Novel pyrazolopyridine derivatives

Abstract

The present application relates to a compound of formula (I) or formula (II), wherein L, R1, R2, R3 and R4 are as defined in the claims. The compounds of formula (I) or formula (II) are useful as medicaments for modulating SIK activity in autoimmune disorders, inflammation and other disorders. (I) and (II).

Description

[0001] This invention relates to organic compounds that can be used for treatment and / or prevention in mammals, and particularly to compounds that modulate SIK activity. The invention further relates to the manufacture of these compounds, pharmaceutical compositions containing them, and their use as therapeutically active substances.

[0002] This invention particularly relates to a compound of formula (I) or (II).

[0003] (I) or (II)

[0004] in

[0005] L is -O-, -NH-, -S-, or does not exist;

[0006] R 1 It is a haloalkyl, hydroxyalkyl, hydroxycycloalkyl, cyano, alkoxyalkyl, R 5 - Carbonyl or heterocyclic alkyl; wherein the heterocyclic alkyl group is optionally substituted with a cyano group;

[0007] R 2 It is aryl or heteroaryl; wherein each instance of aryl and heteroaryl is optionally selected from one, two, three or four independently selected from R 6 Substituents of the substituents;

[0008] R 3 It is hydrogen or alkoxy;

[0009] R 4 It is hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkylalkyl, heteroaryl, or heterocycloalkyl; wherein each example of cycloalkyl, aryl, heterocycloalkylalkyl, heteroaryl, and heterocycloalkyl is optionally derived from one or two independently selected from R 7 Substituents of the substituents;

[0010] R 5 It can be hydrogen, alkyl, alkoxy, alkoxyalkyl, or haloalkyl;

[0011] R 6 In each instance, the groups are independently selected from alkyl, cyano, haloalkyl, halogen, cycloalkyl, aminocarbonyl, and alkoxyalkyl; and

[0012] R 7 In each example, the groups are independently selected from alkyl, cyano, cycloalkyl, haloalkyl, halogen, heterocycloalkyl, heterocycloalkylalkyl, dialkylaminocarbonyl, amino, and alkoxy; wherein the heterocycloalkyl and heterocycloalkylalkyl groups are optionally substituted by one or two substituents independently selected from alkyl, alkoxy, halogen, and heterocycloalkyl.

[0013] Or its pharmaceutically acceptable salt.

[0014] Salt-inducible kinases (SIKs) belong to the AMP-activated protein kinase (AMPK) subfamily, known as AMPK-associated kinases. There are three members, named SIK1, SIK2, and SIK3, with widespread expression. Their primary biological function is to modify gene expression by controlling the phosphorylation and subcellular localization of two key transcriptional regulators: CRTC (cAMP-regulated transcriptional coactivator) and class IIa HDAC (histone deacetylase). In fact, under basal conditions, both CRTC and HDAC are phosphorylated by SIK kinases and isolated in the cytoplasm through their cytoplasmic chaperone 14-3-3. In response to extracellular signals that normally increase intracellular cAMP levels, SIK kinase activity is inhibited, CRTC and HDAC are no longer phosphorylated, and are thus released from 14-3-3. Therefore, they can translocate to the cell nucleus and regulate gene expression (Wein et al. review, Trends Endocrinol Metab. 2018 Oct;29(10):723-735).

[0015] In macrophages, inhibition of SIK kinase leads to 1) CRTC3 shuttles to the nucleus and increases IL-10 transcription; 2) HDAC4 / 5 translocates to the nucleus and is subsequently deacetylated by NF-κB, resulting in reduced transcription of pro-inflammatory cytokines (Clark et al., Proc Natl Acad Sci US A. 2012 Oct 16; 109(42):16986-91.).

[0016] Macrophages are crucial for maintaining tissue homeostasis, mediating inflammation, and promoting inflammatory resolution. To achieve this functional diversity, macrophages are capable of different “polarizations” based on environmental cues. Two extreme phenotypes along their activation continuum are “M1” or “pro-inflammatory macrophages” and “M2” or “pro-remission macrophages”.

[0017] Notably, inhibition of intracellular SIK kinases overrides these extracellular macrophage polarization signals and pushes them toward a pro-remission phenotype. This is accompanied by an increase in IL-10 (through interference with the SIK-CRTC3 pathway) and a corresponding decrease in TNF-α, IL-12, and IL-6 (through interference with the SIK-HDAC4 / 5 and NF-κB pathways). High levels of IL-10 and low levels of pro-inflammatory cytokines following SIK inhibition promote inflammation resolution. The exploration of the SIK pathway was initially described in macrophages (Clark et al., Proc Natl Acad Sci US A. 2012 Oct 16; 109(42):16986-91) and dendritic cells (Sundberg et al., Proc Natl Acad Sci US A. 2014 Aug 26; 111(34):12468-73), and the therapeutic potential of pan-SIK inhibitors has been demonstrated in mouse LPS (lipopolysaccharide) challenge models (Sundberg et al., ACS Chem Biol. 2016 Aug 19; 11(8):2105-11) and colitis models (Fu et al., Inflamm Bowel Dis. 2021 Oct 20; 27(11):1821-1831). Subsequently, SIK has been shown to play an important role in the function of several immune cells, including mast cells (Darling et al., J Biol Chem. 2021 Jan-Jun; 296:100428). Importantly, SIK1 is poorly expressed in macrophages, and one embodiment of the present invention is a SIK2 / 3 inhibitor that does not affect SIK1, thereby limiting potential SIK1-related toxicities.

[0018] SIK inhibitors have high therapeutic potential in the following diseases: 1) diseases characterized by the influx of pro-inflammatory macrophages into tissues and impaired tissue homeostasis and healing function, or 2) diseases in which anti-TNF therapy is beneficial (partially or completely) or IL10 levels are insufficient. Diseases characterized by inflammatory macrophages include, for example, rheumatoid arthritis, juvenile rheumatoid arthritis, NASH, primary sclerosing cholangitis, giant cell vasculitis and inflammatory bowel disease (“IBD”), atherosclerosis, type 2 diabetes, and glomerulonephritis.

[0019] IBD has been confirmed to be a disease associated with IL-10 and TNF-α. Genetic alterations that reduce IL-10 function (such as SNPs in IL-10 or its receptor) are associated with an increased risk of IBD in humans. Furthermore, while anti-TNF therapy is successful, only a small percentage of IBD patients respond, and this limited response largely disappears over time. The dual action of SIK inhibitors (increasing IL-10 and decreasing TNF-α) makes them particularly suitable for the treatment of IBD.

[0020] All three SIK kinase isoforms are widely expressed in human tissues, with SIK1 showing the highest expression in skin and adipose tissue, SIK2 in adipose tissue, and SIK3 in the testes and brain. Similar to their roles in macrophages, SIKs in these cells respond to extracellular signals by phosphorylating CRTCs and class II HDCAs, subsequently altering the expression of several cytokines.

[0021] In addition to its physiological functions, SIK expression dysregulation has been reported to be associated with several diseases. For example, SIK2 has been described as a risk site for primary sclerosing cholangitis, a fibrotic disease commonly associated with IBD. Furthermore, SIK2 and SIK3 are highly expressed in ovarian and prostate cancers and are associated with low survival rates (Miranda et al., Cancer Cell. Aug 8, 2016; 30(2):273-289; Bon et al., MolCancer Res. Apr 2015; 13(4):620-635).

[0022] To date, many diseases caused by innate immune system disorders lack effective treatments, and the medical need for new therapies remains unmet. This invention relates to a novel compound, a highly active SIK inhibitor for the treatment of inflammatory, allergic, and autoimmune diseases. Therefore, in addition to inflammation, allergies, and autoimmune diseases, SIK inhibitors may also have potential associations with cancer, metabolic diseases, bone density disorders, pigmentation-related diseases or cosmetic conditions, fibrotic diseases, and depression.

[0023] In this specification, the term "alkyl" refers, alone or in combination, to a straight-chain or branched alkyl group having 1 to 8 carbon atoms, particularly a straight-chain or branched alkyl group having 1 to 6 carbon atoms, and more particularly a straight-chain or branched alkyl group having 1 to 4 carbon atoms. Examples of straight-chain and branched C1-C8 alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, isopentyl, isohexyl, isoheptyl, and isoctyl, particularly methyl, ethyl, propyl, butyl, and pentyl. Specific examples of alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, and isobutyl. Methyl and ethyl are further specific examples of "alkyl" in compounds of formula (I) or (II).

[0024] The term "cycloalkyl" refers, alone or in combination, to a cycloalkyl ring having 3 to 8 carbon atoms, particularly a cycloalkyl ring having 3 to 6 carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. A specific example of "cycloalkyl" is cyclopropyl.

[0025] The term "cyano" refers to the –CN group, either alone or in combination, in which carbon and nitrogen atoms are linked by a triple bond.

[0026] The term "hydroxycycloalkyl" refers, alone or in combination, to a "hydroxy" group attached to a "cycloalkyl" group. Examples of "hydroxycycloalkyl" include, but are not limited to, 1-hydroxycyclopropyl, 2-hydroxycyclopropyl, 1-hydroxycyclobutyl, 2-hydroxycyclobutyl, and 3-hydroxycyclobutyl. A specific example of "hydroxycycloalkyl" is 1-hydroxycyclopropyl, also known as cyclopropane-1-ol.

[0027] The term "heterocyclic alkyl" alone or in combination refers to a monocyclic or bicyclic system having 4 to 12 ring atoms, either monovalently saturated or partially unsaturated, comprising 1, 2, or 3 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. Bicyclic means consisting of two rings sharing one or two common ring atoms. "Heterocyclic alkyl" may contain a carbonyl group, where carbon is part of the ring system. The ring system can be attached to the remaining compound by atoms selected from C, N, S, and O, particularly by an N atom ("N-heterocyclic alkyl"). Examples of "heterocyclic alkyl" include, but are not limited to, morpholino, morpholin-4-yl, pyrrolyl, pyrrolidine-1-yl, pyrrolidine-3-yl, piperidinyl, piperidin-4-yl, piperidin-4-yl, 2-oxopyrrolidine-1-yl, piperazinyl, piperazin-1-yl, azacyclic butyl, azacyclic butyl, tetrahydrofuran-2-yl, [3-oxo-piperazin-1-yl], (1,1-dioxo-1,2-thiazolidin-2-yl), (4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl), (3-oxo-1,5, (6,8-Tetrahydrooxazolo[3,4-a]pyrazin-7-yl), [racemic-(3aR,6aS)-2,3,3a,5,6,6a-hexahydro-1H-pyrrolo[3,2-b]pyrrolo-4-yl], [racemic-(3aS,6aR)-2,3,3a,5,6,6a-hexahydro-1H-pyrrolo[3,2-b]pyrrolo-4-yl], (4-oxo-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-3-yl), (6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-1) -yl), (4,7-diazaspiro[2.5]octane-7-yl), (2-oxa-5,8-diazaspiro[3.5]nonane-8-yl), 3-azabicyclo[3.2.0]heptane-3-yl), (5-azaspiro[2.4]heptane-5-yl), (2-azabicyclo[2.2.1]heptane-2-yl), 4-oxa-7-azaspiro[2.5]octane-7-yl, (3-azabicyclo[3.1.0]hexane-3-yl), (6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl), 2 -oxa-7-azaspiro[3.4]octane-7-yl, 2-oxa-6-azaspiro[3.3]heptane-6-yl, (2-oxo-1-piperidinyl), (2,3-dihydropyridazino[4,5-b][1,4]oxazin-8-yl), pyrrolidine-1-yl, 2-oxo-pyrimidin-4-yl, 2-oxa-5-azaspiro[3.4]octane-5-yl, oxacyclobutane-3-yl, (2-oxo-1-piperidinyl), 2-oxo-4-piperidinyl, 5-oxo-pyrrolidine-3-yl, 2-oxa-5-azaspiro[3.4] Octane-5-yl, (7,8-dihydro-5H-pyrano[4,3-c]pyridazin-3-yl), [racemic-(4aS,7aR)-4-methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-6-yl], 6,7-dihydro-5H-cyclopentadieno[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-1-yl, 6-azaspiro[3,4]octane-6-yl, and [racemic-(3aS,6aS)-6-oxo-2,3,3a,4,5,6a-hexahydropyrrolo[2,3-c]pyrrolo-1-yl]. Specific examples of “heterocyclic alkyl” are tetrahydrofuran-2-yl, oxetane-3-yl, morpholino-4-yl, piperazin-1-yl; azaheptan-4-yl, pyrrolidin-1-yl, and piperidin-4-yl. In one specific embodiment, the heterocyclic alkyl is “N-heterocyclic alkyl”.

[0028] The term "heteroaryl" alone or in combination refers to an aromatic monocyclic or bicyclic system having 5 to 12 ring atoms, comprising 1, 2, 3, or 4 heteroatoms each independently selected from N, O, and S, with the remaining ring atoms being carbon. The ring system may be linked to the remaining compounds via atoms selected from C, N, S, and O, particularly via N atoms ("N-heteroaryl"). Examples of heteroaryl groups include, but are not limited to, pyrazolyl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyridyl, 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-1-yl, pyrimidinyl, pyrimidin-5-yl, benzotriazolyl, 1H-benzotriazol-4-yl, furanyl, furyl, 2-furanyl, 3-furanyl, [6-oxo-1H [-pyridazin-5-yl], triazolyl, triazol-1-yl, triazol-2-yl, triazol-3-yl, triazol-4-yl, pyridin-2-one, 2-oxo-4-pyridinyl, pyrimidin-2-yl, pyrimidin-5-yl, (1,3,4-oxadiazol-2-yl), (1,3,4-thiadiazol-2-yl), (1,2,4-triazin-3-yl), 2-oxo-pyrimidin-4-yl, (1-methyl-2-oxo-3-pyridinyl), 5-methyl-6-oxo-4H-pyrrolo[3,4-c]pyrazol-2-yl and (2,3-dihydropyridazinolo[4,5-b][1,4]oxazin-8-yl). Specific examples of “heteroaryl” are pyrazol-1-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, with a more specific example being pyridazin-3-yl. In a particular embodiment, the heteroaryl is “N-heteroaryl”.

[0029] The term "aryl" alone or in combination refers to a monocyclic or bicyclic aromatic carbocyclic system containing 6 to 10 carbon ring atoms. Examples of the aryl moiety include phenyl and naphthyl. A specific example of an aryl group is the phenyl group.

[0030] The term “heterocyclic alkyl alkyl”, alone or in combination, refers to a “heterocyclic alkyl” group attached to an “alkyl” group, wherein the alkyl group is further attached to the related compound. Specific examples of “heterocyclic alkyl alkyl” are 2-morpholin-4-ylethyl and 2-morpholin-4-ylmethyl, more specifically 2-morpholin-4-ylethyl.

[0031] The term "alkoxy" or "alkyloxy" alone or in combination represents a group of the formula "alkyl-O-", wherein the term "alkyl" has the meaning previously given, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy. Specific examples of "alkoxy" are methoxy and ethoxy.

[0032] The term "alkoxyalkyl" or "alkyloxyalkyl" refers, alone or in combination, to a group of the following formula in which the term "alkyl" has the previously given meaning: alkyl-O-alkyl, such as, for example, methoxymethyl, methoxyethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, n-butoxymethyl, isobutoxymethyl, sec-butoxymethyl, and tert-butoxymethyl. Specific examples of "alkoxyalkyl" are methoxyethyl and methoxymethyl.

[0033] The term "oxygen group" refers to the -O- group, either alone or in combination.

[0034] The term "halogen" or "halogenated" alone or in combination means fluorine, chlorine, bromine, or iodine, and particularly fluorine or chlorine, and even more particularly fluorine. The term "halogenated" in combination with another group means that the group is substituted with at least one halogen, particularly with one to five halogens, especially one to four halogens, i.e., one, two, three, or four halogens.

[0035] The term "haloalkyl" alone or in combination refers to an alkyl group substituted with at least one halogen, particularly with one to five halogens, particularly with one to three halogens, and more particularly with two to three halogens. Examples of "haloalkyl" include, but are not limited to, fluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl, difluoromethyl, difluoroethyl, trifluoromethyl, and trifluoroethyl. Specific "haloalkyl" groups are difluoromethyl, trifluoromethyl, and trifluoroethyl.

[0036] The term "haloalkoxy" alone or in combination refers to an alkoxy group substituted with at least one halogen, particularly with one to five halogens, especially one to three halogens. Specific "haloalkoxy" groups are fluoromethoxy, fluoroethoxy, and fluoropropoxy.

[0037] The term "hydroxyl" (hydroxyl / hydroxy) refers to the -OH group, either alone or in combination.

[0038] The terms "hydroxyalkyl" and "hydroxyalkyl group" refer, alone or in combination, to a -OH group attached to an alkyl group. Specific "hydroxyalkyl" are hydroxymethyl, hydroxyethyl, and hydroxypropyl, and more particularly 1-hydroxyethyl.

[0039] The term "carbonyl" refers to the -C(O)- group, either alone or in combination.

[0040] The term "amino" alone or in combination represents a primary amino group (-NH2), a secondary amino group (-NH-), or a tertiary amino group (-N-).

[0041] The term "alkylamino" refers to an alkyl group attached to an -NH- group, such as, for example, methylamino, wherein the amino group is further attached to the related compound. The term "dialkylamino" refers to two alkyl groups attached to an -N- atom, such as, for example, dimethylamino, wherein the amino group is further attached to the related compound.

[0042] The term "alkyl carbonyl" refers to an alkyl group attached to a -C(O)- group, wherein the carbonyl group is further attached to the related compound. Specific examples of "alkyl carbonyl" include methyl carbonyl (also known as acetyl) and ethyl carbonyl.

[0043] The term "aminocarbonyl" refers, alone or in combination, to an "amino" group attached to a "carbonyl" group, wherein the carbonyl group is further attached to the related compound.

[0044] The term "dialkylaminocarbonyl" refers, alone or in combination, to a "dialkylamino" group attached to a "carbonyl" group, wherein the carbonyl group is further attached to the related compound.

[0045] The term "sulfonyl" alone or in combination represents the -SO2- group.

[0046] The term "pharmaceutically acceptable salt" means a salt that is not biologically or otherwise undesirable. "Pharmaceutically acceptable salt" includes both acid addition salts and base addition salts. The term "pharmaceutically acceptable acid addition salt" refers to those pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, and phosphoric acid, as well as those pharmaceutically acceptable salts formed with organic acids selected from aliphatic, alicyclic, aromatic, heterocyclic, carboxylic, and sulfonic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, pyric acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. The term "pharmaceutically acceptable base addition salt" refers to those pharmaceutically acceptable salts formed with organic or inorganic bases. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from pharmaceutically acceptable non-toxic organic bases include primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and salts of basic ion exchange resins (such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins).

[0047] The terms “compound of the invention” and “compound of the invention” refer to compounds of formula (I) or (II) and their stereoisomers, tautomers, solvates and salts (e.g., pharmaceutically acceptable salts).

[0048] Tautomers, i.e., structural isomers that tautomerize with compounds of formula (I) or (II), especially in solution, may exist in some cases and should be understood to be included in this invention.

[0049] If the starting material or one of the compounds of formula (I) or (II) contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction steps, a suitable protecting group (such as described, for example, in TW Greene and PGM Wuts, “Protective Groups in Organic Chemistry,” 3rd edition, 1999, Wiley, New York) may be introduced prior to the key steps of a process known in the art. Such protecting groups can be removed using standard methods described in the literature at a later stage of the synthesis. Examples of protecting groups are tert-butoxycarbonyl (Boc), 9-fluorenylmethylcarbamate (Fmoc), 2-trimethylsilylethylcarbamate (Teoc), benzyloxycarbonyl (Cbz), and p-methoxybenzyloxycarbonyl (Moz).

[0050] The compounds of formula (I) or (II) described herein may contain several asymmetric centers and exist in the form of optically pure enantiomers, mixtures of enantiomers (such as, for example, racemates), mixtures of diastereomers, diastereomeric racemates, or mixtures of diastereomeric racemates.

[0051] The term "asymmetric carbon atom" refers to a carbon atom with four different substituents. According to the Cahn-Ingold-Prelog sequence, an asymmetric carbon atom can be either "R" or "S" configuration.

[0052] Furthermore, where applicable, the present invention includes all optical isomers of compounds of formula (I) or (II), namely diastereomers, diastereomer mixtures, racemic mixtures, all their corresponding enantiomers and / or tautomers, and their solvates.

[0053] If necessary, the racemic mixture of the compounds of the present invention can be separated to isolate the individual enantiomers. Separation can be carried out by methods well known in the art, such as coupling the racemic mixture of the compounds to an enantiomerically pure compound to form a diastereomer mixture, and then separating the individual diastereomers by standard methods such as fractional crystallization or chromatography.

[0054] In some embodiments where optically pure enantiomers are provided, an optically pure enantiomer means that the compound contains >90% by weight of the desired isomer, particularly >95% by weight, or more particularly >99% by weight of the desired isomer, said weight percentage based on the total weight of the compound's isomers. Chiral pure compounds or chiral-enriched compounds can be prepared by chiral selective synthesis or by enantiomer separation. Enantiomer separation can be performed on the final product, or alternatively on suitable intermediates.

[0055] The structures described herein are also intended to include compounds that differ only in the presence of one or more isotope-rich atoms. Specific examples of radioactive isotopes are... 2 H, 3 H, 13 C 14 C and 18 F. For example, one or more hydrogen atoms are replaced by deuterium or tritium, or one or more carbon atoms are enriched with... 13 C or 14 Structures with carbon substitution of C are within the scope of this invention.

[0056] Therefore, this invention relates to:

[0057] According to the compound of the present invention, wherein R 1 It is difluoromethyl, hydroxymethyl, 1-hydroxyethyl, 1-hydroxycyclopropyl, cyano, methoxymethyl, R 5 - Carbonyl or heterocyclic alkyl, wherein the heterocyclic alkyl is optionally substituted with a cyano group; the specific heterocyclic alkyl is tetrahydrofuran-2-yl;

[0058] According to the compound of the present invention, wherein R 2 It is an aryl or heteroaryl group selected from pyrazol-1-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 example of aryl and heteroaryl is optionally independently selected from R 6 One or two substituents are substituted;

[0059] According to the compound of the present invention, wherein R 3 It can be methoxy or hydrogen, especially hydrogen;

[0060] According to the compound of the present invention, wherein R 4It is hydrogen, methyl, 2-morpholino-4-ethyl, pyridazin-3-yl, or a heterocyclic alkyl group selected from azircyclic heptane-4-yl, piperazine-1-yl, pyrrolidine-1-yl, 7,8-dihydro-5H-pyrano[4,3-c]pyridazin-3-yl, and piperidin-4-yl; wherein each example of 2-morpholino-4-ethyl, pyridazin-3-yl, and heterocyclic alkyl is optionally independently selected from R 7 One or two substituents are substituted;

[0061] According to the compound of the present invention, wherein R 4 For optional selection by independent selection of R 7 One or two substituents substituted with pyridazine-3-yl;

[0062] According to the compound of the present invention, wherein R 4 It is a pyridazin-3-yl group substituted with an alkyl group (especially a methyl group);

[0063] According to the compound of the present invention, wherein R 5 It can be hydrogen, methyl, or ethyl;

[0064] According to the compound of the present invention, wherein R 6 In each instance, the group is independently selected from methyl, cyano, trifluoroethyl, trifluoromethyl, difluoromethyl, fluorine, chlorine, cyclopropyl, aminocarbonyl, and methoxyethyl.

[0065] According to the compound of the present invention, wherein R 7 In each instance, it is independently selected from methyl, cyclopropyl, difluoromethyl, trifluoroethyl, fluorine, chlorine, dimethylaminocarbonyl, heterocyclic alkyl, and heterocyclic alkylalkyl; wherein R 7 The heterocyclic alkyl group is selected from oxetane-3-yl, morpholin-4-yl, and piperazine-1-yl; wherein R 7 The heterocyclic alkyl group is selected from (azacyclobutane-1-yl)methyl, 2-oxa-6-azaspiro[3.3]heptane-6-ylmethyl, morpholin-4-ylmethyl, morpholin-4-ylethyl, azacyclobutane-1-ylmethyl, and piperazine-1-ylmethyl; and wherein R 7 The heterocyclic alkyl and heterocyclic alkyl groups are optionally substituted by one or two substituents independently selected from alkoxy, halogen, and heterocyclic alkyl groups; and

[0066] According to the compound of the present invention, L is -O-.

[0067] In one embodiment, the compound of the present invention has formula (I).

[0068] (I)

[0069] The substituents are as described in this article.

[0070] In one embodiment, the compound of the present invention has formula (II).

[0071] (II)

[0072] The substituents are as described in this article.

[0073] In one embodiment, the compound of the present invention has formula (I).

[0074] (I)

[0075] in

[0076] L is -O-, -NH-, -S-, or does not exist;

[0077] R 1 It is a haloalkyl, hydroxyalkyl, hydroxycycloalkyl, cyano, alkoxyalkyl, R 5 -Carbonyl or tetrahydrofuran-2-yl; wherein the tetrahydrofuran-2-yl is optionally substituted with a cyano group;

[0078] R 2 It is aryl or heteroaryl; wherein each instance of aryl and heteroaryl is optionally selected from one, two, three or four independently selected from R 6 Substituents of the substituents;

[0079] R 3 It is hydrogen or alkoxy;

[0080] R 4 It is hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkylalkyl, heteroaryl, or heterocycloalkyl; wherein each example of cycloalkyl, aryl, heterocycloalkylalkyl, heteroaryl, and heterocycloalkyl is optionally derived from one or two independently selected from R 7 Substituents of the substituents;

[0081] R 5 It can be hydrogen, alkyl, alkoxy, alkoxyalkyl, or haloalkyl;

[0082] R 6 In each instance, the groups are independently selected from alkyl, cyano, haloalkyl, halogen, cycloalkyl, aminocarbonyl, and alkoxyalkyl; and

[0083] R 7 In each example, the groups are independently selected from alkyl, cyano, cycloalkyl, haloalkyl, halogen, heterocycloalkyl, heterocycloalkylalkyl, dialkylaminocarbonyl, amino, and alkoxy; wherein the heterocycloalkyl and heterocycloalkylalkyl groups are optionally substituted by one or two substituents independently selected from alkoxy, halogen, and heterocycloalkyl.

[0084] Or its pharmaceutically acceptable salt.

[0085] In one embodiment, the compound of formula (II) is the compound of formula (II-a).

[0086] (II-a)

[0087] in

[0088] L is -O-, -NH-, -S-, or does not exist;

[0089] R 1' It can be hydrogen, alkyl, alkoxy, alkoxyalkyl, or haloalkyl;

[0090] R 2 It is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl; wherein each example of cycloalkyl, aryl, heteroaryl, and heterocycloalkyl is optionally derived from one, two, or three independently selected from R 5 Substituents of the substituents;

[0091] R 3 It can be hydrogen, alkoxy, alkyl, haloalkyl, or haloalkoxy;

[0092] R 4 It is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, or heterocycloalkylalkyl; wherein each example of cycloalkyl, aryl, heteroaryl, heterocycloalkyl, and heterocycloalkylalkyl is optionally derived from one or two independently selected from R 6 Substituents of the substituents;

[0093] R 5 It is an alkyl, cyano, haloalkyl, halogen, cycloalkyl, alkoxy, or aminocarbonyl group; and

[0094] R 6 In each instance, the group is independently selected from alkyl, cyano, haloalkyl, halogen, alkoxy, alkoxyheteroalkylalkyl, alkylheteroalkyl, haloalkyl, heteroalkyl, heteroalkylalkyl, haloheteroalkylalkyl, alkoxyheteroalkylalkyl, or amino;

[0095] Or its pharmaceutically acceptable salt.

[0096] In one embodiment, the compound of formula (II) is the compound of formula (II-a).

[0097] (II-a)

[0098] in

[0099] L is -O- or does not exist;

[0100] R 1' It is an alkyl group;

[0101] R 2 To be optionally selected from one or two independent selections from R 5 Substituents of heteroaryl groups;

[0102] R 3 It is hydrogen;

[0103] R 4 It is hydrogen, alkyl, heteroaryl, heterocyclic alkyl, or heterocyclic alkylalkyl; wherein each example of heteroaryl, heterocyclic alkyl, and heterocyclic alkylalkyl is optionally R 6 replace;

[0104] R 5 It is a haloalkyl, halogen, or cycloalkyl; and

[0105] R 6 It is an alkyl or heterocyclic alkyl group;

[0106] Or its pharmaceutically acceptable salt.

[0107] This invention also relates to compounds according to the invention, selected from...

