NLRP3 modulators

Abstract

The present invention relates to compounds or a pharmaceutically acceptable salt or stereoisomer thereof of formula (I) wherein R1, R1a, R2, R3, R4a, R5, R5a, X1, and R5b have the meaning as indicated in the claims and description. The invention further relates to pharmaceutical compositions comprising said compounds, their use as medicament and in a method for treating and / or preventing of one or more diseases, disorders or conditions associated with NLRP3.

Description

NLRP3 MODULATORS BACKGROUND OF THE INVENTION

[0001] NLRP3 is a member of the nucleotide-binding domain (NBD), leucine-rich repeat(LRR)-containing (NLR) protein family that mediates innate inflammatory processes after infection or tissue injury. Upon activation it forms an inflammasome complex with ASC and caspase-1 that leads to IL-1β and IL-18 release and pyroptotic cell death.

[0002] Pathological functions of NLRP3-mediated inflammation have been described ininherited diseases like cryopyrin-associated periodic syndromes (CAPS), as well as chronicinflammatory (e.g. rheumatoid arthritis), metabolic (e.g. diabetes) or neurological diseases (e.g.Alzheimer’s disease, Parkinson’s disease, multiple sclerosis).

[0003] NLRP3 is an intracellular sensor molecule that is activated in a “priming” and an“activation” step. The priming step includes the stimulation of pattern recognition receptors (PRRs) like Toll-like receptors and the activation of the nuclear factor-κB (NFκB) pathway that increases the expression of NLRP3, caspase-1, Gasdermin D and pro-inflammatory cytokines. The NLRP3 activation step leads to formation of the active inflammasome that can be triggered by bacterial, viral and fungal infections (PAMPs; pathogen-associated molecule pattern; e.g.,nigericin, DNA, RNA), sterile inflammation mediated by endogenous molecules (DAMPs;damage-associated molecule pattern; e.g. ATP, cholesterol crystals, α-synuclein, amyloid-β) and exposure to environmental irritants (Swanson et al., Nature Review Immunology, 2019, Vol 19., 477–489).

[0004] PAMPs and DAMPs cause cellular stress that is sensed by NLRP3. Many of themactivate NLRP3 by causing a decrease in cytosolic potassium ions that induces conformational changes in the inactive NLRP3 protein leading to the formation of an NLRP3 complex that recruits ASC (adaptor protein apoptosis-associated speck-like protein containing a CARD). ASC binds pro-caspase-1 which is activated within the multiprotein inflammasome complex (also called ASC speck). Active caspase-1 cleaves the proinflammatory cytokines IL-1β and IL-18, as well as GSDMD (Gasdermin D) which form pores within the membrane, allowing the release of mature IL-1β and IL-18, and can trigger pyroptotic cell death. During pyroptosis, the release of intracellular contents, including NLRP3 inflammasomes, high-mobility groupprotein B1 (HMGB1), leukotrienes and prostaglandin, amplifies the inflammatory response andcontributes to inflammatory pathology (Mangan et al., Nature Reviews Drug Discovery, 2018, Vol.17, 588-606; Swanson et al., Nature Review Immunology, 2019, Vol 19., 477–489).

[0005] Pathological consequences of NLRP3 activation are observed in patients withinherited, autosomal dominant mutations in NLRP3 that promote NLRP3 inflammasome activation. Patients with these gain-of-function mutations develop rare systemic auto- inflammatory syndromes called cryopyrin-associated periodic syndromes (CAPS), characterized by an inflammation-related phenotype with periodic fevers, sterile urticaria, and joint inflammation. CAPS incorporate three overlapping disease entities: familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS), and neonatal-onset multisystem autoinflammatory syndrome (NOMID).

[0006] Pre-clinical studies with NLRP3 genetic deletions or small molecule inhibitorsassociates NLRP3-mediated inflammation with plenty of peripheral and central diseases. That includes chronic inflammatory diseases, including gout, rheumatoid arthritis, and inflammatory bowel disease (IBD) including Crohn’s disease and ulcerative colitis, metabolic diseases likeatherosclerosis, diabetes, metabolic syndrome, obesity, and liver steatosis, nonalcoholicsteatohepatitis (NASH) and liver fibrosis, and neurological diseases, including Alzheimer’sdisease (AD) and Parkinson’s disease (PD), multiple sclerosis (MS), Huntington’s disease(HD), Amyotrophic Lateral Sclerosis (ALS), Prion disease, Traumatic Brain Injury (TBI) and stroke, as well as asthma and allergic airway inflammation, hypertension, myocardialinfarction, hyperinflammation following influenza and / or severe acute respiratory syndrome-coronavirus 2 (SARS CoV-2), Graft-versus-host disease, silicosis, myelodysplastic syndrome, contact hypersensitivity and joint inflammation triggered by chikungunya virus (Mangan et al., Nature Reviews Drug Discovery, 2018, Vol. 17, 588-606; Holbrook et al., Frontiers in Pharmacology, 2021, Vo.l 12, Article 643254; Coll et al., Trends in Pharmacological Science, 2022, Vol. 43, 653-668; Thornton et al., Journal of Pharmacology and Experimental Therapeutics, March 2024, 388(3) 813-826).

[0007] Several small molecules have been reported that directly or indirectly inhibitNLRP3. They have either weak potencies in the micromolar range and / or off target effects (Coll et al., Trends in Pharmacological Science, 2022, Vol.43, 653-668). MCC950 is used in many pre-clinical studies as a tool compound with good potency and selectivity over NLRC4 and NLRP1. However, high dosing in clinical studies resulted in liver toxicity (Mangan et al., Nature Reviews Drug Discovery, 2018, Vol.17, 588-606).

[0008] The pro-inflammatory cytokine IL-1β is a potent NLRP3-dependent effector andtherefore a major target for limiting NLRP3 driven pathology. Biologics like anakinra,canakinumab and rilonacept inhibit the IL1 axis, are approved for therapeutic use in CAPS andtested in clinical trial for rheumatoid arthritis and gout. However, biologics require administration by injection, they cause inflammation at the injection site and have poor brain permeability (Mangan et al., Nature Reviews Drug Discovery, 2018, Vol.17, 588-606).

[0009] There is a need for orally available and preferably brain-permeable NLRP3inhibitors with improved potency and selectivity. SUMMARY OF THE INVENTION

[0010] The present application relates generally to compounds, compositions and methodsfor modulating the activity of NLRP3. Also disclosed herein are compounds, compositions andmethods for treating a disease, disorder, or condition which include but are not limited to (i) diseases associated with NLRP3-mediated inflammation, including but not limited to cryopyrin-associated periodic syndromes (CAPS), familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS), and neonatal-onset multisystem autoinflammatorysyndrome (NOMID); (ii) chronic inflammatory diseases (e.g., gout, rheumatoid arthritis,inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis), (iii)metabolic diseases (e.g., atherosclerosis, diabetes, metabolic syndrome, obesity, liver steatosis,nonalcoholic steatohepatitis (NASH), and liver fibrosis); (iv) neurological diseases (e.g.,Alzheimer’s disease (AD) and Parkinson’s disease (PD), multiple sclerosis (MS), Huntington’s disease (HD), Amyotrophic Lateral Sclerosis (ALS), Prion disease, Traumatic Brain Injury(TBI) and stroke); (v) diseases associated with inherited, autosomal dominant mutations inNLRP3 that promote NLRP3 inflammasome; (vi) asthma and allergic airway inflammation;(vii) hypertension; (viii) myocardial infarction; (ix) hyperinflammation following influenzaand / or severe acute respiratory syndrome-coronavirus 2 (SARS CoV-2); (x) Graft-versus-hostdisease; (xi) silicosis; (xii) myelodysplastic syndrome; (xiii) contact hypersensitivity and joint inflammation triggered by chikungunya virus.

[0011] In one aspect, the disclosure encompasses a compound of formula (I)or a pharmaceutically acceptable salt or stereoisomer thereof, whereinR1 is CN, C1-4 alkyl, O-C1-4 alkyl or halogen, wherein C1-4 alkyl and O-C1-4 alkyl areoptionally substituted with one or more F, and R1ais H, C1-4alkyl or halogen; or R1and R1aare joined to form, together with the carbon atoms to which they areattached, a C4-6 cycloalkyl or an unsubstituted saturated 4- to 6-membered heterocycle;R2is H, CH3, CH2CH3, CF3, CHF2, OCH3, Cl, CN or cyclopropyl and R3is H or CH3, provided that not both, R2and R3, are H; X1is C(R4) or N;R4 is H, C1-4 alkyl, C3-5 cycloalkyl, unsubstituted saturated 4- to 6- memberedheterocyclyl, OCH3, CN, Cl or F, wherein C1-4alkyl and C3-5cycloalkyl are unsubstitutedor substituted with one or more F; orR3 and R4 are joined to form -CH2-CH2-CH2- or -CH2-O-CH2-;R4a is H, CH3, OCH3 or CN;R5a and R5b are independently selected from the group consisting of H and CH3 and R5 isR6; or R5is H and R5aand R5bare joined to form, together with the carbon atom to which they are attached, a ring T1; or R5, R5a, R5bare joined to form, together with the carbon atom to which they are attached, a bicyclic ring T2;T1 is C3-7 cycloalkyl, saturated 4- to 7-membered heterocyclyl containing one or twohetero ring atoms, which are independently selected from the group consisting of O,N(R7) and S(O)2 or saturated 7- to 12-membered heterobicyclyl containing one or twohetero ring atoms, which are independently selected from the group consisting of O, N(R7) and S(O)2, wherein T1is optionally substituted with one or more R8, which are the same or different; T2is bicyclo[1.1.1]pentanyl, wherein T2is substituted with one OH or one CH2OH;R6is C1-6 alkyl, T3or CH2T3, wherein C1-6 alkyl is substituted with one or more R6a, which are the same or different; R6ais OH, OC1-4 alkyl or C(O)OC1-4 alkyl; R7is C1-4alkyl, S(O)2-C1-4alkyl, C(O)CH2OCH3, S(O)2T4, C(O)T4, wherein each C1-4alkyl is independently unsubstituted or substituted with one OH; R8is oxo (=O), OH, CH2OH, F, CH3or OCH3; T3 is C3-7 cycloalkyl, bicyclo[1.1.1]pentanyl, saturated 4- to 7-membered heterocyclyl, orsaturated 7- to 12-membered heterobicyclyl, wherein T3 is unsubstituted or substitutedwith one or more R9, which are the same or different; T4 is C3-7 cycloalkyl, bicyclo[1.1.1]pentanyl, saturated 4- to 7-membered heterocyclyl,saturated 7- to 12-membered heterobicyclyl, wherein T4 is unsubstituted or substitutedwith one or more R9a, which are the same or different; R9and R9aare independently selected from the group consisting of C1-4alkyl, oxo (=O), OH, CH2OH, S(O)2-C1-4 alkyl, C(O)OC1-4 alkyl, T5, CH2T5and F, wherein each C1-4 alkyl is independently unsubstituted or substituted with one or more F; T5 is saturated 4- to 7-membered heterocyclyl or C3-7 cycloalkyl, wherein T5 isunsubstituted or substituted with one or more F.

[0012] In another aspect, the disclosure encompasses a compound of formula (I)or a pharmaceutically acceptable salt or stereoisomer thereof, whereinR1 is CN, C1-4 alkyl, O-C1-4 alkyl or halogen, wherein C1-4 alkyl and O-C1-4 alkyl areoptionally substituted with one or more F, and R1ais H, C1-4 alkyl or halogen; or R1and R1aare joined to form, together with the carbon atoms to which they areattached, a C4-6 cycloalkyl or an unsubstituted saturated 4- to 6-membered heterocycle;R2is H, CH3, CH2CH3, CF3, CHF2, OCH3, Cl, CN or cyclopropyl and R3is H or CH3, provided that not both, R2and R3, are H; X1is C(R4) or N;R4 is H, C1-4 alkyl, C3-5 cycloalkyl, unsubstituted saturated 4- to 6- memberedheterocyclyl, OCH3, CN, Cl or F, wherein C1-4 alkyl and C3-5 cycloalkyl are unsubstitutedor substituted with one or more F; orR3 and R4 are joined to form -CH2-CH2-CH2- or -CH2-O-CH2-;R4a is H, CH3, OCH3 or CN;R5aand R5bare H and R5is R6; or R5is H and R5aand R5bare joined to form, together with the carbon atom to which they are attached, a ring T1; or R5, R5a, R5bare joined to form, together with the carbon atom to which they are attached, a bicyclic ring T2;T1 is C3-7 cycloalkyl, saturated 4- to 7-membered heterocyclyl containing one or twohetero ring atoms, which are independently selected from the group consisting of O,N(R7) and S(O)2 or saturated 7- to 12-membered heterobicyclyl containing one or twohetero ring atoms, which are independently selected from the group consisting of O, N(R7) and S(O)2, wherein T1is optionally substituted with one or more R8, which are the same or different; T2is bicyclo[1.1.1]pentanyl, wherein T2is substituted with one OH or one CH2OH;R6is C1-6 alkyl, T3or CH2T3, wherein C1-6 alkyl is substituted with one OH or OCH3; R7is C1-4 alkyl, S(O)2-C1-4 alkyl, C(O)CH2OCH3, S(O)2T4, C(O)T4, wherein each C1-4 alkyl is independently unsubstituted or substituted with one OH; R8is oxo (=O), OH, CH2OH, F, CH3or OCH3; T3 is C3-7 cycloalkyl, bicyclo[1.1.1]pentanyl, saturated 4- to 7-membered heterocyclyl, orsaturated 7- to 12-membered heterobicyclyl, wherein T3 is unsubstituted or substitutedwith one or more R9, which are the same or different; T4 is C3-7 cycloalkyl, bicyclo[1.1.1]pentanyl, saturated 4- to 7-membered heterocyclyl,saturated 7- to 12-membered heterobicyclyl, wherein T4 is unsubstituted or substitutedwith one or more R9a, which are the same or different; R9and R9aare independently selected from the group consisting of C1-4 alkyl, oxo (=O), OH, CH2OH, S(O)2-C1-4 alkyl, C(O)OC1-4 alkyl, and F, wherein each C1-4 alkyl is independently unsubstituted or substituted with one or more F.

[0013] In another aspect for the compound of formula (I), R1 is CN, CH3, CF3, CHF2,OCH3, OCHF2, OCF3 or halogen and R1ais H.

[0014] In another aspect for the compound of formula (I), R1 is F, Cl or CF2CH3 and R1a isH.

[0015] In another aspect for the compound of formula (I), R1 is CF3 and R1a is H.

[0016] In another aspect for the compound of formula (I), R1 is CH3 and R1a is H.

[0017] In another aspect for the compound of formula (I), R2 is CH3. In another aspectfor the compound of formula (I), R2is CH3, Cl or CHF2.

[0018] In another aspect for the compound of formula (I), R3 is H. In just another aspectfor the compound of formula (I), R3is CH3.

[0019] In another aspect for the compound of formula (I), R1 is CF3, R1a is H, R2 is CH3,and R3is H.

[0020] In another aspect for the compound of formula (I), R1 is CH3, R1a is H, R2 isCH3, and R3 is H.

[0021] In another aspect for the compound of formula (I), X1 is CH, C(CH3), C(CHF2) orC(OCH3). In another aspect for the compound of formula (I), X1 is C(CH2CH2CH3) orC(azetidin-1-yl).

[0022] In another aspect for the compound of formula (I), X1 is CH.

[0023] In another aspect for the compound of formula (I), X1 is N.

[0024] In another aspect for the compound of formula (I), R4a is H or CH3.

[0025] In another aspect for the compound of formula (I), R4a is H.

[0026] In another aspect for the compound of formula (I), R5 is H and R5a and R5b arejoined to form, together with the carbon atom to which they are attached, a ring T1.

[0027] In another aspect for the compound of formula (I), T1 is a saturated 4- to 7-membered heterocyclyl containing one hetero ring atom, which is O, wherein T1is unsubstituted or substituted with one or two R8, which are the same or different.

[0028] In another aspect for the compound of formula (I), R8 is methyl.

[0029] In another aspect for the compound of formula (I), T1 is oxan‐4‐yl, oxolan-3-yl, 5-oxaspiro[3.5]nonan-8-yl, 2,2-dimethyloxan‐4‐yl, or 2,6‐dimethyloxan‐4‐yl. In anotheraspect for the compound of formula (I), T1is oxepan‐4‐yl.

[0030] In another aspect for the compound of formula (I), T1 is C3-7 cycloalkyl orsaturated 4- to 7-membered heterocyclyl containing one or two hetero ring atoms, which areN(R7), wherein T1is optionally substituted with one or two R8, which are the same or different.

[0031] In another aspect for the compound of formula (I), T1 ishydroxymethylcyclobutyl, hydroxycyclobutyl, 1‐(ethanesulfonyl)piperidin‐4‐yl, 1‐ methanesulfonylpiperidin‐4‐yl, 1‐cyclopropanecarbonylpiperidin‐4‐yl, 1‐(1‐methylpyrrolidine‐3‐carbonyl)piperidin‐4‐yl, thiane-1,1-dioxo-4-yl, 1-cyclopropanecarbonylpiperidin-4-yl, 1‐(cyclobutanesulfonyl)piperidin‐4‐yl, 1-methoxymethylcarbonylpiperidin‐4‐yl, 1-(oxolane-3-carbonyl)piperidin-4-yl, 1-(1- methylpyrrolidine-3-carbonyl)piperidin-4-yl, 1-(1-fluorocyclopropanecarbonyl)piperidin-4-yl, 1-[1-(trifluoromethyl)cyclopropanecarbonyl]piperidin-4-yl, or 1-(3,3-difluoroazetidine-1-carbonyl)piperidin-4-yl. In another aspect for the compound of formula (I), T1 is 1‐(2,2‐difluorocyclopropanecarbonyl)piperidin‐4‐yl, 1‐(1‐methylcyclopropanecarbonyl)piperidin‐4‐yl, or 1‐(2,2‐difluoro‐1‐methylcyclopropanecarbonyl)piperidin‐4‐yl.

[0032] In another aspect for the compound of formula (I), R5a and R5b are selectedfrom the group consisting of H and CH3; and R5is R6. In another aspect for the compound of formula (I), R5aand R5bare H and R5is R6.

[0033] In another aspect for the compound of formula (I), R6 is C1-6 alkyl, whereinC1-6 alkyl is substituted with one OH or OCH3, preferably one OCH3. In another aspect for thecompound of formula (I), C1-6 alkyl is substituted with one OCH3. In another aspect for thecompound of formula (I), R6is C1-6 alkyl, wherein C1-6 alkyl is substituted with one C(O)OCH2CH3.

[0034] In another aspect for the compound of formula (I), R6 is hydroxyethyl,methoxyethyl, hydroxymethyl or 2‐hydroxy‐2‐methylpropyl. In another aspect for thecompound of formula (I), R6is ethyloxycarbonylethyl.

[0035] In another aspect for the compound of formula (I), R6 is T3 and T3 is asaturated 4- to 7-membered heterocyclyl, wherein T3 is substituted with one, two or three R9,which are the same or different.

[0036] In another aspect for the compound of formula (I), R6 is T3 and T3 is 1-methylpiperidinyl, 1-ethylpiperidinyl, 1-methylpyrrolidinyl or 4-methylmorpholinyl, whereinT3 is optionally further substituted with one or more R9. In another aspect for the compoundof formula (I), R6is T3and T3is 1-methylazetidinyl, wherein T3is optionally further substituted with one or more R9.

[0037] In another aspect for the compound of formula (I), R9 and R9a areindependently selected from the group consisting of C1-4 alkyl, oxo (=O), OH, CH2OH, S(O)2- C1-4alkyl, C(O)OC1-4alkyl and F, wherein each C1-4alkyl is independently unsubstituted or substituted with one or more F.

[0038] In another aspect for the compound of formula (I), R6 is 3‐fluoro‐1‐methylpiperidin‐3‐yl, 1‐ethyl‐3‐fluoropiperidin‐3‐yl, 1-methylpyrrolidin-2-oxo-3-yl, 1- methylpyrrolidin-2-oxo-4-yl, 3‐fluoro‐1‐methylpyrrolidin‐3‐yl, 4,4-difluoro‐1‐ methylpiperidin‐3‐yl, 1-methylpyrrolidin-3-yl, 1-ethylpiperidin-3-yl, or 4-methylmorpholin- 2-yl.

[0039] In another aspect for the compound of formula (I), R6 is 1‐ethyl‐4,4‐difluoropiperidin‐3‐yl, 5,5-difluoro‐1‐methylpiperidin‐3‐yl; 4,4-difluoro-1-methylpyrrolidin-2-ylmethyl; 1-methyl-3-fluoro-pyrrolidin-3-yl or 4‐methylmorpholin‐3‐yl.

[0040] In another aspect for the compound of formula (I), R6 is T3 and T3 is 1-(oxetan-3-yl)pyrrolidin-3-yl, 1‐[(3‐fluorooxetan‐3‐yl)methyl]pyrrolidin‐3‐yl, 1‐[(1‐fluorocyclopropyl)methyl]piperidin‐3‐yl; (3-fluorooxetan-3-yl)methylpiperidin-3-yl or 1‐[(1‐fluorocyclopropyl)methyl]pyrrolidin‐3‐yl.

[0041] In another aspect for the compound of formula (I), R6 is T3 and T3 issubstituted with at least one F.

[0042] In another aspect for the compound of formula (I), R6 is T3 and T3 issubstituted with T5or CH2T5.

[0043] In another aspect for the compound of formula (I), R6 is T3 and T3 is oxan-4-yl or oxetan-3-yl, wherein T3is unsubstituted or substituted with one R9. In another aspect for the compound of formula (I), R6is T3and T3is oxan-4-yl, 3-(butyloxycarbonyl)oxetan-3-yl or 3‐(hydroxymethyl)oxetan‐3‐yl.

[0044] In another aspect for the compound of formula (I), R6 is thietane‐1,1‐dioxo-3-yl, 1-methanesulfonylazetidin-3-yl, or 1-ethoxycarbonylcycloprop-1-yl.

[0045] In another aspect for the compound of formula (I), R6 is 1-hydroxymethylcycloprop-1-yl or 3-hydroxycyclobut-1-yl.

[0046] In another aspect of the disclosure for the compounds described herein, thecompound is: 2‐[2‐(3‐hydroxypropyl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐3‐methyl‐5‐ (trifluoromethyl)phenol; cis 2‐{2‐[3‐(hydroxymethyl)cyclobutyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐5‐(trifluoromethyl)phenol; trans 2‐{2‐[3‐(hydroxymethyl)cyclobutyl]‐2H-pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐5‐ (trifluoromethyl)phenol; trans- 2‐[2‐(3‐hydroxycyclobutyl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐3‐methyl‐5‐(trifluoromethyl)phenol; rac-2‐{2‐[(3‐fluoro‐1‐methylpiperidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐ methyl‐5‐(trifluoromethyl)phenol; rac-2‐{2‐[(1‐ethyl‐3‐fluoropiperidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐ methyl‐5‐(trifluoromethyl)phenol; 2‐{2‐[1‐(ethanesulfonyl)piperidin‐4‐yl]‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl}‐3‐methyl‐5‐ (trifluoromethyl)phenol; 2‐[2‐(1‐methanesulfonylpiperidin‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl]‐3‐methyl‐5‐ (trifluoromethyl)phenol; 2‐[2‐(1‐cyclopropanecarbonylpiperidin‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl]‐3‐methyl‐ 5‐(trifluoromethyl)phenol; rac-3‐methyl‐2‐{2‐[1‐(1‐methylpyrrolidine‐3‐carbonyl)piperidin‐4‐yl]‐2H‐pyrazolo[3,4‐ b]pyrazin‐6‐yl}‐5‐(trifluoromethyl)phenol; 3‐methyl‐2‐[2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐5‐(trifluoromethyl)phenol; 3‐methyl‐2‐[2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl]‐5‐(trifluoromethyl)phenol; 5‐methoxy‐3‐methyl‐2‐[2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]phenol; rac-3-methyl-2-[2-(oxolan-3-yl)-2H-pyrazolo[3,4-b]pyridin-6-yl]-5- (trifluoromethyl)phenol, 3R-, 3S-enantiomer; 3-methyl-2-[4-methyl-2-(oxan-4-yl)-2H-pyrazolo[3,4-b]pyridin-6-yl]-5- (trifluoromethyl)phenol; 3‐methyl‐2‐[3‐methyl‐2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl]‐5‐ (trifluoromethyl)phenol; 3-methyl-2-[3-methyl-2-(oxan-4-yl)-2H-pyrazolo[3,4-b]pyridin-6-yl]-5- (trifluoromethyl)phenol;4-{6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-2H-pyrazolo[3,4-b]pyridin-2-yl}- 1λ⁶-thiane-1,1-dione; rac-3-({6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-2H-pyrazolo[3,4-b]pyrazin-2- yl}methyl)-1-methylpyrrolidin-2-one; rac-4-({6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-2H-pyrazolo[3,4-b]pyrazin-2- yl}methyl)-1-methylpyrrolidin-2-one; rac-3-methyl-2-(2-{5-oxaspiro[3.5]nonan-8-yl}-2H-pyrazolo[3,4-b]pyridin-6-yl)-5- (trifluoromethyl)phenol; rac-2‐{2‐[(3‐fluoro‐1‐methylpyrrolidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐ methyl‐5‐(trifluoromethyl)phenol; rac-2‐{2‐[(4,4‐difluoro‐1‐methylpiperidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐ yl}‐3‐methyl‐5‐(trifluoromethyl)phenol; 3‐({6‐[2‐hydroxy‐6‐methyl‐4‐(trifluoromethyl)phenyl]‐2H‐pyrazolo[3,4‐b]pyridin‐2‐ yl}methyl)-1λ6-thietane-1,1-dione; 2‐[2‐(3‐methoxypropyl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐3‐methyl‐5‐ (trifluoromethyl)phenol; 2‐[2‐(2‐hydroxyethyl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐3‐methyl‐5‐ (trifluoromethyl)phenol; 2‐[2‐(3‐hydroxy‐3‐methylbutyl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐3‐methyl‐5‐ (trifluoromethyl)phenol; 2‐[4‐(difluoromethyl)‐2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐3‐methyl‐5‐ (trifluoromethyl)phenol; 2‐[4‐methoxy‐2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐3‐methyl‐5‐ (trifluoromethyl)phenol; 2-[2-(1-cyclopropanecarbonylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridin-6-yl]-3-methyl- 5-(trifluoromethyl)phenol; rac-3-methyl-2-{2-[(1-methylpyrrolidin-3-yl)methyl]-2H-pyrazolo[3,4-b]pyrazin-6-yl}- 5-(trifluoromethyl)phenol, 3R-, 3S-enantiomer; rac-3-methyl-2-{2-[(1-methylpyrrolidin-3-yl)methyl]-2H-pyrazolo[3,4-b]pyridin-6-yl}- 5-(trifluoromethyl)phenol; 2-{2-[(1-methanesulfonylazetidin-3-yl)methyl]-2H-pyrazolo[3,4-b]pyridin-6-yl}-3- methyl-5-(trifluoromethyl)phenol; rac-2-{2-[(1-ethylpiperidin-3-yl)methyl]-2H-pyrazolo[3,4-b]pyridin-6-yl}-3-methyl-5- (trifluoromethyl)phenol;2-[2-(1-methanesulfonylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridin-6-yl]-3-methyl-5- (trifluoromethyl)phenol; 2-{2-[1-(ethanesulfonyl)piperidin-4-yl]-2H-pyrazolo[3,4-b]pyridin-6-yl}-3-methyl-5- (trifluoromethyl)phenol; 2‐{2‐[1‐(cyclobutanesulfonyl)piperidin‐4‐yl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐ 5‐(trifluoromethyl)phenol; 1‐(4‐{6‐[2‐hydroxy‐6‐methyl‐4‐(trifluoromethyl)phenyl]‐2H‐pyrazolo[3,4‐b]pyridin‐2‐ yl}piperidin‐1‐yl)‐2‐methoxyethan‐1‐one; 1-(4-{6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-2H-pyrazolo[3,4-b]pyrazin-2- yl}piperidin-1-yl)-2-methoxyethan-1-one; rac-3-methyl-2-{2-[1-(oxolane-3-carbonyl)piperidin-4-yl]-2H-pyrazolo[3,4-b]pyridin-6- yl}-5-(trifluoromethyl)phenol, 3R-, 3S-enantiomer; rac-3-methyl-2-{2-[1-(1-methylpyrrolidine-3-carbonyl)piperidin-4-yl]-2H-pyrazolo[3,4- b]pyridin-6-yl}-5-(trifluoromethyl)phenol; 2‐{2‐[1‐(1‐fluorocyclopropanecarbonyl)piperidin‐4‐yl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐ 3‐methyl‐5‐(trifluoromethyl)phenol; 3‐methyl‐5‐(trifluoromethyl)‐2‐(2‐{1‐[1‐ (trifluoromethyl)cyclopropanecarbonyl]piperidin‐4‐yl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐ yl)phenol; 2‐{2‐[1‐(3,3‐difluoroazetidine‐1‐carbonyl)piperidin‐4‐yl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐ yl}‐3‐methyl‐5‐(trifluoromethyl)phenol; rac-2‐[2‐(2,2‐dimethyloxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐3‐methyl‐5‐ (trifluoromethyl)phenol; 3‐methyl‐2‐(2‐{[(2R)‐4‐methylmorpholin‐2‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl)‐ 5‐(trifluoromethyl)phenol; 3‐methyl‐2‐(2‐{[(2S)‐4‐methylmorpholin‐2‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl)‐ 5‐(trifluoromethyl)phenol; ethyl 1‐({6‐[2‐hydroxy‐6‐methyl‐4‐(trifluoromethyl)phenyl]‐2H‐pyrazolo[3,4‐b]pyridin‐ 2‐yl}methyl)cyclopropane‐1‐carboxylate; 2‐{2‐[(2R,6S)‐2,6‐dimethyloxan‐4‐yl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐ 3‐methyl‐5‐ (trifluoromethyl)phenol; 3‐methyl‐2‐{2‐[(2R,4r,6S)‐2,6‐dimethyloxan‐4‐yl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐5‐ (trifluoromethyl)phenol;3‐methyl‐2‐{2‐[(2R,4s,6S)‐2,6‐dimethyloxan‐4‐yl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐5‐ (trifluoromethyl)phenol; 2‐(2‐{[(3R)‐1‐ethylpiperidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl)‐3‐methyl‐5‐ (trifluoromethyl)phenol; 2‐(2‐{[(3S)‐1‐ethylpiperidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl)‐3‐methyl‐5‐ (trifluoromethyl)phenol; 3‐methyl‐2‐{2‐[(3R)‐oxolan‐3‐yl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐5‐ (trifluoromethyl)phenol; 3‐methyl‐2‐{2‐[(3S)‐oxolan‐3‐yl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐5‐ (trifluoromethyl)phenol; 3‐methyl‐2‐(2‐{1‐[(3R)‐oxolane‐3‐carbonyl]piperidin‐4‐yl}‐2H‐pyrazolo[3,4‐b]pyridin‐ 6‐yl)‐5‐(trifluoromethyl)phenol; 3‐methyl‐2‐(2‐{1‐[(3S)‐oxolane‐3‐carbonyl]piperidin‐4‐yl}‐2H‐pyrazolo[3,4‐b]pyridin‐ 6‐yl)‐5‐(trifluoromethyl)phenol; 3‐methyl‐2‐(2‐{[(3R)‐1‐methylpyrrolidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl)‐ 5‐(trifluoromethyl)phenol; 3‐methyl‐2‐(2‐{[(3S)‐1‐methylpyrrolidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl)‐ 5‐(trifluoromethyl)phenol; orRac-2‐{2‐[(1‐ethylpiperidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl}‐3‐methyl‐5‐ (trifluoromethyl)phenol, 3R-, 3S-enantiomer.

[0047] Additional exemplary specific compounds of the present invention areselected from the group consisting of: rac-2-{2-[(4,4-difluoro-1-methylpiperidin-3-yl)methyl]-2H-pyrazolo[3,4-b]pyridin-6-yl}-3,5- dimethylphenol; 2-(2-{[(3S)-4,4-difluoro-1-methylpiperidin-3-yl]methyl}-2H-pyrazolo[3,4-b]pyridin-6-yl)- 3,5-dimethylphenol; and 2-(2-{[(3R)-4,4-difluoro-1-methylpiperidin-3-yl]methyl}-2H-pyrazolo[3,4-b]pyridin-6-yl)- 3,5-dimethylphenol.

[0048] Additional exemplary specific compounds of the present invention areselected from the group consisting of: rac-2‐{2‐[(1‐ethyl‐4,4‐difluoropiperidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐ methyl‐5‐(trifluoromethyl)phenol;2‐(2‐{[(3S)‐1‐ethyl‐4,4‐difluoropiperidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl)‐3‐ methyl‐5‐(trifluoromethyl)phenol; 2‐(2‐{[(3R)‐1‐ethyl‐4,4‐difluoropiperidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl)‐3‐ methyl‐5‐(trifluoromethyl)phenol; rac-2-{2-[(3-fluoro-1-methylpyrrolidin-3-yl)methyl]-2H-pyrazolo[3,4-b]pyrazin-6-yl}-3- methyl-5-(trifluoromethyl)phenol; cis-2-[2-(3-hydroxycyclobutyl)-2H-pyrazolo[3,4-b]pyridin-6-yl]-3-methyl-5- (trifluoromethyl)phenol; rac-3-methyl-2-[2-(oxepan-4-yl)-2H-pyrazolo[3,4-b]pyridin-6-yl]-5-(trifluoromethyl)phenol; 3‐methyl‐2‐{2‐[(4R)‐oxepan‐4‐yl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐5‐trifluoromethyl)phenol; 3‐methyl‐2‐{2‐[(4S)‐oxepan‐4‐yl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐5‐trifluoromethyl)phenol; 3‐methyl‐2‐{2‐[(oxan‐4‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐5‐ (trifluoromethyl)phenol; 3‐methyl‐2‐(2‐{[(3R)‐4‐methylmorpholin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl)‐5‐ (trifluoromethyl)phenol; 3,5‐dimethyl‐2‐[2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]phenol; 5‐chloro‐3‐methyl‐2‐[2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]phenol; 3,5‐dichloro‐2‐[2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]phenol; 5‐fluoro‐3‐methyl‐2‐[2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]phenol; 2‐(2‐{1‐[(1S)‐2,2‐difluorocyclopropanecarbonyl]piperidin‐4‐yl}‐2H‐pyrazolo[3,4‐b]pyridin‐ 6‐yl)‐3‐methyl‐5‐(trifluoromethyl)phenol; 2‐(2‐{1‐[(1R)‐2,2‐difluorocyclopropanecarbonyl]piperidin‐4‐yl}‐2H‐pyrazolo[3,4‐b]pyridin‐ 6‐yl)‐3‐methyl‐5‐(trifluoromethyl)phenol; 3‐methyl‐2‐{2‐[1‐(1‐methylcyclopropanecarbonyl)piperidin‐4‐yl]‐2H‐pyrazolo[3,4‐b]pyridin‐ 6‐yl}‐5‐(trifluoromethyl)phenol; rac-2‐{2‐[1‐(2,2‐difluoro‐1‐methylcyclopropanecarbonyl)piperidin‐4‐yl]‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl}‐3‐methyl‐5‐(trifluoromethyl)phenol; rac-ethyl 3‐{6‐[2‐hydroxy‐6‐methyl‐4‐(trifluoromethyl)phenyl]‐2H‐pyrazolo[3,4‐b]pyridin‐2‐ yl}butanoate; 3‐methyl‐2‐(2‐{[(3S)‐1‐(oxetan‐3‐yl)pyrrolidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐ yl)‐5‐(trifluoromethyl)phenol;3‐methyl‐2‐(2‐{[(3R)‐1‐(oxetan‐3‐yl)pyrrolidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐ yl)‐5‐(trifluoromethyl)phenol; 2‐(2‐{[(3S)‐1‐[(3‐fluorooxetan‐3‐yl)methyl]pyrrolidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl)‐3‐methyl‐5‐(trifluoromethyl)phenol; 2‐(2‐{[(3R)‐1‐[(3‐fluorooxetan‐3‐yl)methyl]pyrrolidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl)‐3‐methyl‐5‐(trifluoromethyl)phenol; 2‐(2‐{[(3S)‐1‐[(1‐fluorocyclopropyl)methyl]pyrrolidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl)‐3‐methyl‐5‐(trifluoromethyl)phenol; 2‐(2‐{[(3R)‐1‐[(1‐fluorocyclopropyl)methyl]pyrrolidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl)‐3‐methyl‐5‐(trifluoromethyl)phenol; butyl 3‐({6‐[2‐hydroxy‐6‐methyl‐4‐(trifluoromethyl)phenyl]‐2H‐pyrazolo[3,4‐b]pyridin‐2‐ yl}methyl)oxetane‐3‐carboxylate; 2‐(2‐{[3‐(hydroxymethyl)oxetan‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl)‐3‐methyl‐5‐ (trifluoromethyl)phenol; 2‐(2‐{[1‐(hydroxymethyl)cyclopropyl]methyl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl)‐3‐methyl‐5‐ (trifluoromethyl)phenol; rac-2‐[2‐(4‐hydroxybutan‐2‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐3‐methyl‐5‐ (trifluoromethyl)phenol; 3‐methyl‐2‐{2‐[(1‐methylazetidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐5‐ (trifluoromethyl)phenol; 3‐methyl‐2‐[5‐methyl‐2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl]‐5‐ (trifluoromethyl)phenol; 5‐(difluoromethyl)‐3‐methyl‐2‐[2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]phenol; 3‐(difluoromethyl)‐5‐methyl‐2‐[2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]phenol; trans-2‐{2‐[(3‐hydroxycyclobutyl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐5‐ (trifluoromethyl)phenol; cis-2‐{2‐[(3hydroxycyclobutyl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐5‐ (trifluoromethyl)phenol; 2-(2-{[(3R)-1-ethyl-3-fluoropiperidin-3-yl]methyl}-2H-pyrazolo[3,4-b]pyridin-6-yl)-3- methyl-5-(trifluoromethyl)phenol;2-(2-{[(3S)-1-ethyl-3-fluoropiperidin-3-yl]methyl}-2H-pyrazolo[3,4-b]pyridin-6-yl)-3- methyl-5-(trifluoromethyl)phenol; 2-(2-{[(3S)-4,4-difluoro-1-methylpiperidin-3-yl]methyl}-2H-pyrazolo[3,4-b]pyridin-6-yl)-3- methyl-5-(trifluoromethyl)phenol; 2-(2-{[(3R)-4,4-difluoro-1-methylpiperidin-3-yl]methyl}-2H-pyrazolo[3,4-b]pyridin-6-yl)-3- methyl-5-(trifluoromethyl)phenol; rac-2‐{2‐[(4,4‐difluoro‐1‐methylpiperidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐5‐ methoxy‐3‐methylphenol; 2‐(2‐{[(3S)‐4,4‐difluoro‐1‐methylpiperidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl)‐5‐ methoxy‐3‐methylphenol; 2‐(2‐{[(3R)‐4,4‐difluoro‐1‐methylpiperidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl)‐5‐ methoxy‐3‐methylphenol; 2‐{2‐[(4‐fluoro‐1‐methylpiperidin‐4‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐5‐ (trifluoromethyl)phenol;rac- 2‐{2‐[(5,5‐difluoro‐1‐methylpiperidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐5‐(trifluoromethyl)phenol; 2‐{2‐[(3‐fluoro‐1‐methylazetidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐5‐ (trifluoromethyl)phenol; 2‐(2‐{2‐[(2R)‐4,4‐difluoro‐1‐methylpyrrolidin‐2‐yl]ethyl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl)‐3‐ methyl‐5‐(trifluoromethyl)phenol; 3‐methyl‐2‐[2‐(oxan‐4‐yl)‐4‐propyl‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐5‐ (trifluoromethyl)phenol; 2‐[4‐(azetidin‐1‐yl)‐2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐3‐methyl‐5‐ (trifluoromethyl)phenol; 5‐(1,1‐difluoroethyl)‐3‐methyl‐2‐[2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]phenol; 3‐methyl‐2‐(2‐{[(3S)‐1‐(oxetan‐3‐yl)piperidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl)‐ 5‐(trifluoromethyl)phenol; 3‐methyl‐2‐(2‐{[(3R)‐1‐(oxetan‐3‐yl)piperidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐ yl)‐5‐(trifluoromethyl)phenol; 2‐(2‐{[(3S)‐1‐[(1‐fluorocyclopropyl)methyl]piperidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl)‐3‐methyl‐5‐(trifluoromethyl)phenol; 2‐(2‐{[(3R)‐1‐[(1‐fluorocyclopropyl)methyl]piperidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl)‐3‐methyl‐5‐(trifluoromethyl)phenol;2‐(2‐{[(3S)‐1‐[(3‐fluorooxetan‐3‐yl)methyl]piperidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl)‐3‐methyl‐5‐(trifluoromethyl)phenol; 2‐(2‐{[(3R)‐1‐[(3‐fluorooxetan‐3‐yl)methyl]piperidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl)‐3‐methyl‐5‐(trifluoromethyl)phenol; 3‐methyl‐2‐[5‐methyl‐2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐5‐ (trifluoromethyl)phenol; 3,5‐dimethyl‐2‐[2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl]phenol; rac-2‐{2‐[(4,4‐difluoro‐1‐methylpiperidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl}‐3‐ methyl‐5‐(trifluoromethyl)phenol;rac- 2‐{2‐[(4,4‐difluoro‐1‐methylpiperidin‐3‐yl)methyl]‐3‐methyl‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐5‐(trifluoromethyl)phenol; 2‐(2‐{[(3S)‐4,4‐difluoro‐1‐methylpiperidin‐3‐yl]methyl}‐3‐methyl‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl)‐3‐methyl‐5‐(trifluoromethyl)phenol; 2‐(2‐{[(3R)‐4,4‐difluoro‐1‐methylpiperidin‐3‐yl]methyl}‐3‐methyl‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl)‐3‐methyl‐5‐(trifluoromethyl)phenol; 2‐(2‐{[(3R)‐3‐fluoro‐1‐methylpyrrolidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl)‐3‐methyl‐5‐(trifluoromethyl)phenol; and2‐(2‐{[(3S)‐3‐fluoro‐1‐methylpyrrolidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl)‐3‐ methyl‐5‐(trifluoromethyl)phenol.

[0049] The invention provides a compound of formula (I). The invention also provides apharmaceutical composition comprising any of the compounds described herein. The inventionalso provides the use of a compound of formula (I) as medicament and (for use) in methods oftreating and / or preventing of one or more diseases, disorders or conditions associated with NLRP3.

[0050] In yet another aspect, described is a method of treating and / or preventing one ormore diseases and / or disorders associated with NLRP3 with a compound described herein, ora compound or composition described herein (for use) in a method of treating and / or preventingone or more diseases, disorders or conditions associated with NLRP3.

[0051] Both the foregoing summary and detailed description are exemplary andexplanatory. They are intended to provide further details of the invention, but are not to beconstrued as limiting. Other objects, advantages, and novel features will be readily apparent tothose skilled in the art from the following detailed description of the invention.DETAILED DESCRIPTION OF THE INVENTION

[0052] An object of the present invention is to provide a new class of compounds asmodulators of NLRP3, which may be effective in the treatment of NLRP3 related diseases and disorders and which may show improved pharmaceutically relevant properties including oral availability, brain-permeability, activity, solubility, selectivity, ADMET properties and / or reduced side effects.

[0053] Pathological functions of NLRP3-mediated inflammation have been described ininherited diseases like CAPS, as well as chronic inflammatory (e.g., rheumatoid arthritis),metabolic (e.g., diabetes) or neurological diseases (e.g., Alzheimer’s disease, Parkinson’sdisease, multiple sclerosis). Also, as noted above, NLRP3-mediated inflammation is associatedwith peripheral and central diseases. These include chronic inflammatory diseases, includinggout, rheumatoid arthritis, and inflammatory bowel disease (IBD) including Crohn’s disease and ulcerative colitis, metabolic diseases like atherosclerosis, diabetes, metabolic syndrome and liver steatosis, nonalcoholic steatohepatitis (NASH) and liver fibrosis, and neurologicaldiseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), multiple sclerosis(MS), Huntington’s disease (HD), Amyotrophic Lateral Sclerosis (ALS), Prion disease, Traumatic Brain Injury (TBI) and stroke, as well as asthma and allergic airway inflammation,hypertension, myocardial infarction, hyperinflammation following influenza and / or severeacute respiratory syndrome-coronavirus 2 (SARS CoV-2), Graft-versus-host disease, silicosis, myelodysplastic syndrome, contact hypersensitivity and joint inflammation triggered by chikungunya virus. This also includes obesity as metabolic disease.

