyazetidin- l-yl)methyl] pyridazin-3- yl]amino]pyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile

[0268] Step 1: 3-chloro-6-[(3-methoxyazetidin-l-yl)methyl]pyridazine

[0269] Under Argon, to a suspension of 3 -methoxyazetidine hydrochloride (2.9 g, 17.8 mmol, Eq. 1; CAS [148644-09-1]) in THF (20 mL) was added DIPEA (8.48 mL, 48.55 mmol), stirred for 1 hour at RT. 3-Chloro-6-(chloromethyl)pyridazine (2 g, 16.18 mmol; CAS [120276-59-7]) was added and stirred for 5 days at RT. The crude was subjected to silica gel purification eluting with 0 - 4 % MeOH in DCM to give the title compound as a brown oil (2.4 g, 65% yield). MS (ESP) m / z = 214.1 [M+H]+

[0270] Step 2: A-[(2,4-dimethoxyphenyl)methyl]-6-[(3-methoxyazetidin-l-yl)methyl]pyridazin-3-amine

[0271]

[0272] A mixture of 3-chloro-6-[(3-methoxyazetidin-l-yl)methyl]pyridazine (540 mg, 2.4 mmol, Eq. 1) with 2,4-Dimethoxybenzylamin (4.01 g, 3.61 mL, 24.0 mmol, Eq. 10; CAS [20781-20-8]) was irradiated at 140 °C in microwave synthesizer for 45 minutes. Water was added and the resulting solution was extracted with DCM. The organic layer was dried over ISfeSCU and concentrated in vacuum. The residue was purified by flash chromatography on silica gel eluting with 0 - 7% MeOH in DCM to give the title compound as light brown oil (149 mg, 18% yield). MS (ESP) m / z = 345.2 [M+H]+

[0273] Step 3: 6-[(3-methoxyazetidin-l-yl)methyl]pyridazin-3-amine

[0274] Under Argon, A-[(2,4-di methoxyphenyl )methyl]-6-[(3-methoxyazetidin- l -yl)methyl]pyridazin-3- amine (137 mg, 0.39 mmol) was dissolved in TFA (3.0 mL) and stirred for 1 hour at 70 °C. Water was added and the resulting solution was washed with DCM. The water layer was lyophilized. 5N NaOH and NaCl was added and the mixture was diluted with THF and EtOAc (1 : 1). The organic layer was dried over ISfeSCU and concentrated in vacuum. Trituration with

[0275] DCM resulted in a suspension. After filtering off the solid, the filtrate was evaporated to give the title compound as a brown oil (36 mg, 43% yield). MS (ESP) m / z = 195.1 [M+H]+ Step 4: l-[3-acetyl-6-[6-[[6-[(3-methoxyazetidin-l-yl)methyl]pyridazin-3-yl]amino]pyrazolo[l,5- a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile

[0276] Under Argon in a sealed tube, l-[3-acetyl-6-(6-bromopyrazolo[l,5-a]pyridin-3-yl)pyridin-2-yl]- 5-methylpyrazole-3-carbonitrile (50 mg, 0.113 mmol, Eq. 1) (for preparation see example 1, step 4) in 1,4-dioxane (1.5 mL) was added 6-[(3-methoxyazetidin-l-yl)methyl]pyridazin-3-amine (43.8 mg, 0.226 mmol), followed by CS2CO3 (110.2 mg, 0.338 mmol) Argon was bubbled through the mixture for 5 minutes. [tBuBrettPhos Pd(allyl)]Otf (16.2 mg, 0.023 mmol; CAS [1798782-17-8]) was added and stirred for 2 hours at 80 °C. The crude was subjected to flash chromatography on silica gel eluting with 0 - 5% (10 : 1 MeOH : NH4OH) in DCM to give the title compound as a yellow solid (31 mg, 51% yield). MS (ESP) m / z = 535.3 [M+H]+

[0277] Step 5: l-[3-(l-hydroxyethyl)-6-[6-[[6-[(3-methoxyazetidin-l-yl)methyl]pyridazin-3- yl]amino]pyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile Under Argon, l-[3-acetyl-6-[6-[[6-[(3-methoxyazetidin-l-yl)methyl]pyridazin-3- yl]amino]pyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile (31 mg, 0.058 mmol, Eq. 1) was dissolved in methanol (2 mL), cooled to 0 °C and sodium borohydride (8.9 mg, 0.236 mmol; CAS[16940-66-2]) was added and the mixture stirred for 90 minutes at 0 °C. Water was added and the resulting solution was extracted with DCM. The organic layer was dried over Na2SO4 and concentrated in vacuum. The residue separated by preparative HPLC to give the title compound as a white solid (2.5 mg, 8% yield). MS (ESP) m / z = 537.2 [M+H]+

[0278] Example 7

[0279] 1- [6- [6- [ [6- [(3-fluoroazetidin-l-yl)methylJ pyridazin -3-yl] amino] pyrazolo [1 ,5-a] pyridin-3- yl]-3-(l-hydroxyethyl)pyridin-2-yl]-5-methylpyrazole-3-carbonitrile

[0280] Step 1 : 3-chloro-6-[(3-fluoroazetidin-l-yl)methyl]pyridazine

[0281]

[0282] To a solution 3 -fluoroazetidine hydrochloride (273.7 mg, 2.45 mmol, Eq. 1; CAS [1375472-05- 1]) in DMF (8 mL) was added CS2CO3 (2g, 6.13 mmol) and 3-chloro-6-(chloromethyl)pyridazine (400 mg, 2.45 mmol; CAS [120276-59-7]) under argon. The mixture was stirred for 5.5 hours at RT. Water was added and the resulting solution was extracted with DCM. The organic layer was extracted with 2N HC1. The aqueous layer was basified with 32% NaOH and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated in vacuum. The residue was purified by flash chromatography on silica gel eluting with 0 - 3 % MeOH in DCM to give the title compound as a light yellow oil (186 mg, 35% yield). MS (ESP) m / z = 202.0 [M+H]+

[0283] Step 2: 7V-[6-[(3-fluoroazetidin-l-yl)methyl]pyridazin-3-yl]-l,l-diphenylmethanimine

[0284] To a solution of 3-chloro-6-[(3-fluoroazetidin-l-yl)methyl]pyridazine (70 mg, 0.33 mmol, Eq. 1) in toluene (5 mL) was added benzophenone imine (83 ul, 0.495 mmol; CAS [1013-88-3]), CS2CO3 (322.4 mg, 0.989 mmol) and BINAP (41.1 mg, 0.066 mmol) under argon. Argon was bubbled through the solution for 5 minutes. Tris(dibenzylideneacetone)dipalladium(0) (30.2 mg, 0.033 mmol; CAS [51364-51-3]) was added. The mixture was stirred at 100 °C for 16 hours. Water was added and the resulting solution was extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuum. The residue was purified by flash chromatography on silica gel eluting with 0 - 5 % MeOH in DCM give the title compound as a yellow oil (20 mg, 17% yield). MS (ESP) m / z = 347.2 [M+H]+

[0285] Step 3: 6-[(3-fluoroazetidin-l-yl)methyl]pyridazin-3-amine

[0286] Under Argon, to a solution of A-[6-[(3-fluoroazetidin-l-yl)methyl]pyridazin-3-yl]-l,l- diphenylmethanimine (90 mg, 0.23 mmol) in THF (6 mL) was added 4 M HC1 (0.047 mL, 0.19 mmol). The mixture was stirred for 1 hour at RT. Water was added and the resulting solution was extracted with EtOAc. The water layer was basified to pH 10 with 3N NaOH and satured with solid NaCl and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuum to give the title compound as a light yellow solid (22 mg, 71% yield). MS (ESP) m / z = 183.1[M+H]+

[0287] Step 4: l-[3-acetyl-6-[6-[[6-[(3-fluoroazetidin-l-yl)methyl]pyridazin-3-yl]amino]pyrazolo[l,5- a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile

[0288]

[0289] Under Argon in a sealed tube, to l-[3-acetyl-6-(6-bromopyrazolo[l,5-a]pyridin-3-yl)pyridin-2- yl]-5-methylpyrazole-3-carbonitrile (55 mg, 0.13 mmol, Eq. 1) (for preparation see example 1, step 4) in 1,4-dioxane (1.6 mL) was added 6-[(3-fluoroazetidin-l-yl)methyl]pyridazin-3-amine (22 mg, 0.12 mmol) followed by CS2CO3 (117 mg, 0.36 mmol). Argon was bubbled through the mixture for 5 minutes. [tBuBrettPhos Pd(allyl)]OTf (19 mg, 0.024 mmol; CAS [1798782-17-8]) was added and the mixture was stirred for 2 hours at 80 °C. The mixture was subjected to flash chromatography on silica gel eluting with 0 - 10% MeOH in DCM to give the title compound as a yellow solid (26 mg, 41% yield). MS (ESP) m / z = 523.3 [M+H]+

[0290] Step 5: l-[6-[6-[[6-[(3-fluoroazetidin-l-yl)methyl]pyridazin-3-yl]amino]pyrazolo[l,5-a]pyridin-

[0291] 3-yl]-3-(l-hydroxyethyl)pyridin-2-yl]-5-methylpyrazole-3-carbonitrile

[0292]

[0293] Under Argon, l-[3-acetyl-6-[6-[[6-[(3-fluoroazetidin-l-yl)methyl]pyridazin-3- yl]amino]pyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile (26 mg, 0.049 mmol, Eq. 1) was dissolved in isopropanol (2 mL) and THF (2 mL). At 0 °C sodium borohydride (3.7 mg, 0.097 mmol; CAS [16940-66-2]) was added and the mixture was stirred for 5 minutes at 0 °C. Water was added and the resulting solution was extracted with DCM. The organic layer was dried over Na2SO4 and concentrated in vacuum. The crude was purified by flash chromatography on silica gel eluting with 0 - 10 % MeOH in DCM to give the title ompound as a light yellow solid (13 mg, 53% yield). MS (ESP) m / z = 525.3 [M+H]+

[0294] Example 8

[0295] 1- [6- [6- [ [6- [(3,3-difluoroazetidin-l-yl)methyl] pyridazin-3-yl] amino] pyrazolo [1 ,5-a] pyridin- 3-yl] -3-(l -hydroxy ethyl)pyridin-2-yl] -5-methylpyrazole-3-carbonitrile

[0296]

[0297] Step 1 : 3-chloro-6-[(3,3-difluoroazetidin-l-yl)methyl]pyridazine

[0298] Under Argon, to a solution 3,3 -difluoroazetidine hydrochloride (318 mg, 2.45 mmol, Eq. 1; CAS [288315-03-7]) in DMF (2 mL) and THF (8 mL) was added DIPEA (2.1 mL, 11.9 mmol) and 3- chloro-6-(chloromethyl)pyridazine (400 mg, 2.45 mmol; CAS [120276-59-7]) and the mixture was stirred for 16 hours at RT. Water was added and the resulting solution was extracted with DCM. The organic layer was dried over ISfeSCU and concentrated in vacuum. The crude was purified by flash chromatography on silica gel eluting with 0 - 10 % MeOH in DCM to give the title compound as a light brown solid (356 mg, 63% yield). MS (ESP) m / z = 220.1 [M+H]+

[0299] Step 2: A-[6-[(3,3-difluoroazetidin-l-yl)methyl]pyridazin-3-yl]-l,l-diphenylmethanimine

[0300]

[0301] Under Argon, to a solution of 3-chloro-6-[(3,3-difluoroazetidin-l-yl)methyl]pyridazine (356 mg, 1.5 mmol, Eq. 1) in toluene (10 mL) was added benzophenone imine (0.39 mL, 2.3 mmol); CAS [1013-88-3]), CS2CO3(1.51 g, 4.62 mmol) and BINAP (192 mg, 0.31 mmol; CAS [98327-87-8]). Argon was bubbled through the solution for 5 minutes. Tris(dibenzylideneacetone)dipalladium(0) (141 mg, 0.154 mmol; CAS [51364-51-3]) was added. The mixture was stirred at 100 °C for 16 hours. Water was added and the resulting solution was extracted with DCM. The organic layer was dried over Na2SO4 and concentrated in vacuum. The residue was purified by flash chromatography on silica gel eluting with 0 - 2 % MeOH in to give the title compound as a brown oil (222 mg, 36% yield). MS (ESP) m / z = 365.1 [M+H]+

[0302] Step 3: 6-[(3,3-difluoroazetidin-l-yl)methyl]pyridazin-3-amine

[0303] Under Argon, to a solution of A-[6-[(3,3-difhioroazetidin-l-yl)methyl]pyridazin-3-yl]-l,l- diphenylmethanimine (222 mg, 0.56 mmol) in THF (8 mL) was added 4M HC1 (0.15 mL, 0.61 mmol). The mixture was stirred for 1 hour at RT. Water was added and the resulting solution was extracted with EtOAc. The water layer was basified to pH 10 with 3N NaOH and satured with solid NaCl and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuum to give the title compound as a light yellow solid (80 mg, 70% yield). MS (ESP) m / z = 201.1[M+H]+

[0304] Step 4: l-[3-acetyl-6-[6-[[6-[(3,3-difluoroazetidin-l-yl)methyl]pyridazin-3- yl]amino]pyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile

[0305] Under Argon in a sealed tube, to l-[3-acetyl-6-(6-bromopyrazolo[l,5-a]pyridin-3-yl)pyridin-2- yl]-5-methylpyrazole-3-carbonitrile (91 mg, 0.22 mmol, Eq. 1) (for preparation see example 1, step 4) in 1,4-dioxane (1.6 mL) was added 6-[(3,3-difluoroazetidin-l-yl)methyl]pyridazin-3- amine (79.6 mg, 0.386 mmol), followed by CS2CO3 (211.1 mg, 0.648mmol). Argon was bubbled through the mixture for 5 minutes. [tBuBrettPhos Pd(allyl)]OTf (34 mg, 0.043 mmol; CAS [1798782-17-8]) was added and the mixture was stirred for 2 hours at 80 °C. The mixture was subjected to flash chromatography on silica gel eluting with 0 - 5 % MeOH in DCM to give the title compound as a yellow solid (82 mg, 69% yield). MS (ESP) m / z = 541.3 [M+H]+

[0306] Step 5: l-[6-[6-[[6-[(3,3-difluoroazetidin-l-yl)methyl]pyridazin-3-yl]amino]pyrazolo[l,5- a]pyridin-3-yl]-3-(l-hydroxyethyl)pyridin-2-yl]-5-methylpyrazole-3-carbonitrile

[0307]

[0308] Under Argon, l-[3-acetyl-6-[6-[[6-[(3,3-difluoroazetidin-l-yl)methyl]pyridazin-3- yl]amino]pyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile (82 mg, 0.15 mmol, Eq. 1) was dissolved in isopropanol (5 mL) and THF (5 mL), cooled to 0 °C and sodium borohydride (8.4 mg, 0.223 mmol; CAS[16940-66-2]) was added and the mixture was stirred for 5 minutes at 0 °C. Water was added and the resulting solution was extracted with DCM / Methanol (10: 1). The organic layer was dried over Na2SO4 and concentrated in vacuum. The crude was purified by flash chromatography on silica gel eluting with 0 - 5 % MeOH in DCM to give the title compound as a light yellow solid (28 mg, 35% yield). MS (ESP) m / z = 543.1 [M+H]+

[0309] Example 9

[0310] 1- [3- [(15)-l-hydroxyethyl]-6-[6- [[6-(2-oxa-6-azaspiro [3.3] heptan-6-ylmethyl)pyridazin-3- yl]amino]pyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile

[0311]

[0312] Step 1 : 6-[(6-chloropyridazin-3-yl)methyl]-2-oxa-6-azaspiro[3.3]heptane

[0313] Under Argon, to a solution 3-chloro-6-(chloromethyl)pyridazine (400 mg, 2.45 mmol, Eq. 1;

[0314] CAS [120276-59-7]) and 2-oxa-6-azaspiro[3.3]heptane (355 mg, 3.58 mmol; CAS [174-78-7]) in DMF (2 mL) and THF (8 mL) was added DIPEA (2.1 mL, 11.9 mmol) and the mixture was stirred for 16 hours at RT. Water was added and the resulting solution was extracted with DCM. The organic layer was dried over Na2SO4 and concentrated in vacuum. The crude was purified by flash chromatography on silica gel eluting with 0 - 6 % MeOH in DCM to give the title compound as a light brown solid (168 mg, 28% yield). MS (ESP) m / z = 226.1 [M+H]+

[0315] Step 2: A-[6-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)pyridazin-3-yl]-l,l-diphenylmethanimine

[0316]

[0317] Under Argon, to a solution of 6-[(6-chloropyridazin-3-yl)methyl]-2-oxa-6-azaspiro[3.3]heptane (168 mg, 0.69 mmol, Eq. 1) in toluene (4.5 mL) was added benzophenone imine (116.4 ul, 0.694 mmol; CAS [1013-88-3]), CS2CO3 (677.9 mg, 2.08 mmol) and BINAP (86 mg, 0.14 mmol; CAS [98327-87-8]). Argon was bubbled through the solution for 5min.

[0318] Tris(dibenzylideneacetone)dipalladium(0) (64 mg, 0.069 mmol; CAS [51364-51-3]) was added. The mixture was stirred at 100 °C for 16 hours. Water was added and the resulting solution was extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuum. The residue was purified by flash chromatography on silica gel eluting with 0 - 10 % MeOH in DCM to give the title compound as a brown oil (48 mg, 18% yield). MS (ESP) m / z = 371.2 [M+H]+

[0319] Step 3: 6-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)pyridazin-3-amine;2,2,2-trifluoroacetic acid

[0320] Under Argon, to a solution of A-[6-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)pyridazin-3-yl]-l,l- diphenylmethanimine (48 mg, 0.13 mmol) in DCM (8 mL) was added TFA (0.1 mL). The mixture was stirred for 5 minutes at RT. Water was added and the resulting solution was extracted with DCM. The water layer was lyophilized to give the title compound as a brown oil (36 mg, 81% yield). MS (ESP) m / z = 207.2[M+H]+

[0321] Step 4: l-[3-acetyl-6-[6-[[6-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)pyridazin-3- yl]amino]pyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile

[0322] Under Argon in a sealed tube, to l-[3-acetyl-6-(6-bromopyrazolo[l,5-a]pyridin-3-yl)pyridin-2- yl]-5-methylpyrazole-3-carbonitrile (28 mg, 0.066 mmol, Eq. 1) (for preparation see example 1, step 4) in 1,4-dioxane (0.9 mL) was added 6-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)pyridazin- 3-amine;2,2,2-trifluoroacetic acid (36 mg, 0.10 mmol) followed by CS2CO3 (217 mg, 0.67 mmol) Argon was bubbled through the mixture for 5 minutes. [tBuBrettPhos Pd(allyl)]OTf (10 mg, 0.013 mmol; [1798782-17-8]) was added and the mixture was stirred for 2.5 hours at 80 °C. The crude was subjected to flash chromatography on silica gel eluting with 0 - 14% MeOH in DCM to give the title compound as a yellow solid (9 mg, 21% yield). MS (ESP) m / z = 547.2 [M+H]+

[0323] Step 5: l-[3-[(15)-l-hydroxyethyl]-6-[6-[[6-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)pyridazin-

[0324] 3-yl]amino]pyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile

[0325] Under Argon, l-[3-acetyl-6-[6-[[6-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)pyridazin-3- yl]amino]pyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile(8.7 mg, 0.014 mmol, Eq. 1) was dissolved in isopropanol (0.9 m ) and cooled to 0 °C and sodium borohydride (0.77 mg, 0.021 mmol; CAS[16940-66-2]) was added and stirred for 35 minutes at 0 °C. Water was added and the resulting solution was extracted with DCM / Methanol (10: 1). The organic layer was dried over Na2SO4 and concentrated in vacuum. The crude was purified by flash chromatography on silica gel eluting with 0 - 12 % MeOH in DCM followed by chiral SFC separation to give the title compound as the first eluting isomer as a light yellow solid (2 mg, 31% yield). MS (ESP) m / z = 549.2 [M+H]+

[0326] Example 10

[0327] 1- [3- [(17?)- 1-hydroxy ethyl] -6- [6- [ [6- [(3-methoxy azetidin- l-yl)methyl] pyridazin-3- yl]amino]pyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile

[0328] l-[3-(l-hydroxyethyl)-6-[6-[[6-[(3-methoxyazetidin-l-yl)methyl]pyridazin-3- yl]amino]pyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile (32 mg, 0.048 mmol) (see example 6) was separated by chiral SFC to give the title compound as the second eluting isomer as a light yellow lyophilized solid (4 mg, 15 % yield). MS (ESP) m / z = 535.5 [M+H]+

[0329] Example 11 l-[3-[(15)-l-hydroxyethyl]-6-[6-[[6-[(3-methoxyazetidin-l-yl)methyl]pyridazin-3- yl]amino]pyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile l-[3-(l-hydroxyethyl)-6-[6-[[6-[(3-methoxyazetidin-l-yl)methyl]pyridazin-3- yl]amino]pyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile (32 mg, 0.048 mmol) (see example 6) was separated by chiral SFC to give the title compound as the first eluting isomer as a light yellow lyophilized solid compound as a white solid (4.5 mg, 17.5 % yield). MS (ESP) m / z = 535.5 [M+H]+

[0330] Example 12 l-[3-[(15)-l-hydroxyethyl]-6-[5-methoxy-6-[(6-methylpyridazin-3-yl)amino]pyrazolo[l,5- a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile

[0331] Step 1 : amino 2,4,6-trimethylbenzenesulfonate

[0332] A solution of tert-butyl N-[(2,4,6-trimethylbenzenesulfonyl)oxy]carbamate (2.3 g, 11.0 mmol; CAS[36016-39-4]) in TFA (50 mL) was stirred at 0 °C for 2 hours. The mixture was poured on water. The solid was filtered off and washed with water. The solid was dissolved in DCM (50 mL) and dried over Na2SO4to give the title compound as a solution in DCM, which was used directly in step 3. MS (ESP) m / z = 216.1 [M+H]+

[0333] Step 2: 2-(5-bromo-4-methoxypyridin-2-yl)ethynyl-trimethylsilane

[0334] To a mixture of trimethylsilylacetylene CAS [1066-54-2] (1.8 g, 18.36 mmol, 1 eq), Copper(I) iodide CAS [7681-65-4] (345 mg, 1.8 mmol, 0.1 eq), DIPEA (6.4 mL, 36.7 mmol, 2 eq) and 2,5- dibromo-4-methoxypyridine CAS [1211520-71-6] (4.9 g, 18.4 mmol, 1 eq) in DMF (50 mL) was added bis(triphenylphosphine) palladium chloride CAS [13965-03-2] (644 mg, 0.92 mmol, 0.05 eq) and stirred at RT for 16 hours under an atmosphere of nitrogen. Water was added and the resulting solution was extracted with EtOAc. The organic layer was dried over ISfeSCU and concentrated in vacuum. The crude was purified by flash chromatography on silica gel eluting with 10% EtOAc in petroleum ether to give the title compound as a dark green oil (2.8 g, 53.7% yield). MS (ESP) m / z = 283.9 [M+H]+

[0335] Step 3: 5-bromo-4-methoxy-2-(2 -trimethyl silyl ethynyl)pyridin-l-ium-l-amine;2, 4,6- trimethylbenzenesulfonate

[0336] To a solution of 2-(5-bromo-4-methoxypyridin-2-yl)ethynyl-trimethylsilane (2.9 g, 10.2 mmol, 1 eq) in DCM (15 mL) was added dropwise a solution of amino 2,4,6-trimethylbenzenesulfonate (2.37 g, 11.0 mmol, 1.08 eq) in DCM (45 mL) at RT. The reaction mixture was concentrated. The residue was dissolved in EtOAc (10 mL). TBME (30 mL) was added and the resulting mixture was stirred at RT for 30 min. The brown solid obtained was filtered and washed with TBME (3 x 10 mL) and dried to give the title compound as a light brown solid (4.2 g, 83% yield). MS (ESP) m / z = 300.9 [M+H]+

[0337] Step 4: (6-bromo-5-methoxypyrazolo[l,5-a]pyridin-2-yl)-trimethylsilane

[0338] A mixture of silver carbonate (116 mg, 0.42 mmol, 0.05 eq) in DMF (50 mL) was added to5- bromo-4-methoxy-2-(2 -trimethyl silyl ethynyl)pyridin- 1 -ium- 1 -amine;2,4,6- trimethylbenzenesulfonate (4.2 g, 8.4 mmol, 1.0 eq). The reaction mixture was stirred at RT for 12 hours. The mixture was filtered, washed with EtOAc (30 mL><3). The filtrate was mixed with water (20 mL) and extracted with EtOAc (3 x 30mL). The combined organic layers were dried over Na?SO4 and concentrated in vacuum. The crude was purified by flash chromatography on silica gel eluting with 25% EtOAc in petroleum ether to provide 6-bromo-5-methoxy- pyrazolo[l,5-a]pyridine as a light yellow solid (0.6 g, 31% yield), MS (ESP) m / z = 226.9 [M+H]+and the title compound as an off-white solid (1.2 g, 48% yield). MS (ESP) m / z = 299.0 [M+H]+

[0339] Step 5: 6-bromo-5-methoxypyrazolo[l,5-a]pyridine

[0340] A mixture of (6-bromo-5-methoxypyrazolo[l,5-a]pyridin-2-yl)-trimethylsilane (1.1 g, 3.7 mmol, 1.0 eq) and IM tetrabutylammonium fluoride in THF (18.4 mL, 18.4 mmol, 5.0 eq) in 1,4- dioxane (20 mL) was heated to 100 °C for 12 hours and then cooled to RT. The reaction mixture was concentrated under reduce pressure and subjected to purification by silica chromatography eluting with 20% EtOAc in petroleum ether to provide the title compound (330 mg, 1.5 mmol, 40% yield) as a light yellow solid. MS (ESP) m / z = 226.9 [M+H]+ Step 6: 6-bromo-3-iodo-5-methoxypyrazolo[l,5-a]pyridine

[0341] To a mixture of 6-bromo-5-methoxypyrazolo[l,5-a]pyridine (330 mg, 1.45 mmol, 1 eq) in ACN (10 mL) was added N-iodosuccinimide (360 mg, 1.6 mmol) at RT. The mixture was stirred at RT for 12 hours. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 1 - 10% EtOAc in petroleum ether to give the title compound as an off-white solid (320 mg, 63% yield). MS (ESP) m / z = 354.8 [M+H]+

[0342] Step 7: l-[6-chloro-3-[(15)-l-hydroxyethyl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile

[0343] To a mixture of l-(3-acetyl-6-chloropyridin-2-yl)-5-methylpyrazole-3-carbonitrile (for preparation see example 1, step 1) (3.0 g, 11.5 mmol, 1 eq) in Methanol (90 mL) and DCM (5 mL) was added at 0 °C sodium borohydride (1.8 g, 48 mmol). The mixture was stirred at 0 °C for 2 hours. The mixture was poured into saturated NH4CI (100 mL) and extracted with EtOAc (50 mL x 3). The organic layer was dried over Na2SO4 and concentrated in vacuum. The crude was purified by flash chromatography on Silica gel eluting with 5 - 25 % EtOAc in petroleum ether. The colorless oil was purified by chiral SFC (Daicel Chiral Pak IG (250 x 30mm, lOum), (0.1% NH3.H2O MeOH)) to give the title compound as a white solid (1.5 g, 50% yield). MS (ESP) m / z = 245.0 [M-18+H]+

[0344] Step 8: l-[3-[(15)-l-hydroxyethyl]-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]- 5-methylpyrazole-3-carbonitrile

[0345]

[0346] To a mixture of l-[6-chloro-3-[(15)-l-hydroxyethyl]pyridin-2-yl]-5-methylpyrazole-3- carbonitrile (50.0 mg, 0.190 mmol, 1 eq), bis(pinacolato)diboron (193.3 mg, 0.760 mmol) and potassium acetate (74.7 mg, 0.760 mmol) in 1,4-Dioxane (3 mL) was added 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (8 mg, 0.01 mmol; CAS [95464-05-4]). The mixture was degassed by nitrogen three times and stirred at 100 °C for 4 hours. The mixture was cooled to room temperature and 70 mg SiliaMetS (Metal Scavenger) was added and stirred at RT for 1 hour. The mixture was filtered and washed with dioxane (10 mL). The filtrate was concentrated in vacuum to give the title compound as a dark brown oil (67 mg, 97% yield). MS (ESP) m / z = 255.2 [M-18+H]+

[0347] Step 9: l-[6-(6-bromo-5-methoxypyrazolo[l,5-a]pyridin-3-yl)-3-[(15)-l-hydroxyethyl]pyridin-2- yl]-5-methylpyrazole-3-carbonitrile

[0348] To a mixture of l-[3-[(15)-l-hydroxyethyl]-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2-yl]-5-methylpyrazole-3-carbonitrile (62 mg, 0.17 mmol, 1 eq) l-[6-chloro-3-[(15)-l- hydroxyethyl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile (for preparation see example 12, step 7) (55 mg, 0.15 mmol) and cesium carbonate (111 mg, 0.34 mmol) in THF (2.4 mL) and water (0.4 mL) was added l,r-bis(diphenylphosphino)ferrocene-palladium(II)di chloride di chloromethane complex (7 mg, 0.01 mmol; CAS [95464-05-4]). The mixture was degassed with nitrogen three times and stirred at 65 °C for 3 hours. The mixture was poured in water (20 mL) and extracted with EtOAc (15 mL x 3). The organic layer was dried over Na2SO4 and concentrated in vacuum. The crude was purified by flash chromatography on Silica gel eluting with 65% EtOAc in petroleum ether to give the title compound as a yellow oil (26 mg, 33% yield). MS (ESP) m / z = 437.0 [M-18+ H]+