[0108] 1-[3-(1-hydroxyethyl)-6-[6-[4-(oxecyclobutan-3-yl)piperazin-1-yl]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile;

[0109] 1-[3-(1-hydroxyethyl)-6-[6-[racemic-(3R,4R)-3-amino-4-fluoropyrrolidone-1-yl]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile;

[0110] 1-[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile;

[0111] 1-[3-[(1S)-1-hydroxyethyl]-6-[6-[(6-methylpyridazin-3-yl)amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile;

[0112] 1-[3-[(1R)-1-hydroxyethyl]-6-[6-[(6-methylpyridazin-3-yl)amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile;

[0113] 1-[3-(1-hydroxyethyl)-6-[6-[[6-[(3-methoxyazacyclobutane-1-yl)methyl]pyrazin-3-yl]amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile;

[0114] 1-[6-[6-[[6-[(3-fluorozacricyclobutane-1-yl)methyl]pyridazin-3-yl]amino]pyrazolo[1,5-a]pyridin-3-yl]-3-(1-hydroxyethyl)pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile;

[0115] 1-[6-[6-[[6-[(3,3-difluoroazacyclobutane-1-yl)methyl]pyrazin-3-yl]amino]pyrazolo[1,5-a]pyridin-3-yl]-3-(1-hydroxyethyl)pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile;

[0116] 1-[3-[(1S)-1-hydroxyethyl]-6-[6-[[6-(2-oxa-6-azaspiro[3.3]heptane-6-ylmethyl)pyrazin-3-yl]amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile;

[0117] 1-[3-[(1R)-1-hydroxyethyl]-6-[6-[[6-[(3-methoxyazacyclobutane-1-yl)methyl]pyrazin-3-yl]amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile;

[0118] 1-[3-[(1S)-1-hydroxyethyl]-6-[6-[[6-[(3-methoxyazacyclobutane-1-yl)methyl]pyrazin-3-yl]amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile;

[0119] 1-[3-[(1S)-1-hydroxyethyl]-6-[5-methoxy-6-[(6-methylpyridazin-3-yl)amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile;

[0120] 3-[3-(1-hydroxyethyl)-6-[6-(2-morpholin-4-ylethoxy)pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]benzonitrile;

[0121] 1-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile;

[0122] 1-[3-[(1S)-1-hydroxyethyl]-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile;

[0123] 1-[3-[(1R)-1-hydroxyethyl]-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile;

[0124] 3-Fluoro-4-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-1-(2,2,2-trifluoroethyl)pyridin-2-one;

[0125] (1S)-1-[2-[3-(difluoromethyl)-5-methylpyrazol-1-yl]-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-3-yl]ethanol;

[0126] (1R)-1-[2-[3-(difluoromethyl)-5-methylpyrazol-1-yl]-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-3-yl]ethanol;

[0127] 1-[3-(hydroxymethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile;

[0128] 5-(difluoromethyl)-1-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]pyrazol-3-carboxynitrile;

[0129] 5-(difluoromethyl)-1-[3-[(1S)-1-hydroxyethyl]-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]pyrazol-3-carboxynitrile;

[0130] 5-(difluoromethyl)-1-[3-[(1R)-1-hydroxyethyl]-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]pyrazol-3-carboxynitrile;

[0131] 1-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]ethanol;

[0132] 1-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-2-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]ethanol;

[0133] 5-Chloro-2-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]pyrazol-3-carboxylonitrile;

[0134] 5-Cyclopropyl-1-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]pyrazol-3-carboxynitrile;

[0135] 5-Cyclopropyl-2-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]pyrazol-3-carboxynitrile;

[0136] 5-(difluoromethyl)-1-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]pyrazol-3-carboxamide;

[0137] 2-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazol-3-carboxynitrile;

[0138] 1-[6-[6-(6-chloropyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-3-(1-hydroxyethyl)pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile;

[0139] 2-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-3,5-dimethyl-4H-pyrrolo[3,4-c]pyrazol-6-one;

[0140] 1-[2-[3-methyl-1-(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;

[0141] 1-[2-[3-methyl-1-(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;

[0142] 1-[2-[5-methyl-1-(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;

[0143] 1-[6-[6-[6-(difluoromethyl)pyridazin-3-yl]oxypyrazolo[1,5-a]pyridin-3-yl]-3-[(1S)-1-hydroxyethyl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile;

[0144] 1-[6-[6-[6-(4-methylpiperazin-1-yl)pyridazin-3-yl]oxypyrazolo[1,5-a]pyridin-3-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]ethanol;

[0145] 1-[2-[3-(difluoromethyl)-5-methylpyrazol-1-yl]-6-[6-[6-[(3-methoxyazacyclobutane-1-yl)methyl]pyridazin-3-yl]oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-3-yl]ethanol;

[0146] 1-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)thiopyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile;

[0147] 1-[3-(1-hydroxyethyl)-6-pyrazolo[1,5-a]pyridin-3-ylpyridin-2-yl]-5-methylpyrazol-3-carboxynitrile;

[0148] 1-[2-[6-[4-(oxecyclobutane-3-yl)piperazin-1-yl]pyrazolo[1,5-a]pyridin-3-yl]-4-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-1,3-thiazolyl-5-yl]ethanol;

[0149] 1-Cyclopropyl-4-[5-(1-hydroxyethyl)-2-(6-methoxypyrazolo[1,5-a]pyridin-3-yl)-1,3-thiazolyl-4-yl]pyridin-2-one;

[0150] 4-[5-(1-hydroxyethyl)-2-[6-(2-morpholin-4-ylethoxy)pyrazolo[1,5-a]pyridin-3-yl]-1,3-thiazolyl-4-yl]-1-(2,2,2-trifluoroethyl)pyridin-2-one;

[0151] 1-[2-[6-(2-morpholin-4-ylethoxy)pyrazolo[1,5-a]pyridin-3-yl]-4-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-1,3-thiazolyl-5-yl]ethanol;

[0152] 1-[2-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-4-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-1,3-thiazolyl-5-yl]ethanol;

[0153] 3-Fluoro-4-[5-(1-hydroxyethyl)-2-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-1,3-thiazolyl-4-yl]-1-(2,2,2-trifluoroethyl)pyridin-2-one;

[0154] 1-[2-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-4-[2-(2,2,2-trifluoroethyl)triazol-4-yl]-1,3-thiazolyl-5-yl]ethanol;

[0155] 1-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile;

[0156] 1-[3-formyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile;

[0157] 2-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazol-3-carboxynitrile;

[0158] 1-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-cyclopropylpyrazol-3-carboxynitrile;

[0159] 2-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-cyclopropylpyrazol-3-carboxynitrile;

[0160] 1-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-(difluoromethyl)pyrazol-3-carboxynitrile;

[0161] 1-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-2-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]propane-1-one;

[0162] 1-[3-(difluoromethyl)-6-[5-methoxy-6-[(6-methylpyridazin-3-yl)amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile;

[0163] 1-[3-(difluoromethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile;

[0164] 3-[5-(difluoromethyl)-6-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-2-yl]-6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridine;

[0165] 3-[5-(difluoromethyl)-6-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-2-yl]-6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridine;

[0166] 1-[3-(methoxymethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile;

[0167] 5-Methyl-1-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-3-[trans-4-cyanoxacyclopentan-2-yl]pyridin-2-yl]pyrazol-3-carboxylonitrile;

[0168] 5-Methyl-1-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-3-[cis-4-cyanoxacyclopentan-2-yl]pyridin-2-yl]pyrazol-3-carboxynitrile;

[0169] 1-[3-(1-hydroxyethyl)-6-[6-[1-(oxecyclobutan-3-yl)piperidin-4-yl]oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile;

[0170] 3-[3-[6-(3-cyano-5-methylpyrazol-1-yl)-5-(1-hydroxyethyl)pyridin-2-yl]pyrazolo[1,5-a]pyridin-6-yl]oxy-N,N,6-trimethylpyridazine-4-carboxamide;

[0171] 3-[5-(difluoromethyl)-6-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-2-yl]-6-[6-[[4-(oxecyclobutane-3-yl)piperazin-1-yl]methyl]pyridazin-3-yl]oxypyrazolo[1,5-a]pyridine;

[0172] 3-[5-(difluoromethyl)-6-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-2-yl]-6-[6-[[4-(oxecyclobutane-3-yl)piperazin-1-yl]methyl]pyridazin-3-yl]oxypyrazolo[1,5-a]pyridine;

[0173] 4-[[6-[3-[5-(difluoromethyl)-6-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-2-yl]pyrazolo[1,5-a]pyridin-6-yl]oxypyridazin-3-yl]methyl]morpholine;

[0174] 2-[3-(difluoromethyl)-5-methylpyrazol-1-yl]-6-[5-methoxy-6-[(6-methylpyridazin-3-yl)amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-3-carboxynitrile;

[0175] (1S)-1-[2-[3,5-bis(difluoromethyl)pyrazol-1-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;

[0176] 5-Methyl-1-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-3-propionylpyridin-2-yl]pyrazol-3-carboxylonitrile;

[0177] 1-[3-(1-hydroxyethyl)-6-[6-[1-(oxecyclobutan-3-yl)azacycloheptane-4-yl]oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile;

[0178] 1-[3-(difluoromethyl)-6-[6-[[1-(oxecyclobutan-3-yl)piperidin-4-yl]amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile;

[0179] 1-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-2-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]cyclopropane-1-ol;

[0180] (1S)-1-[2-[3-(2-methoxyethyl)-5-methylpyrazol-1-yl]-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-3-yl]ethanol;

[0181] 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-methylpyrazol-3-carboxynitrile; and

[0182] 1-[6-[6-(1-cyclopropylpiperidin-4-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-3-[(1S)-1-hydroxyethyl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile;

[0183] Or its pharmaceutically acceptable salt.

[0184] In particular, the present invention further relates to compounds according to the present invention, which are selected from...

[0185] 1-[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile;

[0186] 1-[3-[(1S)-1-hydroxyethyl]-6-[6-[(6-methylpyridazin-3-yl)amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile;

[0187] 1-[3-[(1S)-1-hydroxyethyl]-6-[5-methoxy-6-[(6-methylpyridazin-3-yl)amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile;

[0188] 1-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile; and

[0189] 1-[3-[(1S)-1-hydroxyethyl]-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile;

[0190] Or its pharmaceutically acceptable salt.

[0191] The present invention also relates to a method for preparing the compound according to the invention, the method comprising at least one of the following steps:

[0192] (a) Make the compound of formula (A1)

[0193] (A1)

[0194] Compound of formula (A2)

[0195] R 4 -LH (A2),

[0196] The reaction takes place in the presence of a suitable catalyst, a suitable solvent, and a suitable base.

[0197] (b) Make compound (B1)

[0198] (B1)

[0199] With a suitable reducing agent,

[0200] The reaction takes place in the presence of a suitable solvent; or

[0201] (c) Make the compound of formula (C1)

[0202] (C1)

[0203] Compounds of formula (C2)

[0204] R 2 -(B(OH)2 (C2)

[0205] The reaction takes place in the presence of a suitable catalyst, a suitable solvent, and a suitable base.

[0206] Among them, L and R 1 R 2 R 3 and R 4 As defined in this article;

[0207] In step (a) of the above method, the catalyst may be a suitable Pd catalyst, such as, for example, chloro(crotonyl)[1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene]palladium(II);

[0208] In step (a) of the above method, the solvent may be an aprotic and nonpolar organic solvent, such as, for example, 1,4-dioxane;

[0209] In step (a) of the above method, the base may be a suitable inorganic base, such as, for example, Cs2CO3;

[0210] In step (b) of the above method, the reducing agent may be, for example, NaBH4;

[0211] In step (b) of the above method, the solvent may be a suitable organic solvent, such as, for example, MeOH, THF or a mixture thereof;

[0212] In step (c) of the above method, the catalyst may be a suitable Pd catalyst, such as, for example, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) chloride;

[0213] In step (c) of the above method, the solvent may be, for example, DMF, THF, 1,4-dioxane, water, or a mixture thereof; preferably, the solvent is a mixture of DMF and water;

[0214] In step (c) of the above method, the base may be a suitable inorganic base, such as, for example, K2CO3, Na2CO3 or Cs2CO3;

[0215] The present invention also relates to compounds according to the present invention manufactured according to the methods described herein.

[0216] The present invention further relates to:

[0217] A compound according to the present invention, which is used as a therapeutically active substance;

[0218] A pharmaceutical composition comprising a compound according to the invention and a therapeutically inert carrier;

[0219] The use of a compound according to the present invention for the treatment or prevention of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes, or glomerulonephritis.

[0220] The use of a compound according to the present invention for preparing a medicament for treating or preventing rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes, or glomerulonephritis.

[0221] The compounds according to the present invention are useful for treating or preventing rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes, or glomerulonephritis; and

[0222] A method for treating or preventing rheumatoid arthritis, juvenile rheumatoid arthritis, nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes, or glomerulonephritis, comprising administering an effective amount of the compound according to the invention to a patient in need.

[0223] A method for treating rheumatoid arthritis, juvenile rheumatoid arthritis, nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes, or glomerulonephritis, comprising administering an effective amount of the compound according to the invention to a patient in need.

[0224] General synthesis scheme

[0225] The synthesis of compounds of formula (I) or (II) can be carried out, for example, according to the non-exhaustive procedure described in the following general schemes 1 to 4. In some cases, the order of the reaction steps can be changed, and the steps of different schemes can be combined in different ways as disclosed herein and in accordance with common general knowledge. Generally, the reaction conditions and reaction schedules provided below can be further modified in some cases according to the procedure described herein and in accordance with common general knowledge.

[0226] Option 1

[0227] In Scheme 1, the synthesis of compounds of formula (Ia), (I-a'), (SI-a'), or (RI-a') is described. Compounds of formula (Ia), (I-a'), (SI-a'), or (RI-a') are compounds of formula (I), wherein R... 2 It is a heteroaryl group; L, R 3 and R 4 As described in this article. In compounds of formula (Ia), R 1 As described herein. In compounds of formula (I-a'), (SI-a'), or (RI-a'), R 1 It is hydroxyethyl.

[0228]

[0229] Step A: 1-(6-chloro-2-fluoropyridin-3-yl)acetone 1 can react with heteroaryl 2 in the presence of a base (such as, for example, DIPEA) in a solvent (such as, for example, DMSO) under heating (e.g., 80°C) to produce intermediate 3.

[0230] Step B: Intermediate 5 can be obtained from intermediate 6-bromopyrazolo[1,5-a]pyridine 3 by the following sequence: (1) iodination in a suitable solvent (such as acetonitrile) with a suitable reagent (such as NIS) at a suitable temperature (such as room temperature), and (2) metallization in a suitable solvent (such as THF) with a suitable reagent (such as isopropylmagnesium chloride) in the presence of a suitable agent (such as isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxane).

[0231] 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 example, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) chloride) and a suitable base (such as, for example, K2CO3) in a suitable solvent (such as, for example, DMF (DME)) under heating (e.g., 45°C to 120°C).

[0232] Step D: The compound of formula (Ia) can be obtained by intermediate 6 via a cross-coupling reaction with a suitable 7 and a suitable catalyst (such as, for example, chloro(crotonyl)[1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene]palladium(II)) and a suitable base (such as, for example, Cs2CO3) in a suitable solvent (such as, for example, 1,4-dioxane) under heating (e.g., 85°C).

[0233] Step E: If R 1 If the group is acetyl, then the compound of formula (I-a') can be obtained by reducing the compound of formula (Ia) in a solvent (such as MeOH) with a suitable reagent (such as, for example, NaBH4).

[0234] Step F: Compounds of formula (SI-a') and (RI-a') can be obtained by chiral separation of racemic compounds of formula (Ia) using appropriate separation techniques (such as, for example, chiral SFC).

[0235] Option 2

[0236] In Scheme 2, an alternative synthesis of compound (Ia) is described. Compound (Ia) is the same as compound (I), wherein R...2 It is a heteroaryl group; L, R 1 R 3 and R 4 As described in this article.

[0237]

[0238]

[0239] Step A: Intermediate 3 can be obtained by the following sequence: (1) reacting starting material 1 with heteroaryl 2 in the presence of a base (such as DIPEA) in a solvent (such as DMSO) under heating (e.g., 50°C), and (2) borylating with a suitable agent (such as bis(pinacol)diboron) and a suitable catalyst (such as bis(triphenylphosphine)palladium(II) chloride and dry potassium acetate) in a suitable solvent (such as 1,4-dioxane) under heating (e.g., 100°C) to obtain intermediate 3.

[0240] Step B: Intermediate 5 can be obtained from starting material 4 by iodination with a suitable agent (such as NIS) in a suitable solvent (such as acetonitrile) at a suitable temperature (e.g., room temperature).

[0241] 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 example, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride) and a suitable base (such as, for example, Cs2CO3) in a suitable solvent (such as, for example, a mixture of THF and water) under heating (e.g., 65°C).

[0242] Step D: The compound of formula (Ia) can be obtained by intermediate 6 via a cross-coupling reaction with a suitable 7 and a suitable catalyst (such as, for example, chloro(crotonyl)[1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene]palladium(II)) and a suitable base (such as, for example, Cs2CO3) in a suitable solvent (such as, for example, 1,4-dioxane) under heating (e.g., 85°C).

[0243] Option 3

[0244] Scheme 3 describes the alternative synthesis of compound (Ia). In the following schemes, compound (Ia) is the same as compound (I).

[0245]

[0246] Step A: Intermediate 3 can be obtained by reacting 1 with a suitable electrophile 2 (X is a leaving group, such as, for example, a halide) in the presence of a base (such as, for example, Cs2CO3) in a solvent (such as, for example, DMF) under heating (e.g., 120°C).

[0247] Step B: Intermediate 4 can be obtained by the following sequence: (1) bromination of 3 with a suitable agent (such as NBS or bromine) in a solvent (such as, for example, acetic acid or acetonitrile), (2) boronization in a suitable solvent (such as, for example, B2pin2 (bis(pinacol)diboron)) and a suitable catalyst (such as, for example, bis(triphenylphosphine)palladium(II) chloride and dry potassium acetate) on heating (e.g., 100°C).

[0248] 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 example, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) chloride) and a suitable base (such as, for example, Cs2CO3) in a suitable solvent (such as, for example, a mixture of DMF and water) under heating (e.g., 100°C).

[0249] Step D: The compound of formula (Ia) can be obtained by a cross-coupling reaction (Suzuki-Miyaura) of intermediate 6 and suitable boric acid 7 with a suitable catalyst (such as, for example, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) chloride) and a suitable base (such as, for example, K2CO3) in a suitable solvent (such as, for example, a mixture of DMF and water) under heating (e.g., 90°C).

[0250] Option 4

[0251] In Scheme 4, the synthesis of compounds of formula (II-a) or (II-a') is carried out. Compounds of formula (II-a) or (II-a') are compounds of formula (II), wherein R... 1 Hydroxyethyl; L, R 2 R 3 and R 4 As described in this article.

[0252]

[0253] Step A: Intermediate 2 can be obtained from 2-amino-4-chloro-thiazol-5-carboxaldehyde 1 by the following sequence: (1) protection with a suitable agent (such as di-tert-butyl dicarbonate) in a solvent (such as, for example, 1,4-dioxane) and a base (such as 4-dimethylaminopyridine), (2) addition of an agent (such as, for example, magnesium methyl bromide) in a solvent (such as THF), and (3) oxidation with an agent (such as, for example, manganese dioxide) in a suitable solvent (such as, for example, dichloromethane).

[0254] Step B: Intermediate 4 can be obtained from intermediates 2 and 3 via a cross-coupling reaction (Suzuki-Miyaura) with a suitable catalyst (such as, for example, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride) and a suitable base (such as, for example, Na₂CO₃) in a suitable solvent (such as, for example, a mixture of DMF and water) under heating (e.g., 100°C). Deprotection may occur in the same step, or may have to be carried out alone with an agent (such as, for example, trifluoroacetic acid).

[0255] Step C: Intermediate 5 can be obtained from 4 by reacting it with a suitable reagent (such as, for example, isoamyl nitrite and cuprous chloride (II)) in a solvent (such as acetonitrile) under heating (e.g., 65°C).

[0256] Step D: Compound of formula (II-a) can be obtained from intermediates 5 and 6 by a cross-coupling reaction (Suzuki-Miyaura) with a suitable catalyst (such as, for example, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) chloride) and a suitable base (such as, for example, Na2CO3) in a suitable solvent (such as, for example, a mixture of DMF and water) under heating (e.g., 100°C).

[0257] Step E: Compound of formula (II-a') can be obtained by reducing compound (II-a) in a solvent (such as MeOH) with a suitable reagent (such as, for example, NaBH4).

[0258] This invention also specifically relates to:

[0259] Compounds of formula (I) or (II) as described herein, or pharmaceutically acceptable salts thereof, are used as therapeutically active substances;

[0260] 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;

[0261] The use of a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes mellitus, or glomerulonephritis, particularly inflammatory bowel disease (IBD);

[0262] 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 prevention of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes mellitus, or glomerulonephritis, particularly inflammatory bowel disease (IBD);

[0263] A compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of rheumatoid arthritis, juvenile rheumatoid arthritis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes mellitus, or glomerulonephritis, particularly inflammatory bowel disease (IBD); and

[0264] A method for treating or preventing rheumatoid arthritis, juvenile rheumatoid arthritis, nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell vasculitis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes, or glomerulonephritis, comprising administering to a patient in need an effective amount of a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof.

[0265] Pharmaceutical Composition

[0266] Another embodiment of the invention provides a pharmaceutical composition or medicament comprising the compound of the invention and a therapeutically inert carrier, diluent, or excipient, and a method for preparing such compositions and medicaments using the compound of the invention. In one example, the compound of formula (I) or (II) can be formulated into a crude drug form by mixing it with a physiologically acceptable carrier (i.e., a carrier that is non-toxic to the recipient at the dose and concentration used) at a suitable pH at ambient temperature and with the desired purity. The pH of the formulation depends primarily on the specific use and concentration of the compound, but is preferably in the range of about 3 to about 8. In one example, the compound of formula (I) 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 can be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0267] The composition shall be prepared, measured, and administered in accordance with good medical practice. Factors to be considered in this context include the specific disease being treated, the specific mammal being treated, the individual patient's clinical condition, the cause of the disease, the site of delivery, the method of administration, the timing of administration, and other factors known to the practicing physician.

[0268] The compounds of the present invention may be administered by any suitable manner, including oral, topical (including sublingual and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, epidural, and intranasal administration, and intralesional administration if local treatment is required. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0269] The compounds of this invention can be administered in any convenient form, such as tablets, powders, capsules, solutions, dispersants, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional to pharmaceutical formulations, such as diluents, carriers, pH adjusters, sweeteners, fillers, and other active agents.

[0270] Conventional formulations are prepared by mixing the compounds of the present invention with a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel, Howard C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams and Wilkins, 2004; Gennaro, Alfonso R. et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams and Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulation may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, flow aids, processing aids, colorants, sweeteners, flavorings, diluents, and other known additives to provide an aesthetically pleasing presentation of the drug (i.e., the compound of the present invention or a pharmaceutical composition thereof) or to facilitate the preparation of the pharmaceutical product (i.e., the drug).

[0271] The invention will now be illustrated by the following examples, which are not intended to be limiting.

[0272] Example

[0273] abbreviation:

[0274]

[0275] Example 1

[0276] 1-[3-(1-hydroxyethyl)-6-[6-[4-(oxecyclobutane-3-yl)piperazin-1-yl]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0277]

[0278] Step 1: 1-(3-acetyl-6-chloropyridin-2-yl)-5-methylpyrazole-3-carboxynitrile

[0279]

[0280] Under argon atmosphere, 1-(6-chloro-2-fluoropyridin-3-yl)acetone (10 g, 57.6 mmol, Eq: 1; CAS [1260663-13-5]) was dissolved in dry DMSO (70 mL) at room temperature, and 5-methyl-1H-pyrazole-3-carboxynitrile (5.9 g, 54.7 mmol; CAS [38693-82-2]) and DIPEA were added. (28.6 mL, 172.8 mmol). The mixture was stirred at 80 °C for 4 hours. Water was added and the resulting solution was extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by rapid chromatography on silica gel by elution with 0% to 35% EtOAc in petroleum ether to give the title compound as a pale 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] +

[0281] Step 2: 6-Bromo-3-iodopyrazolo[1,5-a]pyridine

[0282]

[0283] Under argon atmosphere, 6-bromopyrazolo[1,5-a]pyridine (3.5 g, 17.8 mmol, Eq: 1; CAS [1264193-11-4]) was dissolved in acetonitrile (35 mL) at room temperature, and N-iodosuccinimide (4.4 g, 19.5 mmol, 1.1 eq; CAS [516-12-1]) was added in portions and stirred at room temperature for 1 h. Water was added, and the resulting solution was extracted with TBME. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by rapid chromatography on silica gel by elution with 0% to 20% EtOAc in heptane to give the title compound (7.7 g, 99% yield) as a grayish-white solid. MS (ESP) m / z = 322.8 [M+H] +

[0284] Step 3: 6-Bromo-3-(4,4,5,5-Tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridine

[0285]

[0286] Under argon atmosphere, 6-bromo-3-iodopyrazolo[1,5-a]pyridine (2.0 g, 6.19 mmol, Eq 1) was dissolved in dry THF (40 mL). Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxane (1.9 mL, 9.3 mmol; CAS [61676-62-8]) was added at 0 °C, followed by dropwise addition of 1.3 M isopropyl magnesium chloride in THF (4.76 mL, 6.19 mmol), and the mixture was stirred at 0 °C for 1 hour. Additional isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxane (1.9 mL, 9.3 mmol) and 1.3 M isopropyl magnesium chloride in THF (4.76 mL, 6.19 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The mixture was poured over water, and the resulting solution was extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by rapid chromatography on silica gel by elution with 0% to 20% EtOAc in heptane to give the title compound (1.66 g, 75% yield) as a colorless oil. MS (ESP) m / z = 323.0 [M+H] +

[0287] Step 4: 1-[3-acetyl-6-(6-bromopyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0288]

[0289] Under argon atmosphere, 6-bromo-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridine (110 mg, 0.307 mmol, 1 Eq.) was dissolved in DMF (2 mL) and water (1 mL). 1-(3-acetyl-6-chloropyridin-2-yl)-5-methylpyrazol-3-carboxynitrile (96 mg, 0.368 mmol) and K2CO3 (127.1 mg, 0.92 mmol) were added. Argon was bubbled through the mixture for 5 minutes, then 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloromethane complex (25 mg, 31 mmol; CAS [95464-05-4]) was added, and the mixture was stirred at 45 °C for 16 hours. The mixture was poured onto water and the resulting solution was extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by rapid chromatography on silica gel by elution with 0% to 40% EtOAc in heptane to give the title compound (81.8 mg, 63% yield) as a colorless oil. MS (ESP) m / z = 421.1 [M+H] +

[0290] Step 5: 1-[3-acetyl-6-[6-[4-(oxecyclobutane-3-yl)piperazin-1-yl]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0291]

[0292] Under argon atmosphere, 1-(3-oxacyclobutane)-piperazine (10.1 mg, 0.071 mmol; CAS [1254115-23-5]) was added to 1-[3-acetyl-6-(6-bromopyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile (20 mg, 0.047 mmol, Eq.1) in 1,4-dioxane (2 mL), followed by the addition of Cs₂CO₃ (30.9 mg, 0.095 mmol) and water (8.5 μL, 0.470 mmol). Argon was bubbled through the mixture for 5 minutes. Chloro(crotonyl)[1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene]palladium(II) (3.45 mg, 0.004 mmol; CAS [1252598-33-6]) was added and the mixture was stirred at 85 °C for 16 h. The crude mixture was purified by silica gel elution with 0% to 100% EtOAc in heptane to give the title compound (8.3 mg, 35% yield) as a light brown solid. MS (ESP) m / z = 483.2 [M+H]+

[0293] Step 6: 1-[3-(1-hydroxyethyl)-6-[6-[4-(oxecyclobutane-3-yl)piperazin-1-yl]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0294]

[0295] Under argon atmosphere, 1-[3-acetyl-6-[6-[4-(oxecyclobutan-3-yl)piperazin-1-yl]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile (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 in portions, and the mixture was stirred at room temperature for 30 min. Water was added, and the resulting solution was extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by rapid chromatography on silica gel by elution with 0% to 12% MeOH in DCM to give the title compound (7.5 mg, 30.2% yield) as a pale yellow lyophilized powder. MS (ESP) m / z = 485.2[M+H]+

[0296] Example 2

[0297] 1-[3-(1-hydroxyethyl)-6-[6-[racemic-(3R,4R)-3-amino-4-fluoropyrrolidine-1-yl]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0298]

[0299] Step 1: N-[(3S,4S)-1-[3-[5-acetyl-6-(3-cyano-5-methylpyrazol-1-yl)pyridin-2-yl]pyrazolo[1,5-a]pyridin-6-yl]-4-fluoropyrrolidine-3-yl]tert-butyl carbamate

[0300]

[0301] Under argon atmosphere, (3S,4S)-(4-fluoro-pyrrolidine-3-yl)pyridin-2-yl]-5-methylpyrazole-3-carboxylonitrile (100 mg, 0.237 mmol, Eq.1) (preparation see Example 1, step 4) was added to 1,4-dioxane (6 mL) containing 1-[3-acetyl-6-(6-bromopyrazole-3-yl)pyridin-3-yl)-carbamate tert-butyl hydrochloride (85.7 mg, 0.356 mmol; CAS[2097061-01-1]), followed by the addition of Cs₂CO₃ (232 mg, 0.712 mmol) and water (42.8 μL, 2.37 mmol). Argon was bubbled through the mixture for 5 minutes. Chloro(crotonyl)[1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene]palladium(II) (21.55 mg, 0.024 mmol; CAS [1252598-33-6]) was added and the mixture was stirred at 110 °C for 16 hours. The crude product was coated onto silica gel and purified by rapid chromatography with elution of 0% to 80% EtOAc in heptane to give the title compound (77 mg, approximately 50% purity) as a yellow oil. This material was used as is for the next step. MS (ESP) m / z = 545.3 [M+H] +

[0302] Step 2: N-[racemic-(3R,4R)-1-[3-[6-(3-cyano-5-methylpyrazol-1-yl)-5-(1-hydroxyethyl)pyridin-2-yl]pyrazolo[1,5-a]pyridin-6-yl]-4-fluoropyrrolidine-3-yl]tert-butyl carbamate

[0303]

[0304] Under argon atmosphere, N-[(3S,4S)-1-[3-[5-acetyl-6-(3-cyano-5-methylpyrazol-1-yl)pyridin-2-yl]pyrazolo[1,5-a]pyridin-6-yl]-4-fluoropyrrolidine-3-yl]tert-butyl carbamate (77 mg, approximately 50% purity, 0.071 mmol, Eq. 1) was suspended in methanol (18 mL) and sodium borohydride (18.7 mg, 0.495 mmol; CAS [16940-66-2]) was added, and the mixture was stirred at room temperature for 30 minutes. Water was added, and the resulting solution was extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by rapid chromatography on silica gel by elution with 0% to 5% MeOH in DCM to give the title compound (14 mg, yield 34.4%) as a light brown solid. MS (ESP) m / z = 547.1 [M+H]+

[0305] Step 3: 1-[3-(1-hydroxyethyl)-6-[6-[racemic-(3R,4R)-3-amino-4-fluoropyrrolidone-1-yl]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0306]

[0307] Under argon atmosphere, N-[racemic-(3R,4R)-1-[3-[6-(3-cyano-5-methylpyrazol-1-yl)-5-(1-hydroxyethyl)pyridin-2-yl]pyrazolo[1,5-a]pyridin-6-yl]-4-fluoropyrrolidine-3-yl]tert-butyl carbamate (14 mg, 0.024 mmol, Eq. 1) was stirred in 4 M 1,4-dioxane (1 mL) at room temperature for one hour. The reaction mixture was evaporated and purified by preparative HPLC to give the title compound (2.8 mg, 23% yield) as a pale yellow solid. MS (ESP) m / z = 447.1 [M+H] +

[0308] Example 3

[0309] 1-[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0310]

[0311] Similar to Example 1, this example was prepared by replacing 1-(3-oxetanebutyl)-piperazine with 3-amino-6-methylpyridazine in step 5 and replacing chloro(crotonyl)[1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene]palladium(II) with [tBuBrettPhos Pd(allyl)]OTf (CAS [1798782-17-8]) to obtain the title compound as a pale yellow solid. MS (ESP) m / z = 452.3 [M+H] +

[0312] Example 4

[0313] 1-[3-[(1S)-1-hydroxyethyl]-6-[6-[(6-methylpyridazin-3-yl)amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0314]

[0315] N-[racemic-(3R,4R)-1-[3-[6-(3-cyano-5-methylpyrazol-1-yl)-5-(1-hydroxyethyl)pyridin-2-yl]pyrazolo[1,5-a]pyridin-6-yl]-4-fluoropyrrolidine-3-yl]tert-butyl carbamate (37 mg, 0.08 mmol) (see Example 3) (first eluting isomer) was separated by chiral SFC to give the title compound as a grayish-white solid (16 mg, 43% yield). MS (ESP) m / z = 452.2 [M+H] + The absolute configuration is based on the corresponding Mosher ester (see J. Org. Chem. 1969, 34, 9, 2543–2549).