[0054] The present invention provides compounds of the present invention in free orpharmaceutically acceptable salt form or in the form of solvates, hydrates, tautomers orstereoisomers. These can be used in the treatment of diseases or disorders mentioned herein.The same applies to a pharmaceutical composition of the present invention. Accordingly, oneaspect of the present invention is a pharmaceutically acceptable salt of a compound of the present invention. Another aspect of the present invention is a stereoisomer of a compound of the present invention.

[0055] Accordingly, the present invention provides a compound of formula (I):

[0056] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

[0057] R1 is CN, C1-4 alkyl, O-C1-4 alkyl or halogen, wherein C1-4 alkyl and O-C1-4alkyl are optionally substituted with one or more F, and R1ais H, C1-4 alkyl or halogen;

[0058] or R1 and R1a are joined to form, together with the carbon atoms to which theyare attached, a C4-6 cycloalkyl or an unsubstituted saturated 4- to 6-membered heterocycle;

[0059] R2 is H, CH3, CH2CH3, CF3, CHF2, OCH3, Cl, CN or cyclopropyl and R3 is Hor CH3, provided that not both, R2and R3, are H;

[0060] X1 is C(R4) or N;

[0061] R4 is H, C1-4 alkyl, C3-5 cycloalkyl, unsubstituted saturated 4- to 6- memberedheterocyclyl, OCH3, CN, Cl or F, wherein C1-4 alkyl and C3-5 cycloalkyl are unsubstituted or substituted with one or more F; or

[0062] R3 and R4 are joined to form -CH2-CH2-CH2- or -CH2-O-CH2-;

[0063] R4a is H, CH3, OCH3 or CN;

[0064] R5a and R5b are independently selected from the group consisting of H and CH3and R5is R6; or

[0065] R5 is H and R5a and R5b are joined to form, together with the carbon atom towhich they are attached, a ring T1; or

[0066] R5, R5a, R5b are joined to form, together with the carbon atom to which they areattached, a bicyclic ring T2;

[0067] T1 is C3-7 cycloalkyl, saturated 4- to 7-membered heterocyclyl containing oneor two hetero ring atoms, which are independently selected from the group consisting of O,N(R7) and S(O)2 or saturated 7- to 12-membered heterobicyclyl containing one or two heteroring atoms, which are independently selected from the group consisting of O, N(R7) and S(O)2, wherein T1is optionally substituted with one or more R8, which are the same or different;

[0068] T2 is bicyclo[1.1.1]pentanyl, wherein T2 is substituted with one OH or oneCH2OH;

[0069] R6 is C1-6 alkyl, T3 or CH2T3, wherein C1-6 alkyl is substituted with one or moreR6a, which are the same or different;

[0070] R6a is OH, OC1-4 alkyl or C(O)OC1-4 alkyl;

[0071] R7 is C1-4 alkyl, S(O)2-C1-4 alkyl, C(O)CH2OCH3, S(O)2T4, C(O)T4, whereineach C1-4alkyl is independently unsubstituted or substituted with one OH;

[0072] R8 is oxo (=O), OH, CH2OH, F, CH3 or OCH3;

[0073] T3 is C3-7 cycloalkyl, bicyclo[1.1.1]pentanyl, saturated 4- to 7-memberedheterocyclyl, or saturated 7- to 12-membered heterobicyclyl, wherein T3 is unsubstituted orsubstituted with one or more R9, which are the same or different;

[0074] T4 is C3-7 cycloalkyl, bicyclo[1.1.1]pentanyl, saturated 4- to 7-memberedheterocyclyl, saturated 7- to 12-membered heterobicyclyl, wherein T4 is unsubstituted orsubstituted with one or more R9a, which are the same or different;

[0075] R9 and R9a are independently selected from the group consisting of C1-4 alkyl,oxo (=O), OH, CH2OH, S(O)2-C1-4alkyl, C(O)OC1-4alkyl, T5, CH2T5and F, wherein each C1-4 alkyl is independently unsubstituted or substituted with one or more F;

[0076] T5 is saturated 4- to 7-membered heterocyclyl or C3-7 cycloalkyl, wherein T5 isunsubstituted or substituted with one or more F.

[0077] In another aspect, the disclosure encompasses a compound of formula (I)or a pharmaceutically acceptable salt or stereoisomer thereof, whereinR1 is CN, C1-4 alkyl, O-C1-4 alkyl or halogen, wherein C1-4 alkyl and O-C1-4 alkyl areoptionally substituted with one or more F, and R1ais H, C1-4 alkyl or halogen; or R1and R1aare joined to form, together with the carbon atoms to which they areattached, a C4-6 cycloalkyl or an unsubstituted saturated 4- to 6-membered heterocycle;R2is H, CH3, CH2CH3, CF3, CHF2, OCH3, Cl, CN or cyclopropyl and R3is H or CH3, provided that not both, R2and R3, are H; X1is C(R4) or N;R4 is H, C1-4 alkyl, C3-5 cycloalkyl, unsubstituted saturated 4- to 6- memberedheterocyclyl, OCH3, CN, Cl or F, wherein C1-4 alkyl and C3-5 cycloalkyl are unsubstitutedor substituted with one or more F; orR3 and R4 are joined to form -CH2-CH2-CH2- or -CH2-O-CH2-;R4a is H, CH3, OCH3 or CN;R5aand R5bare H and R5is R6; or R5is H and R5aand R5bare joined to form, together with the carbon atom to which they are attached, a ring T1; or R5, R5a, R5bare joined to form, together with the carbon atom to which they are attached, a bicyclic ring T2;T1 is C3-7 cycloalkyl, saturated 4- to 7-membered heterocyclyl containing one or twohetero ring atoms, which are independently selected from the group consisting of O,N(R7) and S(O)2 or saturated 7- to 12-membered heterobicyclyl containing one or twohetero ring atoms, which are independently selected from the group consisting of O, N(R7) and S(O)2, wherein T1is optionally substituted with one or more R8, which are the same or different; T2is bicyclo[1.1.1]pentanyl, wherein T2is substituted with one OH or one CH2OH; R6is C1-6 alkyl, T3or CH2T3, wherein C1-6 alkyl is substituted with one OH or OCH3; R7is C1-4alkyl, S(O)2-C1-4alkyl, C(O)CH2OCH3, S(O)2T4, C(O)T4, wherein each C1-4alkyl is independently unsubstituted or substituted with one OH; R8is oxo (=O), OH, CH2OH, F, CH3or OCH3; T3 is C3-7 cycloalkyl, bicyclo[1.1.1]pentanyl, saturated 4- to 7-membered heterocyclyl, orsaturated 7- to 12-membered heterobicyclyl, wherein T3 is unsubstituted or substitutedwith one or more R9, which are the same or different; T4 is C3-7 cycloalkyl, bicyclo[1.1.1]pentanyl, saturated 4- to 7-membered heterocyclyl,saturated 7- to 12-membered heterobicyclyl, wherein T4 is unsubstituted or substitutedwith one or more R9a, which are the same or different; R9and R9aare independently selected from the group consisting of C1-4alkyl, oxo (=O), OH, CH2OH, S(O)2-C1-4 alkyl, C(O)OC1-4 alkyl, and F, wherein each C1-4 alkyl is independently unsubstituted or substituted with one or more F.

[0078] In case a variable or substituent can be selected from a group of different variantsand such variable or substituent occurs more than once, then the respective variants can be thesame or different.

[0079] Surprisingly, the disclosed example compounds according to the present inventionhave favourable physico-chemical properties and / or selectivity, which combine to help to achieve beneficial therapeutic efficacy whilst limiting unintended liabilities.

[0080] As detailed in the biological assays section of the examples below, compoundsaccording to the disclosure were tested in LPS-primed THP1 cells to assess theirpharmacological capability to inhibit NLRP3 activation with Nigericin and the release of IL-1β into the supernatant. NLRP3 inhibitors decrease LPS / Nigericin-induced IL-1β release which isindicated as a reduction in the HTRF (homogenous time resolved fluorescence) ratio. Theresults surprisingly and unexpectedly showed that multiple compounds according to the invention exhibited favourable IC50 values as disclosed in Table 41.I. Definitions

[0081] Within the meaning of the present invention the terms are used as follows:

[0082] Technical and scientific terms used herein have the meanings commonly understoodby one of ordinary skill in the art, unless otherwise defined. Any suitable materials and / or methodologies known to those of ordinary skill in the art can be utilized in carrying out the methods described herein.

[0083] As used in the description of the invention and the appended claims, the singularforms “a”, “an” and “the” are used interchangeably and intended to include the plural forms as well and fall within each meaning, unless the context clearly indicates otherwise. Also, as used herein, “and / or” refers to and encompasses any and all possible combinations of one or more of the listed items, as well as the lack of combinations when interpreted in the alternative (“or”).

[0084] As used herein, “about” will be understood by persons of ordinary skill in the artand will vary to some extent on the context in which it is used. If there are uses of the termwhich are not clear to persons of ordinary skill in the art given the context in which it is used, “about” will mean up to plus or minus 10% of the particular term.

[0085] The term “optionally substituted” means unsubstituted or substituted. Generally -but not limited to-, “one or more substituents” means one, two or three, preferably one or two substituents and more preferably one substituent. Generally these substituents can be the same or different. The term “one or more substituents” also means by way of example one, two, three, four or five, preferably by way of example one, two, three or four.

[0086] “Alkyl” means a straight-chain or branched hydrocarbon chain. Each hydrogen ofan alkyl carbon may be replaced by a substituent as further specified.

[0087] “Alkenyl” means a straight-chain or branched hydrocarbon chain that contains atleast one carbon-carbon double bond. Each hydrogen of an alkenyl carbon may be replaced by a substituent as further specified.

[0088] “Alkynyl” means a straight-chain or branched hydrocarbon chain that contains atleast one carbon-carbon triple bond. Each hydrogen of an alkynyl carbon may be replaced by a substituent as further specified.

[0089] “C1-4 alkyl” means an alkyl chain having 1 - 4 carbon atoms, e.g. if present at theend of a molecule: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or e.g. -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, -C(CH3)2-, when two moieties of a molecule are linked by the alkyl group. Each hydrogen of a C1-4alkyl carbon may be replaced by a substituent as further specified. The term “C1-3 alkyl” is defined accordingly.

[0090] “C1-6 alkyl” means an alkyl chain having 1 - 6 carbon atoms, e.g. if present at theend of a molecule: C1-4alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, or e.g. -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, - CH(C2H5)-, -C(CH3)2-, when two moieties of a molecule are linked by the alkyl group. Each hydrogen of a C1-6alkyl carbon may be replaced by a substituent as further specified.

[0091] “C2-6 alkenyl” means an alkenyl chain having 2 to 6 carbon atoms, e.g. if present atthe end of a molecule: -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, -CH=CH-CH2-CH3, - CH=CH-CH=CH2, or e.g. -CH=CH-, when two moieties of a molecule are linked by the alkenyl group. Each hydrogen of a C2-6 alkenyl carbon may be replaced by a substituent as further specified.

[0092] “C2-6 alkynyl” means an alkynyl chain having 2 to 6 carbon atoms, e.g. if present atthe end of a molecule: -C^CH, -CH2-C^CH, -CH2-CH2-C^CH, -CH2-C^C-CH3, or e.g. -C^C- when two moieties of a molecule are linked by the alkynyl group. Each hydrogen of a C2-6alkynyl carbon may be replaced by a substituent as further specified.

[0093] “C3-7 cycloalkyl” or “C3-7 cycloalkyl ring” means a cyclic alkyl chain having 3 - 7carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl. Preferably, cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Each hydrogen of a cycloalkyl carbon may be replaced by a substituent as further specified herein. The term “C3-5cycloalkyl” or “C3-5cycloalkyl ring” is definedaccordingly. The term “C4-6 cycloalkyl” or “C4-6 cycloalkyl ring” is defined accordingly.

[0094] “C5 cycloalkylene” refers to a bivalent cycloalkyl with five carbon atoms, i.e. abivalent cyclopentyl ring.

[0095] “C5 cycloalkenylene” refers to a bivalent cycloalkenylene, i.e. a bivalentcyclopentene or cyclopentadiene.

[0096] “C4-12 bicycloalkyl” or “C4-12 bicycloalkyl ring” means a bicyclic fused, bridged orspiro alkyl chain having 4 to 12 carbon atoms, e.g. hexahydroindane, octahydropentalen, bicycle[2.2.1]heptane or spiro(3.2)hexane. Each hydrogen of a bicycloalkyl carbon may be replaced by a substituent as further specified herein.

[0097] “Halogen” means fluoro, chloro, bromo or iodo. It is generally preferred thathalogen is fluoro or chloro.

[0098] “4 to 7 membered heterocyclyl” or “4 to 7 membered heterocycle” means a ringwith 4, 5, 6 or 7 ring atoms that may contain up to the maximum number of double bonds(aromatic or non-aromatic ring which is fully, partially or un-saturated) wherein at least one ring atom up to 4 ring atoms are replaced by a heteroatom selected from the group consistingof sulfur (including -S(O)-, -S(O)2-), oxygen and nitrogen (including =N(O)-) and wherein thering is linked to the rest of the molecule via a carbon or nitrogen atom. Examples for a 4 to 7membered heterocycle are azetidine, oxetane, thietane, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazoline, thiadiazole, thiadiazoline, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyrazine, pyrimidine, piperazine, piperidine, morpholine, tetrazole, triazole, triazolidine, tetrazolidine, diazepane, azepine or homopiperazine. The term “5 to 6 membered heterocyclyl” or “5 to 6 membered heterocycle” is defined accordingly and and includes 5 to 6 membered aromatic heterocyclyl or heterocycle. The term “5 membered heterocyclyl” or “5 membered heterocycle” is defined accordingly and includes 5 memberedaromatic heterocyclyl or heterocycle. The term “4 to 6 membered heterocyclyl” or “4 to 6membered heterocycle” is defined accordingly.

[0099] The term “nitrogen ring atom containing 5-membered heterocyclene” refers to abivalent 5-membered heterocycle, wherein at least one of the five ring atoms is a nitrogen atom and wherein the ring is linked to the rest of the molecule via a carbon or nitrogen atom.

[0100] “Saturated 4 to 7 membered heterocyclyl” or “saturated 4 to 7 memberedheterocycle” means fully saturated “4 to 7 membered heterocyclyl” or “4 to 7 memberedheterocycle”. “Saturated 4 to 6 membered heterocyclyl” or “saturated 4 to 6 memberedheterocycle” means fully saturated “4 to 6 membered heterocyclyl” or “4 to 6 memberedheterocycle”.

[0101] “4 to 7 membered at least partly saturated heterocyclyl” or “4 to 7 membered at leastpartly saturated heterocycle” means an at least partly saturated “4 to 7 membered heterocyclyl” or “4 to 7 membered heterocycle”.

[0102] “5 to 6 membered aromatic heterocyclyl” or “5 to 6 membered aromaticheterocycle” means a heterocycle derived from cyclopentadienyl or benzene, where at least one carbon atom is replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen and nitrogen (including =N(O)-). Examples for such heterocycles are furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine.

[0103] “5 membered aromatic heterocyclyl” or “5 membered aromatic heterocycle” meansa heterocycle derived from cyclopentadienyl, where at least one carbon atom is replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen and nitrogen (including =N(O)-). Examples for such heterocycles are furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, triazole, tetrazole.

[0104] "7 to 12 membered heterobicyclyl" or "7 to 12 membered heterobicycle" means aheterocyclic system of two rings with 7 to 12 ring atoms, where at least one ring atom is sharedby both rings and that may contain up to the maximum number of double bonds (aromatic ornon-aromatic ring which is fully, partially or un-saturated) wherein at least one ring atom up to 6 ring atoms are replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen and nitrogen (including =N(O)-) and wherein the ring is linked to the rest of the molecule via a carbon or nitrogen atom. Examples for a 7 to 12 membered heterobicycle are indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine or pteridine. The term 7 to 12 membered heterobicycle also includes spiro structures of two rings like 6-oxa-2-azaspiro[3,4]octane, 2- oxa-6-azaspiro[3.3]heptan-6-yl or 2,6-diazaspiro[3.3]heptan-6-yl or bridged heterocycles like 8-aza-bicyclo[3.2.1]octane or 2,5-diazabicyclo[2.2.2]octan-2-yl or 3,8-diazabicyclo[3.2.1] octane.

[0105] “Saturated 7 to 12 membered heterobicyclyl” or “saturated 7 to 12 memberedheterobicycle” means fully saturated “7 to 12 membered heterobicyclyl” or “7 to 12 membered heterobicycle”.

[0106] “7 to 12 membered at least partly saturated heterobicyclyl” or “7 to 12 membered atleast partly saturated heterobicycle” means an at least partly saturated “7 to 12 membered heterobicyclyl” or “7 to 12 membered heterobicycle”.

[0107] “9 to 11 membered aromatic heterobicyclyl” or “9 to 11 membered aromaticheterobicycle” means a heterocyclic system of two rings, wherein at least one ring is aromatic and wherein the heterocyclic ring system has 9 to 11 ring atoms, where two ring atoms areshared by both rings and that may contain up to the maximum number of double bonds (fullyor partially aromatic) wherein at least one ring atom up to 6 ring atoms are replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen and nitrogen (including =N(O)-) and wherein the ring is linked to the rest of the molecule via a carbon or nitrogen atom. Examples for an 9 to 11 membered aromatic heterobicycle are indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, dihydro- isoquinoline, benzazepine, purine or pteridine. The terms “9 to 10 membered aromatic heterobicyclyl” or “9 to 10 membered aromatic heterobicycle” are defined accordingly.II. Exemplary Compounds of the Disclosure

[0108] Exemplary compounds of formula (I) are those compounds in which one or more ofthe residues contained therein have the meanings given above or below, with all combinations of preferred substituent definitions being a subject of the present invention. With respect to all preferred compounds of the formula (I) the present invention also includes all tautomeric and stereoisomeric forms and mixtures thereof in all ratios, and their pharmaceutically acceptable salts.

[0109] In exemplary embodiments of the present invention, the substituents mentionedbelow independently have the following meaning. Hence, one or more of these substituents can have the meanings given below.

[0110] In another aspect for the compound of formula (I), R1 is CN, CH3, CF3, CHF2,OCH3, OCHF2, OCF3 or halogen and R1ais H.

[0111] In another aspect for the compound of formula (I), R1 is F, Cl or CF2CH3 andR1ais H.

[0112] In another aspect for the compound of formula (I), R1 is CF3 and R1a is H.

[0113] In another aspect for the compound of formula (I), R1 is CH3 and R1a is H.

[0114] In another aspect for the compound of formula (I), R2 is CH3. In anotherembodiment for the compound of formula (I), R2is CH3, Cl or CHF2.

[0115] In another aspect for the compound of formula (I), R3 is H. In just anotheraspect for the compound of formula (I), R3is CH3.

[0116] In another aspect for the compound of formula (I), R1 is CF3, R1a is H, R2 isCH3, and R3is H.

[0117] In another aspect for the compound of formula (I), R1 is CH3, R1a is H, R2 isCH3, and R3is H.

[0118] In another aspect for the compound of formula (I), X1 is CH, C(CH3),C(CHF2) or C(OCH3). In another aspect for the compound of formula (I), X1 isC(CH2CH2CH3) or C(azetidin-1-yl).

[0119] In another aspect for the compound of formula (I), X1 is CH.

[0120] In another aspect for the compound of formula (I), X1 is N.

[0121] In another aspect for the compound of formula (I), R4a is H or CH3.

[0122] In another aspect for the compound of formula (I), R4a is H.

[0123] In another aspect for the compound of formula (I), R5 is H and R5a and R5b arejoined to form, together with the carbon atom to which they are attached, a ring T1.

[0124] In another aspect for the compound of formula (I), T1 is a saturated 4- to 7-membered heterocyclyl containing one hetero ring atom, which is O, wherein T1is unsubstituted or substituted with one or two R8, which are the same or different.

[0125] In another aspect for the compound of formula (I), R8 is methyl.

[0126] In another aspect for the compound of formula (I), T1 is oxan‐4‐yl, oxolan-3-yl, 5-oxaspiro[3.5]nonan-8-yl, 2,2-dimethyloxan‐4‐yl, or 2,6‐dimethyloxan‐4‐yl. In anotheraspect for the compound of formula (I), T1is oxepan‐4‐yl.

[0127] In another aspect for the compound of formula (I), T1 is C3-7 cycloalkyl orsaturated 4- to 7-membered heterocyclyl containing one or two hetero ring atoms, which areN(R7), wherein T1is optionally substituted with one or two R8, which are the same or different.

[0128] In another aspect for the compound of formula (I), T1 ishydroxymethylcyclobutyl, hydroxycyclobutyl, 1‐(ethanesulfonyl)piperidin‐4‐yl, 1‐ methanesulfonylpiperidin‐4‐yl, 1‐cyclopropanecarbonylpiperidin‐4‐yl, 1‐(1‐ methylpyrrolidine‐3‐carbonyl)piperidin‐4‐yl, thiane-1,1-dioxo-4-yl, 1- cyclopropanecarbonylpiperidin-4-yl, 1‐(cyclobutanesulfonyl)piperidin‐4‐yl, 1- methoxymethylcarbonylpiperidin‐4‐yl, 1-(oxolane-3-carbonyl)piperidin-4-yl, 1-(1- methylpyrrolidine-3-carbonyl)piperidin-4-yl, 1-(1-fluorocyclopropanecarbonyl)piperidin-4-yl, 1-[1-(trifluoromethyl)cyclopropanecarbonyl]piperidin-4-yl, or 1-(3,3-difluoroazetidine-1-carbonyl)piperidin-4-yl. In another aspect for the compound of formula (I), T1 is 1‐(2,2‐difluorocyclopropanecarbonyl)piperidin‐4‐yl, 1‐(1‐methylcyclopropanecarbonyl)piperidin‐4‐yl, or 1‐(2,2‐difluoro‐1‐methylcyclopropanecarbonyl)piperidin‐4‐yl.

[0129] In another aspect for the compound of formula (I), R5a and R5b are selectedfrom the group consisting of H and CH3; and R5is R6. In another aspect for the compound offormula (I), R5a and R5b are H and R5 is R6.

[0130] In another aspect for the compound of formula (I), R6 is C1-6 alkyl, wherein C1-6 alkyl is substituted with one OH or OCH3, preferably one OCH3. In another aspect for thecompound of formula (I), C1-6 alkyl is substituted with one OCH3. In another aspect for thecompound of formula (I), R6is C1-6 alkyl, wherein C1-6 alkyl is substituted with one C(O)OCH2CH3.

[0131] In another aspect for the compound of formula (I), R6 is hydroxyethyl,methoxyethyl, hydroxymethyl or 2‐hydroxy‐2‐methylpropyl. In another aspect for thecompound of formula (I), R6is ethyloxycarbonylethyl.

[0132] In another aspect for the compound of formula (I), R6 is T3 and T3 is a saturated4- to 7-membered heterocyclyl, wherein T3 is substituted with one, two or three R9, which arethe same or different.

[0133] In another aspect for the compound of formula (I), R6 is T3 and T3 is 1-methylpiperidinyl, 1-ethylpiperidinyl, 1-methylpyrrolidinyl or 4-methylmorpholinyl, whereinT3 is optionally further substituted with one or more R9. In another aspect for the compound offormula (I), R6is T3and T3is 1-methylazetidinyl, wherein T3is optionally further substituted with one or more R9.

[0134] In another aspect for the compound of formula (I), R9 and R9a are independentlyselected from the group consisting of C1-4alkyl, oxo (=O), OH, CH2OH, S(O)2-C1-4alkyl, C(O)OC1-4 alkyl and F, wherein each C1-4 alkyl is independently unsubstituted or substituted with one or more F.

[0135] In another aspect for the compound of formula (I), R6 is 3‐fluoro‐1‐methylpiperidin‐3‐yl, 1‐ethyl‐3‐fluoropiperidin‐3‐yl, 1-methylpyrrolidin-2-oxo-3-yl, 1- methylpyrrolidin-2-oxo-4-yl, 3‐fluoro‐1‐methylpyrrolidin‐3‐yl, 4,4-difluoro‐1‐ methylpiperidin‐3‐yl, 1-methylpyrrolidin-3-yl, 1-ethylpiperidin-3-yl, or 4-methylmorpholin-2-yl. In another aspect for the compound of formula (I), R6 is 1‐ethyl‐4,4‐difluoropiperidin‐3‐yl,5,5-difluoro‐1‐methylpiperidin‐3‐yl; 4,4-difluoro-1-methylpyrrolidin-2-ylmethyl; 1-methyl-3-fluoro-pyrrolidin-3-yl or 4‐methylmorpholin‐3‐yl. In another aspect for the compound offormula (I), R6 is T3 and T3 is 1-(oxetan-3-yl)pyrrolidin-3-yl, 1‐[(3‐fluorooxetan‐3‐yl)methyl]pyrrolidin‐3‐yl ‐[(1‐fluorocyclopropyl)methyl]piperidin‐3‐yl; (3-fluorooxetan-3-yl)methylpiperidin-3-yl or 1‐[(1‐fluorocyclopropyl)methyl]pyrrolidin‐3‐yl.

[0136] In another aspect for the compound of formula (I), R6 is T3 and T3 is substitutedwith at least one F. In another aspect for the compound of formula (I), R6 is T3 and T3 issubstituted with T5 or CH2T5. In another aspect for the compound of formula (I), R6 is T3 andT3 is oxan-4-yl or oxetan-3-yl, wherein T3 is unsubstituted or substituted with one R9. In anotheraspect for the compound of formula (I), R6is T3and T3is oxan-4-yl, 3- (butyloxycarbonyl)oxetan-3-yl or 3‐(hydroxymethyl)oxetan‐3‐yl.

[0137] In another aspect for the compound of formula (I), R6 is thietane‐1,1‐dioxo-3-yl, 1-methanesulfonylazetidin-3-yl, or 1-ethoxycarbonylcycloprop-1-yl. In another aspect forthe compound of formula (I), R6is 1-hydroxymethylcycloprop-1-yl or 3-hydroxycyclobut-1-yl.

[0138] Compounds of the present invention in which some or all of the above-mentionedgroups have the preferred or more preferred meanings are also an object of the present invention.

[0139] Exemplary specific compounds of the present invention are selected from the groupconsisting of: 2‐[2‐(3‐hydroxypropyl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐3‐methyl‐5‐ (trifluoromethyl)phenol; cis 2‐{2‐[3‐(hydroxymethyl)cyclobutyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐5‐(trifluoromethyl)phenol; trans 2‐{2‐[3‐(hydroxymethyl)cyclobutyl]‐2H-pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐ 5‐(trifluoromethyl)phenol; trans- 2‐[2‐(3‐hydroxycyclobutyl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐3‐methyl‐5‐(trifluoromethyl)phenol; rac-2‐{2‐[(3‐fluoro‐1‐methylpiperidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐ 3‐methyl‐5‐(trifluoromethyl)phenol; rac-2‐{2‐[(1‐ethyl‐3‐fluoropiperidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐ methyl‐5‐(trifluoromethyl)phenol; 2‐{2‐[1‐(ethanesulfonyl)piperidin‐4‐yl]‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl}‐3‐methyl‐5‐ (trifluoromethyl)phenol; 2‐[2‐(1‐methanesulfonylpiperidin‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl]‐3‐methyl‐5‐ (trifluoromethyl)phenol; 2‐[2‐(1‐cyclopropanecarbonylpiperidin‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl]‐3‐ methyl‐5‐(trifluoromethyl)phenol; rac-3‐methyl‐2‐{2‐[1‐(1‐methylpyrrolidine‐3‐carbonyl)piperidin‐4‐yl]‐2H‐ pyrazolo[3,4‐b]pyrazin‐6‐yl}‐5‐(trifluoromethyl)phenol; 3‐methyl‐2‐[2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐5‐(trifluoromethyl)phenol;3‐methyl‐2‐[2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl]‐5‐ (trifluoromethyl)phenol; 5‐methoxy‐3‐methyl‐2‐[2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]phenol; rac-3-methyl-2-[2-(oxolan-3-yl)-2H-pyrazolo[3,4-b]pyridin-6-yl]-5- (trifluoromethyl)phenol, 3R-, 3S-enantiomer; 3-methyl-2-[4-methyl-2-(oxan-4-yl)-2H-pyrazolo[3,4-b]pyridin-6-yl]-5- (trifluoromethyl)phenol; 3‐methyl‐2‐[3‐methyl‐2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl]‐5‐ (trifluoromethyl)phenol; 3-methyl-2-[3-methyl-2-(oxan-4-yl)-2H-pyrazolo[3,4-b]pyridin-6-yl]-5- (trifluoromethyl)phenol; 4-{6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-2H-pyrazolo[3,4-b]pyridin-2- yl}-1λ⁶-thiane-1,1-dione; rac-3-({6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-2H-pyrazolo[3,4- b]pyrazin-2-yl}methyl)-1-methylpyrrolidin-2-one; rac-4-({6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-2H-pyrazolo[3,4- b]pyrazin-2-yl}methyl)-1-methylpyrrolidin-2-one; rac-3-methyl-2-(2-{5-oxaspiro[3.5]nonan-8-yl}-2H-pyrazolo[3,4-b]pyridin-6-yl)-5- (trifluoromethyl)phenol; rac-2‐{2‐[(3‐fluoro‐1‐methylpyrrolidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐ yl}‐3‐methyl‐5‐(trifluoromethyl)phenol; rac-2‐{2‐[(4,4‐difluoro‐1‐methylpiperidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐ yl}‐3‐methyl‐5‐(trifluoromethyl)phenol; 3‐({6‐[2‐hydroxy‐6‐methyl‐4‐(trifluoromethyl)phenyl]‐2H‐pyrazolo[3,4‐b]pyridin‐2‐ yl}methyl)‐1λ6‐thietane‐1,1‐dione; 2‐[2‐(3‐methoxypropyl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐3‐methyl‐5‐ (trifluoromethyl)phenol; 2‐[2‐(2‐hydroxyethyl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐3‐methyl‐5‐ (trifluoromethyl)phenol; 2‐[2‐(3‐hydroxy‐3‐methylbutyl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐3‐methyl‐5‐ (trifluoromethyl)phenol; 2‐[4‐(difluoromethyl)‐2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐3‐methyl‐5‐ (trifluoromethyl)phenol;2‐[4‐methoxy‐2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐3‐methyl‐5‐ (trifluoromethyl)phenol; 2-[2-(1-cyclopropanecarbonylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridin-6-yl]-3- methyl-5-(trifluoromethyl)phenol; rac-3-methyl-2-{2-[(1-methylpyrrolidin-3-yl)methyl]-2H-pyrazolo[3,4-b]pyrazin-6- yl}-5-(trifluoromethyl)phenol, 3R-, 3S-enantiomer; rac-3-methyl-2-{2-[(1-methylpyrrolidin-3-yl)methyl]-2H-pyrazolo[3,4-b]pyridin-6- yl}-5-(trifluoromethyl)phenol; 2-{2-[(1-methanesulfonylazetidin-3-yl)methyl]-2H-pyrazolo[3,4-b]pyridin-6-yl}-3- methyl-5-(trifluoromethyl)phenol; rac-2-{2-[(1-ethylpiperidin-3-yl)methyl]-2H-pyrazolo[3,4-b]pyridin-6-yl}-3-methyl- 5-(trifluoromethyl)phenol; 2-[2-(1-methanesulfonylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridin-6-yl]-3-methyl-5- (trifluoromethyl)phenol; 2-{2-[1-(ethanesulfonyl)piperidin-4-yl]-2H-pyrazolo[3,4-b]pyridin-6-yl}-3-methyl-5- (trifluoromethyl)phenol; 2‐{2‐[1‐(cyclobutanesulfonyl)piperidin‐4‐yl]‐2H‐ pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐5‐(trifluoromethyl)phenol; 1‐(4‐{6‐[2‐hydroxy‐6‐methyl‐4‐(trifluoromethyl)phenyl]‐2H‐pyrazolo[3,4‐b]pyridin‐ 2‐yl}piperidin‐1‐yl)‐2‐methoxyethan‐1‐one; 1-(4-{6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-2H-pyrazolo[3,4-b]pyrazin- 2-yl}piperidin-1-yl)-2-methoxyethan-1-one; rac-3-methyl-2-{2-[1-(oxolane-3-carbonyl)piperidin-4-yl]-2H-pyrazolo[3,4-b]pyridin- 6-yl}-5-(trifluoromethyl)phenol, 3R-, 3S-enantiomer; rac-3-methyl-2-{2-[1-(1-methylpyrrolidine-3-carbonyl)piperidin-4-yl]-2H- pyrazolo[3,4-b]pyridin-6-yl}-5-(trifluoromethyl)phenol; 2‐{2‐[1‐(1‐fluorocyclopropanecarbonyl)piperidin‐4‐yl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐ yl}‐3‐methyl‐5‐(trifluoromethyl)phenol; 3‐methyl‐5‐(trifluoromethyl)‐2‐(2‐{1‐[1‐ (trifluoromethyl)cyclopropanecarbonyl]piperidin‐4‐yl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐ yl)phenol; 2‐{2‐[1‐(3,3‐difluoroazetidine‐1‐carbonyl)piperidin‐4‐yl]‐2H‐pyrazolo[3,4‐b]pyridin‐ 6‐yl}‐3‐methyl‐5‐(trifluoromethyl)phenol;rac-2‐[2‐(2,2‐dimethyloxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐3‐methyl‐5‐ (trifluoromethyl)phenol; 3‐methyl‐2‐(2‐{[(2R)‐4‐methylmorpholin‐2‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐ yl)‐5‐(trifluoromethyl)phenol; 3‐methyl‐2‐(2‐{[(2S)‐4‐methylmorpholin‐2‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐ yl)‐5‐(trifluoromethyl)phenol; ethyl 1‐({6‐[2‐hydroxy‐6‐methyl‐4‐(trifluoromethyl)phenyl]‐2H‐pyrazolo[3,4‐ b]pyridin‐2‐yl}methyl)cyclopropane‐1‐carboxylate; 2‐{2‐[(2R,6S)‐2,6‐dimethyloxan‐4‐yl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐ 3‐methyl‐5‐ (trifluoromethyl)phenol; 3‐methyl‐2‐{2‐[(2R,4r,6S)‐2,6‐dimethyloxan‐4‐yl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐ 5‐(trifluoromethyl)phenol; 3‐methyl‐2‐{2‐[(2R,4s,6S)‐2,6‐dimethyloxan‐4‐yl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐ 5‐(trifluoromethyl)phenol; 2‐(2‐{[(3R)‐1‐ethylpiperidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl)‐3‐methyl‐ 5‐(trifluoromethyl)phenol; 2‐(2‐{[(3S)‐1‐ethylpiperidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl)‐3‐methyl‐ 5‐(trifluoromethyl)phenol; 3‐methyl‐2‐{2‐[(3R)‐oxolan‐3‐yl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐5‐ (trifluoromethyl)phenol; 3‐methyl‐2‐{2‐[(3S)‐oxolan‐3‐yl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐5‐ (trifluoromethyl)phenol; 3‐methyl‐2‐(2‐{1‐[(3R)‐oxolane‐3‐carbonyl]piperidin‐4‐yl}‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl)‐5‐(trifluoromethyl)phenol; 3‐methyl‐2‐(2‐{1‐[(3S)‐oxolane‐3‐carbonyl]piperidin‐4‐yl}‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl)‐5‐(trifluoromethyl)phenol; 3‐methyl‐2‐(2‐{[(3R)‐1‐methylpyrrolidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐ yl)‐5‐(trifluoromethyl)phenol; 3‐methyl‐2‐(2‐{[(3S)‐1‐methylpyrrolidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐ yl)‐5‐(trifluoromethyl)phenol; and Rac-2‐{2‐[(1‐ethylpiperidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl}‐3‐methyl‐ 5‐ (trifluoromethyl)phenol, 3R-, 3S-enantiomer.

[0140] Additional exemplary specific compounds of the present invention are selectedfrom the group consisting of: rac-2-{2-[(4,4-difluoro-1-methylpiperidin-3-yl)methyl]-2H-pyrazolo[3,4-b]pyridin-6-yl}-3,5- dimethylphenol; 2-(2-{[(3S)-4,4-difluoro-1-methylpiperidin-3-yl]methyl}-2H-pyrazolo[3,4-b]pyridin-6-yl)- 3,5-dimethylphenol; and 2‐(2‐{[(3R)‐4,4‐difluoro‐1‐methylpiperidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl)‐ 3,5‐dimethylphenol.

[0141] Additional exemplary specific compounds of the present invention areselected from the group consisting of: rac-2‐{2‐[(1‐ethyl‐4,4‐difluoropiperidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐ methyl‐5‐(trifluoromethyl)phenol; 2‐(2‐{[(3S)‐1‐ethyl‐4,4‐difluoropiperidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl)‐3‐ methyl‐5‐(trifluoromethyl)phenol; 2‐(2‐{[(3R)‐1‐ethyl‐4,4‐difluoropiperidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl)‐3‐ methyl‐5‐(trifluoromethyl)phenol; rac-2-{2-[(3-fluoro-1-methylpyrrolidin-3-yl)methyl]-2H-pyrazolo[3,4-b]pyrazin-6-yl}-3- methyl-5-(trifluoromethyl)phenol; cis-2‐[2‐(3‐hydroxycyclobutyl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐3‐methyl‐5‐ (trifluoromethyl)phenol; rac-3‐methyl‐2‐[2‐(oxepan‐4‐yl)‐2H-pyrazolo[3,4‐b]pyridin‐6‐yl]‐5-(trifluoromethyl)phenol; 3‐methyl‐2‐{2‐[(4R)‐oxepan‐4‐yl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐5‐trifluoromethyl)phenol; 3‐methyl‐2‐{2‐[(4S)‐oxepan‐4‐yl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐5‐trifluoromethyl)phenol; 3‐methyl‐2‐{2‐[(oxan‐4‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐5‐ (trifluoromethyl)phenol; 3‐methyl‐2‐(2‐{[(3R)‐4‐methylmorpholin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl)‐5‐ (trifluoromethyl)phenol; 3,5‐dimethyl‐2‐[2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]phenol; 5‐chloro‐3‐methyl‐2‐[2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]phenol; 3,5‐dichloro‐2‐[2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]phenol; 5‐fluoro‐3‐methyl‐2‐[2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]phenol; 2‐(2‐{1‐[(1S)‐2,2‐difluorocyclopropanecarbonyl]piperidin‐4‐yl}‐2H‐pyrazolo[3,4‐b]pyridin‐ 6‐yl)‐3‐methyl‐5‐(trifluoromethyl)phenol;2‐(2‐{1‐[(1R)‐2,2‐difluorocyclopropanecarbonyl]piperidin‐4‐yl}‐2H‐pyrazolo[3,4‐b]pyridin‐ 6‐yl)‐3‐methyl‐5‐(trifluoromethyl)phenol; 3‐methyl‐2‐{2‐[1‐(1‐methylcyclopropanecarbonyl)piperidin‐4‐yl]‐2H‐pyrazolo[3,4‐b]pyridin‐ 6‐yl}‐5‐(trifluoromethyl)phenol; rac-2‐{2‐[1‐(2,2‐difluoro‐1‐methylcyclopropanecarbonyl)piperidin‐4‐yl]‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl}‐3‐methyl‐5‐(trifluoromethyl)phenol; rac-ethyl 3‐{6‐[2‐hydroxy‐6‐methyl‐4‐(trifluoromethyl)phenyl]‐2H‐pyrazolo[3,4‐b]pyridin‐2‐ yl}butanoate; 3‐methyl‐2‐(2‐{[(3S)‐1‐(oxetan‐3‐yl)pyrrolidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐ yl)‐5‐(trifluoromethyl)phenol; 3‐methyl‐2‐(2‐{[(3R)‐1‐(oxetan‐3‐yl)pyrrolidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐ yl)‐5‐(trifluoromethyl)phenol; 2‐(2‐{[(3S)‐1‐[(3‐fluorooxetan‐3‐yl)methyl]pyrrolidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl)‐3‐methyl‐5‐(trifluoromethyl)phenol; 2‐(2‐{[(3R)‐1‐[(3‐fluorooxetan‐3‐yl)methyl]pyrrolidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl)‐3‐methyl‐5‐(trifluoromethyl)phenol; 2‐(2‐{[(3S)‐1‐[(1‐fluorocyclopropyl)methyl]pyrrolidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl)‐3‐methyl‐5‐(trifluoromethyl)phenol; 2‐(2‐{[(3R)‐1‐[(1‐fluorocyclopropyl)methyl]pyrrolidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl)‐3‐methyl‐5‐(trifluoromethyl)phenol; butyl 3‐({6‐[2‐hydroxy‐6‐methyl‐4‐(trifluoromethyl)phenyl]‐2H‐pyrazolo[3,4‐b]pyridin‐2‐ yl}methyl)oxetane‐3‐carboxylate; 2‐(2‐{[3‐(hydroxymethyl)oxetan‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl)‐3‐methyl‐5‐ (trifluoromethyl)phenol; 2‐(2‐{[1‐(hydroxymethyl)cyclopropyl]methyl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl)‐3‐methyl‐5‐ (trifluoromethyl)phenol; rac-2‐[2‐(4‐hydroxybutan‐2‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐3‐methyl‐5‐ (trifluoromethyl)phenol; 3‐methyl‐2‐{2‐[(1‐methylazetidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐5‐ (trifluoromethyl)phenol; 3‐methyl‐2‐[5‐methyl‐2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl]‐5‐ (trifluoromethyl)phenol; 5‐(difluoromethyl)‐3‐methyl‐2‐[2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]phenol; 3‐(difluoromethyl)‐5‐methyl‐2‐[2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]phenol;trans-2‐{2‐[(3‐hydroxycyclobutyl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐5‐ (trifluoromethyl)phenol; cis-2‐{2‐[(3hydroxycyclobutyl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐5‐ (trifluoromethyl)phenol; 2-(2-{[(3R)-1-ethyl-3-fluoropiperidin-3-yl]methyl}-2H-pyrazolo[3,4-b]pyridin-6-yl)-3- methyl-5-(trifluoromethyl)phenol; 2-(2-{[(3S)-1-ethyl-3-fluoropiperidin-3-yl]methyl}-2H-pyrazolo[3,4-b]pyridin-6-yl)-3- methyl-5-(trifluoromethyl)phenol; 2-(2-{[(3S)-4,4-difluoro-1-methylpiperidin-3-yl]methyl}-2H-pyrazolo[3,4-b]pyridin-6-yl)-3- methyl-5-(trifluoromethyl)phenol; 2-(2-{[(3R)-4,4-difluoro-1-methylpiperidin-3-yl]methyl}-2H-pyrazolo[3,4-b]pyridin-6-yl)-3- methyl-5-(trifluoromethyl)phenol; rac-2‐{2‐[(4,4‐difluoro‐1‐methylpiperidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐5‐ methoxy‐3‐methylphenol; 2‐(2‐{[(3S)‐4,4‐difluoro‐1‐methylpiperidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl)‐5‐ methoxy‐3‐methylphenol; 2‐(2‐{[(3R)‐4,4‐difluoro‐1‐methylpiperidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl)‐5‐ methoxy‐3‐methylphenol; 2‐{2‐[(4‐fluoro‐1‐methylpiperidin‐4‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐5‐ (trifluoromethyl)phenol;rac- 2‐{2‐[(5,5‐difluoro‐1‐methylpiperidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐5‐(trifluoromethyl)phenol; 2‐{2‐[(3‐fluoro‐1‐methylazetidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐5‐ (trifluoromethyl)phenol; 2‐(2‐{2‐[(2R)‐4,4‐difluoro‐1‐methylpyrrolidin‐2‐yl]ethyl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl)‐3‐ methyl‐5‐(trifluoromethyl)phenol; 3‐methyl‐2‐[2‐(oxan‐4‐yl)‐4‐propyl‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐5‐ (trifluoromethyl)phenol; 2‐[4‐(azetidin‐1‐yl)‐2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐3‐methyl‐5‐ (trifluoromethyl)phenol; 5‐(1,1‐difluoroethyl)‐3‐methyl‐2‐[2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]phenol; 3‐methyl‐2‐(2‐{[(3S)‐1‐(oxetan‐3‐yl)piperidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl)‐ 5‐(trifluoromethyl)phenol;3‐methyl‐2‐(2‐{[(3R)‐1‐(oxetan‐3‐yl)piperidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐ yl)‐5‐(trifluoromethyl)phenol; 2‐(2‐{[(3S)‐1‐[(1‐fluorocyclopropyl)methyl]piperidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl)‐3‐methyl‐5‐(trifluoromethyl)phenol; 2‐(2‐{[(3R)‐1‐[(1‐fluorocyclopropyl)methyl]piperidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl)‐3‐methyl‐5‐(trifluoromethyl)phenol; 2‐(2‐{[(3S)‐1‐[(3‐fluorooxetan‐3‐yl)methyl]piperidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl)‐3‐methyl‐5‐(trifluoromethyl)phenol; 2‐(2‐{[(3R)‐1‐[(3‐fluorooxetan‐3‐yl)methyl]piperidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl)‐3‐methyl‐5‐(trifluoromethyl)phenol; 3‐methyl‐2‐[5‐methyl‐2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐5‐ (trifluoromethyl)phenol; 3,5‐dimethyl‐2‐[2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl]phenol; rac-2‐{2‐[(4,4‐difluoro‐1‐methylpiperidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl}‐3‐ methyl‐5‐(trifluoromethyl)phenol;rac- 2‐{2‐[(4,4‐difluoro‐1‐methylpiperidin‐3‐yl)methyl]‐3‐methyl‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐5‐(trifluoromethyl)phenol; 2‐(2‐{[(3S)‐4,4‐difluoro‐1‐methylpiperidin‐3‐yl]methyl}‐3‐methyl‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl)‐3‐methyl‐5‐(trifluoromethyl)phenol; 2‐(2‐{[(3R)‐4,4‐difluoro‐1‐methylpiperidin‐3‐yl]methyl}‐3‐methyl‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl)‐3‐methyl‐5‐(trifluoromethyl)phenol; 2‐(2‐{[(3R)‐3‐fluoro‐1‐methylpyrrolidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl)‐3‐ methyl‐5‐(trifluoromethyl)phenol; and 2‐(2‐{[(3S)‐3‐fluoro‐1‐methylpyrrolidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl)‐3‐ methyl‐5‐(trifluoromethyl)phenol.