[0349] Step 10: l-[3-[(15)-l-hydroxyethyl]-6-[5-methoxy-6-[(6-methylpyridazin-3- yl)amino]pyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile

[0350] Under Argon in a sealed tube, to l-[3-[(15)-l-hydroxyethyl]-6-[5-methoxy-6-[(6- methylpyridazin-3-yl)amino]pyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3- carbonitrile (21 mg, 0.046 mmol, Eq. 1) in 1,4-dioxane (2 mL) was added 3-amino-6- methylpyridazine (6 mg, 0.05 mmol) followed by CS2CO3 (30 mg, 0.005 mmol). Argon was bubbled through the mixture for 5 minutes. [tBuBrettPhos Pd(allyl)]OTf (4 mg, 0.01 mmol; CAS [1798782-17-8]) was added and the mixture was stirred for 3 hours at 80 °C. 20 mg SiliaMetS (Metal Scavenger) were added and the mixture was stirred for 1 hour. The mixture was filtered off and washed with dioxane (3 mL). The organic layer was concentrated in vacuum. The residue was purified by preparative HPLC to give the title compound as a yellow solid (6 mg, 26% yield). MS (ESP) m / z = 482.2 [M+H]+

[0351] Example 13 3-[3-(l-hydroxyethyl)-6-[6-(2-morpholin-4-ylethoxy)pyrazolo[l,5-a]pyridin-3-yl]pyridin-2- yl] benzonitrile

[0352] Step 1 : l-(6-bromo-2-chloropyri din-3 -yl)ethanol

[0353] To a solution of 6-bromo-2-chloro-nicotinaldehyde (500 mg, 2.3 mmol; CAS [1125410-08-3]) in THF (10 mL) was added dropwise at 0 °C 3.4M methylmagnesium bromide in 2- methyltetrahydrofuran (0.73 mL, 2.5 mmol). This mixture was stirred for 30 minutes at 0 °C. Saturated ammoniumchloride (2 mL) was added, followed by water and the mixture was extracted with EtOAc. The organic layer was dried over ISfeSCU and concentrated in vacuum to give the title compound as an orange oil (550 mg, 97% yield). MS (ESP) m / z = 235.9 [M+H]+

[0354] Step 2: 4-(2-pyrazolo[l,5-a]pyridin-6-yloxyethyl)morpholine

[0355] To a suspension of pyrazolo[l,5-a]pyridin-6-ol (2.5 g, 18. mmol, 1 eq; CAS [184473-24-3]) in 2- butanone (53 mL) and 4-(2-iodoethyl)morpholine;hydroiodide (7.31 g, 19.8 mmol) was added K2CO3 (7.46 g, 54.01 mmol) and the mixture was stirred for 2 hours at 80 °C before it was cooled to RT. The suspension was filtered off and washed with EtOAc The organic layer was concentrated in vacuum. The crude was coated on Silica gel and purified by flash chromatography on Silica gel eluting with 0 - 9%MeOH in DCM, to give the title compound as a light yellow solid (3.5 g, 80% yield). MS (ESP) m / z = 248.2 [M+H]+

[0356] Step 3 : 4-[2-(3-bromopyrazolo[l,5-a]pyridin-6-yl)oxyethyl]morpholine

[0357] To a stirred solution of 4-(2-pyrazolo[l,5-a]pyridin-6-yloxyethyl)morpholine (1.5 g, 6.07 mmol, 1 eq) in acetic acid (68 mL) was added at RT bromine (0.31 mL, 6.07 mmol) and the mixture was stirred for 1 hour at RT. The reaction mixture was poured on water at 0 °C and concentrated NaOH was added to reach pH 10. The mixture was extracted with DCM, the organic layer was dried over Na2SO4 and concentrated in vacuum. The crude was purified by flash chromatography on Silica gel eluting with 0 - 6% MeOH in DCM to give the title compound as an off-white solid (1.6 g, 81% yield). MS (ESP) m / z = 328.1 [M+H]+

[0358] Step 4: 4-[2-[3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridin-6- yl]oxyethyl]morpholine

[0359] Under Argon, 4-[2-(3-bromopyrazolo[l,5-a]pyridin-6-yl)oxyethyl]morpholine (1 g, 3.07 mmol, 1 eq) was dissolved in 1,4-dioxane (15 mL). Bis(pinacolato)diboron (3.5 g, 13.6 mmol) was added followed dry potassium acetate (1.07 g, 10.9 mmol). Argon was bubbled through the suspension for 5 minutes. Bis(triphenylphosphine)palladium (II) chloride (108 mg, 0.15 mmol; CAS [13965- 03-2]) was added. Argon was bubbled through the suspension for 5 minutes. The reaction was stirred at 100 °C for 3 hours and then cooled to RT. 10 mL dioxane and 5 gSiliaMetS (Metal Scavenger) were added. The suspension was stirred for Ihour and filtered off. Water was added and the mixture was extracted with DCM. The organic layer was dried over Na2SO4 and concentrated in vacuum. Trituration with heptane gave the title compound as an off white solid (410 mg, 34%). MS (ESP) m / z = 374.3 [M+H]+

[0360] Step 5: l-[2-chloro-6-[6-(2-morpholin-4-ylethoxy)pyrazolo[l,5-a]pyridin-3-yl]pyridin-3- yl] ethanol

[0361] In a pressure tube, a mixture of 4-[2-[3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyrazolo[l,5-a]pyridin-6-yl]oxyethyl]morpholine (210 mg, 0.53 mmol, 1 eq), DMF (4 mL) and water (2 mL), l-(6-bromo-2-chl oro-3 -pyridyl)ethanol (133 mg, 0.53 mmol) (for preparation see example 13, step 1) and K2CO3 (148 mg, 1.07 mmol) was degased with argon for 5 minutes, [l,r-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (44 mg, 0.053 mmol; CAS [95464-05-4]) was added and heated up to 100 °C for 30 minutes. After cooling to RT 1g SiliaMetS (Metal Scavenger) was added and the mixture was stirred for 30 minutes, filtered off and washed with EtOAc. The organic layer was washed with water, dried over Na2SO4 and concentrated in vacuum The crude was purified by flash chromatography on Silica gel eluting with 0 - 8 % MeOH in DCM to give the title compound as a yellow oil (160 mg, 68% yield). MS (ESP) m / z = 403.1 [M+H]+

[0362] Step 6: 3-[3-(l-hydroxyethyl)-6-[6-(2-morpholin-4-ylethoxy)pyrazolo[l,5-a]pyridin-3-yl]pyridin- 2-yl]benzonitrile

[0363] In a pressure tube under Argon, a mixture of l-[2-chloro-6-[6-(2- morpholinoethoxy)pyrazolo[l,5-a]pyridin-3-yl]-3-pyridyl]ethanol (147 mg, 0.36 mmol, 1 eq) in DMF (2 mL) and water (1 mL), (3-cyanophenyl)boronic acid (64 mg, 0.44 mmol) and K2CO3 (50 mg, 0.36 mmol) was degased with argon for 5 minutes. [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with di chloromethane (CAS [95464-05-4]) was added (30 mg, 0.036 mmol) and the mixture was heated at 90 °C for 3 hours. After cooling to RT, 2g SiliaMetS (Metal Scavengers) were added and the mixture was stirred for 30 minutes, filtered off and washed with EtOAc. The organic layer was washed with water, dried over Na2SC>4 and concentrated in vacuum. The crude was purified by preparative HPLC to give the title compound as a red solid (38 mg, 22% yield). MS (ESN) m / z = 514.4 [M+HCOO]'

[0364] Example 14 l-[3-(l-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin- 2-yl]-5-methylpyrazole-3-carbonitrile

[0365] Step 1 : 6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridine

[0366] To a suspension of pyrazolo[l,5-a]pyridin-6-ol (250 mg, 1.8 mmol, 1 eq; CAS [184473-24-3]) in DMF (6.25 mL) and 3-chloro-6-methyl-pyridazine (254.6 mg, 1.98 mmol) was added K2CO3 (746.5 mg, 5.4 mmol) and stirred for 16 hours at 120 °C. The mixture was pourred onto water and extracted with EtOAc. The organic layers were washed with water, dried over Na2SO4 and concentrated in vacuum. The crude was purified by flash chromatography on silica gel eluting with 0% to 5% MeOH in DCM to give the title compound as an off-white solid (299 mg, 73.5% yield). MS (ESP) m / z = 227.2 [M+H]+

[0367] Step 2: 3-bromo-6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridine

[0368] To a stirred solution of 6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridine (318 mg, 1.41 mmol, 1 eq) in acetic acid (15.8 mL) was added at RT bromine (0.07 mL, 1.41 mmol) and the mixture was stirred for 2 hours. The reaction mixture was poured on water at 0 °C and concentrated NaOH was added to reach pH 10. The mixture was extracted with DCM and the organic layer was dried over Na2SO4 and concentrated in vacuum. The crude was purified by flash chromatography on silica gel eluting with 0 - 5 % MeOH in DCM to give the title compound as an off-white solid (365 mg, 85% yield). MS (ESP) m / z = 305.0 [M+H]+

[0369] Step 3 : 6-(6-methylpyridazin-3-yl)oxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl )pyrazol o [ 1 , 5 -a] pyri dine

[0370]

[0371] Under Argon, 3-bromo-6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridine (365 mg, 1.2 mmol, 1 eq) was dissolved in 1,4-dioxane (6 mL). Bis(pinacolato)diboron (1.35 g, 5.32 mmol) was added followed by dry potassium acetate (417 mg, 4.25 mmol). Argon was bubbled through the suspension for 5 minutes. Bis(triphenylphosphine)palladium (II) chloride (42 mg, 0.06 mmol; CAS [13965-03-2]) was added. Argon was bubbled through the suspension for 5 minutes. The reaction was stirred at 100 °C for 3 hours. After coolint to RT, 1,4-dioxane (5 mL) and 5 g SiliaMetS (Metal Scavenger) were added. The suspension was stirred for 1 hour and filtered off. The organic layer was concentrated in vacuum. Trituration with heptane gave the title compound as a light brown solid (260 mg, 50 %). MS (ESP) m / z = 353.2 [M+H]+

[0372] Step 4: l-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5- methylpyrazole-3 -carbonitrile

[0373] Under Argon in a sealed tube, 6-(6-methylpyridazin-3-yl)oxy-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine (100 mg, 0.23 mmol, 1 eq) was dissolved in DMF (2 mL) and water (1 mL), and l-(3-acetyl-6-chloropyridin-2-yl)-5-methylpyrazole-3-carbonitrile (71 mg, 0.27 mmol,) (for preparation see example 1, step 1) and K2CO3 (94 mg, 0.68 mmol) were added. Argon was bubbled through the mixture for 5 minutes. 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (19 mg, 0.023 mmol; CAS [95464-05-4]) was added and the mixture was stirred at 45 °C for 1 hour. The reaction was cooled down, poured on water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuum. The crude was purified by flash chromatography on Silica gel eluting with 0 - 100 % EtOAc in heptane to give the title compound as a light brown oil (98 mg, 88% yield). MS (ESP) m / z = 451.1 [M+H]+

[0374] Step 5 : 1 -[3 -( 1 -hydroxy ethyl)-6-[6-(6-methylpyridazin-3 -yl)oxypyrazolo[ 1 ,5-a]pyri din-3 - yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile

[0375] To a suspension of l-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-2- pyridyl]-5-methyl-pyrazole-3-carbonitrile (98 mg, 0.2 mmol, 1 eq) in methanol (10 mL) was added sodium borohydride (53 mg, 1.4 mmol). This mixture was stirred for 30 minutes and water was added. The mixture was extracted with DCM, the organic layer was dried over Na2SO4 and concentrated in vacuum. The crude was purified by preparative HPLC to give the title compound as a white lyophilized solid (21 mg, 23% yield). MS (ESP) m / z = 497.2 [M+H]+

[0376] Example 15 l-[3-[(15)-l-hydroxyethyl]-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile

[0377] l-[3-(l-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-2- yl]-5-methylpyrazole-3-carbonitrile (541 mg, 1.1 mmol) (for preparation see example 14, step 5) was separated by chiral SFC to give the title compound as the first eluting isomer as a white solid (151 mg, 30 % yield). Structure was confirmed as (S) by NMR on the Mosher ester. MS (ESP) m / z = 497.2 [M+H]+. The absolute configuration was assigned based on the corresponding Mosher’s ester (see J. Org. Chem. 1969, 34, 9, 2543-2549).

[0378] Example 16 l-[3-[(ll?)-l-hydroxyethyl]-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile

[0379] This example was prepared in analogy to example 15 as the second eluting isomer to give the title compound as a white solid (112 mg, 23 % yield). MS (ESP) m / z = 452.2 [M+H]+. The absolute configuration was assigned based on the corresponding Mosher’s ester (see J. Org. Chem. 1969, 34, 9, 2543-2549). Example 17

[0380] 3-fluoro-4-[3-(l-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-l-(2,2,2-trifluoroethyl)pyridin-2-one

[0381] Step 1 : 3-fluoro-4-iodo-l-(2,2,2-trifluoroethyl)pyridin-2-one

[0382] To a solution of 3-fluoro-4-iodo-2-pyridone (250 mg, 0.99 mmol, 1 eq) in DMF (3 mL), trifluoromethanesulfonic acid 2,2,2-trifluoroethyl ester (0.33 mL, 1.99 mmol) and CS2CO3 (971 mg, 3.0 mmol) were added. The reaction mixture was stirred at RT for 1 hour and poured on water (25 mL) and extracted with ethyl acetate. The organic layer was dried over MgSCh and concentrated in vacuum. The crude was purified by flash chromatography on Silica gel eluting with 0 - 30 % EtOAc in to give the title compound as an off-white solid (165 mg, 51% yield). MS (ESP) m / z = 322.0 [M+H]+

[0383] Step 2: 3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-(2,2,2-trifluoroethyl)pyridin-

[0384] 2-one

[0385] Under Argon, 3-fhroro-4-iodo-l-(2,2,2-trifhroroethyl)-2-pyridone (168 mg, 0.514 mmol, 1 eq) was dissolved in 1,4-di oxane (3 mL). Argon was bubbled through the solution for 10 minutes. Potassium acetate (76 mg, 0.77 mmol), bis(pinacolato)diboron (157 mg, 0.62 mmol), tricyclohexylphosphine (17 mg, 0.062 mmol) and tris(dibenzylideneacetone)dipalladium(0) CAS [51364-51-3] (6.5 mg, 0.026 mmol) were added. The reaction mixture was stirred at 85 °C for 3.5 hours and at 100 °C overnight. The reaction was cooled to RT, filtered through celite and the filtrate was concentrated in vacuum. The crude was purified by flash chromatography on Silica gel eluting with 0 - 10 % MeOH in DCM to give the title compound as a white solid (120 mg, 65% yield). MS (ESP) m / z = 240.05 [M-pinacol+H]+

[0386] Step 3: l-[2-chloro-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-3- yl] ethanol

[0387] In a pressure tube, a mixture of 6-(6-methylpyridazin-3-yl)oxy-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine(for preparation see example 14, step 3) (500 mg, 1.42 mmol, 1 eq) in DMF (10 mL) and water (5 mL) with l-(6-bromo-2-chl oro-3 -pyridyl)ethanol (for preparation see example 13, step 1) (361 mg, 1.42 mmol) and K2CO3 (392 mg, 2.84 mmol) was degassed with argon for 5 minutes. [l,l'Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with di chloromethane (116 mg, 0.142 mmol; CAS [95464-05-4]) was added and the mixture was stirred at 45 °C for 30 minutes. The reaction was cooled to RT, poured on water and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated in vacuum. The crude was purified by flash chromatography on Silica gel eluting with 0 - 5 % MeOH in DCM to give the title compound as an off-white solid (420 mg, 75% yield). MS (ESP) m / z = 382.1 [M+H]+

[0388] Step 4: l-[2-chloro-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-3- yl] ethanone

[0389] To a solution of l-[2-chloro-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-3- pyridyl] ethanol (350 mg, 0.89 mmol, 1 eq) in 1,2-di chloroethane (10 mL) was added manganese dioxide (3.09 g, 35.6 mmol). The reaction was stirred at RT overnight. The reaction was heated to 40°C for 16h and then filtered off. The filter cake was washed with AcOEt and concentrated in vacuum. The crude was purified by flash chromatography on Silica gel eluting with 0 - 5 % MeOH in DCM to give the title compound as a yellow solid (208 mg, 62 % yield). MS (ESP) m / z = 380.1 [M+H]+

[0390] Step 5: 4-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-3- fluoro- 1 -(2,2,2-trifluoroethyl)pyridin-2-one In a sealed tube under Argon, l-[2-chloro-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5- a]pyridin-3-yl]-3-pyridyl]ethanone (25 mg, 0.066 mmol, 1 eq) was dissolved in DMF (ImL). 3- fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-(2,2,2-trifluoroethyl)-2-pyridone (for preparation see example 17, step 2) (42 mg, 0.13 mmol), K2CO3 (27.3 mg, 0.197 mmol) and water (0.5 mL) were added. Argon was bubbled through the mixture for 5 min and [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with di chloromethane (5.4 mg, 0.007 mmol; CAS [95464-05-4]) was added. After stirring at 45°C for 1 hour, the mixture was poured on water and extracted with 10: 1 DCM:methanol. The organic layer was dried over Na2SC>4 and concentrated in vacuum. The crude was purified by flash chromatography on Silica gel eluting with 0 - 3 % MeOH in DCM to give the title compound as a light yellow oil (9 mg, 25 % yield). MS (ESP) m / z = 539.2 [M+H]+

[0391] Step 6: 3-fluoro-4-[3-(l-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-

[0392] 3 -yl]pyridin-2-yl]-l -(2, 2, 2 -tri fluoroethyl )pyridin-2-one

[0393] To a solution of 4-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-2- pyridyl]-3-fluoro-l-(2,2,2-trifluoroethyl)-2-pyridone (9 mg, 0.016 mmol, 1 eq) in methanol (0.85 mL) was added NaBEL (1.23 mg, 0.032 mmol) at 0°C. The mixture was stirred for 15 min and then poured on water and extracted with DCM. The organic layer was dried over ISfeSCU and concentrated in vacuum. The crude was purified by flash chromatography on Silica gel eluting with 0 - 5 % MeOH in DCM to give the title compound as a light yellow solid (6 mg, 63 % yield). MS (ESP) m / z = 541.2 [M+H]+

[0394] Example 18 (15)-l-[2-[3-(difluoromethyl)-5-methylpyrazol-l-yl]-6-[6-(6-methylpyridazin-3- yl)oxypyrazolo [1 ,5-a] pyridin-3-yl] pyridin-3-yl] ethanol

[0395] Step 1 : l-(6-chloro-2-fluoropyri din-3 -yl)ethanone

[0396] To diisopropylamine (4.62 g, 6.5 mL, 45.61 mmol) in tetrahydrofuran (37.5 mL) at -78°C under Argon was added 1.6 M n-butyllithium (28.5 mL, 45.6 mmol, 1.2 eq) and the mixture was stirred for 30 min at -78°C. A solution of 2-chloro-6-fluoro-pyridine (5 g, 38. mmol, 1 eq) in tetrahydrofuran (62 mL) was added dropwise over 1 hour and the mixture was stirred for 30 min at -78 °C and then at -40 °C for 1 hour. A solution of N-methoxy-N-methyl-acetamide (4.31 g, 4.45 mL, 41.8 mmol, 1.1 eq) in tetrahydrofuran (20 mL) was added at -75 °C and the mixture was stirred at -78°C for 20 min and then 0 °C for 2 hours. The reaction mixture was diluted with sat. NH4CI (200mL) and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuum. The crude was purified by flash chromatography on Silica gel eluting with 0 - 30 % EtOAc in heptane to give the title compound as a light yellow solid (1.26 g, 19% yield). MS (ESP) m / z = 174.0 [M+H]+

[0397] Step 2: l-(6-chloro-2-fluoropyri din-3 -yl)ethanol To a solution of l-(6-chloro-2-fluoro-3-pyridyl)ethanone (630 mg, 3.63 mmol, 1 eq) in methanol (5 mL) was added NaBEL (206 mg, 5.4 mmol, 1.5 eq) at 0 °C. The reaction was stirred for 10 minutes at 0°C and then quenched with water and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated in vacuum to give the title compound as a light yellow solid (1.26 g, 19% yield). MS (ESP) m / z = 176.0 [M+H]+

[0398] Step 3: l-[2-fluoro-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-3- yl] ethanol

[0399] In a pressure tube, a mixture of 6-(6-methylpyridazin-3-yl)oxy-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine (for preparation see example 14, step 3) (702 mg, 1.99 mmol, 1 eq) in DMF (8 mL) and water 4 mL) with l-(6-chloro-2-fluoropyri din-3 -yl)ethanol (350 mg, 1.99 mmol) and K2CO3 (551 mg, 3.99 mmol) was degased with argon for 5 minutes. [l,l'Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (163 mg, 0.199 mmol; CAS [95464-05-4]) was added and the mixture was stirred at 45 °C for 30 minutes before cooling the RT. The mixture was poured on water and extracted with DCM and the organic layer was dried over ISfeSCU and concentrated in vacuum. The crude was purified by flash chromatography on Silica gel eluting with 0 - 3 % MeOH in DCM to give the title compound as an off-white solid (315 mg, 43% yield). MS (ESP) m / z = 366.2 [M+H]+

[0400] Step 4: l-[2-fluoro-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-3- yl] ethanone

[0401] To a solution of l-[2-fluoro-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-3- pyridyl] ethanol (200 mg, 0.55 mmol, 1 eq) in 1,2-di chloroethane (5 mL) was added manganese dioxide (1.9 g, 22 mmol). The reaction was stirred at rt for 90 min. Then, further manganese dioxide (476 mg, 5.5 mmol), and, after further 2h, more manganese dioxide (476 mg, 5.5 mmol) was added. The reaction was left stirring overnight. The suspension was filtered over Dicalite and and the filtrate was concentrated in vacuum. The crude was purified by flash chromatography on Silica gel eluting with 0 - 5 % MeOH in DCM to give the title compound as an off-white solid (162 mg, 81% yield). MS (ESP) m / z = 364.1 [M+H]+

[0402] Step 5: l-[2-[3-(difhioromethyl)-5-methylpyrazol-l-yl]-6-[6-(6-methylpyridazin-3- yl )oxypyrazol o [ 1 , 5 -a] pyri din-3 -yl ] pyri din-3 -yl ] ethanone

[0403] To a solution of l-[2-fluoro-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-3- pyridyl] ethanone (80 mg, 0.22 mmol, 1 eq) in DMF (2.48 mL) was added 3-(difluoromethyl)-5- methyl-lH-pyrazole (32 mg, 0.24 mmol) and K2CO3 (46 mg, 0.33 mmol). This mixture was stirred at 60 °C overnight and then poured on water and extracted with 9: 1 DCM:Methanol. The organic layer was dried over ISfeSCU and concentrated in vacuum. The crude was purified by preparative HPLC followd by SFC purification to give the title compound as a light yellow solid (21 mg, 19% yield). MS (ESP) m / z = 476.1 [M+H]+ Step 6: (15)-l-[2-[3-(difhioromethyl)-5-methylpyrazol-l-yl]-6-[6-(6-methylpyridazin-3- yl )oxypyrazol o [ 1 , 5 -a] pyri din-3 -yl ] pyri din-3 -yl ] ethanol

[0404] To a solution of l-[2-[3-(difluoromethyl)-5-methyl-pyrazol-l-yl]-6-[6-(6-methylpyridazin-3- yl)oxypyrazolo[l,5-a]pyridin-3-yl]-3-pyridyl]ethanone (21 mg, 0.044 mmol, 1 eq) in methanol (5 mL) and tetrahydrofuran (5 mL) was added at 0 °C NaBT (1.67 mg, 0.044 mmol, 1 eq) and sthe mixture was stirred for 1 hour followed by two additions of more NaBT (1.67 mg, 0.044 mmol, 1 eq) and stirred for 1 hour at 0 °C. The mixture was poured on water and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated in vacuum. The crude was purified by chiral SFC to give the title compound as first eluting isomer as a white solid (7 mg, 31% yield). MS (ESN) m / z = 522.2 [M+HCOO]'

[0405] Example 19 (ll?)-l-[2-[3-(difluoromethyl)-5-methylpyrazol-l-yl]-6-[6-(6-methylpyridazin-3- yl)oxypyrazolo [1 ,5-a] pyridin-3-yl] pyridin-3-yl] ethanol

[0406] This example was isolated in analogy to example 18 (see step 6) to give the title compound as the second eluting isomer as a white solid (6 mg, 28% yield). MS (ESP) m / z = 522.2 [M+HCOO]' Example 20 l-[3-(hydroxymethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin- 2-yl]-5-methylpyrazole-3-carbonitrile

[0407] Step 1 : l-(6-chl oro-3 -formylpyridin-2-yl)-5-methylpyrazole-3 -carbonitrile

[0408] 6-Chloro-2-fluoro-nicotinaldehyde (1 g, 6.27 mmol, 1 eq; CAS [1093880-37-5]) was dissolved in DMF (25 mL) and 5-methyl-lH-pyrazole-3-carbonitrile (739 mg, 6.89 mmol; CAS [38693-82- 2]) and K2CO3 (1.3 g, 9.4 mmol) were added at RT. The mixture was stirred for 1 hour at RT. The reaction mixture was diluted with water and extracted with EtOAc, the organic layer was dried over MgSC and concentrated in vacuum. The crude was purified by flash chromatography on silica gel eluting with 0 - 100 % ethyl acetate in heptane to give the title compound as light brown solid (1.42 g, 92% yield). MS (ESP) m / z = 246.0 [M+H]+

[0409] Step 2: l-[3-formyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]- 5-methylpyrazole-3-carbonitrile

[0410]

[0411] Under Argon, 6-(6-methylpyridazin-3-yl)oxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyrazolo[l,5-a]pyridine (72 mg, 0.20 mmol, 1 eq) (for preparation see example 14, step 3) and l-(6-chloro-3-formyl-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile (50 mg, 0.203 mmol, 1 eq) were suspended in DMF (1.5 mL) and water (0.75 mL). K2CO3 (84 mg, 0.61 mmol) was added followed by l,r-bis(diphenylphosphino)ferrocene-palladium(II)di chloride dichloromethane complex (17 mg, 0.02 mmol; CAS [95464-05-4]). The mixture was stirred for 1 hour at 45 °C and then diluted with water and extracted with EtOAc. The water phase, containing the product as a suspension, was filtered and the solid was washed with water and diethylether to give the title compound as a yellow solid solid (53 mg, 58% yield). MS (ESP) m / z = 437.2 [M+H]+

[0412] Step 3 : l-[3-(hydroxymethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile l-[3-formyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-2-pyridyl]-5-methyl- pyrazole-3 -carbonitrile (30 mg, 0.069 mmol, 1 eq) was suspended in methanol (1 mL) and tetrahydrofuran (1 mL). NaBEL (5 mg, 0.1 mmol) was added at RT. The mixture was stirred for 1 hour at RT. The reaction mixture was diluted with sat. NaHCCh and extracted with EtOAc. The organic layer was dried over MgSCU and concentrated in vacuum. The crude was purified by flash chromatography on silica gel eluting with 0 - 25 % methanol in DCM to give the title compound as a white solid (22 mg, 72% yield). MS (ESP) m / z = 439.2 [M+H]+

[0413] Example 21

[0414] 5-(difluoromethyl)-l-[3-(l-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5- a] pyridin-3-yl] pyridin-2-yl] pyrazole-3-carbonitrile

[0415] Step 1 : 5-(difhiorornethyl)-lJ / -pyrazole-3-carboxamide

[0416] To a solution of 5-(difluoromethyl)-lH-pyrazole-3-carboxylic acid (1.0 g, 6.2 mmol, 1 eq; CAS [681034-51-5 ]) in DMF (16 mL) was added l,l'-Carbonyl diimidazole (1.3 g, 8.0 mmol; CAS [530-62-1]). This solution was stirred at RT for 3 hours. Then, saturated ammonium hydroxide (4.8 mL) was added and the mixture was stirred for 1 hour. The mixture was poured on water and extracted with EtOAc, the organic layer was dried over Na2SO4 and concentrated in vacuum. Trituration with DCM gave the title compound as a white solid (600 mg, 59% yield). MS (ESP) m / z = 162.0 [M+H]+ Step 2: l-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5-

[0417] (difluoromethyl)pyrazole-3-carboxamide

[0418] This example was prepared in analogy Example 18 step 5 by using 5-(difluoromethyl)-UT- pyrazole-3 -carboxamide (CAS [2137578-81-3]) instead of 3-(difluoromethyl)-5-methyl-lH- pyrazole to give the title compound as light yellow solid. MS (ESP) m / z = 505.2 [M+H]+

[0419] Step 3: l-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5-

[0420] (difluoromethyl)pyrazole-3-carbonitrile

[0421] To an icecold solution of l-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3- yl]-2-pyridyl]-5-(difluoromethyl)pyrazole-3-carboxamide (50 mg, 0.1 mmol, 1 eq) in DCM (3 mL) was added triethylamine (0.04 mL) followed by trifluoroacetic anhydride (0.04 mL, 0.3 mmol). This reaction mixture was stirred at 0 °C for 1 hour. The crude reaction mixture was subjected to flash chromatography on silica gel eluting with 0 - 5 % methanol in DCM to give the title compound as a yellow solid (39 mg, 81% yield). MS (ESP) m / z = 487.2 [M+H]+

[0422] Step 4 : 5 -(difluoromethyl)- 1 - [3 -( 1 -hydroxyethyl)-6-[6-(6-methylpyridazin-3 -yl)oxypyrazolo[ 1,5- a]pyridin-3-yl]pyridin-2-yl]pyrazole-3-carbonitrile

[0423]

[0424] This example was prepared in analogy to step 6 of example 17 to give the title compound as light yellow solid. MS (ESP) m / z = 489.3 [M+H]+

[0425] Example 22

[0426] 5-(difluoromethyl)-l-[3-[(lS)-l-hydroxyethyl]-6-[6-(6-methylpyridazin-3- yl)oxypyrazolo [1 ,5-a] pyridin-3-yl] pyridin-2-yl] pyrazole-3-carbonitrile

[0427] 5-(difluoromethyl)-l-[3-(l-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5- a]pyridin-3-yl]pyridin-2-yl]pyrazole-3-carbonitrile (20 mg, 0.04 mmol) (for preparation see example 21, step 4) was separated by chiral SFC to give the title compound as the first eluting isomer as a white solid (6 mg, 33 % yield). MS (ESP) m / z = 489.3 [M+H]+. The absolute configuration was assigned based on the corresponding Mosher’s ester (see J. Org. Chem. 1969, 34, 9, 2543-2549).