[0316] Example 5

[0317] 1-[3-[(1R)-1-hydroxyethyl]-6-[6-[(6-methylpyridazin-3-yl)amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0318]

[0319] Similar to Example 4, this example (second eluting isomer) was isolated to give the title compound as a grayish-white solid (14 mg, 37% yield). MS (ESP) m / z = 452.2 [M+H] +

[0320] Example 6

[0321] 1-[3-(1-hydroxyethyl)-6-[6-[[6-[(3-methoxyazacyclobutane-1-yl)methyl]pyrazin-3-yl]amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0322]

[0323] Step 1: 3-Chloro-6-[(3-methoxyazacyclobutane-1-yl)methyl]pyridazine

[0324]

[0325] Under argon atmosphere, DIPEA (8.48 mL, 48.55 mmol) was added to a suspension of 3-methoxyazacyclobutane hydrochloride (2.9 g, 17.8 mmol, Eq. 1; CAS [148644-09-1]) in THF (20 mL), and the mixture was stirred at room temperature for 1 h. 3-Chloro-6-(chloromethyl)pyridazine (2 g, 16.18 mmol; CAS [120276-59-7]) was added, and the mixture was stirred at room temperature for 5 days. The crude product was purified by silica gel elution with 0% to 4% MeOH in DCM to give the title compound (2.4 g, 65% yield) as a brown oil. MS (ESP) m / z = 214.1 [M+H] +

[0326] Step 2: N-[(2,4-dimethoxyphenyl)methyl]-6-[(3-methoxyazacyclobutane-1-yl)methyl]pyridazine-3-amine

[0327]

[0328] A mixture of 3-chloro-6-[(3-methoxyazacyclobutane-1-yl)methyl]pyridazine (540 mg, 2.4 mmol, Eq. 1) and 2,4-dimethoxybenzylamine (4.01 g, 3.61 mL, 24.0 mmol, Eq. 10; CAS [20781-20-8]) was irradiated in a microwave synthesizer at 140 °C for 45 min. Water was added, and the resulting solution was extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by rapid chromatography on silica gel by elution with 0% to 7% MeOH in DCM to give the title compound (149 mg, 18% yield) as a light brown oil. MS (ESP) m / z = 345.2 [M+H]+

[0329] Step 3: 6-[(3-methoxyazacyclobutane-1-yl)methyl]pyridazine-3-amine

[0330]

[0331] Under argon atmosphere, N-[(2,4-dimethoxyphenyl)methyl]-6-[(3-methoxyazacyclobutane-1-yl)methyl]pyridazine-3-amine (137 mg, 0.39 mmol) was dissolved in TFA (3.0 mL) and stirred at 70 °C for 1 hour. Water was added and the resulting solution was washed with DCM. The aqueous layer was lyophilized. 5N NaOH and NaCl were added, and the mixture was diluted with THF and EtOAc (1:1). The organic layer was dried over Na2SO4 and concentrated under vacuum. The mixture was ground with DCM to produce a suspension. After filtering off the solid, the filtrate was evaporated to give the title compound (36 mg, 43% yield) as a brown oil. MS (ESP) m / z = 195.1 [M+H] +

[0332] Step 4: 1-[3-acetyl-6-[6-[[6-[(3-methoxyazacyclobutane-1-yl)methyl]pyrazin-3-yl]amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0333]

[0334] Under argon atmosphere, in a sealed tube, 6-[(3-methoxyazine-6-(6-bromopyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl]-5-methylpyrazol-3-carboxylonitrile (50 mg, 0.113 mmol, Eq. 1) (preparation see Example 1, step 4) was added to 1,4-dioxane (1.5 mL), followed by the addition of 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 at 80 °C for 2 hours. The crude product was subjected to rapid chromatography, eluting on silica gel with 0% to 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] +

[0335] Step 5: 1-[3-(1-hydroxyethyl)-6-[6-[[6-[(3-methoxyazacyclobutane-1-yl)methyl]pyrazin-3-yl]amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0336]

[0337] Under argon atmosphere, 1-[3-acetyl-6-[6-[[6-[(3-methoxyazacyclobutane-1-yl)methyl]pyrazin-3-yl]amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile (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. The mixture was stirred at 0 °C for 90 min. Water was added and the resulting solution was extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was separated by preparative HPLC to give the title compound (2.5 mg, 8% yield) as a white solid. MS (ESP) m / z = 537.2 [M+H]+

[0338] Example 7

[0339] 1-[6-[6-[[6-[(3-fluorozacricyclobutane-1-yl)methyl]pyridazin-3-yl]amino]pyrazolo[1,5-a]pyridin-3-yl]-3-(1-hydroxyethyl)pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0340]

[0341] Step 1: 3-Chloro-6-[(3-Fluorozyne-1-yl)methyl]pyridazine

[0342]

[0343] Under argon atmosphere, Cs₂CO₃ (2 g, 6.13 mmol) and 3-chloro-6-(chloromethyl)pyridazine (400 mg, 2.45 mmol; CAS [120276-59-7]) were added to a solution of 3-fluorozacyclobutane hydrochloride (273.7 mg, 2.45 mmol, Eq. 1; CAS [1375472-05-1]) in DMF (8 mL). The mixture was stirred at room temperature for 5.5 h. Water was added, and the resulting solution was extracted with DCM. The organic layer was extracted with 2N HCl. The aqueous layer was alkalized with 32% NaOH and extracted with DCM. The organic layer was dried over Na₂SO₄ and concentrated under vacuum. The residue was purified by rapid chromatography on silica gel by elution with 0% to 3% MeOH in DCM to give the title compound (186 mg, 35% yield) as a pale yellow oil. MS (ESP) m / z = 202.0 [M+H] +

[0344] Step 2: N-[6-[(3-fluorozacricyclobutane-1-yl)methyl]pyridazin-3-yl]-1,1-diphenylmethylene

[0345]

[0346] Under argon atmosphere, benzophenone imine (83 μL, 0.495 mmol; CAS [1013-88-3]), Cs₂CO₃ (322.4 mg, 0.989 mmol), and BINAP (41.1 mg, 0.066 mmol) were added to a solution of 3-chloro-6-[(3-fluorozacyclobutan-1-yl)methyl]pyridazine (70 mg, 0.33 mmol, Eq. 1) in toluene (5 mL). Argon was bubbled through the solution for 5 min. Tris(dibenzylacetone)dipalladium(O) (30.2 mg, 0.033 mmol; CAS [51364-51-3]) was added. The mixture was stirred at 100 °C for 16 h. Water was added, and the resulting solution was extracted with EtOAc. The organic layer was dried over Na₂SO₄ and concentrated under vacuum. The residue was purified by rapid chromatography on silica gel by elution with 0% to 5% MeOH in DCM to give the title compound (20 mg, 17% yield) as a yellow oil. MS (ESP) m / z = 347.2 [M+H] +

[0347] Step 3: 6-[(3-fluorozacricyclobutan-1-yl)methyl]pyridazine-3-amine

[0348]

[0349] Under argon atmosphere, 4 M HCl (0.047 mL, 0.19 mmol) was added to a solution of N-[6-[(3-fluorozacyclobutan-1-yl)methyl]pyridazin-3-yl]-1,1-diphenylmethyleneimine (90 mg, 0.23 mmol) in THF (6 mL). The mixture was stirred at room temperature for 1 hour. Water was added, and the resulting solution was extracted with EtOAc. The aqueous layer was alkalized to pH 10 with 3NNaOH, saturated with solid NaCl, and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under vacuum to give the title compound (22 mg, 71% yield) as a pale yellow solid. MS (ESP) m / z = 183.1 [M+H] +

[0350] Step 4: 1-[3-acetyl-6-[6-[[6-[(3-fluorozacricyclobutan-1-yl)methyl]pyridazin-3-yl]amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0351]

[0352] Under argon atmosphere, in a sealed tube, 6-[(3-fluorozacriane-1-yl)methyl]pyridazin-3-amine (22 mg, 0.12 mmol) was added to 1-[3-acetyl-6-(6-bromopyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl]-5-methylpyrazol-3-carboxylonitrile (55 mg, 0.13 mmol, Eq. 1) (preparation see Example 1, step 4) in 1,4-dioxane (1.6 mL), followed by the addition of 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 at 80 °C for 2 hours. The mixture was subjected to rapid chromatography, eluting on silica gel with 0% to 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] +

[0353] Step 5: 1-[6-[6-[[6-[(3-fluorozacriane-1-yl)methyl]pyrazin-3-yl]amino]pyrazolo[1,5-a]pyridin-3-yl]-3-(1-hydroxyethyl)pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0354]

[0355] Under argon atmosphere, 1-[3-acetyl-6-[6-[[6-[(3-fluorozacyclobutane-1-yl)methyl]pyrazin-3-yl]amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile (26 mg, 0.049 mmol, Eq. 1) was dissolved in isopropanol (2 mL) and THF (2 mL). Sodium borohydride (3.7 mg, 0.097 mmol; CAS [16940-66-2]) was added at 0 °C and the mixture was stirred at 0 °C for 5 min. Water was added and the resulting solution was extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 0% to 10% MeOH in DCM to give the title compound (13 mg, 53% yield) as a pale yellow solid. MS (ESP) m / z = 525.3 [M+H] +

[0356] Example 8

[0357] 1-[6-[6-[[6-[(3,3-difluoroazacyclobutane-1-yl)methyl]pyrazin-3-yl]amino]pyrazolo[1,5-a]pyridin-3-yl]-3-(1-hydroxyethyl)pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0358]

[0359] Step 1: 3-Chloro-6-[(3,3-difluoroazacyclobutane-1-yl)methyl]pyridazine

[0360]

[0361] Under argon atmosphere, DIPEA (2.1 mL, 11.9 mmol) and 3-chloro-6-(chloromethyl)pyridazine (400 mg, 2.45 mmol; CAS [288315-03-7]) were added to a solution of 3,3-difluorozazide hydrochloride (318 mg, 2.45 mmol; CAS [120276-59-7]) in DMF (2 mL) and THF (8 mL), and the mixture was stirred at room temperature for 16 hours. Water was added, and the resulting solution was extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 0% to 10% MeOH in DCM to give the title compound (356 mg, 63% yield) as a light brown solid. MS (ESP) m / z = 220.1 [M+H] +

[0362] Step 2: N-[6-[(3,3-difluoroazacyclobutane-1-yl)methyl]pyridazin-3-yl]-1,1-diphenylmethylene

[0363]

[0364] Under argon atmosphere, 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]) were added to a solution of 3-chloro-6-[(3,3-difluoroazacyclobutane-1-yl)methyl]pyridazine (356 mg, 1.5 mmol, Eq. 1) in toluene (10 mL). Argon was bubbled through the solution for 5 min. Tris(dibenzylacetone)dipalladium(0) (141 mg, 0.154 mmol; CAS [51364-51-3]) was added. The mixture was stirred at 100 °C for 16 h. Water was added, and the resulting solution was extracted with DCM. The organic layer was dried over Na₂SO₄ and concentrated under vacuum. The residue was purified by rapid chromatography on silica gel by elution with 0% to 2% MeOH to give the title compound (222 mg, 36% yield) as a brown oil. MS (ESP) m / z = 365.1 [M+H] +

[0365] Step 3: 6-[(3,3-difluoroazacyclobutane-1-yl)methyl]pyridazine-3-amine

[0366]

[0367] Under argon atmosphere, 4M HCl (0.15 mL, 0.61 mmol) was added to a solution of N-[6-[(3,3-difluoroazacyclobutan-1-yl)methyl]pyridazin-3-yl]-1,1-diphenylmethyleneimine (222 mg, 0.56 mmol) in THF (8 mL). The mixture was stirred at room temperature for 1 hour. Water was added, and the resulting solution was extracted with EtOAc. The aqueous layer was alkalized to pH 10 with 3NNaOH, saturated with solid NaCl, and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under vacuum to give the title compound (80 mg, 70% yield) as a pale yellow solid. MS (ESP) m / z = 201.1 [M+H] +

[0368] Step 4: 1-[3-acetyl-6-[6-[[6-[(3,3-difluoroazacyclobutane-1-yl)methyl]pyrazin-3-yl]amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0369]

[0370] Under argon atmosphere, in a sealed tube, 6-[(3,3-difluorozacriane-1-yl)methyl]pyridazin-3-amine (79.6 mg, 0.386 mmol) was added to 1-[3-acetyl-6-(6-bromopyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile (91 mg, 0.22 mmol, Eq. 1) (preparation see Example 1, step 4) in 1,4-dioxane (1.6 mL), followed by the addition of Cs₂CO₃ (211.1 mg, 0.648 mmol). 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 at 80 °C for 2 hours. The mixture was subjected to rapid chromatography, eluting on silica gel with 0% to 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] +

[0371] Step 5: 1-[6-[6-[[6-[(3,3-difluoroazacyclobutane-1-yl)methyl]pyrazin-3-yl]amino]pyrazolo[1,5-a]pyridin-3-yl]-3-(1-hydroxyethyl)pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0372]

[0373] Under argon atmosphere, 1-[3-acetyl-6-[6-[[6-[(3,3-difluoroazacyclobutane-1-yl)methyl]pyrazin-3-yl]amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile (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. The mixture was stirred at 0 °C for 5 min. Water was added and the resulting solution was extracted with DCM / methanol (10:1). The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 0% to 5% MeOH in DCM to give the title compound (28 mg, 35% yield) as a pale yellow solid. MS (ESP) m / z = 543.1 [M+H]+

[0374] Example 9

[0375] 1-[3-[(1S)-1-hydroxyethyl]-6-[6-[[6-(2-oxa-6-azaspiro[3.3]heptane-6-ylmethyl)pyrazin-3-yl]amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0376]

[0377] Step 1: 6-[(6-chloropyridazine-3-yl)methyl]-2-oxa-6-azaspiro[3.3]heptane

[0378]

[0379] Under argon atmosphere, DIPEA (2.1 mL, 11.9 mmol) was added to a solution of 3-chloro-6-(chloromethyl)pyridazine (400 mg, 2.45 mmol, Eq. 1; 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), and the mixture was stirred at room temperature for 16 hours. Water was added, and the resulting solution was extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 0% to 6% MeOH in DCM to give the title compound (168 mg, 28% yield) as a light brown solid. MS (ESP) m / z = 226.1 [M+H] +

[0380] Step 2: N-[6-(2-oxa-6-azaspiro[3.3]heptane-6-ylmethyl)pyridazin-3-yl]-1,1-diphenylmethylene

[0381]

[0382] Under argon atmosphere, benzophenone imine (116.4 μL, 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]) were added 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). Argon gas was bubbled through the solution for 5 minutes.

[0383] Tris(dibenzylacetone)dipalladium(0) (64 mg, 0.069 mmol; CAS [51364-51-3]) was added. The mixture was stirred at 100 °C for 16 h. Water was added, and the resulting solution was extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by rapid chromatography on silica gel by elution with 0% to 10% MeOH in DCM to give the title compound (48 mg, 18% yield) as a brown oil. MS (ESP) m / z = 371.2 [M+H] +

[0384] Step 3: 6-(2-oxa-6-azaspiro[3.3]heptane-6-ylmethyl)pyridazine-3-amine; 2,2,2-trifluoroacetic acid

[0385]

[0386] Under argon atmosphere, TFA (0.1 mL) was added to a solution of N-[6-(2-oxa-6-azaspiro[3.3]heptane-6-ylmethyl)pyridazin-3-yl]-1,1-diphenylmethylene (48 mg, 0.13 mmol) in DCM (8 mL). The mixture was stirred at room temperature for 5 min. Water was added, and the resulting solution was extracted with DCM. The aqueous layer was lyophilized to give the title compound (36 mg, 81% yield) as a brown oil. MS (ESP) m / z = 207.2 [M+H] +

[0387] Step 4: 1-[3-acetyl-6-[6-[[6-(2-oxa-6-azaspiro[3.3]heptane-6-ylmethyl)pyrazin-3-yl]amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxylonitrile

[0388]

[0389] Under argon atmosphere, in a sealed tube, 6-(2-oxa-6-(6-bromopyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl]-5-methylpyrazol-3-carboxylonitrile (28 mg, 0.066 mmol, Eq. 1) (preparation see Example 1, step 4) was added to 1,4-dioxane (0.9 mL); 2,2,2-trifluoroacetic acid (36 mg, 0.10 mmol) was added, 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 at 80 °C for 2.5 h. The crude product was subjected to rapid chromatography, eluting on silica gel with 0% to 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] +

[0390] Step 5: 1-[3-[(1S)-1-hydroxyethyl]-6-[6-[[6-(2-oxa-6-azaspiro[3.3]heptane-6-ylmethyl)pyrazin-3-yl]amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0391]

[0392] Under argon atmosphere, 1-[3-acetyl-6-[6-[[6-(2-oxa-6-azaspiro[3.3]heptane-6-ylmethyl)pyrazin-3-yl]amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile (8.7 mg, 0.014 mmol, Eq. 1) was dissolved in isopropanol (0.9 mL) and cooled to 0 °C. Sodium borohydride (0.77 mg, 0.021 mmol; CAS [16940-66-2]) was added and the mixture was stirred at 0 °C for 35 min. Water was added and the resulting solution was extracted with DCM / methanol (10:1). The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 0% to 12% MeOH in DCM, followed by chiral SFC separation to give the title compound as a pale yellow solid, the first eluting isomer (2 mg, 31% yield). MS (ESP) m / z = 549.2 [M+H] +

[0393] Example 10

[0394] 1-[3-[(1R)-1-hydroxyethyl]-6-[6-[[6-[(3-methoxyazacyclobutane-1-yl)methyl]pyrazin-3-yl]amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0395]

[0396] 1-[3-(1-hydroxyethyl)-6-[6-[[[6-[(3-methoxyazacyclobutane-1-yl)methyl]pyrazin-3-yl]amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile (32 mg, 0.048 mmol) (see Example 6) was isolated by chiral SFC to give the title compound as a pale yellow lyophilized solid, which was the second eluting isomer (4 mg, 15% yield). MS (ESP) m / z = 535.5 [M+H] +

[0397] Example 11

[0398] 1-[3-[(1S)-1-hydroxyethyl]-6-[6-[[6-[(3-methoxyazacyclobutane-1-yl)methyl]pyrazin-3-yl]amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0399]

[0400] 1-[3-(1-hydroxyethyl)-6-[6-[[[6-[(3-methoxyazacyclobutane-1-yl)methyl]pyrazin-3-yl]amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile (32 mg, 0.048 mmol) (see Example 6) was separated by chiral SFC to give a pale yellow lyophilized solid compound and a white solid title compound, which was the first eluting isomer (4.5 mg, yield 17.5%). MS (ESP) m / z = 535.5 [M+H] +

[0401] Example 12

[0402] 1-[3-[(1S)-1-hydroxyethyl]-6-[5-methoxy-6-[(6-methylpyridazin-3-yl)amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0403]

[0404] Step 1: Amino-2,4,6-trimethylbenzenesulfonate

[0405]

[0406] A solution of N-[(2,4,6-trimethylbenzenesulfonyl)oxy]tert-butyl 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 over water. The solid was filtered off and washed with water. The solid was dissolved in DCM (50 mL) and dried over Na2SO4 to give the title compound in solution in DCM, which was used directly in step 3. MS (ESP) m / z = 216.1 [M+H] +

[0407] Step 2: 2-(5-bromo-4-methoxypyridin-2-yl)ethynyl-trimethylsilane

[0408]

[0409] A mixture of trimethylsilylacetylene CAS [1066-54-2] (1.8 g, 18.36 mmol, 1 eq), cuprous iodide (I) 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 stirred at room temperature under a nitrogen atmosphere for 16 hours. Water was added, and the resulting solution was extracted with EtOAc. The organic layer was dried over Na₂SO₄ and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 10% EtOAc in petroleum ether to give the title compound (2.8 g, 53.7% yield), a dark green oil. MS (ESP) m / z = 283.9 [M+H] +

[0410] Step 3: 5-Bromo-4-methoxy-2-(2-trimethylsilylethynyl)pyridine-1-onthium-1-amine; 2,4,6-trimethylbenzenesulfonate

[0411]

[0412] At room temperature, a solution of amino-2,4,6-trimethylbenzenesulfonate (2.37 g, 11.0 mmol, 1.08 eq) in DCM (45 mL) was added dropwise to a solution of 2-(5-bromo-4-methoxypyridin-2-yl)ethynyltrimethylsilane (2.9 g, 10.2 mmol, 1 eq) in DCM (15 mL). 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 room temperature for 30 min. The resulting brown solid was filtered, washed with TBME (3 x 10 mL), and dried to give the title compound (4.2 g, 83% yield) as a light brown solid. MS (ESP) m / z = 300.9 [M+H] +

[0413] Step 4: (6-bromo-5-methoxypyrazolo[1,5-a]pyridin-2-yl)-trimethylsilane

[0414]

[0415] A mixture of silver carbonate (116 mg, 0.42 mmol, 0.05 eq) in DMF (50 mL) was added to 5-bromo-4-methoxy-2-(2-trimethylsilylethynyl)pyridine-1-onthium-1-amine; 2,4,6-trimethylbenzenesulfonate (4.2 g, 8.4 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 12 hours. The mixture was filtered and washed with EtOAc (30 mL × 3). The filtrate was mixed with water (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 25% EtOAc in petroleum ether to provide a pale yellow solid of 6-bromo-5-methoxy-pyrazolo[1,5-a]pyridine (0.6 g, 31% yield), MS (ESP) m / z = 226.9 [M+H]. + The title compound, a grayish-white solid (1.2 g, 48% yield), was also observed. MS (ESP) m / z = 299.0 [M+H] +

[0416] Step 5: 6-Bromo-5-methoxypyrazolo[1,5-a]pyridine

[0417]

[0418] A mixture of (6-bromo-5-methoxypyrazolo[1,5-a]pyridin-2-yl)-trimethylsilane (1.1 g, 3.7 mmol, 1.0 eq) and 1M 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 room temperature. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography with elution of 20% EtOAc in petroleum ether to provide the title compound as a pale yellow solid (330 mg, 1.5 mmol, 40% yield). MS (ESP) m / z = 226.9 [M+H] +

[0419] Step 6: 6-Bromo-3-iodo-5-methoxypyrazolo[1,5-a]pyridine

[0420]

[0421] N-iodosuccinimide (360 mg, 1.6 mmol) was added to a mixture of 6-bromo-5-methoxypyrazolo[1,5-a]pyridine (330 mg, 1.45 mmol, 1 eq) in ACN (10 mL) at room temperature. The mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under vacuum. The residue was purified by rapid chromatography on silica gel by elution with 1% to 10% EtOAc in petroleum ether to give the title compound as a grayish-white solid (320 mg, 63% yield). MS (ESP) m / z = 354.8 [M+H] +

[0422] Step 7: 1-[6-chloro-3-[(1S)-1-hydroxyethyl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0423]

[0424] Sodium borohydride (1.8 g, 48 mmol) was added to a mixture of 1-(3-acetyl-6-chloropyridin-2-yl)-5-methylpyrazol-3-carboxynitrile (see Example 1, Step 1 for preparation) (3.0 g, 11.5 mmol, 1 eq) in methanol (90 mL) and DCM (5 mL) at 0 °C. The mixture was stirred at 0 °C for 2 hours. The mixture was poured into saturated NH4Cl (100 mL) and extracted with EtOAc (50 mL x 3). The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 5% to 25% EtOAc in petroleum ether. The colorless oil was purified by chiral SFC (Daicel Chiral Pak IG (250 x 30 mm, 10 μm), (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] +

[0425] Step 8: 1-[3-[(1S)-1-hydroxyethyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0426]

[0427] Add 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (8 mg, 0.01 mmol; CAS [95464-05-4]) to a mixture of 1-[6-chloro-3-[(1S)-1-hydroxyethyl]pyridin-2-yl]-5-methylpyrazol-3-carboxylonitrile (50.0 mg, 0.190 mmol, 1 eq), bis(pinacol)diborone (193.3 mg, 0.760 mmol), and potassium acetate (74.7 mg, 0.760 mmol) in 1,4-dioxane (3 mL). Degas the mixture three times with nitrogen and stir at 100 °C for 4 h. Cool the mixture to room temperature and add 70 mg of SiliaMetS (metal scavenger) and stir at room temperature for 1 h. Filter the mixture and wash with dioxane (10 mL). The filtrate was concentrated under vacuum to give the title compound, a dark brown oil (67 mg, 97% yield). MS (ESP) m / z = 255.2 [M-18+H] +

[0428] Step 9: 1-[6-(6-bromo-5-methoxypyrazolo[1,5-a]pyridin-3-yl)-3-[(1S)-1-hydroxyethyl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0429]

[0430] Add 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (7 mg, 0.01 mmol; CAS [95464-05-4]) to a mixture of 1-[3-[(1S)-1-hydroxyethyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)pyridin-2-yl]-5-methylpyridin-3-yl]-5-methylpyrazol-3-yl (55 mg, 0.15 mmol) and cesium carbonate (111 mg, 0.34 mmol) in THF (2.4 mL) and water (0.4 mL). The mixture was degassed three times with nitrogen and stirred at 65°C for 3 hours. The mixture was poured into water (20 mL) and extracted with EtOAc (15 mL x 3). The organic layer was dried over Na₂SO₄ and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 65% EtOAc in petroleum ether to give the title compound (26 mg, 33% yield) as a yellow oil. MS (ESP) m / z = 437.0 [M⁻¹⁸ + H] +

[0431] Step 10: 1-[3-[(1S)-1-hydroxyethyl]-6-[5-methoxy-6-[(6-methylpyridazin-3-yl)amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0432]

[0433] Under argon atmosphere, in a sealed tube, 3-amino-6-methylpyridazine (6 mg, 0.05 mmol) was added to 1-[3-[(1S)-1-hydroxyethyl]-6-[5-methoxy-6-[(6-methylpyridazin-3-yl)amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile (21 mg, 0.046 mmol, Eq.1) in 1,4-dioxane (2 mL), followed by the addition of 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 at 80 °C for 3 hours. 20 mg SiliaMetS (metal scavenger) was added and the mixture was stirred for 1 hour. The mixture was filtered and washed with dioxane (3 mL). The organic layer was concentrated under 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] +

[0434] Example 13

[0435] 3-[3-(1-hydroxyethyl)-6-[6-(2-morpholin-4-ylethoxy)pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]benzonitrile

[0436]

[0437] Step 1: 1-(6-bromo-2-chloropyridin-3-yl)ethanol

[0438]

[0439] At 0 °C, 3.4 M methyl magnesium bromide (0.73 mL, 2.5 mmol) in 2-methyltetrahydrofuran was added dropwise to a solution of 6-bromo-2-chloronicotinaldehyde (500 mg, 2.3 mmol; CAS [1125410-08-3]) in THF (10 mL). This mixture was stirred at 0 °C for 30 min. Saturated ammonium chloride (2 mL) was added, followed by water, and the mixture was extracted with EtOAc. The organic layer was dried over Na₂SO₄ and concentrated under vacuum to give the title compound (550 mg, 97% yield) as an orange oil. MS (ESP) m / z = 235.9 [M+H] +

[0440] Step 2: 4-(2-pyrazolo[1,5-a]pyridin-6-yloxyethyl)morpholine

[0441]

[0442] Pyrazolo[1,5-a]pyridin-6-ol (2.5 g, 18. mmol, 1 eq; CAS [184473-24-3]) was added to 2-butanone (53 mL) and 4-(2-iodoethyl)morpholine; hydrogen iodide (7.31 g, 19.8 mmol) with K2CO3 (7.46 g, 54.01 mmol). The mixture was stirred at 80 °C for 2 h and then cooled to room temperature. The suspension was filtered off and washed with EtOAc. The organic layer was concentrated under vacuum. The crude product was coated onto silica gel and purified by rapid chromatography on silica gel by elution with 0% to 9% MeOH in DCM to give the title compound (3.5 g, 80% yield) as a pale yellow solid. MS (ESP) m / z = 248.2 [M+H] +

[0443] Step 3: 4-[2-(3-bromopyrazolo[1,5-a]pyridin-6-yl)oxyethyl]morpholine

[0444]

[0445] Bromine (0.31 mL, 6.07 mmol) was added to a stirred solution of 4-(2-pyrazolo[1,5-a]pyridin-6-yloxyethyl)morpholine (1.5 g, 6.07 mmol, 1 eq) in acetic acid (68 mL) at room temperature, and the mixture was stirred at room temperature for 1 hour. At 0 °C, the reaction mixture was poured over water and concentrated NaOH was added to achieve pH 10. The mixture was extracted with DCM, the organic layer was dried over Na2SO4, and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 0% to 6% MeOH in DCM to give the title compound (1.6 g, 81% yield) as a grayish-white solid. MS (ESP) m / z = 328.1 [M+H] +

[0446] Step 4: 4-[2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridin-6-yl]oxyethyl]morpholine

[0447]

[0448] Under argon atmosphere, 4-[2-(3-bromopyrazolo[1,5-a]pyridin-6-yl)oxyethyl]morpholine (1 g, 3.07 mmol, 1 eq) was dissolved in 1,4-dioxane (15 mL). Bis(pinacol)diboron (3.5 g, 13.6 mmol) was added, followed by dry potassium acetate (1.07 g, 10.9 mmol). Argon gas 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 gas was bubbled through the suspension for 5 minutes. The reaction was stirred at 100 °C for 3 hours and then cooled to room temperature. 10 mL of dioxane and 5 g of SiliaMetS (metal scavenger) were added. The suspension was stirred for 1 hour and filtered. Water was added, and the mixture was extracted with DCM. The organic layer was dried with Na₂SO₄ and concentrated under vacuum. Milling with heptane yielded the title compound as a grayish-white solid (410 mg, 34%). MS (ESP) m / z = 374.3 [M+H] +

[0449] Step 5: 1-[2-chloro-6-[6-(2-morpholin-4-ylethoxy)pyrazolo[1,5-a]pyridin-3-yl]pyridin-3-yl]ethanol

[0450]

[0451] In a pressure tube, a mixture of 4-[2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridin-6-yl]oxyethyl]morpholine (210 mg, 0.53 mmol, 1 eq), DMF (4 mL), water (2 mL), 1-(6-bromo-2-chloro-3-pyridyl)ethanol (133 mg, 0.53 mmol) (see Example 13, step 1 for preparation) and K2CO3 (148 mg, 1.07 mmol) was degassed with argon for 5 min, and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane complex (44 mg, 0.053 mmol; CAS [95464-05-4]) was added and heated to 100 °C for 30 min. After cooling to room temperature, 1 g of SiliaMetS (metal scavenger) was added and the mixture was stirred for 30 minutes. The mixture was filtered and washed with EtOAc. The organic layer was washed with water, dried over Na2SO4, and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 0% to 8% MeOH in DCM to give the title compound (160 mg, 68% yield) as a yellow oil. MS (ESP) m / z = 403.1 [M+H] +

[0452] Step 6: 3-[3-(1-hydroxyethyl)-6-[6-(2-morpholin-4-ylethoxy)pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]benzonitrile

[0453]

[0454] In a pressure tube under argon atmosphere, a mixture of 1-[2-chloro-6-[6-(2-morpholinylethoxy)pyrazolo[1,5-a]pyridin-3-yl]-3-pyridyl]ethanol (147 mg, 0.36 mmol, 1 eq), (3-cyanophenyl)boronic acid (64 mg, 0.44 mmol), and K2CO3 (50 mg, 0.36 mmol) in DMF (2 mL) and water (1 mL) was degassed with argon for 5 min. [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane complex (CAS[95464-05-4]) (30 mg, 0.036 mmol) was added, and the mixture was heated at 90 °C for 3 h. After cooling to room temperature, 2 g of SiliaMetS (metal scavenger) was added and the mixture was stirred for 30 minutes. The mixture was filtered and washed with EtOAc. The organic layer was washed with water, dried over Na2SO4, and concentrated under vacuum. The crude product 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] -

[0455] Example 14

[0456] 1-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0457]

[0458] Step 1: 6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridine

[0459]

[0460] K₂CO₃ (746.5 mg, 5.4 mmol) was added to a suspension of pyrazolo[1,5-a]pyridin-6-ol (250 mg, 1.8 mmol, 1 eq; CAS [184473-24-3]) in DMF (6.25 mL) and 3-chloro-6-methylpyridazine (254.6 mg, 1.98 mmol), and the mixture was stirred at 120 °C for 16 h. The mixture was poured over water and extracted with EtOAc. The organic layer was washed with water, dried over Na₂SO₄, and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 0% to 5% MeOH in DCM to give the title compound as a grayish-white solid (299 mg, 73.5% yield). MS (ESP) m / z = 227.2 [M+H]⁺

[0461] Step 2: 3-Bromo-6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridine

[0462]

[0463] Bromine (0.07 mL, 1.41 mmol) was added to a stirred solution of 6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridine (318 mg, 1.41 mmol, 1 eq) in acetic acid (15.8 mL) at room temperature, and the mixture was stirred for 2 hours. At 0 °C, the reaction mixture was poured over water and concentrated NaOH was added to achieve pH 10. The mixture was extracted with DCM, and the organic layer was dried over Na₂SO₄ and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 0% to 5% MeOH in DCM to give the title compound (365 mg, 85% yield) as a grayish-white solid. MS (ESP) m / z = 305.0 [M+H] +

[0464] Step 3: 6-(6-methylpyridazin-3-yl)oxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridine

[0465]

[0466] Under argon atmosphere, 3-bromo-6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridine (365 mg, 1.2 mmol, 1 eq) was dissolved in 1,4-dioxane (6 mL). Bis(pinacol)diboron (1.35 g, 5.32 mmol) was added, followed by dry potassium acetate (417 mg, 4.25 mmol). Argon gas 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 gas was bubbled through the suspension for 5 minutes. The reaction was stirred at 100 °C for 3 hours. After cooling to room temperature, 1,4-dioxane (5 mL) and 5 g SiliaMetS (metal scavenger) were added. The suspension was stirred for 1 hour and filtered. The organic layer was concentrated under vacuum. The title compound (260 mg, 50%) was obtained as a light brown solid after grinding with heptane. MS (ESP) m / z = 353.2 [M+H] +

[0467] Step 4: 1-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0468]

[0469] Under argon atmosphere, in a sealed tube, 6-(6-methylpyridazin-3-yl)oxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridine (100 mg, 0.23 mmol, 1 eq) was dissolved in DMF (2 mL) and water (1 mL), and 1-(3-acetyl-6-chloropyridin-2-yl)-5-methylpyrazol-3-carboxynitrile (71 mg, 0.27 mmol) (see Example 1, Step 1 for preparation) 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) dichloromethane complex (19 mg, 0.023 mmol; CAS [95464-05-4]) was added, and the mixture was stirred at 45 °C for 1 h. The reaction was cooled, poured onto water, and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 0% to 100% EtOAc in heptane to give the title compound (98 mg, 88% yield) as a light brown oil. MS (ESP) m / z = 451.1 [M+H] +

[0470] Step 5: 1-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0471]

[0472] Sodium borohydride (53 mg, 1.4 mmol) was added to a suspension of 1-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-2-pyridyl]-5-methylpyrazol-3-carboxynitrile (98 mg, 0.2 mmol, 1 eq) in methanol (10 mL). The mixture was stirred for 30 min and water was added. The mixture was extracted with DCM, the organic layer was dried over Na2SO4, and concentrated under vacuum. The crude product was purified by preparative HPLC to give the title compound (21 mg, 23% yield) as a white lyophilized solid. MS (ESP) m / z = 497.2 [M+H] +

[0473] Example 15

[0474] 1-[3-[(1S)-1-hydroxyethyl]-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0475]

[0476] 1-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxylonitrile (541 mg, 1.1 mmol) was isolated by chiral SFC (see Example 14, step 5) to give the title compound as a white solid, which was the first eluting isomer (151 mg, 30% yield). The structure was confirmed as (S) by NMR on Mosher ester. MS (ESP) m / z = 497.2 [M+H] + The absolute configuration is based on the corresponding Mosher ester (see J. Org. Chem. 1969, 34, 9, 2543–2549).