[0142] Where tautomerism, like e.g., keto-enol tautomerism, of compounds of formula (I)may occur, the individual forms, like e.g., the keto and enol form, are comprised separately andtogether as mixtures in any ratio. Same applies to stereoisomers, like e.g. enantiomers, cis / trans isomers, conformers and the like.

[0143] Especially, when enantiomeric or diastereomeric forms are given in a compoundaccording to formula (I), each pure form separately and any mixture of at least two of the pureforms in any ratio is comprised by formula (I) and is a subject of the present invention.

[0144] Isotopic labeled compounds of formula (I) are also within the scope of the presentinvention. Methods for isotope labeling are known in the art. Preferred isotopes are those of the elements H, C, N, O and S. Thus, compounds of the present invention are especially alsoencompassed, which have one or more hydrogens in the form of 2H / deuterium D. Solvates andhydrates of compounds of formula (I) are also within the scope of the present invention.

[0145] If desired, isomers can be separated by methods well known in the art, e.g., by liquidchromatography. Same applies for enantiomers by using e.g., chiral stationary phases.Additionally, enantiomers may be isolated by converting them into diastereomers, i.e., couplingwith an enantiomerically pure auxiliary compound, subsequent separation of the resulting diastereomers and cleavage of the auxiliary residue. Alternatively, any enantiomer of a compound of formula (I) may be obtained from stereoselective synthesis using optically pure starting materials, reagents and / or catalysts.

[0146] In case the compounds according to formula (I) contain one or more acidic or basicgroups, the invention also comprises their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts. Thus, the compounds ofthe formula (I) which comprise acidic groups can be used according to the invention, forexample, as alkali metal salts, alkaline earth metal salts or as ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids. Compounds of the formula (I) which contain one or more basicgroups, i.e., groups which can be protonated, can be present and can be used according to theinvention in the form of their addition salts with inorganic or organic acids. Examples forsuitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid,nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to the person skilled in the art. If the compounds of the formula (I) simultaneously contain acidic and basic groups in the molecule, the invention also includes, in addition to the salt forms mentioned, inner salts orbetaines (zwitterions). The respective salts according to the formula (I) can be obtained by customary methods which are known to the person skilled in the art like, for example by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts. The present invention also includes all salts of the compounds of the formula (I) which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.III. Pharmaceutical Compositions

[0147] As shown below in the Examples, compounds of the present invention are suitablefor modulating NLRP3.

[0148] Accordingly, an aspect of the present invention is a compound or a pharmaceuticallyacceptable salt, solvate, hydrate, tautomer or stereoisomer thereof of the present invention for use as a medicament as mentioned above. The same applies to a pharmaceutical composition of the present invention.

[0149] A further aspect of the present invention is a compound or a pharmaceuticallyacceptable salt, solvate, hydrate, tautomer or stereoisomer thereof or a pharmaceutical composition of the present invention for use in a method of treating and / or preventing one or more disorders or diseases mentioned herein.

[0150] A further aspect of the present invention is the use of a compound or apharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof or a pharmaceutical composition of the present invention for the manufacture of a medicament for the treatment or prophylaxis of one or more disorders or diseases associated with NLRP3.

[0151] Yet another aspect of the present invention is a pharmaceutical compositioncomprising at least one compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof of the present invention together with a pharmaceutically acceptable carrier, optionally in combination with one or more other bioactive compounds orpharmaceutical compositions. In one aspect, the one or more bioactive compounds aremodulators of NLRP3 other than compounds of the present invention.

[0152] "Pharmaceutical composition" means one or more active ingredients, and one ormore inert ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types ofreactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.

[0153] A pharmaceutical composition of the present invention may comprise one or moreadditional compounds as active ingredients like a mixture of compounds of formula (I) in the composition or other modulators of NLRP3.

[0154] The active ingredients may be comprised in one or more different pharmaceuticalcompositions (combination of pharmaceutical compositions).

[0155] The term "pharmaceutically acceptable salts" refers to salts prepared frompharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids.

[0156] Starting materials for the synthesis of preferred embodiments of the invention maybe purchased from commercially available sources such as Array, Sigma Aldrich, Acros, Fisher, Fluka, ABCR.

[0157] In general, several methods are applicable to prepare compounds of the presentinvention. In some cases, various strategies can be combined. Sequential or convergent routes may be used. Exemplary synthetic routes are described below.IV. Methods of Treatment

[0158] The present invention provides a compound or a pharmaceutically acceptable salt,solvate, hydrate, tautomer or stereoisomer thereof, or a pharmaceutical composition of thepresent invention, to be used in the treatment or prevention of one or more diseases or disordersassociated with NLRP3.

[0159] The therapeutic method described may be applied to mammals such as dogs, cats,cows, horses, rabbits, monkeys and humans. Preferably, the mammalian patient is a human patient.

[0160] Yet another aspect of the present invention is a method for treating, controlling,delaying and / or preventing in a mammalian patient in need of the treatment of one or morediseases, disorders or conditions associated with NLRP3, wherein the method comprisesadministering to the patient a therapeutically effective amount of a compound or apharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof or apharmaceutical composition of the present invention.

[0161] Yet another aspect of the present invention is a method for treating, controlling,delaying and / or preventing in a mammalian patient in need of the treatment of one or morediseases, disorders or conditions mentioned herein, wherein the method comprisesadministering to the patient a therapeutically effective amount of a compound or apharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof or a pharmaceutical composition of the present invention.

[0162] Diseases or disorders amenable to treatment using the compounds and compositionsof the invention include but are not limited to: (i) diseases associated with NLRP3-mediatedinflammation, including but not limited to cryopyrin-associated periodic syndromes (CAPS), familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS), and neonatal-onset multisystem autoinflammatory syndrome (NOMID); (ii) chronic inflammatorydiseases (e.g., gout, rheumatoid arthritis, inflammatory bowel disease (IBD), including Crohn’sdisease and ulcerative colitis), (iii) metabolic diseases (e.g., atherosclerosis, diabetes, metabolicsyndrome, obesity, liver steatosis, nonalcoholic steatohepatitis (NASH), and liver fibrosis); (iv)neurological diseases (e.g., Alzheimer’s disease (AD) and Parkinson’s disease (PD), multiplesclerosis (MS), Huntington’s disease (HD), Amyotrophic Lateral Sclerosis (ALS), Prion disease, Traumatic Brain Injury (TBI) and stroke); (v) diseases associated with inherited, autosomal dominant mutations in NLRP3 that promote NLRP3 inflammasome; (vi) asthma andallergic airway inflammation; (vii) hypertension; (viii) myocardial infarction; (ix)hyperinflammation following influenza and / or severe acute respiratory syndrome-coronavirus2 (SARS CoV-2); (x) Graft-versus-host disease; (xi) silicosis; (xii) myelodysplastic syndrome;(xiii) contact hypersensitivity and joint inflammation triggered by chikungunya virus.

[0163] Any suitable route of administration may be employed for providing a mammal,especially a human, with an effective dose of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. Preferably compounds of formula (I) are administered orally.

[0164] The effective dosage of active ingredient employed may vary depending on theparticular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.

[0165] EXAMPLESI Chemical synthesisExperimental procedures: The following Abbreviations and Acronyms are used:A>B Apical to Basolateral directionACN acetonitrileAgilent RapidFire MS systemMS system replacing the traditional liquid chromatography (LC)separation step with solid-phase extraction (SPE)AMU atomic mass unitB>A Basolateral to Apical directionBBr3 boron tribromide BCRP Breast Cancer Resistant ProteinBippyPhos 5-(di-tert-butylphosphino)-1′, 3′, 5′-triphenyl-1′H-[1,4′]bipyrazoleBrine saturated solution of NaCl in waterBQL Below the limit of quantificationBSA Bovine Serum AlbuminCDCl3 deuterated chloroformCDI 1,1’-carbonyldiimidazole(CH3)2S·BH3borane dimethyl sulfide complexcHex cyclohexaneCLint Intrinsic clearanceCPME cyclopentyl methyl etherCyJohnPhos 2-(dicyclohexylphosphino)biphenyl ordicyclohexyl-(2-phenylphenyl)phosphane Cs2CO3cesium carbonateDAST (Diethylamino)sulfur trifluorideDCM dichloromethaneDIBAL-H Diisobutylaluminum hydrideDIPEA N-ethyl-N-isopropyl-propan-2-amineDME 1,2 dimethoxyethaneDMEM Dulbecco’s Modified Eagle MediumDMF N,N-dimethylformamideDMSO dimethylsulfoxideDMSO-d6 deuterated dimethylsulfoxideDNA Deoxyribonucleic AcidER Efflux RatioESI+positive ionisation mode ESI- negative ionisation modeEtOAc ethyl acetateEtOH ethanolFBS fetal bovine serumGLP Good laboratory practiceh hour(s)HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphateHBSSH Hank’s Balanced Salt Solution + 12.5 mM HEPESHCl hydrochloric acidHCOOH formic acidHCOONH4ammonium formateHI Heat InactivatedHPLC high-performance liquid chromatographyHTRF homogenous time resolved fluorescenceIL-1β interleukin-1 betaIS internal standardK2CO3 potassium carbonate LiAlH4lithium aluminium hydrideLiOH lithium hydroxideLC liquid chromatographyLPS lipopolysaccharidesLY Lucifer Yellowm multipletmCPBA 3-Chloroperoxybenzoic acidM MolarMDCKII-BCRP Madin Darby Canine Kidney clone II cell line heterologouslyexpressing the human BCRP transporterMDCKII-MDR1 Madin Darby Canine Kidney clone II cell line heterologouslyexpressing the human MDR1 proteinMDR1 Human MultiDrug Resistance protein 1 also known as P-glycoproteinMeMgBr methylmagnesium bromideMeI iodomethaneMeOH methanolMeOD-d4 deuterated methanolMEM Minimum Essential Mediummg milligram(s)MgSO4 magnesium sulphateMHz megahertzmin minutesmL millilitre (s)mM millimolarMS Mass spectrometryMW Molecular weightN2 nitrogen atmosphere NaHCO3sodium bicarbonateNa(OAc)3BH sodium triacetoxyborohydrideNaOH sodium hydroxideNa2S2O3 sodium thiosulfate Na2SO4sodium sulfateNa2SO4•10H2O sodium sulfate decahydrateNEAA Non-Essential Amino AcidsNH3ammoniaNH4Cl ammonium chlorideNLRP3 nucleotide-binding domain (NBD), leucine-rich repeat (LRR)-containing (NLR) protein 3NMP N-Methyl-2-pyrrolidoneNMR Nuclear Magnetic ResonanceOH hydroxyPBS Phosphate Buffered SalinePd / C palladium over carbonPd2(dba)3 tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl2[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(OAc)2palladium(II)acetateRNA Ribonucleic Acidr.t. room temperatureRFU Relative Fluorescence UnitRT retention timeRT-qPCR Real Time Quantitative Polymerase Chain ReactionSCX strong cation exchange cartridgeSD Standard deviationSEM-Cl 2-(trimethylsilyl)ethoxymethyl chlorideSMA Spinal Muscular AtrophyTBAF tetrabutylammonium fluorideTEA triethylamineTFA Trifluoroacetic acidTFAA Trifluoroacetic anhydrideTf2O Trifluoromethanesulfonic anhydrideTHF tetrahydrofuranUPLC Ultra Performance Liquid ChromatographyV VolumeVs. VersusµM micromolar

[0166] Analytical LCMS conditions were as follows:UPLC / MS retention times were estimated to be affected by an experimental error of +0.5 min. LCMS may be recorded under the following conditions: diode array DAD chromatographic traces, mass chromatograms and mass spectra may be taken on UPLC / PDA / MS AcquityTMsystem coupled with Micromass ZQTMor Waters SQD single quadrupole mass spectrometer operated in positive and / or negative electron spray (ES) ionization mode and / or Fractionlynx system used in analytical mode coupled with ZQTMsingle quadrupole operated in positive and / or negative ES ionisation mode. Quality Control methods used operated under low pH conditions or under high pH conditions.

[0167] System 1 (S1): Low pH conditionsColumn: Acquity CSH C18 2.1x50mm 1.7 µm, the column temperature was 40 °C; mobilephase solvent A was milliQ water+0.1% HCOOH, mobile phase solvent B ACN+0.1% HCOOH. The flow rate was 0.9 mL / min. The gradient table was t= 0 min 97% A 3% B, t= 1.4 min 0.1% A 99.9% B, t= 1.9 min 0.1% A 99.9% B and t= 2 min 97% A 3% B. The UV detection range was 210-350 nm and ES+ / ES-range was 100 to 1000 AMU. Data were integrated and reported using Waters MassLynx andOpenLynx software.

[0168] System 2 (S2): High pH conditionsColumn: Acquity Kinetex 1.7 µm EVO C18100A, 2.1x50mm, the column temperature was 40 °C; mobile phase solvent A was 10 mM aqueous solution of NH4HCO3 adjusted to pH= 10 with ammonia, mobile phase solvent B ACN. The flow rate was 0.9 mL / min. The gradient table was t= 0 min 97% A 3% B, t= 1.4 min 0.1% A 99.9% B, t= 1.9 min 0.1% A 99.9% B and t= 2 min97% A 3% B. The UV detection range was 210-350 nm and ES+ / ES- range was 100 to 1000AMU. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0169] System 3 (S3): ACIDIC IPC METHODAnalytical (MET / uPLC / 1704) UHPLC-MS were performed in reverse phase system using a Waters UPLCTMBEHTMC18 column (2.1 mm × 50 mm, 1.7 µm; temperature: 40 °C), with aninjection volume of 1 µL at a flow rate of 0.9 mL / min and a gradient of 5 – 100% B over 1.10min, then 100% B for 0.25 min, where A = 0.1% formic acid in water, and B = 0.1% formicacid in ACN. A second gradient of 100 – 5% B was then applied over 0.05 min and held for0.10 min. UV spectra were recorded at 215, 254 and 280 nm. Mass spectra were obtained using a Waters QDA detector; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0170] System 4 (S4): ACIDIC FINAL METHODAnalytical (MET / uPLC / AB101) UHPLC-MS were performed in reverse phase using a Phenomenex Kinetex-XB C18 column (2.1 mm × 100 mm, 1.7 µm; temperature: 40 °C), withan injection volume of 1 µL at a flow rate of 0.6 mL / min and a gradient of 5 – 100% B over5.30 min, then 100% B for 0.50 min, where A = 0.1% formic acid in water, and B = 0.1%formic acid in ACN. A second gradient of 100 – 5% B was then applied over 0.02 min and heldfor 1.18 min. UV spectra were recorded at 215, 254 and 280 nm. ELS data was collected on a Waters ELS detector when reported. Mass spectra were obtained using a Waters QDA detector;ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0171] Purification methods were as follows:Purifications by chromatography on silica gel were performed on Biotage Isolera systems using the appropriate Sfär Duo cartridge.

[0172] NMR ConditionsUnless otherwise stated,1H-NMR spectra were performed on a Varian MR-400 spectrometer operating at 400 MHz (proton frequency), equipped with: a self-shielded Z-gradient coil 5 mm 1H / nX broadband probe head for reverse detection, deuterium digital lock channel unit, quadrature digital detection unit with transmitter offset frequency shift, or on AgilentVNMRS-500, or on a Bruker Avance 400 spectrometers, or on a Agilent Inova 600 operating at 600MHzequipped with 5mm PFG ΡΕΝΤΑ Probe spectrometers. Chemical shifts are reported as 6 valuesin ppm relative to trimethylsilane (TMS) as an internal standard. Coupling constants (J values)are given in hertz (Hz) and multiplicities are reported using the following abbreviation (s=singlet, d= doublet, t= triplet, q= quartet, m= multiplet, br. s.= broad singlet, br. d.= broaddoublet, br. dd.= broad doublet-doublet, br. t.= broad triplet, dd= double-doublet, ddd= double-double-doublet, ddq= double-double-quartet, ddt= double-double-triplet, dddd= double-double-double-doublet, dt= double triplet, dq= double quartet, dtd= double-triple douplet, qd=quartet of doublet, quin= quintuplet, sxt= sextet, td= triple doublet, tdd= triple-double-doublet,tt= triple triplet, quin= quintuplet).

[0173] General synthesis:Scheme for route 1:Intermediate 1: 3-methyl-5-(trifluoromethyl)phenol

[0174] To a degassed mixture of 1-bromo-3-methyl-5-(trifluoromethyl)benzene (100g, 418.4 mmol) and LiOH (31.3 g, 1255.1 mmol) in 1,4-dioxane (650 mL) and water (122 mL) was added a degassed mixture of Pd2(dba)3 (3.8 g, 4.2 mmol) and BippyPhos (4.1 g, 8.0 mmol) in 1,4-dioxane (50 mL). The reaction was stirred at 90 °C under a N2atmosphere for 18 h. Thereaction mixture was cooled to r.t. and filtered through glass fibre filter paper. The filtrate wasconcentrated in vacuo, dissolved in EtOAc and washed with 1 M HCl. After phase separation, the organic layer was concentrated in vacuo. The crude product was then stirred in an aqueous5 M NaOH solution for 15 min. Next, heptane was added, and the biphasic mixture was stirredfor 5 min. After phase separation, the basic aqueous layer was cooled to 0 °C and acidified with an aqueous 5 M HCl solution until pH=4 was achieved. The aqueous layer was then extracted with heptane. The combined organic phases were washed with brine, dried over MgSO4andconcentrated in vacuo to yield the title compound (55.0 g, 306.2 mmol, 73% yield) as an orangeliquid. 1H NMR (400 MHz, DMSO-d6) δ = 9.96 (s, 1H), 6.93 (qd, J = 1.6, 0.9 Hz, 1H), 6.88 –6.80 (m, 2H), 2.29 (s, 3H). MS (ESI); M / Z: 221 [M +HCOOH- H]-, ESI-, RT = 0.88 (S3).

[0175] Scheme for route 2:Intermediate 2: 2-iodo-3-methyl-5-(trifluoromethyl)phenol

[0176] 3-methyl-5-(trifluoromethyl)phenol (Intermediate 1, 55 g, 306.2 mmol) wasdissolved in toluene (500 mL) and cooled to 0 °C under a N2 atmosphere. NaH (60% dispersionin mineral oil, 24.5 g, 612.3 mmol) was added portion-wise over 45 min. Next, a solution of iodine (77.7 g, 306.2 mmol) in toluene (500 mL) was added dropwise over 8 h at 0 °C. After stirring at r.t., the reaction was quenched to pH=7 with an aqueous 6 M HCl solution at 0 °C. The mixture was partially concentrated in vacuo, before being extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (0-100% EtOAc in heptane, followed by 0-20% MeOH in EtOAc) to yield the title compound (90% purity, 74.3 g,221.3 mmol, 72% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ = 10.95 (s,1H), 7.15 – 7.10 (m, 1H), 6.96 – 6.90 (m, 1H), 2.44 (s, 3H); MS (ESI); M / Z: 301 [M-H]-, ESI-,RT = 1.00 (S4).

[0177] Intermediate compound in Table 1 was synthesised according to the generalroute 2 as exemplified by Intermediate 2 using the corresponding startingmaterials / intermediates. Table 1 IntermeStructure Name StartingLCMS1H NMR diate materials data 32‐iodo‐5‐3-methoxy-5- M / Z: 2651H NMR (400 MeO I methoxy‐3‐ methylphenol [M+H]+, MHz, DMSO) δ OH methylphenol ESI+, RT = 10.21 (s, 1H), 0.86 (S3). 6.45 (dd, J = 2.9,0.7 Hz, 1H), 6.31 (d, J = 2.8 Hz,1H), 3.68 (s, 3H), 2.31 (s, 3H).

[0178] Scheme for route 3:Intermediate 4: 2-iodo-1-methoxy-3-methyl-5-(trifluoromethyl)benzene

[0179] MeI (0.36 mL, 5.83 mmol) was added to a stirred mixture of 2-iodo-3-methyl-5-(trifluoromethyl)phenol (Intermediate 2, 0.8 g, 2.65 mmol) and K2CO3 (0.92 g, 6.62 mmol)in ACN (8 mL). The reaction was stirred at r.t. for 4 h. The mixture was taken up with EtOAcand water, transferred to a separatory funnel. The phases were separated, the organic one waswashed with 10% aqueous Na2S2O3 (2x) and brine (1x), then filtered through a phase separatorand concentrated in vacuo to yield the title compound (900 mg, 2.85 mmol, recovery assumedquantitative) as white solid.1H NMR (400 MHz, DMSO-d6) δ = 7.33 (dd, J = 2.1, 1.0 Hz, 1H),7.09 – 7.04 (m, 1H), 3.93 (s, 3H), 2.49 (s, 3H). M / Z: no ionisation, RT = 1.30 (S1).

[0180] Scheme for route 4:Intermediate 5: 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- (trifluoromethyl)phenolIntermediate 5

[0181] To a degassed solution of 2-iodo-3-methyl-5-(trifluoromethyl)phenol(Intermediate 2, 20.00 g, 49.7 mmol), TEA (21 mL, 149.0 mmol), pinacol borane (22 mL, 149.0mmol) and CyJohnPhos (3.48 g, 9.9 mmol) in 1,4-dioxane (20 mL) was added Pd(OAc)2 (1.12g, 5.0 mmol) and the reaction was heated to 80 °C under a N2 atmosphere for 22 h. The reaction mixture was cooled to r.t. and filtered through glass fibre filter paper. The filter cake washed with EtOAc and the filtrate was partially concentrated in vacuo. The organic layer was washedwith a saturated aqueous solution of NH4Cl and water, dried over MgSO4 and concentrated invacuo. The crude product was purified by chromatography on silica gel (0-12% EtOAc in heptane) to yield the title compound (8.18 g, 26.5 mmol, 53% yield) as a red oil.1H NMR (500MHz, DMSO-d6) δ = 9.79 (s, 1H), 6.92 (s, 1H), 6.83 (s, 1H), 2.30 (s, 3H), 1.31 (s, 12H). 19FNMR (376 MHz, DMSO-d6) δ = -61.57.

[0182] Intermediate compounds in Table 2 were synthesised according to the generalroute 4 as exemplified by Intermediate 5 using the corresponding startingmaterials / intermediates. Table 2 IntermeStructure Name StartingLCMS1H NMR diate materials data 62‐[2‐methoxy‐2‐iodo‐1‐ M / Z:1H NMR (400 O F3C B 6‐methyl‐4‐ methoxy‐3‐ 317.1 MHz, DMSO-d6) O OMe (trifluoromethy methyl‐5‐ [M+H]+,δ = 7.13 – 7.10l)phenyl]‐ (trifluorometh ESI+, RT = (m, 1H), 7.02 (s, 4,4,5,5‐ yl)benzene 1.35 (S1). 1H), 3.79 (s, 3H), tetramethyl‐ (Intermediate 2.33 (s, 3H), 1.32 1,3,2‐ 4) (s, 12H). dioxaborolane 75-methoxy-3-2-iodo-5- No LCMS1H NMR (500 methyl-2- methoxy-3- available MHz, DMSO-d6) (4,4,5,5- methyl-phenol δ = 8.80 (s, 1H), tetramethyl- (Intermediate6.23 (dd, J = 2.3,1,3,2- 3) 0.8 Hz, 1H), 6.15 dioxaborolan-(d, J = 2.2 Hz,2-yl)phenol 1H), 3.69 (s, 3H), 2.29 (s, 3H), 1.29 (s, 12H).

[0183] Scheme for route 5:Intermediate 8: rac-(3-fluoro-1-methylpyrrolidin-3-yl)methanolIntermediate 8

[0184] Formaldehyde 37% w / w (0.28 mL, 3.76 mmol) was added to an ice cooledsolution of rac-(3-fluoropyrrolidin-3-yl)methanol hydrochloride (390 mg, 2.51 mmol) inMeOH (15 mL). After 30 min Na(OAc)3BH (1.59 g, 7.52 mmol) was added portion-wise, andstirred at r.t. for 1 h. Volatiles were removed in vacuo and the residue charged on SCX, washingwith MeOH and eluting with 1N NH3 in MeOH to yield the title compound (220 mg, 1.65mmol, 66% yield).1H NMR (400 MHz, CDCl3) δ = 3.89 – 3.62 (m, 2H), 2.98 – 2.76 (m, 3H),2.74 – 2.65 (m, 1H), 2.45 (s, 3H), 2.15 – 1.97 (m, 3H). MS (ESI); M / Z: 134.1 [M+H]+, ESI+,RT = 0.14 (S1).

[0185] Intermediate compound in Table 3 was synthesised according to the generalroute 5 as exemplified by Intermediate 8 using the corresponding startingmaterials / intermediates. Table 3 IntermeStructure Name StartingLCMS1H NMR diate materials data 9 Frac-(4,4‐ rac (4,4-M / Z: F difluoro‐1‐ difluoropiperid 166.2 HO N methylpiperidi in-3- [M+H]+, n‐3‐ yl)methanol ESI+, RT yl)methanol= 0.47 (S2).Intermediate 10: 4-bromo-2-methylbutan-2-ol

[0187] A solution of ethyl 3-bromopropanoate (0.71 mL, 5.52 mmol) in diethyl ether(80 mL) was cooled to -5°C, 3 M methylmagnesium bromide in diethyl ether (4.6 mL, 13.81mmol) was added dropwise, and the solution was allowed to warm to r.t. while stirring overnight. The reaction was quenched with saturated aqueous NH4Cl, extracted with EtOAc,washed with brine, dried over Na2SO4, filtered, and evaporated in vacuo. Since NMR analysisshowed a 1:1 mixture of desired product and starting material, a second run using the sameconditions was done to yield the title compound (704 mg, 4.21 mmol, 76% yield) that was usedin the next step without further purification. 1H NMR (400 MHz, CDCl3) δ = 3.56 – 3.47 (m,2H), 2.16 – 2.09 (m, 2H), 1.29 (s, 6H).

[0188] Scheme for route 7:

[0189] Intermediate 11: 1,1-dioxo-1λ6-thian-4-yl methanesulfonate

[0190] Methanesulfonyl chloride (0.33 mL, 4.33 mmol) was added dropwise to an icecooled solution of 1,1-dioxothian-4-ol (0.5 g, 3.33 mmol) and TEA (1.39 mL, 9.99 mmol) inDCM (15 mL). When the addiction was complete the reaction mixture was allowed to stirovernight at r.t.. The day after it was quenched with water and extracted with DCM (3x).Organic phases were reunited, dried with a phase separator, and evaporated in vacuo to yieldthe title compound (90% purity, 780 mg, 3.33 mmol, recovery assumed quantitative) as paleorange solid, used as such in the next step.1H NMR (400 MHz, CDCl3) δ = 5.06 (tt, J = 4.9,2.5 Hz, 1H), 3.41 – 3.28 (m, 2H), 3.12 (s, 3H), 3.09 – 2.98 (m, 2H), 2.62 – 2.39 (m, 4H).

[0191] Intermediate compounds in Table 4 were synthesised according to the generalroute 7 as exemplified by Intermediate 11 using the corresponding startingmaterials / intermediates. Table 4 IntermeStructure Name StartingLCMS1H NMR diate materials data 12 rac-(1‐rac-(1- No1H NMR (500 MHz, ethylpiperidin‐3‐ ethylpiperidin- LCMS CDCl3) δ = 4.21 - yl)methyl 3-yl)methanol availabl 4.07 (m, 2H), 3.03 methanesulfonate e(s, 3H), 3.03 - 2.97(m, 1H), 2.97 - 2.87(m, 1H), 2.56 - 2.43(m, 2H), 2.20 (br. s,1H), 2.08 (br. d., J =10.4 Hz, 1H), 1.95 (br. s., 1H), 1.85 -1.71 (m, 3H), 1.15(br. t., J = 7.1 Hz,4H)13 rac-(1‐rac-(1-methyl- No1H NMR (400 MHz, methylpyrrolidin‐ 3- LCMSDMSO-d6) δ = 4.123‐yl)methyl pyrrolidinyl)me availabl– 4.06 (m, 2H), 3.18methanesulfonate thanol e(s, 3H), 2.55 (dd, J =9.8, 6.4 Hz, 2H), 2.48 (ddd, J = 7.4,4.8, 2.5 Hz, 1H), 2.44 – 2.30 (m, 2H),2.27 (s, 3H), 1.91 (dddd, J = 12.9, 9.3,7.7, 5.3 Hz, 1H), 1.45 (dddd, J = 13.0,8.0, 6.4, 5.0 Hz, 1H).14 rac-(1‐methyl‐2‐rac-3- No1H NMR (400 MHz, oxopyrrolidin‐3‐ (hydroxymethy LCMSCDCl3) δ = 4.55 –yl)methyl l)-1-methyl- availabl 4.41 (m, 2H), 3.42 – methanesulfonate pyrrolidin-2- e 3.36 (m, 2H), 3.06 one(s, 3H), 2.90 (d, J =0.7 Hz, 3H), 2.88 – 2.78 (m, 1H), 2.29 (ddt, J = 13.1, 9.3,5.3 Hz, 1H), 2.12 (dq, J = 13.1, 8.7 Hz,1H).15 rac-(1‐methyl‐5‐rac-4- M / Z:1H NMR (400 MHz, oxopyrrolidin‐3‐ (hydroxymethy 208.1CDCl3) δ = 4.31 –yl)methyl l)-1-methyl- [M+H] 4.14 (m, 2H), 3.57 methanesulfonate pyrrolidin-2-+, ESI+,(dd, J = 10.2, 8.1 Hz,one RT =1H), 3.28 (dd, J =0.46 10.2, 5.2 Hz, 1H), (S1). 3.07 (s, 3H), 2.91 – 2.79 (m, 4H), 2.61(ddd, J = 17.1, 9.4, 0.9 Hz, 1H), 2.23 (ddd, J = 17.1, 6.1, 0.9 Hz, 1H).16 rac-5‐rac-5- No1H NMR (400 MHz, oxaspiro[3.5]nona oxaspiro[3.5]no LCMSCDCl3) δ = 4.86 (tt,n‐8‐yl nan-8-ol availablJ = 10.0, 4.5 Hz,methanesulfonate e1H), 3.83 (dt, J =12.1, 4.1 Hz, 1H), 3.49 (ddd, J = 12.2,10.8, 2.7 Hz, 1H), 3.03 (s, 3H), 2.26 (ddd, J = 12.7, 4.4,1.9 Hz, 1H), 2.22 – 2.12 (m, 1H), 2.07 – 1.98 (m, 4H), 1.86 – 1.64 (m, 4H).17 rac-(3‐fluoro‐1‐rac-(3‐fluoro‐ No1H NMR (400 MHz, methylpyrrolidin‐ 1‐ LCMSCDCl3) δ = 4.61 –3‐yl)methyl methylpyrrolidi availabl 4.43 (m, 2H), 3.73 methanesulfonate n‐3‐ e(d, J = 22.9 Hz, 1H),yl)methanol3.54 (d, J = 7.4 Hz,(Intermediate 1H), 3.20-3.07 (m, 8) 5H), 2.81 (s, 3H), 2.55 – 2.26 (m, 2H).18 rac- (4,4‐difluoro‐rac-(4,4‐ M / Z: 1‐ difluoro‐1‐ 244.2 methylpiperidin‐ methylpiperidin [M+H] 3‐yl)methyl ‐3‐yl)methanol+, ESI+, methanesulfonate (Intermediate RT = 9) 0.63 (S2).19 cis methyl 3‐ cis methyl -3-No1H NMR (400 MHz, (methanesulfonyl hydroxycyclob LCMSCDCl3) δ = 5.01 –oxy)cyclobutane‐ utanecarboxylat availabl 4.91 (m, 1H), 3.73 1‐carboxylate e e (s, 3H), 3.02 (s, 3H), 2.81 – 2.67 (m, 3H),2.67 – 2.54 (m, 2H).20 rac-2,2‐rac-2,2- No1H NMR (400 MHz, dimethyloxan‐4‐ dimethyltetrahy LCMSDMSO-d6) δ = 4.92yl dropyran-4-ol availabl(tt, J = 10.2, 4.7 Hz,methanesulfonate e1H), 3.71 (ddd, J =12.2, 5.1, 3.1 Hz, 1H), 3.60 (ddd, J =12.1, 11.1, 2.5 Hz, 1H), 3.20 (s, 3H), 1.96 (ddd, J = 12.6,4.6, 1.6 Hz, 2H), 1.61 – 1.43 (m, 2H),1.21 – 1.16 (m, 6H).21 [(2R)‐4‐[(2R)-4- M / Z: methylmorpholin‐ methylmorphol 210.1 2‐yl]methyl in-2- [M+H] methanesulfonate yl]methanol+, ESI+, RT = 0.16 (S1).22 [(2S)‐4‐[(2S)-4- M / Z: methylmorpholin‐ methylmorphol 210.1 2‐yl]methyl in-2- [M+H] methanesulfonate yl]methanol+, ESI+, RT = 0.16 (S1).23 cis-3‐cis-3- No1H NMR (400 MHz, (benzyloxy)cyclo benzyloxycyclo LCMSCDCl3) δ = 7.38 –butyl butanol availabl 7.27 (m, 5H), 4.65 methanesulfonate e(p, J = 7.3 Hz, 1H),4.44 (s, 2H), 3.74 (tt, J= 7.4, 6.4 Hz, 1H),2.98 (s, 3H), 2.93 – 2.77 (m, 2H), 2.40 – 2.27 (m, 2H).

[0192] Scheme for route 8:Intermediate 24: 6-chloro-4-methoxy-1H-pyrazolo[3,4-b]pyridine

[0193] In a microwave vial, 4,6-dichloro-1H-pyrazolo[5,4-b]pyridine (200 mg, 1.06mmol) was dissolved in Methanol (3 mL), then MeONa (86 mg, 1.6 mmol) was added. The vialwas sealed and irradiated at 110 °C for 3 h. Further MeONa (45 mg) was added, the vial wassealed and heated at 110 °C for 1 h. The mixture was evaporated, and the residue was purifiedby chromatography on silica gel (0-94% MeOH in DCM) to yield title compound (107 mg, 0.58mmol, 55% yield) as white solid. M / Z: 184.0 [M+H]+, ESI+, RT = 0.72 (S1).

[0194] Scheme for route 9:

[0195] Intermediate 25: 6-chloro-2-(oxan-4-yl)-2H-pyrazolo[3,4-b]pyridine

[0196] In a microwave vial, 6-chloro-1H-pyrazolo[3,4-b]pyridine (300 mg, 1.95mmol) and 4-bromooxane (0.44 mL, 3.91 mmol) were dissolved in DMF (10 mL), then Cs2CO3(1280 mg, 3.91 mmol) was added. The vial was sealed and heated at 110 °C overnight. Waterwas added to the reaction mixture, and it was extracted with EtOAc. The organic layer wasdried over a phase separator and evaporated. The crude product was purified bychromatography on silica gel (0-20% EtOAc in cHex) to yield the title compound (91% purity,90 mg, 0.38 mmol, 19% yield). 1H NMR (400 MHz, DMSO-d6) δ = 8.60 (s, 1H), 8.28 (d, J =8.6 Hz, 1H), 7.14 (d, J = 8.7 Hz, 1H), 4.87 - 4.68 (m, 1H), 4.05 - 3.94 (m, 2H), 3.57 - 3.43 (m,2H), 2.17 - 2.00 (m, 4H). MS (ESI); M / Z: 238.1 [M+H]+, ESI+, RT = 0.71 (S1). Also the otherregioisomer, 6‐chloro 1‐(oxan‐4‐yl)‐1H‐pyrazolo[3,4‐b]pyridine (215 mg, 0.90 mmol, 46% yield), was isolated.