[0428] Example 23 5-(difluoromethyl)- 1- [3- [(11?)- 1-hydroxyethyl] -6- [6-(6-methylpyridazin-3- yl)oxypyrazolo [1 ,5-a] pyridin-3-yl] pyridin-2-yl] pyrazole-3-carbonitrile

[0429] This example prepared in analogy to example 22 to give the title compound as the second eluting isomer as an off-white solid (5 mg, 27 % yield). MS (ESP) m / z = 489.3 [M+H]+. The absolute configuration was assigned based on the corresponding Mosher’s ester (see J. Org. Chem. 1969, 34, 9, 2543-2549).

[0430] Examples 24 and25 l-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-2-[3-methyl-l-(2,2,2- trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]ethanol; and l-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-2-[5-methyl-l-(2,2,2- trifluoroethyl)pyrazol-4-yl] pyridin-3-yl] ethanol

[0431]

[0432] Step 1 : 4-bromo-5-methyl-l-(2,2,2-trifluoroethyl)pyrazole and 4-bromo-3 -methyl- 1 -(2,2,2- trifluoroethyl)pyrazole

[0433] A mixture of 4-bromo-3-methylpyrazole (15.0 g, 93.2 mmol, 1 eq; CAS [13808-64-5]), 2,2,2- trifluoroethyl trifluoromethanesulfonate (22.7 g, 97.8 mmol) and CS2CO3 (25.3 g, 186.3 mmol, 2 eq) in DMF (150 mL) was stirred at 100 °C for 12 hours. The reaction mixture was filtered and the filtrate was diluted with H2O (250 mL) and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuum. The crude was purified by flash chromatography on silica gel eluting with 10 % to 20 % ethyl acetate in petroleum ether to give a mixture of the title compounds (19.5 g, 86% yield). MS (ESP) m / z = 242.9 [M+H]+

[0434] Step 2: 5-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-(2,2,2-trifluoroethyl)pyrazole and 3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-(2,2,2-trifluoroethyl)pyrazole

[0435]

[0436] To a mixture of 4-bromo-5-methyl-l-(2,2,2-trifluoroethyl)pyrazole / 4-bromo-3 -methyl- 1 -(2,2,2- trifluoroethyl)pyrazole (11.0 g, 45.3 mmol, 1 eq), bis(pinacolato)diboron (17.2 g, 70 mmol) in 1,4-dioxane (200 mL), potassium acetate (8.9 g, 90.5 mmol) was added followed by [1,1 '- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with di chloromethane (3.7 g, 4.5 mmol; CAS [95464-05-4]). The mixture was stirred at 100 °C for 16 hours under nitrogen. The mixture was subjected to flash chromatography on silica gel eluting with 10 - 20 % ethyl acetate in petroleum ether followed by preparative HPLC to give a mixture of the title compounds as a yellow oil (18 g, 61 % yield). MS (ESP) m / z = 291.1 [M+H]+

[0437] Step 3: tert-butyl A-(3-acetyl-6-chloropyridin-2-yl)carbamate

[0438] A solution of tert-butyl N-(6-chloro-2-pyridyl)carbamate (4.0 g, 17.5 mmol, 1 eq) in THF (60 mL was cooled to -50° C. 2.5M n-butyllithium in THF (17.5 mL, 43.7 mmol) was added dropwise and the reaction was then slowly warmed to 0° C and was stirred at that temperature for 2 hours. Then, at -40 °C, 1 -morpholinoethanone (4.52 g, 35.0 mmol) dissolved in THF (20 mL) was added slowly. The reaction solution was stirred at - 40 °C for 1 hour. Saturated NH4CI (200 mL) was added and the mixture was extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuum. The crude was purified by flash chromatography on silica gel eluting with 20 % ethyl acetate in petroleum ether to give the title compounds as a brown gum (2.65 g, 56 % yield). MS (ESP) m / z = 215 [M-tert.butyl+H]+

[0439] Step 4: l-(2-amino-6-chloroopyri din-3 -yl)ethanone

[0440] To a mixture of tert-butyl A-(3-acetyl-6-chloropyridin-2-yl)carbamate (2.6 g, 9.6 mmol, 1 eq) in DCM (20 mL) was added TFA (5 mL, 64.0 mmol) at RT. The mixture was stirred at RT of 2 hours. The mixture was concentrated in vacuum and quenched with saturated NaHCCh and extracted with EtOAc. The organic layer was dried over ISfeSCU and concentrated in vacuum to give the title compound as a brown solid (1.53 g, 91% yield). MS (ESP) m / z = 171.1 [M+H]+

[0441] Step 5: l-(2-bromo-6-chloropyridin-3-yl)ethanone

[0442] A mixture of, l-(2-amino-6-chloroopyri din-3 -yl)ethanone (1.0 g, 5.9 mmol, 1 eq), copper(II) bromide (2.75 g, 12.3 mmol) and THF (60 mL) was stirred at 50 °C. A solution of tert-butyl nitrite (2.79 mL, 23.5 mmol, 4 eq) in TEIF (15 mL) was added dropwise and the resulting mixture was stirred at 50 °C for 1.5 hours. The reaction mixture was cooled to room temperature and concentrated in vacuum. The crude was purified by flash chromatography on silica gel eluting with 20 % ethyl acetate in petroleum ether to give the title compound as a white solid (640 mg, 47% yield). MS (ESP) m / z = 235.9 [M+H]+ Step 6: l-[6-chloro-2-[5-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]ethanone and 1- [6-chloro-2-[3-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]ethanone

[0443] A mixture of l-(2-bromo-6-chloropyridin-3-yl)ethanone (162 mg, 0.69 mmol, 1 eq), 5-methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-(2,2,2-trifluoroethyl)pyrazole / 3-methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-(2,2,2-trifluoroethyl)pyrazole (preparation see example 24, step 2) (200 mg, 0.69 mmol, 1 eq), potassium carbonate (191 mg, 1.38 mmol, 2 eq) and Pd(dppf)C12'CH2C12 CAS [95464-05-4] (56 mg, 0.07 mmol, 0.10 eq) in 1,4-dioxane (5 mL) and water (0.500 mL) was stirred at 80 °C under nitrogen for 12 hours. The reaction mixture was cooled to room temperature and concentrated in vacuum. The crude was purified by flash chromatography on silica gel eluting with 0 % to 20 % ethyl acetate in petroleum ether to give the mixture of the title compounds as a white solid (210 mg, 96 % yield). MS (ESP) m / z = 318.1 [M+H]+

[0444] Step 7: l-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-2-[5-methyl-l-(2,2,2- trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]ethanone and l-[6-[6-(6-methylpyridazin-3- yl)oxypyrazolo[l,5-a]pyridin-3-yl]-2-[3-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-3- yl] ethanone

[0445]

[0446] Under Argon, a mixture of l-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-2- [5-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]ethanone / l-[6-[6-(6-methylpyridazin- 3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-2-[3-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-3- yl]ethanone (200 mg, 0.63 mmol, Eq.l), 6-(6-methylpyridazin-3-yl)oxy-3-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine (288 mg, 0.203 mmol) (for preparation see example 14, step 3) and K2CO3 (174 mg, 1.26 mmol) was suspended in 1,4-dioxane (5 mL) and water (0.5 mL). l,r-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (51 mg, 0.02 mmol; CAS [95464-05-4]) was added and the mixture was stirred for 12 hours at 100 °C. The residue was purified by preparative HPLC followed by SFC purification to give the title compounds l-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-2-[3- methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanone as a white solid (60 mg, 40% yield), (ESP) m / z = 508.0 [M+H]+, and l-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5- a]pyridin-3-yl]-2-[5-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanone (20 mg, 13% yield), MS (ESP) m / z = 508.0 [M+H]+, as an off-white solid.

[0447] Step 8: l-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-2-[3-methyl-l-(2,2,2- trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]ethanol, Example 24

[0448]

[0449] To a solution of l-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-2-[3-methyl-l- (2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanone (55 mg, 0.11 mmol, 1 eq) in methanol (3 m ) was added NaBEU (21 mg, 0.54 mmol) at -70 °C. The mixture was stirred at -70 °C for 30 minutes. The reaction mixture was quenched by saturated NH4CI. The reaction mixture was purified by preparative HPLC to give of the title compound as a white solid (36 mg, 65% yield). MS (ESP) m / z = 509.9 [M+H]+

[0450] Step 9: l-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-2-[5-methyl-l-(2,2,2- trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]ethanol, Example 25

[0451] This example was prepared in analogy to example 24 by using l-[6-[6-(6-methylpyridazin-3- yl)oxypyrazolo[l,5-a]pyridin-3-yl]-2-[5-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-3- yl]ethanone instead of l-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-2-[3- methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]ethanone to give the title compound as a white solid. MS (ESP) m / z = 509.9 [M+H]+

[0452] Example 26

[0453] 5-chloro-2- [3-(l-hydroxyethyl)-6- [6-(6-methylpyridazin-3-yl)oxypyrazolo [1,5-a] pyridin-3- yl] pyridin-2-yl] pyrazole-3-carbonitrile

[0454] Step 1 : methyl 5-chloro-l-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate

[0455] To a solution of 2-(trimethylsilyl)ethoxymethyl chloride (1.2 mL, 7.0 mmol) in DMF (20 mL) was added 60% sodium hydride (239 mg, 6.0 mmol, 1.2 eq) portionwise at 0 °C. The mixture was stirred at 20 °C for 1 hour. The mixture was cooled to 0 °C and methyl 5-chloro-lH- pyrazole-3 -carboxylate (800 mg, 5.0 mmol, 1 eq) was added. The mixture was stirred at 20 °C for 16 hours. The mixture was poured into water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuum. The crude was purified by flash chromatography on silica gel eluting with 20 % ethyl acetate in petroleum ether to give the title compounds as a colorless oil (750 mg, 52 % yield). MS (ESP) m / z = 232.2 [M+H]+ Step 2: 5-chloro-l-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxamide

[0456] In a pressure tube a solution of methyl 5-chloro-l-(2-trimethylsilylethoxymethyl)pyrazole-3- carboxylate (750 mg, 2.58 mmol, 1 eq) in sat. NH3 in MeOH (20 mL, 140 mmol) was stirred at 80 °C for 60 minutes. The mixture was concentrated in vacuum to give the title compound as a light yellow oil (900 mg, quant, yield), which was used as such in the next step. MS (ESP) m / z = 218.0 [M+H]+

[0457] Step 3 : 5-chloro-l-(2-trimethylsilylethoxymethyl)pyrazole-3-carbonitrile

[0458] To a solution of 5-chloro-l-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxamide (900 mg, 3.26 mmol, 1 eq) in pyridine (20 mL, 247 mmol) was added trifluoroacetic anhydride (1.84 mL, 13.05 mmol) dropwise at 0 °C under nitrogen. The mixture was stirred at 0 °C for 1 hour The reaction mixture concentrated in vacuum and the crude was purified by flash chromatography on silica gel eluting with 0 - 10 % ethyl acetate in petroleum ether to give the title compound as a colorless liquid (800 mg, 95% yield). 1H NMR (400 MHz, DMSO-d6) 5 = 7.47 (s, 1H), 5.58 (s, 2H), 3.59 (t, J = 7.9 Hz, 2H), 0.86 (t, J = 7.9 Hz, 2H), -0.01 - -0.11 (m, 9H).

[0459] Step 4: 5-chloro-U / -pyrazole-3-carbonitrile

[0460] Trifluoroacetic acid (5.0 mL) was added to 5-chloro-l-(2 -trimethylsilyl ethoxymethyl)pyrazole-3- carbonitrile (800 mg, 3.1 mmol) at 0 °C and the mixture was stirred at RT for 1 hour. The mixture was concentrated and the residue was treated with 25% NH3 (4.0 mL) at 0 °C and the mixture was stirred at RT fori hour. The reaction mixture was concentrated in vacuum The crude was purified flash chromatography on silica gel eluting with 30 % ethyl acetate in petroleum ether to give the title compounds as a white gum (350 mg, 88 % yield). 1H NMR (400 MHz, DMSO-d6) 5 = 7.22 (s, 1H)

[0461] Step 5: 2-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5- chi oropyrazol e-3 -carb onitril e

[0462] This example was prepared in analogy to example 18, step 5, by using 5-chloro-U / -pyrazole-3- carbonitrile instead of 3-(difluoromethyl)-5-methyl-lH-pyrazole to give the title compound as a yellow solid. MS (ESP) m / z = 471.0 [M+H]+

[0463] Step 6: 5-chloro-2-[3-(l-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin- 3-yl]pyridin-2-yl]pyrazole-3-carbonitrile

[0464]

[0465] This example was prepared in analogy to example 17, step 6, to give the title compound as a white solid solid. MS (ESP) m / z = 473.2 [M+H]+

[0466] Example 27

[0467] 5-cyclopropyl-l-[3-(l-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5- a] pyridin-3-yl] pyridin-2-yl] pyrazole-3-carbonitrile

[0468] This example was prepared in analogy to step 6 of example 18 by using 5 -cyclopropyl -1H- pyrazole-3 -carbonitrile (CAS [1290696-95-5]) instead of 3-(difluoromethyl)-5-methyl-lH- pyrazole to give the title compound as a yellow solid. MS (ESN) m / z = 523.5 [M+HCOO]'

[0469] Example 28

[0470] 5-cyclopropyl-2-[3-(l-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5- a] pyridin-3-yl] pyridin-2-yl] pyrazole-3-carbonitrile

[0471]

[0472] This example was preparaed in analogy to example 27. In step 6, 5-cyclopropyl-lH-pyrazole-3- carbonitrile was obtained as an isomer and the synthesis was completed using that intermediate to give the title compound as a white lyophilized solid. MS (ESP) m / z = 479.4 [M+H]+

[0473] Example 29

[0474] 5-(difluoromethyl)-l-[3-(l-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5- a] pyridin-3-yl] pyridin-2-yl] pyrazole-3-carboxamide

[0475] This example was prepared in analogy to step 4 of example 21 step by using l-[3-acetyl-6-[6-(6- methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5-(difluoromethyl)pyrazole- 3-carboxamide (for preparation see example 21, step 2) instead of l-[3-acetyl-6-[6-(6- methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5-(difluoromethyl)pyrazole- 3 -carbonitrile to give the title compound as a white lyophilized solid (60 mg, 92% yield). MS (ESN) m / z = 551.5 [M+HCOO]’ Example 30

[0476] 2-[3-(l-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-

[0477] 2-yl]-5-(trifluoromethyl)pyrazole-3-carbonitrile

[0478] This example was prepared in analogy to example 18 using 3-(trifluoromethyl)-lH-pyrazole-5- carbonitrile instead 3-(difluoromethyl)-5-methyl-lH-pyrazole (CAS [934759-09-8]) to give the title compound as a white lyophilized powder (2 mg, 24.1% yield). MS (ESP) m / z = 507.3 [M+H]+

[0479] Example 31

[0480] 1- [6- [6-(6-chloropyridazin-3-yl)oxypyrazolo [1,5-a] pyridin-3-yl]-3-(l-hydroxyethyl)pyridin- 2-yl]-5-methylpyrazole-3-carbonitrile

[0481] Step 1: pyrazolo[l,5-a]pyridin-6-ol

[0482] To a solution of 6-methoxypyrazolo[l,5-a]pyridine (10.0 g, 67.5 mmol, 1 eq; CAS [1427374-36- 4]) in DCM (150 mL) was added boron tribromide (18.9 mL, 202 mmol) at 0 °C. The reaction mixture was slowly warmed to RT and stirred for 12 hours. The reaction mixture was slowly quenched with ice water (500 mL) and the pH was adjusted to 7~8 by addition of 2M sodium hydroxide. The mixture was extracted with EtOAc and the organic layer was dried over ISfeSCU and concentrated in vacuum. The crude was purified by flash chromatography on silica gel eluting with 20 % ethyl acetate in petroleum ether to give the title compound as a light brown solid (7.8 g, 86 % yield). MS (ESP) m / z = 135.0 [M+H]+

[0483] Step 2: 3-bromopyrazolo[l,5-a]pyridin-6-ol

[0484] To a solution of pyrazolo[l,5-a]pyridin-6-ol (1.2 g, 8.95 mmol, 1 eq) in Methanol (20 mL) was added NBS (1.59 g, 8.95 mmol, 1 eq) at -10 °C. The reaction mixture was stirred at -10 °C for 2 hours. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuum. The crude was purified by flash chromatography on silica gel eluting with 30 % to 50 % ethyl acetate in petroleum ether to give the title compound as a grey solid (1.5 g, 79 % yield). MS (ESP) m / z = 213.0 [M+H]+

[0485] Step 3: 3-bromo-6-phenylmethoxypyrazolo[l,5-a]pyridine To a solution of benzyl bromide (1.26 mL, 10.6 mmol) in acetonitrile (20 mL) and DMF (2 mL) was added K2CO3 (4.87 g, 35.2 mmol). At 0 °C, 3-bromopyrazolo[l,5-a]pyridin-6-ol (1.5 g, 7.0 mmol, 1 eq) was added and the reaction was stirred at RT for 12 hours. The mixture was diluted with water and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated in vacuum. The crude was purified by flash chromatography on Silica gel eluting with 25 % (ethyl acetate:DCM 9: 1) in petroleum ether to give the title compound as a white solid (1.5 g, 56 % yield). MS (ESP) m / z = 302.9 [M+H]+

[0486] Step 4: 6-phenylmethoxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine

[0487] To a solution of bis(pinacolato)diboron (2.51 g, 9.9 mmol) in diglyme (40 mL) and water (0.2 mL) was added 3-bromo-6-phenylmethoxypyrazolo[l,5-a]pyridine (1.2 g, 4.0 mmol, 1 eq), palladium (II) acetate (89 mg, 0.4 mmol), tricyclohexyl phosphine (222 mg, 0.79 mmol), K2CO3 (766 mg, 5.5 mmol) and the reaction was stirred at 100 °C for 2 hours under nitrogen. The mixture was diluted with water and extracted with EtOAc, the organic layer was dried over Na2SO4 and concentrated in vacuum. The crude was purified by flash chromatography on Silica gel eluting with petroleum ether to give the title compound as a mixture with debrominated starting material (1 : 1) as a solution in diglyme (about 10 mL), which was used in the next step as such. MS (ESP) m / z = 351.1 [M+H]+

[0488] Step 5: 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridin-6-ol

[0489]

[0490] To a solution of 6-phenylmethoxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5- a]pyridine (8.0 mL, 1.71 mmol, 1 eq, dissolved in 10 mL diglyme ) in Methanol (30 mL), 10% Pd / C (200 mg, 0.17 mmol, 0.1 eq) was added The reaction mixture was stirred at RT for 4 hours under hydrogen (15 psi). The catalyst was filtered off through celite and the filtrate was concentrated in vacuum to give the title compound (in diglyme), which was used in the next step directly as such.

[0491] Step 6: l-[3-acetyl-6-(6-hydroxypyrazolo[l,5-a]pyridin-3-yl)pyridin-2-yl]-5-methylpyrazole-3- carbonitrile

[0492] To a solution of 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridin-6-ol (8.0 mL, 1.92 mmol, 1 eq) in water (3 mL) and DMF (6 mL) was added l-(3-acetyl-6-chloro- 2pyridyl)-5-methyl-pyrazole-3-carbonitrile (551 mg, 2.1 mmol, 1.1 eq). [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with di chloromethane (157 mg, 0.19 mmol; CAS [95464-05-4]) and K2CO3 (797 mg, 5.8 mmol). The reaction mixture was stirred at 80 °C for 3 hours under nitrogen. The reaction was diluted with water and extracted with EtOAc, the organic layer was dried over ISfeSCU and concentrated in vacuum. The crude was purified by flash chromatography on silica gel eluting with 50 % to 100 % ethyl acetate in petroleum ether to give the title compound as a yellow solid. (230 mg, 33% yield). MS (ESP) m / z = 358.9 [M+H]+

[0493] Step 7: l-[3-acetyl-6-[6-(6-chloropyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5- methylpyrazole-3 -carbonitrile

[0494] To a solution of l-[3-acetyl-6-(6-hydroxypyrazolo[l,5-a]pyridin-3-yl)-2-pyridyl]-5- methylpyrazole-3 -carbonitrile (60 mg, 0.17 mmol, 1 eq) in DMF (3 mL) was added 3,6- dichloropyridazine (27 mg, 0.18 mmol) and CS2CO3 (164 mg, 0.5 mmol). The reaction mixture was stirred at 100 °C for 3 hours. The reaction was diluted with H2O (50 mL) and extracted with EtOAc, the organic layer was dried over Na2SO4 and concentrated in vacuum. The crude was purified by flash chromatography on silica gel eluting with 50 % ethyl acetate in petroleum ether to give the title compound as a yellow solid (20 mg, 25% yield). MS (ESP) m / z = 471.0 [M+H]+

[0495] Step 8: l-[6-[6-(6-chloropyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-3-(l- hydroxyethyl)pyridin-2-yl]-5-methylpyrazole-3-carbonitrile To a solution of l-[3-acetyl-6-[6-(6-chloropyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-2- pyridyl]-5-methylpyrazole-3-carbonitrile (20 mg, 0.04 mmol, 1 eq) in methanol (1 mL) and DCM (1 mL) was added sodium borohydride (5 mg, 0.13 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes. The mixture was quenched with saturated NH4CI at 0 °C and extracted with EtOAc, the organic layer was dried over ISfeSCU and concentrated in vacuum. The crude was purified by preparative HPLC to give give the title compound as a white solid (3 mg, 13% yield). MS (ESP) m / z = 473.2 [M+H]+

[0496] Example 32

[0497] 2-[3-(l-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin- 2-yl] -3,5-dimethyl-4H-pyrrolo [3,4-c] pyrazol-6-one

[0498] Step 1 : methyl 5-methyl-l-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate To a solution of methyl 5-methyl-lH-pyrazole-3-carboxylate (9.0 g, 64.22 mmol, 1 eq; CAS [25016-17-5]) in DMF (90 mL) was added sodium hydride (3.083 g, 77.07 mmol) in portions at 0 °C. A lot of solid was precipitated. Then to the reaction mixture was added DMF (50 mL) slowly. The mixture was stirred at 0°C for 30 minutes. Then 2-(trimethylsilyl)ethoxym ethyl chloride (17.05 mL, 96.33 mmol) was added into the reaction mixture dropwise. The reaction mixture was stirred at 0 °C for 2 hours. The reaction mixture was quenched with satured NFLCl-solution (800 ml) and extracted with EtOAc, the organic layer was dried over Na2SO4 and concentrated in vacuum. The crude was purified by flash chromatography on silica gel eluting with 20 % to 30 % ethyl acetate in petroleum ether to give the title compound (mixture of 2 regioisomers) as a yellow oil. (17 g, 97.9% yield). MS (ESP) m / z = 271.2 [M+H]+

[0499] Step 2: methyl 4-bromo-5-methyl-l-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate

[0500] To a solution of methyl 5-methyl-l-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (18 g, 66.57 mmol, 1 eq) (mixture of 2 regioisomers) in Acetonitrile (180 mL) was added NBS (17.8 g, 100 mmol) at 0 °C in portions. The reaction mixture was stirred at RT for 12 hours. The reaction mixture was concentrated in vacuum The crude was purified by flash chromatography on silica gel eluting with 20 % ethyl acetate in petroleum ether to give the title compound (mixture of 2 regioisomers) as a colorless oil (22 g, 95 % yield). Separation of the regioisomers (12 g, 34.4 mmol)was achieved by another flash chromatography on silica gel eluting with 10 % ethyl acetate in petroleum ether to give the title compound as a yellow oil (7 g). MS (ESP) m / z = 291.0 [M-C00Me+H]+

[0501] Step 3: methyl 5-methyl-4-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]-l-(2- trimethylsilylethoxymethyl)pyrazole-3-carboxylate

[0502]

[0503] To a mixture methyl 4-bromo-5-methyl-l-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (3.0 g, 8.6 mmol, 1 eq) and potassium N-BOC-aminomethyltrifluoroborate (5.09 g, 21.5 mmol) in 1,4-di oxane (30 mL) and Water (3 mL) was added CS2CO3 (6.99 g, 21.5 mmol), Xphos (1.6 g, 3.4 mmol; CAS [564483-18-7]) and Pd(OAc)2 (386 mg, 1.72 mmol). The suspension was degassed with nitrogen 3 times and stirred at 110 °C for 16 hours. The reaction mixture was dilutet with water and extracted with EtOAc, the organic layer was dried over Na2SO4 and concentrated in vacuum. The crude was purified by flash chromatography on silica gel eluting with 20 % ethyl acetate in petroleum ether to give the title compound as a yellow oil (3 g, 87.4% yield). MS (ESP) m / z = 400.1 [M+H]+

[0504] Step 4: methyl 4-(aminomethyl)-5-methyl-l-(2-trimethylsilylethoxymethyl)pyrazole-3- carboxylate

[0505] To a solution of methyl 5-methyl-4-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]-l-(2- trimethylsilylethoxymethyl)pyrazole-3-carboxylate (2.5 g, 6.3 mmol, 1 eq) in DCM (20 mL) was added TFA (2.0 mL). The reaction mixture was stirred at RT for 8 hours. The reaction mixture was poured on sat. NaHCCh and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated in vacuum, to give the title compound as a yellow oil (1.6 g, 85.4% yield). MS (ESP) m / z = 300.3 [M+H]+

[0506] Step 5: 4-(aminomethyl)-5-methyl-l-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylic acid

[0507] To a mixture of methyl 4-(aminomethyl)-5-methyl-l-(2-trimethylsilylethoxymethyl)pyrazole-3- carboxylate (1.6 g, 5.3 mmol, 1 eq) in THF (8 mL), methanol (8 mL) and water (1 mL) was added LiOH (320 mg, 13.4 mmol). The mixture was stirred at RT for 1 hour. The pH was adjusted to 7 with IM HC1 and the mixture was concentrated in vacuum to give the title compound as a colorless oil (1.5 g, 98% yield). MS (ESP) m / z = 286.1 [M+H]+

[0508] Step 6: 3-methyl-2-(2 -trimethylsilyl ethoxymethyl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6-one

[0509] To a solution of 4-(aminomethyl)-5-methyl-l-(2-trimethylsilylethoxymethyl)pyrazole-3- carboxylic acid (1.5 g, 5.3 mmol, 1 eq) in DMF (60 mL) was added DIPEA (0.78 mL, 15.8 mmol) and HATU (1.48 g, 6.31 mmol). The reaction mixture was stirred at RT for 12 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuum. The crude was purified by flash chromatography on silica gel eluting with 50 % methanol in DCM to give the title compound as a yellow oil (320 mg, 23% yield). MS (ESP) m / z = 268.1 [M+H]+

[0510] Step 7 : 3,5-dimethyl-2-(2-trimethylsilylethoxymethyl)-47 / -pyrrolo[3,4-c]pyrazol-6-one

[0511] To a solution of 3-methyl-2-(2-trimethylsilylethoxymethyl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6- one (400 mg, 1.5 mmol, 1 eq) in DMF (8 mL) was added 60% sodium hydride in mineral oil (96 mg, 2.4 mmol) at 0 °C in portions. The mixture was stirred at 0°C for 30 min. Methyliodide (0.92 mL, 15 mmol) was added dropwise. The reaction mixture was stirred at RT for 2 hours. The reaction mixture was poured into saturated NH4CI and extracted with EtOAc, the organic layer was dried over Na2SO4 and concentrated in vacuum to give the title compound as a yellow oil (350 mg, 83% yield). MS (ESP) m / z = 282.1 [M+H]+