[0477] Example 16

[0478] 1-[3-[(1R)-1-hydroxyethyl]-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0479]

[0480] This example was prepared similarly to Example 15 to obtain the title compound as a white solid, which was the second eluting isomer (112 mg, 23% yield). MS (ESP) m / z = 452.2 [M+H] + The absolute configuration is based on the corresponding Mosher ester (see J. Org. Chem. 1969, 34, 9, 2543–2549).

[0481] Example 17

[0482] 3-Fluoro-4-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-1-(2,2,2-trifluoroethyl)pyridin-2-one

[0483]

[0484] Step 1: 3-Fluoro-4-iodo-1-(2,2,2-trifluoroethyl)pyridin-2-one

[0485]

[0486] To a solution of 3-fluoro-4-iodo-2-pyridone (250 mg, 0.99 mmol, 1 eq) in DMF (3 mL), 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.33 mL, 1.99 mmol) and Cs₂CO₃ (971 mg, 3.0 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour, poured onto water (25 mL), and extracted with ethyl acetate. The organic layer was dried over MgSO₄ and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 0% to 30% EtOAc to give the title compound (165 mg, 51% yield) as a grayish-white solid. MS (ESP) m / z = 322.0 [M+H] +

[0487] Step 2: 3-Fluoro-4-(4,4,5,5-Tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1-(2,2,2-trifluoroethyl)pyridin-2-one

[0488]

[0489] 3-Fluoro-4-iodo-1-(2,2,2-trifluoroethyl)-2-pyridone (168 mg, 0.514 mmol, 1 eq) was dissolved in 1,4-dioxane (3 mL) under argon atmosphere. Argon was bubbled through the solution for 10 minutes. Potassium acetate (76 mg, 0.77 mmol), bis(pinacol)diborone (157 mg, 0.62 mmol), tricyclohexylphosphine (17 mg, 0.062 mmol), and tris(dibenzylacetone)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 h and then at 100 °C overnight. The reaction was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 0% to 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+] +

[0490] Step 3: 1-[2-chloro-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-3-yl]ethanol

[0491]

[0492] In a pressure tube, a mixture of 6-(6-methylpyridazin-3-yl)oxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridine (preparation see Example 14, step 3) (500 mg, 1.42 mmol, 1 eq) in DMF (10 mL) and water (5 mL) with 1-(6-bromo-2-chloro-3-pyridyl)ethanol (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. Add the [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane complex (116 mg, 0.142 mmol; CAS [95464-05-4]) and stir the mixture at 45 °C for 30 min. Cool the reaction to room temperature, pour onto water, and extract with DCM. Dry the organic layer with Na2SO4 and concentrate under vacuum. Purify the crude product by rapid chromatography on silica gel, eluting with 0% to 5% MeOH in DCM, to give the title compound as a grayish-white solid (420 mg, 75% yield). MS (ESP) m / z = 382.1 [M+H] +

[0493] Step 4: 1-[2-chloro-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-3-yl]acetone

[0494]

[0495] To a solution of 1-[2-chloro-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-3-pyridyl]ethanol (350 mg, 0.89 mmol, 1 eq) in 1,2-dichloroethane (10 mL), manganese dioxide (3.09 g, 35.6 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction was heated to 40 °C and held for 16 h, and then filtered. The filter cake was washed with AcOEt and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 0% to 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] +

[0496] Step 5: 4-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-3-fluoro-1-(2,2,2-trifluoroethyl)pyridin-2-one

[0497]

[0498] Under argon atmosphere in a sealed tube, 1-[2-chloro-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-3-pyridyl]acetone (25 mg, 0.066 mmol, 1 eq) was dissolved in DMF (1 mL). 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1-(2,2,2-trifluoroethyl)-2-pyridinone (see Example 17, step 2 for preparation) (42 mg, 0.13 mmol), K₂CO₃ (27.3 mg, 0.197 mmol), and water (0.5 mL) were added. Argon gas was bubbled through the mixture for 5 minutes, and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane complex (5.4 mg, 0.007 mmol; CAS [95464-05-4]) was added. After stirring at 45 °C for 1 hour, the mixture was poured over water and extracted with 10:1 DCM:methanol. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 0% to 3% MeOH in DCM to give the title compound (9 mg, 25% yield) as a pale yellow oil. MS (ESP) m / z = 539.2 [M+H] +

[0499] Step 6: 3-Fluoro-4-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-1-(2,2,2-trifluoroethyl)pyridin-2-one

[0500]

[0501] NaBH4 (1.23 mg, 0.032 mmol) was added to a solution of 4-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-2-pyridyl]-3-fluoro-1-(2,2,2-trifluoroethyl)-2-pyridinone (9 mg, 0.016 mmol, 1 eq) in methanol (0.85 mL) at 0 °C. The mixture was stirred for 15 min and then poured onto water and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 0% to 5% MeOH in DCM to give the title compound as a pale yellow solid (6 mg, 63% yield). MS (ESP) m / z = 541.2 [M+H] +

[0502] Example 18

[0503] (1S)-1-[2-[3-(difluoromethyl)-5-methylpyrazol-1-yl]-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-3-yl]ethanol

[0504]

[0505] Step 1: 1-(6-chloro-2-fluoropyridin-3-yl)ethyl ketone

[0506]

[0507] 1.6 M n-butyllithium (28.5 mL, 45.6 mmol, 1.2 eq) was added to diisopropylamine (4.62 g, 6.5 mL, 45.61 mmol) in tetrahydrofuran (37.5 mL) at -78 °C under argon atmosphere, and the mixture was stirred at -78 °C for 30 min. A solution of 2-chloro-6-fluoropyridine (5 g, 38. mmol, 1 eq) in tetrahydrofuran (62 mL) was added dropwise over 1 hour, and the mixture was stirred at -78 °C for 30 min, and then at -40 °C for 1 hour. A solution of N-methoxy-N-methylacetamide (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 h, and then at 0 °C for 2 h. The reaction mixture was diluted with saturated NH4Cl (200 mL) and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 0% to 30% EtOAc in heptane to give the title compound (1.26 g, 19% yield) as a pale yellow solid. MS (ESP) m / z = 174.0 [M+H] +

[0508] Step 2: 1-(6-chloro-2-fluoropyridin-3-yl)ethanol

[0509]

[0510] NaBH4 (206 mg, 5.4 mmol, 1.5 eq) was added to a solution of 1-(6-chloro-2-fluoro-3-pyridyl)acetone (630 mg, 3.63 mmol, 1 eq) in methanol (5 mL) at 0 °C. The reaction was stirred at 0 °C for 10 min, then quenched with water and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under vacuum to give the title compound as a pale yellow solid (1.26 g, 19% yield). MS (ESP) m / z = 176.0 [M+H] +

[0511] Step 3: 1-[2-fluoro-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-3-yl]ethanol

[0512]

[0513] In a pressure tube, a mixture of 6-(6-methylpyridazin-3-yl)oxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridine (preparation see Example 14, step 3) (702 mg, 1.99 mmol, 1 eq) in DMF (8 mL) and water (4 mL) with 1-(6-chloro-2-fluoropyridin-3-yl)ethanol (350 mg, 1.99 mmol) and K2CO3 (551 mg, 3.99 mmol) was degassed with argon for 5 minutes. Add [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane complex (163 mg, 0.199 mmol; CAS [95464-05-4]) and stir the mixture at 45 °C for 30 min, then cool to room temperature. Pour the mixture onto water and extract with DCM. Dry the organic layer with Na2SO4 and concentrate under vacuum. Purify the crude product by rapid chromatography on silica gel with 0% to 3% MeOH in DCM to give the title compound as a grayish-white solid (315 mg, 43% yield). MS (ESP) m / z = 366.2 [M+H] +

[0514] Step 4: 1-[2-fluoro-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-3-yl]acetone

[0515]

[0516] Manganese dioxide (1.9 g, 22 mmol) was added to a solution of 1-[2-fluoro-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-3-pyridyl]ethanol (200 mg, 0.55 mmol, 1 eq) in 1,2-dichloroethane (5 mL). The reaction was stirred at room temperature for 90 min. Then, additional manganese dioxide (476 mg, 5.5 mmol) was added, and after another 2 hours, more manganese dioxide (476 mg, 5.5 mmol) was added. The reaction was stirred overnight. The suspension was filtered on a Dicalite film and the filtrate was concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 0% to 5% MeOH in DCM to give the title compound as a grayish-white solid (162 mg, 81% yield). MS (ESP) m / z = 364.1 [M+H] +

[0517] Step 5: 1-[2-[3-(difluoromethyl)-5-methylpyrazol-1-yl]-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-3-yl]acetone

[0518]

[0519] Add 3-(difluoromethyl)-5-methyl-1H-pyrazole (32 mg, 0.24 mmol) and K₂CO₃ (46 mg, 0.33 mmol) to a solution of 1-[2-fluoro-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-3-pyridyl]acetone (80 mg, 0.22 mmol, 1 eq) in DMF (2.48 mL). Stir this mixture overnight at 60 °C, then pour it onto water and extract with 9:1 DCM:methanol. The organic layer was dried over Na₂SO₄ and concentrated under vacuum. The crude product was purified by preparative HPLC followed by SFC separation to give the title compound (21 mg, 19% yield) as a pale yellow solid. MS (ESP) m / z = 476.1 [M+H] +

[0520] Step 6: (1S)-1-[2-[3-(difluoromethyl)-5-methylpyrazol-1-yl]-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-3-yl]ethanol

[0521]

[0522] NaBH4 (1.67 mg, 0.044 mmol, 1 eq) was added to a solution of 1-[2-[3-(difluoromethyl)-5-methylpyrazol-1-yl]-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-3-pyridyl]acetone (21 mg, 0.044 mmol, 1 eq) in methanol (5 mL) and tetrahydrofuran (5 mL) at 0 °C, and the mixture was stirred for 1 hour. Then, more NaBH4 (1.67 mg, 0.044 mmol, 1 eq) was added twice, and the mixture was stirred at 0 °C for 1 hour. The mixture was poured over water and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by chiral SFC to give the title compound as a white solid, the first eluting isomer (7 mg, 31% yield). MS (ESN) m / z = 522.2 [M+HCOO] -

[0523] Example 19

[0524] (1R)-1-[2-[3-(difluoromethyl)-5-methylpyrazol-1-yl]-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-3-yl]ethanol

[0525]

[0526] Similar to Example 18 (see step 6), this example was isolated to obtain the title compound as a white solid, which was the second eluting isomer (6 mg, 28% yield). MS (ESP) m / z = 522.2 [M+HCOO] -

[0527] Example 20

[0528] 1-[3-(hydroxymethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0529]

[0530] Step 1: 1-(6-chloro-3-formylpyridin-2-yl)-5-methylpyrazol-3-carboxynitrile

[0531]

[0532] 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-1H-pyrazole-3-carboxynitrile (739 mg, 6.89 mmol; CAS [38693-82-2]) and K₂CO₃ (1.3 g, 9.4 mmol) were added at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over MgSO₄ and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 0% to 100% ethyl acetate in heptane to give the title compound (1.42 g, 92% yield) as a light brown solid. MS (ESP) m / z = 246.0 [M+H] +

[0533] Step 2: 1-[3-formyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0534]

[0535] Under argon atmosphere, 6-(6-methylpyridazin-3-yl)oxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridine (72 mg, 0.20 mmol, 1 eq) (preparation see Example 14, step 3) and 1-(6-chloro-3-formyl-2-pyridinyl)-5-methyl-pyrazol-3-carboxynitrile (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 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (17 mg, 0.02 mmol; CAS [95464-05-4]). The mixture was stirred at 45 °C for 1 hour, then diluted with water and extracted with EtOAc. The aqueous phase containing the product in suspension was filtered, and the solid was washed with water and diethyl ether to give the title compound as a yellow solid (53 mg, 58% yield). MS (ESP) m / z = 437.2 [M+H] +

[0536] Step 3: 1-[3-(hydroxymethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0537]

[0538] 1-[3-formyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-2-pyridyl]-5-methylpyrazol-3-carboxynitrile (30 mg, 0.069 mmol, 1 eq) was suspended in methanol (1 mL) and tetrahydrofuran (1 mL). NaBH4 (5 mg, 0.1 mmol) was added at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with saturated NaHCO3 and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 0% to 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] +

[0539] Example 21

[0540] 5-(difluoromethyl)-1-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]pyrazol-3-carboxynitrile

[0541]

[0542] Step 1: 5-(difluoromethyl)-1H-pyrazole-3-carboxamide

[0543]

[0544] 1,1'-carbonyldiimidazole (1.3 g, 8.0 mmol; CAS [681034-51-5]) was added to a solution of 5-(difluoromethyl)-1H-pyrazole-3-carboxylic acid (1.0 g, 6.2 mmol, 1 eq; CAS [681034-51-5]) in DMF (16 mL). The solution was stirred at room temperature for 3 h. Then, saturated ammonium hydroxide (4.8 mL) was added and the mixture was stirred for 1 h. The mixture was poured over water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under vacuum. The solution was ground with DCM to give the title compound as a white solid (600 mg, 59% yield). MS (ESP) m / z = 162.0 [M+H] +

[0545] Step 2: 1-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-(difluoromethyl)pyrazol-3-carboxamide

[0546]

[0547] Similar to step 5 of Example 18, this example was prepared by using 5-(difluoromethyl)-1H-pyrazole-3-carboxamide (CAS [2137578-81-3]) instead of 3-(difluoromethyl)-5-methyl-1H-pyrazole to obtain the title compound as a pale yellow solid. MS (ESP) m / z = 505.2 [M+H] +

[0548] Step 3: 1-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-(difluoromethyl)pyrazol-3-carboxynitrile

[0549]

[0550] Triethylamine (0.04 mL) was added to an ice-cold solution of 1-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-2-pyridyl]-5-(difluoromethyl)pyrazol-3-carboxamide (50 mg, 0.1 mmol, 1 eq) in DCM (3 mL), followed by the addition of trifluoroacetic anhydride (0.04 mL, 0.3 mmol). The reaction mixture was stirred at 0 °C for 1 h. The crude reaction mixture was subjected to rapid chromatography, eluting on silica gel with 0% to 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] +

[0551] Step 4: 5-(difluoromethyl)-1-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]pyrazol-3-carboxynitrile

[0552]

[0553] This example was prepared similarly to step 6 of Example 17 to obtain the title compound as a pale yellow solid. MS (ESP) m / z = 489.3 [M+H] +

[0554] Example 22

[0555] 5-(difluoromethyl)-1-[3-[(1S)-1-hydroxyethyl]-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]pyrazol-3-carboxynitrile

[0556]

[0557] 5-(difluoromethyl)-1-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]pyrazol-3-carboxylonitrile (20 mg, 0.04 mmol) was isolated by chiral SFC (see Example 21, step 4) to give the title compound as a white solid, which was the first eluting isomer (6 mg, 33% yield). MS (ESP) m / z = 489.3 [M+H] + The absolute configuration is based on the corresponding Mosher ester (see J.Org. Chem. 1969, 34, 9, 2543–2549).

[0558] Example 23

[0559] 5-(difluoromethyl)-1-[3-[(1R)-1-hydroxyethyl]-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]pyrazol-3-carboxynitrile

[0560]

[0561] This example was prepared similarly to Example 22 to obtain the title compound as a grayish-white solid, which was the second eluting isomer (5 mg, 27% yield). MS (ESP) m / z = 489.3 [M+H] + The absolute configuration is based on the corresponding Mosher ester (see J. Org. Chem. 1969, 34, 9, 2543–2549).

[0562] Examples 24 and 25

[0563] 1-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]ethanol; and

[0564] 1-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-2-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]ethanol

[0565] and

[0566] Step 1: 4-Bromo-5-methyl-1-(2,2,2-trifluoroethyl)pyrazole and 4-Bromo-3-methyl-1-(2,2,2-trifluoroethyl)pyrazole

[0567] and

[0568] 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 h. 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 under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 10% to 20% ethyl acetate in petroleum ether to give the title compound mixture (19.5 g, 86% yield). MS (ESP) m / z = 242.9 [M+H] +

[0569] Step 2: 5-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1-(2,2,2-trifluoroethyl)pyrazole and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1-(2,2,2-trifluoroethyl)pyrazole

[0570] and

[0571] Potassium acetate (8.9 g, 90.5 mmol) was added to a mixture of 4-bromo-5-methyl-1-(2,2,2-trifluoroethyl)pyrazole / 4-bromo-3-methyl-1-(2,2,2-trifluoroethyl)pyrazole (11.0 g, 45.3 mmol, 1 eq) and bis(pinacol)diboron (17.2 g, 70 mmol) in 1,4-dioxane (200 mL), followed by the addition of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane complex (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 rapid chromatography, eluting on silica gel with 10% to 20% ethyl acetate in petroleum ether, followed by preparative HPLC to give a yellow, oily mixture of the title compounds (18 g, 61% yield). MS (ESP) m / z = 291.1 [M+H] +

[0572] Step 3: N-(3-acetyl-6-chloropyridin-2-yl)tert-butyl carbamate

[0573]

[0574] A solution of N-(6-chloro-2-pyridyl)carbamate tert-butyl ester (4.0 g, 17.5 mmol, 1 eq) in THF (60 mL) was cooled to -50 °C. 2.5 M n-butyllithium (17.5 mL, 43.7 mmol) was added dropwise to THF, and the reaction was slowly heated to 0 °C and stirred at that temperature for 2 h. Then, at -40 °C, 1-morpholinoacetone (4.52 g, 35.0 mmol) dissolved in THF (20 mL) was slowly added. The reaction solution was stirred at -40 °C for 1 h. Saturated NH4Cl (200 mL) was added, and the mixture was extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 20% ethyl acetate in petroleum ether to give the brown, colloidal title compound (2.65 g, 56% yield). MS (ESP) m / z = 215 [M-tert-butyl + H] +

[0575] Step 4: 1-(2-amino-6-chloropyridin-3-yl)acetone

[0576]

[0577] TFA (5 mL, 64.0 mmol) was added to a mixture of N-(3-acetyl-6-chloropyridin-2-yl)carbamate (2.6 g, 9.6 mmol, 1 eq) in DCM (20 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under vacuum and quenched with saturated NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under vacuum to give the title compound as a brown solid (1.53 g, 91% yield). MS (ESP) m / z = 171.1 [M+H] +

[0578] Step 5: 1-(2-bromo-6-chloropyridin-3-yl)acetone

[0579]

[0580] A mixture of 1-(2-amino-6-chloropyridin-3-yl)acetone (1.0 g, 5.9 mmol, 1 eq), cuprous(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 THF (15 mL) was added dropwise, and the resulting mixture was stirred at 50 °C for 1.5 h. The reaction mixture was cooled to room temperature and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 20% ethyl acetate in petroleum ether to give the title compound (640 mg, 47% yield) as a white solid. MS (ESP) m / z = 235.9 [M+H] +

[0581] Step 6: 1-[6-chloro-2-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-3-yl] acetone and 1-[6-chloro-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-3-yl] acetone

[0582]

[0583] The following reagents were prepared: 1-(2-bromo-6-chloropyridin-3-yl)acetone (162 mg, 0.69 mmol, 1 eq), 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1-(2,2,2-trifluoroethyl)pyrazole / 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1-(2,2,2-trifluoroethyl)pyrazole (see Example 24, step 2 for preparation) (200 mg, 0.69 mmol, 1 eq), potassium carbonate (191 mg, 1.38 mmol, 2 eq), and Pd(dppf)Cl2·CH2Cl2 CAS [95464-05-4] (56 mg, 0.07 mmol, 0.10 eq). The mixture in 1,4-dioxane (5 mL) and water (0.500 mL) was stirred at 80 °C for 12 h under nitrogen. The reaction mixture was cooled to room temperature and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 0% to 20% ethyl acetate in petroleum ether to give a white solid mixture of the title compounds (210 mg, 96% yield). MS (ESP) m / z = 318.1 [M+H] +

[0584] Step 7: 1-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-2-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-3-yl] acetone and 1-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-3-yl] acetone

[0585]

[0586] Under argon atmosphere, 1-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-2-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]acetone / 1-[6-[6-(6-methylpyridazin-3-yl)oxypyrazol[1,5-a]pyridin-3-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]acetone (200 mg, 0.63 mmol, Eq.1) and 6-(6-methylpyridazin-3-yl)oxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)pyrazolo[1,5-a]pyridine (288 mg, 0.203 mmol, Eq.1) were prepared. A mixture of 1,4-dioxane (5 mL) and water (0.5 mL) was suspended in Example 14, step 3 for preparation. 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (51 mg, 0.02 mmol; CAS [95464-05-4]) was added and the mixture was stirred at 100 °C for 12 hours. The residue was purified by preparative HPLC followed by SFC to give the title compound as a white solid, 1-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]acetone (60 mg, 40% yield), (ESP) m / z = 508.0 [M+H] + And a grayish-white solid, 1-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-2-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]acetone (20 mg, yield 13%), MS (ESP) m / z = 508.0 [M+H]+ .

[0587] Step 8: 1-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]ethanol, Example 24

[0588]

[0589] NaBH4 (21 mg, 0.54 mmol) was added to a solution of 1-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]acetone (55 mg, 0.11 mmol, 1 eq) in methanol (3 mL) at -70 °C. The mixture was stirred at -70 °C for 30 min. The reaction mixture was quenched with saturated NH4Cl. The reaction mixture was purified by preparative HPLC to give the title compound (36 mg, 65% yield) as a white solid. MS (ESP) m / z = 509.9 [M+H] +

[0590] Step 9: 1-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-2-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]ethanol, Example 25

[0591]

[0592] Similar to Example 24, this example was prepared by replacing 1-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-2-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]acetone with 1-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-3-pyridyl]acetone to obtain the title compound as a white solid. MS (ESP) m / z = 509.9 [M+H] +

[0593] Example 26

[0594] 5-Chloro-2-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]pyrazol-3-carboxynitrile

[0595]

[0596] Step 1: Methyl 5-chloro-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate

[0597]

[0598] Add 60% sodium hydride (239 mg, 6.0 mmol, 1.2 eq) in portions to a solution of 2-(trimethylsilyl)ethoxymethyl chloride (1.2 mL, 7.0 mmol) in DMF (20 mL) at 0 °C. Stir the mixture at 20 °C for 1 hour. Cool the mixture to 0 °C and add methyl 5-chloro-1H-pyrazole-3-carboxylate (800 mg, 5.0 mmol, 1 eq). Stir the mixture at 20 °C for 16 hours. Pour the mixture into water and extract with EtOAc. Dry the organic layer with Na2SO4 and concentrate under vacuum. Purify the crude product by rapid chromatography on silica gel, eluting with 20% ethyl acetate in petroleum ether, to give the title compound (750 mg, 52% yield) as a colorless oil. MS (ESP) m / z = 232.2 [M+H] +

[0599] Step 2: 5-Chloro-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxamide

[0600]

[0601] A solution of methyl 5-chloro-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (750 mg, 2.58 mmol, 1 eq) in saturated NH3 in MeOH (20 mL, 140 mmol) was stirred in a pressure tube at 80 °C for 60 min. The mixture was concentrated under vacuum to give the title compound (900 mg, quantitative yield) as a pale yellow oil, which was used as is in the next step. MS (ESP) m / z = 218.0 [M+H] +

[0602] Step 3: 5-Chloro-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxynitrile

[0603]

[0604] Under nitrogen atmosphere at 0 °C, trifluoroacetic anhydride (1.84 mL, 13.05 mmol) was added dropwise to a solution of 5-chloro-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxamide (900 mg, 3.26 mmol, 1 eq) in pyridine (20 mL, 247 mmol). The mixture was stirred at 0 °C for 1 hour. The reaction mixture was concentrated under vacuum and the crude product was purified by rapid chromatography on silica gel by elution with 0% to 10% ethyl acetate in petroleum ether to give the title compound (800 mg, 95% yield) as a colorless liquid. 1H NMR (400 MHz, DMSO-d6) δ = 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).

[0605] Step 4: 5-Chloro-1H-pyrazole-3-carboxynitrile

[0606]

[0607] Trifluoroacetic acid (5.0 mL) was added to 5-chloro-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxynitrile (800 mg, 3.1 mmol) at 0 °C, and the mixture was stirred at room temperature 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 room temperature for 1 hour. The reaction mixture was concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 30% ethyl acetate in petroleum ether to give a white, gel-like title compound (350 mg, 88% yield). ¹H NMR (400 MHz, DMSO-d6) δ = 7.22 (s, 1H)

[0608] Step 5: 2-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-chloropyrazol-3-carboxynitrile

[0609]

[0610] Similar to step 5 of Example 18, this example was prepared by replacing 3-(difluoromethyl)-5-methyl-1H-pyrazole with 5-chloro-1H-pyrazole to obtain the title compound as a yellow solid. MS (ESP) m / z = 471.0 [M+H] +

[0611] Step 6: 5-Chloro-2-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]pyrazol-3-carboxynitrile

[0612]

[0613] This example was prepared similarly to step 6 of Example 17 to obtain the title compound as a white solid. MS (ESP) m / z = 473.2 [M+H] +

[0614] Example 27

[0615] 5-Cyclopropyl-1-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]pyrazol-3-carboxynitrile

[0616]

[0617] Similar to step 6 of Example 18, this example was prepared by using 5-cyclopropyl-1H-pyrazole-3-carboxynitrile (CAS [1290696-95-5]) instead of 3-(difluoromethyl)-5-methyl-1H-pyrazole to obtain the title compound as a yellow solid. MS (ESN) m / z = 523.5 [M+HCOO] -

[0618] Example 28

[0619] 5-Cyclopropyl-2-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]pyrazol-3-carboxynitrile

[0620]

[0621] This example was prepared similarly to Example 27. In step 6, the isomer 5-cyclopropyl-1H-pyrazole-3-carboxynitrile was obtained, and this intermediate was used to complete the synthesis to give the title compound as a white lyophilized solid. MS (ESP) m / z = 479.4 [M+H] +

[0622] Example 29

[0623] 5-(difluoromethyl)-1-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]pyrazol-3-carboxamide

[0624]

[0625] Similar to step 4 of Example 21, this example was prepared by using 1-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-(difluoromethyl)pyrazol-3-carboxamide (see Example 21, step 2 for preparation) instead of 1-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-(difluoromethyl)pyrazol-3-carboxynitrile to give the title compound (60 mg, 92% yield) as a white lyophilized solid. MS (ESN) m / z = 551.5 [M+HCOO] -

[0626] Example 30

[0627] 2-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazol-3-carboxynitrile

[0628]

[0629] Similar to Example 18, this example was prepared using 3-(trifluoromethyl)-1H-pyrazole-5-carboxynitrile instead of 3-(difluoromethyl)-5-methyl-1H-pyrazole (CAS [934759-09-8]) to obtain the title compound as a white lyophilized powder (2 mg, yield 24.1%). MS (ESP) m / z = 507.3 [M+H] +

[0630] Example 31

[0631] 1-[6-[6-(6-chloropyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-3-(1-hydroxyethyl)pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0632]

[0633] Step 1: Pyrazolo[1,5-a]pyridine-6-ol

[0634]

[0635] Boron tribromide (18.9 mL, 202 mmol) was added to a solution of 6-methoxypyrazolo[1,5-a]pyridine (10.0 g, 67.5 mmol, 1 eq; CAS [1427374-36-4]) in DCM (150 mL) at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred for 12 h. The reaction mixture was slowly quenched with ice water (500 mL) and the pH was adjusted to 7 to 8 by adding 2 M sodium hydroxide. The mixture was extracted with EtOAc, and the organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 20% ethyl acetate in petroleum ether to give the title compound (7.8 g, 86% yield) as a light brown solid. MS (ESP) m / z = 135.0 [M+H] +

[0636] Step 2: 3-Bromoxypyrazolo[1,5-a]pyridine-6-ol

[0637]

[0638] NBS (1.59 g, 8.95 mmol, 1 eq) was added to a solution of pyrazolo[1,5-a]pyridin-6-ol (1.2 g, 8.95 mmol, 1 eq) in methanol (20 mL) at -10 °C. The mixture was stirred at -10 °C for 2 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 30% to 50% ethyl acetate in petroleum ether to give the title compound (1.5 g, 79% yield) as a gray solid. MS (ESP) m / z = 213.0 [M+H] +

[0639] Step 3: 3-Bromo-6-phenylmethoxypyrazolo[1,5-a]pyridine

[0640]

[0641] K₂CO₃ (4.87 g, 35.2 mmol) was added to a solution of benzyl bromide (1.26 mL, 10.6 mmol) in acetonitrile (20 mL) and DMF (2 mL). At 0 °C, 3-bromopyrazolo[1,5-a]pyridine-6-ol (1.5 g, 7.0 mmol, 1 eq) was added, and the reaction was stirred at room temperature for 12 h. The mixture was diluted with water and extracted with DCM. The organic layer was dried over Na₂SO₄ and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 25% petroleum ether (ethyl acetate:DCM 9:1) to give the title compound (1.5 g, 56% yield) as a white solid. MS (ESP) m / z = 302.9 [M+H] +

[0642] Step 4: 6-Phenylacetoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridine

[0643]

[0644] To a solution of bis(pinacol)diboron (2.51 g, 9.9 mmol) in diethylene glycol dimethyl ether (40 mL) and water (0.2 mL), 3-bromo-6-phenylmethoxypyrazolo[1,5-a]pyridine (1.2 g, 4.0 mmol, 1 eq), palladium(II) acetate (89 mg, 0.4 mmol), tricyclohexylphosphine (222 mg, 0.79 mmol), and K₂CO₃ (766 mg, 5.5 mmol) were added, and the reaction was stirred at 100 °C for 2 h under nitrogen. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over Na₂SO₄ and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with petroleum ether to give a solution of the title compound in diethylene glycol dimethyl ether (approximately 10 mL), which was a mixture with the debromination starting material (1:1) and used as is in the next step. MS (ESP) m / z = 351.1 [M+H] +

[0645] Step 5: 3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridine-6-ol

[0646]

[0647] To a solution of 6-phenylmethoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridine (8.0 mL, 1.71 mmol, 1 eq, dissolved in 10 mL diethylene glycol dimethyl ether) in methanol (30 mL), 10% Pd / C (200 mg, 0.17 mmol, 0.1 eq) was added. The reaction mixture was stirred at room temperature for 4 hours under hydrogen (15 psi). The catalyst was filtered through diatomaceous earth, and the filtrate was concentrated under vacuum to give the title compound (in diethylene glycol dimethyl ether), which was used directly as is in the next step.