[0197] Intermediate compounds in Table 5 were synthesised according to the generalroute 9 as exemplified by Intermediate 25 using the corresponding startingmaterials / intermediates. Table 5 IntermeStructure Name StartingLCMS1H NMR diate materials data 26 6‐chloro‐2‐ 6‐chloro‐1H‐ M / Z: (oxan‐4‐yl)‐ pyrazolo[3,4 239.3 2H‐ ‐b]pyrazine [M+H]+, pyrazolo[3,4‐ with 4- ESI+, RT In 1 / 1.6 mixture with the b]pyrazine bromooxane = 0.69 other regioisomer(S1). 27 rac-6‐chloro‐2‐6-chloro-1H- M / Z:1H NMR (400 (oxolan‐3‐yl)‐ pyrazolo[3,4224.1 MHz, DMSO-d6) 2H‐ -b]pyridine [M+H]+,δ = 8.59 (s, 1H),pyrazolo[3,4‐ with rac-3- ESI+, RT8.29 (d, J = 8.6b]pyridine bromotetrah = 0.69 Hz, 1H), 7.16 (d, ydrofuran (S1).J = 8.6 Hz, 1H),5.40 (ddt, J =8.1, 6.5, 3.4 Hz, 1H), 4.15 – 4.00(m, 3H), 3.90 (td, J = 8.3, 5.3 Hz, 1H), 2.61 – 2.52(m, 1H), 2.48 – 2.32 (m, 1H).28 6‐chloro‐4‐6-chloro-4- M / Z:1H NMR (400 methyl‐2‐ methyl-1H- 252.2 MHz, CDCl3) δ (oxan‐4‐yl)‐ pyrazolo[3,4 [M+H]+,= 7.98 (d, J = 0.42H‐ -b]pyridine ESI+, RT Hz, 1H), 6.89 (q, pyrazolo[3,4‐ with 4- = 0.82J = 1.0 Hz, 1H),b]pyridine bromooxane (S1).4.67 (ddd, J =15.7, 9.0, 7.2 Hz, 1H), 4.19 (dt, J =11.6, 3.5 Hz, 2H), 3.68 – 3.56(m, 2H), 2.56 (d, J= 1.0 Hz, 3H),2.32 – 2.22 (m,4H).29 6‐chloro‐3‐6-chloro-3- M / Z:1H NMR (400 methyl‐2‐ methyl-1H- 253.1 MHz, DMSO-d6) (oxan‐4‐yl)‐ pyrazolo[3,4 [M+H]+,δ = 8.55 (s, 1H),2H‐ -b]pyrazine ESI+, RT4.91 (tt, J = 11.4,pyrazolo[3,4‐ with 4- = 0.77 4.2 Hz, 1H), 4.04 b]pyrazine bromooxane (S1).(dd, J = 11.2, 4.7Hz, 2H), 3.64 – 3.53 (m, 2H), 2.76 (s, 3H), 2.19(dd, J = 12.1, 4.5Hz, 2H), 1.95 (dd, J = 12.0, 4.0Hz, 2H).30 6‐chloro‐3‐6-chloro-3- M / Z:1H NMR (400 methyl‐2‐ methyl-1H- 252.3 MHz, DMSO-d6) (oxan‐4‐yl)‐ pyrazolo[3,4 [M+H]+,δ = 8.29 (d, J =2H‐ -b]pyridine ESI+, RT 8.5 Hz, 1H), 7.06 pyrazolo[3,4‐ with 4- = 0.76(d, J = 8.6 Hz,b]pyridine bromooxane (S1).1H), 4.80 (tt, J =11.4, 4.3 Hz, 1H), 4.03 (dd, J = 11.5, 4.6 Hz, 2H), 3.56 (td, J =12.0, 2.0 Hz, 2H), 2.70 (s, 3H), 2.17 (tt, J = 12.2,6.3 Hz, 2H), 1.91 (ddd, J = 12.5,4.3, 2.0 Hz, 2H) 31 tert‐butyl 4‐{6‐ 6-chloro-1H- M / Z: chloro‐2H‐ pyrazolo[3,4281.2 [M-pyrazolo[3,4‐ 56+H]+, -b]pyridine b]pyridin‐2‐+with 1-tert-ESI , RT In 1:1.5 mixture with the yl}piperidine‐ = 1.01 butoxycarbo other regioisomer 1‐carboxylate (S1). nyl-4- bromopiperi dine32 tert‐butyl 4‐{6‐M / Z:1H NMR (500 6‐chloro‐1H‐ chloro‐2H‐282.3 [M-MHz, DMSO-d6) pyrazolo[3,4 pyrazolo[3,4‐ 56+H]+, ‐b]pyrazineδ = 9.03 (s, 1H),b]pyrazin‐2‐ ESI+, RT 8.64 (s, 1H), 4.79 with 1-tert-yl}piperidine‐ butoxycarbo = 1.01(tt, J = 3.9, 11.51‐carboxylate (S1). Hz, 1H), 4.24 - nyl-4- 3.99 (m, 2H), bromopiperi 2.99 (br. s., 2H), dine 2.15 (br. dd., J =2.1, 12.2 Hz, 2H), 1.97 (dq, J = 4.4, 12.2 Hz, 2H), 1.43 (s, 9H).33 tert-butyl 3-6-chloro-1H- M / Z: ({6-chloro-2H- pyrazolo[3,4267.1 [M-pyrazolo[3,4- 56+H]+, -b]pyridine b]pyridin-2-+with tert-ESI , RT yl}methyl)azeti = 0.98 butyl 3- dine-1- (S1). (bromometh carboxylate yl)azetidine- 1- carboxylate34 2‐{3‐[(tert‐6-chloro-1H- M / Z:1H NMR (400 butyldimethylsi pyrazolo[3,4326.2 MHz, DMSO-d6) lyl)oxy]propyl} -b]pyridine [M+H]+,δ = 8.51 (s, 1H),‐6‐chloro‐2H‐with (3-ESI+, RT8.29 (d, J = 8.6pyrazolo[3,4‐ bromopropo = 1.33 Hz, 1H), 7.14 (d, b]pyridine xy)-tert- (S1).J = 8.6 Hz, 1H),butyldimeth4.51 (t, J = 7.0ylsilane Hz, 2H), 3.62 (t, J= 6.1 Hz, 2H),2.13 (quin, J =6.5 Hz, 2H), 0.87 (s, 9H).35 4‐{6‐chloro‐6-chloro-1H- M / Z:1H NMR (400 2H‐ pyrazolo[3,4286.1 MHz, CDCl3) δ pyrazolo[3,4‐ -b]pyridine [M+H]+,= 8.04 – 7.98 (m,b]pyridin‐2‐with 1,1‐ESI+, RT1H), 7.13 (d, J =yl}‐1λ6‐thiane‐ dioxo‐1λ6‐ = 0.80 8.6 Hz, 1H), 4.79 1,1‐dione thian‐4‐yl (S1).(quin, J = 5.6 Hz,methanesulf 1H), 3.68 (dt, J = onate 13.3, 6.2 Hz, (Intermediat1H), 3.16 (dt, J =e 11) 14.1, 6.1 Hz, 1H), 2.77 (q, J =5.9 Hz, 2H).36 rac-3‐({6‐6‐chloro‐1H‐ M / Z: chloro‐2H‐ pyrazolo[3,4266.3 pyrazolo[3,4‐ ‐b]pyrazine [M+H]+, b]pyrazin‐2‐with rac-(1‐ESI+, RT yl}methyl)‐1‐ methyl‐2‐ = 0.65 methylpyrrolidi oxopyrrolidi (S1). n‐2‐one n‐3‐ yl)methyl methanesulf onate (Intermediat e 14)37 rac-4‐({6‐6‐chloro‐1H‐ M / Z: chloro‐2H‐ pyrazolo[3,4266.1 pyrazolo[3,4‐ ‐b]pyrazine [M+H]+, b]pyrazin‐2‐with rac-(1‐ESI+, RT yl}methyl)‐1‐ methyl‐5‐ = 0.66 methylpyrrolidi oxopyrrolidi (S1). n‐2‐one n‐3‐ yl)methyl methanesulf onate (Intermediat e15)38 rac-6‐chloro‐2‐6-chloro-1H- M / Z: {5‐ pyrazolo[3,4278.3 oxaspiro[3.5]n -b]pyridine [M+H]+, onan‐8‐yl}‐2H‐with rac-5‐ESI+, RT pyrazolo[3,4‐ oxaspiro[3.5 = 0.90 b]pyridine ]nonan‐8‐yl (S1). methanesulf onate (In termediate 16)39 rac-3‐({6‐6-chloro-1H- M / Z: chloro‐2H‐ pyrazolo[3,4269.1 pyrazolo[3,4‐ -b]pyridine [M+H]+, b]pyridin‐2‐with rac-(3‐ESI+, RT yl}methyl)‐3‐ fluoro‐1‐ = 0.46 fluoro‐1‐ methylpyrrol (S1). methylpyrrolidi idin‐3‐ ne yl)methyl methanesulf onate (Intermediat e 17)40 rac-3‐({6‐6-chloro-1H- M / Z:1H NMR (400 chloro‐2H‐ pyrazolo[3,4301.1 MHz, DMSO-d6) pyrazolo[3,4‐ -b]pyridine [M+H]+,δ = 8.59 (s, 1H),b]pyridin‐2‐with rac-ESI+, RT8.30 (d, J = 8.6yl}methyl)‐4,4‐ (4,4‐ = 0.45 Hz, 1H), 7.15 (d, difluoro‐1‐ difluoro‐1‐ (S1).J = 8.6 Hz, 1H),methylpiperidi methylpiperi4.74 (dd, J = 4.7,ne din‐3‐ 13.7 Hz, 1H), yl)methyl4.51 (dd, J = 9.2,methanesulf 13.6 Hz, 1H), onate2.88 - 2.74 (m,(Intermediat1H), 2.72 - 2.61e 18) (m, 1H), 2.41 (br d, J = 11.5 Hz,1H), 2.30 - 2.19(m, 1H), 2.15 (s, 3H), 2.18 - 1.93(m, 3H).41 3‐({6‐chloro‐6-chloro-1H- M / Z:1H NMR (400 2H‐ pyrazolo[3,4272.1 MHz, DMSO-d6) pyrazolo[3,4‐ -b]pyridine [M+H]+,δ = 8.64 (s, 1H),b]pyridin‐2‐ with 3- ESI+, RT8.32 (dd, J = 8.5,yl}methyl)‐ (bromometh = 0.66 4.0 Hz, 1H), 7.17 1λ6‐thietane‐ yl)thietane (S1).(d, J = 8.6 Hz,1,1‐dione 1,1-dioxide1H), 4.75 (d, J =7.4 Hz, 2H), 4.34 –4.20 (m, 2H),4.16 – 4.05 (m,2H), 3.26 – 3.13(m, 1H).42 6‐chloro‐2‐(3‐6-chloro-1H- M / Z:1H NMR (400 methoxypropyl pyrazolo[3,4226.1 MHz, DMSO-d6) )‐2H‐ -b]pyridine [M+H]+,δ = 8.53 (s, 1H),pyrazolo[3,4‐ with 1- ESI+, RT8.29 (d, J = 8.6b]pyridine bromo-3- = 0.73 Hz, 1H), 7.14 (d, methoxypro (S1).J = 8.6 Hz, 1H),pane4.50 (t, J = 7.0Hz, 2H), 3.33 (d, J= 6.1 Hz, 2H),3.24 (s, 3H), 2.16 (tt, J = 7.0, 6.1Hz, 2H).43 6‐chloro‐4‐6-chloro-4- M / Z:1H NMR (400 (difluoromethy (difluoromet 288.2 MHz, DMSO-d6) l)‐2‐(oxan‐4‐ hyl)-1H- [M+H]+,δ = 8.34 (d, J =yl)‐2H‐ pyrazolo[3,4 ESI+, RT 1.3 Hz, 1H), 7.68 pyrazolo[3,4‐ -b]pyridine = 0.87– 7.26 (m, 2H),b]pyridine with 4- (S1).5.07 (tt, J = 11.6,bromooxane 4.3 Hz, 1H), 4.07 –3.97 (m, 2H),3.61 (td, J =12.0, 2.1 Hz, 2H), 2.26 – 2.11(m, 2H), 1.98 – 1.88 (m, 2H).44 4‐{6‐chloro‐6-chloro-1H- M / Z:1H NMR (500 2H‐ pyrazolo[3,4240.3 MHz, CDCl3) δ pyrazolo[3,4‐ -b]pyridine [M+H]+,= 8.00 - 7.92 (m,b]pyridin‐2‐ with 4‐ ESI+, RT2H), 7.06 (d, J =yl}‐2‐ bromo‐2‐ = 0.69 8.6 Hz, 1H), 4.63 methylbutan‐2‐ methylbutan (S1).- 4.57 (m, 2H),ol ‐2‐ol2.26 - 2.21 (m,(Intermediat 2H), 1.31 (s, 6H) e 10)45 6‐chloro‐4‐6‐chloro‐4‐ M / Z:1H NMR (400 methoxy‐2‐ methoxy‐ 268.1 MHz, DMSO-d6) (oxan‐4‐yl)‐ 1H‐ [M+H]+,δ = 8.59 (s, 1H),2H‐ pyrazolo[3,4 ESI+, RT 6.64 (s, 1H), 4.69 pyrazolo[3,4‐ ‐b]pyridine = 0.77(ddd, J = 14.7,b]pyridine (Intermediat (S1). 9.9, 4.7 Hz, 1H), e24) with 4-4.02 (s, 5H), 3.50 bromooxane(td, J = 11.3, 3.8Hz, 2H), 2.08 (td, J= 10.2, 4.1 Hz,4H).46 rac-tert‐butyl6-chloro-1H- M / Z:1H NMR (400 N F ClNN3‐({6‐chloro‐ pyrazolo[3,4313.1 [M- MHz, DMSO-d6) O N 2H‐ -b]pyridine tBu]+,δ = 8.49 (s, 1H),O pyrazolo[3,4‐with rac-ESI+, RT 8.32 (d, J = 8.7 b]pyridin‐2‐ tert-butyl 3- = 1.03 Hz, 1H), 7.17 (d, yl}methyl)‐3‐ (bromometh (S1). J = 8.6 Hz, 1H), fluoropiperidin yl)-3-fluoro-4.88 - 4.64 (m,e‐1‐carboxylate piperidine-1- 2H), 3.81 (br d, J carboxylate = 12.7 Hz, 1H), 3.71 (br s, 1H), 3.15 (br s, 1H), 2.84 (br s, 1H), 1.79 - 1.61 (m,2H), 1.60 - 1.49(m, 2H), 1.44 - 1.20 (m, 9H)47 cis methyl 3‐6-chloro-1H- M / Z:1H NMR (400 {6‐chloro‐2H‐ pyrazolo[3,4266.2 MHz, DMSO-d6) pyrazolo[3,4‐ -b]pyridine [M+H]+,δ = 8.59 (s, 1H),b]pyridin‐2‐ with cis ESI+, RT8.27 (d, J = 8.6yl}cyclobutane methyl 3‐ = 0.81 Hz, 1H), 7.14 (d, ‐1‐carboxylate (methanesulf (S1).J = 8.6 Hz, 1H),onyloxy)cycl5.16 (quin, J =obutane‐1‐ 8.3 Hz, 1H), 3.66 carboxylate (s, 3H), 3.13 (Intermediat(quin, J = 9.0 Hz,e 19)1H), 2.87 - 2.72(m, 4H).48 trans methyl 3‐6-chloro-1H- M / Z:1H NMR (400 {6‐chloro‐2H‐ pyrazolo[3,4266.2 MHz, DMSO-d6) pyrazolo[3,4‐ -b]pyridine [M+H]+,δ = 8.62 (s, 1H),b]pyridin‐2‐ with cis ESI+, RT8.28 (d, J = 8.6yl}cyclobutane methyl 3‐ = 0.84 Hz, 1H), 7.14 (d, ‐1‐carboxylate (methanesulf (S1).J = 8.6 Hz, 1H),onyloxy)cycl5.37 (quin, J =obutane‐1‐ 7.8 Hz, 1H), 3.69 carboxylate (s, 3H), 3.38 - (Intermediat 3.32 (m, 1H), e 19)2.98 - 2.87 (m,2H), 2.85 - 2.72(m, 2H)49 rac-6‐chloro‐2‐6-chloro-1H- M / Z:1H NMR (400 (2,2‐ pyrazolo[3,4266.1 MHz, DMSO-d6) dimethyloxan‐ -b]pyridine [M+H]+,δ = 8.60 (s, 1H),4‐yl)‐2H‐with rac-2,2‐ESI+, RT8.28 (d, J = 8.6pyrazolo[3,4‐ dimethyloxa = 0.85 Hz, 1H), 7.13 (d, b]pyridine n‐4‐yl (S1).J = 8.6 Hz, 1H),methanesulf 4.97 (s, 1H), 3.85 onate– 3.72 (m, 2H),(Intermediat2.09 – 1.90 (m,e 20) 4H), 1.30 (s, 3H), 1.23 (s, 3H).50 (2R)‐2‐({6‐6-chloro-1H- M / Z: chloro‐2H‐ pyrazolo[3,4267.1 pyrazolo[3,4‐ -b]pyridine [M+H]+, b]pyridin‐2‐with [(2R)‐ESI+, RT yl}methyl)‐4‐ 4‐ = 0.38 methylmorphol methylmorp (S1). ine holin‐2‐ yl]methyl methanesulf onate (Intermediat e 21)51 (2S)‐2‐({6‐6-chloro-1H- M / Z: chloro‐2H‐ pyrazolo[3,4267.1 pyrazolo[3,4‐ -b]pyridine [M+H]+, b]pyridin‐2‐with [(2S)‐4‐ESI+, RTIn 1:2 mixture with the yl}methyl)‐4‐ methylmorp = 0.38 other regioisomer methylmorphol holin‐2‐ (S1). ine yl]methyl methanesulf onate (Intermediat e 22) 52 trans-2‐[3‐6-chloro-1H- M / Z:1H NMR (500 (benzyloxy)cyc pyrazolo[3,4314.1 MHz, DMSO-d6) lobutyl]‐6‐ -b]pyridine [M+H]+,δ = 8.60 (s, 1H),chloro‐2H‐with cis-3‐ESI+, RT8.27 (d, J = 8.5pyrazolo[3,4‐ (benzyloxy)c = 1.12 Hz, 1H), 7.43 - b]pyridine yclobutyl (S1). 7.24 (m, 5H), methanesulf7.14 (d, J = 8.5onate Hz, 1H), 5.34 (tt, (IntermediatJ = 5.3, 8.5 Hz,e 23)1H), 4.54 - 4.48(m, 1H), 4.47 (s, 2H), 2.83 - 2.72(m, 2H), 2.69 - 2.61 (m, 2H) 53 ethyl 1‐({6‐6-chloro-1H- M / Z:1H NMR (400 chloro‐2H‐ pyrazolo[3,4280.3 MHz, DMSO-d6) pyrazolo[3,4‐ -b]pyridine [M+H]+,δ = 8.52 (s, 1H),b]pyridin‐2‐with ethyl 1-ESI+, RT8.29 (d, J = 8.6yl}methyl)cycl (bromometh = 0.91 Hz, 1H), 7.13 (d, opropane‐1‐ yl)cycloprop (S1).J = 8.6 Hz, 1H),carboxylate anecarboxyl 4.68 (s, 2H), 4.02 ate(q, J = 7.1 Hz,2H), 1.28 (s, 4H), 1.10 (t, J = 7.1Hz, 3H)

[0198] Scheme for route 10:Intermediate 54: 2-{6-chloro-2H-pyrazolo[3,4-b]pyridin-2-yl}ethan-1-olStep 10.a

[0199] In a microwave vial, 6-chloro-1H-pyrazolo[3,4-b]pyridine (200 mg, 1.3 mmol)and 2-bromoethoxy-tert-butyl-dimethyl-silane (0.56 mL, 2.60 mmol) were dissolved in DMF(4.2 mL), then Cs2CO3 (853 mg, 2.60 mmol) was added. The vial was sealed and heated at 110°C for 20 h. Water was added to the reaction mixture, and it was extracted with EtOAc. Theorganic layer was dried over a phase separator and evaporated to afford a mixture ofregioisomers, partial silyl deprotection was observed for both. This material was used as such in the next step. Step 10.b

[0200] The material obtained in step a was dissolved in THF (7 mL), cooled at 0 °C,then 1 M TBAF in THF (1.28 mL, 1.28 mmol) was added. The mixture was allowed to stir atr.t. for 2 h.

[0201] Volatiles were evaporated and the crude product was purified bychromatography on silica gel (0-50% MeOH in DCM) to yield the title compound (50 mg, 0.25mmol, 73% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ = 8.49 (s, 1H), 8.28 (d, J= 8.6 Hz, 1H), 7.13 (d, J = 8.6 Hz, 1H), 4.97 (t, J = 5.4 Hz, 1H), 4.47 (t, J = 5.4 Hz, 2H), 3.87(q, J = 5.3 Hz, 2H). MS (ESI); M / Z: 198.2 [M+H]+, ESI+, RT = 0.54 (S1).

[0202] Scheme for route 11:

[0203] In a Parr autoclave, palladium over carbon, 10% wt (429 mg, 0.40 mmol) wasadded to a solution of 2,6-dimethylpyran-4-one (1.0 g, 8.06 mmol) in ethanol (30 mL). Thereaction was held at 6 bar hydrogen and stirred vigorously at r.t. for 3 h. The reaction wasfiltered over a pad of celite® and the filtrate was concentrated in vacuo to yield the titlecompound as 80:20 mixture of isomers (709 mg, 5.45 mmol, 68% yield) as yellow oil. Majorisomer ((2R,4r,6S)‐ 2,6‐dimethyloxan‐4‐ol) characterization 1H NMR (500 MHz, CDCl3) δ =3.83 - 3.77 (m, 1H), 3.50 - 3.42 (m, 2H), 1.93 (dd, J = 4.7, 11.5 Hz, 2H), 1.26 - 1.21 (m, 6H),1.14 (q, J = 11.4 Hz, 2H). Minor isomer ((2R,4s,6S)‐ 2,6‐dimethyloxan‐4‐ol) characterization1H NMR (500 MHz, CDCl3) δ = 4.27 - 4.19 (m, 1H), 3.97 - 3.88 (m, 2H), 1.68 - 1.62 (m, 2H),1.49 - 1.41 (m, 2H), 1.18 - 1.15 (m, 6H).

[0204] Intermediate 55: 6-chloro-2-[(2R,6S)-2,6-dimethyloxan-4-yl]-2H-pyrazolo[3,4-b]pyridineStep 11.b

[0205] Methanesulfonyl chloride (0.23 mL, 3 mmol) was added dropwise to an icecooled solution of (2R,6S)-2,6-dimethyloxan-4-ol (mixture of isomers 80:20 from Step 11.a,300 mg, 2.3 mmol) and TEA (0.96 mL, 6.91 mmol) in DCM (9 mL). When the addiction wascomplete the reaction mixture was allowed to warm to r.t. and it was stirred for 1h. Volatileswere removed in vacuo, the crude material was taken-up with EtOAc, that was washed withwater (2x). The organic phase was filtered through a phase separator and evaporated in vacuo. This material was used as such in the next step. Step 11.c

[0206] Intermediate 55 (31 mg, 0.58 mmol, 18% yield) was synthesised as mixture ofisomers 20:80 according to the procedure exemplified by Intermediate 25 using 6-chloro-1H- pyrazolo[3,4-b]pyridine (100 mg, 0.65 mmol), and the mesylate compound obtained in Step 11.b (271 mg, 1.3 mmol). Major isomer (6‐chloro‐2‐[(2R,4s,6S)‐2,6‐dimethyloxan‐4‐yl]‐2H‐pyrazolo[3,4‐b]pyridine) 1H NMR (400 MHz, DMSO-d6) δ = 8.58 (s, 1H), 8.27 (br d, J = 8.3Hz, 1H), 7.13 (br d, J = 8.6 Hz, 1H), 4.92 - 4.70 (m, 1H), 3.72 - 3.59 (m, 2H), 2.12 (br. dd., J =4.2, 11.8 Hz, 2H), 1.83 - 1.64 (m, 2H), 1.19 (d, J = 6.1 Hz, 6H). Minor isomer (6‐chloro‐2‐[(2R,4r,6S)‐2,6‐dimethyloxan‐4‐yl]‐2H‐pyrazolo[3,4‐b]pyridine) 1H NMR (400 MHz, DMSO-d6) δ = 8.70 (s, 1H), 8.28 (d, J = 8.6 Hz, 1H), 7.15 (d, J = 8.6 Hz, 1H), 4.97 (br s, 1H), 3.89 -3.73 (m, 2H), 2.34 (br d, J = 13.0 Hz, 2H), 1.84 - 1.70 (m, 2H), 1.10 (d, J = 6.2 Hz, 6H); M / Z:266.1 [M+H]+, ESI+, RT = 0.88, 0.90 (S1).

[0207] Scheme for route 12:Intermediate 56: rac-3‐({6‐chloro‐2H‐pyrazolo[3,4‐b]pyridin‐2‐yl}methyl)‐ 1‐ethylpiperidine

[0208] 6-chloro-1H-pyrazolo[3,4-b]pyridine (120 mg, 0.78 mmol) was dissolved inDMF (2 mL) and cooled with an ice bath, NaH (60% dispersion in oil) (31 mg, 0.78 mmol) was added and stirred until gas evolution ceased. The solution became dark brown, then a solution of rac-(1‐ethylpiperidin‐3‐yl)methyl methanesulfonate (Intermediate 12, 207 mg, 0.94 mmol) in DMF (1 mL) was added dropwise and the resulting mixture was heated at 100 °C for 90 min. The reaction was cooled, diluted with water, and extracted with EtOAc (3x). Organic phaseswere washed with brine, dried and evaporated. The crude material was purified by reverse chromatography on C18 cartridge (0-5% of ACN +0.1% HCOOH in H2O+0.1% HCOOH) toyield the title compound (32 mg, 0.11 mmol, 15% yield) as sticky colourless oil, the regioisomerwas also isolated. 1H NMR (400 MHz, CDCl3) δ = 8.42 (s, 1H), 8.11 (s, 1H), 8.02 (d, J = 8.6Hz, 1H), 7.10 (d, J = 8.6 Hz, 1H), 4.49 (quin, J = 5.2 Hz, 2H), 3.27 (s, 2H), 2.99 – 2.79 (m,3H), 2.63 – 2.52 (m, 2H), 2.07 – 1.79 (m, 4H), 1.28 (t, J = 7.3 Hz, 3H). MS (ESI); M / Z: 279.3[M+H]+, ESI+, RT = 0.43 (S1).

[0209] Intermediate compounds in Table 6 were synthesised according to the generalroute 12 as exemplified by Intermediate 56 using the corresponding startingmaterials / intermediates. Table 6 IntermeStructure Name StartingLCMS1H NMR diate materials data 57 rac-3-({6- 6‐chloro‐1H‐ M / Z: chloro-2H- pyrazolo[3,4‐ 252.2 pyrazolo[3,4- b]pyrazine [M+H]+, b]pyrazin-2- with rac-(1‐ ESI+, RT In 1:2 mixture with the yl}methyl)-1- methylpyrroli = 0.71 other regioisomer methylpyrrolidi din‐3‐ (S2). ne yl)methyl methanesulfo nate (Intermediate 13) 58 rac-3‐({6‐6-chloro-1H- M / Z:1H NMR (400 chloro‐2H‐ pyrazolo[3,4- 224.1 MHz, DMSO-d6) pyrazolo[3,4‐ b]pyridine [M+H]+, δ = 8.59 (s, 1H), b]pyridin‐2‐ with rac-(1‐ ESI+, RT8.29 (d, J = 8.6yl}methyl)‐1‐ methylpyrroli = 0.69 Hz, 1H), 7.16 (d, J methylpyrrolidi din‐3‐ (S2). = 8.6 Hz, 1H), ne yl)methyl5.40 (ddt, J = 8.1,methanesulfo 6.5, 3.4 Hz, 1H),nate4.15 – 4.00 (m,(Intermediate 3H), 3.90 (td, J = 13) 8.3, 5.3 Hz, 1H), 2.61 – 2.52 (m,1H), 2.48 – 2.32(m, 1H). 59 rac-3‐({6‐ 6‐chloro‐1H‐ M / Z: chloro‐2H‐ pyrazolo[3,4‐ 280.3 pyrazolo[3,4‐ b]pyrazine [M+H]+, In 1:1.5 mixture with b]pyrazin‐2‐ with rac-(1‐ ESI+, RT the other regioisomer yl}methyl)‐1‐ ethylpiperidin = 0.37 ethylpiperidine ‐3‐yl)methyl (S1). methanesulfo nate (Intermediate 12)

[0210] Scheme for route 13:Intermediate 60: 4-{6-chloro-2H-pyrazolo[3,4-b]pyrazin-2-yl}piperidine

[0211] A mixture of tert‐butyl 4‐{6‐chloro‐2H‐pyrazolo[3,4‐b]pyrazin‐2‐yl}piperidine‐1‐carboxylate (Intermediate 32, 39 mg, 0.12 mmol) and TFA (0.01 mL, 0.12mmol) in DCM (2 mL) was stirred at r.t. for 20 min, then volatiles were removed. The crudematerial was dissolved in MeOH, loaded on a 5g SCX, washed with MeOH and eluted withammonia solution 2M in MeOH. The basic fraction was evaporated to the yield title compound(27 mg, 0.11 mmol, 98% yield) as yellowish solid.1H NMR (400 MHz, DMSO-d6) δ = 9.00 (s,1H), 8.64 (s, 1H), 5.76 (s, 1H), 4.63 (tt, J= 11.6, 4.3 Hz, 1H), 3.10 (d, J= 12.5 Hz, 2H), 2.64(dd, J= 12.4, 2.6 Hz, 2H), 2.08 (d, J= 12.3 Hz, 2H), 2.01 – 1.93 (m, 2H). M / Z: 238.3 [M+H]+,ESI+, RT = 0.33 (S1).

[0212] Intermediate compound in Table 7 was synthesised according to the generalroute 13 as exemplified by Intermediate 60 using the corresponding startingmaterials / intermediates. Table 7 IntermStructure Name StartingLCMS1H NMR ediate materials data 61 4‐{6‐chloro‐ tert‐butyl 4‐{6‐ M / Z: 2H‐ chloro‐2H‐ 237.1 pyrazolo[3,4‐ pyrazolo+In 1:2 mixture with the [3,4‐ [M+H] , b]pyridin‐2‐ b]p+other regioisomer yridin‐2‐ ESI , RT yl}piperidine yl}piperidine‐ =0.41 1‐carboxylate (S1). (Intermediate 31)

[0213] Scheme for route 14:Intermediate 62: 3‐({6‐chloro‐2H‐pyrazolo[3,4‐b]pyridin‐2‐yl}methyl)‐1-methanesulfonylazetidineIntermediate 62Step 14.a

[0214] TFA (0.4 mL, 5.27 mmol) was added to a solution of tert-butyl 3-({6-chloro-2H-pyrazolo[3,4-b]pyridin-2-yl}methyl)azetidine-1-carboxylate (Intermediate 33, 170 mg,0.53 mmol) in DCM (6 mL). The solution was stirred at r.t. for 1 h, then volatiles were removedin vacuo.Step 14.b

[0215] The material obtained in step a was dissolved with DCM (4 mL), cooled at 0°C, DIPEA (0.28 mL, 1.58 mmol) was added followed by dropwise addiction ofmethanesulfonyl chloride (0.04 mL, 0.58 mmol). After stirring at the same temperature for 10min the reaction was partitioned between water and DCM. Organic phase was collected, dried and evaporated. The crude material was purified by chromatography on silica gel (0-50%EtOAc / EtOH 3 / 1 in cHex) to yield the title compound (130 mg, 0.43 mmol, 82% yield) as paleyellow solid, it was used as such in the next step. M / Z: 301.2 [M+H]+, ESI+, RT = 0.71 (S1).

[0216] Scheme for route 15:Intermediate 63: 4-{6-chloro-2H-pyrazolo[3,4-b]pyridin-2-yl}-1-methanesulfonylpiperidine

[0217] 4‐{6‐chloro‐2H‐pyrazolo[3,4‐b]pyridin‐2‐yl}piperidine (Intermediate 61, in1:2 mixture with the other regioisomer 200 mg, 0.84 mmol) was dissolved in DCM (3 mL).DIPEA (0.33 mL, 1.86 mmol) was added. At 0 °C, methanesulfonyl chloride (116 mg, 1.01 mmol) was added and the reaction mixture was brought to r.t. and stirred for 4 h. EtOAc was added followed by brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated to afford a crude which was purified by reverse chromatography on C18 cartridge(0-80% of ACN+0.1% HCOOH in H2O+0.1% HCOOH) to the yield title compound (23 mg,0.07 mmol, 8% yield). 1H NMR (500 MHz, DMSO-d6) δ = 8.62 (s, 1H), 8.29 (d, J = 8.6 Hz,1H), 7.15 (d, J = 8.5 Hz, 1H), 4.71 (tt, J = 4.1, 11.3 Hz, 1H), 3.72 (br.d., J = 12.3 Hz, 2H), 3.00(dt, J = 2.6, 12.1 Hz, 2H), 2.95 (s, 3H), 2.29 - 2.21 (m, 2H), 2.19 - 2.10 (m, 2H). M / Z: 315.3[M+H]+, ESI+, RT = 0.74 (S1).

[0218] Intermediate compounds in Table 8 were synthesised according to the generalroute 15 as exemplified by Intermediate 63 using the corresponding startingmaterials / intermediates. Table 8 IntermeStructure Name StartingLCMS1H NMR diate materials data 64 4‐{6‐chloro‐2H‐4‐{6‐chloro‐2H‐ M / Z:1H NMR (400 pyrazolo[3,4‐ pyrazolo[3,4‐ 329.2 MHz, DMSO-d6) b]pyridin‐2‐yl}‐ b]pyridin‐2‐ [M+H]+, δ = 8.62 (s, 1H), 1‐ yl}piperidine ESI+, RT7.16 (d, J = 8.6 Hz,(ethanesulfonyl) (Intermediate 61) =0.791H), 4.74 (tt, J =piperidine with (S1). 11.3, 4.1 Hz, 1H), ethanesulfonyl3.78 (d, J = 12.3chloride Hz, 3H), 3.21 – 3.04 (m, 5H), 2.27 –2.15 (m, 2H),2.17 – 1.95 (m,2H), 1.26 (t, J =7.3 Hz, 3H) 65 4‐{6‐chloro‐2H‐4‐{6‐chloro‐2H‐ M / Z: pyrazolo[3,4‐ pyrazolo[3,4‐ 355.2 b]pyridin‐2‐yl}‐ b]pyridin‐2‐ [M+H]+, 1‐ yl}piperidine ESI+, RT (cyclobutanesulf (Intermediate 61) =0.90 onyl)piperidine with (S1).cyclobutanesulfo nyl chloride66 1-(4-{6-chloro-4‐{6‐chloro‐2H‐ M / Z:1H NMR (500 2H- pyrazolo[3,4‐ 309.2 MHz, DMSO-d6) pyrazolo[3,4- b]pyridin‐2‐ [M+H]+,δ = 8.60 - 8.56 (m,b]pyridin-2- yl}piperidine ESI+, RT1H), 8.30 - 8.24yl}piperidin-1- (Intermediate 61) =0.66 (m, 1H), 7.18 - yl)-2- with (S1). 7.08 (m, 1H), 4.88 methoxyethan- methoxyacetyl- 4.74 (m, 1H),1-one chloride4.23 - 4.07 (m,2H), 4.52 - 3.83(m, 2H), 3.32 - 3.31 (m, 3H), 3.25 -2.75 (m, 2H),2.22 - 1.80 (m, 4H)67 1‐(4‐{6‐chloro‐4-{6-chloro-2H- M / Z:1H NMR (400 2H‐ pyrazolo[3,4- 310.2 MHz, MeOD-d4) δ pyrazolo[3,4‐ b]pyrazin-2- [M+H]+, = 8.71 (s, 1H), b]pyrazin‐2‐ yl}piperidine ESI+, RT 8.54 (s, 1H), 4.88 yl}piperidin‐1‐ (Intermediate 60) =0.64(td, J = 7.0, 3.4 Hz,yl)‐2‐ with (S1).1H), 4.74 – 4.64methoxyethan‐ methoxyacetyl (m, 1H), 4.21 (t, J 1‐one chloride = 15.0 Hz, 2H), 4.14 – 4.06 (m,1H), 3.43 (s, 3H), 3.42 – 3.40 (m,1H), 2.95 (t, J =12.9 Hz, 1H), 2.33 –2.13 (m, 4H).68 4‐{6‐chloro‐2H‐4‐{6‐chloro‐2H‐ M / Z:1H NMR (400 pyrazolo[3,4‐ pyrazolo[3,4‐ 305.2 MHz, MeOD-d4 ) b]pyridin‐2‐yl}‐ [M+H]+,δ = 8.43 (s, 1H),1‐ b]pyridin‐2‐ ESI+, RT8.21 (d, J = 8.7 Hz,cyclopropanecar yl}piperidine =0.751H), 7.14 (d, J =bonylpiperidine (Intermediate 61) (S1). 8.6 Hz, 1H), 4.89 - with 4.76 (m, 1H), 4.74 cyclopropanecarb- 4.61 (m, 1H),onyl chloride4.60 - 4.41 (m,1H), 3.52 - 3.35(m, 1H), 3.03 - 2.82 (m, 1H), 2.42 -2.00 (m, 4H),2.08 - 1.99 (m,1H), 1.01 - 0.63(m, 4H).69 rac-4‐{6‐4‐{6‐chloro‐2H‐ M / Z:1H NMR (400 chloro‐2H‐ pyrazolo[3,4‐ 335.2 MHz, DMSO-d6) pyrazolo[3,4‐ b]pyridin‐2‐ [M+H]+,δ = 8.61 (s, 1H),b]pyridin‐2‐yl}‐ yl}piperidine ESI+, RT8.29 (d, J = 8.6 Hz,1‐(oxolane‐3‐ (Intermediate 61) =0.691H), 7.15 (d, J =carbonyl)piperid with rac- (S1). 8.6 Hz, 1H), 4.89 – ine tetrahydrofuran- 4.79 (m, 1H), 4.55 3-carbonyl(d, J = 13.4 Hz,chloride1H), 4.15 (d, J =14.1 Hz, 1H), 3.91 (q, J = 7.9 Hz, 1H),3.82 – 3.65 (m,2H), 3.44 (quin, J = 7.6 Hz, 1H), 2.83 (t, J = 12.8Hz, 1H), 2.18 (t, J = 14.2 Hz, 2H), 2.12 – 1.88 (m,2H).

[0219] Scheme for route 16:Intermediate 70: rac-4-{6-chloro-2H-pyrazolo[3,4-b]pyridin-2-yl}-1-(1-methylpyrrolidine-3-carbonyl)piperidine

[0220] DIPEA (0.15 mL, 0.89 mmol), HATU (169 mg, 0.44 mmol) and rac-1-methylpyrrolidine-3-carboxylic acid (46 mg, 0.35 mmol) were mixed in DMF (1.5 mL) andstirred for 10 min, then 4‐{6‐chloro‐2H‐pyrazolo[3,4‐b]pyridin‐2‐yl}piperidine (Intermediate61, 70 mg, 0.300 mmol) was added and stirred at r.t. for 3 h. The reaction mixture was chargedon SCX (5g) washing with MeOH and eluting with 1N NH3 in MeOH. Evaporation of basicfraction afforded the title compound (: 35 mg, 0.10 mmol, 34% yield), as yellow oil. M / Z: 348.2[M+H]+, ESI+, RT =0.47 (S1).

[0221] Intermediate compounds in Table 9 were synthesised according to the generalroute 16 as exemplified by Intermediate 70 using the corresponding startingmaterials / intermediates. Table 9 IntermeStructure Name StartingLCMS1H NMR diate materials data 71 4‐{6‐chloro‐2H‐4‐{6‐chloro‐2H‐ M / Z: pyrazolo[3,4‐ pyrazolo[3,4‐ 323.2 b]pyridin‐2‐yl}‐ b]pyridin‐2‐ [M+H]+, 1‐(1‐ yl}piperidine ESI+, RT fluorocycloprop (Intermediate 61) =0.83 anecarbonyl)pip with 1- (S1) eridine fluorocyclopropane-1-carboxylic acid 72 4‐{6‐chloro‐2H‐4‐{6‐chloro‐2H‐ M / Z: pyrazolo[3,4‐ pyrazolo[3,4‐ 373.2 b]pyridin‐2‐yl}‐ b]pyridin‐2‐ [M+H]+, 1‐[1‐ yl}piperidine ESI+, RT (trifluoromethyl (Intermediate 61) =0.91 )cyclopropanecawith 1-(S1) rbonyl]piperidin (trifluoromethyl) e cyclopropanecarb oxylic acid

[0222] Scheme for route 17:Intermediate 73: 4-{6-chloro-2H-pyrazolo[3,4-b]pyridin2-yl}-1-(3,3-difluoroazetidine-1- carbonyl)piperidine

[0223] CDI (100 mg, 0.62 mmol) was added to a stirred solution of 3,3-difluoroazetidine hydrochloride (64 mg, 0.49 mmol) and TEA (0.07 mL, 0.49 mmol) in DMF (2 mL). The solution was stirred at 65 °C for 2 h. Then 4‐{6‐chloro‐2H‐pyrazolo[3,4‐b]pyridin‐2‐yl}piperidine (Intermediate 61, 110 mg, 0.41 mmol) was added and the reaction mixturecontinued heating at 65 °C. After about 2 h, further 1 eq of 3,3-difluoroazetidine hydrochloride and 1 eq of TEA were added and the reaction mixture was heated to 80 °C overnight. Thereaction was cooled, diluted with water and extracted with EtOAc. The organic layer was driedover a phase separator and evaporated to yield the title compound (0.41 mmol, recoveryassumed quantitative), as yellow oil that was used as such. M / Z: 356.2 [M+H]+, ESI+, RT =0.84(S1).

[0224] Scheme for route 18:

[0225] Step 18.a: rac-tert-butyl 3-fluoro-3-({6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-2H-pyrazolo[3,4-b]pyridin-2-yl}methyl)piperidine-1- carboxylate

[0226] In a suitable vial, a mixture of 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (Intermediate 5, 87 mg, 0.26 mmol), rac-tert‐butyl 3‐({6‐chloro‐2H‐pyrazolo[3,4‐b]pyridin‐2‐yl}methyl)‐3‐fluoropiperidine‐1‐carboxylate(Intermediate 46, 80 mg, 0.22 mmol), Pd(dppf)Cl2 complex with DCM (3 mg, 0.040 mmol) andK3PO4(93 mg, 0.43 mmol) was suspended in 1,2-dimethoxyethane (2 mL) / Water (0.700 mL). The vial was sealed, degassed (N2 / Vacuum) then heated at 110 °C for 1 h. The mixture was diluted with a saturated aqueous NH4Cl solution and extracted with EtOAc. The organic phase was then filtered through a phase separator and concentrated under reduced pressure. The crudematerial was purified by chromatography on silica gel (0-40% EtOAc in cHex) to the yield titlecompound (105 mg, 0.21 mmol, 95% yield). M / Z: 509.2 [M+H]+, ESI+, RT =1.21 (S1).

[0227] Intermediate 74 (Step 18.b): rac-2-{2-[(3-fluoropiperidin-3-yl)methyl]-2H-pyrazolo[3,4-b]pyridin-6-yl}-3-methyl-5-(trifluoromethyl)phenol

[0228] To a solution of rac-tert‐butyl 3‐fluoro‐3‐({6‐[2‐hydroxy‐6‐methyl‐4‐(trifluoromethyl)phenyl]‐2H‐pyrazolo[3,4‐b]pyridin‐2‐yl}methyl)piperidine‐1‐carboxylate (105 mg, 0.21 mmol) in DCM (2 mL), 3 M HCl in CPME (0.34 mL, 1.03 mmol) was added.The reaction was stirred at r.t. for 1.5 h. Volatiles were removed in vacuo. The residual materialwas taken up with MeOH and loaded on SCX (2g, washing with MeOH, and eluting withammonia solution 1M in MeOH) to yield the title compound (60 mg, 0.15 mmol, 71% yield)as brownish solid. 1H NMR (400 MHz, DMSO-d6) δ = 10.08 (s, 1H), 8.39 (d, J = 1.0 Hz, 1H),8.24 (d, J = 8.5 Hz, 1H), 7.08 (t, J = 9.5 Hz, 3H), 4.84 – 4.68 (m, 2H), 2.91 – 2.55 (m, 4H),2.10 (s, 3H), 1.81 – 1.47 (m, 4H). M / Z: 409.2 [M+H]+, ESI+, RT =0.66 (S1).

[0229] Scheme for route 19:

[0230] Step 19.a: 6-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[3,4-b]pyrazine and 6-chloro-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[3,4- b]pyrazine

[0231] NaH (60% dispersion in oil) (714 mg, 17.86 mmol) was added portionwise toan ice-cold solution of 6-chloro-1H-pyrazolo[4,5-b]pyrazine (2.3 g, 14.88 mmol) in DMF (69mL). The mixture was stirred at 0°C for 20 min, then 2-(trimethylsilyl)ethoxymethyl chloride (2.9 mL, 16.37 mmol) was added dropwise. The reaction mixture was allowed to reach r.t. in 40 min, and then stirred at r.t. for further 40 min. The reaction was quenched with water (450 mL) and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by chromatography on silica gel (0-50% EtOAc in cHex) to the yield title compounds as mixture of regioisomers. (3.15 g, 11.06mmol, 74% yield) as a yellowish oil. M / Z: 285.2 [M+H]+, ESI+, RT = 1.16, 1.27 (S1).

[0232] Intermediate 75 and 76 (Step 19.b): 6-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[3,4- b]pyrazine and 6-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-2-{[2- (trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[3,4-b]pyrazine

[0233] A mixture of 2‐[2‐methoxy‐6‐methyl‐4‐(trifluoromethyl)phenyl]‐4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolane (Intermediate 6, 3.85 g, 12.17 mmol), Pd(dppf)Cl2 complexwith DCM (905 mg, 1.11 mmol) and K3PO4 (2.35 g, 11.06 mmol) was submitted to 3 vacuum / N2cycles, then a solution of 6‐chloro‐1‐{[2‐(trimethylsilyl)ethoxy]methyl}‐1H‐pyrazolo[3,4‐b]pyrazine and 6‐chloro‐2‐{[2‐(trimethylsilyl)ethoxy]methyl}‐2H‐pyrazolo[3,4‐b]pyrazine(3.15 g, 11.06 mmol) in CPME (67 mL) was added, followed by water (27 mL). The mixturewas degassed again, and then stirred over night at 90 °C. Reaction mixture was left to reach r.t.,then water and EtOAc were added. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were dried over a phase separator and evaporated. The crude materialwas purified by chromatography on silica gel (0-25% EtOAc in cHex) to the yield titlecompound regioisomers. First eluted Intermediate 75 (2.9 g, 6.6 mmol, 60% yield): 1H NMR(400 MHz, DMSO-d6) δ = 8.71 (s, 1H), 8.63 (s, 1H), 7.40 (dt, J = 1.6, 0.8 Hz, 1H), 7.34 (d, J =1.6 Hz, 1H), 5.81 (s, 2H), 3.79 (s, 3H), 3.65 – 3.58 (m, 2H), 2.16 (s, 3H), 0.83 (dd, J = 8.5, 7.5Hz, 2H), -0.13 (s, 9H). M / Z: 439.4 [M+H]+, ESI+, RT = 1.45 (S1). Second eluted Intermediate76 (0.94 g, 2.15 mmol, 19% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.59 (s, 1H),7.40 (d, J = 1.7 Hz, 1H), 7.34 (s, 1H), 5.83 (s, 2H), 3.81 (s, 3H), 3.75 – 3.68 (m, 2H), 2.18 (s,3H), 0.96 – 0.87 (m, 2H), -0.07 (s, 9H). M / Z: 439.4 [M+H]+, ESI+, RT = 1.35 (S1).

[0234] Scheme for route 20:

[0235] Step 20.a: 6-chloro-2-[(4-methoxyphenyl)methyl]-2H-pyrazolo[3,4-b]pyrazine

[0236] A mixture of K2CO3 (4912 mg, 3.56 mmol), 6-chloro-1H-pyrazolo[3,4-b]pyrazine (330 mg, 2.14 mmol) and 4-methoxybenzyl chloride (0.29 ml, 2.14 mmol) in ACN (8.9 mL) was stirred at 60 °C for 4 h. After this time the reaction was cooled down to r.t.,water was added, and the reaction was extracted with EtOAc (3x). The combined organicfractions were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Theresidue was purified by chromatography on silica gel (0-70% EtOAc in cHex) to yield thetitle compound 225 mg, 0.82 mmol, 38% yield).1H NMR (400 MHz, DMSO-d6) δ = 9.03 (s,1H), 8.63 (s, 1H), 7.23 (dt, J = 8.7, 0.7 Hz, 2H), 6.90 – 6.86 (m, 2H), 5.64 (s, 2H), 3.74 (s,3H). M / Z: 275.2 [M+H]+, ESI+, RT = 0.94 (S1).

[0237] Intermediate 77 (Step 20.b): 6-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-2-[(4-methoxyphenyl)methyl]-2H-pyrazolo[3,4-b]pyrazine

[0238] Title compound (Intermediate 77, 250 mg, 0.58 mmol, 75% yield) wassynthesised according to the procedure exemplified by Intermediate 75 (Step 19.b) using 6‐chloro‐2‐[(4‐methoxyphenyl)methyl]‐2H‐pyrazolo[3,4‐b]pyrazine (214 mg, 0.78 mmol), and2-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Intermediate 6, 246 mg, 0.78 mmol). 1H NMR (400 MHz, DMSO-d6) δ = 8.97 (s, 1H), 8.53(s, 1H), 7.47 – 7.40 (m, 2H), 7.40 – 7.36 (m, 1H), 7.31 (s, 1H), 7.27 – 7.19 (m, 2H), 5.66 (s,2H), 3.78 (s, 3H), 3.74 (s, 3H), 2.15 (s, 3H). M / Z: 429.3 [M+H]+, ESI+, RT = 1.21 (S1).

[0239] Scheme for route 21:Method AIntermediate 76 Method AIntermediate 78Method B

[0240] Intermediate 78: 6-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyrazineIntermediate 78Method A

[0241] 1 M TBAF in THF (6.74 mL, 6.74 mmol) was added to a solution of 6‐[2‐methoxy‐6‐methyl‐4‐(trifluoromethyl)phenyl]‐2‐{[2‐(trimethylsilyl)ethoxy]methyl}‐2H‐pyrazolo[3,4‐b]pyrazine (Intermediate 76, 640 mg, 2.25 mmol) in THF (32 mL). The reactionmixture was stirred overnight at 70 °C. Volatiles were removed and the residual material wasdissolved in EtOAc. A saturated aqueous solution of NaHCO3 was added and phases wereseparated, the organic one was dried over Na2SO4, filtered and concentrated, the crude materialwas purified by chromatography on silica gel (5-40% EtOAc in cHex) to yield the titlecompound (296 mg, 0.96 mmol, 43% yield) as white solid.

[0242] NOTE: the procedure has been exemplified for one regioisomer, however it canbe applied also to the other regioisomer Intermediate 75 to yield Intermediate 78. Method B

[0243] A solution of 6-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-2-[(4-methoxyphenyl)methyl]-2H-pyrazolo[3,4-b]pyrazine (Intermediate 77, 410 mg, 0.96 mmol) inDCM (2 mL) and TFA (5 mL) was stirred overnight at 70 °C. The day after the reaction wascooled down to r.t. and concentrated in vacuo. The residue was purified by chromatography onsilica gel (0-80% EtOAc / EtOH 3 / 1 in cHex) to yield the title compound (230 mg, 0.75 mmol,78% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 8.57 (s, 1H), 8.50 (s, 1H), 7.39(d, J = 1.4 Hz, 1H), 7.32 (s, 1H), 3.78 (s, 3H), 2.15 (s, 3H). M / Z: 309.2 [M+H]+, ESI+, RT =1.00 (S1).

[0244] Scheme for route 22:

[0245] Step 22.a: tert-butyl 4-{6-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-2H-pyrazolo[3,4‐b]pyrazin-2-yl}piperidine-1-carboxylate

[0246] A mixture of 6‐[2‐methoxy‐6‐methyl‐4‐(trifluoromethyl)phenyl]‐1H‐pyrazolo[3,4‐b]pyrazine (Intermediate 78, 760 mg, 2.47 mmol), 4-bromo-1-piperidinecarboxylic acid tert-butyl ester (977 mg, 3.7 mmol) and Cs2CO3 (1600 mg, 4.93mmol) in ACN (16.5 mL) was stirred over night at 70 °C. Volatiles were removed andH2O / EtOAc were added. Phases were separated, the organic one washed with brine, dried overNa2SO4, filtered, and concentrated in vacuo. The crude material was purified bychromatography on silica gel (0-10% EtOAc in cHex) to yield the title compound (209 mg,0.42 mmol, 17% yield) as-yellowish oil. 1H NMR (400 MHz, DMSO-d6) δ = 8.97 (s, 1H), 8.54(s, 1H), 7.39 (dd,J= 1.7, 0.8 Hz, 1H), 7.32 (d,J= 1.6 Hz, 1H), 4.82 (tt,J= 11.4, 4.1 Hz, 1H), 4.14(d,J= 13.3 Hz, 2H), 3.79 (s, 3H), 3.01 (s, 2H), 2.17 (s, 5H), 2.08 – 2.01 (m, 2H), 1.45 (s, 9H).M / Z: 492.4 [M+H]+, ESI+, RT = 1.24 (S1).