[0512] Step 8: 3,5-dimethyl-2,4-dihydropyrrolo[3,4-c]pyrazol-6-one A solution of 3,5-dimethyl-2-(2-trimethylsilylethoxymethyl)-4H-pyrrolo[3,4-c]pyrazol-6-one (350 mg, 1.24 mmol, 1 eq) in TFA (3.0 mL) was stirred at 50 °C for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (5 mL) and satured NaHCCL was added to adjust the pH to 6~7. The mixture concentrated under reduced pressure. DCM (lOmL) and MeOH (ImL) was added and the resulting the suspension was stirred at 20 °C for 10 minutes. After filtering off the solids, the filtrate was concentrated in vacuum to give the title compound (180 mg, 1.2 mmol, 96% yield) as a yellow oil. The crude product was used directly in the next step without further purification. MS (ESP) m / z = 152.1 [M+H]+

[0513] Step 9: 2-(3-acetyl-6-chloropyridin-2-yl)-3,5-dimethyl-4J7-pyrrolo[3,4-c]pyrazol-6-one

[0514] This compound was prepared in analogy to example 1, step 1, by using 3,5-dimethyl-2,4- dihydropyrrolo[3,4-c]pyrazol-6-one instead of 5-methyl-lH-pyrazole-3-carbonitrile and K2CO3 instead of DIPEA to give the title compound as a yellow oil. MS (ESP) m / z = 305.0 [M+H]+

[0515] Step 10: 2-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-

[0516] 3,5-dimethyl-4J7-pyrrolo[3,4-c]pyrazol-6-one This compound was prepared in analogy to example 20, step 2, by using 2-(3-acetyl-6- chloropyridin-2-yl)-3,5-dimethyl-4J / -pyrrolo[3,4-c]pyrazol-6-one instead of 1 -(6-chl oro-3 - formyl-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile to give the title compound as a grey solid. MS (ESP) m / z = 495.3 [M+H]+

[0517] Step 11 : 2-[3-(l-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3- yl]pyri din-2 -yl]-3,5-dimethyl-4J / -pyrrolo[3,4-c]pyrazol-6-one

[0518] This compound was prepared in analogy to example 17, step 6, by using 2-[3-acetyl-6-[6-(6- methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-3,5-dimethyl-4J7-pyrrolo[3,4- c]pyrazol-6-one instead of 4-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin- 3-yl]-2-pyridyl]-3-fluoro-l-(2,2,2-trifluoroethyl)-2-pyridone to give the title compound as a yellow solid. MS (ESP) m / z = 497.2 [M+H]+

[0519] Example 33 l-[2-[3-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]-6-[6-(6-morpholin-4-ylpyridazin-3- yl)oxypyrazolo [1 ,5-a] pyridin-3-yl] pyridin-3-yl] ethanol

[0520]

[0521] Step 1: 4-[6-[3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridin-6- yl]oxypyridazin-3-yl]morpholine

[0522] This compound was prepared in analogy to steps 1-3 of example 14 by using 4-(6- chloropyridazin-3-yl)morpholine instead of 3-chloro-6-methyl-pyridazine to give the title compound as an off-white solid. MS (ESP) m / z = 424.2 [M+H]+

[0523] Step 2: l-[2-[3-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]-6-[6-(6-morpholin-4-ylpyridazin-3- yl )oxypyrazol o [ 1 , 5 -a] pyri din-3 -yl ] pyri din-3 -yl ] ethanol

[0524]

[0525] This example was prepared in analogy to step 7-8 of example 24 by using 4-[6-[3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridin-6-yl]oxypyridazin-3-yl]morpholine Instead of 6-(6-methylpyridazin-3-yl)oxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyrazolo[l,5-a]pyridine to give the title compound as a white solid. MS (ESP) m / z = 581.2 [M+H]+

[0526] Example 34 l-[2-[3-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]-6-[6-[6-(morpholin-4- ylmethyl)pyridazin-3-yl] oxypyrazolo [1 ,5-a] pyridin-3-yl] pyridin-3-yl] ethanol

[0527]

[0528] Step 1: 4-[(6-chloropyridazin-3-yl)methyl]morpholine

[0529] A mixture of 3-chloro-6-(chloromethyl)pyridazine (1.5 g, 9.2 mmol, 1 eq; CAS [120276-59-7]), morpholine hydrochloride (1.36 g, 11.04 mmol) and KHCO3 (1.84 g, 18.4 mmol, 2 eq) in acetonitrile (30 mL) was stirred at 30 °C for 12 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by preparative HPLC to give the title compound as a yellow solid (1g, 51% yield). MS (ESP) m / z = 214.0 [M+H]+

[0530] Step 2: 4-[[6-[3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridin-6- yl]oxypyridazin-3-yl]methyl]morpholine

[0531]

[0532] This compound was prepared in analogy to step 1-3 of example 14 by using 4-[(6- chloropyridazin-3-yl)methyl]morpholine instead of 3-chloro-6-methyl-pyridazine to give the title compound as a yellow oil. MS (ESP) m / z = 438.1 [M+H]+

[0533] Step 3 : l-[2-[3-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]-6-[6-[6-(morpholin-4- ylmethyl)pyridazin-3-yl]oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-3-yl]ethanol

[0534] This example was prepared in analogy to step 7-8 of example 24 by using 4-[[6-[3-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridin-6-yl]oxypyridazin-3- yl]methyl]morpholine instead of 6-(6-methylpyridazin-3-yl)oxy-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine to give the title compound as a white solid. MS (ESP) m / z = 595.2 [M+H]+ Example 35: l-[2-[5-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]-6-[6-(6-morpholin-4-ylpyridazin-3- yl)oxypyrazolo [1 ,5-a] pyridin-3-yl] pyridin-3-yl] ethanol

[0535] This example was prepared in analogy to example 25 by using 4-[[6-[3-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridin-6-yl]oxypyridazin-3-yl]methyl]morpholine Instead of 6-(6-methylpyridazin-3-yl)oxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyrazolo[l,5-a]pyridine to give the title compound as a white solid. MS (ESP) m / z = 581.2 [M+H]+

[0536] Example 36 l-[6-[6-[6-(difluoromethyl)pyridazin-3-yl]oxypyrazolo[l,5-a]pyridin-3-yl]-3-[(15)-l- hydroxyethyl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile

[0537]

[0538] Step 1 : 6-[6-(difluoromethyl)pyridazin-3-yl]oxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl )pyrazol o [ 1 , 5 -a] pyri dine

[0539] This compound was prepared in analogy to step 1-3 of example 14 by using 3-Chloro-6- (difluoromethyl)pyridazine (CAS [1706439-95-3]) instead of 3-chloro-6-methyl-pyridazine to give the title compound as a light brown oil. MS (ESP) m / z = 389.3 [M+H]+

[0540] Step 2: l-[6-[6-[6-(difluoromethyl)pyridazin-3-yl]oxypyrazolo[l,5-a]pyridin-3-yl]-3-[(15)-l- hydroxyethyl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile To a solution of 6-[6-(difluoromethyl)pyridazin-3-yl]oxy-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine (117 mg, 0.15 mmol) in DMF (3 mL) was added l-[6- chloro-3-[(LS')- l -hydroxy ethyl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile (preparation see example 12, step 7) (39.6 mg, 0.15 mmol) and K2CO3 (63 mg, 0.45 mmol) and water (1 mL). Argon was bubbled through the mixture for 5 minutes. l,l'bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (12 mg, 0.015 mmol; CAS [564483-18-7]) was added to the reaction mixture. The reaction was stirred for 10 minutes at RT and then heated to 45 °C for 30 minutes. The reaction was cooled to RT, poured on water and extracted with EtOAc, the organic layer was dried over ISfeSCU and concentrated in vacuum. The crude was purified by flash chromatography on silica gel eluting with 0 - 5 % methanol in DCM followed by preparative HPLC to give the title compound as a white lyophilized solid. (ESP) m / z = 533.4 [M+H]+

[0541] Example 37 l-[6-[6-[6-(4-methylpiperazin-l-yl)pyridazin-3-yl]oxypyrazolo[l,5-a]pyridin-3-yl]-2-[3- methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]ethanol

[0542] Step 1 : 6-(6-chloropyridazin-3-yl)oxypyrazolo[l,5-a]pyridine This example was prepared in analogy to step 1 example 34 by using 3,6-dichloropyridazine (CAS [141-30-0]) instead of morpholine hydrochloride to give the title compound as a yellow solid. MS (ESP) m / z = 247.1 [M+H]+

[0543] Step 2: 6-[6-(4-methylpiperazin-l-yl)pyridazin-3-yl]oxypyrazolo[l,5-a]pyridine

[0544] A mixture of 6-(6-chloropyridazin-3-yl)oxypyrazolo[l,5-a]pyridine (700 mg, 2.8 mmol), 1- methylpiperazine (56 mg, 5.7 mmol) and KHCO3 (568 mg, 5.7 mmol) in DMF (15 m ) was stirred at 130 °C for 12 hours. The reaction mixture was filtered and the filtrate was poured on water and extracted with EtOAc, the organic layer was dried over ISfeSCU and concentrated in vacuum. The crude was purified by preparative HPLC to give the title compound as a brown solid (350 mg, 34% yield). MS (ESP) m / z = 311.1 [M+H]+

[0545] Step 3: 6-[6-(4-methylpiperazin-l-yl)pyridazin-3-yl]oxy-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazolo[ 1 , 5-a]pyridine

[0546] This compound was prepared in analogy to steps 2-3 of example 14 by using 6-[6-(4- methylpiperazin-l-yl)pyridazin-3-yl]oxypyrazolo[l,5-a]pyridine instead of 6-(6-methylpyridazin- 3-yl)oxypyrazolo[l,5-a]pyridine to give the title compound as a white solid. MS (ESP) m / z = 437.3 [M+H]+ Step 4: l-[6-[6-[6-(4-methylpiperazin-l-yl)pyridazin-3-yl]oxypyrazolo[l,5-a]pyridin-3-yl]-2-[3- methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]ethanol

[0547] This example was prepared in analogy to steps 7-8 of example 24 by using 6-[6-(4- methylpiperazin-l-yl)pyridazin-3-yl]oxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyrazolo[l,5-a]pyridine instead of 6-(6-methylpyridazin-3-yl)oxy-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine to give the title compound as a white solid. MS (ESP) m / z = 594.2 [M+H]+

[0548] Example 38

[0549] 1- [2- [3-(difluoromethyl)-5-methylpyrazol- 1-yl] -6- [6- [6- [(3-methoxyazetidin- 1 - yl)methyl] pyr idazin-3-yl] oxypyrazolo [1 ,5-a] pyridin-3-yl] pyridin-3-yl] ethanol Step 1: 3-chloro-6-[(3-methoxyazetidin-l-yl)methyl]pyridazine

[0550] This compound was prepared in analogy to step 1 of example 34 by using 3- methoxyazetidine;hydrochloride instead of morpholine hydrochloride and DIPEA instead of KHCO3 and THF instead of Acetonitrile to give the title compound as a brown oil. MS (ESP) m / z = 214.2 [M+H]+

[0551] Step 2: 3-bromo-6-[6-[(3-methoxyazetidin-l-yl)methyl]pyridazin-3-yl]oxypyrazolo[l,5- a]pyridine

[0552] This compound was prepared in analogy to steps 2-3 of example 14 by using 3-chloro-6-[(3- methoxyazetidin-l-yl)methyl]pyridazine instead of 4-(2-pyrazolo[l,5-a]pyridin-6- yloxyethyl)morpholine to give the title compound as an off-white solid. MS (ESP) m / z = 390.2 [M+H]+

[0553] Step 3: l-[2-[3-(difhroromethyl)-5-methylpyrazol-l-yl]-6-(4,4,5,5-tetramethyl-l,3,2- di oxab orol an-2-yl)pyri din-3 -yl ] ethanone

[0554]

[0555] In analogy to step 7 of example 12 by using 3-(difluoromethyl)-5-methyl-lH-pyrazole instead of 5-methyl-lH-pyrazole-3-carbonitrile, K2CO3 instead of DIPEA and DMF instead of DMSO, the title compound was obtained as a yellow oil. MS (ESP) m / z = 296.2 [M-pinacol+H]+

[0556] Step 4: l-[2-[3-(difluoromethyl)-5-methylpyrazol-l-yl]-6-[6-[6-[(3-methoxyazetidin-l- yl)methyl]pyridazin-3-yl]oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-3-yl]ethanone

[0557] In analogy to step 9, example 12, by using 3-bromo-6-[6-[(3-methoxyazetidin-l- yl)methyl]pyridazin-3-yl]oxypyrazolo[l,5-a]pyridine instead of l-[6-chloro-3-[(15)-l- hydroxyethyl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile and l-[2-[3-(difluoromethyl)-5- methylpyrazol-l-yl]-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-3-yl]ethanone instead of l-[3-[(15)-l-hydroxyethyl]-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2- yl]-5-methylpyrazole-3-carbonitrile the title compound was obtained as a yellow gum. MS (ESP) m / z = 561.4 [M+H]+

[0558] Step 5: l-[2-[3-(difluoromethyl)-5-methylpyrazol-l-yl]-6-[6-[6-[(3-methoxyazetidin-l- yl)methyl]pyridazin-3-yl]oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-3-yl]ethanol

[0559]

[0560] This example was prepared in analogy to step 6 of example 17 to give the title compound as a white solid. MS (ESP) m / z = 563.3 [M+H]+

[0561] Example 39 l-[3-(l-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)sulfanylpyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile

[0562] Step 1 : 6-(6-methylpyridazin-3-yl)sulfanylpyrazolo[l,5-a]pyridine A mixture of 6-bromopyrazolo[l,5-a]pyridine (1 g, 5.1 mmol, 1 eq) in DMF (8 mL) with 6- methylpyridazine-3-thiol (640 mg, 5.08 mmol; CAS [5788-47-6]), K2CO3 (2.1 g, 15.2 mmol) and copper(I)iodide (967 mg, 5.08 mmol) was stirred for 72 hours at 150 °C. The reaction was cooled to RT, poured on Methanol, stirred for 10 minutes and filtered over Celite and concentrated in vacuum. Water was added and the mixture was extracted with TBME, the organic layer was dried over Na2SO4 and concentrated in vacuum. The crude was purified by flash chromatography on silica gel eluting with 0 - 5 % methanol in DCM to give the title compound as a light yellow solid. (220 mg, 17% yield). MS (ESP) m / z = 242.1 [M+H]+

[0563] Step 2: 3-iodo-6-(6-methylpyridazin-3-yl)sulfanylpyrazolo[l,5-a]pyridine

[0564] To a stirred solution of 6-(6-methylpyridazin-3-yl)sulfanylpyrazolo[l,5-a]pyridine (220 mg, 0.85 mmol, 1 eq) in acetonitrile (5 mL) was added N-iodosuccinimide (211 mg, 0.94 mmol). The reaction was stirred for 1 hour. The reaction mixture was purified by flash chromatography on silica gel eluting with 0 % to 8 % methanol in DCM to give the title compound as a light brown solid (430 mg, quant, yield) which was used as such in the next step. MS (ESP) m / z = 369.0 [M+H]+

[0565] Step 3 : 6-(6-methylpyridazin-3-yl)sulfanyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl )pyrazol o [ 1 , 5 -a] pyri dine

[0566] To a stirred solution of 3-iodo-6-(6-methylpyridazin-3-yl)sulfanylpyrazolo[l,5-a]pyridine (330 mg, 0.81 mmol, 1 eq) in THF (5.1 mL) at 0 °C was added Isopropoxy-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (675 mg, 0.74 mL, 3.63 mmol), followed by dropwise addition of 1.3M isopropylmagnesium chloride LiCl in THF (0.62 mL, 0.81 mmol). This reaction mixture was stirred at 0 °C for 30 minutes. Two further additions of 1.3M isopropylmagnesium chloride LiCl in THF (0.62 mL, 0.81 mmol) each were added and the reaction was stirred for 30 minutes at 0 °C. The reaction mixture poured on water and extracted with EtOAc, the organic layer was dried over Na2SO4 and concentrated in vacuum. The crude was purified by flash chromatography on silica gel eluting with 0 - 5 % methanol in DCM to give the title compound as a light yellow oil (51 mg, 16% yield). MS (ESP) m / z = 369.2 [M+H]+

[0567] Step 4: l-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)sulfanylpyrazolo[l,5-a]pyridin-3-yl]pyridin-2- yl]-5-methylpyrazole-3-carbonitrile

[0568] To a solution of 6-(6-methylpyridazin-3-yl)sulfanyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyrazolo[l,5-a]pyridine (51 mg 0.13 mmol, 1 eq) in DMF (0.8 mL) and water (0.4 mL) was added l-(3-acetyl-6-chloropyridin-2-yl)-5-methylpyrazole-3-carbonitrile (preparation see example 1, step 1) (36 mg, 0.14 mmol) and K2CO3 (52 mg, 0.37 mmol). Argon was bubbled through the mixture and l,l'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride di chloromethane complex (21 mg, 0.022 mmol, 0.2 eq; CAS [95464-05-4]) was added. This reaction was stirred at 45 °C for 30 minutes The mixture was poured on water and extracted with EtOAc, the organic layer was dried over Na2SO4 and concentrated in vacuum. The crude was purified by flash chromatography on silica gel eluting with 0 - 5 % methanol in DCM followed by a second flash chromatography on silica gel eluting with 0 - 2 % methanol in ethyl acetate to give the title compound as a light yellow solid (48 mg, 95% yield). MS (ESP) m / z = 467.2 [M+H]+

[0569] Step 5: l-[3-(l-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)sulfanylpyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile

[0570]

[0571] To a solution of l-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)sulfanylpyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile (20 mg, 0.043 mmol, 1 eq) in methanol (4 mL) and tetrahydrofuran (4 mL) was added NaBEL (2 mg, 0.1 mmol) at 0 °C. The mixture was poured on water and extracted with DCM, the organic layer was dried over ISfeSCU and concentrated in vacuum. The crude was purified by flash chromatography on silica gel eluting with 0 - 5 % methanol in DCM to give the title compound as a light yellow solid (19 mg, 95% yield). MS (ESP) m / z = 469.2 [M+H]+

[0572] Example 40 l-[3-(l-hydroxyethyl)-6-pyrazolo[l,5-a]pyridin-3-ylpyridin-2-yl]-5-methylpyrazole-3- carbonitrile

[0573] Isolated by product during the preparation of Example 2 to give the title compound as a white lyophilized solid (5.4 mg, 40.7% yield). MS (ESP) m / z = 327.1 [M+H]+ Example 41 l-[2-[6-[4-(oxetan-3-yl)piperazin-l-yl]pyrazolo[l,5-a]pyridin-3-yl]-4-[l-(2,2,2- trifluoroethyl)pyrazol-4-yl]-l,3-thiazol-5-yl]ethanol

[0574] Step 1 : tert-butyl A-(4-chloro-5-formyl-l,3-thiazol-2-yl)carbamate

[0575] To a suspension of 2-amino-4-chloro-thiazole-5-carbaldehyde (3.5 g, 21.53 mmol; CAS [76874- 79-8]) in 1,4-dioxane (35 mL) was added di-tert butyl dicarbonate (5.64 g, 25.83 mmol; CAS [24424-99-5]) and 4-dimethylaminopyridine (262,97 mg, 2,15 mmol; CAS [1122-58-3 ]). The mixture was stirred overnight at RT and then poured on 5% potassium hydrogen sulfate solution and extracted with EtOAc, the organic layer was dried over Na2SO4 and concentrated in vacuum. The crude was purified by flash chromatography on silica gel eluting with DCM to give the title compound as a yellow solid (5.29 g, 94% yield). MS (ESP) m / z = 261.2 [M+H]+

[0576] Step 2: tert-butyl A-[4-chloro-5-(hydroxymethyl)-l,3-thiazol-2-yl]carbamate

[0577] tert-Butyl A-(4-chloro-5-formyl-l,3-thiazol-2-yl)carbamate (7.7 g, 29.3 mmol, 1 eq) was dissolved in tetrahydrofuran (113 mL). At 0 °C, 3.2M methylmagnesium bromide in 2-methyl tetrahydrofuran (27.5 mL, 87.9 mmol) was added dropwise. The reaction was stirred for 30 minutes at 0 °C. The reaction mixture was poured on sat uratedNBLCl solution and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuum to give the title compound as a yellow solid (8.68 g, quant, yield). The product was used in the next step immediately. MS (ESP) m / z = 279.1 [M+H]+

[0578] Step 3: tert-butyl A-(4-chloro-5-formyl-l,3-thiazol-2-yl)carbamate

[0579] To a solution of tert-butyl A-[4-chloro-5-(hydroxymethyl)-l,3-thiazol-2-yl]carbamate(8.68 g, 31.1 mmol, 1 eq) in 1,2-di chloroethane (216 mL) was added manganese dioxide (97 g, 1.1 mol). The reaction was stirred overnight at RT nitrogen The mixture was filtered over celite and the filtrate was concentrated in vacuum. The crude was purified by flash chromatography on silica gel eluting with ethyl acetate to give the title compound as a yellow solid (6.5 g, 75% yield). MS (ESN) m / z = 275.2 [M+H]’

[0580] Step 4: l-[2-amino-4-[l-(2,2,2-trifluoroethyl)pyrazol-4-yl]-l,3-thiazol-5-yl]ethanone

[0581] To a solution of tert-butyl A-(4-chloro-5-formyl-l,3-thiazol-2-yl)carbamate (2 g, 7.23 mmol, 1 eq) in DMF (20 mL) was added 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l- (2,2,2trifluoroethyl)-lH-pyrazole CAS [1049730-42-8] (2.49 g, 9.03 mmol), Na2CO3(2.3 g, 21.7 mmol) and water (10 mL). Argon was bubbled through the mixture for 5 minutes and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane CAS [95464-05-4] (590 mg, 0.72 mmol) was added to the reaction mixture. The mixture was stirred at 100 °C for 1.5 hours. The reaction was concentrated in vacuum and the residue was dissolved in di chloromethane (20 mL) and TFA (5.6 mL) was added. The reaction was stirred for 3 hours at RT. The reaction mixture was poured on water and extracted with DCM. The organic layer was extracted twice with 4N HC1. The combined aqueous layers were basified until pH 10 by addition of 32% NaOH. The water layer was then extracted with DCM, washed with with water and sat. NaCl, dried over Na2SO4 and concentrated in vacuum to give the title compound as a yellow solid (1.6 g, 76% yield). MS (ESP) m / z = 291.1 [M+H]+

[0582] Step 5: l-[2-chloro-4-[l-(2,2,2-trifluoroethyl)pyrazol-4-yl]-l,3-thiazol-5-yl]ethanone

[0583] To a suspension of copper(II)chloride (1.48 g, 11.0 mmol) in acetonitrile (100 mL) was added isoamyl nitrite (1.61 g, 1.85 mL, 13.8 mmol). The mixture was heated to 65 °C. A suspension of l-[2-amino-4-[l-(2,2,2-trifhroroethyl)pyrazol-4-yl]-l,3-thiazol-5-yl]ethanone (1.6 g, 5.5 mmol, 1 eq) in acetonitrile (50 mL) was added to the reaction mixture. The reaction was stirred for 10 min at 65. The reaction mixture was cooled to RT and poured on 2M HC1 and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuum. The crude was purified by flash chromatography on silica gel eluting with 0 - 50 % ethyl acetate in heptane to give the title compound as a yellow solid (1.08 g, 63% yield). MS (ESP) m / z = 310.0 [M+H]+

[0584] Step 6: l-[2-[6-[4-(oxetan-3-yl)piperazin-l-yl]pyrazolo[l,5-a]pyridin-3-yl]-4-[l-(2,2,2- trifluoroethyl)pyrazol-4-yl]-l,3-thiazol-5-yl]ethanol

[0585] This example was prepared in analogy to steps 4-6 of example 1, by using l-[2-chloro-4-[l- (2,2,2-trifluoroethyl)pyrazol-4-yl]-l,3-thiazol-5-yl]ethanone instead of l-(3-acetyl-6- chloropyridin-2-yl)-5-methylpyrazole-3 -carbonitrile in step 4 to give the title compound as a white yellow solid. MS (ESP) m / z = 534.2 [M+H]+

[0586] Example 42 l-cyclopropyl-4-[5-(l-hydroxyethyl)-2-(6-methoxypyrazolo[l,5-a]pyridin-3-yl)-l,3-thiazol- 4-yl] pyridin-2-one

[0587]

[0588] Step 1 : 4-bromo-l-cyclopropylpyridin-2-one

[0589] To a solution of cyclopropylboronic acid (11.35 g, 132.18 mmol; CAS [411235-57-9]) and 4- bromo-lH-pyridin-2-one (10.0 g, 57.47 mmol, 1 eq; CAS36953-37-4) in 1,2-di chloroethane (300 m ) was added 2-pyridin-2-ylpyridine (9.6 g, 61.49 mmol; CAS [77790-61-5]), ISfeCCh (18.27 g, 172.41 mmol) and cupric acetate (11.17 g, 61.49 mmol). The mixture was stirred open to air at 70 °C for 40 h. The reaction was cooled to RT and concentracted in vacuum. The residue was dissolved in EtOAc, filtered, and the filtrate was washed with IM HC1 (200.0 ml). The organic layer was dried over Na2SO4 and concentrated in vacuum. The crude was purified by flash chromatography on silica gel eluting with 2 - 80 % ethyl acetate in petroleum ether to give the title compound as an off-white solid (6 g, 49% yield). MS (ESP) m / z = 214.0 [M+H]+

[0590] Step 2: (l-cyclopropyl-2-oxopyridin-4-yl)boronic acid A solution of boron isopropoxide (8.62 mL, 37.4 mmol) in THF (50 mL) was cooled to -15 °C and treated with 4-bromo-l-cyclopropyl-pyridin-2-one (5 g, 23.4 mmol, 1 eq) in THF (10 mL), 1.3M isopropylmagnesium chloride lithium chloride in THF (26.95 mL, 35.04 mmol) was added dropwise and the reaction was stirred at - 10 °C for 12 hours. The mixture was poured into IM HC1 the aqueous layer was washed EtOAc and DCM. The water layer was lyophilized to give the title compound as an off-white solid (4 g, 96% yield). MS (ESP) m / z = 180.0 [M+H]+

[0591] Step 3: l-(2,4-dichloro-l,3-thiazol-5-yl)ethanol

[0592] To a solution of 2,4-dichlorothiazole-5-carbaldehyde CAS [92972-48-0] (500 mg, 2.8 mmol) in THF (10 mL) was added 3M methylmagnesium bromide in THF (1.1 mL, 3.3 mmol) at -78 °C under nitrogen. The mixture was warmed to -40 °C and stirred for 1 hour. The mixture was poured on saturated NH4CI and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated in vacuum to give the title compound as colorless oil (520 mg, 96% yield). MS (ESP) m / z = 197.8 [M+H]+

[0593] Step 4: l-(2,4-dichloro-l,3-thiazol-5-yl)ethanone

[0594] To a solution of l-(2,4-dichloro-l,3-thiazol-5-yl)ethanol (520 mg, 2.6 mmol) in DCM (10 mL) was added Dess-Martin periodinane (1.67 g, 3.94 mmol; CAS [87413-09-0]) at 0 °C. The mixture was stirred at RT for 1 hour, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel eluting with 0 - 20 % ethyl acetate in petroleum ether to give the

[0595] I dO title compound as a colorless (450 mg, 87% yield). 1H NMR (400 MHz, CHLOROFORM-d) 5 =

[0596] 2.70 (s, 3H)

[0597] Step 5: 6-methoxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine

[0598] This compound was prepared in analogy to step 4 of example 31 step, with 3-bromo-6-methoxy- pyrazolo[l,5-a]pyridine (CAS [1823050-60-7]) instead of 6-benzyloxy-3-bromo-pyrazolo[l,5- a]pyridine and without water to give the title compound as an off-white solid. MS (ESP) m / z = 275.0 [M+H]+

[0599] Step 6: l-[4-chloro-2-(6-methoxypyrazolo[l,5-a]pyridin-3-yl)-l,3-thiazol-5-yl]ethanone

[0600] To a solution 6-methoxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine (201 mg, 1.12 mmol) and l-(2,4-dichloro-l,3-thiazol-5-yl)ethanone (210 mg, 1.07 mmol) (preparation see example 42, step 4) in 1,4-di oxane (5 mL) and water (0.500 mL) was added 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichlormethan complex (175 mg, 0.21 mmol; CAS [95464-05-4]) and ISfeCCL (227 mg, 2.1 mmol) and the mixture was heated at 100 °C for 12 hours under nitrogen. The mixture was evaporated to dryness and the resiude was purified by flash chromatography on silica gel eluting with 20 % ethyl acetate in petroleum ether to give the title compound as a yellow solid (180 mg, 55% yield). MS (ESP) m / z = 307.9 [M+H]+ Step 7 : 4-[5-acetyl-2-(6-methoxypyrazolo[ 1 , 5-a]pyri din-3 -yl)- 1 ,3 -thiazol-4-yl]- 1 - cyclopropylpyridin-2-one