[0648] Step 6: 1-[3-acetyl-6-(6-hydroxypyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0649]

[0650] To a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridin-6-ol (8.0 mL, 1.92 mmol, 1 eq) in water (3 mL) and DMF (6 mL), 1-(3-acetyl-6-chloro-2-pyridyl)-5-methyl-pyrazol-3-carboxynitrile (551 mg, 2.1 mmol, 1.1 eq), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane complex (157 mg, 0.19 mmol; CAS [95464-05-4]), and K2CO3 (797 mg, 5.8 mmol) were added. The reaction mixture was stirred at 80 °C under nitrogen for 3 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution 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] +

[0651] Step 7: 1-[3-acetyl-6-[6-(6-chloropyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0652]

[0653] To a solution of 1-[3-acetyl-6-(6-hydroxypyrazolo[1,5-a]pyridin-3-yl)-2-pyridyl]-5-methylpyrazol-3-carboxynitrile (60 mg, 0.17 mmol, 1 eq) in DMF (3 mL), 3,6-dichloropyridazine (27 mg, 0.18 mmol) and Cs₂CO₃ (164 mg, 0.5 mmol) were added. The reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was diluted with H₂O (50 mL) and extracted with EtOAc. The organic layer was dried over Na₂SO₄ and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution 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] +

[0654] Step 8: 1-[6-[6-(6-chloropyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-3-(1-hydroxyethyl)pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0655]

[0656] Sodium borohydride (5 mg, 0.13 mmol) was added to a solution of 1-[3-acetyl-6-[6-(6-chloropyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-2-pyridyl]-5-methylpyrazol-3-carboxynitrile (20 mg, 0.04 mmol, 1 eq) in methanol (1 mL) and DCM (1 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. The mixture was quenched with saturated NH4Cl at 0 °C and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by preparative HPLC to give the title compound (3 mg, 13% yield) as a white solid. MS (ESP) m / z = 473.2 [M+H] +

[0657] Example 32

[0658] 2-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-3,5-dimethyl-4H-pyrrolo[3,4-c]pyrazol-6-one

[0659]

[0660] Step 1: Methyl 5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate

[0661]

[0662] Sodium hydride (3.083 g, 77.07 mmol) was added dropwise to a solution of methyl 5-methyl-1H-pyrazole-3-carboxylate (9.0 g, 64.22 mmol, 1 eq; CAS[25016-17-5]) in DMF (90 mL) at 0 °C. A large amount of solid precipitate formed. DMF (50 mL) was then slowly added to the reaction mixture. The mixture was stirred at 0 °C for 30 min. Then 2-(trimethylsilyl)ethoxymethyl chloride (17.05 mL, 96.33 mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with saturated NH4Cl- solution (800 mL) and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 20% to 30% ethyl acetate in petroleum ether to give the yellow oily title compound (a mixture of two positional isomers). (17 g, 97.9% yield). MS (ESP) m / z = 271.2 [M+H] +

[0663] Step 2: Methyl 4-bromo-5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate

[0664]

[0665] NBS (17.8 g, 100 mmol) was added fractionally to a solution of methyl 5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (18 g, 66.57 mmol, 1 eq) (a mixture of two positional isomers) in acetonitrile (180 mL) at 0 °C. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 20% ethyl acetate in petroleum ether to give a colorless oily title compound (a mixture of two positional isomers) (22 g, 95% yield). The positional isomers (12 g, 34.4 mmol) were separated by another rapid chromatography on silica gel by elution with 10% ethyl acetate in petroleum ether to give a yellow oily title compound (7 g). MS (ESP) m / z = 291.0 [M-COOMe+H] +

[0666] Step 3: Methyl 5-methyl-4-[[(2-methylprop-2-yl)oxycarbonylamino]methyl]-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylic acid methyl ester

[0667]

[0668] 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) were added to a mixture of methyl 4-bromo-5-methyl-1-(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-dioxane (30 mL) and water (3 mL). The suspension was degassed three times with nitrogen and stirred at 110 °C for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over Na₂SO₄ and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 20% ethyl acetate in petroleum ether to give the title compound (3 g, yield 87.4%) as a yellow oil. MS (ESP) m / z = 400.1 [M+H] +

[0669] Step 4: Methyl 4-(aminomethyl)-5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate

[0670]

[0671] TFA (2.0 mL) was added to a solution of methyl 5-methyl-4-[[(2-methylprop-2-yl)oxycarbonylamino]methyl]-1-(2-trimethylsilylethoxymethyl)pyrazol-3-carboxylate (2.5 g, 6.3 mmol, 1 eq) in DCM (20 mL). The reaction mixture was stirred at room temperature for 8 hours. The reaction mixture was poured onto saturated NaHCO3 and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under vacuum to give the title compound as a yellow oil (1.6 g, 85.4% yield). MS (ESP) m / z = 300.3 [M+H] +

[0672] Step 5: 4-(aminomethyl)-5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylic acid

[0673]

[0674] Methyl 4-(aminomethyl)-5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylate (1.6 g, 5.3 mmol, 1 eq) was added to THF (8 mL), methanol (8 mL), and water (1 mL) with LiOH (320 mg, 13.4 mmol). The mixture was stirred at room temperature for 1 hour. The pH was adjusted to 7 with 1 M HCl, and the mixture was concentrated under vacuum to give the title compound (1.5 g, 98% yield) as a colorless oil. MS (ESP) m / z = 286.1 [M+H] +

[0675] Step 6: 3-Methyl-2-(2-trimethylsilylethoxymethyl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6-one

[0676]

[0677] DIPEA (0.78 mL, 15.8 mmol) and HATU (1.48 g, 6.31 mmol) were added to a solution of 4-(aminomethyl)-5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-3-carboxylic acid (1.5 g, 5.3 mmol, 1 eq) in DMF (60 mL). The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 50% methanol in DCM to give the title compound (320 mg, 23% yield) as a yellow oil. MS (ESP) m / z = 268.1 [M+H] +

[0678] Step 7: 3,5-Dimethyl-2-(2-trimethylsilylethoxymethyl)-4H-pyrrolo[3,4-c]pyrazol-6-one

[0679]

[0680] At 0 °C, 60% sodium hydride (96 mg, 2.4 mmol) in mineral oil was added in portions 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). The mixture was stirred at 0 °C for 30 min. Iodomethane (0.92 mL, 15 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured into saturated NH4Cl and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under vacuum to give the title compound (350 mg, 83% yield) as a yellow oil. MS (ESP) m / z = 282.1 [M+H] +

[0681] Step 8: 3,5-Dimethyl-2,4-dihydropyrrolo[3,4-c]pyrazol-6-one

[0682]

[0683] 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 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (5 mL), and saturated NaHCO3 was added to adjust the pH to 6-7. The mixture was concentrated under reduced pressure. DCM (10 mL) and MeOH (1 mL) were added, and the resulting suspension was stirred at 20 °C for 10 min. After filtering off the solid, the filtrate was concentrated under vacuum to give the title compound as a yellow oil (180 mg, 1.2 mmol, 96% yield). The crude product was used directly in the next step without further purification. MS (ESP) m / z = 152.1 [M+H] +

[0684] Step 9: 2-(3-acetyl-6-chloropyridin-2-yl)-3,5-dimethyl-4H-pyrrolo[3,4-c]pyrazol-6-one

[0685]

[0686] Similar to Step 1 of Example 1, this compound was prepared by using 3,5-dimethyl-2,4-dihydropyrrolo[3,4-c]pyrazol-6-one instead of 5-methyl-1H-pyrazol-3-carboxynitrile and K₂CO₃ instead of DIPEA to give the yellow, oily title compound. MS (ESP) m / z = 305.0 [M+H] +

[0687] Step 10: 2-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-3,5-dimethyl-4H-pyrrolo[3,4-c]pyrazol-6-one

[0688]

[0689] Similar to step 2 of Example 20, this compound was prepared by replacing 1-(6-chloro-3-formyl-2-pyridinyl)-3,5-dimethyl-4H-pyrrolo[3,4-c]pyrazol-6-one with 2-(3-acetyl-6-chloropyridinyl)-5-methylpyrazol-3-carboxynitrile to obtain the title compound as a gray solid. MS (ESP) m / z = 495.3 [M+H] +

[0690] Step 11: 2-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-3,5-dimethyl-4H-pyrrolo[3,4-c]pyrazol-6-one

[0691]

[0692] Similar to step 6 of Example 17, this compound was prepared by replacing 4-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-3,5-dimethyl-4H-pyrrolo[3,4-c]pyrazol-6-one with 2-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-2-pyridyl]-3-fluoro-1-(2,2,2-trifluoroethyl)-2-pyridinone to obtain the title compound as a yellow solid. MS (ESP) m / z = 497.2 [M+H] +

[0693] Example 33

[0694] 1-[2-[3-methyl-1-(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

[0695]

[0696] Step 1: 4-[6-[3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridin-6-yl]oxypyridazin-3-yl]morpholine

[0697]

[0698] Similar to steps 1 to 3 of Example 14, this compound was prepared by using 4-(6-chloropyridazine-3-yl)morpholine instead of 3-chloro-6-methylpyridazine to obtain the title compound as a grayish-white solid. MS (ESP) m / z = 424.2 [M+H] +

[0699] Step 2: 1-[2-[3-methyl-1-(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

[0700]

[0701] Similar to steps 7 and 8 of Example 24, this example was prepared by using 4-[6-[3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridin-6-yl]oxypyridazin-3-yl]morpholine instead of 6-(6-methylpyridazin-3-yl)oxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridine to obtain the title compound as a white solid. MS (ESP) m / z = 581.2 [M+H] +

[0702] Example 34

[0703] 1-[2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-6-[6-[6-[6-(morpholin-4-ylmethyl)pyridazin-3-yl]oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-3-yl]ethanol

[0704]

[0705] Step 1: 4-[(6-chloropyridazine-3-yl)methyl]morpholine

[0706]

[0707] 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 h. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative HPLC to give the title compound (1 g, 51% yield) as a yellow solid. MS (ESP) m / z = 214.0 [M+H] +

[0708] Step 2: 4-[[6-[3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridin-6-yl]oxypyridazin-3-yl]methyl]morpholine

[0709]

[0710] Similar to steps 1 to 3 of Example 14, this compound was prepared by using 4-[(6-chloropyridazine-3-yl)methyl]morpholine instead of 3-chloro-6-methylpyridazine to give the yellow, oily title compound. MS (ESP) m / z = 438.1 [M+H] +

[0711] Step 3: 1-[2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-6-[6-[6-[6-(morpholin-4-ylmethyl)pyridazin-3-yl]oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-3-yl]ethanol

[0712]

[0713] Similar to steps 7 and 8 of Example 24, this example was prepared by using 4-[[6-[3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridin-6-yl]oxypyridazin-3-yl]methyl]morpholine instead of 6-(6-methylpyridazin-3-yl)oxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridine to obtain the title compound as a white solid. MS (ESP) m / z = 595.2 [M+H] +

[0714] Example 35:

[0715] 1-[2-[5-methyl-1-(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

[0716]

[0717] Similar to Example 25, this example was prepared by using 4-[[6-[3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridin-6-yl]oxypyridazin-3-yl]methyl]morpholine instead of 6-(6-methylpyridazin-3-yl)oxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridine to give the title compound as a white solid. MS (ESP) m / z = 581.2 [M+H] +

[0718] Example 36

[0719] 1-[6-[6-[6-(difluoromethyl)pyridazin-3-yl]oxypyrazolo[1,5-a]pyridin-3-yl]-3-[(1S)-1-hydroxyethyl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0720]

[0721] Step 1: 6-[6-(difluoromethyl)pyridazin-3-yl]oxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridine

[0722]

[0723] Similar to steps 1 to 3 of Example 14, this compound was prepared by using 3-chloro-6-(difluoromethyl)pyridazine (CAS [1706439-95-3]) instead of 3-chloro-6-methylpyridazine to obtain the light brown, oily title compound. MS (ESP) m / z = 389.3 [M+H] +

[0724] Step 2: 1-[6-[6-[6-(difluoromethyl)pyridazin-3-yl]oxypyrazolo[1,5-a]pyridin-3-yl]-3-[(1S)-1-hydroxyethyl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0725]

[0726] Add 1-[6-chloro-3-[(1S)-1-hydroxyethyl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile (see Example 12, step 7 for preparation) (39.6 mg, 0.15 mmol), K2CO3 (63 mg, 0.45 mmol), and water (1 mL) to a solution of 6-[6-(difluoromethyl)pyridazin-3-yl]oxy-3-yl]-5-methylpyrazol-3-carboxynitrile (see Example 12, step 7 for preparation) in DMF (3 mL). Bubble the mixture with argon gas for 5 minutes. A 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (12 mg, 0.015 mmol; CAS [564483-18-7]) was added to the reaction mixture. The reaction was stirred at room temperature for 10 min and then heated to 45 °C for 30 min. The reaction mixture was cooled to room temperature, poured onto water, and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel, eluting with 0% to 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] +

[0727] Example 37

[0728] 1-[6-[6-[6-(4-methylpiperazin-1-yl)pyridazin-3-yl]oxypyrazolo[1,5-a]pyridin-3-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]ethanol

[0729]

[0730] Step 1: 6-(6-chloropyridazine-3-yl)oxypyrazolo[1,5-a]pyridine

[0731]

[0732] Similar to Step 1 of Example 34, this example was prepared by using 3,6-dichloropyridazine (CAS [141-30-0]) instead of morpholine hydrochloride to obtain the title compound as a yellow solid. MS (ESP) m / z = 247.1 [M+H] +

[0733] Step 2: 6-[6-(4-methylpiperazin-1-yl)pyridazin-3-yl]oxypyrazolo[1,5-a]pyridine

[0734]

[0735] A mixture of 6-(6-chloropyridazine-3-yl)oxypyrazolo[1,5-a]pyridine (700 mg, 2.8 mmol), 1-methylpiperazine (56 mg, 5.7 mmol), and KHCO3 (568 mg, 5.7 mmol) in DMF (15 mL) was stirred at 130 °C for 12 h. The reaction mixture was filtered, and the filtrate was poured over water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by preparative HPLC to give the title compound (350 mg, 34% yield) as a brown solid. MS (ESP) m / z = 311.1 [M+H] +

[0736] Step 3: 6-[6-(4-methylpiperazin-1-yl)pyridazin-3-yl]oxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridine

[0737]

[0738] Similar to steps 2 and 3 of Example 14, this compound was prepared by replacing 6-(6-methylpyrazin-1-yl)pyrazin-3-yl]oxypyrazolo[1,5-a]pyridine with 6-[6-methylpyrazin-3-yl)oxypyrazolo[1,5-a]pyridine to give the title compound as a white solid. MS (ESP) m / z = 437.3 [M+H] +

[0739] Step 4: 1-[6-[6-[6-(4-methylpiperazin-1-yl)pyridazin-3-yl]oxypyrazolo[1,5-a]pyridin-3-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]ethanol

[0740]

[0741] Similar to steps 7 and 8 of Example 24, this example was prepared by using 6-[6-(4-methylpiperazin-1-yl)pyridazin-3-yl]oxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridine instead of 6-(6-methylpyridazin-3-yl)oxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridine to obtain the title compound as a white solid. MS (ESP) m / z = 594.2 [M+H] +

[0742] Example 38

[0743] 1-[2-[3-(difluoromethyl)-5-methylpyrazol-1-yl]-6-[6-[6-[(3-methoxyazacyclobutane-1-yl)methyl]pyridazin-3-yl]oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-3-yl]ethanol

[0744]

[0745] Step 1: 3-Chloro-6-[(3-methoxyazacyclobutane-1-yl)methyl]pyridazine

[0746]

[0747] Similar to step 1 of Example 34, this compound was prepared by using 3-methoxyazacyclobutane hydrochloride instead of morpholine hydrochloride, DIPEA instead of KHCO3, and THF instead of acetonitrile to obtain the brown, oily title compound. MS (ESP) m / z = 214.2 [M+H] +

[0748] Step 2: 3-Bromo-6-[6-[(3-methoxyazacyclobutane-1-yl)methyl]pyridazin-3-yl]oxypyrazolo[1,5-a]pyridine

[0749]

[0750] Similar to steps 2 and 3 of Example 14, this compound was prepared by replacing 4-(2-pyrazolo[1,5-a]pyridin-6-yloxyethyl)morpholine with 3-chloro-6-[(3-methoxyazacyclobutane-1-yl)methyl]pyridazine to obtain the title compound as a grayish-white solid. MS (ESP) m / z = 390.2 [M+H] +

[0751] Step 3: 1-[2-[3-(difluoromethyl)-5-methylpyrazol-1-yl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyridin-3-yl] acetone

[0752]

[0753] Similar to step 7 of Example 12, the yellow oily title compound was obtained by using 3-(difluoromethyl)-5-methyl-1H-pyrazole instead of 5-methyl-1H-pyrazole-3-carboxynitrile, K2CO3 instead of DIPEA, and DMF instead of DMSO. MS (ESP) m / z = 296.2 [M-pinacol + H] +

[0754] Step 4: 1-[2-[3-(difluoromethyl)-5-methylpyrazol-1-yl]-6-[6-[6-[(3-methoxyazacyclobutane-1-yl)methyl]pyridazin-3-yl]oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-3-yl]acetone

[0755]

[0756] Similar to step 9 of Example 12, the yellow gelatinous title compound was obtained by replacing 1-[6-chloro-3-[(1S)-1-hydroxyethyl]pyridazin-3-carboxylonitrile] with 3-bromo-6-[6-[(3-methoxyazino-1-yl)methyl]pyridazin-3-yl]oxypyrazolo[1,5-a]pyridine, and by replacing 1-[3-[(1S)-1-hydroxyethyl]pyridin-2-yl]-5-methylpyrazol-3-carboxylonitrile with 1-[2-[3-(difluoromethyl)-5-methylpyrazol-1-yl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyridin-3-yl]acetone. MS (ESP) m / z = 561.4 [M+H] +

[0757] Step 5: 1-[2-[3-(difluoromethyl)-5-methylpyrazol-1-yl]-6-[6-[6-[(3-methoxyazacyclobutane-1-yl)methyl]pyridazin-3-yl]oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-3-yl]ethanol

[0758]

[0759] This example was prepared similarly to step 6 of Example 17 to obtain the title compound as a white solid. MS (ESP) m / z = 563.3 [M+H] +

[0760] Example 39

[0761] 1-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)thiopyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0762]

[0763] Step 1: 6-(6-methylpyridazin-3-yl)thiopyrazolo[1,5-a]pyridine

[0764]

[0765] A mixture of 6-bromopyrazolo[1,5-a]pyridine (1 g, 5.1 mmol, 1 eq) in DMF (8 mL) with 6-methylpyridazin-3-thiol (640 mg, 5.08 mmol; CAS [5788-47-6]), K₂CO₃ (2.1 g, 15.2 mmol), and cuprous iodide (I) (967 mg, 5.08 mmol) was stirred at 150 °C for 72 h. The reaction was cooled to room temperature, poured onto methanol, stirred for 10 min, filtered through diatomaceous earth, and concentrated under vacuum. Water was added, and the mixture was extracted with TBME. The organic layer was dried over Na₂SO₄ and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 0% to 5% methanol in DCM to give the title compound as a pale yellow solid (220 mg, 17% yield). MS (ESP) m / z = 242.1 [M+H] +

[0766] Step 2: 3-Iodo-6-(6-methylpyridazin-3-yl)thiopyrazolo[1,5-a]pyridine

[0767]

[0768] N-iodosuccinimide (211 mg, 0.94 mmol) was added to a stirred solution of 6-(6-methylpyridin-3-yl)thiopyrazolo[1,5-a]pyridine (220 mg, 0.85 mmol, 1 eq) in acetonitrile (5 mL). The reaction mixture was stirred for 1 h. The reaction mixture was purified by rapid chromatography on silica gel by elution with 0% to 8% methanol in DCM to give the title compound (430 mg, quantitative yield) as a light brown solid, which was used as is in the next step. MS (ESP) m / z = 369.0 [M+H] +

[0769] Step 3: 6-(6-methylpyridazin-3-yl)thio-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridine

[0770]

[0771] At 0 °C, isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane (675 mg, 0.74 mL, 3.63 mmol) was added to a stirred solution of 3-iodo-6-(6-methylpyridin-3-yl)thiopyrazolo[1,5-a]pyridine (330 mg, 0.81 mmol, 1 eq) in THF (5.1 mL), followed by dropwise addition of 1.3 M isopropyl magnesium chloride LiCl (0.62 mL, 0.81 mmol) in THF. The reaction mixture was stirred at 0 °C for 30 min. Two more additions of 1.3 M isopropyl magnesium chloride LiCl in THF were made, each time 0.62 mL, 0.81 mmol, and the reaction was stirred at 0 °C for 30 min. The reaction mixture was poured over water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 0% to 5% methanol in DCM to give the title compound (51 mg, 16% yield) as a pale yellow oil. MS (ESP) m / z = 369.2 [M+H] +

[0772] Step 4: 1-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)thiopyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0773]

[0774] To a solution of 6-(6-methylpyridazin-3-yl)thio-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridine (51 mg 0.13 mmol, 1 eq) in DMF (0.8 mL) and water (0.4 mL), 1-(3-acetyl-6-chloropyridin-2-yl)-5-methylpyrazol-3-carboxynitrile (see Example 1, Step 1) (36 mg, 0.14 mmol) and K2CO3 (52 mg, 0.37 mmol) were added. Argon gas was bubbled through the mixture and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (21 mg, 0.022 mmol, 0.2 eq; CAS [95464-05-4]) was added. The reaction was stirred at 45 °C for 30 min. The mixture was poured over water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel, eluting with 0% to 5% methanol in DCM, followed by a second rapid chromatography on silica gel, eluting with 0% to 2% methanol in ethyl acetate, to give the title compound as a pale yellow solid (48 mg, 95% yield). MS (ESP) m / z = 467.2 [M+H] +

[0775] Step 5: 1-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)thiopyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0776]

[0777] At 0 °C, NaBH4 (2 mg, 0.1 mmol) was added to a solution of 1-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)thiopyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile (20 mg, 0.043 mmol, 1 eq) in methanol (4 mL) and tetrahydrofuran (4 mL). The mixture was poured over water and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 0% to 5% methanol in DCM to give the title compound (19 mg, 95% yield) as a pale yellow solid. MS (ESP) m / z = 469.2 [M+H] +

[0778] Example 40

[0779] 1-[3-(1-hydroxyethyl)-6-pyrazolo[1,5-a]pyridin-3-ylpyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0780]

[0781] In the preparation process of Example 2, the byproducts were isolated to obtain the title compound as a white lyophilized solid (5.4 mg, yield 40.7%). MS (ESP) m / z = 327.1 [M+H] +

[0782] Example 41

[0783] 1-[2-[6-[4-(oxecyclobutane-3-yl)piperazin-1-yl]pyrazolo[1,5-a]pyridin-3-yl]-4-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-1,3-thiazolyl-5-yl]ethanol

[0784]

[0785] Step 1: N-(4-chloro-5-formyl-1,3-thiazolyl-2-yl)tert-butyl carbamate

[0786]

[0787] Di-tert-butyl dicarbonate (5.64 g, 25.83 mmol; CAS [76874-79-8]) and 4-dimethylaminopyridine (262.97 mg, 2.15 mmol; CAS [1122-58-3]) were added to a suspension of 2-amino-4-chloro-thiazolyl-5-carboxaldehyde (3.5 g, 21.53 mmol; CAS [24424-99-5]) in 1,4-dioxane (35 mL). The mixture was stirred overnight at room temperature and then poured onto a 5% potassium bisulfate solution and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by DCM elution to give the title compound as a yellow solid (5.29 g, 94% yield). MS (ESP) m / z = 261.2 [M+H] +

[0788] Step 2: N-[4-chloro-5-(hydroxymethyl)-1,3-thiazolyl-2-yl] tert-butyl carbamate

[0789]

[0790] N-(4-chloro-5-formyl-1,3-thiazolyl-2-yl)carbamate tert-butyl ester (7.7 g, 29.3 mmol, 1 eq) was dissolved in tetrahydrofuran (113 mL). 3.2 M methylmagnesium bromide (27.5 mL, 87.9 mmol) was added dropwise to 2-methyltetrahydrofuran at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was poured onto a saturated NH4Cl solution and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under vacuum to give the title compound as a yellow solid (8.68 g, quantitative yield). The product was used immediately for the next step. MS (ESP) m / z = 279.1 [M+H] +

[0791] Step 3: N-(4-chloro-5-formyl-1,3-thiazolyl-2-yl)tert-butyl carbamate

[0792]

[0793] Manganese dioxide (97 g, 1.1 mol) was added to a solution of N-[4-chloro-5-(hydroxymethyl)-1,3-thiazolyl-2-yl]carbamate tert-butyl (8.68 g, 31.1 mmol, 1 eq) in 1,2-dichloroethane (216 mL). The reaction was stirred overnight at room temperature under nitrogen. The mixture was filtered through diatomaceous earth and the filtrate was concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution 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] -

[0794] Step 4: 1-[2-amino-4-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-1,3-thiazolyl-5-yl] ethyl ketone

[0795]

[0796] To a solution of N-(4-chloro-5-formyl-1,3-thiazolyl-2-yl)carbamate tert-butyl ester (2 g, 7.23 mmol, 1 eq) in DMF (20 mL), 4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole CAS [1049730-42-8] (2.49 g, 9.03 mmol), Na2CO3 (2.3 g, 21.7 mmol), and water (10 mL) were added. Argon gas was bubbled through the mixture for 5 minutes, and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane complex 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 under vacuum, and the residue was dissolved in dichloromethane (20 mL) with the addition of TFA (5.6 mL). The reaction was stirred at room temperature for 3 hours. The reaction mixture was poured over water and extracted with DCM. The organic layer was extracted twice with 4N HCl. The combined aqueous layers were alkalized to pH 10 by adding 32% NaOH. The aqueous layer was then extracted with DCM, washed with water and saturated NaCl, and then subjected to Na... The sample was dried over 2SO4 and concentrated under vacuum to give the title compound as a yellow solid (1.6 g, 76% yield). MS (ESP) m / z = 291.1 [M+H] +

[0797] Step 5: 1-[2-chloro-4-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-1,3-thiazolyl-5-yl] ethyl ketone

[0798]

[0799] Amyl nitrite (1.61 g, 1.85 mL, 13.8 mmol) was added to a suspension of copper(II) chloride (1.48 g, 11.0 mmol) in acetonitrile (100 mL). The mixture was heated to 65 °C. A suspension of 1-[2-amino-4-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-1,3-thiazolyl-5-yl]acetone (1.6 g, 5.5 mmol, 1 eq) in acetonitrile (50 mL) was added to the reaction mixture. The reaction was stirred at 65 °C for 10 min. The reaction mixture was cooled to room temperature, poured onto 2 M HCl, and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 0% to 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] +

[0800] Step 6: 1-[2-[6-[4-(oxecyclobutane-3-yl)piperazin-1-yl]pyrazolo[1,5-a]pyridin-3-yl]-4-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-1,3-thiazolyl-5-yl]ethanol

[0801]

[0802] Similar to steps 4 through 6 of Example 1, this example was prepared by replacing 1-(3-acetyl-6-chloropyridin-2-yl)-5-methylpyrazol-3-carboxynitrile with 1-[2-chloro-4-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-1,3-thiazolyl-5-yl]acetophenone in step 4 to obtain the title compound as a white-yellow solid. MS (ESP) m / z = 534.2 [M+H] +

[0803] Example 42

[0804] 1-Cyclopropyl-4-[5-(1-hydroxyethyl)-2-(6-methoxypyrazolo[1,5-a]pyridin-3-yl)-1,3-thiazolyl-4-yl]pyridin-2-one

[0805]

[0806] Step 1: 4-Bromo-1-cyclopropylpyridin-2-one

[0807]

[0808] To a solution of cyclopropylboronic acid (11.35 g, 132.18 mmol; CAS [411235-57-9]) and 4-bromo-1H-pyridin-2-one (10.0 g, 57.47 mmol, 1 eq; CAS 36953-37-4) in 1,2-dichloroethane (300 mL), 2-pyridin-2-ylpyridine (9.6 g, 61.49 mmol; CAS [77790-61-5]), Na₂CO₃ (18.27 g, 172.41 mmol) and copper acetate (11.17 g, 61.49 mmol) were added. The mixture was stirred at 70 °C for 40 hours. The reaction was cooled to room temperature and concentrated under vacuum. The residue was dissolved in EtOAc, filtered, and the filtrate was washed with 1M HCl (200.0 ml). The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 2% to 80% ethyl acetate in petroleum ether to give the title compound as a grayish-white solid (6 g, 49% yield). MS (ESP) m / z = 214.0 [M+H] +

[0809] Step 2: (1-Cyclopropyl-2-oxopyridin-4-yl)boronic acid

[0810]

[0811] 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-1-cyclopropyl-pyridin-2-one (5 g, 23.4 mmol, 1 eq) in THF (10 mL). 1.3 M isopropylmagnesium chloride-lithium chloride (26.95 mL, 35.04 mmol) in THF was added dropwise, and the reaction was stirred at -10 °C for 12 h. The mixture was poured into 1 M HCl, and the aqueous layer was washed with EtOAc and DCM. The aqueous layer was lyophilized to give the title compound as a grayish-white solid (4 g, 96% yield). MS (ESP) m / z = 180.0 [M+H] +

[0812] Step 3: 1-(2,4-dichloro-1,3-thiazo-5-yl)ethanol

[0813]

[0814] Under nitrogen atmosphere, at -78°C, 3M methyl magnesium bromide (1.1 mL, 3.3 mmol) in THF was added to a solution of 2,4-dichlorothiazol-5-carboxaldehyde CAS [92972-48-0] (500 mg, 2.8 mmol) in THF (10 mL). The mixture was heated to -40°C and stirred for 1 hour. The mixture was poured onto saturated NH4Cl and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under vacuum to give the title compound (520 mg, 96% yield) as a colorless oil. MS (ESP) m / z = 197.8 [M+H] +

[0815] Step 4: 1-(2,4-Dichloro-1,3-thiazo-5-yl)acetone

[0816]

[0817] Add Desmond-Martin periodane (1.67 g, 3.94 mmol; CAS [87413-09-0]) to a solution of 1-(2,4-dichloro-1,3-thiazo-5-yl)ethanol (520 mg, 2.6 mmol) in DCM (10 mL) at 0 °C. Stir the mixture at room temperature for 1 hour, filter, and evaporate to dryness. Purify the residue by rapid chromatography on silica gel, eluting with 0% to 20% ethyl acetate in petroleum ether, to give the colorless title compound (450 mg, 87% yield). ¹H NMR (400 MHz, chloroform-d) δ = 2.70 (s, 3H)

[0818] Step 5: 6-Methoxy-3-(4,4,5,5-Tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridine

[0819]

[0820] Similar to step 4 of Example 31, this compound was prepared by replacing 6-benzyloxy-3-bromo-pyrazolo[1,5-a]pyridine with 3-bromo-6-methoxy-pyrazolo[1,5-a]pyridine (CAS [1823050-60-7]) and by being anhydrous, to obtain the title compound as a grayish-white solid. MS (ESP) m / z = 275.0 [M+H] +

[0821] Step 6: 1-[4-chloro-2-(6-methoxypyrazolo[1,5-a]pyridin-3-yl)-1,3-thiazolyl-5-yl] ethyl ketone

[0822]

[0823] To a solution of 6-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridine (201 mg, 1.12 mmol) and 1-(2,4-dichloro-1,3-thiazolyl-5-yl)acetone (210 mg, 1.07 mmol) (see Example 42, step 4 for preparation) in 1,4-dioxane (5 mL) and water (0.500 mL), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (175 mg, 0.21 mmol; CAS [95464-05-4]) and Na2CO3 (227 mg, 2.1 mmol) were added, and the mixture was heated at 100 °C for 12 hours under nitrogen. The mixture was evaporated to dryness, and the residue was purified by rapid chromatography on silica gel by elution 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] +

[0824] Step 7: 4-[5-acetyl-2-(6-methoxypyrazolo[1,5-a]pyridin-3-yl)-1,3-thiazolyl-4-yl]-1-cyclopropylpyridin-2-one

[0825]

[0826] To a brown solution of 1-[4-chloro-2-(6-methoxypyrazolo[1,5-a]pyridin-3-yl)-1,3-thiazo-5-yl]acetone (180.0 mg, 0.580 mmol) and (1-cyclopropyl-2-oxopyridin-4-yl)boronic acid (see Example 42, Step 2 for preparation) (120.4 mg, 0.670 mmol) in 1,4-dioxane (5 mL) and water (0.500 mL), Na₂CO₃ (124 mg, 1.17 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloromethane complex (95.4 mg, 0.120 mmol) were added to the mixture. 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 under vacuum. The crude product 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] +

[0827] Step 8: 1-Cyclopropyl-4-[5-(1-hydroxyethyl)-2-(6-methoxypyrazolo[1,5-a]pyridin-3-yl)-1,3-thiazolyl-4-yl]pyridin-2-one

[0828]

[0829] Sodium borohydride (6 mg, 0.2 mmol) was added to a solution of 4-[5-acetyl-2-(6-methoxypyrazolo[1,5-a]pyridin-3-yl)thiazolyl]-1-cyclopropylpyridin-2-one (40 mg, 0.10 mmol) in methanol (3 mL) at 0 °C. The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured onto saturated NH4Cl and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by preparative HPLC to give the title compound (26.1 mg, 65% yield) as a white solid. MS (ESP) m / z = 409.1 [M+H] +

[0830] Example 43

[0831] 4-[5-(1-hydroxyethyl)-2-[6-(2-morpholin-4-ylethoxy)pyrazolo[1,5-a]pyridin-3-yl]-1,3-thiazolyl]-1-(2,2,2-trifluoroethyl)pyridin-2-one

[0832]

[0833] Step 1: N-(4-chloro-5-formyl-1,3-thiazolyl-2-yl)tert-butyl carbamate

[0834]

[0835] To a suspension of 2-amino-4-chloro-thiazolyl-5-carboxaldehyde (4.96 g, 30.5 mmol; CAS [76874-79-8]) in 1,4-dioxane (49.6 mL), di-tert-butyl dicarbonate (7.99 g, 36.6 mmol) and 4-dimethylaminopyridine (373 mg, 3.15 mmol) were added. The suspension was stirred at room temperature for three days. The reaction mixture was poured onto a 5% potassium hydrogen sulfate solution and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution 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] +

[0836] Step 2: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1-(2,2,2-trifluoroethyl)pyridin-2-one

[0837]