[0247] Intermediate 79 (Step 22.b): 4-{6-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-2H-pyrazolo[3,4-b]pyrazin-2-yl}piperidineIntermediate 79

[0248] Title compound (Intermediate 79, 145 mg, 0.37 mmol, 87% yield) wassynthesised according to the procedure exemplified by Intermediate 60 starting from tert‐butyl4‐{6‐[2‐methoxy‐6‐methyl‐4‐(trifluoromethyl)phenyl]‐2H‐pyrazolo[3,4‐b]pyrazin‐2‐yl}piperidine‐1-carboxylate (209 mg, 0.43 mmol). 1H NMR (400 MHz, DMSO-d6 ) δ = 8.93(s, 1H), 8.52 (s, 1H), 7.38 (s, 1H), 7.31 (s, 1H), 4.64 (tt, J = 4.2, 11.4 Hz, 1H), 3.78 (s, 3H),3.12 (br. d., J = 12.5 Hz, 2H), 2.67 (dt, J = 2.3, 12.2 Hz, 2H), 2.71 (br. s., 1H), 2.16 (s, 3H),2.14 - 2.07 (m, 2H), 2.07 - 1.94 (m, 2H). M / Z: 392.4 [M+H]+, ESI+, RT = 0.66 (S1).

[0249] Scheme for route 23:

[0250] Intermediate 80: 1-(ethanesulfonyl)-4-{6-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-2H-pyrazolo[3,4-b]pyrazin-2-yl}piperidine

[0251] DIPEA (0.07 mL, 0.39 mmol) was added to a solution of 4‐{6‐[2‐methoxy‐6‐methyl‐4‐(trifluoromethyl)phenyl]‐2H‐pyrazolo[3,4‐b]pyrazin‐2‐yl}piperidine (Intermediate79, 70 mg, 0.18 mmol) in DCM (2 mL). The solution was cooled at 0 °C, ethanesulfonylchloride (0.02 mL, 0.21 mmol) was added, then the reaction mixture was brought to r.t. andstirred for 2 h. EtOAc was added followed by water. The organic layer was separated, driedover Na2SO4, filtered, and concentrated in vacuo. The crude material was purified bychromatography on silica gel (20-100% EtOAc in cHex) to yield the title compound (47 mg,0.10 mmol, 54% yield) as white solid. 1H NMR (500 MHz, DMSO-d6) δ = 8.99 (s, 1H), 8.55(s, 1H), 7.39 (d, J = 1.4 Hz, 1H), 7.32 (d, J = 1.6 Hz, 1H), 4.86 – 4.77 (m, 1H), 3.79 (s, 5H),3.20 – 3.10 (m, 4H), 2.33 – 2.20 (m, 2H), 2.17 (s, 4H). M / Z: 484.3 [M+H]+, ESI+, RT = 1.08(S1).

[0252] Intermediate compounds in Table 10 were synthesised according to thegeneral route 23 as exemplified by Intermediate 80 using the corresponding startingmaterials / intermediates. Table 10 IntermeStructure Name StartingLCMS1H NMR diate materials data 81 1‐4‐{6‐[2‐ M / Z:1H NMR (400 methanesulfon methoxy‐6‐ 470.4 MHz, DMSO-d6) yl‐4‐{6‐[2‐ methyl‐4‐ [M+H]+, δ = 9.00 (s, 1H), methoxy‐6‐ (trifluoromet ESI+, RT 8.55 (s, 1H), 7.39 methyl‐4‐ hyl)phenyl]‐ =1.04 (dt, J = 1.5, 0.8 (trifluoromethy 2H‐ (S1). Hz, 1H), 7.32 (d, l)phenyl]‐2H‐ pyrazolo[3,4‐J = 1.6 Hz, 1H),pyrazolo[3,4‐ b]pyrazin‐2‐4.85 – 4.73 (m,b]pyrazin‐2‐ yl}piperidine 1H), 3.79 (s, 5H), yl}piperidine (Intermediate3.05 (td, J =79) with12.1, 2.8 Hz, methanesulfo 2H), 2.98 (s, 3H), nyl chloride2.32 (t, J = 7.9Hz, 2H), 2.29 – 2.19 (m, 2H), 2.17 (s, 3H).82 1‐4‐{6‐[2‐ M / Z:1H NMR (400 cyclopropanec methoxy‐6‐ 460.3 MHz, CDCl3) δ arbonyl‐4‐{6‐ methyl‐4‐ [M+H]+, = 8.54 (s, 1H), [2‐methoxy‐6‐ (trifluoromet ESI+, RT 8.32 (s, 1H), 7.25 methyl‐4‐ hyl)phenyl]‐ =1.07 (s, 1H), 7.10 (d, J (trifluoromethy 2H‐ (S1). = 1.6 Hz, 1H), l)phenyl]‐2H‐ pyrazolo[3,4‐4.78 (tt, J = 11.2,pyrazolo[3,4‐ b]pyrazin‐2‐ 4.2 Hz, 2H), 4.57 b]pyrazin‐2‐ yl}piperidine– 4.39 (m, 1H),yl}piperidine (Intermediate 3.81 (s, 3H), 3.51 79) with – 3.35 (m, 1H),cyclopropane3.04 – 2.86 (m,carbonyl 1H), 2.30 (s, 6H), chloride1.83 (tt, J = 8.0,4.7 Hz, 1H), 1.28 (t, J = 7.1 Hz, 1H), 1.06 (dt, J =6.3, 3.2 Hz, 2H), 0.84 (dq, J = 7.0,3.9 Hz, 2H).

[0253] Scheme for route 24:Intermediate 83: rac-4-{6-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-2H-pyrazolo[3,4-b]pyrazin-2-yl}-1-(1-methylpyrrolidine-carbonyl)piperidine

[0254] Intermediate 83 (65 mg, 0.13 mmol, 72% yield) was synthesised according tothe general route 16 using 4‐{6‐[2‐methoxy‐6‐methyl‐4‐(trifluoromethyl)phenyl]‐2H‐pyrazolo[3,4‐b]pyrazin‐2‐yl}piperidine (Intermediate 79, 70 mg, 0.18 mmol) and rac-1-methylpyrrolidine-3-carboxylic acid (28 mg, 0.21 mmol). M / Z: 503.4 [M+H]+, ESI+, RT =0.69 (S1).

[0255] Scheme for route 25:

[0256] Intermediate 84: 2-(2-{3-[(tert‐butyldimethylsilyl)oxy]propyl}-2H-pyrazolo[3,4-b]pyridin-6-yl)-3-methyl-5-(trifluoromethyl)phenol

[0257] In a suitable vial, a mixture of 2‐{3‐[(tert‐butyldimethylsilyl)oxy]propyl}‐6‐chloro‐2H‐pyrazolo[3,4‐b]pyridine (Intermediate 34, 173 mg, 0.53 mmol) and 3-methyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (Intermediate 5, 214mg, 0.64 mmol), Pd(dppf)Cl2 complex with DCM (43 mg, 0.05 mmol) and K3PO4 (343 mg,1.59 mmol) was suspended in 1,4-dioxane (6.5 mL) / Water (1.2 mL). The vial was sealed, degassed (N2 / Vacuum) then heated at 90 °C for 1 h. The mixture was diluted with water and extracted with EtOAc (3x). The organic phase was then filtered through a phase separator and concentrated under reduced pressure. The crude material was purified by chromatography onsilica gel (0-20% EtOAc in cHex) to yield the title compound (171 mg, 0.37 mmol, 69%yield).1H NMR (400 MHz, DMSO-d6) δ = 8.45 (s, 1H), 8.22 (d, J = 8.5 Hz, 1H), 7.13 – 6.99(m, 3H), 4.53 (t, J = 7.0 Hz, 2H), 3.66 (t, J = 6.0 Hz, 2H), 2.22 – 2.06 (m, 6H), 0.89 (s, 10H),0.05 (s, 6H). M / Z: 466.4 [M+H]+, ESI+, RT = 1.46 (S1).