[0601] To a brown solution of l-[4-chloro-2-(6-methoxypyrazolo[l,5-a]pyridin-3-yl)-l,3-thiazol-5- yl]ethanone (180.0 mg, 0.580 mmol) and (l-cyclopropyl-2-oxopyridin-4-yl)boronic acid (preparation see example 42 step 2 (120.4 mg, 0.670 mmol) in 1,4-dioxane (5 mL) and water (0.500 mL) was added Na2CO3 (124 mg, 1.17 mmol) and 1,1'- Bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichlormethan complex (95.4 mg, 0.120 mmol). The mixture was stirred at 100 °C for 12 hours under nitrogen. Thiourea resin was added to the reaction mixture and the mixture was stirred at 30 °C for 12 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuum. The crude was purified by preparative HPLC to give the title compound as a yellow solid (50 mg, 20% yield). MS (ESP) m / z = 407.1 [M+H]+

[0602] Step 8 : 1 -cy cl opropyl-4-[5-(l -hydroxy ethyl)-2-(6-methoxypyrazolo[ 1 ,5 -a]pyri din-3 -yl)- 1,3- thiazol-4-yl]pyridin-2-one To a solution of 4-[5-acetyl-2-(6-methoxypyrazolo[l,5-a]pyridin-3-yl)thiazol-4-yl]-l- cyclopropylpyridin-2-one (40 mg, 0.10 mmol) in methanol (3 mL) was added sodium borohydride (6 mg, 0.2 mmol) at 0 °C. The mixture was stirred at RT for 2 hours. The reaction mixture was poured on saturated NH4CI and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuum. The residue was purified by preparative HPLC to give the title compound as a white solid (26.1 mg, 65% yield). MS (ESP) m / z = 409.1 [M+H]+

[0603] Example 43

[0604] 4-[5-(l-hydroxyethyl)-2-[6-(2-morpholin-4-ylethoxy)pyrazolo[l,5-a]pyridin-3-yl]-l,3- thiazol-4-yl]-l-(2,2,2-trifluoroethyl)pyridin-2-one

[0605] Step 1 : tert-butyl A-(4-chloro-5-formyl-l,3-thiazol-2-yl)carbamate

[0606] To a suspension of 2-amino-4-chloro-thiazole-5-carbaldehyde (4.96 g, 30.5 mmol; CAS [76874- 79-8]) in 1,4-dioxane (49.6 mL) was added di-tert-butyldicarbonat (7.99 g, 36.6 mmol) and 4- dimethylaminopyridine (373 mg, 3.15 mmol). The suspension was stirred for three days at RT. The reaction mixture was poured on 5% potassium hydrogen sulfate solution and extracted with EtOAc, the organic layer was dried over Na2SO4 and concentrated in vacuum. The crude was purified by flash chromatography on silica gel eluting with 50% ethyl acetate in heptane to give the title compound as a yellow solid (7.09 g, 88% yield). MS (ESP) m / z = 261.2 [M+H]+

[0607] Step 2: 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-(2,2,2-trifluoroethyl)pyridin-2-one

[0608] This example was prepared in analogy to steps 1-2 of example 17 by using 4-bromo-lJ / -pyridin- 2-one (CAS [36953-37-4]) instead of 3-fluoro-4-iodo-2-pyridone for step 1 and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (CAS [95464- 05-4]) instead of tris(dibenzylideneacetone)dipalladium(0) at 35 °C instead of 100 °C to give the title compound as a grey solid. MS (ESP) m / z = 222.1 [M-pinacolester+H]+

[0609] Step 3: tert-butyl A-[5-formyl-4-[2-oxo-l-(2,2,2-trifluoroethyl)pyridin-4-yl]-l,3-thiazol-2- yl]carbamate To a solution tert-butyl A-(4-chloro-5-formyl-l,3-thiazol-2-yl)carbamate (1.61 g, 6.14 mmol) in DMF (40 mL) was added 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-(2,2,2- trifluoroethyl)pyridin-2-one (1.96 g, 6.14 mmol) and ISfeCCh (2.05 g, 19.4 mmol) and water (20 mL). Argon was bubbled through the mixture for 30 minutes and XPhosPd G2 (407 mg, 0.52 mmol; CAS [1310584-14-5]) was added to the reaction mixture. The mixture was stirred at 110 °C for 1 hour. The reaction was poured on water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuum. The crude was purified by flash chromatography on silica gel eluting with 0 %-100 % ethyl acetate in heptane to give the title compound as a yellow solid (1.24 g, 46% yield). MS (ESP) m / z = 404.2 [M+H]+

[0610] Step 4: tert-butyl 7V-[5-(l-hydroxyethyl)-4-[2-oxo-l-(2,2,2-trifluoroethyl)pyridin-4-yl]-l,3- thi azol -2-yl ] carb amate tert-Butyl A-[5-formyl-4-[2-oxo-l-(2,2,2-trifluoroethyl)pyridin-4-yl]-l,3-thiazol-2-yl]carbamate (1.14 g, 2.57 mmol) was dissolved in THF (18 mL). At 0 °C, 3.2 M methylmagnesium bromide in 2-methyl tetrahydrofuran (2.41 mL, 7.72 mmol) was added dropwise. The reaction was stirred for 50 minutes at 0 °C and then poured on sat. NH4CI. The mixture was extracted with EtOAc, the organic layer was dried over Na2SO4 and concentrated in vacuum. The crude was triturated with DCM to give the title compound as a white solid (1.05 g, 97% yield). MS (ESP) m / z = 420.2 [M+H]+

[0611] Step 5: tert-butyl A-[5-acetyl-4-[2-oxo-l-(2,2,2-trifluoroethyl)pyridin-4-yl]-l,3-thiazol-2- yl]carbamate

[0612]

[0613] To a solution ofterLbutyl A-[5-acetyl-4-[2-oxo-l-(2,2,2-trifluoroethyl)pyridin-4-yl]-l,3-thiazol- 2-yl]carbamate (560 mg, 1.34 mmol) in 1,2-di chloroethane (10 mL) was added manganese dioxide (2.32 g, 26.7 mmol). The reaction was stirred at 60 °C for 30 minutes unter nitrogen. The suspension was filtered over celite and the filtrate was evaporated in vacuum to give the title compound as a brown solid (474 mg, 82% yield). MS (ESN) m / z = 416.3 [M+H]'

[0614] Step 6: 4-(5-acetyl-2-amino-l,3-thiazol-4-yl)-l-(2,2,2-trifluoroethyl)pyridin-2-one

[0615] To a solution of tert-butyl 7V-[5-acetyl-4-[2-oxo-l-(2, 2, 2-trifluoroethyl)pyridin-4-yl]-l,3-thiazol- 2-yl]carbamate (474 mg, 1.14 mmol) in DCM (5 mL) was added TFA (5 mL). The solution was stirred for 2 hours at RT. The solution was poured on sat. NaHCCh and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuum to give the title compound as a yellow solid (346 mg, 96% yield). MS (ESP) m / z = 318.1 [M+H]+

[0616] Step 7: 4-(5-acetyl-2-chloro-l,3-thiazol-4-yl)-l-(2,2,2-trifluoroethyl)pyridin-2-one

[0617]

[0618] To a suspension of copper (II) chloride (396 mg, 2.95 mmol) in acetonitrile (10 mL) was added isoamyl nitrite (0.49 mL, 3.7 mmol). The mixture was heated to 65 °C and a suspension of 4-(5- acetyl-2-amino-l,3-thiazol-4-yl)-l-(2,2,2-trifluoroethyl)pyridin-2-one (468 mg, 1.47 mmol, 1 eq) in acetonitrile (20 mL) was added to the reaction mixture. The reaction was stirred for 10 minutes at 65 °C. The reaction mixture was cooled to RT and poured on 2M HC1. The solution was extracted with EtOAc. The organic layer was dried over ISfeSCU and concentrated in vacuum. The crude was purified by flash chromatography on silica gel eluting with 0 - 50% ethyl acetate in heptane to give the title compound as a yellow oil (302 mg, 61% yield). MS (ESP) m / z = 337.0 [M+H]+

[0619] Step 8: 4-[5-acetyl-2-[6-(2-morpholin-4-ylethoxy)pyrazolo[l,5-a]pyridin-3-yl]-l,3-thiazol-4-yl]- l-(2,2,2-trifluoroethyl)pyridin-2-one

[0620] To a solution of 4-[2-[3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridin-6- yl]oxyethyl]morpholine (for preparation see example 13, step 4) (50 mg, 0.13 mmol) in DMF (3 mL) was added 4-(5-acetyl-2-chloro-l,3-thiazol-4-yl)-l-(2,2,2-trifluoroethyl)pyridin-2-one (51 mg, 0.15 mmol), K2CO3 (53 mg, 0.38 mmol) and water (1.5 mL). Argon was bubbled through the mixture for 5 minutes. l,l'-Bis(diphenylphosphino)ferrocene-palladium(II)di chloride di chloromethane complex (10 mg, 0.013 mmol; CAS [95464-05-4]) was added and the reaction mixture was stirred at 100 °C for 1 hour. The reaction was cooled to RT, EtOAc was added followed by 5 g SiliaMetS (Metal Scavengers) and the mixture was stirred 1 hour. After filtration, water was added and the aqueous layers was extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuum to give the title compound as a dark brown oil (200 mg, quant, yield). The crude product was directly used in the next step without further purification.

[0621] Step 9: 4-[5-(l-hydroxyethyl)-2-[6-(2-morpholin-4-ylethoxy)pyrazolo[l,5-a]pyridin-3-yl]-l,3- thiazol-4-yl]-l-(2,2,2-trifluoroethyl)pyridin-2-one

[0622] To a solution of 4-[5-acetyl-2-[6-(2-morpholin-4-ylethoxy)pyrazolo[l,5-a]pyridin-3-yl]-l,3- thiazol-4-yl]-l-(2,2,2-trifluoroethyl)pyridin-2-one (200 mg, 0.13 mmol) in methanol (5 mL) was added NaBEE (34 mg, 0.90 mmol). This mixture was stirred for 30 minutes at RT. Water was added the mixture was extracted with DCM, the organic layer was dried over ISfeSCU and concentrated in vacuum. The crude was purified by preparative HPLC to give the title compound as white solid (24 mg, 34% yield). MS (ESP) m / z = 550.3 [M+H]+

[0623] Example 44 l-[2-[6-(2-morpholin-4-ylethoxy)pyrazolo[l,5-a]pyridin-3-yl]-4-[l-(2,2,2- trifluoroethyl)pyrazol-4-yl]-l,3-thiazol-5-yl]ethanol

[0624]

[0625] This example was prepared in analogy example 43, by using l-[2-chloro-4-[l -(2,2,2- trifluoroethyl)pyrazol-4-yl]-l,3-thiazol-5-yl]ethanone instead of 4-(5-acetyl-2-chloro-l,3- thiazol-4-yl)-l-(2,2,2-trifluoroethyl)pyridin-2-one in step 8 to give the title compound as a white solid. MS (ESN) m / z = 567.3 [M+HCOO]’

[0626] Example 45

[0627] 1- [2- [6-(6-methylpyridazin-3-yl)oxypyrazolo [1 ,5-a] pyridin-3-yl] -4- [l-(2,2,2- trifluoroethyl)pyrazol-4-yl]-l,3-thiazol-5-yl]ethanol

[0628] This example was prepared in analogy example 14, by using l-[2-chloro-4-[l -(2,2,2- trifluoroethyl)pyrazol-4-yl]-l,3-thiazol-5-yl]ethanone instead of l-[3-acetyl-6-(6- bromopyrazolo[l,5-a]pyridin-3-yl)pyridin-2-yl]-5-methylpyrazole-3-carbonitrile and 100 °C instead of 45 °C in step 4 used to give the title compound as an off-white solid. MS (ESN) m / z =

[0629] 546.3 [M+HCOO]'

[0630] Example 46

[0631] 3-fluoro-4-[5-(l-hydroxyethyl)-2-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3- yl] - 1 ,3-thiazol-4-yl] - l-(2,2,2-trifluoroethyl)pyridin-2-one

[0632] Step 1 : l-[4-chloro-2-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-l,3-thiazol-5- yl] ethanone

[0633] To a solution of 6-(6-methylpyridazin-3-yl)oxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyrazolo[l,5-a]pyridine (200 mg, 0.17 mmol) (for preparation see example 14, step 3) in DMF (3 mL) was added l-(2,4-dichlorothiazol-5-yl)ethanone (40 mg, 0.20 mmol) (for preparation see example 42, step 4), K2CO3 (71 mg, 0.51 mmol) and water (0.75 mL). Argon was bubbled through the mixture for 5 minutes. l,l'-Bis(diphenylphosphino)ferrocene-palladium(II)di chloride di chloromethane complex (14 mg, 0.017 mmol; CAS [95464-05-4]) was added and the mixture was stirred at 45 °C for 1 hour. The reaction was cooled to RT, poured on water and extracted with DCM, the organic layer was dried over ISfeSCU and concentrated in vacuum. The crude was purified by flash chromatography on silica gel eluting with 0 - 5 % methanol in DCM to give the title compound as a light brown solid (46 mg, 60% yield). MS (ESP) m / z = 386.1 [M+H]+

[0634] Step 2: 4-[5-acetyl-2-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-l,3-thiazol-4- yl]-3-fluoro-l-(2,2,2-trifluoroethyl)pyridin-2-one

[0635] To a solution of l-[4-chloro-2-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3- yl]thiazol-5-yl]ethanone (46 mg, 0.10 mmol) in 1,4-dioxane (4 mL) and water (0.4 mL) was added Na2CC>3 (27 mg, 0.25 mmol) and l,l'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (17 mg, 0.02 mmol; CAS [95464-05-4]). The mixture was degassed with argon and heated to 80 °C. 3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l-(2,2,2-trifluoroethyl)pyridin-2-one (for preparation see example 17, step 2) (63 mg, 0.15 mmol) in 1,4-dioxane (2 mL) was added and stirring was continued at 80 °C for 30 minutes. More 3-fhioro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-(2,2,2- trifluoroethyl)pyridin-2-one (42 mg, 0.10 mmol) was added and stirring was continued for 30 min at 80 °C. The mixture was cooled to RT and concentrated in vacuum. The crude was purified by flash chromatography on silica gel eluting with 0 - 5 % methanol in DCM to give the title compound as a brown solid, which was used without further purification in the next step (100 mg, quant, yield). MS (ESP) m / z = 545. 1 [M+H]+

[0636] Step 3: 3-fluoro-4-[5-(l-hydroxyethyl)-2-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-

[0637] 3-yl]-l,3-thiazol-4-yl]-l-(2,2,2-trifluoroethyl)pyridin-2-one

[0638]

[0639] To a solution of 4-[5-acetyl-2-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-l,3- thiazol-4-yl]-3-fluoro-l-(2,2,2-trifluoroethyl)pyridin-2-one (100 mg, 0.12 mmol) in methanol (10 mL) was added NaBEU (32 mg, 0.85 mmol). This mixture was stirred for 1 hour at RT before it was poured on water and and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated in vacuum. The crude was purified by flash chromatography on silica gel eluting with 0 - 5 % methanol in DCM followed by preparative HPLC to give the title compound as a light brown solid (10 mg, 15% yield). MS (ESP) m / z = 547.1 [M+H]+

[0640] Example 47

[0641] 1- [2- [6-(6-methylpyridazin-3-yl)oxypyrazolo [1 ,5-a] pyridin-3-yl] -4- [2-(2,2,2- trifluoroethyl)triazol-4-yl]-l,3-thiazol-5-yl]ethanol

[0642] Step 1 : 4,5-dibromo-2-(2,2,2-trifluoroethyl)triazole

[0643] To a solution of 4,5-dibromo-2H-triazole (5.0 g, 22 mmol; CAS [22300-52-3]) in acetonitrile (50 mL) was added CS2CO3 (7.18 g, 22.0 mmol). Trifluoromethanesulfonic acid 2,2,2-trifluoroethyl ester (5.12 g, 3.18 mL, 22.0 mmol; CAS [6226-25-1]) was added dropwise at 0 °C. The reaction mixture was stirred for 4.5 hours at RT. The reaction mixture was poured on water, extracted with EtOAc, the organic layer was dried over ISfeSCU and concentrated in vacuum. The crude was purified by flash chromatography on silica gel eluting with 0 - 30 % ethyl acetate in heptane to give the title compound as a colorless oil. (851 mg, 13% yield). MS (ESP) m / z = 309.9 [M+H]+

[0644] Step 2: 4-bromo-2-(2,2,2-trifluoroethyl)triazole

[0645] To a solution of 4,5-dibromo-2-(2,2,2-trifluoroethyl)triazole (2.0 g, 6.5 mmol) in THF (20 mL) at - 78 °C was added 2M isopropylmagnesium chloride solution in THF (3.24 mL, 6.48 mmol). The mixture was warmed to RT and stirred for 30 minutes. These two steps were repeated two times. Then, the reaction mixture was poured on sat. NH4CI and extracted with diethyl ether, the organic layer was dried over Na2SO4 and concentrated in vacuum. The crude was purified by a Kugelrohr distillation. The fraction collected at 175 °C gave the title compound as a light brown liquid (950 mg, 64% yield) which was used as such in the next step as such.

[0646] Step 3 : 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethyl)triazole

[0647]

[0648] To a solution of 4-bromo-2-(2,2,2-trifluoroethyl)triazole (150 mg, 0.65 mmol) in 1,4-dioxane (4.5 m ) was added bis(pinacolato)diboron (745 mg, 2.93 mmol) and dry K2CO3 (224 mg, 2.28 mmol). Argon was bubbled through the suspension for 5 minutes.

[0649] Bis(triphenylphosphine)palladium (II) chloride (46 mg, 0.065 mmol; CAS [13965-03-2]) was added and the reaction mixture was stirred at 100 °C for 4.5 hours. The reaction was cooled to RT and 1,4-dioxane and SiliaMetS were added. The suspension was stirred for 1 hour. After filtering off the mixture was poured on water and extracted with EtOAc, the organic layer was dried over Na2SO4 and concentrated in vacuum, to give the title compound as brown solid, which was used as such in the next step. MS (ESP) m / z = 196.0 [M-pinacol+H]+

[0650] Step 4: l-[2-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-4-[2-(2,2,2- tri fluoroethyl )tri azol -4-yl ] - 1 , 3 -thi azol - 5 -yl ] ethanone

[0651] To a solution of l-[4-chloro-2-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-l,3- thiazol-5-yl]ethanone (for preparation see example 46, step 1) (100 mg, 0.26 mmol) in 1,4- dioxane (1 mL) was added 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-(2,2,2- trifluoroethyl)triazole (276 mg, 0.26 mmol), ISfeCCL (82 mg, 0.78 mmol) and water (0.5 mL). Argon was bubbled through the suspension for 5 minutes. XPhosPd G2 (21 mg, 0.026 mmol; CAS [1310584-14-5]) was added and the mixture was stirred a 100 °C for 1 hour. The reaction was poured on water and extracted with EtOAc, the organic layer was dried over Na2SO4 and concentrated in vacuum. The crude was purified by flash chromatography on silica gel eluting with 0 - 100 % ethyl acetate in heptane, to give the title compound as a yellow solid (38 mg, 28% yield). MS (ESP) m / z = 501.2 [M+H]+

[0652] Step 5: l-[2-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-4-[2-(2,2,2- tri fluoroethyl )tri azol -4-yl ] - 1 , 3 -thi azol - 5 -yl ] ethanol

[0653] This example was prepared in analogy to example 46, step 3, by using l-[2-[6-(6- methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-4-[2-(2,2,2-trifluoroethyl)triazol-4-yl]-l,3- thiazol-5-yl]ethanone instead of 4-[5-acetyl-2-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5- a]pyridin-3-yl]-l,3-thiazol-4-yl]-3-fluoro-l-(2,2,2-trifluoroethyl)pyridin-2-one to give the title compound as a light yellow solid. MS (ESP) m / z = 503.1 [M+H]+

[0654] Example 48

[0655] 1- [3-acetyl-6- [6-(6-methylpyridazin-3-yl)oxypyrazolo [1 ,5-a] pyridin-3-yl] pyridin-2-yl] -5- methylpyrazole-3-carbonitrile

[0656]

[0657] Under Argon in a sealed tube, 6-(6-methylpyridazin-3-yl)oxy-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine (100 mg, 0.23 mmol, 1 eq) (see example 14, step 5) was dissolved in DMF (2 mL) and water (1 mL). l-[3-acetyl-6-(6-bromopyrazolo[l,5-a]pyridin- 3-yl)pyridin-2-yl]-5-methylpyrazole-3-carbonitrile (71 mg, 0.27 mmol) (for preparation see example 1, step 4) and K2CO3 (94 mg, 0.68 mmol) were added. Argon was bubbled through the mixture for 5 minutes. l,l'-Bis(diphenylphosphino)ferrocene-palladium(II)di chloride di chloromethane complex (19 mg, 0.023 mmol; CAS [95464-05-4]) was added and the mixture was stirred at 45 °C for 1 hour. The reaction was cooled to RT, poured on water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuum. The crude was purified by flash chromatography on Silica gel eluting with 0 - 100 % EtOAc in heptane to give the title compound as a light brown oil (98 mg, 88% yield). MS (ESP) m / z = 451.1 [M+H]+

[0658] Example 49 l-[3-formyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5- methylpyrazole-3-carbonitrile Under Argon, 6-(6-methylpyridazin-3-yl)oxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyrazolo[l,5-a]pyridine (71 mg, 0.20 mmol, 1 eq) (for preparation see example 14, step 3) and l-(6-chloro-3-formyl-2-pyridyl)-5-methyl-pyrazole-3-carbonitrile (50 mg, 0.20 mmol, 1 eq) (for preparation see example 20, step 1) were suspended in DMF (1.5 mL) and water (0.75 mL).

[0659] K2CO3 (84 mg, 0.61) was added, followed by l,l'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (17 mg, 0.02 mmol; CAS [95464-05-4]). The mixture was stirred for 1 hour at 45 °C. The reaction mixture was diluted with water and extracted with EtOAc. The water phase, containing the product as a suspension, was filtered and washed with water and diethylether to give the title compound as a yellow solid (53 mg, 58% yield). MS (ESP) m / z = 437.2 [M+H]+

[0660] Example 50

[0661] 2- [3-acetyl-6- [6-(6-methylpyridazin-3-yl)oxypyrazolo [1 ,5-a] pyridin-3-yl] pyridin-2-yl] -5- (trifluoromethyl)pyrazole-3-carbonitrile

[0662] This example was prepared in analogy to l-[2-[3-(difluoromethyl)-5-methylpyrazol-l-yl]-6-[6- (6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-3-yl]ethanone (see example 18, step 5) by using 5-(trifluoromethyl)-lH-pyrazole-3-carbonitrile (CAS [2166776-07-2]) instead of 3-(difluoromethyl)-5-methyl-lH-pyrazole to give the title compound as a brown solid. MS (ESP) m / z = 505.1 [M+H]+

[0663] Example 51 1- [3-acetyl-6- [6-(6-methylpyridazin-3-yl)oxypyrazolo [1 ,5-a] pyridin-3-yl] pyridin-2-yl] -5- cyclopropylpyrazole-3-carbonitrile

[0664] This example was prepared in analogy to l-[2-[3-(difluoromethyl)-5-methylpyrazol-l-yl]-6-[6- (6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-3-yl]ethanone (see example 18, step 5) by using 5-cyclopropyl-lH-pyrazole-3-carbonitrile (CAS [1290696-95-5]) instead of 3- (difluoromethyl)-5-methyl-lH-pyrazole. Preparative reverse phase HPLC gave the title compound as a white powder. MS (ESP) m / z = 477.2 [M+H]+

[0665] Example 52

[0666] 2- [3-acetyl-6- [6-(6-methylpyridazin-3-yl)oxypyrazolo [1 ,5-a] pyridin-3-yl] pyridin-2-yl] -5- cyclopropylpyrazole-3-carbonitrile

[0667] This example was prepared together with example 51 and separated in the last step with preparative reverse phase HPLC to give the title compound as a light yellow solid. MS (ESP) m / z = 477.2 [M+H]+ Example 53

[0668] 1- [3-acetyl-6- [6-(6-methylpyridazin-3-yl)oxypyrazolo [1 ,5-a] pyridin-3-yl] pyridin-2-yl] -5- (difluoromethyl)pyrazole-3-carbonitrile

[0669] To an icecold solution of l-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3- yl]-2-pyridyl]-5-(difluoromethyl)pyrazole-3-carboxamide (50 mg, 0.099 mmol, 1 eq) (for preparation see example 21, step 3) in DCM (3 mL) was added triethylamine (30.09 mg, 41.45 u), followed by trifluoroacetic anhydride (62.45 mg, 42. uL, 0.297 mmol). The reaction mixture was stirred at 0 °C for 1 hour. Then triethylamine (30.09 mg, 41.45 uL, 0.297 mmol) was added followed by trifluoroacetic anhydride (62.45 mg, 42. uL, 0.297 mmol) and the reaction mixture was stirred for 1 hour at 0 °C. The crude reaction mixture was evaporated on silica gel and purified by flash chromatography on silica gel eluting with 0 - 5 % methanol in DCM to give the title compound as a yellow solid (39 mg, 81% yield). MS (ESP) m / z = 487.2 [M+H]+

[0670] Example 54

[0671] 1- [6- [6-(6-methylpyridazin-3-yl)oxypyrazolo [1 ,5-a] pyridin-3-yl] -2- [l-(2,2,2- trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]propan-l-one Step 1 : [l-(2,6-dichloropyridin-3-yl)cyclopropyl] acetate

[0672] To a solution of l-(2,6-dichloro-3-pyridyl)cyclopropanol (150 mg, 0.735 mmol, 1.0 eq; CAS [1935604-03-7]) in acetic anhydride (1.5 mL) at room temperature was added 4- dimethylaminopyridine (9.0 mg, 0.074 mmol, 0.1 eq). This mixture was stirred for 30 minutes at 80 °C. The mixture was cooled to room temperature, diluted with water and extracted three times with DCM dried over ISfeSCU and evaporated. The crude was purified on silica gel eluting with 0 - 2% MeOH in DCM to give the tile compound as colorless oil (175 mg, 97%) as colorless oil. MS (ESP) m / z = 246.1 [M+H]+

[0673] Step 2: [l-[2-chloro-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-3- yl] cyclopropyl] acetate

[0674] To a solution of 6-(6-methylpyridazin-3-yl)oxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyrazolo[l,5-a]pyridine (100 mg, 0.28 mmol, 1.0 eq) (for preparation see example 14, step 3) in N,N-Dimethylformamide (3 mL) was added [l-(2,6-dichloropyridin-3-yl)cyclopropyl] acetate (84 mg, 0.34 mmol, 1.2 eq) and K2CO3 (118 mg, 0.85 mmol, 3.0 eq) as well as water (1.25 mL). Argon was bubbled through the mixture for 5 minutes and then 1,1'- Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (23 mg, 0.028 mmol, 0.1 eq; CAS [95464-05-4]) was added. The mixture was heated to 45 °C and stirred for 15 minutes. The reaction was cooled, poured on water and extracted three times with EtOAc, dried over Na2SO4 and evaporated. Chromatography on SiO2eluting with 0 - 7% MeOH in DCM afforded the title compound as a white solid (125 mg, 87% yield). MS (ESP) m / z = 436.2 [M+H]+

[0675] Step 3: l-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-2-[l-(2,2,2- trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]propan-l-one

[0676] Argon was bubbled through a mixture of [l-[2-chloro-6-[6-(6-methylpyridazin-3- yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-3-yl]cyclopropyl] acetate (30 mg, 0.059 mmol, 1.0 eq) and 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-(2,2,2trifluoroethyl)-lH-pyrazole (20 mg, 0.071 mmol, 1.2 eq; CAS [1049730-42-8]) and K2CO3(16 mg, 0.118 mmol, 2.0 eq) in 1,4- dioxane (1 mL) and water (1 mL) for 5 minutes. l,l'-Bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (4.8 mg, 0.006 mmol, 0.1 eq) was added and this mixture was stirred for three hours at 100 °C. The mixture was subjected to column chromatography on SiO2eluting with 0 - 5% MeOH in DCM followed by preparative HPLC to give the title compound as an orange solid (7 mg, 23% yield). MS (ESN) m / z = 552.3 [M+HCOO]'

[0677] Example 55

[0678] 1- [3-(difluoromethyl)-6- [5-methoxy-6- [(6-methylpyridazin-3-yl)amino] pyrazolo [1,5- a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile

[0679]

[0680] Step 1 : 6-chloro-3-(difluoromethyl)-2-fluoropyridine

[0681] To the solution of 6-chloro-2-fhioro-pyridine-3-carbaldehyde (3.0 g, 18.8 mmol, 1.0 eq CAS [1093880-37-5]) in DCM (30 mL) was added (Diethylamino)sulfur trifluoride (7. 5 mL, 56.4 mmol, 3.0 eq; CAS [38078-09-0]) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes. The reaction mixture was added to saturated NaHCCL solution (300 mL) under stirring and extracted with DCM (3 x 100 mL). The combined extracts were concentrated under vacuum to give 6-chloro-3-(difhroromethyl)-2-fluoro-pyridine (3.0 g, 17 mmol, 88% yield) as a yellow oil. MS (ESP) m / z = 182.1 [M+H]+