[0838] Similar to steps 1 and 2 of Example 17, for step 1, 3-fluoro-4-iodo-2-pyridinone was replaced with 4-bromo-1H-pyridin-2-one (CAS [36953-37-4]), and tris(dibenzylacetone)dipalladium(II)dichloromethane complex (CAS [95464-05-4]) was replaced with [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane complex (CAS [95464-05-4]) to obtain the title compound as a gray solid. MS (ESP) m / z = 222.1 [M-pinacol ester + H] +

[0839] Step 3: N-[5-formyl-4-[2-oxo-1-(2,2,2-trifluoroethyl)pyridin-4-yl]-1,3-thiazolyl]tert-butyl carbamate

[0840]

[0841] To a solution of N-(4-chloro-5-formyl-1,3-thiazolyl-2-yl)carbamate tert-butyl ester (1.61 g, 6.14 mmol) in DMF (40 mL), 4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1-(2,2,2-trifluoroethyl)pyridin-2-one (1.96 g, 6.14 mmol), Na₂CO₃ (2.05 g, 19.4 mmol), and water (20 mL) were added. Argon gas was bubbled through the mixture for 30 min, 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 h. The reaction mixture was poured over water and extracted with EtOAc. The organic layer was dried over Na₂SO₄ and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 0% to 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] +

[0842] Step 4: N-[5-(1-hydroxyethyl)-4-[2-oxo-1-(2,2,2-trifluoroethyl)pyridin-4-yl]-1,3-thiazolyl]tert-butyl carbamate

[0843]

[0844] N-[5-formyl-4-[2-oxo-1-(2,2,2-trifluoroethyl)pyridin-4-yl]-1,3-thiazo-2-yl]tert-butyl carbamate (1.14 g, 2.57 mmol) was dissolved in THF (18 mL). 3.2 M methyl magnesium bromide (2.41 mL, 7.72 mmol) in 2-methyltetrahydrofuran was added dropwise at 0 °C. The reaction was stirred at 0 °C for 50 min and then poured onto saturated NH4Cl. The mixture was extracted with EtOAc, the organic layer was dried over Na2SO4, and concentrated under vacuum. The crude product was ground with DCM to give the title compound as a white solid (1.05 g, 97% yield). MS (ESP) m / z = 420.2 [M+H] +

[0845] Step 5: N-[5-acetyl-4-[2-oxo-1-(2,2,2-trifluoroethyl)pyridin-4-yl]-1,3-thiazolyl]tert-butyl carbamate

[0846]

[0847] Manganese dioxide (2.32 g, 26.7 mmol) was added to a solution of N-[5-acetyl-4-[2-oxo-1-(2,2,2-trifluoroethyl)pyridin-4-yl]-1,3-thiazo-2-yl]carbamate tert-butyl (560 mg, 1.34 mmol) in 1,2-dichloroethane (10 mL). The reaction was stirred at 60 °C under nitrogen for 30 min. The suspension was filtered through diatomaceous earth, and the filtrate was evaporated under vacuum to give the title compound as a brown solid (474 ​​mg, 82% yield). MS (ESN) m / z = 416.3 [M+H] -

[0848] Step 6: 4-(5-acetyl-2-amino-1,3-thiazolyl-4-yl)-1-(2,2,2-trifluoroethyl)pyridin-2-one

[0849]

[0850] TFA (5 mL) was added to a solution of N-[5-acetyl-4-[2-oxo-1-(2,2,2-trifluoroethyl)pyridin-4-yl]-1,3-thiazo-2-yl]carbamate (474 ​​mg, 1.14 mmol) in DCM (5 mL). The solution was stirred at room temperature for 2 hours. The solution was poured onto saturated NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under vacuum to give the title compound as a yellow solid (346 mg, 96% yield). MS (ESP) m / z = 318.1 [M+H] +

[0851] Step 7: 4-(5-acetyl-2-chloro-1,3-thiazolyl-4-yl)-1-(2,2,2-trifluoroethyl)pyridin-2-one

[0852]

[0853] Amyl nitrite (0.49 mL, 3.7 mmol) was added to a suspension of copper(II) chloride (396 mg, 2.95 mmol) in acetonitrile (10 mL). The mixture was heated to 65 °C, and a suspension of 4-(5-acetyl-2-amino-1,3-thiazolyl-4-yl)-1-(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 at 65 °C for 10 min. The reaction mixture was cooled to room temperature and poured onto 2 M HCl. The solution was extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 0% to 50% ethyl acetate in heptane to give the title compound (302 mg, 61% yield) as a yellow oil. MS (ESP) m / z = 337.0 [M+H] +

[0854] Step 8: 4-[5-acetyl-2-[6-(2-morpholin-4-ylethoxy)pyrazolo[1,5-a]pyridin-3-yl]-1,3-thiazolyl-4-yl]-1-(2,2,2-trifluoroethyl)pyridin-2-one

[0855]

[0856] Add 4-(5-acetyl-2-chloro-1,3-thiazolyl-2-yl)pyrazolo[1,5-a]pyridin-6-yl]oxyethyl]morpholine (see Example 13, step 4 for preparation) (50 mg, 0.13 mmol) to a solution of 4-[2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-1-(2,2,2-trifluoroethyl)pyridin-2-one (51 mg, 0.15 mmol), K2CO3 (53 mg, 0.38 mmol), and water (1.5 mL) to a solution of 4-[2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-1-(2,2,2-trifluoroethyl)pyridin-2-one (51 mg, 0.15 mmol), K2CO3 (53 mg, 0.38 mmol), and water (1.5 mL). Bubble the mixture with argon gas for 5 minutes. 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (10 mg, 0.013 mmol; CAS [95464-05-4]) was added, and the reaction mixture was stirred at 100 °C for 1 h. The reaction was cooled to room temperature, EtOAc was added, followed by 5 g of SiliaMetS (metal scavenger), and the mixture was stirred for 1 h. After filtration, water was added, and the aqueous layer was extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under vacuum to give the title compound as a dark brown oil (200 mg, quantitative yield). The crude product was used directly in the next step without further purification.

[0857] Step 9: 4-[5-(1-hydroxyethyl)-2-[6-(2-morpholin-4-ylethoxy)pyrazolo[1,5-a]pyridin-3-yl]-1,3-thiazolyl]-1-(2,2,2-trifluoroethyl)pyridin-2-one

[0858]

[0859] To a solution of 4-[5-acetyl-2-[6-(2-morpholin-4-ylethoxy)pyrazolo[1,5-a]pyridin-3-yl]-1,3-thiazolyl]-1-(2,2,2-trifluoroethyl)pyridin-2-one (200 mg, 0.13 mmol) in methanol (5 mL), NaBH4 (34 mg, 0.90 mmol) was added. The mixture was stirred at room temperature for 30 min. Water was added, and the mixture was extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by preparative HPLC to give the title compound as a white solid (24 mg, 34% yield). MS (ESP) m / z = 550.3 [M+H] +

[0860] Example 44

[0861] 1-[2-[6-(2-morpholin-4-ylethoxy)pyrazolo[1,5-a]pyridin-3-yl]-4-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-1,3-thiazolyl-5-yl]ethanol

[0862]

[0863] Similar to Example 43, this example was prepared in step 8 by replacing 4-(5-acetyl-2-chloro-1,3-thiazolyl-4-yl)-1-(2,2,2-trifluoroethyl)pyridin-2-one with 1-[2-chloro-4-[1-(2,2,2-trifluoroethyl)pyridin-4-yl]-1,3-thiazolyl-5-yl]acetone to obtain the title compound as a white solid. MS (ESN) m / z = 567.3 [M+HCOO] -

[0864] Example 45

[0865] 1-[2-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-4-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-1,3-thiazolyl-5-yl]ethanol

[0866]

[0867] Similar to Example 14, this example was prepared by replacing 1-[3-acetyl-6-(6-bromopyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl]-5-methylpyrazol-3-carboxylonitrile with 1-[2-chloro-4-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-1,3-thiazolyl-5-yl]acetonitrile and using 100 °C instead of 45 °C to obtain the title compound as a grayish-white solid. MS (ESN) m / z = 546.3 [M+HCOO] -

[0868] Example 46

[0869] 3-Fluoro-4-[5-(1-hydroxyethyl)-2-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-1,3-thiazolyl]-1-(2,2,2-trifluoroethyl)pyridin-2-one

[0870]

[0871] Step 1: 1-[4-chloro-2-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-1,3-thiazolyl]acetone

[0872]

[0873] To a solution of 6-(6-methylpyridazin-3-yl)oxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridine (200 mg, 0.17 mmol) (see Example 14, step 3 for preparation), 1-(2,4-dichlorothiazol-5-yl)acetone (40 mg, 0.20 mmol) (see Example 42, step 4 for preparation), K2CO3 (71 mg, 0.51 mmol), and water (0.75 mL) were added. Argon gas was bubbled through the mixture for 5 minutes. 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane 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 mixture was cooled to room temperature, poured onto water, and extracted with DCM. The organic layer was dried over Na₂SO₄ and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 0% to 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] +

[0874] Step 2: 4-[5-acetyl-2-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-1,3-thiazolyl-4-yl]-3-fluoro-1-(2,2,2-trifluoroethyl)pyridin-2-one

[0875]

[0876] To a solution of 1-[4-chloro-2-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]thiazolyl-5-yl]acetone (46 mg, 0.10 mmol) in 1,4-dioxane (4 mL) and water (0.4 mL), Na₂CO₃ (27 mg, 0.25 mmol) and a 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloromethane complex (17 mg, 0.02 mmol; CAS [95464-05-4]) were added. The mixture was degassed with argon and heated to 80 °C. 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1-(2,2,2-trifluoroethyl)pyridin-2-one (see Example 17, step 2) (63 mg, 0.15 mmol) was added to 1,4-dioxane (2 mL), and stirring was continued at 80 °C for 30 min. More 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1-(2,2,2-trifluoroethyl)pyridin-2-one (42 mg, 0.10 mmol) was added, and stirring was continued at 80 °C for 30 min. The mixture was cooled to room temperature and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 0% to 5% methanol in DCM to give the title compound as a brown solid, which could be used directly in the next step without further purification (100 mg, quantitative yield). MS (ESP) m / z = 545.1 [M+H] +

[0877] Step 3: 3-Fluoro-4-[5-(1-hydroxyethyl)-2-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-1,3-thiazolyl]-1-(2,2,2-trifluoroethyl)pyridin-2-one

[0878]

[0879] To a solution of 4-[5-acetyl-2-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-1,3-thiazo-4-yl]-3-fluoro-1-(2,2,2-trifluoroethyl)pyridin-2-one (100 mg, 0.12 mmol) in methanol (10 mL), NaBH4 (32 mg, 0.85 mmol) was added. This mixture was stirred at room temperature for 1 hour, then poured onto water and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by preparative HPLC by rapid chromatography on silica gel, eluting with 0% to 5% methanol in DCM, to give the title compound as a light brown solid (10 mg, 15% yield). MS (ESP) m / z = 547.1 [M+H] +

[0880] Example 47

[0881] 1-[2-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-4-[2-(2,2,2-trifluoroethyl)triazol-4-yl]-1,3-thiazolyl-5-yl]ethanol

[0882]

[0883] Step 1: 4,5-Dibromo-2-(2,2,2-trifluoroethyl)triazole

[0884]

[0885] Cs₂CO₃ (7.18 g, 22.0 mmol) was added to a solution of 4,5-dibromo-2H-triazole (5.0 g, 22 mmol; CAS [22300-52-3]) in acetonitrile (50 mL). 2,2,2-trifluoroethyl trifluoromethanesulfonic acid (5.12 g, 3.18 mL, 22.0 mmol; CAS [6226-25-1]) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 4.5 h. The reaction mixture was poured over water, extracted with EtOAc, and the organic layer was dried over Na₂SO₄ and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 0% to 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] +

[0886] Step 2: 4-Bromo-2-(2,2,2-trifluoroethyl)triazole

[0887]

[0888] At -78 °C, 2M isopropyl magnesium chloride (3.24 mL, 6.48 mmol) in THF was added to a solution of 4,5-dibromo-2-(2,2,2-trifluoroethyl)triazole (2.0 g, 6.5 mmol) in THF (20 mL). The mixture was warmed to room temperature and stirred for 30 min. Both steps were repeated twice. The reaction mixture was poured onto saturated NH4Cl and extracted with diethyl ether. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by Kugelrohr distillation. The fraction collected at 175 °C gave the title compound (950 mg, 64% yield) as a light brown liquid, which was used as is in the next step.

[0889] Step 3: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2-(2,2,2-trifluoroethyl)triazole

[0890]

[0891] To a solution of 4-bromo-2-(2,2,2-trifluoroethyl)triazole (150 mg, 0.65 mmol) in 1,4-dioxane (4.5 mL), add bis(pinacol)diboron (745 mg, 2.93 mmol) and dry K₂CO₃ (224 mg, 2.28 mmol). Bubble the suspension with argon for 5 min. Add bis(triphenylphosphine)palladium(II) dichloride (46 mg, 0.065 mmol; CAS [13965-03-2]) and stir the reaction mixture at 100 °C for 4.5 h. Cool the reaction to room temperature and add 1,4-dioxane and SiliaMetS. Stir the suspension for 1 h. After filtration, pour the mixture onto water and extract with EtOAc. The organic layer is dried over Na₂SO₄ and concentrated under vacuum to give the title compound as a brown solid, which is used as is in the next step. MS (ESP) m / z = 196.0 [M-Pinalol + H] +

[0892] Step 4: 1-[2-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-4-[2-(2,2,2-trifluoroethyl)triazol-4-yl]-1,3-thiazolyl-5-yl]acetone

[0893]

[0894] Add 4-(4,4,5,5-tetramethyl-1,3,2-dioxane-3-yl)-1,3-thiazolyl-5-yl]acetone (see Example 46, step 1 for preparation) (100 mg, 0.26 mmol) to a solution of 1-[4-chloro-2-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-1,3-thiazolyl-5-yl]acetone (276 mg, 0.26 mmol), Na2CO3 (82 mg, 0.78 mmol), and water (0.5 mL) to a solution of 1,4-dioxane (1 mL). Bubble argon gas through the suspension for 5 minutes. XPhosPd G2 (21 mg, 0.026 mmol; CAS [1310584-14-5]) was added, and the mixture was stirred at 100 °C for 1 hour. The reaction mixture was poured over water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 0% to 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] +

[0895] Step 5: 1-[2-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-4-[2-(2,2,2-trifluoroethyl)triazol-4-yl]-1,3-thiazolyl-5-yl]ethanol

[0896]

[0897] Similar to step 3 of Example 46, this example was prepared by replacing 4-[5-acetyl-2-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-4-[2-(2,2,2-trifluoroethyl)triazol-4-yl]-1,3-thiazolyl-5-yl] acetonitrile with 4-[5-acetyl-2-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-1,3-thiazolyl]-3-fluoro-1-(2,2,2-trifluoroethyl)pyridin-2-one to obtain the title compound as a pale yellow solid. MS (ESP) m / z = 503.1 [M+H] +

[0898] Example 48

[0899] 1-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0900]

[0901] Under argon atmosphere, in a sealed tube, 6-(6-methylpyridazin-3-yl)oxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyrazolo[1,5-a]pyridine (100 mg, 0.23 mmol, 1 eq) (see Example 14, step 5) was dissolved in DMF (2 mL) and water (1 mL). 1-[3-acetyl-6-(6-bromopyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl]-5-methylpyrazol-3-carboxylonitrile (71 mg, 0.27 mmol) (preparation see Example 1, step 4) 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) dichloromethane complex (19 mg, 0.023 mmol; CAS [95464-05-4]) was added, and the mixture was stirred at 45 °C for 1 h. The reaction was cooled to room temperature, poured onto water, and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by rapid chromatography on silica gel by elution with 0% to 100% EtOAc in heptane to give the title compound (98 mg, 88% yield) as a light brown oil. MS (ESP) m / z = 451.1 [M+H] +

[0902] Example 49

[0903] 1-[3-formyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0904]

[0905] Under argon atmosphere, 6-(6-methylpyridazin-3-yl)oxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridine (71 mg, 0.20 mmol, 1 eq) (preparation see Example 14, step 3) and 1-(6-chloro-3-formyl-2-pyridyl)-5-methyl-pyrazol-3-carboxynitrile (50 mg, 0.20 mmol, 1 eq) (preparation see Example 20, step 1) were suspended in DMF (1.5 mL) and water (0.75 mL). K₂CO₃ (84 mg, 0.61 mmol) was added, followed by the addition of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloromethane complex (17 mg, 0.02 mmol; CAS [95464-05-4]). The mixture was stirred at 45 °C for 1 hour. The reaction mixture was diluted with water and extracted with EtOAc. The aqueous phase containing the product in suspension was filtered and washed with water and diethyl ether to give the title compound as a yellow solid (53 mg, 58% yield). MS (ESP) m / z = 437.2 [M+H] +

[0906] Example 50

[0907] 2-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazol-3-carboxynitrile

[0908]

[0909] Similar to 1-[2-[3-(difluoromethyl)-5-methylpyrazol-1-yl]-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-3-yl]acetone (see Example 18, step 5), this example was prepared by using 5-(trifluoromethyl)-1H-pyrazol-3-carboxynitrile (CAS [2166776-07-2]) instead of 3-(difluoromethyl)-5-methyl-1H-pyrazol to obtain the title compound as a brown solid. MS (ESP) m / z = 505.1 [M+H] +

[0910] Example 51

[0911] 1-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-cyclopropylpyrazol-3-carboxynitrile

[0912]

[0913] Similar to 1-[2-[3-(difluoromethyl)-5-methylpyrazol-1-yl]-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-3-yl]acetone (see Example 18, step 5), this example was prepared by using 5-cyclopropyl-1H-pyrazol-3-carboxynitrile (CAS [1290696-95-5]) instead of 3-(difluoromethyl)-5-methyl-1H-pyrazol. Preparative reversed-phase HPLC yielded the title compound as a white powder. MS (ESP) m / z = 477.2 [M+H] +

[0914] Example 52

[0915] 2-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-cyclopropylpyrazol-3-carboxynitrile

[0916]

[0917] This example was prepared together with Example 51 and separated in the final step by preparative reversed-phase HPLC to obtain the title compound as a pale yellow solid. MS (ESP) m / z = 477.2 [M+H] +

[0918] Example 53

[0919] 1-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-(difluoromethyl)pyrazol-3-carboxynitrile

[0920]

[0921] Triethylamine (30.09 mg, 41.45 u) was added to an ice-cold solution of 1-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-2-pyridyl]-5-(difluoromethyl)pyrazol-3-carboxamide (50 mg, 0.099 mmol, 1 eq) in DCM (3 mL), 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 at 0 °C for 1 hour. The crude reaction mixture was evaporated on silica gel and purified by rapid chromatography on silica gel by elution with 0% to 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] +

[0922] Example 54

[0923] 1-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-2-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]propane-1-one

[0924]

[0925] Step 1: Acetate [1-(2,6-dichloropyridin-3-yl)cyclopropyl] ester

[0926]

[0927] 4-Dimethylaminopyridine (9.0 mg, 0.074 mmol, 0.1 eq) was added to a solution of 1-(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. This mixture was stirred at 80 °C for 30 min. The mixture was cooled to room temperature, diluted with water, and extracted three times with DCM, dried over Na₂SO₄, and evaporated. The crude product was eluted on silica gel with 0% to 2% MeOH in DCM to give a colorless oily title compound (175 mg, 97%). MS (ESP) m / z = 246.1 [M+H] +

[0928] Step 2: Acetic acid [1-[2-chloro-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-3-yl]cyclopropyl] ester

[0929]

[0930] Add [1-(2,6-dichloropyridazin-3-yl)oxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridine (100 mg, 0.28 mmol, 1.0 eq) (see Example 14, step 3 for preparation) to a solution of 6-(6-methylpyridin-3-yl)cyclopropyl acetate (84 mg, 0.34 mmol, 1.2 eq) and K2CO3 (118 mg, 0.85 mmol, 3.0 eq) and water (1.25 mL) to a solution of 6-(6-methylpyridin-3-yl)oxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridine (100 mg, 0.28 mmol, 1.0 eq) in N,N-dimethylformamide (3 mL) Argon gas was bubbled through the mixture for 5 minutes, and then 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) 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 onto water, and extracted three times with EtOAc, dried over Na2SO4, and evaporated. Chromatography was performed on SiO2, eluting with 0% to 7% MeOH in DCM, to give the title compound as a white solid (125 mg, 87% yield). MS (ESP) m / z = 436.2 [M+H] +

[0931] Step 3: 1-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-2-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]propane-1-one

[0932]

[0933] Argon gas was bubbled through a mixture of acetic acid [1-[2-chloro-6-[6-(6-methylpyridin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-3-yl]cyclopropyl] ester (30 mg, 0.059 mmol, 1.0 eq) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1-(2,2,2-trifluoroethyl)-1H-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. 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (4.8 mg, 0.006 mmol, 0.1 eq) was added, and the mixture was stirred at 100 °C for three hours. The mixture was subjected to column chromatography, eluting on SiO2 with 0% to 5% MeOH in DCM, followed by preparative HPLC to give the title compound (7 mg, 23% yield) as an orange solid. MS (ESN) m / z = 552.3 [M+HCOO] -

[0934] Example 55

[0935] 1-[3-(difluoromethyl)-6-[5-methoxy-6-[(6-methylpyridazin-3-yl)amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0936]

[0937] Step 1: 6-Chloro-3-(difluoromethyl)-2-fluoropyridine

[0938]

[0939] At 0 °C, (diethylamino)sulfur trifluoride (7.5 mL, 56.4 mmol, 3.0 eq; CAS [1093880-37-5]) was added to a solution of 6-chloro-2-fluoro-pyridin-3-carboxaldehyde (3.0 g, 18.8 mmol, 1.0 eq; CAS [38078-09-0]) in DCM (30 mL). The reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was then added to a saturated NaHCO3 solution (300 mL) with stirring and extracted with DCM (3 × 100 mL). The combined extracts were concentrated under vacuum to give a yellow oily 6-chloro-3-(difluoromethyl)-2-fluoro-pyridine (3.0 g, 17 mmol, 88% yield). MS (ESP) m / z = 182.1 [M+H] +

[0940] Step 2: 1-[6-chloro-3-(difluoromethyl)pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0941]

[0942] A solution of 5-methyl-1H-pyrazole-3-carboxynitrile (590 mg, 5.5 mmol, 1.0 eq; CAS [38693-82-2]), 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 h. The reaction mixture was cooled to room temperature, added to water (200 mL), and 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 by elution on silica gel with 10% ethyl acetate in petroleum ether to give the title compound as a yellow solid (650 mg, 2.4 mmol, 44% yield). MS (ESP) m / z = 269.2 [M+H] +

[0943] Step 3: 1-[3-(difluoromethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0944]

[0945] Under a nitrogen atmosphere at 20°C, bis(pinacol)diboron CAS [73183-34-3] (378 mg, 1.5 mmol, 4.0 eq), 1-[6-chloro-3-(difluoromethyl)pyridin-2-yl]-5-methylpyrazol-3-carboxylonitrile (100 mg, 0.37 mmol, 1.0 eq), and dry potassium acetate (0.09 mL, 1.49 mmol, 4.0 eq) in a suspension of 1,4-dioxane (1 mL) was added to bis(triphenylphosphine)palladium(II) chloride CAS [13965-03-2] (13 mg, 0.02 mmol, 0.05 eq). The reaction mixture was stirred at 100°C for 3 hours. Thiourea resin was added to the mixture under stirring. One hour later, the mixture was filtered and the filtrate was concentrated to give the black, oily title compound (130 mg, 0.36 mmol, 97% yield), which was used as is in the next step. MS (ESP) m / z = 279.2 [M-82+H] +

[0946] Step 4: 1-[6-(6-bromo-5-methoxypyrazolo[1,5-a]pyridin-3-yl)-3-(difluoromethyl)pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0947]

[0948] Under a nitrogen atmosphere at 20°C, 140 mg, 0.4 mmol, 1.1 eq of 6-bromo-3-iodo-5-methoxypyrazolo[1,5-a]pyridine (preparation see Example 12, step 6), 130 mg, 0.36 mmol, 1.0 eq of 1-[3-(difluoromethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyridin-2-yl]-5-methylpyrazol-3-carboxylonitrile (Cs2CO3) (353 mg, 1.1 mmol, 3.0 eq) in a mixture of THF (3.0 mL) and water (0.5 mL) was added to a mixture of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane complex v (59 mg, 0.07 mmol, 0.2 eq). 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 with elution of 10% MeOH in DCM to give a solid, which was ground and stirred in DMSO (1 mL) for 30 min. The resulting white solid was filtered, washed with petroleum ether (5 mL), and dried under vacuum to give the title compound as a white solid (15 mg, 9% yield). MS (ESP) m / z = 461.0 [M+H] +

[0949] Step 5: 1-[3-(difluoromethyl)-6-[5-methoxy-6-[(6-methylpyridazin-3-yl)amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0950]

[0951] Cesium carbonate (32 mg, 0.1 mmol, 3.0 eq) was added to a solution of 1-[6-(6-bromo-5-methoxypyrazolo[1,5-a]pyridin-3-yl)-3-(difluoromethyl)pyridin-2-yl]-5-methylpyrazol-3-carboxylonitrile (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). The air in the flask was purged three times with nitrogen. [tBuBrettPhos Pd(allyl)]OTf (5 mg, 0.01 mmol, 0.2 eq; CAS [1798782-17-8]) was added to the mixture, and the air in the flask was purged three times with nitrogen. 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 with 10% MeOH in DCM as elution. Further purification by preparative HPLC gave the title compound as a yellow solid (4 mg, 17% yield). MS (ESP) m / z = 488.1 [M+H] +

[0952] Example 56

[0953] 1-[3-(difluoromethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0954]

[0955] At room temperature, 6-(6-methylpyridazin-3-yl)oxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridine (66 mg, 0.19 mmol, 1.0 eq) (preparation see Example 14, step 3) and 1-[6-chloro-3-(difluoromethyl)pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile (50 mg, 0.19 mmol, 1.0 eq) (preparation see Example 55, step 2) were dissolved in N,N-dimethylformamide (1.5 mL), and K2CO3 (77 mg, 0.56 mmol, 3.0 eq) dissolved in water (0.750 mL) was added, followed by the addition of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloromethane complex (15... mg, 0.019 mmol, 0.1 eq; CAS [95464-05-4]). The reaction mixture was diluted with water and extracted twice with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated to dryness. The crude material was purified by rapid chromatography on silica gel by elution with 0% to 4% MeOH in DCM to obtain the title compound as a light brown solid (63 mg, 73% yield). MS (ESP) m / z = 459.2 [M+H] +

[0956] Examples 57 and 58

[0957] 3-[5-(difluoromethyl)-6-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-2-yl]-6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridine;

[0958] 3-[5-(difluoromethyl)-6-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-2-yl]-6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridine

[0959] and

[0960] Similar to Examples 24 and 25, these examples were prepared by replacing 1-(2-bromo-6-chloro-3-(difluoromethyl)pyridine (CAS [1805299-47-1]) with 1-(2-bromo-6-chloropyridin-3-yl)acetone in step 6. Following this final step, the positional isomers were isolated by SFC to give the title compound as a white solid. MS (ESP) m / z = 516.2 [M+H]+ (For both instances)

[0961] Example 59

[0962] 1-[3-(methoxymethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0963]

[0964] Step 1: 1-(6-chloro-3-formylpyridin-2-yl)-5-methylpyrazol-3-carboxynitrile

[0965]

[0966] 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-1H-pyrazole-3-carboxynitrile (CAS [38693-82-2] 738 mg, 6.9 mmol, 1.1 eq) and potassium carbonate (1.3 g, 9.4 mmol, 1.5 eq) was added at room temperature. The mixture was stirred for one hour. The reaction mixture was diluted with water and extracted three times with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated to dryness. The crude material was purified by rapid chromatography on silica gel by elution with 0% to 100% EtOAc in heptane to obtain the title compound (1.4 g, 92% yield) as a light brown solid. MS (ESP) m / z = 246.0 [M+H] +

[0967] Step 2: 1-[3-formyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0968]

[0969] 6-(6-methylpyridazin-3-yl)oxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridine (71 mg, 0.2 mmol, 1.0 eq) (preparation see Example 14, step 3) and 1-(6-chloro-3-formylpyridin-2-yl)-5-methylpyrazol-3-carboxynitrile (50 mg, 0.2 mmol, 1.0 eq) were suspended in N,N-dimethylformamide (1.5 mL), and K2CO3 dissolved in water (0.750 mL) (84 mg, 0.6 mmol, 3.0 eq) was added, followed by 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii)dichloromethane complex (17 mg, 0.02 mmol, 0.1 eq). (eq; CAS [95464-05-4]). The mixture was stirred at 45°C for one hour. The reaction mixture was diluted with water and washed twice with EtOAc. The suspension in the aqueous phase was filtered off, and the resulting solid was washed with water and diethyl ether to obtain the title compound as a yellow solid (53 mg, 58% yield). MS (ESP) m / z = 437.2 [M+H] +

[0970] Step 3: 1-[3-(hydroxymethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0971]

[0972] 1-[3-formyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile (30 mg, 0.069 mmol, 1.0 eq) was suspended in methanol (1 mL) and tetrahydrofuran (1 mL), and NaBH4 (5 mg, 0.14 mmol, 2.0 eq) was added at room temperature. The mixture was stirred for 1 hour. The reaction mixture was diluted with saturated NaHCO3 and extracted twice with EtOAc. The organic layer was dried over MgSO4 and concentrated to dryness. The crude material was purified by rapid chromatography on silica gel by elution with 0% to 5% MeOH in DCM to obtain the title compound as a white solid (22 mg, 71% yield). MS (ESP) m / z = 439.2 [M+H] +

[0973] Step 4: 1-[3-(methoxymethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0974]

[0975] 1-[3-(hydroxymethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile (14 mg, 0.032 mmol, 1.0 eq) was dissolved in tetrahydrofuran (1 mL) and N,N-dimethylformamide (0.2 mL). 60% NaH (1.5 mg, 0.038 mmol, 1.2 eq) in mineral oil was added at 0 °C. The mixture was stirred at 0 °C for 15 min, and then iodomethane (2.8 μL, 0.045 mmol, 1.4 eq) was added. The reaction mixture was heated to room temperature and stirred for 1 h. The reaction mixture was quenched with water and extracted twice with DCM. The organic layer was dried over MgSO4 and concentrated to dryness. The crude material was purified by rapid chromatography on silica gel by elution with 0% to 5% MeOH in DCM to obtain the title compound as a white solid (13 mg, 93% yield). MS (ESP) m / z = 453.2 [M+H] +

[0976] Example 60

[0977] 5-Methyl-1-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-3-[trans-4-cyanoxacyclopentan-2-yl]pyridin-2-yl]pyrazol-3-carboxynitrile

[0978] and

[0979] Step 1: 1-(6-chloro-2-fluoropyridin-3-yl)but-3-en-1-ol

[0980]

[0981] 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 allyl magnesium bromide (65.8 mL, 65.8 mmol, 1.05 eq) in diethyl ether was slowly added at 0 °C. The reaction mixture was stirred at 0 °C for 3 h, quenched with saturated NH4Cl, and extracted twice with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated to dryness. The crude material was purified by rapid chromatography on silica gel (330 g, 0% to 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] +

[0982] Step 2: 1-(6-chloro-2-fluoropyridin-3-yl)-2-(oxepane-2-yl)ethanol

[0983]

[0984] 1-(6-chloro-2-fluoropyridin-3-yl)but-3-en-1-ol (6.58 g, 32.63 mmol, 1.0 eq) was dissolved in dichloromethane (160 mL). 3-chloroperbenzoic 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, then stirred overnight and warmed to room temperature. The reaction mixture was poured into a saturated Na₂CO₃ solution and extracted with DCM (2 x 100 mL). The organic layer was washed with Na₂CO₃ (4 x 100 mL), dried over MgSO₄, filtered, and concentrated under vacuum. The crude material was purified by rapid chromatography on silica gel (330 g, 0% to 100% EtOAc in heptane) to obtain the title compound (5.5 g, 74% yield), a pale yellow oil. MS (ESP)m / z = 218.1 [M+H] +

[0985] Step 3: 5-(6-chloro-2-fluoropyridin-3-yl)oxacyclopentan-3-ol

[0986]

[0987] 1-(6-chloro-2-fluoropyridin-3-yl)-2-(oxepane-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 room temperature. The mixture was stirred at 50 °C for 5 hours. The reaction mixture was carefully quenched with saturated NaHCO₃ and extracted twice with EtOAc. The organic layer was washed twice with saturated NaHCO₃, dried over MgSO₄, and concentrated to dryness. The crude material was purified by rapid chromatography on silica gel (120 g, 0% to 100% EtOAc in heptane) to obtain the title compound (2.4 g, 50% yield) as a pale yellow oil. MS (ESP) m / z = 218.0 [M+H] +

[0988] Step 4: 1-[6-chloro-3-(4-hydroxyoxacyclopentan-2-yl)pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[0989]

[0990] 5-(6-chloro-2-fluoropyridin-3-yl)oxacyclopentan-3-ol (1.92 g, 8.82 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (40 mL), and 5-methyl-1H-pyrazole-3-carboxynitrile 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 room temperature. The mixture was stirred overnight at 70 °C. The reaction mixture was diluted with water and extracted twice with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated to dryness. The crude material was purified by rapid chromatography on silica gel (80 g, 0% to 80% EtOAc in heptane) to obtain a colorless oily title compound (1.58 g, 59% yield). MS (ESP) m / z = 305.1 [M+H] +

[0991] Step 5: Methanesulfonic acid [5-[6-chloro-2-(3-cyano-5-methylpyrazol-1-yl)pyridin-3-yl]oxacyclopentane-3-yl] ester

[0992]

[0993] 1-[6-chloro-3-(4-hydroxyoxacyclopentan-2-yl)pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile (500 mg, 1.64 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL) and triethylamine (686 μL, 4.92 mmol, 3.0 eq), followed by the addition of methanesulfonyl chloride (166 μL, 2.13 mmol, 1.3 eq) at 0 °C. After stirring at 0 °C for one hour, the reaction mixture was diluted with water and extracted twice with EtOAc. The organic layer was dried over MgSO4 and concentrated to dryness to give the title compound (727 mg, quantitative yield) as an orange oil, which was used as is in the next step. MS (ESP) m / z = 383.1 [M+H] +

[0994] Step 6: 1-[6-chloro-3-[trans-4-cyanoxacyclopentan-2-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxylonitrile and 1-[6-chloro-3-[cis-4-cyanoxacyclopentan-2-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxylonitrile

[0995] and

[0996] [5-[6-chloro-2-(3-cyano-5-methylpyrazol-1-yl)pyridin-3-yl]oxacyclopentan-3-yl] ester (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 room temperature. The mixture was stirred at 105 °C for 1 hour. The reaction mixture was diluted with water and extracted twice with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated to dryness. The crude material was purified by rapid chromatography on silica gel (25 g, 0% to 50% EtOAc in heptane) to obtain light brown solids of 1-[6-chloro-3-[trans-4-cyanoxacyclopentan-2-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxylonitrile (82 mg, 11% yield) and 1-[6-chloro-3-[cis-4-cyanoxacyclopentan-2-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxylonitrile (69 mg, 9% yield). For both compounds, MS (ESP) m / z = 314.1 [M+H] + .