[0258] Intermediate compounds in Table 11 were synthesised according to the generalroute 25 as exemplified by Intermediate 84 using the corresponding startingmaterials / intermediates.Table 11 IntermStructure Name StartingLCMS1H NMR ediate materials data 85 cis methyl 3‐cis methyl 3‐{6‐ M / Z:1H NMR (400 O N {6‐[2‐hydroxy‐ chloro‐2H‐ 406.2 MHz, DMSO-d6) NNO FC OH6‐methyl‐4‐ pyrazolo[3,4‐ [M+H]+,δ =10.08 (s, 1H),(trifluoromethy b]pyridin‐2‐ ESI+, RT8.53 (d, J = 0.9l)phenyl]‐2H‐ yl}cyclobutane‐ =1.06 Hz, 1H), 8.21 pyrazolo[3,4‐ 1‐carboxylate (S1).(dd, J = 8.4, 1.8b]pyridin‐2‐ (Intermediate Hz, 1H), 7.17 – yl}cyclobutane 47) with 3- 7.01 (m, 3H), ‐1‐carboxylate methyl-2-5.18 (quin, J =(4,4,5,5- 8.3 Hz, 1H), 3.67 tetramethyl- (s, 3H), 3.14 (p, J 1,3,2- = 8.8 Hz, 1H), dioxaborolan- 2.76 (s, 4H), 2.10 2-yl)-5- (s, 3H). (trifluoromethy l)phenol (Intermediate 5) 86O Ntrans methyl 3‐trans methyl 3‐ M / Z: NNO FC OH{6‐[2‐hydroxy‐ {6‐chloro‐2H‐ 406.2 6‐methyl‐4‐ pyrazolo[3,4‐ [M+H]+, (trifluoromethy b]pyridin‐2‐ ESI+, RT l)phenyl]‐2H‐ yl}cyclobutane‐ =1.08 pyrazolo[3,4‐ 1‐carboxylate (S1). b]pyridin‐2‐ (Intermediate yl}cyclobutane 48) with 3- ‐1‐carboxylate methyl-2- (4,4,5,5- tetramethyl- 1,3,2- dioxaborolan- 2-yl)-5-(trifluoromethy l)phenol (Intermediate 5) 87 trans-2‐{2‐[3‐trans-2‐[3‐ M / Z: (benzyloxy)cyc (benzyloxy)cyc 454.2 lobutyl]‐2H‐ lobutyl]‐6‐ [M+H]+, pyrazolo[3,4‐ chloro‐2H‐ ESI+, RT b]pyridin‐6‐ pyrazolo[3,4‐ =1.27 yl}‐3‐methyl‐ b]pyridine (S1). 5‐ (Intermediate (trifluoromethy 52) with 3- l)phenol methyl-2- (4,4,5,5- tetramethyl- 1,3,2- dioxaborolan- 2-yl)-5- (trifluoromethy l)phenol (Intermediate 5)Intermediate compounds in Table 12 were synthesised according to the general route 4 asexemplified by Intermediate 5 using the corresponding starting materials / intermediates.Table 12 IntermeStructure Name StartingLCMS1H NMR diate materials data 88 3,5‐dimethyl‐2‐2-bromo-3,5- M / Z:1H NMR (400 O B (4,4,5,5‐ dimethylpheno 249.1 MHz, DMSO-d6) O tet+OH ramethyl‐ l [M+H] , δ =8.74 (s, 1H), 1,3,2‐ ESI+, RT = 6.43 (s, 1H), 6.38 dioxaborolan‐ 1.03 (S3). (s, 1H), 2.24 (s, 2‐yl)phenol 3H), 2.16 (s, 3H), 1.29 (s, 12H) 89 5‐chloro‐3‐5-chloro-2- M / Z: O Cl B methyl‐2‐ iodo-3-methyl- 184.9 [M- O (4- -OH ,4,5,5‐ phenol H], ESI, tetramethyl‐ RT = 0.82 1,3,2‐ (S1). dioxaborolan‐ 2‐yl)phenol 90 5‐ 5- M / Z:1H NMR (400 (difluoromethy (difluoromethy283.1 [M-MHz, DMSO-d6) l)‐3‐methyl‐2‐ l)-2-iodo-3- H]-, ESI-,δ = 9.46 (s, 1H),F (4,4,5,5‐ methyl-phenol RT = 4.02,6.87 (t, J = 20.3F tetramethyl‐4.09 (S4).Hz, 1H), 6.82 – O B 1,3,2‐ 6.71 (m, 3H), O dioxaborolan‐ 2.28 (s, 3H), 2.26 OH 2‐yl)phenol and(s, 2H), 1.30 (s, 2:1 mixture 3‐ 12H), 1.28 (s, (difluoromethy 6H). l)‐5‐methyl‐2‐ (4,4,5,5‐ tetramethyl‐ 1,3,2‐ dioxaborolan‐ 2‐yl)phenol91 5‐fluoro‐3‐5-fluoro-2- M / Z:1H NMR (400 methyl‐2‐ iodo-3-methyl- 253.4 MHz, DMSO-d6) (4,4,5,5‐ phenol [M+H]+,δ = 9.40 (s, 1H),tetramethyl‐ ESI+, RT =6.48 – 6.40 (m,1,3,2‐1.07 (S3). 1H), 6.40 – 6.32dioxaborolan‐ (m, 1H), 2.27 (s, 2‐yl)phenol 3H), 1.29 (s, 12H).Intermediate compounds in Table 13 were synthesised according to the general route 7 asexemplified by Intermediate 11 using the corresponding starting materials / intermediates.Table 13 IntermeStructure Name StartingLCMS1H NMR diate materials data 92 rac oxepan‐4‐ylrac-oxepan-4- No1H NMR (400 MHz, methanesulfonate ol LCMS DMSO-d6) δ = 4.87 available(tq, J = 8.0, 3.9 Hz,1H), 3.69 – 3.49 (m,4H), 3.19 (s, 3H), 2.13 – 2.03 (m, 1H),2.03 – 1.85 (m, 3H),1.79 (dddd, J = 17.5,11.3, 5.3, 3.0 Hz, 1H), 1.72 – 1.58 (m,1H). 93 trans-3‐trans-3- M / Z:1H NMR (400 MHz, (benzyloxy)cyclo benzyloxycycl 257.1 DMSO-d6) δ = 7.40 butyl obutanol [M+H]+,– 7.24 (m, 5H), 5.14methanesulfonate ESI+, RT(p, J = 6.1 Hz, 1H),= 0.99 4.39 (s, 2H), 4.24 (p, (S1).J = 5.4 Hz, 1H), 3.16(s, 3H), 2.49 – 2.42(m, 4H).94 [(3R)‐4‐[(3R)-4- M / Z: methylmorpholin‐ methylmorpho 210.1 3‐yl]methyl lin-3- [M+H]+, methanesulfonate yl]methanol ESI+, RT = 0.15 (S1). 95 rac-tert‐butyl 4,4‐rac-tert-butyl M / Z:1H NMR (400 MHz, difluoro‐3‐ 4,4-difluoro- 274.0 CDCl3) δ = 4.53 (dd, [(methanesulfonyl 3- [M-56]+,J = 10.4, 4.3 Hz,oxy)methyl]piperi (hydroxymeth ESI+, RT1H), 4.20 (dd, J =dine‐1‐ yl)piperidine- = 1.01 10.4, 8.7 Hz, 1H), carboxylate 1-carboxylate (S1).3.92 (d, J = 14.0 Hz,1H), 3.33 – 3.12 (m,2H), 3.08 (s, 3H), 2.40 (ddq, J = 18.6,9.1, 4.6 Hz, 1H), 2.13 – 1.84 (m, 2H),1.50 (s, 9H). 96 tert butyl (3S)‐3‐(S)-tert-butyl M / Z: [(methanesulfonyl 3- 224.1 oxy)methyl]pyrrol (hydroxymeth [M-56]+, idine‐1‐ yl)pyrrolidine- ESI+, RT carboxylate 1-carboxylate = 0.89 (S1). 97 tert butyl (3R)‐3‐(R)-tert-butyl M / Z: [(methanesulfonyl 3- 224.1 oxy)methyl]pyrrol (hydroxymeth [M-56]+, idine‐1‐ yl)pyrrolidine- ESI+, RT carboxylate 1-carboxylate = 0.90 (S1).Intermediate compounds in Table 14 were synthesised according to the general route 9 asexemplified by Intermediate 25 using the corresponding starting materials / intermediates.Table 14 IntermeStructure Name StartingLCMS1H NMR diate materials data 98 rac-6‐chloro‐2‐6-chloro-1H- M / Z: (oxepan‐4‐yl)‐ pyrazolo[3,4 252.1 2H‐ -b]pyridine [M+H]+, pyrazolo[3,4‐with racESI+, RT b]pyridine oxepan‐4‐yl = 0.78 methanesulf (S1). onate (Intermediat e 92) 99 6‐chloro‐2‐6-chloro-1H- M / Z:1H NMR (400 [(oxan‐4‐ pyrazolo[3,4 252.1 MHz, DMSO-d6) yl)methyl]‐2H‐ -b]pyridine [M+H]+,δ = 8.52 (s, 1H),pyrazolo[3,4‐ with 4- ESI+, RT8.29 (d, J = 8.7b]pyridine bromomethy = 0.75 Hz, 1H), 7.13 (d, ltetrahydrop (S1).J = 8.7 Hz, 1H),yran4.36 (d, J = 7.2Hz, 2H), 3.82 (br. dd., J = 2.2, 11.5Hz, 2H), 3.25 (dt, J= 2.4, 11.5 Hz,2H), 2.30 - 2.17(m, 1H), 1.41 - 1.34 (m, 2H), 1.33 - 1.22 (m,2H) 100 cis-2‐[3‐6-chloro-1H- M / Z:1H NMR (500 (benzyloxy)cyc pyrazolo[3,4314.1 MHz, DMSO-d6) lobutyl]‐6‐ -b]pyridine [M+H]+, δ = 8.59 (s, 1H), chloro‐2H‐with trans-3‐ESI+, RT =8.26 (d, J = 8.6(benzyloxy)c 1.08 (S1). Hz, 1H), 7.42 -pyrazolo[3,4‐ yclobutyl 7.26 (m, 5H), b]pyridine methanesulf7.14 (d, J = 8.6onate Hz, 1H), 4.94 - (Intermediat 4.77 (m, 1H), e 93) 4.47 (s, 2H), 4.01 (quin, J = 7.1 Hz,1H), 2.95 - 2.82(m, 2H), 2.64 - 2.54 (m, 2H) 101 (3R)‐3‐({6‐ 6-chloro-1H- M / Z: chloro‐2H‐ pyrazolo[3,4210.1 pyrazolo[3,4‐ -b]pyridine [M+H]+, b]pyridin‐2‐ with [(3R)‐4‐ ESI+, RT In 1:1.2 mixture with the yl}methyl)‐4‐ methylmorp = 0.37 other regioisomer methylmorphol holin‐3‐ (S1). ine yl]methyl methanesulf onate (Intermediat e 94)102 rac-tert‐butyl6-chloro-1H- M / Z: N F ClNNF 3‐({6‐chloro‐ pyrazolo[3,4331.3 N 2H‐ -b]pyridine [M+H]+, O O pyrazolo[3,4‐ with rac- ESI+, RT b]pyridin‐2‐ tert‐butyl = 1.08 yl}methyl)‐4,4‐ 4,4‐difluoro‐ (S1). difluoropiperid 3‐ ine‐1‐ [(methanesul carboxylate fonyloxy)me thyl]piperidi ne‐1‐ carboxylate (Intermediat e 95)103Nrac-tert‐butyl6‐chloro‐1H‐ M / Z: N F Cl N N 3‐({6‐chloro‐ pyrazolo[3,4300.0 [M- N 2H‐ ‐b]pyrazine 56]+ +O , ESI , O pyrazolo[3,4‐ with tert- RT = 1.02 b]pyrazin‐2‐ butyl 3- (S1). yl}methyl)‐3‐ (bromometh fluoropyrrolidi yl)-3-fluoro- ne‐1‐ pyrrolidine- carboxylate 1- carboxylate104 tert‐butyl (3S)‐6-chloro-1H- M / Z:1H NMR (400 3‐({6‐chloro‐ pyrazolo[3,4281.0 [M-MHz, DMSO-d6) 2H‐ -b]pyridine 56]+, ESI+,δ = 8.56 (d, J =pyrazolo[3,4‐with tertRT = 1.002.2 Hz, 1H), 8.30 b]pyridin‐2‐ butyl (3S)‐3‐ (S1).(dd, J = 2.5, 8.6yl}methyl)pyrr [(methanesul Hz, 1H), 7.15 olidine‐1‐ fonyloxy)me(dd, J = 2.6, 8.6carboxylate thyl]pyrrolid Hz, 1H), 4.56 - ine‐1‐ 4.42 (m, 2H), carboxylate3.30 - 3.00 (m,(Intermediat4H), 2.90 - 2.73e 96) (m, 1H), 1.93 - 1.52 (m, 2H), 1.38 (d, J = 2.1Hz, 9H)105 tert‐butyl (3R)‐6-chloro-1H- M / Z:1H NMR (400 3‐({6‐chloro‐ pyrazolo[3,4281.0 [M-MHz, DMSO-d6) 2H‐ -b]pyridine 56]+, ESI+,δ = 8.56 (d, J =pyrazolo[3,4‐with tertRT = 1.002.2 Hz, 1H), 8.30 b]pyridin‐2‐ butyl (3R)‐3‐ (S1).(dd, J = 2.5, 8.6yl}methyl)pyrr [(methanesul Hz, 1H), 7.15 olidine‐1‐ fonyloxy)me(dd, J = 2.6, 8.6carboxylate thyl]pyrrolid Hz, 1H), 4.56 - ine‐1‐ 4.42 (m, 2H),carboxylate3.30 - 3.00 (m,(Intermediat4H), 2.90 - 2.73e 97) (m, 1H), 1.93 - 1.52 (m, 2H), 1.38 (d, J = 2.1Hz, 9H) 106 rac-ethyl 3‐{6‐6-chloro-1H- M / Z:1H NMR (400 chloro‐2H‐ pyrazolo[3,4268.1 MHz, DMSO-d6) pyrazolo[3,4‐ -b]pyridine [M+H]+,δ = 8.59 (s, 1H),b]pyridin‐2‐with rac-ESI+, RT =8.27 (d, J = 8.6yl}butanoate ethyl 3-0.88 (S1).Hz, 1H), 7.13 (d, bromobutanJ = 8.6 Hz, 1H),oate5.17 – 5.04 (m,1H), 4.07 – 3.89(m, 2H), 3.17 – 2.95 (m, 2H), 1.56 (d, J = 6.7Hz, 3H), 1.06 (t, J = 7.1 Hz, 3H). Scheme for route 26:Intermediate 107: (3S)‐3‐({6‐chloro‐2H‐pyrazolo[3,4‐b]pyridin‐2‐yl}methyl)pyrrolidineTo a solution of tert‐butyl (3S)‐3‐({6‐chloro‐2H‐pyrazolo[3,4‐b]pyridin‐2‐yl}methyl)pyrrolidine‐1‐carboxylate (Intermediate 104, 520 mg, 1.54 mmol) in DCM (7 mL),3N HCl in CPME (2.57 mL, 7.72 mmol) was added. The reaction was stirred at r.t. for 1.5 h.Volatiles were removed under in vacuo. The residue was taken-up in MeOH and loaded onSCX (10 g, washing with MeOH, and eluting with 1M NH3 in MeOH), to yield the titlecompound (322 mg, 1.36 mmol, 88% yield) as a yellow foam. M / Z: 237.1 [M+H]+, ESI+, RT =0.39 (S1).Intermediate compound in Table 15 was synthesised according to the general route 26 asexemplified by Intermediate 107, using the corresponding starting materials / intermediates.Table 15 IntermeStructure Name StartingLCMS1H NMR diate materials data 108 (3R)‐3‐({6‐tert‐butyl M / Z: chloro‐2H‐ (3R)‐3‐({6‐ 237.2 pyrazolo[3,4‐ chloro‐2H‐ [M+H]+, b]pyridin‐2‐ pyrazolo[3,4‐ ESI+, RT yl}methyl)pyrr b]pyridin‐2‐ = 0.38 olidine yl}methyl)py (S1). rrolidine‐1‐ carboxylate (Intermediate 105) Scheme for route 27:Intermediate 109: (3S)‐3‐({6‐chloro‐2H‐pyrazolo[3,4‐b]pyridin‐2‐yl}methyl)‐1‐(oxetan‐3‐yl)pyrrolidineTo a solution of (3S)‐3‐({6‐chloro‐2H‐pyrazolo[3,4‐b]pyridin‐2‐yl}methyl)pyrrolidine(Intermediate 107, 50 mg, 0.21 mmol) in DCM (1 mL), 3-oxetanone (16 µL, 0.25 mmol) wasadded. After stirring 15 min at r.t. Na(OAc)3BH (63 mg, 0.30 mmol) was added, and thereaction was stirred for 1h. The mixture was diluted with DCM and washed with a saturated aqueous solution of NaHCO3(3x) and brine (1x). The organic phase was filtered through aphase separator and concentrated in vacuo to yield the title compound (45 mg, 0.15 mmol, 73%yield) as a yellow solid, that was used as such. M / Z: 293.1 [M+H]+, ESI+, RT = 0.40 (S1).Intermediate compounds in Table 16 was synthesised according to the general route 27 asexemplified by Intermediate 109, using the corresponding starting materials / intermediates.Table 16 IntermeStructure Name StartingLCMS1H NMR diate materials data 110 (3R)‐3‐({6‐(3R)‐3‐({6‐ M / Z:1H NMR (400 chloro‐2H‐ chloro‐2H‐ 293.1 MHz, DMSO-d6) pyrazolo[3,4‐ pyrazolo[3,4‐ [M+H]+,δ = 8.58 (s, 1H),b]pyridin‐2‐ b]pyridin‐2‐ ESI+, RT8.28 (d, J = 8.6yl}methyl)‐1‐ yl}methyl)py = 0.58 Hz, 1H), 7.13 (d, (oxetan‐3‐ rrolidine (S1).J = 8.6 Hz, 1H),yl)pyrrolidine (Intermediate4.54 (t, J = 6.5108) Hz, 2H), 4.42 (td, J= 6.0, 2.1 Hz,4H), 3.59 – 3.48(m, 1H), 2.86 – 2.75 (m, 1H), 2.54 (dd, J = 8.6,5.3 Hz, 1H), 2.47 –2.36 (m, 2H),2.33 – 2.26 (m,1H), 1.93 – 1.80(m, 1H), 1.60 – 1.47 (m, 1H). Scheme for route 28:Intermediate 111: (3S)‐3‐({6‐chloro‐2H‐pyrazolo[3,4‐b]pyridin‐2‐yl}methyl)‐1‐[(3‐fluorooxetan‐3‐yl)methyl]pyrrolidineStep 28.a To an ice-cooled solution of (3-fluorooxetan-3-yl)methanol (29 mg, 0.27 mmol) in DCM (0.85mL), 2,6-dimethylpyridine (34 µL, 0.30 mmol) and Tf2O (44 µL, 0.26 mmol) were added. Thereaction was stirred at 0 °C for 1h. Water was added, phases separated. The organic phase waswashed with water 2x, filtered through a phase separator, and evaporated in vacuo.Step 28.bTo a solution of triflate intermediate obtained in Step 28.a (50 mg, 0.21 mmol) and (3S)‐3‐({6‐chloro‐2H‐pyrazolo[3,4‐b]pyridin‐2‐yl}methyl)pyrrolidine (Intermediate 107, 50 mg, 0.21mmol) in 1,2-dimethoxyethane (0.50 mL), DIPEA (55 µL, 0.32 mmol) was added and thereaction was heated at 80 °C for 2 hrs. After 1h Step 28.a was repeated, and a second portionof triflate intermediate was added (49 mg), dissolved in 0.3 mL of 1,2-dimethoxyethane. Thereaction was stirred at 80 °C for 1h. Volatiles were removed in vacuo and the residue waspurified by reverse chromatography on C18 cartridge (5-45% of ACN in H2O+0.1% NH4OH)to yield title compound (25 mg, 0.08 mmol, 36% yield) as colorless yellow oil.1H NMR (400MHz, DMSO-d6) δ = 8.57 (s, 1H), 8.30 (d, J = 8.6 Hz, 1H), 7.15 (d, J = 8.6 Hz, 1H), 4.65 –4.48 (m, 4H), 4.42 (d, J = 7.5 Hz, 2H), 2.99 – 2.87 (m, 2H), 2.86 – 2.71 (m, 1H), 2.70 – 2.53(m, 3H), 2.44 (dd, J = 9.4, 5.5 Hz, 1H), 1.91 – 1.77 (m, 1H), 1.60 – 1.47 (m, 1H). M / Z: 325.4[M+H]+, ESI+, RT = 0.62 (S2).Scheme for route 29:Intermediate 112: (1‐fluorocyclopropyl)methyl 4‐methylbenzene‐1‐sulfonateTo an ice cooled solution of (1-fluorocyclopropyl)methanol (100 mg, 1.11 mmol) and TEA (0.31 mL, 2.22 mmol) in DCM (3.7 mL), 4-methylbenzenesulfonyl chloride (222 mg, 1.17 mmol) was added portion-wise. The reaction was allowed to reach r.t. and it was stirred for 3 h. The mixture was diluted with DCM and washed with a saturated aqueous solution of NaHCO3and brine (1x). The organic phase was filtered through a phase separator and concentrated in vacuo. The crude product was purified by chromatography on silica gel (0-10%EtOAc in cHex) to yield the title compound (118 mg, 0.48 mmol, 44% yield) as colorless oil,that solidifies upon cooling.1H NMR (400 MHz, CDCl3) δ = 7.86 – 7.78 (m, 2H), 7.39 – 7.31(m, 2H), 4.28 (dt, J = 21.5, 0.7 Hz, 2H), 2.45 (s, 3H), 1.20 – 1.07 (m, 2H), 0.80 – 0.69 (m, 2H).Scheme for route 30:Intermediate 113: (3R)‐3‐({6‐chloro‐2H‐pyrazolo[3,4‐b]pyridin‐2‐yl}methyl)‐1‐[(1‐ fluorocyclopropyl)methyl]pyrrolidineTo a solution of (3R)‐3‐({6‐chloro‐2H‐pyrazolo[3,4‐b]pyridin‐2‐yl}methyl)pyrrolidine(Intermediate 108, 60 mg, 0.25 mmol) and (1‐fluorocyclopropyl)methyl 4‐methylbenzene‐1‐sulfonate (Intermediate 112, 107 mg, 0.33 mmol) in ACN (1.2 mL) / DMF (0.30 mL), DIPEA(0.11 mL, 0.63 mmol) was added and the reaction was stirred at 80 °C for 3 h.Volatiles were removed in vacuo and the residue was purified by. The residue material waspurified by reverse chromatography on C18 cartridge (3-40% of ACN in H2O+0.1% NH4OH)to yield the title compound (22 mg, 0.07 mmol, 28% yield) as colorless glassy solid. M / Z: 309.4[M+H]+, ESI+, RT = 0.75 (S2).Intermediate compounds in Table 17 were synthesised according to the general route 30 asexemplified by Intermediate 113, using the corresponding starting materials / intermediates.Table 17 IntermeStructure Name StartingLCMS1H NMR diate materials data 114 (3S)‐3‐({6‐((3S)‐3‐({6‐ M / Z: chloro‐2H‐ chloro‐2H‐ 309.1 pyrazolo[3,4‐ pyrazolo[3,4‐ [M+H]+, b]pyridin‐2‐ b]pyridin‐2‐ ESI+, RT yl}methyl)‐1‐ yl}methyl)py = 0.47 [(1‐ rrolidine (S1). fluorocyclopro (Intermediate pyl)methyl]pyr107) and (1‐rolidine fluorocyclopr opyl)methyl 4‐ methylbenzen e‐1‐sulfonate (Intermediate 112)115 (3R)‐3‐({6‐(3R)‐3‐({6‐ M / Z:1H NMR (400 chloro‐2H‐ chloro‐2H‐ 325.3 MHz, DMSO-d6) pyrazolo[3,4‐ pyrazolo[3,4‐ [M+H]+,δ = 8.56 (s, 1H),b]pyridin‐2‐ b]pyridin‐2‐ ESI+, RT8.28 (d, J = 8.6yl}methyl)‐1‐ yl}methyl)py = 0.67 Hz, 1H), 7.13 (d, [(3‐ rrolidine (S2).J = 8.6 Hz, 1H),fluorooxetan‐ (Intermediate4.63 – 4.46 (m,3‐ 108) and4H), 4.40 (d, J =yl)methyl]pyrr commercially 7.5 Hz, 2H), 3.02 olidine available (3-– 2.87 (m, 2H),fluorooxetan-2.83 – 2.74 (m,3-yl)methyl1H), 2.68 – 2.524- (m, 3H), 2.43 (dd, methylbenzenJ = 9.4, 5.5 Hz,esulfonate1H), 1.89 – 1.76(m, 1H), 1.58 – 1.45 (m, 1H). Scheme for route 31:Intermediate 116: 3‐({6‐chloro‐2H‐pyrazolo[3,4‐b]pyridin‐2‐yl}methyl)cyclobutan‐1‐olStep 31.a: Methanesulfonyl chloride (0.58 mL, 7.51 mmol) was added dropwise to an ice cooled solution of [3-[tert-butyl(dimethyl)silyl]oxycyclobutyl]methanol (1.25 g, 5.78 mmol) and TEA (2.42 mL, 17.33 mmol) in DCM (25 mL). When the addiction was complete the reaction mixture wasallowed to warm to r.t. and it was stirred for overnight. The mixture was partitioned between water and DCM and extracted with DCM (2x). The organic phase was filtered through a phase separator and evaporated in vacuo. This material was used as such in the next step. Step 31.b:In a vial, 6-chloro-1H-pyrazolo[3,4-b]pyridine (600 mg, 3.91 mmol), and the mesylatecompound obtained in Step 31.a (5.78 mmol) were dissolved in DMF (8 mL), then Cs2CO3(2.55 g, 7.81 mmol) was added, the vial sealed, and the mixture was heated at 110 °C for 4 h. The mixture was diluted with water and EtOAc, the aqueous phase was extracted with EtOAC (3x), organic phases were reunited, dried, and evaporated in vacuo. The crude material was purified by chromatography on silica gel (0-100 % EtOAC in cHex, then 0-30% MeOH inEtOAc) to yield the title compound (90 mg, 0.38 mmol, 10% yield). M / Z: 238.1 [M+H]+, ESI+,RT = 0.66 (S1).Intermediate compounds in Table 18 were synthesised according to the general route 16 asexemplified by Intermediate 70 using the corresponding starting materials / intermediates.Table 18 IntermeStructure Name StartingLCMS1H NMR diate materials data 117 4‐{6‐chloro‐2H‐ 4‐{6‐chloro‐2H‐ M / Z: pyrazolo[3,4‐ pyrazolo[3,4‐ 341.1 b]pyridin‐2‐yl}‐ b]pyridin‐2‐ [M+H]+, 1‐[(1S)‐2,2‐ yl}piperidine ESI+, RT difluorocyclopr (Intermediate 61) =0.84 opanecarbonyl] with (1S)-2,2- (S1) piperidine difluorocyclopro panecarboxylic acid 118 4‐{6‐chloro‐2H‐4‐{6‐chloro‐2H‐ M / Z: pyrazolo[3,4‐ pyrazolo[3,4‐ 341.1 b]pyridin‐2‐yl}‐ b]pyridin‐2‐ [M+H]+, 1‐[(1R)‐2,2‐ yl}piperidine ESI+, RT difluorocyclopr (Intermediate 61) =0.84 (S1)opanecarbonyl] with (1R)-2,2- piperidine difluorocyclopro panecarboxylic acid 119 4‐{6‐chloro‐2H‐4‐{6‐chloro‐2H‐ M / Z: pyrazolo[3,4‐ pyrazolo[3,4‐ 319.1 b]pyridin‐2‐yl}‐ b]pyridin‐2‐ [M+H]+, 1‐(1‐ yl}piperidine ESI+, RT methylcyclopro (Intermediate 61) =0.82 panecarbonyl)piwith 1-(S1) peridine methylcycloprop anecarboxylic acid 120 rac-4‐{6‐4‐{6‐chloro‐2H‐ M / Z:1H NMR (500 chloro‐2H‐ pyrazolo[3,4‐ 355.1 MHz, CDCl3) δ = pyrazolo[3,4‐ b]pyridin‐2‐ [M+H]+,8.01 (d, J = 8.7 Hz,b]pyridin‐2‐yl}‐ yl}piperidine ESI+, RT2H), 7.10 (d, J =1‐(2,2‐difluoro‐ (Intermediate 61) =0.89 8.6 Hz, 1H), 4.92 – 1‐with rac-2,2-(S1) 4.54 (m, 2H), 4.23 methylcyclopro difluoro-1-– 3.96 (m, 1H),panecarbonyl)pi methyl-3.54 – 3.25 (m,peridine cyclopropanecarb1H), 3.02 – 2.84oxylic acid (m, 1H), 2.55 – 2.05 (m, 4H), 2.01 –1.84 (m, 1H),1.49 (s, 3H), 1.39 –1.27 (m, 1H)Scheme for route 32:Intermediate 121: butyl 3‐({6‐chloro‐2H‐pyrazolo[3,4‐b]pyridin‐2‐yl}methyl)oxetane‐3‐ carboxylateK2CO3 (270 mg, 1.95 mmol), methyl 3-(bromomethyl)oxetane-3-carboxylate (0.26 mL, 1.95 mmol), 6-chloro-1H-pyrazolo[3,4-b]pyridine (150 mg, 0.98 mmol) were suspended in 1- butanol (1 mL). The vial was sealed and heated at 100 °C for 48 h. Volatiles were removed in vacuo, water was added to the residue and the mixture was extracted with EtOAc (3x). Thecombined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo. Theresidue was purified by chromatography on silica gel (0-65% EtOAc in cHex) to yield the titlecompound (260 mg, 0.80 mmol, 82% yield) as a colourless oil. M / Z: 324.1 [M+H]+, ESI+, RT=0.99 (S1).Intermediate compounds in Table 19 were synthesised according to the general route 25 asexemplified by Intermediate 84 using the corresponding starting materials / intermediates.Table 19 IntermStructure Name StartingLCMS1H NMR ediate materials data 122 cis-2‐{2‐[3‐cis-2‐[3‐ M / Z:1H NMR (400 (benzyloxy)cyc (benzyloxy)cyc 454.2 MHz, DMSO-d6) lobutyl]‐2H‐ lobutyl]‐6‐ [M+H]+, δ = 10.08 (s, 1H), pyrazolo[3,4‐ chloro‐2H‐ ESI+, RT 8.53 (s, 1H), 8.20 b]pyridin‐6‐ pyrazolo[3,4‐ =1.24(d, J = 8.5 Hz,yl}‐3‐methyl‐ b]pyridine (S1).1H), 7.42 – 7.265‐ (Intermediate (m, 5H), 7.14 – (trifluoromethy100) with 3-7.02 (m, 3H), l)phenol methyl-2-4.93 – 4.80 (m,(4,4,5,5- 1H), 4.49 (s, 2H), tetramethyl- 4.08-4.00 (m,1,3,2- 1H), 2.90 (dtd, J dioxaborolan- = 9.4, 6.9, 2.8 Hz, 2-yl)-5-2H), 2.67 – 2.58(trifluoromethy (m, 2H), 2.10 (s, l)phenol 3H). (Intermediate 5)123 rac-tert‐butylrac-tert‐butyl M / Z: 4,4‐difluoro‐3‐ 3‐({6‐chloro‐ 527.4 ({6‐[2‐ 2H‐ [M+H]+, hydroxy‐6‐ pyrazolo[3,4‐ ESI+, RT methyl‐4‐ b]pyridin‐2‐ =1.24 (trifluoromethy yl}methyl)‐4,4‐ (S1). l)phenyl]‐2H‐ difluoropiperidi pyrazolo[3,4‐ ne‐1‐ b]pyridin‐2‐ carboxylate yl}methyl)pipe (Intermediate ridine‐1‐102) with 3-carboxylate methyl-2- (4,4,5,5- tetramethyl- 1,3,2- dioxaborolan- 2-yl)-5- (trifluoromethy l)phenol (Intermediate 5) 124 rac-tert‐butyl rac-tert‐butyl M / Z: 3‐fluoro‐3‐({6‐ 3‐({6‐chloro‐440.1 [M-[2‐hydroxy‐6‐ 2H‐ 56]+, ESI+, methyl‐4‐ pyrazolo[3,4‐ RT =1.15 In 1:1 mixture with the (trifluoromethy b]pyrazin‐2‐ (S1). other regioisomer l)phenyl]‐2H‐ yl}methyl)‐3‐ pyrazolo[3,4‐ fluoropyrrolidib]pyrazin‐2‐ ne‐1‐ yl}methyl)pyrr carboxylate olidine‐1‐ (Intermediate carboxylate103) with 3-methyl-2- (4,4,5,5- tetramethyl- 1,3,2- dioxaborolan- 2-yl)-5- (trifluoromethy l)phenol (Intermediate 5)125 tert‐butyl 3‐tert-butyl 3- M / Z:1H NMR (400 ({6‐[2‐ ({6-chloro-2H-463.2 [M-MHz, DMSO-d6) hydroxy‐6‐ pyrazolo[3,4- 56]+, ESI+, δ = 10.13 (s, 1H), methyl‐4‐ b]pyridin-2- RT =1.148.53 (s, 1H), 8.23 (trifluoromethy yl}methyl)azeti (S1).(d, J = 8.5 Hz,l)phenyl]‐2H‐ dine-1-1H), 7.13 – 7.02pyrazolo[3,4‐ carboxylate (m, 3H), 4.70 (dd, b]pyridin‐2‐ (IntermediateJ = 7.6, 4.9 Hz,yl}methyl)azeti 33) with 3-2H), 3.93 (d, J =dine‐1‐ methyl-2- 4.7 Hz, 3H), 3.78 carboxylate (4,4,5,5- (s, 2H), 2.09 (s, tetramethyl- 3H), 1.36 (s, 9H). 1,3,2- dioxaborolan- 2-yl)-5- (trifluoromethy l)phenol (Intermediate 5)126 rac- 3‐({6‐6‐chloro‐1H‐ M / Z: chloro‐2H‐ pyrazolo[3,4‐ 302.1 pyrazolo[3,4‐ b]pyrazine with [M+H]+, b]pyrazin‐2‐ rac-(4,4‐ ESI+, RT = yl}methyl)‐4,4‐ difluoro‐1‐0.41 (S1).difluoro‐1‐ methylpiperidin methylpiperidi ‐3‐yl)methyl ne methanesulfona te (Intermediate 18) 127 rac-3‐({6‐6-chloro-3- M / Z: chloro‐3‐ methyl-1H- 315.1 methyl‐2H‐ pyrazolo[3,4- [M+H]+, pyrazolo[3,4‐ b]pyrazine with ESI+, RT = b]pyridin‐2‐ rac-(4,4‐0.48 (S1).yl}methyl)‐4,4‐ difluoro‐1‐ difluoro‐1‐ methylpiperidin methylpiperidi ‐3‐yl)methyl ne methanesulfona te (Intermediate18)Intermediate compounds in Table 20 were synthesised according to the general route 26 asexemplified by Intermediate 107 using the corresponding starting materials / intermediates.Table 20 IntermeStructure Name StartingLCMS1H NMR diate materials data 128 rac-2‐{2‐[(4,4‐rac-tert‐butyl M / Z: difluoropiperid 4,4‐difluoro‐ 427.2 in‐3‐ 3‐({6‐[2‐ [M+H]+, yl)methyl]‐2H‐ hydroxy‐6‐ ESI+, RT pyrazolo[3,4‐ methyl‐4‐ = 0.76 b]pyridin‐6‐ (trifluoromet (S1).yl}‐3‐methyl‐ hyl)phenyl]‐ 5‐ 2H‐ (trifluoromethy pyrazolo[3,4‐ l)phenol b]pyridin‐2‐ yl}methyl)pip eridine‐1‐ carboxylate (Intermediate 123) 129 rac-2‐{2‐[(3‐rac-tert‐butyl M / Z: fluoropyrrolidi 3‐fluoro‐3‐ 396.1 n‐3‐yl)methyl]‐ ({6‐[2‐ [M+H]+, 2H‐ hydroxy‐6‐ ESI+, RT pyrazolo[3,4‐ methyl‐4‐ =0.64 b]pyrazin‐6‐ (trifluoromet (S1). yl}‐3‐methyl‐ hyl)phenyl]‐ 5‐ 2H‐ (trifluoromethy pyrazolo[3,4‐ l)phenol b]pyrazin‐2‐ yl}methyl)py rrolidine‐1‐ carboxylate (Intermediate 124) Scheme for route 33:Step 33.a: 6‐chloro‐1‐{[2‐(trimethylsilyl)ethoxy]methyl}‐1H‐pyrazolo[3,4‐b]pyrazin‐4‐ ium‐4‐olate and 6‐chloro‐2‐{[2‐(trimethylsilyl)ethoxy]methyl}‐2H‐pyrazolo[3,4‐ b]pyrazin‐4‐ium‐4‐olateTo an ice cooled solution of 6-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[3,4- b]pyrazine and 6-chloro-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[3,4-b]pyrazine (2.5 g, 8.78 mmol) in ACN (21 mL) urea hydrogen peroxide (1.73 g, 18.43 mmol) was added followed by a solution of TFAA (2.44 mL, 17.55 mmol) in ACN (4.3 mL). The reaction mixture was allowed to stir at r.t. for 1 h, then a saturated aqueous solution of NaHCO3 and water wereadded to the mixture. The aqueous layer was extracted with DCM (2x), dried over a phase separator, and evaporated to yield the title compound (N1503-52-1: 3.20 g, recovery assumedquantitative) as a light yellow solid.1H NMR (400 MHz, MeOD-d4) δ = 8.42 (d, J = 19.6 Hz,2H), 5.80 (s, 2H), 3.80 – 3.68 (m, 2H), 1.04 – 0.83 (m, 2H), -0.02 (s, 9H). M / Z: 304.4 [M+H]+,ESI+, RT = 1.18 (S1).Step 33.b: 6‐chloro‐5‐methyl‐1‐{[2‐(trimethylsilyl)ethoxy]methyl}‐1H‐pyrazolo[3,4‐b]pyrazine and 6‐chloro‐5‐methyl‐2‐{[2‐(trimethylsilyl)ethoxy]methyl}‐2H‐pyrazolo[3,4‐ b]pyrazineA solution of 6‐chloro‐1‐{[2‐(trimethylsilyl)ethoxy]methyl}‐1H‐pyrazolo[3,4‐b]pyrazin‐4‐ ium‐4‐olate and 6‐chloro‐2‐{[2‐(trimethylsilyl)ethoxy]methyl}‐2H‐pyrazolo[3,4‐b]pyrazin‐4‐ium‐4‐olate (from Step 33.a, 2.24 g, 7.45 mmol) was dissolved in toluene (45 mL) and cooledat -78 °C. MeMgCl 3 M in THF (7.45 mL, 22.34 mmol) was added slowly. The reaction mixturewas stirred at the same temperature for 3 h. NH4Cl, water and EtOAC were added to themixture. The aqueous layer was extracted with EtOAc (3x), dried over a phase separator andevaporated in vacuo. The crude material was purified by chromatography on silica gel (0-10 %EtOAC in cHex), to yield the title compound (819 mg, 2.74 mmol, 37% yield). M / Z: 299.1[M+H]+, ESI+, RT = 1.34 (S1).Step 33.c: 3‐methyl‐2‐(5‐methyl‐1‐{[2‐(trimethylsilyl)ethoxy]methyl}‐1H‐pyrazolo[3,4‐b]pyrazin‐6‐yl)‐5‐(trifluoromethyl)phenol and 3‐methyl‐2‐(5‐methyl‐2‐{[2‐(trimethylsilyl)ethoxy]methyl}‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl)‐5‐ (trifluoromethyl)phenolA mixture of 6‐chloro‐5‐methyl‐1‐{[2‐(trimethylsilyl)ethoxy]methyl}‐1H‐pyrazolo[3,4‐ b]pyrazine and 6‐chloro‐5‐methyl‐2‐{[2‐(trimethylsilyl)ethoxy]methyl}‐2H‐pyrazolo[3,4‐ b]pyrazine (from Step 33.b, 400 mg, 1.34 mmol), K3PO4(284 mg, 1.34 mmol) and 3-methyl- 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (Intermediate 5, 606 mg, 2.01 mmol), the vial was sealed, degassed (N2 / Vacuum), then a solution of Pd(dppf)Cl2 complex with DCM (219 mg, 0.27 mmol) in CPME (8.5 mL)was added, followed by Water (3.5 mL). The mixture was degassed again, and then stirred overnight at 90 °C. The mixture was diluted with water and extracted with EtOAc (3x). The combined organic layers were driedover a phase separator and evaporated in vacuo to yield the title compound (600 mg, recoveryassumed quantitative) that was used as such for next step. M / Z: 439.3 [M+H]+, ESI+, RT =1.37 (S1). Intermediate 130: 3‐methyl‐2‐{5‐methyl‐1H‐pyrazolo[3,4‐b]pyrazin‐6‐yl}‐5‐ (trifluoromethyl)phenolIntermediate 1301 M TBAF in THF (5.3 mL, 5.3 mmol) was added to a solution of 3‐methyl‐2‐(5‐methyl‐1‐{[2‐ (trimethylsilyl)ethoxy]methyl}‐1H‐pyrazolo[3,4‐b]pyrazin‐6‐yl)‐5‐(trifluoromethyl)phenol and 3‐methyl‐2‐(5‐methyl‐2‐{[2‐(trimethylsilyl)ethoxy]methyl}‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl)‐5‐(trifluoromethyl)phenol (from Step 33.c, 581 mg, 1.33 mmol) in THF (30 mL). Thereaction mixture was stirred overnight at 70 °C. Further 1 M TBAF in THF was added and stirred 5h at 80 °C. Volatiles were removed and the residual material was dissolved in EtOAc. A saturated aqueous solution of NaHCO3 was added and phases were separated, the organic one was dried over Na2SO4, filtered and concentrated, the crude material was purified bychromatography on silica gel (0-20% EtOAc in cHex) to yield the title compound (181 mg,0.59 mmol, 44% yield). M / Z: 309.0 [M+H]+, ESI+, RT =0.92 (S1).Scheme for route 34:Intermediate 131: 2‐[2‐(3,6‐dihydro‐2H‐pyran‐4‐yl)‐5‐methyl‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl]‐3‐methyl‐5‐(trifluoromethyl)phenol:To a solution of 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (245 mg, 1.17 mmol) in pyridine (2 mL), 3‐methyl‐2‐{5‐methyl‐1H‐pyrazolo[3,4‐b]pyrazin‐6‐yl}‐ 5‐(trifluoromethyl)phenol (Intermediate 130, 180 mg, 0.58 mmol) and copper(II) acetate monohydrate (58 mg, 0.29 mmol) were added at r.t.. The suspension was heated at 70 °C under oxygen atmosphere overnight. The day after the mixture purified by reverse chromatography on C18 cartridge (5-65% of ACN +0.1% HCOOH in H2O+0.1% HCOOH), then it was purifiedagain was purified by chromatography on silica gel (0-70% EtOAc in cHex) to yield the titlecompound (50 mg, 0.13 mmol, 22% yield) as pale brown solid. 1H NMR (400 MHz, DMSO-d6) δ = 10.36 (br. s., 1H), 9.03 (s, 1H), 7.20 (s, 1H), 7.11 (s, 1H), 6.74 (br. s., 1H), 4.35 (br. d.,J = 2.7 Hz, 2H), 3.95 (t, J = 5.5 Hz, 2H), 2.85 (br. s., 2H), 2.34 (s, 3H), 2.03 (s, 3H). M / Z: 391.1[M+H]+, ESI+, RT = 1.02 (S1).Scheme for route 35:Step 35.a: 5‐methyl‐1H‐pyrazolo[3,4‐b]pyridin‐7‐ium‐7‐olatemCPBA (616 mg, 3.57 mmol) was added portion-wise to a solution of 5-methyl-1H-pyrazolo[5,4-b]pyridine (396 mg, 2.97 mmol) in NMP (2 mL). The reaction was stirred at r.t.for 1 h. MTBE (3 ml) was added, and the mixture was stirred at 0 °C for 20 min. The mixturewas filtered, and the cake was washed with further MTBE (5 mL). The solid was dried in vacuoto yield the title compound (544 mg, recovery assumed quantitative) as a white solid. M / Z:150.0 [M+H]+, ESI+, RT = 0.41 (S1).Intermediate 132 (Step 35.b): 6‐chloro‐5‐methyl‐1H‐pyrazolo[3,4‐b]pyridine and 4‐chloro‐5‐methyl‐1H‐pyrazolo[3,4‐b]pyridine 1:1 ratioIntermediate 1321:1 ratioTo a solution of 5‐methyl‐1H‐pyrazolo[3,4‐b]pyridin‐7‐ium‐7‐olate (from Step 35.a 490 mg,3.29 mmol) in dry DMF (1.5 mL), cooled at 0 °C, was added POCl3 (0.83 mL, 8.87 mmol). Thereaction was allowed to stir at r.t. for 45 minutes. The reaction was cooled at 0 °C and quenchedwith 20% NaOH aqueous solution until pH= 9. The mixture was diluted with water (3 mL) andfiltered. The cake was dried in vacuo to yield the title compound as 1:1 mixture of regioisomers(0.61 g, 1.82 mmol, 55% yield) as a yellow solid. M / Z: 168.0 [M+H]+, ESI+, RT = 0.78, 0.79(S1). Scheme for route 36:Step 36.a: 3‐(1,1‐difluoroethyl)‐5‐methylphenolDAST (5.50 mL, 41.6 mmol) was added dropwise to a stirred solution of 1-(3-hydroxy-5- methyl-phenyl)ethanone (2.50 g, 16.6 mmol) in DCM (50 mL) at 0 °C, the reaction was allowed to reach r.t., and stirred overnight. The day after it was cooled to 0 °C and further DAST (5.50mL, 41.6 mmol) was added and left stirring overnight at r.t. The reaction mixture was addedslowly onto ice cold saturated aqueous solution of NaHCO3. The layers were separated and theaqueous layer was extracted with DCM (2 x). Combined organics were washed with saturated aqueous solution of NaHCO3(50 mL), then brine (50 mL), the organic one was dried over Na2SO4, filtered and concentrated, the crude material was purified by chromatography on silicagel (0-100% EtOAc in Hep) to yield the title compound (569 mg, 3.11 mmol, 19% yield) as ayellow oil.1H NMR (400 MHz, DMSO) δ 9.61 (s, 1H), 6.78 (s, 1H), 6.75 – 6.63 (m, 2H), 1.89(t, J = 18.8 Hz, 3H).Intermediate 133: 5‐(1,1‐difluoroethyl)‐2‐iodo‐3‐methylphenolHydrogen peroxide 50% wt in water (0.352 mL, 6.21 mmol) and iodine (788 mg, 3.11 mmol) were added to a stirring solution of 3-(1,1-difluoroethyl)-5-methylphenol (from Step 36.a, 569 mg, 3.11 mmol) in water (7.0 mL) / THF (4.5 mL), the resulting reaction mixture was stirred at r.t. for 16 h. The reaction was extracted in EtOAc (3 x). The combined organic layers werewashed with brine (25 ml), dried over anhydrous MgSO4, and concentrated in vacuo. The crudematerial was purified by chromatography on silica gel (0-20% EtOAc in Hep) to afford the titlecompound (377 mg, 1.21 mmol, 39% yield) as light brown oil. M / Z: 297 [M-H]-, ESI-, RT =0.98 (S3). 1H NMR (400 MHz, DMSO) δ 10.62 (s,1H), 7.04 – 6.90 (m, 1H), 6.90 – 6.75, (m,1H), 2.41 (s, 3H), 1.90 (t, J = 18.8 Hz, 3H).Intermediate compound in Table 21 were synthesised according to the general route 4 asexemplified by Intermediate 5 using the corresponding intermediate.Table 21 IntermeStructure Name StartingLCMS1H NMR diate materials data 134 5‐(1,1‐5‐(1,1‐ M / Z: no1H NMR (400 difluoroethyl)‐ difluoroethyl)‐ ionisation, MHz, DMSO-d6) 3‐methyl‐2‐ 2‐iodo‐3‐ RT = 1.16δ = 9.38 (s, 1H),(4,4,5,5‐ methylphenol (S3)6.85 – 6.74 (m,tetramethyl‐ (Intermediate1H), 6.71 (d, J =1,3,2‐ 133) 1.5 Hz, 1H), 2.29 dioxaborolan‐(s, 3H), 1.89 (t, J2‐yl)phenol = 18.8 Hz, 3H), 1.31 (s, 12H).Scheme for route 37:Intermediate 135: tert‐butyl 4‐fluoro‐4‐(hydroxymethyl)piperidine‐1‐carboxylateDi-tert-butyl dicarbonate (2.69 g, 12.32 mmol) was added to a stirred solution of (4-fluoro-4-piperidyl)methanol hydrochloride (1.9 g, 11.2 mmol) and TEA (3.12 mL, 22.4 mmol) in DCM(10 mL). The reaction mixture was stirred at r.t. for 6 h. EtOAc was added followed by water.The organic later was separated, dried over Na2SO4filtered and concentrated to afford the titlecompound (2.9 g, 12.32 mmol, recovery assumed quantitative) as a beige solid.1H NMR (400MHz, CDCl3) δ =3.97 (s, 2H), 3.63 (dd, J = 20.3, 6.2 Hz, 2H), 3.13 (t, J = 12.9 Hz, 2H), 1.96 –1.87 (m, 2H), 1.79 (t, J = 6.7 Hz, 1H), 1.68 – 1.62 (m, 1H), 1.49 (s, 9H). M / Z: no ionisation,RT = 0.78 (S1).Scheme for route 38:Intermediate 136Intermediate 136: tert‐butyl (2R)‐4,4‐difluoro‐2‐(2‐hydroxyethyl)pyrrolidine‐1‐carboxylate2M in THF (CH3)2S·BH3 (1.6 mL, 3.2 mmol) was added dropwise to a solution of 2-[(2R)-1-tert-butoxycarbonyl-4,4-difluoro-pyrrolidin-2-yl]acetic acid (500 mg, 1.89 mmol) in THF (8 mL). The mixture was stirred at 65 °C for 3 h. Then it was cooled, diluted with TBME and quenched with slow addition of ss NaHCO3 until gas evolution ceased. Phases were separated, the aqueous one was extracted with further TBME, organic phases were collected, dried andevaporated in vacuo to yield the title compound (420 mg, 1.67 mmol, 89% yield) as colorlessoil. 1H NMR (400 MHz, CDCl3) δ = 4.43 (s, 1H), 3.85 (d, J = 12.7 Hz, 2H), 3.73 – 3.55 (m,3H), 2.60 (dtd, J = 22.6, 13.7, 9.0 Hz, 1H), 2.23 – 2.08 (m, 1H), 1.77 (d, J = 7.1 Hz, 2H), 1.50(s, 9H).Intermediate compounds in Table 22 were synthesised according to the general route 7 asexemplified by Intermediate 11 using the corresponding starting materials / intermediates.Table 22IntermeStructure Name StartingLCMS1H NMR diate materials data 137 tert‐butyl 4‐tert‐butyl 4‐ M / Z:1H NMR (400 MHz, fluoro‐4‐ fluoro‐4‐ 256.1 CDCl3) δ = 4.21 (d, J [(methanesulfonyl (hydroxymethy [M- = 19.9 Hz, 2H), 3.99 oxy)methyl]piperi l)piperidine‐1‐ 56+H]+,(s, 2H), 3.15 – 3.08dine‐1‐ carboxylate ESI+, (m, 2H), 3.07 (s, carboxylate (Intermediate RT =3H), 1.90 (ddd, J =135) 0.95 14.9, 9.6, 2.6 Hz, (S1).2H), 1.67 (d, J =14.4 Hz, 2H), 1.46 (s, 9H). 138 tert‐butyl (3R)‐3‐tert‐butyl (3R)‐ No1H NMR (400 MHz, [(methanesulfonyl 3‐ LCMS CDCl3) δ = 4.18 – oxy)methyl]piperi (hydroxymethy availabl 4.04 (m, 2H), 4.04 – dine‐1‐ l)piperidine‐1‐ e 3.77 (m, 2H), 3.04 carboxylate carboxylate (s, 3H), 2.94 (ddd, J = 13.5, 10.4, 3.3 Hz, 1H), 2.83 (d, J =16.8 Hz, 1H), 1.98 (dqd, J = 6.9, 5.8, 3.5 Hz, 1H), 1.85 (ddt, J = 13.0, 5.2,3.8 Hz, 1H), 1.73 – 1.61 (m, 2H), 1.48 (s, 9H), 1.34 (dtd, J = 13.9, 10.3, 3.9 Hz, 1H). 139 tert‐butyl (3S)‐3‐tert‐butyl (3S)‐ No1H NMR (400 MHz, [(methanesulfonyl 3‐ LCMS CDCl3) δ = 4.18 – oxy)methyl]piperi (hydroxymethy availabl 4.04 (m, 2H), 4.04 – dine‐1‐ l)piperidine‐1‐ e 3.77 (m, 2H), 3.04 carboxylate carboxylate (s, 3H), 2.94 (ddd, J = 13.5, 10.4, 3.3 Hz,1H), 2.83 (d, J =16.8 Hz, 1H), 1.98 (dqd, J = 6.9, 5.8,3.5 Hz, 1H), 1.85 (ddt, J = 13.0, 5.2,3.8 Hz, 1H), 1.73 – 1.61 (m, 2H), 1.48 (s, 9H), 1.34 (dtd, J = 13.9, 10.3, 3.9 Hz, 1H).140 tert‐butyl 3,3‐tert-butyl 3,3- M / Z: difluoro‐5‐ difluoro-5- 274.1 [(methanesulfonyl (hydroxymethy [M- oxy)methyl]piperi l)piperidine-1- 56+H]+, dine‐1‐ carboxylate ESI+, carboxylate RT = 1.01 (S1).141 tert‐butyl 3‐tert-butyl 3- M / Z:1H NMR (400 MHz, fluoro‐3‐ fluoro-3- 284.1DMSO-d6) δ = 4.63[(methanesulfonyl (hydroxymethy [M+H]+(s, 1H), 4.58 (s, 1H), oxy)methyl]azetid l)azetidine-1- , ESI+,4.09 - 3.92 (m, 4 H),ine‐1‐carboxylate carboxylate RT = 3.29 (s, 3H), 1.39 (s, 0.91 9H). (S1).142Ftert‐butyl (2R)‐tert‐butyl (2R)‐ F abs O 4,4‐difluoro‐2‐[2‐ 4,4‐difluoro‐2‐ N S O O O (methanesulfonyl (2‐ O oxy)ethyl]pyrrolid hydroxyethyl)p ine‐1‐carboxylate yrrolidine‐1‐ carboxylate (Intermediate 136)Intermediate compounds in Table 23 were synthesised according to the general route 32 asexemplified by Intermediate 121 using the corresponding starting materials / intermediates.Table 23 IntermeStructure Name StartingLCMS1H NMR diate materials data 143 tert‐butyl 4‐6-chloro-1H- M / Z:1H NMR (400 N F ClN N({6‐chloro‐2H‐ pyrazolo[3,4 313.1 [M-MHz, CDCl3) δ =N pyrazolo[3,4‐ -b]pyridine 56+H]+, 8.03 (d, J = 1.6 OOb]pyridin‐2‐ with tert‐ ESI+, RT Hz, 1H), 7.99 (d, yl}methyl)‐4‐ butyl 4‐ = 1.05J = 8.6 Hz, 1H),fluoropiperidin fluoro‐4‐ (S1).7.07 (d, J = 8.7e‐1‐carboxylate [(methanesul Hz, 1H), 4.58 (d, fonyloxy)meJ = 21.7 Hz, 2H),thyl]piperidi 3.93 (s, 2H), 3.12 ne‐1‐– 2.99 (m, 2H),carboxylate1.82 – 1.69 (m,(Intermediat 2H), 1.63 (s, 2H), e 137), 1.44 (s, 9H).= DME / DMF 1.6 / 1 as solvent 144 tert‐butyl (3S)‐6-chloro-1H- M / Z: 3‐({6‐chloro‐ pyrazolo[3,4351.2 2H‐ -b]pyridine [M+H]+, pyrazolo[3,4‐ with tert‐ ESI+, RT = b]pyridin‐2‐ butyl (3S)‐3‐1.07 (S1).yl}methyl)pipe [(methanesul ridine‐1‐ fonyloxy)me carboxylate thyl]piperidi ne‐1‐ carboxylate (Intermediate 139 ), DMEas solvent145 tert‐butyl (3R)‐6-chloro-1H- M / Z: 3‐({6‐chloro‐ pyrazolo[3,4351.2 2H‐ -b]pyridine [M+H]+, pyrazolo[3,4‐ with tert‐ ESI+, RT = b]pyridin‐2‐ butyl (3R)‐3‐1.07 (S1).yl}methyl)pipe [(methanesul ridine‐1‐ fonyloxy)me carboxylate thyl]piperidi ne‐1‐ carboxylate (Intermediat e138), DMEas solvent146 rac-tert‐butyl6-chloro-1H- M / Z: 5‐({6‐chloro‐ pyrazolo[3,4351.2 2H‐ -b]pyridine [M+H]+, pyrazolo[3,4‐ with rac- ESI+, RT = b]pyridin‐2‐ tert‐butyl1.10 (S1).yl}methyl)‐3,3‐ 3,3‐difluoro‐ difluoropiperid 5‐ ine‐1‐ [(methanesul carboxylate fonyloxy)me thyl]piperidi ne‐1‐ carboxylate (Intermediat e 140) DME / DMF 1.6 / 1 as solvent147 tert‐butyl 3‐6-chloro-1H- M / Z: ({6‐chloro‐2H‐ pyrazolo[3,4285.0 [M-pyrazolo[3,4‐ -b]pyridine 56+H]+, b]pyridin‐2‐with tert‐ESI+, RT = yl}methyl)‐3‐ butyl 3‐1.02 (S1).fluoroazetidine fluoro‐3‐ ‐1‐carboxylate [(methanesul fonyloxy)me thyl]azetidin e‐1‐ carboxylate (Intermediat e141), DMEas solvent148 tert‐butyl (2R)‐6-chloro-1H- M / Z: 2‐(2‐{6‐chloro‐ pyrazolo[3,4387.2 2H- -b]pyridine [M+H]+, pyrazolo[3,4‐with tert‐ESI+, RT = b]pyridin‐2‐ butyl (2R)‐1.12 (S1).yl}ethyl)‐4,4‐ 4,4‐difluoro‐ difluoropyrroli 2‐[2‐ dine‐1‐ (methanesulf carboxylate onyloxy)eth yl]pyrrolidin e‐1‐ carboxylate (Intermediat e 142)149 6‐chloro‐5‐6‐chloro‐5‐ M / Z: methyl‐2‐ methyl‐1H‐ 252.1 (oxan‐4‐yl)‐ pyrazolo[3,4 [M+H]+, 2H‐ ‐b]pyridine ESI+, RT = pyrazolo[3,4‐ and 4‐ 0.80, 0.81 b]pyridine andchloro‐5‐ (S1).4‐chloro‐5‐ methyl‐1H‐ methyl‐2‐ pyrazolo[3,4 (oxan‐4‐yl)‐ ‐b]pyridine 2H‐ 1:1 ratio pyrazolo[3,4‐ (Intermediat b]pyridinee 132) with1:1 ratio 4- bromooxaneIntermediate compounds in Table 24 were synthesised according to the general route 25 asexemplified by Intermediate 84 using the corresponding starting materials / intermediates.Table 24 IntermStructure Name StartingLCMS1H NMR ediate materials data 150 tert‐butyl 4‐tert‐butyl 4‐ M / Z:1H NMR (400 fluoro‐4‐({6‐ ({6‐chloro‐2H‐ 509.3 MHz, CDCl3N ) δ F NN[2‐hydroxy‐6‐ pyrazolo[3,4‐ [M+H]+,= 8.21 (d, J = 8.8F C OH NOmethyl‐4‐ b]pyridin‐2‐ ESI+, RT Hz, 1H), 8.12 (d, O (trifluoromethy yl}methyl)‐4‐ =1.21J = 1.6 Hz, 1H),l)phenyl]‐2H‐ fluoropiperidin (S1).7.35 (d, J = 8.8pyrazolo[3,4‐ e‐1‐carboxylate Hz, 1H), 7.18 (d, b]pyridin‐2‐ (IntermediateJ = 1.6 Hz, 1H),yl}methyl)pipe 143) with 3-7.08 (d, J = 1.9ridine‐1‐ methyl-2- Hz, 1H), 4.65 (d, carboxylate (4,4,5,5-J = 21.8 Hz, 2H),tetramethyl- 3.97 (s, 2H), 3.07 1,3,2- (s, 2H), 2.56 (s, dioxaborolan-3H), 1.87 – 1.632-yl)-5- (m, 4H), 1.45 (s, (trifluoromethy 9H) l)phenol (Intermediate 5)151 rac-tert‐butylrac-tert‐butyl M / Z: 3,3‐difluoro‐5‐ 5‐({6‐chloro‐ 527.2 ({6‐[2‐ 2H‐ [M+H]+, hydroxy‐6‐ pyrazolo[3,4‐ ESI+, RT methyl‐4‐ b]pyridin‐2‐ =1.25 (trifluoromethy yl}methyl)‐3,3‐ (S1). l)phenyl]‐2H‐ difluoropiperidi pyrazolo[3,4‐ ne‐1‐ b]pyridin‐2‐ carboxylate yl}methyl)pipe (Intermediate ridine‐1‐146) with 3-carboxylate methyl-2- (4,4,5,5- tetramethyl- 1,3,2- dioxaborolan- 2-yl)-5- (trifluoromethy l)phenol (Intermediate 5)152 tert‐butyl 3‐tert‐butyl 3‐ M / Z: fluoro‐3‐({6‐ ({6‐chloro‐2H‐ 481.2 [2‐hydroxy‐6‐ pyrazolo[3,4‐ [M+H]+, methyl‐4‐ b]pyridin‐2‐ ESI+, RT (trifluoromethy yl}methyl)‐3‐ =1.20 l)phenyl]‐2H‐ fluoroazetidine‐ (S1). pyrazolo[3,4‐ 1‐carboxylate b]pyridin‐2‐ (Intermediate yl}methyl)azeti 147) with 3- dine‐1‐ methyl-2- carboxylate (4,4,5,5- tetramethyl- 1,3,2- dioxaborolan-2-yl)-5- (trifluoromethy l)phenol (Intermediate 5) 153 tert‐butyl (2R)‐tert‐butyl (2R)‐ M / Z: 4,4‐difluoro‐2‐ 2‐(2‐{6‐chloro‐ 527.2 (2‐{6‐[2‐ 2H- [M+H]+, hydroxy‐6‐ pyrazolo[3,4‐ ESI+, RT methyl‐4‐ b]pyridin‐2‐ =1.26 (trifluoromethy yl}ethyl)‐4,4‐ (S1). l)phenyl]‐2H‐ difluoropyrroli pyrazolo[3,4‐ dine‐1‐ b]pyridin‐2‐ carboxylate yl}ethyl)pyrroli (Intermediate dine‐1‐ 148) with 3- carboxylate methyl-2- (4,4,5,5- tetramethyl- 1,3,2- dioxaborolan- 2-yl)-5- (trifluoromethy l)phenol (Intermediate 5)Intermediate compounds in Table 25 were synthesised according to the general route 26 asexemplified by Intermediate 107 using the corresponding starting materials / intermediates.Table 25 IntermeStructure Name StartingLCMS1H NMR diate materials data 154 (3S)‐3‐({6‐tert‐butyl M / Z: chloro‐2H‐ (3S)‐3‐({6‐ 251.1 chloro‐2H‐ [M+H]+,pyrazolo[3,4‐ pyrazolo[3,4‐ ESI+, RT b]pyridin‐2‐ b]pyridin‐2‐ =0.40 yl}methyl)pipe yl}methyl)pip (S1). ridine eridine‐1‐ carboxylate (Intermediate 144)155 (3R)‐3‐({6‐tert‐butyl M / Z: chloro‐2H‐ (3R)‐3‐({6‐ 251.1 pyrazolo[3,4‐ chloro‐2H‐ [M+H]+, b]pyridin‐2‐ pyrazolo[3,4‐ ESI+, RT yl}methyl)pipe b]pyridin‐2‐ =0.40 ridine yl}methyl)pip (S1). eridine‐1‐ carboxylate (Intermediate 145)156 2‐{2‐[(4‐tert‐butyl 4‐ M / Z:1H NMR (400 fluoropiperidin fluoro‐4‐({6‐ 409.4 MHz, CDCl3) δ ‐4‐yl)methyl]‐ [2‐hydroxy‐ [M+H]+,=8.21 (d, J = 8.72H‐ 6‐methyl‐4‐ ESI+, RT Hz, 1H), 8.12 (d, pyrazolo[3,4‐ (trifluoromet = 0.65J = 1.7 Hz, 1H),b]pyridin‐6‐ hyl)phenyl]‐ (S1).7.34 (d, J = 8.8yl}‐3‐methyl‐ 2H‐ Hz, 1H), 7.18 (d, 5‐ pyrazolo[3,4‐J = 1.8 Hz, 1H),(trifluoromethy b]pyridin‐2‐7.08 (dt, J = 2.0,l)phenol yl}methyl)pip 0.7 Hz, 1H), 4.65 eridine‐1‐(d, J = 21.8 Hz,carboxylate2H), 2.95 (td, J =(Intermediate 11.7, 5.6 Hz, 4H), 150) 2.54 (s, 3H), 1.87 –1.66 (m, 4H).157 rac-2‐{2‐[(5,5‐rac-tert‐butyl M / Z: difluoropiperid 3,3‐difluoro‐ 427.2in‐3‐ 5‐({6‐[2‐ [M+H]+, yl)methyl]‐2H‐ hydroxy‐6‐ ESI+, RT pyrazolo[3,4‐ methyl‐4‐ = 0.67 b]pyridin‐6‐ (trifluoromet (S1). yl}‐3‐methyl‐ hyl)phenyl]‐ 5- 2H‐ (trifluoromethy pyrazolo[3,4‐ l)phenol b]pyridin‐2‐ yl}methyl)pip eridine‐1‐ carboxylate (Intermediate 151)158 2‐{2‐[(3‐tert‐butyl 3‐ M / Z: fluoroazetidin‐ fluoro‐3‐({6‐ 381.1 3‐yl)methyl]‐ [2‐hydroxy‐ [M+H]+, 2H‐ 6‐methyl‐4‐ ESI+, RT pyrazolo[3,4‐ (trifluoromet = 0.67 b]pyridin‐6‐ hyl)phenyl]‐ (S1). yl}‐3‐methyl‐ 2H‐ 5‐ pyrazolo[3,4‐ (trifluoromethy b]pyridin‐2‐ l)phenol yl}methyl)az etidine‐1‐ carboxylate (Intermediate 152)159 2‐(2‐{2‐[(2R)‐tert‐butyl M / Z: 4,4‐ (2R)‐4,4‐ 427.3 difluoropyrroli difluoro‐2‐(2‐ [M+H]+, din‐2‐ {6‐[2‐ ESI+, RT yl]ethyl}‐2H‐ hydroxy‐6‐ = 0.69 pyrazolo[3,4‐ methyl‐4‐ (S1).b]pyridin‐6‐ (trifluoromet yl)‐3‐methyl‐5‐ hyl)phenyl]‐ (trifluoromethy 2H‐ l)phenol pyrazolo[3,4‐ b]pyridin‐2‐ yl}ethyl)pyrr olidine‐1‐ carboxylate (Intermediate 153)Intermediate compounds in Table 26 were synthesised according to the general route 27 asexemplified by Intermediate 109, using the corresponding starting materials / intermediates Table 26 IntermeStructure Name StartingLCMS1H NMR diate materials data 160 (3S)‐3‐({6‐(3S)‐3‐({6‐ M / Z:1H NMR (400 chloro‐2H‐ chloro‐2H‐ 307.1 MHz, CDCl3) δ = pyrazolo[3,4‐ pyrazolo[3,4‐ [M+H]+,8.07 – 7.89 (m,b]pyridin‐2‐ b]pyridin‐2‐ ESI+, RT2H), 7.08 (d, J =yl}methyl)‐1‐ yl}methyl)pip = 0.408.6 Hz, 1H), 4.73 (oxetan‐3‐ eridine (S1).– 4.28 (m, 6H),yl)piperidine3.42 (p, J = 6.5Hz, 1H), 2.44 (d, J = 12.3 Hz, 3H), 2.07 (s, 1H), 1.90 –1.79 (m, 1H),1.79 – 1.62 (m,3H), 1.32 – 1.11(m, 1H). 161 (3R)‐3‐({6‐(3R)‐3‐({6‐ M / Z:1H NMR (400 chloro‐2H‐ chloro‐2H‐ 307.1 MHz, CDCl3) δ = pyrazolo[3,4‐ pyrazolo[3,4‐ [M+H]+,8.07 – 7.89 (m,b]pyridin‐2‐ b]pyridin‐2‐ ESI+, RT2H), 7.08 (d, J =yl}methyl)‐1‐ yl}methyl)pip = 0.40 8.6 Hz, 1H), 4.73 (oxetan‐3‐ eridine (S1).– 4.28 (m, 6H),yl)piperidine (Intermediate3.42 (p, J = 6.5155) Hz, 1H), 2.44 (d, J= 12.3 Hz, 3H),2.07 (s, 1H), 1.90 –1.79 (m, 1H),1.79 – 1.62 (m,3H), 1.32 – 1.11(m, 1H).Intermediate compounds in Table 27 were synthesised according to the general route 30 asexemplified by Intermediate 113, using the corresponding starting materials / intermediates. Table 27 IntermeStructure Name StartingLCMS1H NMR diate materials data 162 (3S)‐3‐({6‐(3S)‐3‐({6‐ M / Z: chloro‐2H‐ chloro‐2H‐ 323.1 pyrazolo[3,4‐ pyrazolo[3,4‐ [M+H]+, b]pyridin‐2‐ b]pyridin‐2‐ ESI+, RT yl}methyl)‐1‐ yl}methyl)pip = 0.47 [(1‐ eridine (S1). fluorocyclopro (Intermediate pyl)methyl]pip154) and (1‐eridine fluorocyclopr opyl)methyl 4‐ methylbenzen e‐1‐sulfonate (Intermediate 112)163 (3R)‐3‐({6‐(3R)‐3‐({6‐ M / Z: chloro‐2H‐ chloro‐2H‐ 323.1 pyrazolo[3,4‐ pyrazolo[3,4‐ [M+H]+, b]pyridin‐2‐ b]pyridin‐2‐ ESI+, RT yl}methyl)‐1‐ yl}methyl)pip = 0.47 [(1‐ eridine (S1). fluorocyclopro (Intermediate pyl)methyl]pip155) and (1‐eridine fluorocyclopr opyl)methyl 4‐ methylbenzen e‐1‐sulfonate (Intermediate 112)164 (3S)‐3‐({6‐(3S)‐3‐({6‐ M / Z:1H NMR (400 chloro‐2H‐ chloro‐2H‐ 339.1 MHz, CDCl3) δ = pyrazolo[3,4‐ pyrazolo[3,4‐ [M+H]+,8.07 – 7.94 (m,b]pyridin‐2‐ b]pyridin‐2‐ ESI+, RT2H), 7.09 (d, J =yl}methyl)‐1‐ yl}methyl)pip = 0.43 8.6 Hz, 1H), 4.85 [(3‐ eridine (S1)– 4.55 (m, 4H),fluorooxetan‐ (Intermediate4.52 – 4.38 (m,3‐ 154) and2H), 3.42 – 2.43yl)methyl]pipe commercially (m, 7H), 1.74 (dd, ridine available (3-J = 13.3, 4.4 Hz,fluorooxetan-3H), 1.32 – 1.133-yl)methyl (m, 1H) 4- methylbenzen esulfonate165 (3R)‐3‐({6‐(3R)‐3‐({6‐ M / Z:1H NMR (400 chloro‐2H‐ chloro‐2H‐ 339.1 MHz, CDCl3) δ = pyrazolo[3,4‐ pyrazolo[3,4‐ [M+H]+,8.07 – 7.94 (m,b]pyridin‐2‐ b]pyridin‐2‐2H), 7.09 (d, J =yl}methyl)‐1‐ yl}methyl)pip ESI+, RT 8.6 Hz, 1H), 4.85 [(3‐ eridine = 0.43– 4.55 (m, 4H),fluorooxetan‐ (Intermediate (S1)4.52 – 4.38 (m,3‐ 155) and2H), 3.42 – 2.43yl)methyl]pipe commercially (m, 7H), 1.74 (dd, ridineavailable (3- J = 13.3, 4.4 Hz,fluorooxetan-3H), 1.32 – 1.133-yl)methyl (m, 1H) 4- methylbenzen esulfonate Scheme for route 39:Intermediate 166 and Intermediate 167: 4,6‐dichloro‐1‐[(4‐methoxyphenyl)methyl]‐1H‐pyrazolo[3,4‐b]pyridine and 4,6‐dichloro‐2‐[(4‐methoxyphenyl)methyl]‐2H-pyrazolo[3,4‐ b]pyridineA mixture of K2CO3 (1.03 g, 7.42 mmol), 4,6-dichloro-1H-pyrazolo[3,4-b]pyridine (0.93 g,4.95 mmol) and 4-methoxybenzyl chloride (0.7 mL, 5.19 mmol) in ACN (23 mL) was stirredat 60 °C for 4 h. After this time the reaction was cooled down to r.t., water was added, and thereaction was extracted with EtOAc(3x). The combined organic phases were washed with Brine,dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified bychromatography on silica gel (0-60% EtOAc in cHex) to yield the title compoundsregioisomers. First eluted Intermediate 166 (650 mg, 2.10 mmol, 43% yield), white powder.M / Z: 308.0 [M]+, ESI+, RT = 1.32 (S1), 1H NMR (400 MHz, CDCl3) δ = 8.08 (s, 1H), 7.39 –7.33 (m, 2H), 7.20 (s, 1H), 6.90 – 6.82 (m, 2H), 5.60 (s, 2H), 3.79 (s, 3H). Second elutedIntermediate 167 (780 mg, 2.53 mmol, 51% yield), yellowish solid. M / Z: 308.0 [M]+, ESI+, RT= 1.14 (S1), 1H NMR (400 MHz, CDCl3) δ = 7.89 (s, 1H), 7.39 – 7.34 (m, 2H), 7.11 (s, 1H),6.97 – 6.92 (m, 2H), 5.55 (s, 2H), 3.84 (s, 3H).Scheme for route 40:Intermediate 168: 2‐{4‐chloro‐2‐[(4‐methoxyphenyl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐5‐(trifluoromethyl)phenolPd(PPh3)4 (167 mg, 0.14 mmol) was added to a mixture of NaHCO3 (695 mg, 8.27 mmol), 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (Intermediate 5, 892 mg, 2.07 mmol), 4,6‐dichloro‐2‐[(4‐methoxyphenyl)methyl]‐2H-pyrazolo[3,4‐b]pyridine (Intermediate 167, 650.0 mg, 2.07 mmol) in DME (12 mL) / Water(3.60 mL). The mixture was degassed bubbling N2 for 5 min then it was heated at 100 °C for 4h. The mixture was partitioned between water and EtOAc. The organic phase was separated,dried, and evaporated, the residual material was triturated with EtOAc, the solid was filtered toyield the title compound (: 500 mg, 1.11 mmol, 54% yield) as white solid.M / Z: 448.1 [M+H]+, ESI+, RT = 1.40 (S1), 1H NMR (400 MHz, DMSO-d6) δ = 8.32 (s, 1H),7.42 (s, 1H), 7.31 – 7.20 (m, 2H), 7.10 (d, J = 12.1 Hz, 2H), 6.94 – 6.81 (m, 2H), 5.61 (s, 2H),3.71 (s, 3H), 2.09 (s, 3H). Scheme for route 41:Intermediate 169: 2‐{4‐cyclopropyl‐2‐[(4‐methoxyphenyl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐5‐(trifluoromethyl)phenolIntermediate 169In a vial, 2‐{4‐chloro‐2‐[(4‐methoxyphenyl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐5‐(trifluoromethyl)phenol (Intermediate 168, 280 mg, 0.63 mmol), cyclopropylboronicacid (107 mg, 1.24 mmol) and K2CO3 (258 mg, 1.87 mmol) were dissolved in DME (7 mL). / water (1.4 mL). Then Pd(dppf)Cl2 complex with DCM (52 mg, 0.07 mmol) was added, themixture was degassed, the vial sealed and the mixture was heated at 100 °C for 4 h. The mixturewas cooled to r.t., diluted with water and EtOAc. The organic phase was separated, dried andevaporates in vacuo, the residue was purified by chromatography on silica gel (0-60% EtOAcin cHex) to yield the title compound (240 mg, 0.53 mmol, 95% yield), as yellow solid. M / Z:454.2 [M+H]+, ESI+, RT = 1.39 (S1), 1H NMR (400 MHz, DMSO-d6) δ = 10.08 (s, 1H), 8.28(s, 1H), 7.27 – 7.16 (m, 2H), 7.09 (d, J = 12.3 Hz, 2H), 6.90 – 6.78 (m, 3H), 5.55 (s, 2H), 3.70(s, 3H), 2.39 (ddd, J = 13.3, 8.5, 5.0 Hz, 1H), 2.05 (s, 3H), 1.28 – 1.17 (m, 2H), 1.14 – 1.02 (m,2H). Scheme for route 42:Intermediate 170: 2‐[4‐(azetidin‐1‐yl)‐2‐[(4‐methoxyphenyl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐3‐methyl‐5‐(trifluoromethyl)phenolIntermediate 170To a solution of 2‐{4‐chloro‐2‐[(4‐methoxyphenyl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐5‐(trifluoromethyl)phenol (Intermediate 168, 1 g, 2.23 mmol) in 1-butanol (10 mL),DIPEA (1.17 mL, 6.7 mmol) and azetidine (0.38 mL, 5.58 mmol) were added. The reaction mixture was stirred to 110 °C for 1h. UPLC-MS showed formation of desired product. Then the solvent was evaporated, water and EtOAc were added. The organic phase was separated,washed with brine, dried and evaporates in vacuo to yield the title compound (1 g, 2.13 mmol,96% yield). M / Z: 469.2 [M+H]+, ESI+, RT = 0.78 (S1).Scheme for route 43:Intermediate 169 Intermediate 171Intermediate 171: 2‐{4‐cyclopropyl‐1H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐5‐(trifluoromethyl)phenolIntermediate 1712‐{4‐cyclopropyl‐2‐[(4‐methoxyphenyl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐5‐(trifluoromethyl)phenol (Intermediate 169240 mg, 0.53 mmol) was suspended in TFA (2.15mL, 28.14 mmol) and heated at 70 °C for 3 h. DCM and saturated aqueous solution of NaHCO3were added and the product was extracted with DCM (2x). Organic phases were collected anddried in vacuo to yield the title compound (115 mg, 0.34 mmol, 65% yield) as a white off foam.M / Z: 334.1 [M+H]+, ESI+, RT = 1.10 (S1).Intermediate compound in Table 28 was synthesised according to the general route 43 asexemplified by Intermediate 171, using the corresponding starting materials / intermediates. Table 28 IntermeStructure Name StartingLCMS1H NMR diate materials data 172 2‐[4‐(azetidin‐2‐[4‐ M / Z: N 1‐yl)‐1H‐ (azetidin‐1‐ 349.1 N pyrazolo[3,4‐ yl)‐2‐[(4‐ [M+H]+, NNHb]pyridin‐6‐ methoxyphen ESI+, RT F3C OH yl]‐3‐methyl‐5‐ yl)methyl]‐ = 0.64 (trifluoromethy 2H‐ (S1). l)phenol pyrazolo[3,4‐ b]pyridin‐6‐ yl]‐3‐methyl‐ 5‐ (trifluoromet hyl)phenol (Intermediate 170)Intermediate compound in Table 29 was synthesised according to the general route 34 asexemplified by Intermediate 129, using the corresponding starting materials / intermediates. Table 29 IntermeStructure Name StartingLCMS1H NMR diate materials data 173 2‐[4‐2‐{4‐ M / Z: cyclopropyl‐2‐ cyclopropyl‐ 416.2 N O NN(3,6‐dihydro‐ 1H‐ [M+H]+, F3C OH 2H‐pyran‐4‐ pyrazolo[3,4‐ ESI+, RTyl)‐2H‐ b]pyridin‐6‐ = 1.07 pyrazolo[3,4‐ yl}‐3‐methyl‐ (S1). b]pyridin‐6‐ 5‐ yl]‐3‐methyl‐5‐ (trifluoromet (trifluoromethy hyl)phenol l)phenol (Intermediate 171) 174 2‐[4‐(azetidin‐2‐[4‐ M / Z: N 1‐yl)‐2‐(3,6‐ (azetidin‐1‐ 431.2 N O d+NNihydro‐2H‐ yl)‐1H‐ [M+H] , F3C OH pyran‐4‐yl)‐ pyrazolo[3,4‐ ESI+, RT 2H‐ b]pyridin‐6‐ = 0.71 pyrazolo[3,4‐ yl]‐3‐methyl‐ (S1). b]pyridin‐6‐ 5‐ yl]‐3‐methyl‐5‐ (trifluoromet hyl)phenol (trifluoromethy (Intermediate l)phenol 172)Scheme for route 44:

[0259] Example 1: 2‐[2‐(3‐hydroxypropyl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐3‐methyl‐5‐(trifluoromethyl)phenol

[0260] 1 M TBAF in THF (0.37 mL, 0.37 mmol) was added to a solution of 2‐(2‐{3‐[(tert‐butyldimethylsilyl)oxy]propyl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl)‐3‐methyl‐5-(trifluoromethyl)phenol (Intermediate 84, 171 mg, 0.37 mmol) in THF (5 mL) at 0 °C. Reactionwas allowed to stir at r.t. overnight. The reaction was diluted with water and extracted withEtOAc (3x). The organic phase was dried using a phase separator and concentrated under reduced pressure. The crude material was purified by chromatography on silica gel (0-20%EtOAc in cHex) to yield the title compound (58 mg, 0.17 mmol, 45% yield). 1H NMR (400MHz, DMSO-d6) δ = 10.11 (s, 1H), 8.47 (s, 1H), 8.23 (d, J = 8.5 Hz, 1H), 7.14 – 7.00 (m, 3H),4.68 (s, 1H), 4.54 (t, J = 7.1 Hz, 2H), 3.46 (t, J = 6.2 Hz, 2H), 2.14 – 2.04 (m, 5H). M / Z: 352.3[M+H]+, ESI+, RT = 0.87 (S1).