[0682] Step 2: l-[6-chloro-3-(difluoromethyl)pyridin-2-yl]-5-methylpyrazole-3-carbonitrile

[0683] A solution of 5-methyl-lH-pyrazole-3-carbonitrile (590 mg, 5.5 mmol, 1.0 eq; CAS [38693-82-

[0684] 2]), 6-chloro-3-(difluoromethyl)-2-fluoropyridine (1.0 g, 5.5 mmol, 1.0 eq) and DIPEA (2.8 mL, 16.5 mmol, 3.0 eq) in DMSO (20 mL) was stirred at 50 °C for 12 hours. The reaction mixture was cooled to room temperature, added to water (200 mL) and was extracted with ethyl acetate (3 x 150 mL). The combined extracts were washed with brine (200 mL), dried over Na2SO4 and evaporated. The residue was purified on silica gel eluting with 10% ethyl acetate in petroleum ether to give the title compound (650 mg, 2.4 mmol, 44% yield) as a white solid. MS (ESP) m / z = 269.2 [M+H]+

[0685] Step 3: l-[3-(difluoromethyl)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]-5- methylpyrazole-3 -carbonitrile

[0686] To a suspension of bis(pinacolato)diboron CAS [73183-34-3] (378 mg, 1.5 mmol, 4.0 eq), l-[6- chloro-3-(difluoromethyl)pyridin-2-yl]-5-methylpyrazole-3-carbonitrile (100 mg, 0.37 mmol, 1.0 eq) and dry potassium acetate (0.09 mL, 1.49 mmol, 4.0 eq) in 1,4-Dioxane (1 mL) was added bis(triphenylphosphine)palladium(II) chloride CAS [13965-03-2] (13 mg, 0.02 mmol, 0.05 eq) under an atmosphere of nitrogen at 20 °C. The reaction mixture was stirred at 100 °C for 3 hours. To the mixture was added thiourea resin under stirring. After 1 hour, the mixture was filtered and the filtrate was concentrated to give the title compound (130 mg, 0.36 mmol, 97% yield) as a black oil which was used as such in the next step. MS (ESP) m / z = 279.2 [M-82+H]+

[0687] Step 4: l-[6-(6-bromo-5-methoxypyrazolo[l,5-a]pyridin-3-yl)-3-(difluoromethyl)pyridin-2-yl]-5- methylpyrazole-3 -carbonitrile

[0688]

[0689] To a mixture of 6-bromo-3-iodo-5-methoxypyrazolo[l,5-a]pyridine (140 mg, 0.4 mmol, 1.1 eq) (for preparation see example 12, step 6), l-[3-(difluoromethyl)-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-2-yl]-5-methylpyrazole-3-carbonitrile (130 mg, 0.36 mmol, 1.0 eq), CS2CO3 (353 mg, 1.1 mmol, 3.0 eq) in THF (3.0 mL) and Water (0.5 mL) was added [1,1 - Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane v (59 mg, 0.07 mmol, 0.2 eq) at 20°C under an atmosphere of nitrogen. The reaction mixture was stirred at 65 °C for 2 hours. The reaction mixture was cooled to room temperature. EtOAc (10 mL) and water (10 mL) were added and the layers were separated. The aqueous phase was extracted with EtOAc (2 x 10 mL). The combined organic extracts were dried over MgSO4, and concentrated under vacuum. The residue was purified by preparative TLC eluting with 10% MeOH in DCM to give a solid which was triturated in DMSO (1 ml) and stirred for 30 min. The resulting white solid was was filtered, washed with petroleum ether (5 mL) and dried under vacuum to give the title compound (15 mg, 9% yield) as a white solid. MS (ESP) m / z = 461.0 [M+H]+

[0690] Step 5: l-[3-(difluoromethyl)-6-[5-methoxy-6-[(6-methylpyridazin-3-yl)amino]pyrazolo[l,5- a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile

[0691]

[0692] To a solution of l-[6-(6-bromo-5-methoxypyrazolo[l,5-a]pyridin-3-yl)-3- (difluoromethyl)pyridin-2-yl]-5-methylpyrazole-3-carbonitrile (15 mg, 0.03 mmol, 1.0 eq) and 3- amino-6-methylpyridazine (7 mg, 0.07 mmol, 2.0 eq) in 1,4-dioxane (1 mL) were added caesium carbonate (32 mg, 0.1 mmol, 3.0 eq). The air of the flask was replaced by nitrogen for three times. [tBuBrettPhos Pd(allyl)]OTf (5 mg, 0.01 mmol, 0.2 eq; CAS [1798782-17-8]) was added to the mixture and the air of the flask was replaced by nitrogen for three times. The reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was cooled to room temperature. EtOAc (10 mL) and water (10 mL) were added and the layers were separated. The aqueous phase was extracted with EtOAc (2 x 10 mL). The combined extracts were dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by preparative TLC eluting with 10% MeOH in DCM. Further purification by preparative HPLC gave the title compound (4 mg, 17% yield) as a yellow solid. MS (ESP) m / z = 488.1 [M+H]+

[0693] Example 56 l-[3-(difluoromethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-

[0694] 2-yl]-5-methylpyrazole-3-carbonitrile 6-(6-methylpyridazin-3-yl)oxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5- a]pyridine (66 mg, 0.19 mmol, 1.0 eq) (for preparation see example 14, step 3) and 1 -[6-chl oro-3 - (difluoromethyl)pyridin-2-yl]-5-methylpyrazole-3-carbonitrile (50 mg, 0.19 mmol, 1.0 eq) (for preparation see example 55, step 2) were dissolved in N,N-dimethylformamide (1.5 mL) at RT and K2CO3 (77 mg, 0.56 mmol, 3.0 eq) dissolved in water (0.750 mL) was added followed by l,r-bis(diphenylphosphino)ferrocene-palladium(II)di chloride dichloromethane complex (15 mg, 0.019 mmol, 0.1 eq; CAS [95464-05-4]). The reaction mixture was diluted with water and extracted two times with EtOAc. The organic layers were washed with brine, dried over MgSCh and concentrated to dryness. The crude material was purified by flash chromatography on silica gel eluting with 0 - 4% MeOH in DCM to obtain the title compound (63 mg, 73% yield) as a light brown solid. MS (ESP) m / z = 459.2 [M+H]+

[0695] Examples 57 and 58

[0696] 3-[5-(difluoromethyl)-6-[3-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-2-yl]-6-(6- methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridine;

[0697] 3-[5-(difluoromethyl)-6-[5-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-2-yl]-6-(6- methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridine

[0698] These examples were prepared in analogy to examples 24 and 25 by using 2-bromo-6-chloro-3- (difluoromethyl)pyridine (CAS [1805299-47-1]) instead of l-(2-bromo-6-chloropyridin-3- yl)ethanone in step 6. The regioisomers were separated after the last step by SFC to give the title compounds as white solids. MS (ESP) m / z = 516.2 [M+H]+(for both examples) Example 59 l-[3-(methoxymethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-

[0699] 2-yl]-5-methylpyrazole-3-carbonitrile

[0700] Step 1 : l-(6-chl oro-3 -formylpyridin-2-yl)-5-methylpyrazole-3 -carbonitrile

[0701] 6-Chloro-2-fluoro-nicotinaldehyde (1.0 g, 6.3 mmol, 1.0 eq; CAS [1651-29-2]) was dissolved in N,N-dimethylformamide (25 mL) and 5-methyl-lH-pyrazole-3-carbonitrile CAS [38693-82-2] (738 mg, 6.9 mmol, 1.1 eq) and potassium carbonate (1.3 g, 9.4 mmol, 1.5 eq) were added at rt. The mixture was stirred for one hour. The reaction mixture was diluted with water and extracted three times with EtOAc. The organic layers were washed with brine, dried over MgSC and concentrated to dryness. The crude material was purified by flash chromatography on silica gel eluting with 0 - 100 % EtOAc in heptane to obtian the title compound (1.4 g, 92% yield) as a light brown solid. MS (ESP) m / z = 246.0 [M+H]+

[0702] Step 2: l-[3-formyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]- 5-methylpyrazole-3-carbonitrile

[0703]

[0704] 6-(6-methylpyridazin-3-yl)oxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5- a]pyridine (71 mg, 0.2 mmol, 1.0 eq) (for preparation see example 14, step 3) and l-(6-chl oro-3 - formylpyridin-2-yl)-5-methylpyrazole-3-carbonitrile (50 mg, 0.2 mmol, 1.0 eq) were suspended in N,N-dimethylformamide (1.5 mL) and K2CO3 (84 mg, 0.6 mmol, 3.0 eq) dissolved in water (0.750 mL) were added followed by l,l'-bis(diphenylphosphino)ferrocene- palladium(ii)dichloride dichloromethane complex (17 mg, 0.02 mmol, 0.1 eq; CAS [95464-05- 4]). The mixture was stirred at 45 °C for one hour. The reaction mixture was diluted with water and washed two times with EtOAc. The suspension in water phase was filtered off and the obtained solid was washed with water and diethylether to obtain the title compound (53 mg, 58% yield) as a yellow solid. MS (ESP) m / z = 437.2 [M+H]+

[0705] Step 3 : l-[3-(hydroxymethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile l-[3-formyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5- methylpyrazole-3 -carbonitrile (30 mg, 0.069 mmol, 1.0 eq) was suspended in methanol (1 mL) and tetrahydrofuran (1 mL) and NaBEL (5 mg, 0.14 mmol, 2.0 eq) was added at RT. The mixture was stirred for 1 hour. The reaction mixture was diluted with sat. NaHCCh and extracted two times with EtOAc. The organic layers were dried over MgSCU and concentrated to dryness. The crude material was purified by flash chromatography on silica gel eluting with 0 - 5% MeOH in DCM to obtain the title compound (22 mg, 71% yield) as a white solid. MS (ESP) m / z = 439.2 [M+H]+

[0706] Step 4: l-[3-(methoxymethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile l-[3-(hydroxymethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-2- yl]-5-methylpyrazole-3-carbonitrile (14 mg, 0.032 mmol, 1.0 eq) was dissolved in tetrahydrofuran (1 mL) and N,N-dimethylformamide (0.2 mL). 60% NaH in mineral oil (1.5 mg, 0.038 mmol, 1.2 eq) was added at 0°C. The mixture was stirred for 15 minutes at 0°C before iodomethane (2.8 uL, 0.045 mmol, 1.4 eq) was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was quenched with water and extracted two times with DCM. The organic layers were dried over MgSCU and concentrated to dryness. The crude material was purified by flash chromatography on silica gel eluting with 0 - 5 % MeOH in DCM to obtain the title compound (13 mg, 93% yield) as a white solid. MS (ESP) m / z = 453.2 [M+H]+

[0707] Example 60

[0708] 5-methyl-l-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-3-[?ra«s-4- cyanooxolan-2-yl] pyridin-2-yl] pyrazole-3-carbonitrile

[0709]

[0710] Step 1 : l-(6-chloro-2-fluoropyri din-3 -yl)but-3-en-l-ol

[0711] 6-Chloro-2-fluoro-nicotinaldehyde (10 g, 63 mmol, 1.0 eq; CAS [1651-29-2]) was dissolved in tetrahydrofuran (220 mL) and 1 M allylmagnesium bromide in diethyl ether (65.8 mL, 65.8 mmol, 1.05 eq) was added slowly at 0 °C. The reaction mixture was stirred at 0 °C for 3 hours and then quenched with saturated NH4CI and extracted two times with EtOAc. The organic layers were washed with brine, dried over MgSCU and concentrated to dryness. The crude material was purified by flash chromatography on silica gel (330g, 0-100% EtOAc in Heptane) to obtain the title compound (6.6 g, 44% yield) as a red liquid. MS (ESP) m / z = 202.0 [M+H]+

[0712] Step 2: l-(6-chloro-2-fluoropyri din-3 -yl)-2-(oxiran-2-yl)ethanol l-(6-chloro-2-fluoropyri din-3 -yl)but-3-en-l-ol (6.58 g, 32.63 mmol, 1.0 eq) was dissolved in di chloromethane (160 mL). 3 -chloroperoxybenzoic acid (9.65 g, 39.2 mmol, 1.2 eq) was added at 0 °C and the mixture was stirred at 0 °C for 1 hour and then left stirring overnight warming up to room temperature. The reaction mixture was poured into sat. ISfeCCh solution and extracted with DCM (2x 100ml). The organic layers were washed with Na2COs (4 x 100ml), dried over MgSCU, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (330g, EtOAc in Heptane 0-100%) to obtain the title compound (5.5 g, 74% yield) as a light yellow oil. MS (ESP) m / z = 218.1 [M+H]+

[0713] Step 3: 5-(6-chloro-2-fluoropyridin-3-yl)oxolan-3-ol l-(6-chloro-2-fluoropyridin-3-yl)-2-(oxiran-2-yl)ethanol (4.8 g, 22.1 mmol, 1.0 eq) was dissolved in 1,4-dioxane (120 mL) and H2SO4 (1.13 mL, 21.17 mmol, 0.96 eq) was added at rt. The mixture was stirred for 5 hours at 50°C. The reaction mixture was carefully quenched with sat. NaHCCL and extracted two times with EtOAc. The organic layers were washed twice with sat. NaHCOs, dried over MgSO4 and concentrated to dryness. The crude material was purified by flash chromatography on silica gel (120g, EtOAc in Heptane 0-100%) to obtain the title compound (2.4 g, 50% yield) as a light yellow oil. MS (ESP) m / z = 218.0 [M+H]+

[0714] Step 4: l-[6-chloro-3-(4-hydroxyoxolan-2-yl)pyridin-2-yl]-5-methylpyrazole-3-carbonitrile 5-(6-Chloro-2-fluoropyridin-3-yl)oxolan-3-ol (1.92 g, 8.82 mmol, 1.0 eq) was dissolved in N,N- dimethylformamide (40 mL) and 5-methyl-lH-pyrazole-3-carbonitrile CAS [38693-82-2] (1.13 g, 10.6 mmol, 1.2 eq) and potassium carbonate (1.83 g, 13.2 mmol, 1.5 eq) were added at rt. The mixture was stirred at 70 °C overnight. The reaction mixture was diluted with water and extracted two times with EtOAc. The organic layers were washed with brine, dried over MgSCU and concentrated to dryness. The crude material was purified by flash chromatography on silica gel (80g, EtOAc in Heptane 0-80%) to obtain the title compound (1.58 g, 59% yield) as a colorless oil. MS (ESP) m / z = 305.1 [M+H]+

[0715] Step 5: [5-[6-chloro-2-(3-cyano-5-methylpyrazol-l-yl)pyridin-3-yl]oxolan-3-yl] methanesulfonate l-[6-chloro-3-(4-hydroxyoxolan-2-yl)pyridin-2-yl]-5-methylpyrazole-3-carbonitrile (500 mg, 1.64 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL) and triethylamine (686 uL, 4.92 mmol, 3.0 eq) followed by methanesulfonyl chloride (166 uL, 2.13 mmol, 1.3 eq) were added at 0 °C. After one hour stirring at 0 °C the reaction mixture was diluted with water and extracted two times with EtOAc. The organic layers were dried over MgSO4 and concentrated to dryness to give the title compound (727 mg, quantitative yield) as an orange oil, which was used as such in the next step. MS (ESP) m / z = 383.1 [M+H]+

[0716] Step 6: l-[6-chloro-3-[ / raws-4-cyanooxolan-2-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile & l-[6-chloro-3-[cA-4-cyanooxolan-2-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile

[0717]

[0718] [5-[6-chloro-2-(3-cyano-5-methylpyrazol-l-yl)pyridin-3-yl]oxolan-3-yl] methanesulfonate (620 mg, 1.6 mmol, 1.0 eq) was dissolved in dimethyl sulfoxide (9 mL) and potassium cyanide (527 mg, 8 mmol, 5.0 eq) was added at rt. The mixture was stirred for 1 hour at 105 °C. The reaction mixture was diluted with water and extracted two times with EtOAc. The organic layers were washed with brine, dried over MgSC and concentrated to dryness. The crude material was purified by flash chromatography on silica gel (25g, EtOAc in Heptane 0-50%) to obtain l-[6- chloro-3-[ / raw -4-cyanooxolan-2-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile (82 mg, 11% yield) and l-[6-chloro-3-[cA-4-cyanooxolan-2-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile (69 mg, 9% yield) as light brown solids. MS (ESP) m / z = 314.1 [M+H]+for both compounds.

[0719] Step 7: 5-methyl- l -[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[ l ,5-a]pyridin-3-yl]-3-[ / ra / / .s-4- cyanooxolan-2-yl]pyridin-2-yl]pyrazole-3-carbonitrile

[0720] 6-(6-methylpyridazin-3-yl)oxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5- a]pyridine (39 mg, 0.11 mmol, 1.0 eq) (for preparation see example 14, step 3) and 1 -[6-chl oro-3 - |7raw -4-cyanooxolan-2-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile (35 mg, 0.11 mmol, 1.0 eq) were dissolved in N,N-dimethylformamide (1 mL) and K2CO3 (46 mg, 0.34 mmol, 3.0 eq) dissolved in water (0.5 mL) was added followed by l,l'-bis(diphenylphosphino)ferrocene- palladium(ii)di chloride dichloromethane complex (9 mg, 0.01 mmol, 0.1 eq; CAS [95464-05-4]). The mixture was stirred for 1 hour at 45°C. The reaction mixture was diluted with water and extracted two times with EtOAc. The organic layers were washed with brine, dried over MgSCh and concentrated to dryness. The crude material was purified by flash chromatography on silica gel (12g, MeOH in DCM 0-4%) followed by preparative HPLC to give the title compound (also known as5-methyl-l-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-3-[rac- (2R,4R)-4-cyanooxolan-2-yl]pyridin-2-yl]pyrazole-3-carbonitrile) as an off-white solid (17 mg, 30% yield). MS (ESP) m / z = 504.3 [M+H]+

[0721] Example 61

[0722] 5-methyl-l-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-3-[czs-4- cyanooxolan-2-yl] pyridin-2-yl] pyrazole-3-carbonitrile

[0723] This example was prepared in analogy to example 60 by using l-[6-chloro-3-[czs-4-cyanooxolan- 2-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile (for preparation see example 60, step 6) instead of 1 -[6-chl oro-3 -[ / zz / zz.s-4-cyanoox olan-2-yl]pyri din-2 -yl]-5-methylpyrazole-3-carbonitrile in step 7 to give the title compound (also known as 5-methyl-l-[6-[6-(6-methylpyridazin-3- yl)oxypyrazolo[l, 5-a]pyridin-3-yl]-3-[rac-(2R,4S)-4-cyanooxolan-2-yl]pyri din-2 -yl]pyrazole-3- carbonitrile) as light brown solid. MS (ESP) m / z = 504.3 [M+H]+ Example 62

[0724] 1- [3- ( 1 -hydroxy ethyl)-6- [6- [1 -(oxetan-3-yl)piperidin-4-yl] oxypyrazolo [1 ,5-a] pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile

[0725] Step 1 : [1 -(ox etan-3 -yl)piperidin-4-yl] methanesulfonate

[0726] 1 -(Ox etan-3 -yl)piperidin-4-ol (123 mg, 0.78 mmol, 1.0 eq; CAS [1226899-10-0]) was dissolved in DCM (1.56 mL). Triethylamine (218 uL, 1.56 mmol, 2.0 eq) was added followed by methanesulfonyl chloride (91 uL, 1.17 mmol, 1.5 eq). The mixture was stirred at RT for 90 minutes. Water was added and the mixture was extracted with DCM. The organic layer were evaporated to dryness to afford the title compound (193 mg, 99% yield) as an orange solid. MS (ESP) m / z = 236.0 [M+H]+

[0727] Step 2: 6-[l-(oxetan-3-yl)piperidin-4-yl]oxypyrazolo[l,5-a]pyridine [1 -(Ox etan-3 -yl)piperidin-4-yl] methanesulfonate (193 mg, 0.78 mmol, 1.0 eq), pyrazolo[l,5- a]pyridin-6-ol (115 mg, 0.86 mmol, 1.1 eq; CAS [184473-24-3]) and caesium carbonate (508 mg, 1. 6 mmol, 2.0 eq) were stirred in dry N,N-dimethylformamide (3.5 mL) at 80 °C. The reaction mixture was diluted with DCM and washed with water. The organic layer was evaporated to dryness and purified by column chromatography (SiO? 25g, DCM / MeOH 0 - 10%) to afford the title compound (71 mg, 33% yield) as a white solid. MS (ESP) m / z = 274.1 [M+H]+

[0728] Step 3: 3-bromo-6-[l-(oxetan-3-yl)piperidin-4-yl]oxypyrazolo[l,5-a]pyridine

[0729] To a stirred solution of 6-[l-(oxetan-3-yl)piperidin-4-yl]oxypyrazolo[l,5-a]pyridine (85 mg, 0.31 mmol, 1.0 eq) in acetic acid (3.0 mL) at RT was added bromine (17 uL, 0.3 mmol, 1.1 eq) and the mixture was stirred for 20 minutes. The reaction mixture was poured on water at 0 °C and 32% NaOH was added until pH 10 was reached 10. The mixture was extracted with DCM, dried over Na2SO4 and evaporated to dryness. Purification by column chromatography eluting with 0 - 10% MeOH in DCM gabe the title compound (109 mg, 99% yield) as a light yellow solid. MS (ESP) m / z = 352.0 [M+H]+

[0730] Step 4: l-[3-acetyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]-5- methylpyrazole-3 -carbonitrile Under Argon, l-(3-acetyl-6-chloropyridin-2-yl)-5-methylpyrazole-3-carbonitrile (150 mg, 0.58 mmol, 1.0 eq) was dissolved in 1,4-dioxane (1.6 mL). Bis(pinacolato)diboron (650 mg, 2.6 mmol, 4.5 eq; CAS [73183-34-3]) was added followed by dry potassium acetate (200 mg, 2.0 mmol, 3.6 eq). Argon was bubbled through the suspension for 5 minutes followed by the addition of bis(triphenylphosphine)palladium (II) chloride (20 mg, 0.03 mmol, 0.05 eq; CAS [13965-03- 2]). Argon was bubbled through the suspension for 5 minutes. The reaction mixture was heated to 100 °C. After 4 hours, the mixture was cooled to RT and and 1g SiliaMetS® (Metal Scavenger) was added. The suspension was stirred for 1 hour and then filtered off and washed with ethyl acetate to afford the title compound (901 mg, 89% yield) as a grey solid to be used as such in the next step. MS (ESP) m / z = 271.0 [M-pinacol+EEO+El]

[0731] Step 5: l-[3-acetyl-6-[6-[l-(oxetan-3-yl)piperidin-4-yl]oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-2- yl]-5-methylpyrazole-3-carbonitrile

[0732] To a solution of l-[3-acetyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]-5- methylpyrazole-3 -carbonitrile (499 mg, 0.28 mmol, 1.2 eq) in 1,4-dioxane (2.7 mL) was added 3- bromo-6-[l-(oxetan-3-yl)piperidin-4-yl]oxypyrazolo[l,5-a]pyridine (84 mg, 0.24 mmol, 1.0 eq) and caesium carbonate (231 mg, 0.71 mmol, 3.0 eq) and water (0.7 mL). Argon was bubbled through the mixture for 5 minutes. l,l'-Bis(diphenylphosphino)ferrocenedi chloro palladium(II) di chloromethane complex (18 mg, 0.024 mmol, 0.1 eq; CAS [95464-05-4]) was added to the reaction mixture and Argon was bubbled through the solution for 5 minutes. The reaction mixture was stirred overnight at 55 °C. The reaction mixture was cooled to room temperature and poured on water and extracted with EtOAc. The organic layers weredried over sodium sulfate and concentrated under vacuo. The residue was purified with flash chromatography on 25g Silica Gel eluting with 0 - 10% MeOH in DCM to give the title compound (12 mg, 10% yield) as light yellow solid. MS (ESP) m / z = 498.2 [M+H]+

[0733] Step 6: l-[3-(l-hydroxyethyl)-6-[6-[l-(oxetan-3-yl)piperidin-4-yl]oxypyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile

[0734] To a solution of l-[3-acetyl-6-[6-[l-(oxetan-3-yl)piperidin-4-yl]oxypyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile (55 mg, 0.098 mmol, 1 eq) in methanol (3.3 m ) was added at 0 °C NaBEU (3.7 mg, 0.098 mmol, 1 eq) and the mixture was stirred for 1 hour. NaBEU (1.1 mg, 0.029 mmol, 1.2 eq) was added and after 30 minutes the mixture was poured on water and extracted with EtOAc. The organic layers were dried over Na2SO4 and evaporated to dryness. The residuewas purified by flash chromatography on silica gel eluting with 0 - 10% MeOH in DCM to give the title compound (8.6 mg, 69% yield) as a white solid MS (ESP) m / z = 500.2 [M+H]+

[0735] Example 63

[0736] 3-[3-[6-(3-cyano-5-methylpyrazol-l-yl)-5-(l-hydroxyethyl)pyridin-2-yl]pyrazolo[l,5- a] pyridin-6-yl] oxy-N,N,6-trimethylpyridazine-4-carboxamide

[0737]

[0738] Step 1 : methyl 3-chloro-6-methylpyridazine-4-carboxylate

[0739] To a mixture of methyl 3,6-dichloropyridazine-4-carboxylate (10 g, 48 mmol, 1.0 eq; CAS [51149-08-7]) and trimethylboroxine (12 g, 48 mmol, 1.0 eq) in 1,4-dioxane (200 mL) was added potassium carbonate (13 g, 97 mmol, 2.0 eq) and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3.5 g, 4.8 mmol, 0.1 eq; CAS [72287- 26-4]). The mixture was degassed with nitrogen three times and heated to 100 °C for 16 hours. The mixture was poured on water (1000 mL) and extracted with EtOAc (3 x 800 mL). The combined organic phases were washed with brine (3 x 500 mL), dried over ISfeSCL and concentrated under vacuum to give a residue. The residue was purified by reversed phase column chromatography, followed by purification by flash chromatography eluting with 1 : 1 petroleum etherEtOAc to give the title compound as a pink solid (1.0 g, 5.4 mmol, 11% yield). MS (ESP) m / z = 187.2 [M+H]+

[0740] Step 2: 3-bromopyrazolo[l,5-a]pyridin-6-ol

[0741] To a solution of pyrazolo[l,5-a]pyridin-6-ol (1.0 g, 7.5 mmol, 1.0 eq; CAS [184473-24-3]) in Methanol (20 mL) was slowly added NBS (1.2 g, 6.7 mmol, 0.9 eq) at -10 °C. The reaction mixture was stirred at -10 °C for 4 hours. The mixture was poured on water (40 mL) and extracted with EtOAc (50 mL x 3). The combined organic phase was washed with brine (70 mL), dried over Na2SO4 and concentrated under vacuum to give a residue. The residue was purified by SiCL column chromatography (PE / EtOAc=10 / l to PE / EtOAc=3 / l) to give the title compound (610 mg, 38% yield) as an off-white solid. MS (ESP) m / z = 215.1 [M+H]+

[0742] Step 3: methyl 3-(3-bromopyrazolo[l,5-a]pyridin-6-yl)oxy-6-methylpyridazine-4-carboxylate

[0743] To a solution of methyl 3-chloro-6-methylpyridazine-4-carboxylate (300 mg, 1.6 mmol, 1.0 eq) and 3-bromopyrazolo[l,5-a]pyridin-6-ol (343 mg, 1.6 mmol, 1.0 eq) in DMSO (1 mL) was added potassium carbonate (444 mg, 3.2 mmol, 2.0 eq) at 20 °C. The mixture was stirred at 50 °C for 16 hours. The mixture was filtered and purified by reversed phase chromatography followed by SiCh column chromatography eluting with 1 : 1 to 1 :2 petroleum ether:EtOAc to give the title compound (150 mg, 26% yield) as a yellow solid. MS (ESP) m / z = 365.0 [M+H]+

[0744] Step 4: 3-(3-bromopyrazolo[l,5-a]pyridin-6-yl)oxy-N,N,6-trimethylpyridazine-4-carboxamide To a yellow solution of methyl 3-(3-bromopyrazolo[l,5-a]pyridin-6-yl)oxy-6-methylpyridazine- 4-carboxylate (110 mg, 0.3 mmol, 1.0 eq) in THF (2 mL) was added a solution of lithium hydroxide hydrate (38 mg, 0.9 mmol, 3 eq) in water (2 mL) and Methanol (1 mL) at 20 °C. The mixture was stirred at 20 °C for 1 hour. The mixture was concentrated under vacuum to give a white solid. To this was added DMF (4 mL), dimethylamine hydrochloride (32 mg, 0.39 mmol, 1.3 eq), N, A-diisopropyl ethylamine (0.16 mL, 0.9 mmol, 3.0 eq) and O-(7-azabenzotriazol-l-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate (172 mg, 0.45 mmol, 1.5 eq; CAS [148893- 10-1]) at 20 °C. The mixture was stirred at 30 °C for 16 hours. The mixture was purified by reversed phase column chromatography to give the title compound (86 mg, 59% yield) as a white solid. MS (ESP) m / z = 378.0 [M+H]+

[0745] Step 5: 3-[3-[5-acetyl-6-(3-cyano-5-methylpyrazol-l-yl)pyridin-2-yl]pyrazolo[l,5-a]pyridin-6- yl]oxy-N,N,6-trimethylpyridazine-4-carboxamide