[0997] Step 7: 5-Methyl-1-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-3-[trans-4-cyanoxacyclopentan-2-yl]pyridin-2-yl]pyrazol-3-carboxynitrile

[0998] and

[0999] 6-(6-methylpyridazin-3-yl)oxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridine (39 mg, 0.11 mmol, 1.0 eq) (see Example 14, step 3 for preparation) and 1-[6-chloro-3-[trans-4-cyanoxacyclopentane-2-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile (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 the addition of 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii)dichloromethane complex (9 mg, 0.01 mmol, 0.1 eq; CAS [95464-05-4]). The mixture was stirred at 45 °C for 1 hour. The reaction mixture was diluted with water and extracted twice with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated to dryness. The crude material was purified by rapid chromatography on silica gel (12 g, 0 to 4% MeOH in DCM) followed by preparative HPLC to give the title compound (also known as 5-methyl-1-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-3-[racemic-(2R,4R)-4-cyanoxacyclopentan-2-yl]pyridin-2-yl]pyrazol-3-carboxylonitrile) (17 mg, 30% yield). MS (ESP) m / z = 504.3 [M+H] +

[1000] Example 61

[1001] 5-Methyl-1-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-3-[cis-4-cyanoxacyclopentan-2-yl]pyridin-2-yl]pyrazol-3-carboxynitrile

[1002] and

[1003] Similar to Example 60, this example was prepared by replacing 1-[6-chloro-3-[cis-4-cyanoxacyclopentan-2-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxylonitrile (see Example 60, step 6 for preparation) with 1-[6-chloro-3-[trans-4-cyanoxacyclopentan-2-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxylonitrile in step 7 to obtain the light brown solid title compound (also known as 5-methyl-1-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-3-[racemic-(2R,4S)-4-cyanoxacyclopentan-2-yl]pyridin-2-yl]pyrazol-3-carboxylonitrile). MS (ESP) m / z = 504.3 [M+H] +

[1004] Example 62

[1005] 1-[3-(1-hydroxyethyl)-6-[6-[1-(oxecyclobutan-3-yl)piperidin-4-yl]oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[1006]

[1007] Step 1: [1-(oxecyclobutane-3-yl)piperidin-4-yl]methanesulfonate

[1008]

[1009] 1-(oxetane-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 μL, 1.56 mmol, 2.0 eq) was added, followed by methanesulfonyl chloride (91 μL, 1.17 mmol, 1.5 eq). The mixture was stirred at room temperature for 90 min. Water was added, and the mixture was extracted with DCM. The organic layer was evaporated to dryness to give the title compound as an orange solid (193 mg, 99% yield). MS (ESP) m / z = 236.0 [M+H] +

[1010] Step 2: 6-[1-(oxecyclobutane-3-yl)piperidin-4-yl]oxypyrazolo[1,5-a]pyridine

[1011]

[1012] [1-(oxetane-3-yl)piperidin-4-yl]methanesulfonate (193 mg, 0.78 mmol, 1.0 eq), pyrazolo[1,5-a]pyridin-6-ol (115 mg, 0.86 mmol, 1.1 eq; CAS [184473-24-3]), and cesium 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 (SiO2 25 g, DCM / MeOH 0% to 10%) to give the title compound as a white solid (71 mg, 33% yield). MS (ESP) m / z = 274.1 [M+H] +

[1013] Step 3: 3-Bromo-6-[1-(oxetane-3-yl)piperidin-4-yl]oxypyrazolo[1,5-a]pyridine

[1014]

[1015] Bromine (17 μL, 0.3 mmol, 1.1 eq) was added to a stirred solution of 6-[1-(oxecyclobutan-3-yl)piperidin-4-yl]oxypyrazolo[1,5-a]pyridine (85 mg, 0.31 mmol, 1.0 eq) in acetic acid (3.0 mL) at room temperature, and the mixture was stirred for 20 min. The reaction mixture was poured over water at 0 °C, and 32% NaOH was added until pH 10 was reached. The mixture was extracted with DCM, dried over Na2SO4, and evaporated to dryness. Purification was performed by column chromatography, eluting with 0% to 10% MeOH in DCM, to give the title compound (109 mg, 99% yield) as a pale yellow solid. MS (ESP) m / z = 352.0 [M+H] +

[1016] Step 4: 1-[3-acetyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[1017]

[1018] Under argon atmosphere, 1-(3-acetyl-6-chloropyridin-2-yl)-5-methylpyrazol-3-carboxynitrile (150 mg, 0.58 mmol, 1.0 eq) was dissolved in 1,4-dioxane (1.6 mL). Bis(pinacol)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, then bis(triphenylphosphine)palladium(II) chloride (20 mg, 0.03 mmol, 0.05 eq; CAS [13965-03-2]) was added. Argon was bubbled through the suspension for 5 minutes. The reaction mixture was heated to 100 °C. Four hours later, the mixture was cooled to room temperature and 1 g of SiliaMetS® (metal scavenger) was added. The suspension was stirred for 1 hour and then filtered and washed with ethyl acetate to give the title compound as a gray solid (901 mg, 89% yield), which was used as is in the next step. MS (ESP) m / z = 271.0 [M-pinacol + H₂O + H] +

[1019] Step 5: 1-[3-acetyl-6-[6-[1-(oxecyclobutan-3-yl)piperidin-4-yl]oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[1020]

[1021] Add 3-bromo-6-[1-(oxetane-3-yl)piperidin-4-yl]-5-methylpyrazol-3-carboxylonitrile (499 mg, 0.28 mmol, 1.2 eq) and cesium carbonate (231 mg, 0.71 mmol, 3.0 eq) and water (0.7 mL) to a solution of 1-[3-acetyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)pyridin-2-yl]oxypyrazolo[1,5-a]pyridine (84 mg, 0.24 mmol, 1.0 eq) and cesium carbonate (231 mg, 0.71 mmol, 3.0 eq) in 1,4-dioxane (2.7 mL). Bubble the mixture with argon gas for 5 minutes. 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloromethane complex (18 mg, 0.024 mmol, 0.1 eq; CAS [95464-05-4]) was added to the reaction mixture, and argon gas was bubbled through the solution for 5 min. The reaction mixture was stirred overnight at 55 °C. The reaction mixture was cooled to room temperature and poured onto water and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by rapid chromatography on 25 g silica gel by elution with 0% to 10% MeOH in DCM to give the title compound (12 mg, 10% yield) as a pale yellow solid. MS (ESP) m / z = 498.2 [M+H] +

[1022] Step 6: 1-[3-(1-hydroxyethyl)-6-[6-[1-(oxecyclobutan-3-yl)piperidin-4-yl]oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[1023]

[1024] NaBH4 (3.7 mg, 0.098 mmol, 1 eq) was added to a solution of 1-[3-acetyl-6-[6-[1-(oxecyclobutan-3-yl)piperidin-4-yl]oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile (55 mg, 0.098 mmol, 1 eq) in methanol (3.3 mL), and the mixture was stirred for 1 hour. NaBH4 (1.1 mg, 0.029 mmol, 1.2 eq) was added, and after 30 minutes, the mixture was poured over water and extracted with EtOAc. The organic layer was dried over Na2SO4 and evaporated to dryness. The residue was purified by rapid chromatography on silica gel by elution with 0% to 10% MeOH in DCM to obtain the title compound as a white solid (8.6 mg, 69% yield). MS (ESP) m / z = 500.2 [M+H] +

[1025] Example 63

[1026] 3-[3-[6-(3-cyano-5-methylpyrazol-1-yl)-5-(1-hydroxyethyl)pyridin-2-yl]pyrazolo[1,5-a]pyridin-6-yl]oxy-N,N,6-trimethylpyridazine-4-carboxamide

[1027]

[1028] Step 1: Methyl 3-chloro-6-methylpyridazine-4-carboxylate

[1029]

[1030] Potassium carbonate (13 g, 97 mmol, 2.0 eq) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (3.5 g, 4.8 mmol, 0.1 eq; CAS [72287-26-4]) were added to a mixture of methyl 3,6-dichloropyridazine-4-carboxylate (10 g, 48 mmol, 1.0 eq; CAS [51149-08-7]) and trimethyloxacyclohexane (12 g, 48 mmol, 1.0 eq) in 1,4-dioxane (200 mL). The mixture was degassed three times with nitrogen and heated to 100 °C for 16 hours. The mixture was poured onto water (1000 mL) and extracted with EtOAc (3 × 800 mL). The combined organic phases were washed with brine (3 x 500 mL), dried over Na₂SO₄, and concentrated under vacuum to give the residue. The residue was purified by reversed-phase column chromatography, followed by rapid chromatography with elution in a 1:1 petroleum ether:EtOAc solution 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] +

[1031] Step 2: 3-Bromoxypyrazolo[1,5-a]pyridine-6-ol

[1032]

[1033] NBS (1.2 g, 6.7 mmol, 0.9 eq) was slowly added to a solution of pyrazolo[1,5-a]pyridin-6-ol (1.0 g, 7.5 mmol, 1.0 eq; CAS [184473-24-3]) in methanol (20 mL) at -10 °C. The reaction mixture was stirred at -10 °C for 4 h. The mixture was poured onto water (40 mL) and extracted with EtOAc (50 mL × 3). The combined organic phases were washed with brine (70 mL), dried over Na2SO4, and concentrated under vacuum to give the residue. The residue was purified by SiO2 column chromatography (PE / EtOAc = 10 / 1 to PE / EtOAc = 3 / 1) to give the title compound (610 mg, 38% yield) as a grayish-white solid. MS (ESP) m / z = 215.1 [M+H] +

[1034] Step 3: Methyl 3-(3-bromopyrazolo[1,5-a]pyridin-6-yl)oxy-6-methylpyridazine-4-carboxylate

[1035]

[1036] Potassium carbonate (444 mg, 3.2 mmol, 2.0 eq) was slowly added to a solution of methyl 3-chloro-6-methylpyrazine-4-carboxylate (300 mg, 1.6 mmol, 1.0 eq) and 3-bromopyrazolo[1,5-a]pyridine-6-ol (343 mg, 1.6 mmol, 1.0 eq) in DMSO (1 mL). The mixture was stirred at 50 °C for 16 hours. The mixture was filtered and purified by reversed-phase chromatography followed by purification by SiO2 column chromatography with elution of petroleum ether:EtOAc at a ratio of 1:1 to 1:2 to give the title compound as a yellow solid (150 mg, 26% yield). MS (ESP) m / z = 365.0 [M+H] +

[1037] Step 4: 3-(3-bromopyrazolo[1,5-a]pyridin-6-yl)oxy-N,N,6-trimethylpyridazine-4-carboxamide

[1038]

[1039] A solution of lithium hydroxide hydrate (38 mg, 0.9 mmol, 3 eq) in water (2 mL) and methanol (1 mL) was added to a yellow solution of methyl 3-(3-bromopyrazolo[1,5-a]pyridin-6-yl)oxy-6-methylpyridazine-4-carboxylate (110 mg, 0.3 mmol, 1.0 eq) in THF (2 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. DMF (4 mL), dimethylamine hydrochloride (32 mg, 0.39 mmol, 1.3 eq), N,N-diisopropylethylamine (0.16 mL, 0.9 mmol, 3.0 eq), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylureonium hexafluorophosphate (172 mg, 0.45 mmol, 1.5 eq; CAS [148893-10-1]) were added to the mixture at 20 °C. The mixture was stirred at 30 °C for 16 hours. The mixture was purified by column chromatography to give the title compound (86 mg, 59% yield) as a white solid. MS (ESP) m / z = 378.0 [M+H]+

[1040] Step 5: 3-[3-[5-acetyl-6-(3-cyano-5-methylpyrazol-1-yl)pyridin-2-yl]pyrazolo[1,5-a]pyridin-6-yl]oxy-N,N,6-trimethylpyridazine-4-carboxamide

[1041]

[1042] Cesium carbonate (197 mg, 0.61 mmol, 3.0 eq) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (8 mg, 0.01 mmol, 0.05 eq; CAS) were added to a mixture of 3-(3-bromopyrazolo[1,5-a]pyridin-6-yl)oxy-N,N,6-trimethylpyridazine-4-carboxamide (76 mg, 0.2 mmol, 1.0 eq) and 1-[3-acetyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyridin-2-yl]-5-methylpyrazol-3-carboxylonitrile (92 mg, 0.26 mmol, 1.3 eq) (see Example 62, step 4 for preparation) in THF (4 mL). [95464-05-4]) and water (0.7 mL). The mixture was degassed three times with nitrogen and heated at 65 °C for 3 hours. The mixture was poured onto water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, and concentrated under vacuum to give the 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] +

[1043] Step 6: 3-[3-[6-(3-cyano-5-methylpyrazol-1-yl)-5-(1-hydroxyethyl)pyridin-2-yl]pyrazolo[1,5-a]pyridin-6-yl]oxy-N,N,6-trimethylpyridazine-4-carboxamide

[1044]

[1045] Sodium borohydride (16 mg, 0.42 mmol, 3.9 eq) was added to a mixture of 3-[3-[5-acetyl-6-(3-cyano-5-methylpyrazol-1-yl)pyridin-2-yl]pyrazolo[1,5-a]pyridin-6-yl]oxy-N,N,6-trimethylpyridazine-4-carboxamide (56 mg, 0.11 mmol, 1.0 eq) in methanol (4 mL) at 0 °C. The mixture was stirred at 0 °C for 2 h. The mixture was poured onto saturated NH4Cl (15 mL) and extracted with EtOAc (20 mL × 3). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum to give the 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] +

[1046] Examples 64 and 65

[1047] 3-[5-(difluoromethyl)-6-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-2-yl]-6-[6-[[4-(oxecyclobutane-3-yl)piperazin-1-yl]methyl]pyridazin-3-yl]oxypyrazolo[1,5-a]pyridine; and

[1048] 3-[5-(difluoromethyl)-6-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-2-yl]-6-[6-[[4-(oxecyclobutane-3-yl)piperazin-1-yl]methyl]pyridazin-3-yl]oxypyrazolo[1,5-a]pyridine

[1049]

[1050] Step 1: 3-Chloro-6-[[4-(oxecyclobutane-3-yl)piperazin-1-yl]methyl]pyridazine

[1051]

[1052] 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), 1-(oxecyclobutane-3-yl)piperazine (1.44 g, 10.1 mmol, 1.1 eq; CAS [1254115-23-5]) was added, followed by K₂CO₃ (3.81 g, 27.6 mmol, 3.0 eq). The reaction was stirred at 40 °C for 2 h, then at 60 °C for 2 h. The mixture was diluted with ethyl acetate (100 mL) to give a yellow suspension. The mixture was loaded onto silica gel and eluted on the silica gel by rapid chromatography with petroleum ether:ethyl acetate 0:1, followed by purification of the residue with ethyl acetate:MeOH 10:1 to give the title compound as a yellow solid (1.5 g, 61% yield). MS (ESP) m / z = 269.1 [M+H] +

[1053] Step 2: 6-[6-[[4-(oxecyclobutane-3-yl)piperazin-1-yl]methyl]pyridazin-3-yl]oxypyrazolo[1,5-a]pyridine

[1054]

[1055] To a solution of pyrazolo[1,5-a]pyridin-6-ol (275 mg, 2.1 mmol, 1.1 eq; CAS [184473-24-3]) in DMF (10 mL), 3-chloro-6-[[4-(oxecyclobutan-3-yl)piperazin-1-yl]methyl]pyridazine (500 mg, 1.86 mmol, 1.0 eq) was added, followed by the addition of potassium carbonate (771 mg, 5.6 mmol, 3.0 eq). The reaction was stirred at 120 °C for 12 h. The mixture was filtered and purified by column chromatography on silica (ethyl acetate:MeOH = 10:1) to give the title compound as a yellow solid (560 mg, 82% yield). MS (ESP) m / z = 367.2 [M+H] +

[1056] Step 3: 3-Bromo-6-[6-[[4-(oxecyclobutane-3-yl)piperazin-1-yl]methyl]pyridazin-3-yl]oxypyrazolo[1,5-a]pyridine

[1057]

[1058] NBS (241 mg, 1.36 mmol, 1.0 eq) was added to a solution of 6-[6-[[4-(oxecyclobutan-3-yl)piperazin-1-yl]methyl]pyridazin-3-yl]oxypyrazolo[1,5-a]pyridine (500 mg, 1.36 mmol, 1.0 eq) in methanol (10 mL) at -10 °C, and the reaction mixture was stirred at -10 °C for 2 h. The mixture was diluted with H2O (50 mL) and extracted with DCM (2 × 50 mL). The organic phase was washed with brine, dried over Na2SO4, and concentrated to give the 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] +

[1059] Step 4: 6-[6-[[4-(oxecyclobutane-3-yl)piperazin-1-yl]methyl]pyridazin-3-yl]oxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridine

[1060]

[1061] To a solution of 3-bromo-6-[6-[[4-(oxecyclobutan-3-yl)piperazin-1-yl]methyl]pyridazin-3-yl]oxypyrazolo[1,5-a]pyridine (350 mg, 0.79 mmol, 1.0 eq) in diethylene glycol dimethyl ether (10.0 mL) and water (0.05 mL), bis(pinacol) diboron (499 mg, 1.96 mmol, 2.5 eq; CAS [73183-34-3]), tricyclohexylphosphine (44 mg, 0.16 mmol, 0.2 eq), palladium(II) acetate (18 mg, 0.08 mmol, 0.1 eq), and then potassium carbonate (152 mg, 1.1 mmol, 1.4 eq) were added. The mixture was stirred at 100 °C under a nitrogen atmosphere for 3 hours. The mixture was evaporated to dryness and purified by column chromatography on silica gel (petroleum ether:ethyl acetate 1:1 to ethyl acetate:MeOH 5:1) to give a yellow gelatinous title compound (350 mg, 85% yield), which was used as is in the next step. MS (ESP) m / z = 493.3 [M+H] +

[1062] Step 5: 3-[5-(difluoromethyl)-6-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-2-yl]-6-[6-[[4-(oxecyclobutane-3-yl)piperazin-1-yl]methyl]pyridin-3-yl]oxypyrazolo[1,5-a]pyridine (Example 64) and 3-[5-(difluoromethyl)-6-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-2-yl]-6-[6-[[4-(oxecyclobutane-3-yl)piperazin-1-yl]methyl]pyridin-3-yl]oxypyrazolo[1,5-a]pyridine (Example 65)

[1063]

[1064] Similar to Examples 24 and 25, these compounds were prepared by replacing 1-(2-bromo-6-chloro-3-(difluoromethyl)pyridine (CAS [1805299-47-1]) with 2-bromo-6-chloropyridin-3-yl)acetone in step 6 and by replacing 6-(6-methylpyridin-3-yl)piperazin-1-yl]methyl]pyridazin-3-yl]oxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridine with 6-(6-methylpyridazin-3-yl)oxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridine in step 7. Following the final step, the positional isomers were separated by SFC to obtain the title compound as a yellow solid. MS (ESP) m / z = 656.3 [M+H] + (Regarding the two compounds)

[1065] Example 66

[1066] 4-[[6-[3-[5-(difluoromethyl)-6-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-2-yl]pyrazolo[1,5-a]pyridin-6-yl]oxypyridazin-3-yl]methyl]morpholine

[1067]

[1068] Similar to Example 64, this example was prepared by replacing 1-(oxecyclobutane-3-yl)piperazine with morpholine in step 1 to obtain the title compound as a white solid. MS (ESP) m / z = 601.3 [M+H] +

[1069] Example 67

[1070] 2-[3-(difluoromethyl)-5-methylpyrazol-1-yl]-6-[5-methoxy-6-[(6-methylpyridazin-3-yl)amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-3-carboxynitrile

[1071]

[1072] Similar to Example 55, this example was prepared by replacing 6-chloro-3-(difluoromethyl)-2-fluoropyridine with 6-chloro-2-fluoropyridine in step 2 and by replacing 5-methyl-1H-pyrazole with 3-(difluoromethyl)-5-methyl-1H-pyrazole with 3-methyl-1H-pyrazole-3-carboxynitrile in step 2, to obtain the title compound as a white solid. MS (ESP) m / z = 488.4 [M+H] +

[1073] Example 68

[1074] (1S)-1-[2-[3,5-bis(difluoromethyl)pyrazol-1-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

[1075]

[1076] Step 1: 3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridin-6-yl]oxy-7,8-dihydro-5H-pyrano[4,3-c]pyridazine]

[1077]

[1078] Similar to 6-(6-methylpyridazin-3-yl)oxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridine (see Example 14, step 3), this intermediate was prepared in step 1 by replacing 3-chloro-6-methylpyridazin with 3-chloro-7,8-dihydro-5H-pyrano[4,3-c]pyridazine (CAS [1075260-61-5]) to give the title compound as a white solid. MS (ESP) m / z = 395.2 [M+H] +

[1079] Step 2: 1-[2-[3,5-bis(difluoromethyl)pyrazol-1-yl]-6-chloropyridin-3-yl]acetone

[1080]

[1081] Under argon atmosphere and at -78°C, 1-(6-chloro-2-fluoro-3-pyridyl)acetone (200 mg, 1.15 mmol, 1.0 eq; CAS [1260663-13-5]) and 3,5-bis(difluoromethyl)-1H-pyrazole (232 mg, 1.4 mmol, 1.2 eq; CAS [934759-09-8]) were dissolved in N,N-dimethylformamide (5 mL). Cesium carbonate (751 mg, 2.3 mmol, 2.0 eq) was added, and the reaction mixture was stirred at -78°C for 6 hours. The mixture was diluted with water and extracted with DCM. The organic layer was evaporated to dryness, and the residue was purified by rapid chromatography on SiO2 by elution with 0% to 40% heptane (ethyl acetate:ethanol 3:1) to give the title compound (270 mg, 71% yield) as a colorless oil. MS (ESP) m / z = 322.1 [M+H] +

[1082] Step 3: (1S)-1-[2-[3,5-bis(difluoromethyl)pyrazol-1-yl]-6-chloropyridin-3-yl]ethanol

[1083]

[1084] 1-[2-[3,5-bis(difluoromethyl)pyrazol-1-yl]-6-chloropyridin-3-yl]acetone (888 mg, 2.76 mmol, 1.0 eq) was 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 μL) were added, and the mixture was heated to 50 °C. Enzymatic reduction was initiated by adding nicotinamide adenine dinucleotide phosphate (17 mg; CAS [53-59-8]) and ketoreductase KP00006 (Codexis) (170 mg). The mixture was stirred overnight at 50 °C. The mixture was acidified to pH 2.0 by adding 20% ​​H₂SO₄. Add EtOAc (25 mL) and Dicalit (1 g) and stir the mixture at room temperature for 20 minutes. Filter the mixture and adjust the pH of the filtrate to 7 by adding 2 N NaOH. Separate the organic layer and extract the aqueous layer twice with EtOAc. Dry the combined organic layers in Na2SO4 and evaporate to dryness to give the title compound (786 mg, 88% yield) as a pale yellow oil. MS (ESN) m / z = 368.0 [M+HCO2] -

[1085] Step 4: (1S)-1-[2-[3,5-bis(difluoromethyl)pyrazol-1-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

[1086]

[1087] Add K2CO3 (39 mg, 0.029 mmol, 3.0 eq) to a solution of 3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridin-6-yl]oxy-7,8-dihydro-5H-pyrano[4,3-c]pyridazine (41 mg, 0.094 mmol, 1.0 eq) and (1S)-1-[2-[3,5-bis(difluoromethyl)pyrazolo-1-yl]-6-chloropyridin-3-yl]ethanol (30 mg, 0.093 mmol, 1.0 eq) in N,N-dimethylformamide (824 uL) and water (412 uL). The reaction mixture was degassed with argon, and then a 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) 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 room temperature and extracted with ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4, and evaporated to dryness. The residue was purified by rapid chromatography on SiO2 by elution with 0% to 10% MeOH in DCM to give the title compound (33 mg, 60% yield) as a pale yellow foam. MS (ESP) m / z = 556.2 [M+H] +

[1088] Example 69

[1089] 5-Methyl-1-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-3-propionylpyridin-2-yl]pyrazol-3-carboxynitrile

[1090]

[1091] Step 1: 1-(6-chloro-2-fluoropyridin-3-yl)cyclopropane-1-ol

[1092]

[1093] Add titanium isopropoxide (IV) (2.1 g, 2.2 mL, 7.4 mmol, 1.4 eq) to a solution of methyl 6-chloro-2-fluoronicotinate CAS [1093880-34-2] (1 g, 5.28 mmol, 1.0 eq) in tetrahydrofuran (10 mL). Add dropwise 2 M ethyl magnesium chloride (7.4 mL, 14.8 mmol, 2.8 eq) in THF and stir the mixture overnight at room temperature. Pour the mixture onto water and EtOAc and stir for 10 minutes. Filter the mixture through diatomaceous earth and wash with EtOAc. Extract the filtrate with EtOAc, dry it in Na2SO4, and evaporate to dryness. The residue was purified by rapid chromatography on SiO2 with 0% to 6% MeOH in DCM, followed by rapid chromatography on SiO2 with 0% to 30% EtOAc in heptane, to give the title compound (75 mg, 8% yield) as a pale yellow oil. MS (ESP) m / z = 188.0 [M+H] +

[1094] Step 2: Acetate [1-(6-chloro-2-fluoropyridin-3-yl)cyclopropyl] ester

[1095]

[1096] 4-Dimethylaminopyridine (5 mg, 0.04 mmol, 0.1 eq) was added to a mixture of 1-(6-chloro-2-fluoropyridin-3-yl)cyclopropane-1-ol (75 mg, 0.4 mmol, 1.0 eq) and acetic anhydride (2 mL), and the mixture was stirred at room temperature for 30 min. Water and DCM were added, and the organic layer was dried over Na2SO4 and evaporated to dryness. The residue was purified by rapid chromatography on SiO2 by elution with 0% to 50% EtOAc in heptane to give the title compound (72 mg, 78% yield) as a pale yellow oil. MS (ESP) m / z = 230.1 [M+H] +

[1097] Step 3: Acetic acid [1-[2-fluoro-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-3-yl]cyclopropyl] ester

[1098]

[1099] Similar to 1-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxylonitrile (Example 14, step 4), this intermediate was prepared by using [1-(6-chloro-2-fluoropyridin-3-yl)cyclopropyl acetate] instead of 1-(3-acetyl-6-chloropyridin-2-yl)-5-methylpyrazol-3-carboxylonitrile to give the title compound as a white solid. MS (ESP) m / z = 420.1 [M+H] +

[1100] Step 4: 1-[2-fluoro-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-3-yl]cyclopropane-1-ol

[1101]

[1102] Lithium hydroxide (6 mg, 0.24 mmol, 5.0 eq) was added to a solution of [1-[2-fluoro-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-3-yl]cyclopropyl]acetate (20 mg, 0.048 mmol, 1.0 eq) in tetrahydrofuran (4 mL) and water (2 mL) at room temperature, and the mixture was stirred for 30 min. Then a few drops of MeOH were added, and the mixture was stirred for 8 h. 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 as is in the next step.