[0261] Scheme for route 45:

[0262] Example 2: cis 2‐{2‐[3‐(hydroxymethyl)cyclobutyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐5‐(trifluoromethyl)phenolExample 2

[0263] To an ice-cooled solution of cis methyl 3‐{6‐[2‐hydroxy‐6‐methyl‐4‐(trifluoromethyl)phenyl]‐2H‐pyrazolo[3,4‐b]pyridin‐2‐yl}cyclobutane‐1‐carboxylate(Intermediate 85, 50 mg, 0.12 mmol) in THF (1.5 mL), 2 M LiAlH4 in THF (0.09 mL, 0.19mmol) was added dropwise. The reaction was stirred for 30 min at 0 °C. Solid Na2SO4•10H2O was added until the effervescence ceased. Subsequently the mixture was allowed to warm tor.t. and stirred for 30 min, then solids were separated by filtration. The filtrate was concentratedin vacuo and was purified by reverse chromatography on C18 cartridge (5-70 % of ACN+0.1%HCOOH in H2O+0.1% HCOOH) to the yield title compound (25 mg, 0.07 mmol, 54% yield)as off white solid.1H NMR (400 MHz, DMSO-d6) δ =10.18 (br s, 1H), 8.50 (s, 1H), 8.20 (d, J= 8.4 Hz, 1H), 7.11 (s, 1H), 7.07 (s, 1H), 7.04 (d, J = 8.4 Hz, 1H), 5.07 (quin, J = 8.3 Hz, 1H),4.65 (br t, J = 4.8 Hz, 1H), 3.49 (br s, 2H), 2.63 - 2.36 (m, 4H), 2.36 - 2.27 (m, 1H), 2.10 (s,3H). ). M / Z: 378.1 [M+H]+, ESI+, RT = 0.92 (S1).

[0264] Example compound in Table 30 was synthesised according to the general route45 as exemplified by Example 2 using the corresponding starting materials / intermediates.Table 30 ExamStructure Name StartingLCMS1H NMR ple materials data 3 Ntrans 2‐{2‐[3‐ trans methylM / Z:1H NMR (400 NN OHC OH(hydroxymethy 3‐{6‐[2‐ 378.1 MHz, DMSO-d6F) l)cyclobutyl]‐ hydroxy‐6‐ [M+H]+,δ = 10.13 (br s,2H- methyl‐4‐ ESI+, RT = 1H), 8.53 (s, 1H), pyrazolo[3,4‐ (trifluorometh0.93 (S1). 8.20 (d, J = 8.4b]pyridin‐6‐ yl)phenyl]‐ Hz, 1H), 7.12 (s, yl}‐3‐methyl‐5‐ 2H‐ 1H), 7.08 (s, 1H), (trifluoromethy pyrazolo[3,4‐7.04 (d, J = 8.4l)phenol b]pyridin‐2‐ Hz, 1H), 5.27 yl}cyclobutan(quin, J = 7.9 Hz,e‐1‐1H), 4.77 (t, J =carboxylate 5.2 Hz, 1H), 3.58 (Intermediate(t, J = 5.5 Hz,86)2H), 2.79 - 2.68(m, 2H), 2.57 - 2.52 (m, 1H), 2.45 - 2.35 (m,2H), 2.10 (s, 3H)

[0265] Scheme for route 46:

[0266] Example 4: trans- 2‐[2‐(3‐hydroxycyclobutyl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐3‐methyl‐5‐(trifluoromethyl)phenolExample 4

[0267] A solution of trans-2‐{2‐[3‐(benzyloxy)cyclobutyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐5‐(trifluoromethyl)phenol (Intermediate 87, 100 mg, 0.11 mmol),HCOONH4 (334 mg, 5.29 mmol) and 10% Pd / C (11 mg, 0.01 mmol) was refluxed for 6 h. Themixture was diluted, filtered through a celite® pad, washing with MeOH. The filtrate wasevaporated in vacuo. The crude material was purified by chromatography on silica gel (0-100%EtOAc in cHex), and then further purified was purified by reverse chromatography on C18cartridge (4-40% of ACN +0.1% HCOOH in H2O+0.1% HCOOH) to yield the title compound(8 mg, 0.02 mmol, 21% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 10.12 (brs, 1H), 8.53 (s, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.11 (s, 1H), 7.07 (s, 1H), 7.04 (d, J = 8.6 Hz,1H), 5.42 - 5.20 (m, 2H), 4.71 - 4.51 (m, 1H), 2.88 - 2.73 (m, 2H), 2.59 - 2.41 (m, 2H), 2.10 (s,3H). ). M / Z: 364.1 [M+H]+, ESI+, RT = 0.91 (S1).

[0268] Scheme for route 47:

[0269] Example 5: rac-2‐{2‐[(3‐fluoro‐1‐methylpiperidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐5‐(trifluoromethyl)phenol

[0270] To an ice-cooled solution of rac-2‐{2‐[(3‐fluoropiperidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐5‐(trifluoromethyl)phenol (Intermediate 74, 30 mg,0.07 mmol) in MeOH (0.75 mL), formaldehyde 37% w / w (6 µL, 0.08 mmol) was added andthe reaction was stirred at r.t. for 15 min, before adding Na(OAc)3BH (20 mg, 0.10 mmol).After 1 h at the same temperature, volatiles were removed in vacuo. The residue was taken upwith EtOAc and washed with water (2x). The organic phase was filtered through a phaseseparator and concentrated in vacuo. The residue was purified by reverse chromatography onC18 cartridge (5-60% of ACN in H2O+0.1% NH4OH) to yield the title compound (25 mg, 0.06mmol, 81% yield) as pale yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 10.13 (s, 1H), 8.40(d, J = 1.0 Hz, 1H), 8.25 (d, J = 8.5 Hz, 1H), 7.14 – 7.03 (m, 3H), 4.86 – 4.68 (m, 2H), 2.47 –2.40 (m, 2H), 2.39 – 2.32 (m, 1H), 2.28 (s, 1H), 2.18 (s, 3H), 2.10 (s, 3H), 1.70 – 1.52 (m, 4H).M / Z: 423.4 [M+H]+, ESI+, RT = 0.63 (S1).

[0271] Example compound in Table 31 was synthesised according to the general route47 as exemplified by Example 5 using the corresponding starting materials / intermediates.Table 31 ExamStructure Name StartingLCMS1H NMR ple materials data 6rac-2‐{2‐[(1‐rac-2‐{2‐[(3‐ M / Z:1H NMR (400 ethyl‐3‐ fluoropiperidi 437.4 MHz, DMSO-d6) fluoropiperidin‐ n‐3‐ [M+H]+,δ = 10.17 (br s,3‐yl)methyl]‐ yl)methyl]‐ ESI+, RT = 1H), 8.40 (s, 1H), 2H‐ 2H‐ 0.90 (S2).8.25 (d, J = 8.6pyrazolo[3,4‐ pyrazolo[3,4‐ Hz, 1H), 7.12 (s, b]pyridin‐6‐ b]pyridin‐6‐1H), 7.10 - 7.03yl}‐3‐methyl‐5‐ yl}‐3‐methyl‐ (m, 2H), 4.87 - (trifluoromethy 5‐ 4.71 (m, 2H), l)phenol (trifluorometh2.60 - 2.43 (m,yl)phenol2H), 2.43 - 2.28(Intermediate (m, 4H), 2.10 (s, 74)3H), 1.73 - 1.45(m, 4H), 0.98 (t, J = 7.1 Hz, 3H)

[0272] Scheme for route 48:

[0273] Example 7: 2‐{2‐[1‐(ethanesulfonyl)piperidin‐4‐yl]‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl}‐3‐methyl‐5‐(trifluoromethyl)phenol

[0274] 1 M BBr3 in hexane (0.24 mL, 0.24 mmol) was added dropwise to an ice cooledsolution of 1‐(ethanesulfonyl)‐4‐{6‐[2‐methoxy‐6‐methyl‐4‐(trifluoromethyl)phenyl]‐2H‐pyrazolo[3,4‐b]pyrazin‐2‐yl}piperidine (Intermediate 80, 47 mg, 0.100mmol) in DCM (2.6mL). The reaction mixture was slowly left to reach r.t. and stirred for 3 h. EtOAc and a saturated aqueous solution of NaHCO3 were added; the organic one was dried over Na2SO4, filtered andconcentrated. The crude material was purified by reverse chromatography on C18 cartridge (0-50% of ACN +0.1% HCOOH in H2O+0.1% HCOOH) to yield the title compound (33 mg, 0.07mmol, 72% yield) as yellowish solid. 1H NMR (400 MHz, DMSO-d6) δ = 8.96 (s, 1H), 8.57 (s,1H), 7.14 (s, 1H), 7.09 (s, 1H), 4.81 (ddd, J = 15.3, 11.2, 4.1 Hz, 1H), 3.81 (d, J = 12.5 Hz, 2H),3.19 – 3.09 (m, 4H), 2.32 – 2.11 (m, 7H), 1.27 (t, J = 7.4 Hz, 3H). M / Z: 470.4 [M+H]+, ESI+,RT = 0.98 (S1).

[0275] Example compounds in Table 32 were synthesised according to the generalroute 47 as exemplified by Example 7 using the corresponding starting materials / intermediates.Table 32 ExamStructure Name StartingLCMS1H NMR ple materials data 82‐[2‐(1‐1‐ M / Z:1H NMR (400 methanesulfony methanesulfo 456.4 MHz, DMSO-d6) lpiperidin‐4‐ nyl‐4‐{6‐[2‐ [M+H]+,δ = 10.49 (s, 1H),yl)‐2H‐ methoxy‐6‐ ESI+, RT = 8.98 (s, 1H), 8.57 pyrazolo[3,4‐ methyl‐4‐0.95 (S1).(s, 1H), 7.16 (s, b]pyrazin‐6‐ (trifluorometh 1H), 7.11 (s, 1H), yl]‐3‐methyl‐5‐ yl)phenyl]‐4.84 – 4.73 (m,(trifluoromethy 2H‐1H), 3.82 – 3.72l)phenol pyrazolo[3,4‐ (m, 2H), 3.05 (td, J= 12.2, 2.9 Hz,b]pyrazin‐2‐ 2H), 2.98 (s, 3H), yl}piperidine2.37 – 2.20 (m,(Intermediate 4H), 2.17 (s, 3H). 81)9 2‐[2‐(1‐1‐ M / Z:1H NMR (400 cyclopropaneca cyclopropanec 446.4MHz, DMSO- d6rbonylpiperidin arbonyl‐4‐{6‐ [M+H]+,) δ = 10.65 -‐4‐yl)‐2H‐ [2‐methoxy‐6‐ ESI+, RT 10.01 (m, 1H), pyrazolo[3,4‐ methyl‐4‐ = 0.95 8.96 (s, 1H), 8.55 b]pyrazin‐6‐ (trifluorometh (S1) (s, 1H), 7.17 (s, yl]‐3‐methyl‐5‐ yl)phenyl]‐ 1H), 7.10 (s, 1H), (trifluoromethy 2H‐4.90 (tt, J = 4.0,l)phenol pyrazolo[3,4‐ 11.4 Hz, 1H), b]pyrazin‐2‐4.64 - 4.36 (m,yl}piperidine2H), 3.41 - 3.26(Intermediate (m, 1H), 2.94 - 82) 2.76 (m, 1H), 2.16 (s, 3H), 2.11 -2.03 (m, 1H),2.35 - 1.84 (m,4H), 0.92 - 0.64(m, 4H)10 rac-3‐methyl‐rac-4‐{6‐[2‐ M / Z:1H NMR (500 2‐{2‐[1‐(1‐ methoxy‐6‐ 489.4 MHz, DMSO-d6) methylpyrrolidi methyl‐4‐ [M+H]+,δ = 10.95 - 9.96ne‐3‐ (trifluorometh ESI+, RT (m, 1H), 8.99 - carbonyl)piperi yl)phenyl]‐ = 0.64 8.83 (m, 1H), din‐4‐yl]‐2H‐ 2H‐ (S1)8.59 - 8.46 (m,pyrazolo[3,4‐ pyrazolo[3,4‐1H), 7.32 - 6.70b]pyrazin‐6‐ b]pyrazin‐2‐ (m, 2H), 4.94 - yl}‐5‐ yl}‐1‐(1‐ 4.75 (m, 1H), (trifluoromethy methylpyrroli4.64 - 4.01 (m,l)phenol dine‐2H), 3.30 - 2.79carbonyl)pipe (m, 3H), 2.78 - ridine 2.28 (m, 4H), (Intermediate2.25 - 2.23 (m,83)3H), 2.17 - 2.13(m, 3H), 2.28 - 1.89 (m, 6H)

[0276] Scheme for route 49:Example 11: 3‐methyl‐2‐[2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐5‐ (trifluoromethyl)phenol

[0277] In a vial, 6‐chloro‐2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridine (Intermediate 25,90 mg, 0.38 mmol) and 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (Intermediate 5, 157 mg, 0.38 mmol) were dissolved in a mixture ofwater (0.5 mL) and 1,4-dioxane (2.6 mL). Pd(dppf)Cl2 complex with DCM (31 mg, 0.04 mmol)and K3PO4 (245 mg, 1.14 mmol) were added. The mixture was degassed, the vial sealed, andthe mixture was heated at 100 °C for 3 h. Water and EtOAc were added. The aqueous layer wasextracted with EtOAc (3 x). The combined organic layers were dried over a phase separator andevaporated. The crude material was purified by chromatography on silica gel (20-80% EtOAcin cHex), and then by reverse chromatography on C18 cartridge (0-60% of ACN +0.1%HCOOH in H2O+0.1% HCOOH) to yield the title compound (46 mg, 0.12 mmol, 32% yield)as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 10.09 (s, 1H), 8.55 (s, 1H), 8.23 (d, J =8.5 Hz, 1H), 7.11 (dd, J = 16.6, 1.8 Hz, 2H), 7.06 (d, J = 8.5 Hz, 1H), 4.82 (tt, J = 10.6, 4.9 Hz,1H), 4.10 – 4.00 (m, 2H), 3.56 (td, J = 11.6, 3.0 Hz, 2H), 2.25 – 2.10 (m, 7H); M / Z: 378.3[M+H]+, ESI+, RT = 0.98 (S1)

[0278] Example compounds in Table 33 were synthesised according to the generalroute 49 as exemplified by Example 11 using the corresponding startingmaterials / intermediates. Table 33 ExamStructure Name StartingLCMS 1H NMR ple materials data 12N3‐methyl‐2‐[2‐6‐chloro‐2‐ M / Z1N O : H NMR (400 NN(oxan‐4‐yl)‐2H‐ (oxan‐4‐yl)‐ 379.2 MHz, DMSO-d6) F3COH pyrazolo[3,4‐ 2H‐ [M+H]+,δ = 10.55 - 10.22b]pyrazin‐6‐yl]‐ pyrazolo[3,4‐ ESI+, RT = (m, 1H), 8.95 (s, 5‐ b]pyrazine 0.95 1H), 8.55 (s, 1H), (trifluoromethyl) (Intermediate (S1) 7.18 (s, 1H), 7.11 phenol26) and 3-(s, 1H), 4.97 - methyl-2- 4.80 (m, 1H), (4,4,5,5-4.14 - 3.95 (m,tetramethyl-2H), 3.60 - 3.511,3,2- (m, 2H), 2.26 - dioxaborolan- 2.08 (m, 7H) 2-yl)-5- (trifluorometh yl)phenol Intermediate 5 13 N O 5‐methoxy‐3‐6‐chloro‐2‐ M / Z:1H NMR (400 NNmethyl‐2‐[2‐ (oxan‐4‐yl)‐ 340.3 MHz, DMSO-d6) MeO OH (oxan‐4‐yl)‐2H‐ 2H‐ [M+H]+, δ = 9.92 (s, 1H), pyrazolo[3,4‐ pyrazolo[3,4‐ ESI+, RT = 8.50 (s, 1H), 8.16 b]pyridin‐6‐ b]pyridine 0.73(d, J = 8.6 Hz,yl]phenol (Intermediate (S1)1H), 7.08 (d, J =25) and 5-8.5 Hz, 1H), 6.38 methoxy-3-(d, J = 1.0 Hz,methyl-2- 2H), 4.80 (dd, J =(4,4,5,5- 10.6, 5.1 Hz, 1H), tetramethyl-4.11 – 4.00 (m,1,3,2- 2H), 3.75 (s, 3H), dioxaborolan-3.56 (td, J = 11.4,2-yl)phenol 3.1 Hz, 2H), 2.23 (Intermediate– 2.08 (m, 7H).7)14 rac-3-methyl-2-rac-6‐chloro‐ M / Z:1H NMR (400 [2-(oxolan-3-yl)- 2‐(oxolan‐3‐ 364.3 MHz, DMSO-d6) 2H- yl)‐2H‐ [M+H]+, δ = 10.19 (s, 1H), pyrazolo[3,4- pyrazolo[3,4‐ ESI+, RT = 8.53 (s, 1H), 8.22 b]pyridin-6-yl]- b]pyridine 0.97 (S1)(d, J = 8.5 Hz,5- (Intermediate1H), 7.19 – 6.97(trifluoromethyl)27) and 3-(m, 3H), 5.41 phenol methyl-2-(ddd, J = 7.8, 6.2,(4,4,5,5- 3.7 Hz, 1H), 4.21 tetramethyl-– 4.01 (m, 3H),1,3,2-3.92 (td, J = 8.2,dioxaborolan- 5.4 Hz, 1H), 2.60 2-yl)-5-– 2.53 (m, 1H),(trifluorometh2.49 – 2.41 (m,yl)phenol 1H), 2.11 (s, 3H) (Intermediate 5)15 3-methyl-2-[4-6‐chloro‐4‐ M / Z:1H NMR (500 N O N N methyl-2-(oxan- methyl‐2‐ 392.3 MHz, DMSO-d6) F3C OH4-yl)-2H- (oxan‐4‐yl)‐ [M+H]+, δ = 10.04 (s, 1H), pyrazolo[3,4- 2H‐ ESI+, RT = 8.63 (s, 1H), 7.11 b]pyridin-6-yl]- pyrazolo[3,4‐ 0.98 (S1) (s, 1H), 7.07 (s, 5- b]pyridine 1H), 6.85 (s, 1H), (trifluoromethyl) (Intermediate4.77 (tt, J = 5.2,phenol 28) 10.5 Hz, 1H), and 3-methyl-4.08 - 3.99 (m,2-(4,4,5,5-2H), 3.55 (dt, J =tetramethyl- 3.1, 11.3 Hz, 2H), 1,3,2- 2.56 (s, 3H), 2.23 dioxaborolan-- 2.09 (m, 4H),2-yl)-5- 2.09 (s, 3H) (trifluorometh yl)phenol (Intermediate 5)16 3‐methyl‐2‐[3‐6‐chloro‐3‐ M / Z:1H NMR (400 methyl‐2‐(oxan‐ methyl‐2‐ 393.3 MHz, DMSO-d6) 4‐yl)‐2H‐ (oxan‐4‐yl)‐ [M+H]+, δ = 8.46 (s, 1H), pyrazolo[3,4‐ 2H‐ ESI+, RT =7.13 (d, J = 23.9b]pyrazin‐6‐yl]‐ pyrazolo[3,4‐ 0.99 (S1) Hz, 2H), 4.09 – 5‐ b]pyrazine 3.99 (m, 2H), (trifluoromethyl) (Intermediate4.96 – 4.86 (m,phenol29) and 3- 2H), 3.67 – 3.54methyl-2- (m, 2H), 2.78 (s, (4,4,5,5-3H), 2.25 (qd, J =tetramethyl- 12.3, 4.5 Hz, 2H), 1,3,2- 2.16 (s, 3H), 2.02 dioxaborolan-– 1.92 (m, 2H)2-yl)-5- (trifluorometh yl)phenol (Intermediate 5)17 3-methyl-2-[3-6‐chloro‐3‐ M / Z:1H NMR (400 N O NNmethyl-2-(oxan- methyl‐2‐ 392.3 MHz, DMSO-d6) F3C OH4-yl)-2H- (oxan‐4‐yl)‐ [M+H]+,δ = 8.21 (d, J =pyrazolo[3,4- 2H‐ ESI+, RT = 8.4 Hz, 1H), 7.08 b]pyridin-6-yl]- pyrazolo[3,4‐ 0.99 (S1)(d, J = 13.1 Hz,5- b]pyridine2H), 6.97 (d, J =(trifluoromethyl) (Intermediate 8.5 Hz, 1H), 4.87 phenol30) and 3- – 4.65 (m, 1H),methyl-2-4.11 – 3.95 (m,(4,4,5,5-2H), 3.59 (td, J =tetramethyl- 11.9, 1.9 Hz, 2H), 1,3,2- 2.72 (s, 3H), 2.24 dioxaborolan-(qd, J = 12.4, 4.62-yl)-5- Hz, 2H), 2.11 (s, (trifluorometh3H), 2.01 – 1.84yl)phenol (m, 2H) (Intermediate 5)18O4-{6-[2-41N S ‐{6‐chloro‐ M / Z: H NMR (400 N N O FC OHhydroxy-6- 2H‐ 426.2MHz, CDCl3) δ =methyl-4- pyrazolo[3,4‐ [M+H]+, 11.24 (br. s., 1H), (trifluoromethyl) b]pyridin‐2‐ ESI+, RT =8.22 (d, J = 8.8phenyl]-2H- yl}‐1λ⁶‐ 0.98 (S1) Hz, 1H), 8.10 (s, pyrazolo[3,4- thiane‐1,1‐1H), 7.39 (d, J =b]pyridin-2-yl}- dione 8.7 Hz, 1H), 7.21 1λ⁶-thiane-1,1- (Intermediate (s, 1H), 7.11 (s, dione 35)1H), 4.84 (dt, J =and 3-methyl- 7.8, 3.8 Hz, 1H), 2-(4,4,5,5-3.61 (d, J = 11.5tetramethyl- Hz, 2H), 3.22 1,3,2-(ddd, J = 13.9,dioxaborolan- 9.1, 4.4 Hz, 2H), 2-yl)-5- 2.82 (dq, J = 11.5, (trifluorometh 4.4 Hz, 4H), 2.56 yl)phenol (s, 3H) (Intermediate 5)19Nrac-3-({6-[2-rac-3‐({6‐ M / Z:1H NMR (500 O N hydroxy-6- chloro‐2H‐ 406.3 MHz, DMSO-d6) N N N methyl-4- pyrazolo[3,4‐ [M+H]+, δ = 10.42 (br.s., F3C OH(trifluoromethyl) b]pyrazin‐2‐ ESI+, RT = 1H), 8.83 (s, 1H), phenyl]-2H- yl}methyl)‐1‐ 0.93 (S1) 8.56 (s, 1H), 7.18pyrazolo[3,4- methylpyrroli (s, 1H), 7.11 (s, b]pyrazin-2- din‐2‐one1H), 4.80 (dd, J =yl}methyl)-1- (Intermediate 4.6, 13.5 Hz, 1H), methylpyrrolidin36) and 3- 4.60 (dd, J = 8.6,-2-one methyl-2- 13.5 Hz, 1H), (4,4,5,5-3.30 - 3.20 (m,tetramethyl-2H), 3.14 (dq, J =1,3,2- 4.7, 8.8 Hz, 1H), dioxaborolan- 2.75 (s, 3H), 2.16 2-yl)-5- (s, 3H), 2.11 - (trifluorometh 2.00 (m, 1H), yl)phenol1.93 - 1.77 (m,(Intermediate 1H) 5)20Orac-4-({6-[2-rac-4‐({6‐ M / Z:1H NMR (400 N N hydroxy-6- chloro‐2H‐ 406.3 MHz, DMSO-d6) N N N methyl-4- pyrazolo[3,4‐ [M+H]+, δ = 10.39 (s, 1H), F3C OH(trifluoromethyl) b]pyrazin‐2‐ ESI+, RT = 8.93 (s, 1H), 8.58 phenyl]-2H- yl}methyl)‐1‐ 0.92 (S1) (s, 1H), 7.20 (d, J pyrazolo[3,4- methylpyrroli = 1.8 Hz, 1H), b]pyrazin-2- din‐2‐one7.13 (d, J = 1.8yl}methyl)-1- (Intermediate Hz, 1H), 4.61 (d, methylpyrrolidin 37)J = 7.4 Hz, 2H),-2-one and 3-methyl- 3.45 (dd, J = 9.9, 2-(4,4,5,5- 8.1 Hz, 1H), 3.27 tetramethyl-(dd, J = 10.0, 5.41,3,2- Hz, 1H), 3.08 (dq, dioxaborolan-J = 14.6, 7.5 Hz,2-yl)-5-1H), 2.43 (dd, J =(trifluorometh16.8, 9.1 Hz, 1H),yl)phenol 2.18 (s, 4H) (Intermediate 5)21 rac-3-methyl-2-rac-6‐chloro‐ M / Z:1H NMR (400 NON N(2-{5- 2‐{5‐ 418.4[M+ MHz, DMSO-d6) F OH F oxaspiro[3.5]non oxaspiro[3.5] H]+, ESI+,δ = 10.11 (br. s.,F an-8-yl}-2H- nonan‐8‐yl}‐ RT= 1.12 1H), 8.56 (s, 1H), pyrazolo[3,4- 2H‐ (S1)8.22 (d, J = 8.6b]pyridin-6-yl)- pyrazolo[3,4‐ Hz, 1H), 7.11 (s, 5- b]pyridine 1H), 7.07 (s, 1H), (trifluoromethyl) (Intermediate7.05 (d, J = 8.4phenol 38) Hz, 1H), 4.89 - and 3-methyl- 4.73 (m, 1H), 2-(4,4,5,5-3.89 - 3.79 (m,tetramethyl-1H), 3.56 (dt, J =1,3,2- 2.9, 11.7 Hz, 1H), dioxaborolan-2.42 (br. dd., J =2-yl)-5- 2.4, 12.3 Hz, 1H), (trifluorometh2.30 - 2.19 (m,yl)phenol 1H), 2.10 (s, 3H), (Intermediate2.16 - 1.87 (m,5)6H), 1.82 - 1.63(m, 2H)22 rac-2‐{2‐[(3‐rac-3‐({6‐ M / Z:1H NMR (500 fluoro‐1‐ chloro‐2H‐ 409.2MHz, CDCl3) δ =methylpyrrolidin pyrazolo[3,4‐ [M+H]+, 11.27 (br. s., 1H), ‐3‐yl)methyl]‐ b]pyridin‐2‐ ESI+, RT=8.21 (d, J = 8.82H‐ yl}methyl)‐3‐ 0.78 (S1) Hz, 1H), 8.15 (d, pyrazolo[3,4‐ fluoro‐1‐J = 1.1 Hz, 1H),b]pyridin‐6‐yl}‐ methylpyrroli7.36 (d, J = 8.83‐methyl‐5‐ dine Hz, 1H), 7.19 (s, (trifluoromethyl) (Intermediate 1H), 7.09 (s, 1H), phenol 39)4.90 - 4.74 (m,and 3-methyl-2H), 3.16 - 3.012-(4,4,5,5- (m, 1H), 2.98 - tetramethyl- 2.89 (m, 1H), 1,3,2-2.86 - 2.77 (m,dioxaborolan-1H), 2.76 - 2.692-yl)-5- (m, 1H), 2.56 (s, (trifluorometh 3H), 2.44 (s, 3H), yl)phenol2.38 - 2.26 (m,(Intermediate1H), 2.22 - 2.095) (m, 1H)23 rac-2‐{2‐[(4,4‐rac-3‐({6‐ M / Z:1H NMR (400 difluoro‐1‐ chloro‐2H‐ 441.2 MHz, DMSO-d6) methylpiperidin‐ pyrazolo[3,4‐ [M+H]+,δ = 10.14 (br. s,3‐yl)methyl]‐ b]pyridin‐2‐ ESI+, RT= 1H), 8.53 (s, 1H), 2H‐ yl}methyl)‐ 0.92 (S2)8.23 (d, J = 8.5pyrazolo[3,4‐ 4,4‐difluoro‐ Hz, 1H), 7.13 – b]pyridin‐6‐yl}‐ 1‐ 7.03 (m, 3H), 3‐methyl‐5‐ methylpiperid4.76 (dd, J = 13.7,(trifluoromethyl) ine 4.5 Hz, 1H), 4.52 phenol (Intermediate(dd, J = 13.7, 9.240) and 3-Hz, 1H), 2.86 methyl-2-(ddd, J = 18.5,(4,4,5,5- 9.6, 4.9 Hz, 1H), tetramethyl-2.74 – 2.64 (m,1,3,2-1H), 2.25 (d, J =dioxaborolan- 11.7 Hz, 1H), 2-yl)-5-2.14 (d, J = 29.5(trifluorometh Hz, 10H). yl)phenol (Intermediate 5)24 3‐({6‐[2‐3‐({6‐chloro‐ M / Z:1H NMR (400 hydroxy‐6‐ 2H‐ 412.2 MHz, DMSO-d6) methyl‐4‐ pyrazolo[3,4‐ [M+H]+,δ = 10.54 - 9.62(trifluoromethyl) b]pyridin‐2‐ ESI+, RT= (m, 1H), 8.57 (s, phenyl]‐2H‐ yl}methyl)‐1 0.94 (S1)1H), 8.23 (d, J =pyrazolo[3,4‐ λ6‐thietane‐ 8.4 Hz, 1H), 7.16 b]pyridin‐2‐ 1,1‐dione- 6.94 (m, 3H),yl}methyl)‐1λ6‐ (Intermediate4.76 (d, J = 7.5thietane‐1,1‐ 41) and 3- Hz, 2H), 4.45 - dione methyl-2- 4.21 (m, 2H), (4,4,5,5-4.18 - 4.04 (m,tetramethyl-2H), 3.29 - 3.111,3,2- (m, 1H), 2.09 (s, dioxaborolan- 3H). 2-yl)-5- (trifluorometh yl)phenol (Intermediate 5)25 2‐[2‐(3‐6‐chloro‐2‐(3‐ M / Z:1H NMR (400 methoxypropyl)‐ methoxypropy 366.3 MHz, DMSO-d6) 2H‐ l)‐2H‐ [M+H]+,δ = 10.30 - 9.88pyrazolo[3,4‐ pyrazolo[3,4‐ ESI+, RT= (m, 1H), 8.47 (s, b]pyridin‐6‐yl]‐ b]pyridine0.99 (S1) 1H), 8.22 (d, J =3‐methyl‐5‐ (Intermediate 8.4 Hz, 1H), 7.11 (trifluoromethyl) 42) (s, 1H), 7.07 (s, phenol and 3-methyl-1H), 7.05 (d, J =2-(4,4,5,5- 8.4 Hz, 1H), 4.51 tetramethyl-(t, J = 7.0 Hz,1,3,2-2H), 3.38 - 3.34dioxaborolan- (m, 2H), 3.26 (s, 2-yl)-5- 3H), 2.18 (quin, J (trifluorometh = 6.6 Hz, 2H), yl)phenol 2.10 (s, 3H) (Intermediate 5)26 2‐[2‐(2‐2‐{6‐chloro‐ M / Z:1H NMR (400 hydroxyethyl)‐ 2H‐ 338.2 MHz, DMSO-d6) 2H‐ pyrazolo[3,4‐ [M+H]+, δ = 10.15 (br s, pyrazolo[3,4‐ b]pyridin‐2‐ ESI+, RT= 1H), 8.44 (s, 1H), b]pyridin‐6‐yl]‐ yl}ethan‐1‐ol0.83 (S1)8.22 (d, J = 8.43‐methyl‐5‐ (Intermediate Hz, 1H), 7.11 (s, (trifluoromethyl)54) and 3-1H), 7.07 (s, 1H), phenol methyl-2-7.04 (d, J = 8.4(4,4,5,5- Hz, 1H), 5.01 (br tetramethyl-s, 1H), 4.50 (t, J =1,3,2- 5.4 Hz, 2H), 3.91 dioxaborolan- (br s, 2H), 2.10 (s, 2-yl)-5- 3H) (trifluorometh yl)phenol (Intermediate 5)27 2‐[2‐(3‐hydroxy‐4‐{6‐chloro‐ M / Z:1H NMR (400 3‐methylbutyl)‐ 2H‐ 380.3 MHz, DMSO-d6) 2H‐ pyrazolo[3,4‐ [M+H]+, δ = 10.08 (s, 1H), pyrazolo[3,4‐ b]pyridin‐2‐ ESI+, RT= 8.50 (s, 1H), 8.22 b]pyridin‐6‐yl]‐ yl}‐2‐0.94 (S1) (d, J = 8.5 Hz,3‐methyl‐5‐ methylbutan‐1H), 7.15 – 7.07(trifluoromethyl) 2‐ol (m, 2H), 7.05 (d, phenol (IntermediateJ = 8.5 Hz, 1H),44)4.60 – 4.51 (m,and 3-methyl- 3H), 2.11 (s, 3H), 2-(4,4,5,5-2.09 (dd, J = 6.8,tetramethyl- 4.1 Hz, 2H), 1.19 1,3,2- (s, 6H). dioxaborolan- 2-yl)-5- (trifluorometh yl)phenol (Intermediate 5)28 2‐[4‐6‐chloro‐4‐ M / Z:1H NMR (400 (difluoromethyl) (difluorometh 428.4 MHz, DMSO-d6) ‐2‐(oxan‐4‐yl)‐ yl)‐2‐(oxan‐4‐ [M+H]+, δ = 10.23 (br s, 2H‐ yl)‐2H‐ ESI+, RT= 1H), 8.68 (s, 1H), pyrazolo[3,4‐ pyrazolo[3,4‐1.08 (S1)7.28 (s, 1H), 7.34 b]pyridin‐6‐yl]‐ b]pyridine(t, J = 54.8 Hz,3‐methyl‐5‐ (Intermediate 1H), 7.14 (s, 1H), (trifluoromethyl)43) and 3-7.09 (s, 1H), 4.96 phenol methyl-2-- 4.83 (m, 1H),(4,4,5,5-4.10 - 3.97 (m,tetramethyl-2H), 3.60 - 3.471,3,2- (m, 2H), 2.26 - dioxaborolan- 2.12 (m, 4H), 2-yl)-5- 2.11 (s, 3H) (trifluorometh yl)phenol (Intermediate 5)29 2‐[4‐methoxy‐2‐6‐chloro‐4‐ M / Z:1H NMR (400 (oxan‐4‐yl)‐2H‐ methoxy‐2‐ 408.3 MHz, DMSO-d6) pyrazolo[3,4‐ (oxan‐4‐yl)‐ [M+H]+,δ = 10.10 (br s,b]pyridin‐6‐yl]‐ 2H‐ ESI+, RT= 1H), 8.55 (s, 1H), 3‐methyl‐5‐ pyrazolo[3,4‐ 0.77 (S1) 7.10 (s, 1H), 7.06 (trifluoromethyl) b]pyridine (s, 1H), 6.50 (s, phenol (Intermediate1H), 4.79 - 4.6845) and 3-(m, 1H), 4.02 (br methyl-2-dd, J = 3.1, 10.5(4,4,5,5- Hz, 2H), 3.95 (s, tetramethyl-3H), 3.53 (dt, J =1,3,2- 2.6, 11.5 Hz, 2H), dioxaborolan- 2.11 (s, 3H), 2.22 2-yl)-5-- 2.05 (m, 4H)(trifluorometh yl)phenol(Intermediate 5)30O2-[2-(1-1N N 4‐{6‐chloro‐ M / Z: H NMR (400 NNF C OH cyclopropanecar 2H‐ 445.4 MHz, MeOD-d4) bonylpiperidin- pyrazolo[3,4‐ [M+H]+,δ = 8.43 (s, 1H),4-yl)-2H- b]pyridin‐2‐ ESI+, RT =8.27 (d, J = 8.5pyrazolo[3,4- yl}‐1‐ 0.98 (S1) Hz, 1H), 7.69 – b]pyridin-6-yl]- cyclopropanec 7.59 (m, 1H), 3-methyl-5- arbonylpiperi7.16 (d, J = 8.5(trifluoromethyl) dine Hz, 1H), 7.09 (dd, phenol (IntermediateJ = 1.8, 0.9 Hz,68) and 3- 1H), 7.03 (d, J =methyl-2- 1.7 Hz, 1H), 4.92 (4,4,5,5-– 4.81 (m, 1H),tetramethyl-4.69 (d, J = 13.71,3,2- Hz, 1H), 4.55 (d, dioxaborolan-J = 13.8 Hz, 1H),2-yl)-5-3.43 (d, J = 13.1(trifluorometh Hz, 1H), 3.35 (s, yl)phenol0H), 2.96 (t, J =(Intermediate 12.9 Hz, 1H), 5)2.34 (d, J = 8.7Hz, 1H), 2.30 – 2.23 (m, 3H), 2.17 (s, 3H), 2.04 (tt, J = 7.8, 4.7Hz, 1H), 0.96 – 0.89 (m, 2H), 0.92 – 0.80 (m,2H).31 rac-3-methyl-2-rac-3-({6- M / Z:1H NMR (500 {2-[(1- chloro-2H- 392.4 MHz, DMSO-d6) methylpyrrolidin pyrazolo[3,4- [M+H]+,δ = 10.56 (br. s.,-3-yl)methyl]- b]pyrazin-2- 1H), 8.91 (s, 1H),2H- yl}methyl)-1- ESI+, RT = 8.55 (s, 1H), 7.15 pyrazolo[3,4- methylpyrroli 0.78 (S2)(br. s., 1H), 7.10b]pyrazin-6-yl}- dine (s, 1H), 4.54 - 5- (Intermediate 4.40 (m, 2H), (trifluoromethyl) 57)2.94 - 2.80 (m,phenol and 3-methyl-1H), 2.56 (dt, J =2-(4,4,5,5- 5.2, 8.4 Hz, 1H), tetramethyl-2.47 - 2.41 (m,1,3,2-1H), 2.40 - 2.32dioxaborolan- (m, 2H), 2.24 (s, 2-yl)-5- 3H), 2.16 (s, 3H), (trifluorometh1.94 - 1.81 (m,yl)phenol1H), 1.62 - 1.49(Intermediate (m, 1H) 5)32 rac-3-methyl-2-rac-3‐({6‐ M / Z:1H NMR (500 {2-[(1- chloro‐2H‐ 391.3 MHz, DMSO-d6) methylpyrrolidin pyrazolo[3,4‐ [M+H]+,δ = 10.11 (br. s.,-3-yl)methyl]- b]pyridin‐2‐ ESI+, RT = 1H), 8.51 (s, 1H), 2H- yl}methyl)‐1‐ 0.67 (S1)8.22 (d, J = 8.5pyrazolo[3,4- methylpyrroli Hz, 1H), 7.12 (s, b]pyridin-6-yl}- dine 1H), 7.08 (s, 1H), 5- (Intermediate7.04 (d, J = 8.5(trifluoromethyl)58) and 3-Hz, 1H), 4.49 - phenol methyl-2- 4.37 (m, 2H), (4,4,5,5-2.92 - 2.78 (m,tetramethyl-1H), 2.56 (dt, J =1,3,2- 5.3, 8.5 Hz, 1H), dioxaborolan-2.46 - 2.34 (m,2-yl)-5- 3H), 2.24 (s, 3H), (trifluorometh 2.09 (s, 3H), 1.93 yl)phenol- 1.83 (m, 1H),(Intermediate1.60 - 1.50 (m,5) 1H)33 2-{2-[(1-3‐({6‐chloro‐ M / Z:1H NMR (500 methanesulfonyl 2H‐ 441.3 MHz, DMSO-d6) azetidin-3- pyrazolo[3,4‐ [M+H]+,δ = 10.12 (br. s.,yl)methyl]-2H- b]pyridin‐2‐ ESI+, RT = 1H), 8.56 (s, 1H), pyrazolo[3,4- yl}methyl)‐1- 0.96 (S1)8.24 (d, J = 8.5b]pyridin-6-yl}- methanesulfo Hz, 1H), 7.11 (s, 3-methyl-5- nylazetidine1H), 7.07 (br. s.(trifluoromethyl) (Intermediate1H), 7.06 (d, J =phenol 62) 8.6 Hz, 1H), 4.73 and 3-methyl-(d, J = 7.3 Hz,2-(4,4,5,5-2H), 3.99 (t, J =tetramethyl- 8.4 Hz, 2H), 3.83 1,3,2-(dd, J = 6.1, 8.2dioxaborolan- Hz, 2H), 3.28 - 2-yl)-5- 3.16 (m, 1H), (trifluorometh 2.98 (s, 3H), 2.09 yl)phenol (s, 3H) (Intermediate 5)34 rac-2-{2-[(1-rac-3‐({6‐ M / Z:1H NMR (500 ethylpiperidin-3- chloro‐2H‐ 419.5 MHz, DMSO-d6) yl)methyl]-2H- pyrazolo[3,4‐ [M+H]+,δ = 10.17 (br. s.,pyrazolo[3,4- b]pyridin‐2‐ ESI+, RT = 1H), 8.45 (s, 1H), b]pyridin-6-yl}- yl}methyl)‐1‐ 0.71 (S1)8.22 (d, J = 8.43-methyl-5- ethylpiperidin Hz, 1H), 7.10 (br. (trifluoromethyl) e s., 1H), 7.07 (s, phenol (Intermediate1H), 7.05 (d, J =56) and 3-8.4 Hz, 1H), 4.47 methyl-2-- 4.30 (m, 2H),(4,4,5,5-2.69 - 2.55 (m,tetramethyl-2H), 2.32 - 2.201,3,2- (m, 3H), 2.09 (s, dioxaborolan-3H), 1.96 (br. t., J2-yl)-5- = 9.2 Hz, 1H),(trifluorometh1.85 (br. t., J =yl)phenol 9.9 Hz, 1H), 1.65 (Intermediate(td, J = 3.7, 13.05) Hz, 1H), 1.59 - 1.50 (m, 1H), 1.47 - 1.35 (m,1H), 1.10 - 1.00(m, 1H), 0.94 (t, J = 7.1 Hz, 3H)35O NN S 2-[2-(1-4-{6-chloro- M / Z:1H NMR (400 NNO F C OH methanesulfonyl 2H- 455.4MHz, CDCl3) δ =piperidin-4-yl)- pyrazolo[3,4- [M+H]+, 8.20 (d, J = 8.7 2H- b]pyridin-2- ESI+, RT = Hz, 1H), 8.06 (s, pyrazolo[3,4- yl}-1- 0.97 (S1)1H), 7.35 (d, J =b]pyridin-6-yl]- methanesulfo 8.7 Hz, 1H), 7.18 3-methyl-5- nylpiperidine(d, J = 1.8 Hz,(trifluoromethyl) (Intermediate1H), 7.09 (t, J =phenol 63) 1.1 Hz, 1H), 4.66 and 3-methyl-(tt, J = 10.8, 4.32-(4,4,5,5- Hz, 1H), 4.04 (dd, tetramethyl-J = 12.8, 4.0 Hz,1,3,2- 2H), 3.06 (ddd, J dioxaborolan- = 12.6, 11.1, 2.9 2-yl)-5- Hz, 2H), 2.90 (s, (trifluorometh 3H), 2.55 (s, 3H), yl)phenol2.45 (dd, J = 13.2,(Intermediate 3.9 Hz, 2H), 2.40 5)– 2.28 (m, 2H).36 2-{2-[1-4‐{6‐chloro‐ M / Z:1H NMR (500 (ethanesulfonyl) 2H‐ 469.3 MHz, DMSO-d6) piperidin-4-yl]- pyrazolo[3,4‐ [M+H]+,δ = 10.19 (br. s.,2H- b]pyridin‐2‐ ESI+, RT = 1H), 8.55 (s, 1H), pyrazolo[3,4- yl}‐1‐ 1.03 (S1)8.22 (d, J = 8.5b]pyridin-6-yl}- (ethanesulfon Hz, 1H), 7.14 -3-methyl-5- yl)piperidine 7.01 (m, 3H), (trifluoromethyl) (Intermediate4.74 (tt, J = 4.1,phenol64) and 3-11.2 Hz, 1H), methyl-2-3.79 (br. d., J =(4,4,5,5- 12.6 Hz, 2H), tetramethyl-3.20 - 3.03 (m,1,3,2-4H), 2.28 - 2.21dioxaborolan- (m, 2H), 2.15 (dq, 2-yl)-5-J = 4.3, 12.0 Hz,(trifluorometh 2H), 2.09 (s, 3H), yl)phenol 1.25 (t, J = 7.3 (Intermediate Hz, 3H) 5)37 2‐{2‐[1‐4‐{6‐chloro‐ M / Z:1H NMR (500 (cyclobutanesulf 2H‐ 495.3 MHz, DMSO-d6) onyl)piperidin‐4‐ pyrazolo[3,4‐ [M+H]+,δ = 10.08 (s, 1H),yl]‐2H‐ b]pyridin‐2‐ ESI+, RT = 8.56 (s, 1H), 8.23 pyrazolo[3,4‐ yl}‐1‐1.09 (S1) (d, J = 8.5 Hz,b]pyridin‐6‐yl}‐ (cyclobutanes1H), 7.17 – 7.023‐methyl‐5‐ ulfonyl)piperi (m, 3H), 4.80 – (trifluoromethyl) dine 4.68 (m, 1H), phenol (Intermediate4.10 (p, J = 8.465) Hz, 1H), 3.79 (d, and 3-methyl-J = 12.3 Hz, 2H),2-(4,4,5,5-3.08 (t, J = 11.9tetramethyl- Hz, 2H), 2.45 – 1,3,2- 2.20 (m, 6H), dioxaborolan-2.19 – 2.07 (m,2-yl)-5-5H), 2.07 – 1.87(trifluorometh (m, 2H). yl)phenol (Intermediate 5)38O N N1‐(4‐{6‐[2‐1-(4-{6- M / Z:1H NMR (400 N N O FC OHhydroxy‐6‐ chloro-2H- 449.4 MHz, MeOD-d4) methyl‐4‐ pyrazolo[3,4- [M+H]+, δ = 8.42 (s, 1H), (trifluoromethyl) b]pyridin-2- ESI+, RT =8.27 (d, J = 8.5phenyl]‐2H‐ yl}piperidin- 0.90 (S1) Hz, 1H), 7.16 (d, pyrazolo[3,4‐ 1-yl)-2-J = 8.5 Hz, 1H),b]pyridin‐2‐ methoxyethan7.09 (d, J = 0.8yl}piperidin‐1‐ -1-one Hz, 1H), 7.03 (d, yl)‐2‐ (IntermediateJ = 1.7 Hz, 1H),methoxyethan‐1‐ 66)4.86 (dd, J = 11.1,one and 3-methyl- 4.4 Hz, 1H), 4.68 2-(4,4,5,5-(d, J = 13.6 Hz,tetramethyl- 1H), 4.23 1,3,2-(q, J = 14.0 Hz,dioxaborolan-2H), 4.09 (d, J =2-yl)-5- 14.0 Hz, 1H), (trifluorometh 3.43 (s, 3H), 3.38 yl)phenol– 3.32 (m, 1H),(Intermediate2.97 (t, J = 12.85) Hz, 1H), 2.17 (s, 7H)39 1-(4-{6-[2-1‐(4‐{6‐ M / Z:1H NMR (400 hydroxy-6- chloro‐2H‐ 450.4 MHz, MeOD-d4) methyl-4- pyrazolo[3,4‐ [M+H]+, δ = 8.69 (s, 1H), (trifluoromethyl) b]pyrazin‐2‐ ESI+, RT = 8.61 (s, 1H), 7.10 phenyl]-2H- yl}piperidin‐ 0.88 (S1)– 7.06 (m, 1H),pyrazolo[3,4- 1‐yl)‐2‐ 7.04 (s, 1H), 4.92 b]pyrazin-2- methoxyethan (ddd, J = 15.6, yl}piperidin-1- ‐1‐one 11.1, 4.4 Hz, 1H), yl)-2- (Intermediate4.71 (d, J = 13.5methoxyethan-1-67) and 3-Hz, 1H), 4.25 (q, one methyl-2- J = 14.1 Hz, 2H), (4,4,5,5- 4.12 (d, J = 14.1 tetramethyl- Hz, 1H), 3.45 (s,1,3,2-3H), 3.35 (d, J =dioxaborolan- 3.9 Hz, 1H), 2.99 2-yl)-5-(t, J = 12.8 Hz,(trifluorometh 1H), 2.33 (s, 3H), yl)phenol 2.23 (s, 3H), 2.20 (Intermediate– 2.13 (m, 1H)5)40 rac-3-methyl-2-rac-4‐{6‐ M / Z:1H NMR (500 {2-[1-(oxolane- chloro‐2H‐ 475.4 MHz, DMSO-d6) 3- pyrazolo[3,4‐ [M+H]+,δ = 10.52 - 9.58carbonyl)piperid b]pyridin‐2‐ ESI+, RT = (m, 1H), 8.55 (s, in-4-yl]-2H- yl}‐1‐ 0.95 (S1)1H), 8.22 (d, J =pyrazolo[3,4- (oxolane‐3‐ 8.5 Hz, 1H), 7.14 b]pyridin-6-yl}- carbonyl)pipe- 7.00 (m, 3H),5- ridine4.84 (br. t., J =(trifluoromethyl) (Intermediate 10.7 Hz, 1H), phenol69) and 3- 4.65 - 4.08 (m,methyl-2-2H), 3.99 - 3.64(4,4,5,5- (m, 4H), 3.44 tetramethyl-(quin, J = 7.4 Hz,1,3,2-1H), 3.32 - 2.77dioxaborolan- (m, 2H), 2.26 - 2-yl)-5- 2.14 (m, 2H), (trifluorometh 2.09 (s, 3H), 2.09 yl)phenol- 1.88 (m, 4H)(Intermediate 5)41 rac-3-methyl-2-rac-4-{6- M / Z:1H NMR (400 {2-[1-(1- chloro-2H- 488.4 MHz, DMSO-d6) methylpyrrolidin pyrazolo[3,4- [M+H]+, δ = 10.07 (s, 1H), e-3- b]pyridin-2- ESI+, RT = 8.56 (s, 1H), 8.23 carbonyl)piperid yl}-1-(1- 0.71 (S1)(d, J = 8.5 Hz,in-4-yl]-2H- methylpyrroli1H), 7.19 – 6.92pyrazolo[3,4- dine-3- (m, 3H), 4.96 –b]pyridin-6-yl}- carbonyl)pipe 4.65 (m, 1H), 5- ridine4.57 (d, J = 13.3(trifluoromethyl) (Intermediate Hz, 1H), 4.12 (d, phenol 70)J = 13.9 Hz, 1H),and 3-methyl-3.25 (d, J = 13.12-(4,4,5,5- Hz, 2H), 2.88 – tetramethyl- 2.72 (m, 2H), 1,3,2-2.56 (d, J = 8.7dioxaborolan- Hz, 1H), 2.43 – 2-yl)-5- 2.29 (m, 1H), (trifluorometh2.29 – 2.13 (m,yl)phenol 5H), 2.11 (s, 7H) (Intermediate 5)42 2‐{2‐[1‐(1‐4‐{6‐chloro‐ M / Z:1H NMR (400fluorocyclopropa 2H‐ 463.4 MHz, DMSO-d6) necarbonyl)piper pyrazolo[3,4‐ [M+H]+, δ = 10.09 (s, 1H), idin‐4‐yl]‐2H‐ b]pyridin‐2‐ ESI+, RT = 8.57 (s, 1H), 8.23 pyrazolo[3,4‐ yl}‐1‐(1‐1.06 (S1) (d, J = 8.5 Hz,b]pyridin‐6‐yl}‐ fluorocyclopr1H), 7.17 – 6.993‐methyl‐5‐ opanecarbony (m, 3H), 4.91 (tt, (trifluoromethyl) l)piperidineJ = 11.3, 4.1 Hz,phenol (Intermediate1H), 4.48 – 4.3571) and 3-(m, 2H), 2.27 (d, methyl-2-J = 12.2 Hz, 2H),(4,4,5,5- 2.11 (s, 5H), 1.41 tetramethyl-– 1.16 (m, 4H)1,3,2- dioxaborolan- 2-yl)-5- (trifluorometh yl)phenol (Intermediate 5)43 3‐methyl‐5‐4‐{6‐chloro‐ M / Z:1H NMR (400 (trifluoromethyl) 2H‐ 513.3 MHz, DMSO-d6) ‐2‐(2‐{1‐[1‐ pyrazolo[3,4‐ [M+H]+, δ = 10.10 (s, 1H), (trifluoromethyl) b]pyridin‐2‐ ESI+, RT = 8.56 (s, 1H), 8.23 cyclopropanecar yl}‐1‐[1‐1.10 (S1) (d, J = 8.5 Hz,bonyl]piperidin‐ (trifluorometh1H), 7.16 – 6.994‐yl}‐2H‐ yl)cyclopropa (m, 3H), 4.98 – pyrazolo[3,4‐ necarbonyl]pi 4.78 (m, 1H), b]pyridin‐6‐ peridine4.44 (d, J = 13.3yl)phenol (Intermediate Hz, 2H), 3.18 (d, 72) and 3- J = 3.7 Hz, 1H),methyl-2- 2.70 (s, 1H), 2.25 (4,4,5,5-(d, J = 11.8 Hz,tetramethyl- 2H), 2.11 (s, 5H), 1,3,2-1.40 – 1.21 (m,dioxaborolan- 4H). 2-yl)-5- (trifluorometh yl)phenol (Intermediate 5)44 2‐{2‐[1‐(3,3‐4‐{6‐chloro‐ M / Z:1H NMR (400 difluoroazetidine 2H‐ 496.3 MHz, DMSO-d6) ‐1‐ pyrazolo[3,4‐ [M+H]+, δ = 10.07 (s, 1H), carbonyl)piperid b]pyridin‐2‐ ESI+, RT = 8.54 (s, 1H), 8.22 in‐4‐yl]‐2H‐ yl}‐1‐(3,3‐1.04 (S1) (d, J = 8.4 Hz,pyrazolo[3,4‐ difluoroazetid 1H), 7.12 (s, 1H), b]pyridin‐6‐ ine‐1‐ 7.07 (s, 1H), 7.05 yl}‐3‐methyl‐5‐ carbonyl)pipe(d, J = 8.6 Hz,(trifluoromethyl) ridine1H), 4.85 - 4.72phenol (Intermediate (m, 1H), 4.38 (t, J 73) and 3-= 13.0 Hz, 4H), methyl-2-3.95 (br d, J =(4,4,5,5- 13.5 Hz, 2H),tetramethyl- 3.04 (br t, J = 1,3,2- 11.9 Hz, 2H), dioxaborolan-2.21 - 2.12 (m,2-yl)-5- 2H), 2.10 (s, 3H), (trifluorometh2.08 - 1.97 (m,yl)phenol 2H). (Intermediate 5)45 rac-2‐[2‐(2,2‐rac-6‐chloro‐ M / Z:1H NMR (400 dimethyloxan‐4‐ 2‐(2,2‐ 406.2 MHz, DMSO-d6) yl)‐2H‐ dimethyloxan‐ [M+H]+, δ = 10.10 (br s, pyrazolo[3,4‐ 4‐yl)‐2H‐ ESI+, RT = 1H), 8.54 (s, 1H), b]pyridin‐6‐yl]‐ pyrazolo[3,4‐ 1.09 (S1)8.21 (d, J = 8.43‐methyl‐5‐ b]pyridine Hz, 1H), 7.12 (s, (trifluoromethyl) (Intermediate 1H), 7.07 (s, 1H), phenol49) and 3- 7.04 (d, J = 8.4methyl-2- Hz, 1H), 5.08 - (4,4,5,5- 4.90 (m, 1H), tetramethyl-3.89 - 3.72 (m,1,3,2- 2H), 2.10 (s, 3H), dioxaborolan-2.09 - 1.92 (m,2-yl)-5- 4H), 1.32 (s, 3H), (trifluorometh 1.24 (s, 3H) yl)phenol (Intermediate 5)46 3‐methyl‐2‐(2‐(2R)‐2‐({6‐ M / Z:1H NMR (400 {[(2R)‐4‐ chloro‐2H‐ 407.4 MHz, DMSO-d6) methylmorpholi pyrazolo[3,4‐ [M+H]+, δ = 10.13 (s, 1H), n‐2‐yl]methyl}‐ b]pyridin‐2‐ ESI+, RT = 8.45 (s, 1H), 8.23 2H‐ yl}methyl)‐4‐0.65 (S1) (d, J = 8.5 Hz,pyrazolo[3,4‐ methylmorph 1H), 7.12 (s, 1H), b]pyridin‐6‐yl)‐ oline7.10 – 7.02 (m,5‐ (Intermediate2H), 4.59 – 4.48(trifluoromethyl) 50) and 3- (m, 2H), 4.02 (d, phenol methyl-2-J = 8.4 Hz, 1H),(4,4,5,5-3.82 – 3.75 (m,tetramethyl-1H), 3.47 (td, J =1,3,2- 11.2, 2.5 Hz, 1H), dioxaborolan-2.76 (d, J = 11.22-yl)-5- Hz, 1H), 2.58 (d, (trifluoromethJ = 11.2 Hz, 1H),yl)phenol 2.19 (s, 3H), 2.11 (Intermediate (s, 3H), 2.09 – 5) 1.95 (m, 1H), 1.86 (dd, J = 11.2,9.9 Hz, 1H).47 3‐methyl‐2‐(2‐(2S)‐2‐({6‐ M / Z:1H NMR (400 {[(2S)‐4‐ chloro‐2H‐ 407.1 MHz, DMSO-d6) methylmorpholi pyrazolo[3,4‐ [M+H]+, δ = 10.09 (s, 1H), n‐2‐yl]methyl}‐ b]pyridin‐2‐ ESI+, RT = 8.45 (s, 1H), 8.23 2H‐ yl}methyl)‐4‐0.79 (S2) (d, J = 8.5 Hz,pyrazolo[3,4‐ methylmorph1H), 7.18 – 6.98b]pyridin‐6‐yl)‐ oline (m, 3H), 4.62 – 5‐ (Intermediate 4.46 (m, 2H), (trifluoromethyl)51) and 3- 4.02 (q, J = 5.9phenol methyl-2- Hz, 1H), 3.79 (dd, (4,4,5,5- J = 11.5, 2.9 Hz, tetramethyl-1H), 3.47 (td, J =1,3,2- 11.1, 2.5 Hz, 1H), dioxaborolan-2.77 (d, J = 11.22-yl)-5- Hz, 1H), 2.58 (d, (trifluoromethJ = 11.5 Hz, 1H),yl)phenol 2.19 (s, 3H), 2.11 (Intermediate (s, 3H), 2.01 (td, J 5) = 11.2, 3.3 Hz, 1H), 1.91 – 1.78(m, 1H).48 ethyl 1‐({6‐[2‐ethyl 1‐({6‐ M / Z:1H NMR (400 hydroxy‐6‐ chloro‐2H‐ 420.3 MHz, CD3CN-d3) methyl‐4‐ pyrazolo[3,4‐ [M+H]+, δ = 10.32 (s, 1H), (trifluoromethyl) b]pyridin‐2‐ ESI+, RT = 8.36 (s, 1H), 8.29 phenyl]‐2H‐ yl}methyl)cyc1.11 (S1) (d, J = 8.6 Hz,pyrazolo[3,4‐ lopropane‐1‐1H), 7.46 (d, J =b]pyridin‐2‐ carboxylate 7.7 Hz, 1H), 7.30 yl}methyl)cyclo (Intermediate(d, J = 8.6 Hz,propane‐1‐ 53)1H), 7.20 – 7.14carboxylate and 3-methyl- (m, 1H), 7.11 (d, 2-(4,4,5,5- J = 1.9 Hz, 1H), tetramethyl-4.07 (q, J = 7.11,3,2- Hz, 2H), 2.41 (s, dioxaborolan- 3H), 2.14 (s, 2H), 2-yl)-5-1.42 – 1.35 (m,(trifluorometh2H), 1.35 – 1.25yl)phenol (m, 2H), 1.16 (t, J (Intermediate = 7.1 Hz, 3H). 5)