[0746] To a mixture of 3-(3-bromopyrazolo[l,5-a]pyridin-6-yl)oxy-N,N,6-trimethylpyridazine-4- carboxamide (76 mg, 0.2 mmol, 1.0 eq) and l-[3-acetyl-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-2-yl]-5-methylpyrazole-3-carbonitrile (92 mg, 0.26 mmol, 1.3 eq) (for preparation see example 62, step 4) in THF (4 mL) was added caesium carbonate (197 mg, 0.61 mmol, 3.0 eq), l,T-bis(diphenylphosphino)ferrocene-palladium(II)di chloride dichloromethane complex (8 mg, 0.01 mmol, 0.05 eq; CAS [95464-05-4]) and Water (0.7 mL). The mixture was degassed with nitrogen three times and heated at 65 °C for 3 hours. The mixture was poured on water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine (20 mL), dried over ISfeSCL and concentrated under vacuum to give a residue. The residue was purified by reversed phase column chromatography to give the title compound (56 mg, 53% yield) as a yellow oil. MS (ESP) m / z = 522.2 [M+H]+

[0747] Step 6: 3-[3-[6-(3-cyano-5-methylpyrazol-l-yl)-5-(l-hydroxyethyl)pyridin-2-yl]pyrazolo[l,5- a]pyridin-6-yl]oxy-N,N,6-trimethylpyridazine-4-carboxamide

[0748] To a mixture of 3-[3-[5-acetyl-6-(3-cyano-5-methylpyrazol-l-yl)pyridin-2-yl]pyrazolo[l,5- a]pyridin-6-yl]oxy-N,N,6-trimethylpyridazine-4-carboxamide (56 mg, 0.11 mmol, 1.0 eq) in Methanol (4 mL) was added sodium borohydride (16 mg, 0.42 mmol, 3.9 eq) at 0 °C. The mixture was stirred at 0 °C for 2 hour. The mixture was poured on saturated NH4CI (15 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine (30 mL), dried over Na2SO4 and concentrated under vacuum to give a residue. The residue was purified by preparative HPLC to give the title compound (7 mg, 13% yield) as a white solid. MS (ESP) m / z = 524.1 [M+H]+

[0749] Examples 64 and 65

[0750] 3- [5-(difluoromethyl)-6- [3-methyl- l-(2,2,2-trifluoroethyl)pyrazol-4-yl] pyridin-2-yl]-6- [6- [ [4- (oxetan-3-yl)piperazin- 1-yl] methyl] pyridazin-3-yl] oxypyrazolo [1 ,5-a] pyridine; and

[0751] 3- [5-(difluoromethyl)-6- [5-methyl- l-(2,2,2-trifluoroethyl)pyrazol-4-yl] pyridin-2-yl]-6- [6- [ [4- (oxetan-3-yl)piperazin- 1-yl] methyl] pyridazin-3-yl] oxypyrazolo [1 ,5-a] pyridine

[0752]

[0753] Step 1 : 3-chloro-6-[[4-(oxetan-3-yl)piperazin-l-yl]methyl]pyridazine

[0754] To a solution of 3-chloro-6-(chloromethyl)pyridazine (1.5 g, 9.2 mmol, 1.0 eq; CAS [258506-68- 2]) in MeCN (30 mL) was added l-(oxetan-3-yl)piperazine (1.44 g, 10.1 mmol, 1.1 eq; CAS [1254115-23-5]), followed by K2CO3 (3.81 g, 27.6 mmol, 3.0 eq). The reaction was stirred at 40 °C for 2 hours, followed by 60 °C for 2 hours. The mixture was diluted with ethyl acetate(100 mL) to give a yellow suspension. The mixture was loaded on silica gel and purified by flash chromatography on silica gel eluting with petroleum ether: ethyl acetate 0:1 and then ethyl acetate:MeOH 10: 1 to give the title compound (1.5 g, 61% yield) as a yellow solid. MS (ESP) m / z = 269.1 [M+H]+

[0755] Step 2: 6-[6-[[4-(oxetan-3-yl)piperazin-l-yl]methyl]pyridazin-3-yl]oxypyrazolo[l,5-a]pyridine

[0756] To a solution of pyrazolo[l,5-a]pyridin-6-ol (275 mg, 2.1 mmol, 1.1 eq; CAS [184473-24-3]) in DMF (10 mL) was added 3-chloro-6-[[4-(oxetan-3-yl)piperazin-l-yl]methyl]pyridazine (500 mg, 1.86 mmol, 1.0 eq) followed by potassium carbonate (771 mg, 5.6 mmol, 3.0 eq). The reaction was stirred at 120 °C for 12 hours. The mixture was filtered and purified by column chromatography on silica (ethyl acetate:MeOH=10: l) to give the title compound (560 mg, 82% yield) as a yellow solid. MS (ESP) m / z = 367.2 [M+H]+

[0757] Step 3: 3-bromo-6-[6-[[4-(oxetan-3-yl)piperazin-l-yl]methyl]pyridazin-3-yl]oxypyrazolo[l,5- a]pyridine

[0758] To a solution of 6-[6-[[4-(oxetan-3-yl)piperazin-l-yl]methyl]pyridazin-3-yl]oxypyrazolo[l,5- a]pyridine (500 mg, 1.36 mmol, 1.0 eq) in Methanol (10 mL) was added NBS (241 mg, 1.36 mmol, 1.0 eq) at -10 °C and the reaction mixture was stirred at -10°C for 2 hours. The mixture was diluted with H2O (50 mL) and extracted with DCM (2 x 50 mL). The organic phases were washed with brine, dried over Na2SO4 and concentrated to give a residue. The residue was purified by preparative TLC (ethyl acetate:MeOH 10: 1) to give the title compound (400 mg, 66% yield) as a yellow solid. MS (ESP) m / z = 447.1 [M+H]+

[0759] Step 4: 6-[6-[[4-(oxetan-3-yl)piperazin-l-yl]methyl]pyridazin-3-yl]oxy-3-(4,4,5,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)pyrazolo[ 1 , 5-a]pyridine

[0760] To a solution of 3-bromo-6-[6-[[4-(oxetan-3-yl)piperazin-l-yl]methyl]pyridazin-3- yl]oxypyrazolo[l,5-a]pyridine (350 mg, 0.79 mmol, 1.0 eq) in diethylene glycol dimethyl ether (10.0 mL) and water (0.05 mL) was added bis(pinacolato)diboron (499 mg, 1.96 mmol, 2.5 eq; CAS [73183-34-3]), tricyclohexyl phosphine (44 mg, 0.16 mmol, 0.2 eq), palladium (II) acetate (18 mg, 0.08 mmol, 0.1 eq) followed by potassium carbonate (152 mg, 1.1 mmol, 1.4 eq). The mixture was stirred at 100 °C for 3 hours under an atmosphere of nitrogen. The mixture was evaporated to dryness and purified by column chromatography on silica gel (petroleum etherethyl acetate 1 : 1 to ethyl acetate:MeOH 5: 1) to give the title compound (350 mg, 85% yield) as a yellow gum which was used as such in the next step. MS (ESP) m / z = 493.3 [M+H]+

[0761] Step 5: 3-[5-(difluoromethyl)-6-[3-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-2-yl]-6-[6- [[4-(oxetan-3-yl)piperazin-l-yl]methyl]pyridazin-3-yl]oxypyrazolo[l,5-a]pyridine (Example 64) & 3-[5-(difluoromethyl)-6-[5-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-2-yl]-6-[6-[[4- (oxetan-3-yl)piperazin-l-yl]methyl]pyridazin-3-yl]oxypyrazolo[l,5-a]pyridine (Example 65)

[0762] These compounds were prepared in analogy to examples 24 and 25 by using 2-bromo-6-chloro-3- (difluoromethyl)pyridine (CAS [1805299-47-1]) instead of l-(2-bromo-6-chloropyridin-3- yl)ethanone in step 6 and 6-[6-[[4-(oxetan-3-yl)piperazin-l-yl]methyl]pyridazin-3-yl]oxy-3- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine instead of 6-(6- methylpyridazin-3-yl)oxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5- a]pyridine in step 7. The regioisomers were separated after the last step by SFC to give the title compounds as yellow solids. MS (ESP) m / z = 656.3 [M+H]+(for both compounds)

[0763] Example 66

[0764] 4- [ [6- [3- [5-(difluoromethyl)-6- [3-methyl- l-(2,2,2-trifluoroethyl)pyrazol-4-yl] pyridineyl] pyrazolo [1 ,5-a] pyridin-6-yl] oxypyridazin-3-yl] methyl] morpholine

[0765]

[0766] This example was prepared in analogy to example 64 by using morpholine instead of l-(oxetan- 3-yl)piperazine in step 1 to give the title compound as a white solid. MS (ESP) m / z = 601.3 [M+H]+

[0767] Example 67

[0768] 2-[3-(difluoromethyl)-5-methylpyrazol-l-yl]-6-[5-methoxy-6-[(6-methylpyridazin-3- yl)amino]pyrazolo[l,5-a]pyridin-3-yl]pyridine-3-carbonitrile

[0769] This example was prepared in analogy to example 55 by using 6-chloro-2-fluoro-pyridine-3- carbonitrile (CAS [3939-13-7]) instead of 6-chl oro-3 -(difluoromethyl)-2 -fluoropyridine and 3- (difluoromethyl)-5-methyl-lH-pyrazole (CAS [934759-09-8]) instead of 5-methyl-lH-pyrazole- 3 -carbonitrile in step 2 to give the title compound as a white solid. MS (ESP) m / z = 488.4 [M+H]+ Example 68

[0770] (lS)-l-[2-[3,5-bis(difluoromethyl)pyrazol-l-yl]-6-[6-(7,8-dihydro-5H-pyrano[4,3- c] pyridazin-3-yloxy)pyrazolo [1 ,5-a] pyridin-3-yl] pyridin-3-yl] ethanol

[0771] Step 1: 3-[3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridin-6-yl]oxy-7,8- dihydro-5H-pyrano[4,3-c]pyridazine

[0772] This intermediate was prepared in analogy to 6-(6-methylpyridazin-3-yl)oxy-3-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine (see example 14, step 3) by using 3- chloro-7,8-dihydro-5H-pyrano[4,3-c]pyridazine (CAS [1075260-61-5]) instead of 3-chloro-6- methyl-pyridazine in step 1 to give the title compound as a white solid. MS (ESP) m / z = 395.2 [M+H]+

[0773] Step 2: l-[2-[3,5-bis(difluoromethyl)pyrazol-l-yl]-6-chloropyridin-3-yl]ethanone Under Argon, l-(6-chloro-2-fluoro-3-pyridyl)ethanone (200 mg, 1.15 mmol, 1.0 eq; CAS [1260663-13-5]) and 3,5-bis(difluoromethyl)-lH-pyrazole (232 mg, 1.4 mmol, 1.2 eq; CAS [934759-09-8]) were dissolved in N,N-dimethylformamide (5 mL) at -78 °C. Caesium carbonate (751 mg, 2.3 mmol, 2.0 eq) was added and the reaction mixture was stirred for 6 hours at -78°C. The mixture was diluted with water and extracted with DCM. The organic layer was evaporated to dryness and purification of the resulting residue by flash chromatography on SiCh eluting with 0 - 40% (ethyl acetate: ethanol 3: 1) in heptane to give the title compound (270 mg, 71 % yield) as a colorless oil. MS (ESP) m / z = 322.1 [M+H]+

[0774] Step 3: (lS)-l-[2-[3,5-bis(difhioromethyl)pyrazol-l-yl]-6-chloropyridin-3-yl]ethanol l-[2-[3,5-bis(difhioromethyl)pyrazol-l-yl]-6-chloropyridin-3-yl]ethanone (888 mg, 2.76 mmol, 1.0 eq) were dissolved in 2-propanol (3.8 mL) and water (12.5 mL). 1 M potassium phosphate Buffer, pH 7.0 (1.9 mL) and 0.1 M magnesium chloride hexahydrate (500 uL) were added and the mixture was heated to 50 °C. The enzymatic reduction was initiated by addition of nicotinamide adenine dinucleotide phosphate (17 mg; CAS [53-59-8]) and ketoreductase KP00006 (Codexis) (170 mg). The mixture was stirred at 50 °C overnight. The mixture was acidified to pH 2.0 by the addition of 20% H2SO4. EtOAc (25 mL) and Dicalit (1g) were added and the mixture was stirred for 20 minutes at RT. The mixture was filtered and the filtrate was set to pH 7 by addition of 2 N NaOH. The organic layer was separated and the aqueous layer extracted two time with EtOAc. The combined organic layers were dried over Na2SO4 and evaporated to dryness to give the title compound (786 mg, 88% yield) as yellowish oil. MS (ESN) m / z = 368.0 [M+HC02]’

[0775] Step 4: (lS)-l-[2-[3,5-bis(difhioromethyl)pyrazol-l-yl]-6-[6-(7,8-dihydro-5H-pyrano[4,3- c]pyridazin-3-yloxy)pyrazolo[l,5-a]pyridin-3-yl]pyridin-3-yl]ethanol

[0776]

[0777] To a solution of 3-[3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridin-6- yl]oxy-7,8-dihydro-5H-pyrano[4,3-c]pyridazine (41 mg, 0.094 mmol, 1.0 eq) and (1 S)-l-[2-[3,5- bis(difluoromethyl)pyrazol-l-yl]-6-chloropyridin-3-yl]ethanol (30 mg, 0.093 mmol, 1.0 eq) in N,N-dimethylformamide (824 uL) and water (412 uL) was added K2CO3 (39 mg, 0.029 mmol, 3.0 eq). The reaction mixture was degassed with argon and then 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (8 mg, 0.09 mmol, 0.1 eq; CAS [95464-05-4]) was added. The reaction mixture was heated to 45 °C and stirred for 1 hour. The reaction was cooled to rt and extracted with ethyl acetate and water. The organic layer was washed with brine, dried with MgSC and evaporated to dryness. The residue was purified by flash chromatography on SiCh eluting with 0 - 10% MeOH in DCM to give the title compound (33 mg, 60% yield) as a light yellow foam. MS (ESP) m / z = 556.2 [M+H]+

[0778] Example 69

[0779] 5-methyl-l- [6- [6-(6-methylpyridazin-3-yl)oxypyrazolo [1,5-a] pyridin-3-yl]-3- propanoylpyridin-2-yl]pyrazole-3-carbonitrile

[0780] Step 1 : l-(6-chloro-2-fluoropyri din-3 -yl)cy cl opropan-l-ol

[0781] To a solution of 6-chloro-2-fluoro-nicotinic acid methyl ester CAS [1093880-34-2] (1 g, 5.28 mmol, 1.0 eq) in tetrahydrofuran (10 mL) was added titanium (IV) isopropoxide (2.1 g, 2.2 mL, 7.4 mmol, 1.4 eq). To this was added dropwise 2 M ethylmagnesium chloride in THF (7.4 mL, 14.8 mmol, 2.8 eq) and the mixture was stirred overnight at RT. The mixture was poured on water and EtOAc and stirred for 10 minutes. The mixture was filtered over Celite and washed with EtOAc. The filtrate was extracted EtOAc, dried over Na?SO4 evaporated to dryness. Purification of the residue by flash chromatography on SiO? eluting with 0 - 6% MeOH in DCM followed by flash chromatography on SiO? eluting with 0 - 30% EtOAc in heptane gave the title compound (75 mg, 8% yield) as light yellow oil. MS (ESP) m / z = 188.0 [M+H]+

[0782] Step 2: [l-(6-chloro-2-fluoropyri din-3 -yl)cy cl opropyl] acetate

[0783] To a solution of l-(6-chloro-2-fluoropyridin-3-yl)cyclopropan-l-ol (75 mg, 0.4 mmol, 1.0 eq) in acetic anhydride (2 mL) was added 4-dimethylaminopyridine (5 mg, 0.04 mmol, 0.1 eq) and the mixture was stirred for 30 minutes at RT. Water and DCM were added and the organic layer was dried over Na?SO4 and evaporated to dryness. The residue was purified by flash chromatography on SiO? eluting with 0 - 50% EtOAc in heptane to give the title compound (72 mg, 78% yield) as a light yellow oil. MS (ESP) m / z = 230.1 [M+H]+

[0784] Step 3: [l-[2-fluoro-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-3- yl] cyclopropyl] acetate

[0785] This intermediate was prepared in analogy to l-[3-acetyl-6-[6-(6-methylpyridazin-3- yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile (example 14, step 4) by using [l-(6-chloro-2-fluoropyridin-3-yl)cyclopropyl] acetate instead of l-(3-acetyl-6- chloropyridin-2-yl)-5-methylpyrazole-3 -carbonitrile to give the title compound as a white solid. MS (ESP) m / z = 420.1 [M+H]+

[0786] Step 4: l-[2-fluoro-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-3- yl]cyclopropan-l-ol

[0787] To a solution of [l-P-fluoro-b-fb-^-methylpyridazin-S-y^oxypyrazolof l^-alpyridin-S- yllpyridin-S-yl] cyclopropyl] acetate (20 mg, 0.048 mmol, 1.0 eq) in tetrahydrofuran (4 mL) and water (2 mL) was added at RT lithium hydroxide (6 mg, 0.24 mmol, 5.0 eq) and the mixture was stirred for 30 minutes. Then a few drops of MeOH were added and the mixture was stirred for 8 hours. The RM was diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and evaporated to dryness to give the title compound (12 mg, 67% yield) which was used in the next step as such.

[0788] Step 5: 5-methyl-l-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-3- propanoylpyridin-2-yl]pyrazole-3-carbonitrile

[0789]

[0790] A mixture of 5-methyl-lH-pyrazole-3-carbonitrile (10 mg, 0.095 mmol, 3.0 eq; CAS [38693-82- 2]) with l-[2-fluoro-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-3- yl]cyclopropan-l-ol (20 mg, 0.032 mmol, 1.0 eq) and caesium carbonate (52 mg, 0.16 mmol, 5.0 eq) in N,N-dimethylformamide (2 mL) was stirred at RT for 1 hour followed by 6 hours at 60 °C. The mixture was poured on water and extracted with EtOAc and the organic layer was dried over Na2SO4 and evaportated to dryness. The residue was purified by flash chromatography on SiCh eluting with 0 - 3% MeOH in DCM to give the title compound (3 mg, 17% yield) as a white solid. MS (ESP) m / z = 465.1 [M+H]+

[0791] Example 70 l-[3-(l-hydroxyethyl)-6-[6-[l-(oxetan-3-yl)azepan-4-yl]oxypyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile

[0792] Step 1 : tert-butyl 4-pyrazolo[l,5-a]pyridin-6-yloxyazepane-l-carboxylate

[0793] To a solution pyrazolo[l,5-a]pyridin-6-ol (900 mg, 6.71 mmol, 1.0 eq; CAS [184473-24-3]), tertbutyl 4-hydroxyazepane-l -carboxylate (1.73 g, 8.05 mmol, 1.2 eq; CAS [1785523-74-1]) in Toluene (20 mL) was added l,l '-(azodicarbonyl)dipiperidine (2.54 g, 10.06 mmol, 1.5 eq; CAS [10465-81-3]) and tri-n-butylphosphine (2.04 g, 10.06 mmol, 1.5 eq; CAS [998-40-3]), and the reaction mixture was stirred at 110 °C for 3 hours under an atmosphere of nitrogen. The mixture was diluted with water and extracted with ethyl acetate. The organic phases was dried over anhydrous ISfeSCU and concentrated in vacuo to give a residue. The residue was purified by column chromatography on silica (petroleum ether: ethyl acetate=3: l - 0: 1) to give the title compound (1.3 g, 3.9 mmol, 58% yield) as a colorless oil. MS (ESP) m / z = 332.1 [M+H]+

[0794] Step 2: 6-[l-(oxetan-3-yl)azepan-4-yl]oxypyrazolo[l,5-a]pyridine

[0795] To a solution of tert-butyl 4-pyrazolo[l,5-a]pyridin-6-yloxyazepane-l-carboxylate (1.3 g, 3.9 mmol, 1.0 eq) in 1,4-dioxane (5 mL) was added IM HC1 in 1,4-di oxane (5.0 mL, 20.0 mmol, 5.1 eq). The reaction was stirred at 30 °C for 2 hours. The mixture was evaporated to dryness to give a red solid. MS (ESP) m / z = 232.1 [M+H]+. To a solution of the obtained solid and 3-oxetanone (284 mg, 3.9 mmol, 1.1 eq) in Methanol (10 mL) was added two drops of acetic acid. The mixture was stirred at 30 °C for 1 hour. NaBEECN (678 mg, 10.8 mmol, 3.0 eq) was added and the mixture was stirred at 50 °C for 12 hours. The mixture was diluted with H2O (50 mL) and extrated with ethyl acetate (50 mL*3). The organic phases were dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography on silica eluting with 10% MeOH in ethyl acetate to give the title compound (700 mg, 68% yield) as a white solid. MS (ESP) m / z = 288.1 [M+H]+ Step 3: l-[3-(l-hydroxyethyl)-6-[6-[l-(oxetan-3-yl)azepan-4-yl]oxypyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile

[0796] This example was prepared in analogy to example 62 by using 6-[l-(oxetan-3-yl)azepan-4- yl]oxypyrazolo[l,5-a]pyridine instead of 6-[l-(oxetan-3-yl)piperidin-4-yl]oxypyrazolo[l,5- a]pyridine in step 3 to give the title compound as a white solid. MS (ESP) m / z = 514.2 [M+H]+

[0797] Example 71 l-[3-(difluoromethyl)-6-[6-[[l-(oxetan-3-yl)piperidin-4-yl]amino]pyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile

[0798] Step 1 : 6-bromo-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine

[0799]

[0800] To a stirred solution of 6-bromo-3-iodopyrazolo[l,5-a]pyridine (1.43 g, 4.43 mmol, 1 eq; CAS [2340391-55-9]) in tetrahydrofuran (29 mL) at 0 °C was added isopropoxy-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (1.24 g, 1.36 mL, 6.64 mmol, 1.5 eq; CAS [61676-62-8]), followed by the dropwise addition of 1.3 M isopropylmagnesium chloride LiCl in THF (3.41 mL, 4.43 mmol, 1.0 eq). The reaction mixture was stirred at 0 °C for 30 minutes. Further amounts of isopropoxy- 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.24 g, 1.36 mL, 6.64 mmol, 1.5 eq) and 1.3 M isopropylmagnesium chloride LiCl in THF (3.41 mL, 4.43 mmol, 1 eq) were added and the mixture was stirred for 30 minutes at 0 °C. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried with MgSCh and evaporated to dryness. The residue was purified by flash chromatography on SiCh eluting with 0 - 50% ethyl acetate in heptane to give the title compound as a light yellow liquid (945 mg, 54% yield). MS (ESP) m / z = 323.0 [M+H]+

[0801] Step 2: l-[6-(6-bromopyrazolo[l,5-a]pyridin-3-yl)-3-(difluoromethyl)pyridin-2-yl]-5- methylpyrazole-3 -carbonitrile

[0802] To a solution of 6-bromo-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine (115 mg, 0.36 mmol, 1.0 eq) in N,N-dimethylformamide (2 mL) and water (1 uL) was added 1- [6-chloro-3-(difluoromethyl)pyridin-2-yl]-5-methylpyrazole-3-carbonitrile (105 mg, 0.39 mmol, 1.1 eq) (for preparation see example 55, step 2) and K2CO3 (148 mg, 1.07 mmol, 3.0 eq). Argon was bubbled through the mixture and l,l'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (29 mg, 0.035 mmol, 0.1 eq; CAS [95464-05- 4]) was added. The reaction mixture was heated to 45 °C overnight. The mixture was poured on water and extracted with EtOAc, washed with brine and the organic layers were dried over Na2SO4 and evaporated to dryness. The residue was purified by column chromatography on SiCh 5 - 100% (ethyl acetate:EtOH 3: 1) in heptane to give the title compound (50 mg, 20% yield) as a light brown solid. MS (ESP) m / z = 429.1 [M+H]+

[0803] Step 3: l-[3-(difhioromethyl)-6-[6-[[l-(oxetan-3-yl)piperidin-4-yl]amino]pyrazolo[l,5-a]pyridin- 3-yl]pyridin-2-yl]-5-methylpyrazole-3 -carbonitrile

[0804] Through a suspension of l-[6-(6-bromopyrazolo[l,5-a]pyridin-3-yl)-3-(difluoromethyl)pyridin-2- yl]-5-methylpyrazole-3-carbonitrile (50 mg, 0.07 mmol, 1.0 eq), l-(3-oxetanyl)-4-piperidinamine (60 mg, 0.014 mmol, 2.0 eq; CAS [1228948-07-9]) and caesium carbonate (114 mg, 0.35 mmol, 5.0 eq) at rt in 1,4-dioxane (1 mL) was bubbled Argon for 5 minutes. Then [tBuBrettPhos Pd(allyl)]OTf (11 mg, 0.014 mmol, 0.2 eq; CAS [1798782-17-8]) was added and the mixture was heated to 80 °C for 6 hours. The reaction mixture was diluted with water and extracted with DCM. The combined organic phases were washed with brine, dried over Na2SO4 and evaporated. Flash chromatography on SiCh eluting with 0 - 100 % (DCM / MeOH 10 / 1) in DCM to give the title compound (4 mg, 4% yield,) as light yellow solid. MS (ESP) m / z = 505.2 [M+H]+

[0805] Example 72 1- [6- [6-(6-methylpyridazin-3-yl)oxypyrazolo [1 ,5-a] pyridin-3-yl] -2- [l-(2,2,2- trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]cyclopropan-l-ol

[0806] Step 1 : [l-(2,6-dichloropyridin-3-yl)cyclopropyl] acetate

[0807] To a solution of l-(2,6-dichloro-3-pyridyl)cyclopropanol (404 mg, 2.0 mmol, 1.0 eq; CAS [1935604-03-7]) in acetic anhydride (4.0 mL) was added 4-dimethylaminopyridine (24 mg, 0.2 mmol, 0.1 eq). This mixture was stirred for 30 minutes at 80 °C. The mixture was poured on water and extracted with DCM. The organic layers were washed with brine, dried over Na2SO4 evaporated. Flash column chromatography on SiCh eluting with DCM gave the title compound (433 mg, 87% yield) as a colorless oil. MS (ESP) m / z = 246.1 [M+H]+

[0808] Step 2: [l-[2-chloro-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-3- yl] cyclopropyl] acetate

[0809]

[0810] To a solution of [l-(2,6-dichloropyridin-3-yl)cyclopropyl] acetate (200 mg, 0.8 mmol, 1.0 eq) in N,N-dimethylformamide (7 mL) was added 6-(6-methylpyridazin-3-yl)oxy-3-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine (337 mg, 0.96 mmol, 1.2 eq) (for preparation see example 14, step 3), K2CO3 (330 mg, 2.4 mmol, 3.0 eq) and water (3.5 mL). Argon was bubbled through the solution for 5 minutes. Then 1,1'- bis(diphenylphosphino)ferrocene-palladium(ii)dichloride dichloromethane complex (65 mg, 0.08 mmol, 0.1 eq; CAS [95464-05-4]) was added and the mixture was heated at 40 °C for 1 hour. The mixture was poured on water and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and evaporated. Flash column chromatography on SiCL eluting with 0 - 3% MeOH in DCM to give the title compound (296 mg, 75% yield) as a white powder. MS (ESP) m / z = 436.2 [M+H]+

[0811] Step 3 : [ 1 -[6-[6-(6-m ethyl pyridazin-3 -yl)oxypyrazolo[ 1 , 5-a]pyri din-3 -yl]-2-[ 1 -(2,2,2- trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]cyclopropyl] acetate

[0812] Under an atmosphere of argon, to [l-[2-chloro-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5- a]pyridin-3-yl]pyridin-3-yl]cyclopropyl] acetate (50 mg, 0.11 mmol, 1 eq) in isopropyl acetate (2 mL) was added 3.25M K3PO4 (2 eq), [1, 1 '-bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) (17 mg, 0.26 mmol, 0.2 eq; CAS [95408-45-0]) and 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-(2,2,2trifluoroethyl)-lH-pyrazole (47 mg, 0.17 mmol, 1.5 eq; CAS [1049730-42-8]). The mixture was heated at 80 °C for 23 hours and then evaporated and purified by flash chromatography on SiCh eluting with 5% MeOH in DCM followed by preparative HPLC to give the title compound (19 mg, 29% yield) as a white solid. MS (ESP) m / z = 594.3 [M+H]+

[0813] Step 4: l-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-2-[l-(2,2,2- trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]cyclopropan-l-ol

[0814] To a solution of [l-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-2-[l-(2,2,2- trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]cyclopropyl] acetate (19 mg, 0.03 mmol, 1.0 eq) in tetrahydrofuran (5 mL), methanol (2 mL) and water (2 mL) was added LiOH (0.8 mg, 0.03 mmol, 1.0 eq) and the mixture was stirred for 1 hour at RT. The reaction mixture was poured on water and extracted with ethyl acetate, washed with brine, dried over Na2SO4 evaporated. Flash column chromatography on SiCL eluting with 0 - 7% MeOH in DCM gave the title compound (14 mg, 84% yield) as a white solid. MS (ESN) m / z = 552.3 [M+HCO?]’