[1103] Step 5: 5-Methyl-1-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-3-propionylpyridin-2-yl]pyrazol-3-carboxynitrile

[1104]

[1105] A mixture of 5-methyl-1H-pyrazol-3-carboxynitrile (10 mg, 0.095 mmol, 3.0 eq; CAS [38693-82-2]) with 1-[2-fluoro-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-3-yl]cyclopropane-1-ol (20 mg, 0.032 mmol, 1.0 eq) and cesium carbonate (52 mg, 0.16 mmol, 5.0 eq) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 1 hour, followed by stirring at 60 °C for 6 hours. The mixture was poured onto water and extracted with EtOAc, and the organic layer was dried over Na2SO4 and evaporated to dryness. The residue was purified by rapid chromatography on SiO2 by elution with 0% to 3% MeOH in DCM to give the title compound as a white solid (3 mg, 17% yield). MS (ESP) m / z = 465.1 [M+H] +

[1106] Example 70

[1107] 1-[3-(1-hydroxyethyl)-6-[6-[1-(oxecyclobutan-3-yl)azacycloheptane-4-yl]oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[1108]

[1109] Step 1: 4-pyrazolo[1,5-a]pyridin-6-yloxyazine-1-heptane-tert-butyl ester

[1110]

[1111] To a solution of pyrazolo[1,5-a]pyridin-6-ol (900 mg, 6.71 mmol, 1.0 eq; CAS [184473-24-3]), tert-butyl 4-hydroxyazacycloheptan-1-carboxylate (1.73 g, 8.05 mmol, 1.2 eq; CAS [1785523-74-1]) in toluene (20 mL), 1,1'-(azodicarbonyl)piperidine (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]) were added, and the reaction mixture was stirred at 110 °C for 3 hours under a nitrogen atmosphere. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous Na₂SO₄ and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography on silica (petroleum ether:ethyl acetate = 3:1 – 0:1) to give the title compound (1.3 g, 3.9 mmol, 58% yield). MS (ESP) m / z = 332.1 [M+H] +

[1112] Step 2: 6-[1-(oxetane-3-yl)azacycloheptane-4-yl]oxypyrazolo[1,5-a]pyridine

[1113]

[1114] To a solution of 4-pyrazolo[1,5-a]pyridin-6-yloxyaziridine-1-carboxylic acid tert-butyl ester (1.3 g, 3.9 mmol, 1.0 eq) in 1,4-dioxane (5 mL), 1 M HCl (5.0 mL, 20.0 mmol, 5.1 eq) in 1,4-dioxane was added. The reaction was stirred at 30 °C for 2 h. The mixture was evaporated to dryness to give a red solid. MS (ESP) m / z = 232.1 [M+H] +Two drops of acetic acid were added to the resulting solid and a solution of 3-oxetane (284 mg, 3.9 mmol, 1.1 eq) in methanol (10 mL). The mixture was stirred at 30 °C for 1 hour. NaBH3CN (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 extracted with ethyl acetate (50 mL x 3). The organic phase was dried over Na2SO4 and evaporated to dryness. The residue was purified by rapid chromatography on silica by elution with 10% MeOH in ethyl acetate to give the title compound as a white solid (700 mg, 68% yield). MS (ESP) m / z = 288.1 [M+H] +

[1115] Step 3: 1-[3-(1-hydroxyethyl)-6-[6-[1-(oxecyclobutane-3-yl)azacycloheptane-4-yl]oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[1116]

[1117] Similar to Example 62, this example was prepared by replacing 6-[1-(oxetane-3-yl)azacycloheptane-4-yl]oxypyrazolo[1,5-a]pyridine in step 3. MS (ESP) m / z = 514.2 [M+H] +

[1118] Example 71

[1119] 1-[3-(difluoromethyl)-6-[6-[[1-(oxecyclobutan-3-yl)piperidin-4-yl]amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[1120]

[1121] Step 1: 6-Bromo-3-(4,4,5,5-Tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridine

[1122]

[1123] At 0 °C, isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane (1.24 g, 1.36 mL, 6.64 mmol, 1.5 eq; CAS [2340391-55-9]) was added dropwise to a stirred solution of 6-bromo-3-iodopyrazolo[1,5-a]pyridine (1.43 g, 4.43 mmol, 1 eq; CAS [61676-62-8]) in tetrahydrofuran (29 mL), followed by the dropwise addition of 1.3 M isopropylmagnesium chloride LiCl (3.41 mL, 4.43 mmol, 1.0 eq) in THF. The reaction mixture was stirred at 0 °C for 30 min. Additional amounts of isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxane (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 at 0 °C for 30 min. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and evaporated to dryness. The residue was purified by rapid chromatography on SiO2 by elution with 0% to 50% ethyl acetate in heptane to give the title compound (945 mg, 54% yield) as a pale yellow liquid. MS (ESP) m / z = 323.0 [M+H] +

[1124] Step 2: 1-[6-(6-bromopyrazolo[1,5-a]pyridin-3-yl)-3-(difluoromethyl)pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[1125]

[1126] Add 1-[6-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazolo[1,5-a]pyridine (115 mg, 0.36 mmol, 1.0 eq) (see Example 55, step 2) and K2CO3 (148 mg, 1.07 mmol, 3.0 eq) to a solution of 6-bromo-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazol-2-yl]-5-methylpyrazol-3-carboxynitrile (105 mg, 0.39 mmol, 1.1 eq) in N,N-dimethylformamide (2 mL) and water (1 uL). Argon gas was bubbled through the mixture and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) 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 over water and extracted with EtOAc, washed with brine, and the organic layer was dried over Na2SO4 and evaporated to dryness. The residue was purified by rapid chromatography on SiO2 in heptane from 5% to 100% (ethyl acetate:EtOH 3:1) to give the title compound as a light brown solid (50 mg, 20% yield). MS (ESP) m / z = 429.1 [M+H] +

[1127] Step 3: 1-[3-(difluoromethyl)-6-[6-[[1-(oxecyclobutan-3-yl)piperidin-4-yl]amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[1128]

[1129] A suspension of 1-[6-(6-bromopyrazolo[1,5-a]pyridin-3-yl)-3-(difluoromethyl)pyridin-2-yl]-5-methylpyrazol-3-carboxylonitrile (50 mg, 0.07 mmol, 1.0 eq), 1-(3-oxacyclobutyl)-4-piperidinamine (60 mg, 0.014 mmol, 2.0 eq; CAS [1228948-07-9]), and cesium carbonate (114 mg, 0.35 mmol, 5.0 eq) in 1,4-dioxane (1 mL) was bubbled with argon at room temperature for 5 minutes. Then [tBuBrettPhosPd(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. Rapid chromatography was performed, eluting at 0% to 100% (DCM / MeOH 10 / 1) in SiO2 to give the title compound (4 mg, 4% yield) as a pale yellow solid. MS (ESP) m / z = 505.2 [M+H] +

[1130] Example 72

[1131] 1-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-2-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]cyclopropane-1-ol

[1132]

[1133] Step 1: Acetate [1-(2,6-dichloropyridin-3-yl)cyclopropyl] ester

[1134]

[1135] 4-Dimethylaminopyridine (24 mg, 0.2 mmol, 0.1 eq) was added to a solution of 1-(2,6-dichloro-3-pyridyl)cyclopropanol (404 mg, 2.0 mmol, 1.0 eq; CAS[1935604-03-7]) in acetic anhydride (4.0 mL). This mixture was stirred at 80 °C for 30 min. The mixture was poured over water and extracted with DCM. The organic layer was washed with brine, dried over Na₂SO₄, and evaporated. Rapid column chromatography was performed, eluting with DCM on SiO₂, to give the title compound (433 mg, 87% yield) as a colorless oil. MS (ESP) m / z = 246.1 [M+H] +

[1136] Step 2: Acetic acid [1-[2-chloro-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-3-yl]cyclopropyl] ester

[1137]

[1138] Add 6-(6-methylpyridin-3-yl)cyclopropyl acetate (200 mg, 0.8 mmol, 1.0 eq) (preparation see Example 14, step 3), K2CO3 (330 mg, 2.4 mmol, 3.0 eq), and water (3.5 mL) to a solution of [1-(2,6-dichloropyridin-3-yl)cyclopropyl acetate] ester (200 mg, 0.8 mmol, 1.0 eq) in N,N-dimethylformamide (7 mL). Then, a 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii)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 over water and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and evaporated. Rapid column chromatography was performed, eluting on SiO2 with 0% to 3% MeOH in DCM to give the title compound as a white powder (296 mg, 75% yield). MS (ESP) m / z = 436.2 [M+H] +

[1139] Step 3: Acetic acid [1-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-2-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]cyclopropyl] ester

[1140]

[1141] Under an argon atmosphere, 3.25 M K3PO4 (2 eq), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride (17 mg, 0.26 mmol, 0.2 eq; CAS [95408-45-0]), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole (47 mg, 0.17 mmol, 1.5 eq; CAS [95408-45-0]) were added to isopropyl acetate (2 mL) of 1-[2-chloro-6-[6-(6-methylpyridin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-3-yl]cyclopropyl] ester (50 mg, 0.11 mmol, 1 eq) in addition to [1-[2-chloro-6-[6-(6-methylpyridin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]cyclopropyl] ester (50 mg, 0.11 mmol, 1 eq; CAS [95408-45-0]) in addition to [1-[2-chloro-6-[6-(6-methylpyridin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]cyclopropyl] ester (50 mg, 0.11 mmol, CAS [95408-45-0]) in addition to [2 mL] in 4-[2-chloro-6-[6-(6-methylpyridin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]cyclopropyl] ester (50 mg, 0.11 mmol, CAS [95408 [1049730-42-8]). The mixture was heated at 80 °C for 23 hours and then evaporated and purified by rapid chromatography on SiO2 eluted with 5% MeOH in DCM, followed by preparative HPLC purification to give the title compound as a white solid (19 mg, 29% yield). MS (ESP) m / z = 594.3 [M+H] +

[1142] Step 4: 1-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-2-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]cyclopropane-1-ol

[1143]

[1144] LiOH (0.8 mg, 0.03 mmol, 1.0 eq) was added to a solution of [1-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-2-[1-(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), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured onto water and extracted with ethyl acetate, washed with brine, dried over Na2SO4, and evaporated. Rapid column chromatography was performed, eluting on SiO2 with 0% to 7% MeOH in DCM, to give the title compound (14 mg, 84% yield) as a white solid. MS (ESN) m / z = 552.3 [M+HCO2] -

[1145] Example 73

[1146] (1S)-1-[2-[3-(2-methoxyethyl)-5-methylpyrazol-1-yl]-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-3-yl]ethanol

[1147]

[1148] Step 1: 3-[(E)-2-methoxyvinyl]-5-methyl-1-(oxacyclohexane-2-yl)pyrazole

[1149]

[1150] At 0 °C under nitrogen, a solution of 2.5 M butyllithium in hexane (10.7 mL, 26.8 mmol, 2.0 eq) was added to a solution of (methoxymethyl)triphenylphosphonium chloride (9.1 g, 27 mmol, 2.0 eq) in THF (70 mL). The reaction mixture was stirred at 0 °C for 1 hour. At -70 °C, 5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-carboxaldehyde (2.6 g, 13.4 mmol, 1.0 eq; CAS [1418297-46-7]) in THF (20 mL) was added to the reaction mixture and stirred at -70 °C for 1 hour. The reaction mixture was heated to room temperature and stirred for 16 hours. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica column chromatography with petroleum ether:EtOAc elution of 1:0 to 3:1 to give the title compound as a colorless oil (1.6 g, 7.2 mmol, 54% yield). 1H NMR (400 MHz, chloroform-d) δ = 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)

[1151] Step 2: 3-(2-methoxyethyl)-5-methyl-1-(oxacyclohexane-2-yl)pyrazole

[1152]

[1153] To a colorless solution of 3-[(E)-2-methoxyvinyl]-5-methyl-1-(oxacyclohexane-2-yl)pyrazole (1.6 g, 7.2 mmol, 1.0 eq) in ethyl acetate (25 mL), 10% palladium on carbon (766 mg, 0.72 mmol, 0.1 eq) was added. The reaction mixture was stirred at 15 psi and 30 °C for 16 h under hydrogen atmosphere. The reaction mixture was filtered through a diatomaceous earth mat. The filtrate was concentrated under vacuum to give the title compound as a colorless oil (1.5 g, 6.7 mmol, 74% yield). MS (ESP) m / z = 225.3 [M+H] +

[1154] Step 3: 3-(2-methoxyethyl)-5-methyl-1H-pyrazole

[1155]

[1156] 3-(2-methoxyethyl)-5-methyl-1-(oxacyclohexane-2-yl)pyrazole (1.5 g, 6.7 mmol, 1.0 eq) was dissolved in 1M HCl (5.0 mL) in 1,4-dioxane, and the mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography with EtOAc:MeOH = 1:0 - 10:1 (0.1% NH3•H2O as an additive) to give the title compound as a brown solid (700 mg, 5 mmol, 75% yield). MS (ESP) m / z = 141.0 [M+H] +

[1157] Step 4: (1S)-1-[2-[3-(2-methoxyethyl)-5-methylpyrazol-1-yl]-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-3-yl]ethanol

[1158]

[1159] Similar to Example 68, this example was prepared by replacing 3,5-bis(difluoromethyl)-1H-pyrazole with 3-(2-methoxyethyl)-5-methyl-1H-pyrazole in step 2 to obtain the title compound as a grayish-white solid. MS (ESP) m / z = 468.2 [M+H] +

[1160] Example 74

[1161] 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-methylpyrazol-3-carboxynitrile

[1162]

[1163] Similar to Example 62, this example was prepared by replacing 1-(oxecyclobutan-3-yl)piperidinol with 1-(2,2,2-trifluoroethyl)-4-piperidinol (CAS [90633-29-7]) in step 1 to obtain the title compound as a white solid. MS (ESP) m / z = 526.4 [M+H] +

[1164] Example 75

[1165] 1-[6-[6-(1-cyclopropylpiperidin-4-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-3-[(1S)-1-hydroxyethyl]pyridin-2-yl]-5-methylpyrazol-3-carboxynitrile

[1166]

[1167] Similar to Example 62, this example was prepared by replacing 1-(oxecyclobutan-3-yl)piperidin-4-ol with 1-cyclopropyl-piperidin-4-ol (CAS [851847-62-6]) in step 1 to obtain the title compound as a white solid. MS (ESP) m / z = 526.4 [M+H] +

[1168] Example 76 - Phosphorylation determination of SIK1-3:

[1169] In the presence of SIK2 (or SIK1 or SIK3) and ATP, the CHK peptide (KKKVSRSGLYRSPSMPENLNRPR with C-terminal arginine amide modification) is phosphorylated at one of the four viable serine residues. Only one phosphorylation was observed under the assay conditions. A serial dilution series (12 points; dilution factor 3, typically 30 µM to 170 pM) of each compound in 60 nl of DMSO was transferred to the assay plate via acoustic dispensing and pre-incubated for 30 min (ambient temperature) after adding 5 µl of SIK1 (5 nM), 5 µl of SIK2 (0.5 nM), or 7 µl of SIK3 (1.5 nM) to the assay buffer (12.5 mM HEPES (pH 7.0), 10 mM magnesium acetate, 0.005% BSA). Add 10 µM CHK-peptide solution and 5 µl 100 µM ATP to the assay buffer for SIK1 and SIK2, and 3 µl for SIK3, and incubate for 45 min in the environment. Add 40 µl 0.125% formic acid aqueous solution to quench the reaction. Data were generated using RapidFire (RF) mass spectrometry as described below. Multiple charged species (3-5 charges) of phosphorylated and non-phosphorylated forms, measured by MRM (multiple reaction monitoring; API5000 or 6500+) or EIC (extraction ion current; QToF), were summed and the ratio (total phosphorylated species / total all species) was calculated for data evaluation. Normalization was performed using Genedata software based on the non-inhibitory control DMSO and a commercially available SIK inhibitor (CAS No. 1936529-65-5) of 1 µM YKL-05-099. The results are expressed as half-maximal inhibitory concentration (IC50) and are summarized in Table 1 below.

[1170] RapidFire settings:

[1171] Samples were vacuum-absorbed for a maximum of 600 ms and placed in a C4 cartridge (Agilent; G9203A) and treated with 0.1% formic acid aqueous solution at 1.5 mL / min for 3000 ms. The samples were then transferred to an API 5000 (API 6500+) or QToF mass spectrometer and treated with 90% acetonitrile, 10% water, 0.007% TFA, and 0.093% formic acid at 1.25 mL / min for 4000 ms. The cartridge was then treated with 0.1% formic acid aqueous solution for another 500 ms.

[1172] MS settings for Sciex API 5000 / API 6500+:

[1173] Perform all MS analyses in MRM mode using the following MS settings: Electrospray positive ion; Ion spray voltage: 4000V; Temperature: 550℃; Collision gas: 5; Curtain gas: 15; Gas 1: 40; Gas 2: 42; EP: 10; DP = Declustering voltage; CE = Collision energy; CXP = Collision chamber exit voltage.

[1174]

[1175] MS settings for Agilent QToF 6545

[1176] All MS analyses were performed in MS mode using the following MS settings: Dual AJS electrospray positive ion; VCap: 3000V; Drying and sheath gas: 340℃, 8 L / min; Sprayer: 60 psig; Nozzle voltage: 2000V; Fractor: 130V; Skimmer: 35V; Oct1 RF Vpp: 700V; Reference mass at 5 spectra / s

[1177]

[1178] Table 1: IC50 values ​​for inhibition of SIK1, SIK2, and SIK3:

[1179]

[1180] Example A

[1181] Film-coated tablets containing the following ingredients can be manufactured using conventional methods:

[1182]

[1183] The active ingredient was sieved and mixed with microcrystalline cellulose, and the mixture was granulated together with a solution of polyvinylpyrrolidone in water. The granules were then mixed with sodium starch glycolate and magnesium stearate and pressed to obtain cores of 120 or 350 mg, respectively. The cores were coated with an aqueous solution / suspension of the above-described membrane coating.

[1184] Example B

[1185] Capsules containing the following ingredients can be manufactured using conventional methods:

[1186]

[1187] The components were sieved and mixed, and then filled into capsules of size 2.

[1188] Example C

[1189] Injection solutions may have the following compositions:

[1190]

[1191] Dissolve the active ingredient in a mixture of polyethylene glycol 400 and water for injection (partially). Adjust the pH to 5.0 by adding acetic acid. Adjust the volume to 1.0 ml by adding the remaining water. Filter the solution, fill vials with the appropriate excess, and sterilize.

Claims

1. A compound of Formula (I) or Formula (II) (I) or (II) wherein L is -O-, -NH-, -S-, or absent; R 1 haloalkyl, hydroxyalkyl, hydroxycycloalkyl, cyano, alkoxyalkyl, R 5 carbonyl or heterocycloalkyl; wherein heterocycloalkyl is optionally substituted with cyano; R 2 R is aryl or heteroaryl; wherein each instance of aryl and heteroaryl is optionally substituted with one, two, three, or four substituents independently selected from R 6 ​ R 3 is hydrogen or alkoxy; R 4 is 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 R 7 ​ R 5 R is hydrogen, alkyl, alkoxy, alkoxyalkyl, or haloalkyl; R 6 independently selected at each occurrence from alkyl, cyano, haloalkyl, halogen, cycloalkyl, aminocarbonyl, and alkoxyalkyl; and R 7 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.

2. The compound of claim 1, wherein R 1 It is difluoromethyl, hydroxymethyl, 1-hydroxyethyl, 1-hydroxycyclopropyl, cyano, methoxymethyl, R 5 - Carbonyl or heterocyclic alkyl, wherein the heterocyclic alkyl is optionally substituted with a cyano group; the specific heterocyclic alkyl is tetrahydrofuran-2-yl.

3. The compound of claim 1 or 2, wherein R 2 is phenyl or heteroaryl selected from pyrazol-1-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 R 6 .

4. The compound of any one of claims 1 to 3, wherein R 3 is methoxy or hydrogen, in particular hydrogen.

5. The compound of any one of claims 1 to 4, wherein R 4 is hydrogen, methyl, 2-morpholino-4-ethyl, pyridazin-3-yl, or a 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 R 7 .

6. The compound of any one of claims 1 to 5, wherein R 5 R is hydrogen, methyl or ethyl.

7. The compound of any one of claims 1 to 6, wherein R 6 is independently selected in each instance from methyl, cyano, trifluoroethyl, trifluoromethyl, difluoromethyl, fluoro, chloro, cyclopropyl, aminocarbonyl, and methoxyethyl.

8. The compound of any one of claims 1 to 7, wherein R 7 independently selected in each instance from methyl, cyclopropyl, difluoromethyl, trifluoroethyl, fluoro, chloro, dimethylaminocarbonyl, heterocycloalkyl, and heterocycloalkylalkyl; wherein R 7 heterocycloalkyl is selected from oxetan-3-yl, morpholin-4-yl and piperazin-1-yl; wherein R 7 heterocycloalkylalkyl is selected from (azetidin-l-yl)methyl, 2-oxa-6-azaspiro[3.3]heptan-6- ylmethyl, morpholin-4-ylmethyl, morpholin-4-yl-ethyl, azetidin-l-ylmethyl and piperazin- 1-ylmethyl; and wherein R 7 heterocycloalkyl and heterocycloalkylalkyl are optionally substituted with one or two substituents independently selected from alkoxy, halogen and heterocycloalkyl.

9. The compound of any one of claims 1 to 8, wherein L is -O-.

10. The compound of any one of claims 1 to 9, wherein the compound is of Formula (I) (I)。 11. The compound of any one of claims 1 to 9, wherein the compound is of Formula (II) (I) and (II).

12. A compound of Formula (I) (I) wherein L is -O-, -NH-, -S-, or absent; R 1 haloalkyl, hydroxyalkyl, hydroxycycloalkyl, cyano, alkoxyalkyl, R 5 carbonyl or tetrahydrofuran-2-yl; wherein tetrahydrofuran-2-yl is optionally substituted with cyano; R 2 is aryl or heteroaryl; wherein each instance of aryl and heteroaryl is optionally substituted with one, two, three, or four substituents independently selected from R 6 ​ R 3 is hydrogen or alkoxy; R 4 is 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 R 7 ​ R 5 R is hydrogen, alkyl, alkoxy, alkoxyalkyl, or haloalkyl; R 6 independently selected in each instance from alkyl, cyano, haloalkyl, halogen, cycloalkyl, aminocarbonyl, and alkoxyalkyl; and R 7 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 (II-a) (I-a) wherein L is -O-, -NH-, -S-, or absent; R 1' R is hydrogen, alkyl, alkoxy, alkoxyalkyl, or haloalkyl; R 2 R is 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 R 5 ​ R 3 R is hydrogen, alkoxy, alkyl, haloalkyl, or haloalkoxy; R 4 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, or heterocycloalkylalkyl; wherein each instance of cycloalkyl, aryl, heteroaryl, heterocycloalkyl, and heterocycloalkylalkyl is optionally substituted with one or two substituents independently selected from R 6 ​ R 5 R is alkyl, cyano, haloalkyl, halogen, cycloalkyl, alkoxy or aminocarbonyl; and R 6 independently selected in each instance 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 (II-a) (I-a) wherein L is -O- or absent; R 1' R is alkyl; R 2 heteroaryl optionally substituted with one or two substituents independently selected from R 5 heteroaryl optionally substituted with one or two substituents independently selected from R R 3 R is hydrogen; R 4 is hydrogen, alkyl, heteroaryl, heterocycloalkyl, or heterocycloalkylalkyl; wherein each instance of heteroaryl, heterocycloalkyl, and heterocycloalkylalkyl is optionally substituted with R 6 ; R 5 R is haloalkyl, halo, or cycloalkyl; and R 6 R is alkyl or heterocycloalkyl; or a pharmaceutically acceptable salt thereof.

15. The compound of any one of claims 1 to 14, selected from 1-[3-(1-hydroxyethyl)-6-[6-[4-(oxetan-3-yl)piperazin-1-yl]pyrazolo[1,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-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; 1-[3-(1-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]pyrazolo[1,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; 1-[3-[(1S)-1-hydroxyethyl]-6-[6-[(6-methylpyridazin-3-yl)amino]pyrazolo[1,5-a]pyridin- 3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; 1-[3-[(1R)-1-hydroxyethyl]-6-[6-[(6-methylpyridazin-3-yl)amino]pyrazolo[1,5-a]pyridin- 3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-[6-[[6-[(3-methoxyazetidin-1-yl)methyl]pyridazin-3-yl]amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; 1-[6-[6-[[6-[(3-fluoroazetidin-1-yl)methyl]pyridazin-3-yl]amino]pyrazolo[1,5-a]pyridin-3-yl]-3-(1-hydroxyethyl)pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; 1-[6-[6-[[6-[(3,3-difluoroazetidin-1-yl)methyl]pyridazin-3-yl]amino]pyrazolo[1,5-a]pyridin-3-yl]-3-(1-hydroxyethyl)pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; 1-[3-[(1S)-1-hydroxyethyl]-6-[6-[[6-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)pyridazin-3-yl]amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; 1-[3-[(1R)-1-hydroxyethyl]-6-[6-[[6-[(3-methoxyazetidin-1-yl)methyl]pyridazin-3-yl]amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; 1-[3-[(1S)-1-hydroxyethyl]-6-[6-[[6-[(3-methoxyazetidin-1-yl)methyl]pyridazin-3-yl]amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; 1-[3-[(1S)-1-hydroxyethyl]-6-[5-methoxy-6-[(6-methylpyridazin-3-yl)amino]pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; 3-[3-(1-hydroxyethyl)-6-[6-(2-morpholin-4-ylethoxy)pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]benzonitrile; 1-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; 1-[3-[(1S)-1-hydroxyethyl]-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; 1-[3-[(1R)-1-hydroxyethyl]-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; 3-fluoro-4-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5- a]pyridin-3-yl]pyridin-2-yl]-1-(2,2,2-trifluoroethyl)pyridin-2-one; (1S)-1-[2-[3-(difluoromethyl)-5-methylpyrazol-1-yl]-6-[6-(6-methylpyridazin-3- yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-3-yl]ethanol; (1R)-1-[2-[3-(difluoromethyl)-5-methylpyrazol-1-yl]-6-[6-(6-methylpyridazin-3- yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-3-yl]ethanol; 1-[3-(hydroxymethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; 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; 5-(difluoromethyl)-1-[3-[(1S)-1-hydroxyethyl]-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5- a]pyridin-3-yl]pyridin-2-yl]pyrazole-3-carbonitrile; 5-(difluoromethyl)-1-[3-[(1R)-1-hydroxyethyl]-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5- a]pyridin-3-yl]pyridin-2-yl]pyrazole-3-carbonitrile; 1-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-2-[3-methyl-1-(2,2,2- trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]ethanol; 1-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-2-[5-methyl-1-(2,2,2- trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]ethanol; 5-chloro-2-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3- yl]pyridin-2-yl]pyrazole-3-carbonitrile; 5-cyclopropyl-1-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin- 3-yl]pyridin-2-yl]pyrazole-3-carbonitrile; 5-cyclopropyl-2-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin- 3-yl]pyridin-2-yl]pyrazole-3-carbonitrile; 5-(difluoromethyl)-1-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin- 3-yl]pyridin-2-yl]pyrazole-3-carboxamide; 2-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxy pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-3-carbonitrile; 1-[6-[6-(6-chloropyridazin-3-yl)oxy pyrazolo[1,5-a]pyridin-3-yl]-3-(1-hydroxyethyl)pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; 2-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)oxy pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-3,5-dimethyl-4H-pyrrolo[3,4-c]pyrazol-6-one; 1-[2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-6-[6-(6-morpholin-4-ylpyridazin-3-yl)oxy pyrazolo[1,5-a]pyridin-3-yl]pyridin-3-yl]ethanol; 1-[2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-6-[6-[6-(morpholin-4-ylmethyl)pyridazin-3-yl]oxy pyrazolo[1,5-a]pyridin-3-yl]pyridin-3-yl]ethanol; 1-[2-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-6-[6-(6-morpholin-4-ylpyridazin-3-yl)oxy pyrazolo[1,5-a]pyridin-3-yl]pyridin-3-yl]ethanol; 1-[6-[6-[6-(difluoromethyl)pyridazin-3-yl]oxy pyrazolo[1,5-a]pyridin-3-yl]-3-[(1S)-1-hydroxyethyl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; 1-[6-[6-[6-(4-methylpiperazin-1-yl)pyridazin-3-yl]oxy pyrazolo[1,5-a]pyridin-3-yl]-2-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]ethanol; 1-[2-[3-(difluoromethyl)-5-methylpyrazol-1-yl]-6-[6-[6-[(3-methoxyazetidin-1-yl)methyl]pyridazin-3-yl]oxy pyrazolo[1,5-a]pyridin-3-yl]pyridin-3-yl]ethanol; 1-[3-(1-hydroxyethyl)-6-[6-(6-methylpyridazin-3-yl)sulfanyl pyrazolo[1,5-a]pyridin-3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; 1-[3-(1-hydroxyethyl)-6-pyrazolo[1,5-a]pyridin-3-ylpyridin-2-yl]-5-methylpyrazole-3-carbonitrile; 1-[2-[6-[4-(oxetan-3-yl)piperazin-1-yl]pyrazolo[1,5-a]pyridin-3-yl]-4-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-1,3-thiazol-5-yl]ethanol; 1 -cyclopropyl-4-[5-(1 -hydroxyethyl)-2-(6-methoxypyrazolo[1,5-a]pyridin-3-yl)- 1,3-thiazol-4-yl]pyridin-2-one; 4-[5-(1 -hydroxyethyl)-2-[6-(2-morpholin-4-ylethoxy)pyrazolo[1,5-a]pyridin-3-yl]- 1,3-thiazol-4-yl]-1 -(2,2,2-trifluoroethyl)pyridin-2-one; 1 -[2-[6-(2-morpholin-4-ylethoxy)pyrazolo[1,5-a]pyridin-3-yl]-4-[1 -(2,2,2- trifluoroethyl)pyrazol-4-yl]-1,3-thiazol-5-yl]ethanol; 1 -[2-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-4-[1 -(2,2,2- trifluoroethyl)pyrazol-4-yl]-1,3-thiazol-5-yl]ethanol; 3-fluoro-4-[5-(1 -hydroxyethyl)-2-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5- a]pyridin-3-yl]-1,3-thiazol-4-yl]-1 -(2,2,2-trifluoroethyl)pyridin-2-one; 1 -[2-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-4-[2-(2,2,2- trifluoroethyl)triazol-4-yl]-1,3-thiazol-5-yl]ethanol; 1 -[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2- yl]-5-methylpyrazole-3-carbonitrile; 1 -[3-formyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2- yl]-5-methylpyrazole-3-carbonitrile; 2-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2- yl]-5-(trifluoromethyl)pyrazole-3-carbonitrile; 1 -[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2- yl]-5-cyclopropylpyrazole-3-carbonitrile; 2-[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2- yl]-5-cyclopropylpyrazole-3-carbonitrile; 1 -[3-acetyl-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin-2- yl]-5-(difluoromethyl)pyrazole-3-carbonitrile; 1 -[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-2-[1 -(2,2,2- trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]propan-1 -one; 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; 1-[3-(difluoromethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-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]pyridin-2-yl]-6-(6- methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridine; 3-[5-(difluoromethyl)-6-[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-2-yl]-6-(6- methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridine; 1-[3-(difluoromethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin- 2-yl]-5-methylpyrazole-3-carbonitrile; 5-methyl-1-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-3-[trans-4- cyanooxolan-2-yl]pyridin-2-yl]pyrazole-3-carbonitrile; 5-methyl-1-[6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]-3-[cis-4- cyanooxolan-2-yl]pyridin-2-yl]pyrazole-3-carbonitrile; 1-[3-(difluoromethyl)-6-[6-(6-methylpyridazin-3-yl)oxypyrazolo[1,5-a]pyridin-3-yl]pyridin- 2-yl]-5-methylpyrazole-3-carbonitrile; 3-[3-[6-(3-cyano-5-methylpyrazol-1-yl)-5-(1-hydroxyethyl)pyridin-2-yl]pyrazolo[1,5- a]pyridin-6-yl]oxy-N,N,6-trimethylpyridazine-4-carboxamide; 3-[5-(difluoromethyl)-6-[3-methyl-1-(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; 3-[5-(difluoromethyl)-6-[5-methyl-1-(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; 4-[[6-[3-[5-(difluoromethyl)-6-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-2- yl]pyrazolo[1,5-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)oxy-pyrazolo[l,5-a]pyridin-3-yl]-3- propionylpyridin-2-yl]pyrazole-3-carbonitrile; 1-[3-(l-hydroxyethyl)-6-[6-[l-(oxetan-3-yl)piperidin-4-yl]oxy-pyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; 1-[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; 1-[6-[6-(6-methylpyridazin-3-yl)oxy-pyrazolo[l,5-a]pyridin-3-yl]-2-[l-(2,2,2- trifluoroethyl)pyrazol-4-yl]pyridin-3-yl]cyclopropan-l-ol; (lS)-l-[2-[3-(2-methoxyethyl)-5-methylpyrazol-l-yl]-6-[6-(6-methylpyridazin-3- yl)oxy-pyrazolo[l,5-a]pyridin-3-yl]pyridin-3-yl]ethanol; 1-[3-(l-hydroxyethyl)-6-[6-[l-(2,2,2-trifluoroethyl)piperidin-4-yl]oxy-pyrazolo[l,5-a]pyridin- 3-yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; and 1-[6-[6-(l-cyclopropylpiperidin-4-yl)oxy-pyrazolo[l,5-a]pyridin-3-yl]-3-[(lS)-l- hydroxyethyl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; or a pharmaceutically acceptable salt thereof.

16. The compound according to any one of claims 1 to 15, which is selected from 1-[3-(l-hydroxyethyl)-6-[6-[(6-methylpyridazin-3-yl)amino]pyrazolo[l,5-a]pyridin-3- yl]pyridin-2-yl]-5-methylpyrazole-3-carbonitrile; 1-[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; 1-[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; 1-[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; 1 - [3 - [(1 S) -1 -hydroxyethyl] -6- [6-(6-methylpyridazin-3 -yl)oxy pyrazolo [1,5- a] pyridin-3 -yl] pyridin-2 -yl] -5 -methylpyrazole-3 -carbonitrile; 1 - [3 - [(1 S) -1 -hydroxyethyl] -6- [6-(6-methylpyridazin-3 -yl)oxy pyrazolo [1,5- a] pyridin-3 -yl] pyridin-2 -yl] -5 -methylpyrazole-3 -carbonitrile; or a pharmaceutically acceptable salt thereof.

17. A process for the manufacture of a compound according to any one of claims 1 to 15, comprising at least one of the following steps: (a) reacting a compound of formula (A1) (A1) with a compound of formula (A2) R 4 -L-H (A2), in the presence of a suitable catalyst, a suitable solvent and a suitable base; (b) reacting a compound of formula (B1) (B1) with a suitable reducing agent, in the presence of a suitable solvent; or (c) reacting a compound of formula (C1) (C1) with a compound of formula (C2) R 2 - (B(OH)2(C2) in the presence of a suitable catalyst, a suitable solvent and a suitable base; wherein L, R 1 , R 2 , R 3 and R 4 are 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 therapeutic 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, nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell arteritis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis.

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 of rheumatoid arthritis, juvenile rheumatoid arthritis, nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell arteritis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis.

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, nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell arteritis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes or glomerulonephritis.

24. A method for the treatment or prevention of rheumatoid arthritis, juvenile rheumatoid arthritis, nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis, giant cell arteritis, inflammatory bowel disease (IBD), atherosclerosis, type 2 diabetes, or glomerulonephritis, said method comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 16.

25. The application as hereinbefore described.

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