[0815] Example 73

[0816] (lS)-l-[2-[3-(2-methoxyethyl)-5-methylpyrazol-l-yl]-6-[6-(6-methylpyridazin-3- yl)oxypyrazolo [1 ,5-a] pyridin-3-yl] pyridin-3-yl] ethanol

[0817]

[0818] Step 1 : 3-[(E)-2-methoxyethenyl]-5-methyl-l-(oxan-2-yl)pyrazole

[0819] To a solution of (methoxymethyl)triphenylphosphonium chloride (9.1g, 27 mmol, 2.0 eq) in THF (70 mL) was added 2.5M butyllithium solution in hexane (10.7 mL, 26.8 mmol, 2.0 eq) at 0 °C under nitrogen. The reaction mixture was stirred at 0 °C for 1 hour. 5-methyl-l-tetrahydropyran- 2-yl-pyrazole-3-carbaldehyde (2.6 g, 13.4 mmol, 1.0 eq; CAS [1418297-46-7]) in THF (20 mL) was added to the reaction mixture at -70 °C and stirred at -70 °C for 1 hour. The reaction mixture was warmed to room temperature and stirred for 16 hour. The reaction mixture was poured into water(100 mL) and extracted with EtOAc(100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude was purified by silica column chromatography eluting with petroleum ether: EtO Ac 1 :0 - 3: 1 to give the title compound (1.6 g, 7.2 mmol, 54% yield) as a colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) 5 = 7.08 (d, J = 13.2 Hz, 1H), 6.44 (s, 1H), 6.15 (d, J = 6.8 Hz, 1H), 5.98 (s, 1H), 5.82 (d, J = 13.2 Hz, 1H), 5.47 (d, J = 6.7 Hz, 1H), 5.29 - 5.14 (m, 1H), 4.07 (br dd, J = 1.7, 11.4 Hz, 1H), 3.76 (s, 1H), 3.71 - 3.59 (m, 3H), 2.53 - 2.41 (m, 1H), 2.32 (d, J = 8.9 Hz, 3H), 2.11 (br dd, J = 2.7, 10.0 Hz, 1H), 1.97 - 1.87 (m, 1H), 1.74 - 1.52 (m, 3H) Step 2: 3-(2-methoxyethyl)-5-methyl-l-(oxan-2-yl)pyrazole

[0820] To a colorless solution of 3-[(E)-2-methoxyethenyl]-5-methyl-l-(oxan-2-yl)pyrazole (1.6 g, 7.2 mmol, 1.0 eq) in ethyl acetate (25 mL) was added 10% Pd on carbon (766 mg, 0.72 mmol, 0.1 eq). The reaction mixture was stirred at 30 °C under hydrogen at 15 psi for 16 hours. The reaction mixture was filtered with a pad of diatomite. The filtrate was concentrated in vacuo to give the title compound (1.5 g, 6.7 mmol, 74% yield) as a colorless oil. MS (ESP) m / z = 225.3 [M+H]+

[0821] Step 3: 3-(2-methoxyethyl)-5-methyl-lH-pyrazole

[0822] 3-(2-methoxyethyl)-5-methyl-l-(oxan-2-yl)pyrazole (1.5 g, 6.7 mmol, 1.0 eq) was dissolved in IM HC1 in 1,4-dioxane (5.0 mL) and the mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc:MeOH=l :0 - 10: 1 (0.1% NH3»H2O as additive) to give the title compound (700 mg, 5 mmol, 75% yield) as a brown solid. MS (ESP) m / z = 141.0 [M+H]+

[0823] Step 4: (lS)-l-[2-[3-(2-methoxyethyl)-5-methylpyrazol-l-yl]-6-[6-(6-methylpyridazin-3- yl )oxypyrazol o [ 1 , 5 -a] pyri din-3 -yl ] pyri din-3 -yl ] ethanol

[0824]

[0825] This example was prepared in analogy to example 68 by using 3-(2-methoxyethyl)-5-methyl-lH- pyrazole instead of 3,5-bis(difluoromethyl)-lH-pyrazole in step 2 to give the title compound as off-white solid. MS (ESP) m / z = 468.2 [M+H]+

[0826] Example 74

[0827] 1- [3- ( 1 -hydroxy ethyl)-6- [6- [1 -(2,2,2-trifluoroethyl)piperidin-4-yl] oxypyrazolo [1 ,5-a] pyridin- 3-yl] pyridin-2-yl] -5-methylpyrazole-3-carbonitr ile

[0828] This example was prepared in analogy to example 62 by using l-(2,2,2-trifluoroethyl)-4- piperidinol (CAS [90633-29-7]) instead of 1 -(ox etan-3 -yl)piperidin-4-ol in step 1 to give the title compound as a white solid. MS (ESP) m / z = 526.4 [M+H]+ Example 75 l-[6-[6-(l-cyclopropylpiperidin-4-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-3-[(15)-l- hydroxyethyl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile

[0829] This example was prepared in analogy to example 62 by using l-cyclopropyl-piperidin-4-ol (CAS [851847-62-6]) instead of 1 -(ox etan-3 -yl)piperidin-4-ol in step 1 to give the title compound as a white solid. MS (ESP) m / z = 526.4 [M+H]+

[0830] Example 76 - Phosphorylation assay SIK1-3:

[0831] In the presence of SIK2 (resp. SIK1 or SIK3) and ATP the CHK-peptide (KKKVSRSGLYRSPSMPENLNRPR with C-terminal arginine amide modification) were phosphorylated at one of the four feasible serine’s. Only one phosphorylation is observed under the assay conditions. 60 nl of each compound dilution series (12 point; dilution factor 3, generally 30 pM to 170 pM) in DMSO were transferred by acoustic dispensing to the assay plate and 30 minutes pre-incubated (ambient temperature) after the addition of 5 pl SIK1 (5 nM) resp. 5 pl SIK2 (0.5 nM) or 7 pl SIK3 (1.5 nM) in assay-buffer (12.5 mM HEPES (pH 7.0), 10 mM magnesium acetate, 0.005% BSA). 10 pM CHK-peptide solution and 5 pl of 100 pM ATP for SIK1 & SIK2 resp. 3 pl for SIK3 in assay-buffer were added and incubated ambient for 45 minutes. 40 pl of 0.125% formic acid in water were added to quench the reaction. RapidFire (RF) Mass Spectrometry was utilized for data generation as described below. The multiple charged species (3-5 charges) for the phosphorylated and non-phosphorylated form measured by MRM (Multiple Reaction Monitoring; API5000 or 6500+) or EIC (Extracted Ion Current; QToF) were summed up and the ratio calculated (sum phosphorylated species / sum all species) for data evaluation. Normalization was performed by Genedata software based on the non-inhibition control DMSO and the commercially available SIK inhibitor @ IpM YKL-05-099 (CAS number 1936529-65-5). The results of the assay are expressed in half-maximal inhibitory concentrations (IC50s) and are summarized below in Table 1.

[0832] RapidFire Setup:

[0833] Samples were aspirated by vacuum for max. 600ms and loaded to C4-cartridge (Agilent;

[0834] #G9203A) for 3000ms@1.5ml / min with 0.1% formic acid in water. Afterwards samples were transferred to the API5000 (API6500+) or QToF mass spectrometer for 4000ms@1.25ml / min with 90% acetonitrile; 10% water; 0.007% TFA; 0.093 formic acid. The cartridge was reconditioned for additional 500ms with 0.1% formic acid in water.

[0835] MS-Setup Sciex API5000 / API6500+:

[0836] All MS analyses using the following MS-setup in MRM mode: Electrospray positive; Ion Spray Voltage: 4000V; Temperature: 550 °C; Collision Gas: 5; Curtain Gas: 15; Gas 1 : 40; Gas 2: 42; EP: 10. DP = declustering potential; CE = collision energy; CXP = cell exit potential.

[0837] MS-Setup Agilent QToF 6545

[0838] All MS analyses using the following MS-setup in Mode MS: Dual AJS Electrospray positive;

[0839] VCap: 3000V; Drying & Sheath gas: 340 °C@81 / min; Nebulizer: 60psig; Nozzle Voltage: 2000V; Fragmentor: 130V; Skimmer: 35V; Octi RF Vpp: 700V; Ref masses on@5spectra / s

[0840] Table 1: IC50 values for inhibition of SIK1, SIK2 and SIK3:

[0841] Example A

[0842] Film coated tablets containing the following ingredients can be manufactured in a conventional manner:

[0843] The active ingredient is sieved and mixed with microcrystalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidone in water. The granulate is then mixed with sodium starch glycolate and magnesium stearate and compressed to yield kernels of 120 or 350 mg respectively. The kernels are lacquered with an aq. solution / suspension of the above mentioned film coat.

[0844] Example B

[0845] Capsules containing the following ingredients can be manufactured in a conventional manner:

[0846] The components are sieved and mixed and filled into capsules of size 2.

[0847] Example C

[0848] Injection solutions can have the following composition:

[0849] The active ingredient is dissolved in a mixture of Polyethylene glycol 400 and water for injection (part). The pH is adjusted to 5.0 by addition of acetic acid. The volume is adjusted to 1.0 ml by addition of the residual amount of water. The solution is filtered, filled into vials using an appropriate overage and sterilized.

Claims

Claims1. A compound of formula (I) or (II)whereinL is -O-, -NH-, -S- or absent;R1is haloalkyl, hydroxyalkyl, hydroxycycloalkyl, cyano, alkoxyalkyl, R5-carbonyl, or heterocycloalkyl; wherein heterocycloalkyl is optionally substituted with cyano;R2is aryl or heteroaryl; wherein each instance of aryl and heteroaryl is optionally substituted with one, two, three or four substituents independently selected from R6;R3is hydrogen or alkoxy;R4is hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkylalkyl, heteroaryl or heterocycloalkyl; wherein each instance of cycloalkyl, aryl, heterocycloalkylalkyl, heteroaryl and heterocycloalkyl is optionally substituted with one or two substituents independently selected from R7;R5is hydrogen, alkyl, alkoxy, alkoxyalkyl or haloalkyl;R6is at each instance independently selected from alkyl, cyano, haloalkyl, halogen, cycloalkyl, aminocarbonyl and alkoxyalkyl; andR7is at each instance independently selected from alkyl, cyano, cycloalkyl, haloalkyl, halogen, heterocycloalkyl, heterocycloalkylalkyl, dialkylaminocarbonyl, amino and alkoxy; wherein heterocycloalkyl and heterocycloalkylalkyl are optionally substitutedwith one or two substituents independently selected from alkyl, alkoxy, halogen and heterocycloalkyl; or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, whereinR1is difluoromethyl, hydroxymethyl, 1 -hydroxy ethyl, 1 -hydroxycyclopropyl, cyano, methoxymethyl, R5-carbonyl, or heterocycloalkyl, wherein heterocycloalkyl is optionally substituted with cyano; a particular heterocycloalkyl is tetrahydrofuran-2- yi.

3. A compound according to claim 1 or 2, whereinR2is phenyl or heteroaryl selected from pyrazol-l-yl, pyrazol-4-yl, pyridin-2-one, tri azol - 4-yl and 5-methyl-6-oxo-4H-pyrrolo[3,4-c]pyrazol-2-yl; wherein each instance of phenyl and heteroaryl is optionally substituted with one or two substituents independently selected from R6.

4. A compound according to any one of claims 1 to 3, whereinR3is methoxy or hydrogen, in particular hydrogen.

5. A compound according to any one of claims 1 to 4, whereinR4is hydrogen, methyl, 2-morpholino-4-ethyl, pyridazin-3-yl or heterocycloalkyl selected from azepan-4-yl, piperazin- 1-yl, pyrrolidin-l-yl, 7,8-dihydro-5H-pyrano[4,3- c]pyridazin-3-yl and piperidin-4-yl, wherein each instance of 2-morpholino-4-ethyl, pyridazin-3-yl and heterocycloalkyl is optionally substituted with one or two substituents independently selected from R7.

6. A compound according to any one of claims 1 to 5, whereinR5is hydrogen, methyl or ethyl.

7. A compound according to any one of claims 1 to 6, whereinR6is at each instance independently selected from methyl, cyano, trifluoroethyl, trifluoromethyl, difluoromethyl, fluoro, chloro, cychlopropyl, aminocarbonyl and methoxy ethyl.

8. A compound according to any one of claims 1 to 7, whereinR7is at each instance independently selected from methyl, cyclopropyl, difluoromethyl, trifluoroethyl, fluoro, chloro, dimethylaminocarbonyl, heterocycloalkyl and heterocycloalkyl alkyl; wherein heterocycloalkyl of R7is selected from oxetan-3-yl, morpholin-4-yl and piperazin- i-yi; wherein heterocycloalkyl alkyl of R7is selected from (azetidin-l-yl)methyl, 2-oxa-6- azaspiro[3 ,3]heptan-6-ylmethyl, morpholin-4-ylmethyl, morpholin-4-ylethyl, azetidin-l-ylmethyl and piperazin-l-ylmethyl; and wherein heterocycloalkyl and heterocycloalkylalkyl of R7are optionally substituted with one or two substituents independently selected from alkoxy, halogen and heterocycloalkyl.

9. A compound according to any one of claims 1 to 8, whereinL is -O-.

10. A compound according to any one of claims 1 to 9, wherein the compound is of formula (I)(I).

11. A compound according to any one of claims 1 to 9, wherein the compound is of formula(II)2. A compound of formula (I)whereinL is -0-, -NH-, -S- or absent;R1is haloalkyl, hydroxyalkyl, hydroxycycloalkyl, cyano, alkoxyalkyl, R5-carbonyl, or tetrahydrofuran-2-yl; wherein tetrahydrofuran-2-yl is optionally substituted with cyano;R2is aryl or heteroaryl; wherein each instance of aryl and heteroaryl is optionally substituted with one, two, three or four substituents independently selected from R6;R3is hydrogen or alkoxy;R4is hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkylalkyl, heteroaryl or heterocycloalkyl; wherein each instance of cycloalkyl, aryl, heterocycloalkylalkyl, heteroaryl and heterocycloalkyl is optionally substituted with one or two substituents independently selected from R7;R5is hydrogen, alkyl, alkoxy, alkoxyalkyl or haloalkyl;R6is at each instance independently selected from alkyl, cyano, haloalkyl, halogen, cycloalkyl, aminocarbonyl and alkoxyalkyl; andR7is at each instance independently selected from alkyl, cyano, cycloalkyl, haloalkyl, halogen, heterocycloalkyl, heterocycloalkylalkyl, dialkylaminocarbonyl, amino and alkoxy; wherein heterocycloalkyl and heterocycloalkylalkyl are optionally substituted with one or two substituents independently selected from alkoxy, halogen and heterocycloalkyl; or a pharmaceutically acceptable salt thereof.

13. A compound of formula (Il-a)whereinL is -O-, -NH-, -S- or absent;R1is hydrogen, alkyl, alkoxy, alkoxyalkyl or haloalkyl;R2is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl; wherein each instance of cycloalkyl, aryl, heteroaryl and heterocycloalkyl is optionally substituted with one, two or three substituents independently selected from R5;R3is hydrogen, alkoxy, alkyl, haloalkyl, or haloalkoxy;R4is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl or heterocycloalkyl alkyl; wherein each instance of cycloalkyl, aryl, heteroaryl, heterocycloalkyl and heterocycloalkylalkyl is optionally substituted with one or two substituents independently selected from R6;R5is alkyl, cyano, haloalkyl, halogen, cycloalkyl, alkoxy or aminocarbonyl; andR6is at each instance independently selected from alkyl, cyano, haloalkyl, halogen, alkoxy, alkoxyheterocycloalkylalkyl, alkylheterocycloalkyl, haloalkyl, heterocycloalkyl, heterocycloalkylalkyl, haloheterocycloalkylalkyl, alkoxyheterocycloalkylalkyl or amino; or a pharmaceutically acceptable salt thereof.

14. A compound of formula (Il-a)whereinL is -O-, or absent;R1is alkyl;R2is heteroaryl optionally substituted with one or two substituents independently selected from R5;R3is hydrogen;R4is hydrogen, alkyl, heteroaryl, heterocycloalkyl or heterocycloalkylalkyl; wherein each instance of heteroaryl, heterocycloalkyl and heterocycloalkylalkyl is optionally substituted with R6;R5is haloalkyl, halogen or cycloalkyl; andR6is alkyl or heterocycloalkyl; or a pharmaceutically acceptable salt thereof.

15. A compound according to any one of claims 1 to 14 selected froml-[3-(l-hydroxyethyl)-6-[6-[4-(oxetan-3-yl)piperazin-l-yl]pyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[3-(l-hydroxyethyl)-6-[6-[rac-(3R,4R)-3-amino-4-fluoropyrrolidin-l-yl]pyrazolo[l,5- a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[3-(l-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]pyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[3-[(lS)-l-hydroxyethyl]-6-[6-[(6-methylpyridazin-3-yl)amino]pyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[3-[(lR)-l-hydroxyethyl]-6-[6-[(6-methylpyridazin-3-yl)amino]pyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[3-(l-hydroxyethyl)-6-[6-[[6-[(3-methoxyazetidin-l-yl)methyl]pyridazin-3- yl]amino]pyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[6-[6-[[6-[(3-fluoroazetidin-l-yl)methyl]pyridazin-3-yl]amino]pyrazolo[l,5-a]pyridin-3- yl]-3-(l-hydroxyethyl)pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[6-[6-[[6-[(3,3-difluoroazetidin-l-yl)methyl]pyridazin-3-yl]amino]pyrazolo[l,5- a]pyridin-3-yl]-3-(l-hydroxyethyl)pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[3-[(lS)-l-hydroxyethyl]-6-[6-[[6-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)pyridazin-3- yl]amino]pyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[3-[(lR)-l-hydroxyethyl]-6-[6-[[6-[(3-methoxyazetidin-l-yl)methyl]pyridazin-3- yl]amino]pyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[3-[(lS)-l-hydroxyethyl]-6-[6-[[6-[(3-methoxyazetidin-l-yl)methyl]pyridazin-3- yl]amino]pyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[3-[(lS)-l-hydroxyethyl]-6-[5-methoxy-6-[(6-methylpyridazin-3-yl)amino]pyrazolo[l,5- a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile;3-[3-(l-hydroxyethyl)-6-[6-(2-morpholin-4-ylethoxy)pyrazolo[l,5-a]pyridin-3-yl]pyri din-2- yl]benzonitrile; l-[3-(l-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[3-[(lS)-l-hydroxyethyl]-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[3-[(lR)-l-hydroxyethyl]-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile;3-fluoro-4-[3-(l -hydroxy ethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-l-(2,2,2-trifluoroethyl)pyridin-2-one;(lS)-l-[2-[3-(difluoromethyl)-5-methylpyrazol-l-yl]-6-[6-(6-methylpyridazin-3- yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-3-yl]ethanol;(lR)-l-[2-[3-(difluoromethyl)-5-methylpyrazol-l-yl]-6-[6-(6-methylpyridazin-3- yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-3-yl]ethanol; l-[3-(hydroxymethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile;5-(difluoromethyl)-l-[3-(l-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5- a]pyridin-3-yl]pyridin-2-yl]pyrazole-3-carbonitrile;5-(difluoromethyl)-l-[3-[(lS)-l-hydroxyethyl]-6-[6-(6-methylpyridazin-3- yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]pyrazole-3-carbonitrile;5-(difluoromethyl)-l-[3-[(lR)-l-hydroxyethyl]-6-[6-(6-methylpyridazin-3- yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]pyrazole-3-carbonitrile; l-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-2-[3-methyl-l-(2,2,2- trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]ethanol;1-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyri din-3-yl]-2-[5-methyl-l -(2,2,2- trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]ethanol;5-chloro-2-[3-(l-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyri din-3- yl]pyridin-2-yl]pyrazole-3-carbonitrile;5-cyclopropyl-l-[3-(l-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5- a]pyridin-3-yl]pyridin-2-yl]pyrazole-3-carbonitrile;5-cyclopropyl-2-[3-(l-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5- a]pyridin-3-yl]pyridin-2-yl]pyrazole-3-carbonitrile;5-(difluoromethyl)-l-[3-(l-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5- a]pyridin-3-yl]pyridin-2-yl]pyrazole-3-carboxamide;2-[3-(l-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-3-carbonitrile;1-[6-[6-(6-chloropyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-3-(l- hydroxyethyl)pyridin-2-yl]-5-methylpyrazole-3-carbonitrile;2-[3-(l-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-3,5-dimethyl-4H-pyrrolo[3,4-c]pyrazol-6-one;1 -[2-[3-methyl-l -(2, 2, 2-tri fluoroethyl )pyrazol-4-yl]-6-[6-(6-morpholin-4-ylpyridazin-3- yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-3-yl]ethanol;1 -[2-[3-methyl-l -(2, 2, 2-tri fluoroethyl )pyrazol-4-yl]-6-[6-[6-(morpholin-4- ylmethyl)pyridazin-3-yl]oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-3-yl]ethanol; l-[2-[5-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]-6-[6-(6-morpholin-4-ylpyridazin-3- yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-3-yl]ethanol; l-[6-[6-[6-(difluoromethyl)pyridazin-3-yl]oxypyrazolo[l,5-a]pyridin-3-yl]-3-[(lS)-l- hydroxyethyl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[6-[6-[6-(4-methylpiperazin-l-yl)pyridazin-3-yl]oxypyrazolo[l,5-a]pyridin-3-yl]-2-[3- methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]ethanol; l-[2-[3-(difluoromethyl)-5-methylpyrazol-l-yl]-6-[6-[6-[(3-methoxyazetidin-l- yl)methyl]pyridazin-3-yl]oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-3-yl]ethanol; l-[3-(l-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)sulfanylpyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[3-(l-hydroxyethyl)-6-pyrazolo[l,5-a]pyridin-3-ylpyridin-2-yl]-5-methylpyrazole-3- carbonitrile; l-[2-[6-[4-(oxetan-3-yl)piperazin-l-yl]pyrazolo[l,5-a]pyridin-3-yl]-4-[l-(2,2,2- trifluoroethyl)pyrazol-4-yl]-l,3-thiazol-5-yl]ethanol; l-cyclopropyl-4-[5-(l-hydroxyethyl)-2-(6-methoxypyrazolo[l,5-a]pyridin-3-yl)-l,3-thiazol- 4-yl]pyridin-2-one; -[5-(l-hydroxyethyl)-2-[6-(2-morpholin-4-ylethoxy)pyrazolo[l,5-a]pyridin-3-yl]-l,3- thiazol-4-yl]-l-(2,2,2-trifluoroethyl)pyridin-2-one; l-[2-[6-(2-morpholin-4-ylethoxy)pyrazolo[l,5-a]pyridin-3-yl]-4-[l-(2,2,2- trifluoroethyl)pyrazol-4-yl]-l,3-thiazol-5-yl]ethanol; l-[2-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-4-[l-(2,2,2- trifluoroethyl)pyrazol-4-yl]-l,3-thiazol-5-yl]ethanol;3-fluoro-4-[5-(l -hydroxy ethyl)-2-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3- yl]-l,3-thiazol-4-yl]-l-(2,2,2-trifluoroethyl)pyridin-2-one; l-[2-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-4-[2-(2,2,2- trifluoroethyl)triazol -4-yl ] - 1 , 3 -thiazol-5 -yl] ethanol ; l-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5- methylpyrazole-3 -carbonitrile;1-[3-formyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5- methylpyrazole-3 -carbonitrile; -[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-3-carbonitrile;1-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5- cyclopropylpyrazole-3-carbonitrile; -[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5- cyclopropylpyrazole-3-carbonitrile; l-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-2-yl]-5- (difluoromethyl)pyrazole-3-carbonitrile; l-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-2-[l-(2,2,2- trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]propan-l-one; l-[3-(difluoromethyl)-6-[5-methoxy-6-[(6-methylpyridazin-3-yl)amino]pyrazolo[l,5- a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[3-(difluoromethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile;3-[5-(difluoromethyl)-6-[3-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-2-yl]-6-(6- methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridine;3-[5-(difluoromethyl)-6-[5-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-2-yl]-6-(6- methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridine; l-[3-(methoxymethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyri din-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile;5-methyl-l-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-3-[trans-4- cyanooxolan-2-yl]pyridin-2-yl]pyrazole-3-carbonitrile;5-methyl-l-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-3-[cis-4- cyanooxolan-2-yl]pyridin-2-yl]pyrazole-3-carbonitrile; l-[3-(l-hydroxyethyl)-6-[6-[l-(oxetan-3-yl)piperidin-4-yl]oxypyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile;3-[3-[6-(3-cyano-5-methylpyrazol-l-yl)-5-(l-hydroxyethyl)pyridin-2-yl]pyrazolo[l,5- a]pyridin-6-yl]oxy-N,N,6-trimethylpyridazine-4-carboxamide;3-[5-(difluoromethyl)-6-[3-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-2-yl]-6-[6- [[4-(oxetan-3-yl)piperazin-l-yl]methyl]pyridazin-3-yl]oxypyrazolo[l,5-a]pyridine;3-[5-(difluoromethyl)-6-[5-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-2-yl]-6-[6-[[4-(oxetan-3-yl)piperazin-l-yl]methyl]pyridazin-3-yl]oxypyrazolo[l,5-a]pyridine;4-[[6-[3-[5-(difluoromethyl)-6-[3-methyl-l-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyri din-2- yl]pyrazolo[l,5-a]pyridin-6-yl]oxypyridazin-3-yl]methyl]morpholine;2-[3-(difluoromethyl)-5-methylpyrazol-l-yl]-6-[5-methoxy-6-[(6-methylpyridazin-3- yl)amino]pyrazolo[l,5-a]pyridin-3-yl]pyridine-3-carbonitrile;(lS)-l-[2-[3,5-bis(difluoromethyl)pyrazol-l-yl]-6-[6-(7,8-dihydro-5H-pyrano[4,3- c]pyridazin-3-yloxy)pyrazolo[l,5-a]pyridin-3-yl]pyridin-3-yl]ethanol;5-methyl-l-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-3- propanoylpyridin-2-yl]pyrazole-3-carbonitrile;1 -[3 -(1 -hydroxy ethyl)-6-[6-[ 1 -(ox etan-3 -yl)azepan-4-yl]oxypyrazolo[ 1 , 5-a]pyri din-3 - yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[3-(difluoromethyl)-6-[6-[[l-(oxetan-3-yl)piperidin-4-yl]amino]pyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-2-[l-(2,2,2- tri fluoroethyl)pyrazol-4-yl]pyri din-3 -yl]cyclopropan- 1 -ol;(lS)-l-[2-[3-(2-methoxyethyl)-5-methylpyrazol-l-yl]-6-[6-(6-methylpyridazin-3- yl)oxypyrazolo[l,5-a]pyridin-3-yl]pyridin-3-yl]ethanol;1 -[3 -(1 -hydroxy ethyl)-6-[6-[ 1 -(2,2,2-trifluoroethyl)piperidin-4-yl]oxypyrazolo[ 1,5- a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; and l-[6-[6-(l-cyclopropylpiperidin-4-yl)oxypyrazolo[l,5-a]pyridin-3-yl]-3-[(lS)-l- hydroxyethyl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; or a pharmaceutically acceptable salt thereof.

16. A compound according to any one of claims 1 to 15 selected from l-[3-(l-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]pyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[3-[(lS)-l-hydroxyethyl]-6-[6-[(6-methylpyridazin-3-yl)amino]pyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[3-[(lS)-l-hydroxyethyl]-6-[5-methoxy-6-[(6-methylpyridazin-3-yl)amino]pyrazolo[l,5- a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; l-[3-(l-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; andl-[3-[(lS)-l-hydroxyethyl]-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; or a pharmaceutically acceptable salt thereof.

17. A process for the preparation of a compound according to any one of claims 1 to 15, comprising at least one of the following steps:(a) the reaction of a compound of formula (Al)with a compound of formula (A2)R4-L-H (A2), in presence of a suitable catalyst, a suitable solvent and a suitable base;(b) the reaction of a compound of formula (Bl)with a suitable reduction agent, in presence of a suitable solvent; or(c) the reaction of a compound of formula (Cl)with a compound of formula (C2)R2-(B(OH)2(C2) in presence of a suitable catalyst, a suitable solvent and a suitable base; wherein L, R1, R2, R3and R4are according to any one of the preceding claims.

18. A compound according to any one of claims 1 to 16 when manufactured according to a process of claim 17.

19. A compound according to any one of claims 1 to 16, for use as therapeutically active substance.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16, and a therapeutically inert carrier.

21. The use of a compound according to any one of claims 1 to 16, for the treatment or prophylaxis of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel diseases (IBD), atherosclerosis, type 2 diabetes or glom erul onephriti s .

22. The use of a compound according to any one of claims 1 to 16, for the preparation of a medicament for the treatment or prophylaxis rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel diseases (IBD), atherosclerosis, type 2 diabetes or glom erul onephriti s .

23. A compound according to any one of claims 1 to 16, for use in the treatment or prophylaxis of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis,inflammatory bowel diseases (IBD), atherosclerosis, type 2 diabetes or glom erul onephriti s .

24. A method for the treatment or prophylaxis of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel diseases (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis, which method comprises administering an effective amount of a compound according to any one of claims 1 to 16, to a patient in need thereof.

25. The invention as hereinbefore described.

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