[0279] Example 49 and Example 50Isomeric mixture of 2‐{2‐[(2R,6S)‐2,6‐dimethyloxan‐4‐yl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐5‐(trifluoromethyl)phenol was synthesised according to the general route 49 asexemplified by Example 11 starting from 6‐chloro‐2‐[(2R,6S)‐2,6‐dimethyloxan‐4‐yl]‐2H‐pyrazolo[3,4‐b]pyridine (Intermediate 55, 30 mg, 0.11 mmol) and 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (Intermediate 5, 44 mg, 0.13mmol). It was separated by preparative HPLC to yield single isomers: MDAP Waters with mass spectrometry detection (MS:ZQ2000). Column: CSH C18 (30x100mm, 5µm). Conditions: [A1: Water + 0.1% HCOOH]; [B1: ACN].Preparative HPLC protocolGradient: from 50.0% B1 to 51.0% B1 in 10min (flow:40.00mL / min). Detection: UV / Vis detection range 210 nm to 350nm MS(ES+ / ES-) Scan range 100 to 1000 AMUEx Structure Name Characterisation49 3‐methyl‐2‐{2‐ M / Z:406.3 [M+H]+, ESI+, RT = 1.11 (S1)[(2R,4r,6S)‐ 2,6‐1H NMR (400 MHz, DMSO-d6) δ = 10.24dimethyloxan‐(br. s, 1H), 8.51 (s, 1H), 8.20 (d, J = 8.5 Hz,4‐yl]‐2H‐1H), 7.11 – 7.01 (m, 3H), 4.83 (ddt, J =pyrazolo[3,4‐11.9, 8.3, 4.1 Hz, 1H), 3.68 (ddd, J = 12.3,b]pyridin‐6‐7.0, 5.3 Hz, 2H), 2.20 – 2.12 (m, 2H), 2.10yl}‐5‐(s, 3H), 1.76 (q, J = 11.8 Hz, 2H), 1.20 (d, J(trifluorometh = 6.2 Hz, 6H). yl)phenol 50 3‐methyl‐2‐{2‐ M / Z:406.3 [M+H]+, ESI+, RT = 1.13 (S1)[(2R,4s,6S)‐ 2,6‐1H NMR (400 MHz, DMSO-d6) δ = 10.14dimethyloxan‐(br. s, 1H), 8.63 (s, 1H), 8.22 (d, J = 8.5 Hz,4‐yl]‐2H‐1H), 7.13 – 7.02 (m, 3H), 5.04 – 4.92 (m,pyrazolo[3,4‐1H), 3.95 – 3.83 (m, 2H), 2.42 – 2.34 (m,b]pyridin‐6‐2H), 2.10 (s, 3H), 1.78 (ddd, J = 15.1, 11.5,yl}‐5‐ 4.7 Hz, 2H), 1.12 (d, J = 6.2 Hz, 6H). (trifluorometh yl)phenol

[0280] Example 51 and Example 52:Rac-2‐{2‐[(1‐ethylpiperidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl}‐3‐methyl‐5‐(trifluoromethyl)phenol was synthesised according to the general route 49 as exemplified byExample 11 starting from rac-3‐({6‐chloro‐2H‐pyrazolo[3,4‐b]pyrazin‐2‐yl}methyl)‐1‐ ethylpiperidine (Intermediate 59, 1:1.5 mixture with the other regioisomer, 134 mg, 0.24 mmol) and 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (Intermediate 5, 145 mg. 0.48 mmol) It was separated by preparativechiral HPLC to yield single enantiomers:Column Chiralpak AD-H (25 x 2.0 cm), 5µm, Mobil phase Preparative chiral n-Hexane / (Ethanol / Methanol 1 / 1) 85 / 15 % v / v, Flow rate chromatography protocol 17 mL / min, DAD detection 220 nm, , Loop 2500 μLEx Structure Name Characterisation51 Enantiomer 1:RT= 21.6 min, 100 % ee 2‐(2‐{[(3R orM / Z:420.3 [M+H]+, ESI+, RT = 0.68 (S1) 3S)‐1‐ ethylpiperidin‐1H NMR (400 MHz, MeOD-d4) δ = 8.64 (s,3‐yl]methyl}‐ 1H), 8.60 (s, 1H), 7.14 (s, 1H), 7.07 (s, 1H), 2H‐4.49 (d, J = 7.1 Hz, 2H), 2.98 - 2.91 (m, 1H),pyrazolo[3,4‐2.89 - 2.83 (m, 1H), 2.47 (q, J = 7.2 Hz, 2H),b]pyrazin‐6‐2.52 - 2.35 (m, 1H), 2.23 (s, 3H), 2.12 - 2.02yl)‐3‐methyl‐(m, 1H), 1.97 (t, J = 10.9 Hz, 1H), 1.85 -5‐1.71 (m, 2H), 1.69 - 1.54 (m, 1H), 1.26 -(trifluorometh 1.12 (m, 1H), 1.08 (t, J = 7.2 Hz, 3H yl)phenol 52 Enantiomer 2:RT= 23.8 min, 100% ee 2‐(2‐{[(3S orM / Z:420.3 [M+H]+, ESI+, RT = 0.68 (S1) 3R)‐1‐ ethylpiperidin‐1H NMR (400 MHz, MeOD-d4) δ = 8.64 (s,3‐yl]methyl}‐ 1H), 8.60 (s, 1H), 7.14 (s, 1H), 7.07 (s, 1H), 2H‐4.49 (d, J = 7.1 Hz, 2H), 2.98 - 2.91 (m, 1H),pyrazolo[3,4‐2.89 - 2.83 (m, 1H), 2.47 (q, J = 7.2 Hz, 2H),b]pyrazin‐6‐2.52 - 2.35 (m, 1H), 2.23 (s, 3H), 2.12 - 2.02yl)‐3‐methyl‐(m, 1H), 1.97 (t, J = 10.9 Hz, 1H), 1.85 -5‐1.71 (m, 2H), 1.69 - 1.54 (m, 1H), 1.26 -(trifluorometh 1.12 (m, 1H), 1.08 (t, J = 7.2 Hz, 3H yl)phenol

[0281] Example 53 and Example 54:Rac-3-methyl-2-[2-(oxolan-3-yl)-2H-pyrazolo[3,4-b]pyridin-6-yl]-5-(trifluoromethyl)phenol(Example 14) was separated into the single enantiomers by preparative chiral HPLC to yieldsingle enantiomers: Column Chiralpak AD-H (25 x 2.0 cm), 5µm, Modifier Preparative chiral Methanol 20 % v / v, Flow rate 45 mL / min, Pressure 120 bar, chromatography protocol Temperature 40 °C, UV detection 220 nm, Loop 850 μLEx Structure Name Characterization53O NEnantiomer 1:RT= 12.1 min, 98.6% ee NN3‐methyl‐2‐{2‐ M / Z: 364.3 [M+H]+, ESI+, RT = 0.97 (S1) F3C OH[(3R or 3S)‐oxolan‐3‐yl]‐1H NMR (400 MHz, DMSO-d6) δ = 10.192H‐(s, 1H), 8.53 (s, 1H), 8.22 (d, J = 8.5 Hz,pyrazolo[3,4‐1H), 7.19 – 6.97 (m, 3H), 5.41 (ddd, J = 7.8,b]pyridin‐6‐6.2, 3.7 Hz, 1H), 4.21 – 4.01 (m, 3H), 3.92yl}‐5‐(td, J = 8.2, 5.4 Hz, 1H), 2.60 – 2.53 (m,(trifluorometh1H), 2.49 – 2.41 (m, 1H), 2.11 (s, 3H)yl)phenol 54O NEnantiomer 2:RT= 13.9 min, 99.4% ee NN3‐methyl‐2‐{2‐ M / Z: 364.3 [M+H]+, ESI+, RT = 0.97 (S1) F3C OH[(3S or 3R)‐oxolan‐3‐yl]‐1H NMR (400 MHz, DMSO-d6) δ = 10.192H‐(s, 1H), 8.53 (s, 1H), 8.22 (d, J = 8.5 Hz,pyrazolo[3,4‐1H), 7.19 – 6.97 (m, 3H), 5.41 (ddd, J = 7.8,b]pyridin‐6‐6.2, 3.7 Hz, 1H), 4.21 – 4.01 (m, 3H), 3.92yl}‐5‐(td, J = 8.2, 5.4 Hz, 1H), 2.60 – 2.53 (m,(trifluorometh1H), 2.49 – 2.41 (m, 1H), 2.11 (s, 3H)yl)phenol

[0282] Example 55 and Example 56:Rac-3-methyl-2-{2-[1-(oxolane-3-carbonyl)piperidin-4-yl]-2H-pyrazolo[3,4-b]pyridin-6-yl}-5-(trifluoromethyl)phenol (Example 40) was separated into the single enantiomers bypreparative chiral HPLC to yield single enantiomers: Column Chiralpak AD-H (25 x 2.0 cm), 5µm, Modifier Preparative chiral Methanol 35 % v / v, Flow rate 45 mL / min, Pressure 120 bar, chromatography protocol Temperature 40 °C, UV detection 220 nm, Loop 800 μLEx Structure Name Characterization55 Enantiomer 1:RT= 10.2 min, 100% ee 3‐methyl‐2‐(2‐ M / Z: 475.3 [M+H]+, ESI+, RT = 0.95 (S1) {1‐[(3R or 3S)‐oxolane‐3‐1H NMR (400 MHz, DMSO-d6 ) δ = 10.52carbonyl]piper- 9.58 (m, 1H), 8.55 (s, 1H), 8.22 (d, J = 8.5idin‐4‐yl}‐2H‐Hz, 1H), 7.14 - 7.00 (m, 3H), 4.84 (br. t., Jpyrazolo[3,4‐= 10.7 Hz, 1H), 4.65 - 4.08 (m, 2H), 3.99 -b]pyridin‐6‐3.64 (m, 4H), 3.44 (quin, J = 7.4 Hz, 1H),yl)‐5‐3.32 - 2.77 (m, 2H), 2.26 - 2.14 (m, 2H),(trifluorometh2.09 (s, 3H), 2.09 - 1.88 (m, 4H)yl)phenol 56 Enantiomer 2:RT= 17.0 min, 100% ee 3‐methyl‐2‐(2‐ M / Z: 475.3 [M+H]+, ESI+, RT = 0.97 (S1) {1‐[(3S or 3R)‐oxolane‐3‐1H NMR (400 MHz, DMSO-d6 ) δ = 10.52carbonyl]piper- 9.58 (m, 1H), 8.55 (s, 1H), 8.22 (d, J = 8.5idin‐4‐yl}‐2H‐Hz, 1H), 7.14 - 7.00 (m, 3H), 4.84 (br. t., Jpyrazolo[3,4‐= 10.7 Hz, 1H), 4.65 - 4.08 (m, 2H), 3.99 -b]pyridin‐6‐3.64 (m, 4H), 3.44 (quin, J = 7.4 Hz, 1H),yl)‐5‐3.32 - 2.77 (m, 2H), 2.26 - 2.14 (m, 2H),(trifluorometh2.09 (s, 3H), 2.09 - 1.88 (m, 4H)yl)phenol

[0283] Example 57 and Example 58Rac-3-methyl-2-{2-[(1-methylpyrrolidin-3-yl)methyl]-2H-pyrazolo[3,4-b]pyrazin-6-yl}-5-(trifluoromethyl)phenol (Example 31) was separated into the single enantiomers bypreparative chiral HPLC to yield single enantiomers: Column Chiralpak AD-H (25 x 2.0 cm), 5µm, Modifier Preparative chiral(Methanol +0.1 isopropylamine) 20% v / v, Flow rate 45chromatography protocol mL / min, Pressure 120 bar, Temperature 40 °C, UV detection 220 nm, Loop 500 μLEx Structure Name Characterization57 Enantiomer 1:RT= 14 min, 100% ee 3‐methyl‐2‐(2‐ M / Z: 392.2 [M+H]+, ESI+, RT = 0.62 (S1) {[(3R or 3S)‐1‐methylpyrrolid1H NMR (400 MHz, MeOD-d4 ) δ = 8.68 (s,in‐3‐1H), 8.62 (s, 1H), 7.15 (t, J = 1.0 Hz, 1H),yl]methyl}‐7.11 – 7.06 (m, 1H), 4.59 (d, J = 7.6 Hz,2H‐2H), 3.14 – 2.98 (m, 1H), 2.77 – 2.58 (m,pyrazolo[3,4‐3H), 2.54 (dd, J = 10.0, 6.1 Hz, 1H), 2.41 (s,b]pyrazin‐6‐3H), 2.25 (s, 3H), 2.09 (dddd, J = 13.3, 9.5,yl)‐5‐7.7, 5.7 Hz, 1H), 1.80 – 1.68 (m, 1H).(trifluorometh yl)phenol 58 Enantiomer 2:RT= 15.2 min, 94.4% ee 3‐methyl‐2‐(2‐ M / Z: 392.2 [M+H]+, ESI+, RT = 0.62 (S1) {[(3S or 3R)‐1‐methylpyrrolid1H NMR (400 MHz, MeOD-d4 ) δ = 8.68 (s,in‐3‐1H), 8.62 (s, 1H), 7.15 (t, J = 1.0 Hz, 1H),yl]methyl}‐7.11 – 7.06 (m, 1H), 4.59 (d, J = 7.6 Hz,2H‐2H), 3.14 – 2.98 (m, 1H), 2.77 – 2.58 (m,pyrazolo[3,4‐3H), 2.54 (dd, J = 10.0, 6.1 Hz, 1H), 2.41 (s,b]pyrazin‐6‐3H), 2.25 (s, 3H), 2.09 (dddd, J = 13.3, 9.5,yl)‐5‐7.7, 5.7 Hz, 1H), 1.80 – 1.68 (m, 1H).(trifluorometh yl)phenolExample compounds in Table 34 were synthesised according to the general route 47 asexemplified by Example 5 using the corresponding starting materials / intermediates.Table 34 ExamStructure Name StartingLCMS1H NMR ple materials data59 rac-2‐{2‐[(1‐rac-2‐{2‐ M / Z:1H NMR (400 ethyl‐4,4‐ [(4,4‐ 455.2 MHz, DMSO-d6) difluoropiperidi difluoropiperi [M+H]+,δ = 10.10 (br. s.,n‐3‐yl)methyl]‐ din‐3‐ ESI+, RT = 1H), 8.53 (s, 1H), 2H‐ yl)methyl]‐ 0.72 (S1).8.24 (d, J = 8.6pyrazolo[3,4‐ 2H‐ Hz, 1H), 7.17 - b]pyridin‐6‐ pyrazolo[3,4‐ 7.03 (m, 3H), yl}‐3‐methyl‐5‐ b]pyridin‐6‐4.76 (dd, J = 4.6,(trifluoromethy yl}‐3‐methyl‐ 13.7 Hz, 1H), l)phenol 5‐4.53 (dd, J = 9.1,(trifluorometh 13.6 Hz, 1H), yl)phenol2.93 - 2.79 (m,(Intermediate1H), 2.41 - 2.31128). (m, 2H), 2.78 - Commercial 2.16 (m, 4H), acetaldehyde 2.10 (s, 3H), 2.22 was used- 1.88 (m, 2H),instead of0.93 (t, J = 7.2formaldehyde. Hz, 3H)60 rac-2‐{2‐[(3‐rac-2‐{2‐[(3‐ M / Z:1H NMR (400 fluoro‐1‐ fluoropyrrolid 410.1 MHz, DMSO-d6) methylpyrrolidi in‐3‐ [M+H]+,δ =10.50 (br. s.,n‐3‐yl)methyl]‐ yl)methyl]‐ ESI+, RT = 1H), 8.83 (s, 1H), 2H‐ 2H‐0.63 (S1).8.58 (s, 1H), 7.16 pyrazolo[3,4‐ pyrazolo[3,4‐ (s, 1H), 7.10 (s, b]pyrazin‐6‐ b]pyrazin‐6‐1H), 4.99 - 4.80yl}‐3‐methyl‐5‐ yl}‐3‐methyl‐ (m, 2H), 2.98 - (trifluoromethy 5‐ 2.80 (m, 1H), l)phenol (trifluorometh2.78 - 2.60 (m,yl)phenol2H), 2.48 - 2.42(Intermediate (m, 1H), 2.26 (s, 129)3H), 2.39 - 2.21(m, 1H), 2.17 (s,3H), 2.05 - 1.88(m, 1H)Example 61: cis- 2‐[2‐(3‐hydroxycyclobutyl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐3‐methyl‐5‐(trifluoromethyl)phenolA solution of cis-2‐{2‐[3‐(benzyloxy)cyclobutyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐5‐(trifluoromethyl)phenol (Intermediate 122, 100 mg, 0.22 mmol) in EtOH (2.5 mL), 10% Pd / C(23 mg, 0.02 mmol) and was put in H2 atmosphere and stirred for 24 h. The reaction mixture was filtered over a pad of celite® (washing with EtOH) and volatiles were removed in vacuo.This material was purified by reverse chromatography on C18 cartridge (5-50% of ACN +0.1%HCOOH in H2O+0.1% HCOOH) to yield the title compound (50 mg, 0.14 mmol, 62% yield).1H NMR (400 MHz, DMSO-d6) δ = 10.10 (br. s., 1H), 8.51 (s, 1H), 8.20 (d, J = 8.4 Hz, 1H),7.12 (s, 1H), 7.08 (s, 1H), 7.05 (d, J = 8.4 Hz, 1H), 5.39 (d, J = 6.7 Hz, 1H), 4.82 - 4.66 (m,1H), 4.06 (sxt, J = 7.1 Hz, 1H), 2.92 - 2.80 (m, 2H), 2.59 - 2.52 (m, 2H), 2.10 (s, 3H). M / Z:364.1 [M+H]+, ESI+, RT = 0.91 (S1).Example compounds in Table 35 were synthesised according to the general route 49 asexemplified by Example 11 using the corresponding starting materials / intermediates.Table 35 ExamStructure Name StartingLCMS 1H NMR ple materials data 62O Nrac-3‐methyl‐2‐rac-6‐chloro‐ M / Z:1H NMR (400 NN[2‐(oxepan‐4‐ 2‐(oxepan‐4‐ 392.3 MHz, DMSO-d6) F C OHyl)‐2H- yl)‐2H‐ [M+H]+, δ = 10.10 (s, 1H), pyrazolo[3,4‐ pyrazolo[3,4‐ ESI+, RT = 8.53 (s, 1H), 8.22 b]pyridin‐6‐yl]‐ b]pyridine 1.01(d, J = 8.5 Hz,5- (Intermediate (S1)1H), 7.18 – 6.98(trifluoromethyl)98) and 3-(m, 3H), 4.85 phenol methyl-2-(ddd, J = 14.3,(4,4,5,5- 10.2, 4.3 Hz, 1H), tetramethyl-3.90 – 3.62 (m,1,3,2-4H), 2.45 – 2.16dioxaborolan- (m, 4H), 2.11 (s, 2-yl)-5-3H), 1.92 – 1.81(trifluorometh (m, 2H). yl)phenol (Intermediate 5)63N3‐methyl‐2‐{2‐6‐chloro‐2‐ M / Z:1H NMR (400 NN[(oxan‐4‐ [(oxan‐4‐ 392.2 MHz, DMSO-d6) FCOHOyl)methyl]‐2H‐ yl)methyl]‐ [M+H]+,δ = 10.12 (s, 1H),pyrazolo[3,4‐ 2H‐ ESI+, RT = 8.45 (s, 1H), 8.22 b]pyridin‐6‐yl}‐ pyrazolo[3,4‐ 1.00(d, J = 8.5 Hz,5‐ b]pyridine (S1)1H), 7.14 – 6.99(trifluoromethyl) (Intermediate (m, 3H), 4.37 (d, phenol 99)J = 7.1 Hz, 2H),and 3-methyl-3.88 – 3.79 (m,2-(4,4,5,5- 2H), 3.26 (dd, J = tetramethyl- 11.6, 2.4 Hz, 2H), 1,3,2-2.27 (ddd, J =dioxaborolan- 11.3, 7.4, 4.0 Hz, 2-yl)-5- 1H), 2.10 (s, 3H), (trifluorometh1.47 – 1.21 (m,yl)phenol 4H). (Intermediate 5)64 3‐methyl‐2‐(2‐(3R)‐3‐({6‐ M / Z1N : H NMR (400 NNN O{[(3R)‐4‐ chloro‐2H‐ 407.1 MHz, DMSO-d6) F C OH methylmorpholi pyrazolo[3,4‐ [M+H]+,δ = 10.09 (s, 1H),n‐3‐yl]methyl}‐ b]pyridin‐2‐ ESI+, RT = 8.50 (s, 1H), 8.23 2H‐ yl}methyl)‐4‐ 0.68(d, J = 8.4 Hz,pyrazolo[3,4‐ methylmorph (S1) 1H), 7.12 (s, 1H), b]pyridin‐6‐yl)‐ oline 7.08 (s, 1H), 7.06 5‐ (Intermediate(d, J = 8.4 Hz,(trifluoromethyl) 101)1H), 4.71 (dd, J =phenol and 3-methyl- 3.7, 13.9 Hz, 1H), 2-(4,4,5,5-4.51 (dd, J = 7.2,tetramethyl- 13.9 Hz, 1H), 1,3,2-3.65 (td, J = 3.2,dioxaborolan- 11.1 Hz, 1H), 2-yl)-5-3.54 (dd, J = 3.0,(trifluorometh 11.3 Hz, 1H), yl)phenol3.51 - 3.43 (m,(Intermediate 1H), 3.31-3.26 5) (m, 1H), 2.77 - 2.67 (m, 2H), 2.39 (s, 3H), 2.31 -2.21 (m, 1H),2.10 (s, 3H)65 N O 3,5‐dimethyl‐2‐6‐chloro‐2‐ M / Z:1H NMR (400 NN[2‐(oxan‐4‐yl)‐ (oxan‐4‐yl)‐ 324.1 MHz, DMSO-d6) OH 2H‐ 2H‐ [M+H]+, δ = 9.47 (s, 1H), pyrazolo[3,4‐ pyrazolo[3,4‐ ESI+, RT = 8.51 (s, 1H), 8.16 b]pyridin‐6‐ b]pyridine 0.81(d, J = 8.5 Hz,yl]phenol (Intermediate (S1)1H), 7.05 (d, J =25) with 3,5‐ 8.5 Hz, 1H), 6.62 dimethyl‐2‐– 6.56 (m, 2H),(4,4,5,5‐4.79 (tt, J = 10.6,tetramethyl‐ 4.9 Hz, 1H), 4.08 1,3,2‐– 3.98 (m, 2H),dioxaborolan‐3.56 (td, J = 11.5,2‐yl)phenol 3.0 Hz, 2H), 2.25 (Intermediate (s, 3H), 2.23 – 88) 2.08 (m, 4H), 2.06 (s, 3H)66 5‐chloro‐3‐6‐c1N O hloro‐2‐ M / Z: H NMR (400 NNmethyl‐2‐[2‐ (oxan‐4‐yl)‐ 344.1 MHz, DMSO-d6) Cl OH (oxan‐4‐yl)‐2H‐ 2H‐ [M+H]+,δ = 9.94 (br. s.,pyrazolo[3,4‐ pyrazolo[3,4‐ ESI+, RT = 1H), 8.52 (s, 1H), b]pyridin‐6‐ b]pyridine 0.818.18 (d, J = 8.4yl]phenol (Intermediate (S1) Hz, 1H), 7.02 (d, 25) with 5‐J = 8.6 Hz, 1H),chloro‐3‐ 6.84 (s, 1H), 6.82 methyl‐2‐ (s, 1H), 4.89 - (4,4,5,5‐ 4.69 (m, 1H), tetramethyl‐4.10 - 3.96 (m,1,3,2‐2H), 3.54 (dt, J =dioxaborolan‐ 2.8, 11.4 Hz, 2H), 2‐yl)phenol2.23 - 2.06 (m,(Intermediate 4H), 2.04 (s, 3H) 89)67Cl N O3,5‐dichloro‐2‐6‐chloro‐2‐ M / Z:1H NMR (500 NN[2‐(oxan‐4‐yl)‐ (oxan‐4‐yl)‐ 364.0 MHz, DMSO-d6) Cl OH 2H‐ 2H‐ [M+H]+,δ = 10.58 (br. s.,pyrazolo[3,4‐ pyrazolo[3,4‐ ESI+, RT = 1H), 8.54 (s, 1H), b]pyridin‐6‐ b]pyridine 1.048.21 (d, J = 8.4yl]phenol (Intermediate (S1) Hz, 1H), 7.02 (d, 25) with (2,4-J = 8.5 Hz, 1H),dichloro-6-7.13 - 6.98 (m,hydroxy-1H), 6.91 (br. s.,phenyl)boroni1H), 4.85 - 4.76c acid (m, 1H), 4.03 (br. dd., J = 3.6, 10.4Hz, 2H), 3.55 (dt,J = 2.5, 11.6 Hz,2H), 2.23 - 2.06(m, 4H)68N O5‐fluoro‐3‐6‐chloro‐2‐ M / Z:1H NMR (500 NNmethyl‐2‐[2‐ (oxan‐4‐yl)‐ 328.1 MHz, DMSO-d6) F OH (oxan‐4‐yl)‐2H‐ 2H‐ [M+H]+,δ = 9.97 (br s,pyrazolo[3,4‐ pyrazolo[3,4‐ ESI+, RT = 1H), 8.52 (s, 1H), b]pyridin‐6‐ b]pyridine 0.838.17 (d, J = 8.4yl]phenol (Intermediate (S1) Hz, 1H), 7.02 (d, 25) with 5‐ J = 8.5 Hz, 1H),fluoro‐3‐6.66 - 6.51 (m,methyl‐2‐2H), 4.84 - 4.73(4,4,5,5‐ (m, 1H), 4.03 (br. tetramethyl‐dd., J = 3.2, 10.71,3,2‐ Hz, 2H), 3.54 (dt, dioxaborolan‐J = 2.5, 11.6 Hz,2‐yl)phenol2H), 2.22 - 2.08(Intermediate (m, 4H), 2.05 (s, 91) 3H)69 2‐(2‐{1‐[(1S)‐4‐{6‐chloro‐ M / Z:1H NMR (400 2,2‐ 2H‐ 481.2 MHz, DMSO-d6) difluorocyclopro pyrazolo[3,4‐ [M+H]+,δ = 9.62 (br. s.,panecarbonyl]pi b]pyridin‐2‐ ESI+, RT =1H), 8.63 - 8.47peridin‐4‐yl}‐ yl}‐1‐[(1S)‐ 0.96 (m, 1H), 8.28 - 2H‐ 2,2‐ (S1) 8.15 (m, 1H), pyrazolo[3,4‐ difluorocyclo 7.12 (s, 1H), 7.08 b]pyridin‐6‐yl)‐ propanecarbo (s, 1H), 7.07 - 3‐methyl‐5‐ nyl]piperidine 7.02 (m, 1H), (trifluoromethyl) (Intermediate5.01 - 4.76 (m,phenol 117) with and1H), 4.61 - 4.113-methyl-2- (m, 2H), 3.55 - (4,4,5,5- 2.83 (m, 3H), tetramethyl- 2.10 (s, 3H), 2.37 1,3,2-- 1.76 (m, 6H)dioxaborolan- 2-yl)-5- (trifluorometh yl)phenol (Intermediate 5) 2‐(2‐{1‐[(1R)‐ 4‐{6‐chloro‐ M / Z:1H NMR (400 70 2,2‐ 2H‐ 481.3 MHz, DMSO-d6) difluorocyclopro pyrazolo[3,4‐ [M+H]+,δ = 9.62 (br. s.,panecarbonyl]pi b]pyridin‐2‐ ESI+, RT =1H), 8.63 - 8.47peridin‐4‐yl}‐ yl}‐1‐[(1R)‐ 0.95 (m, 1H), 8.28 - 2H‐ 2,2‐ (S1) 8.15 (m, 1H), pyrazolo[3,4‐ difluorocyclo 7.12 (s, 1H), 7.08 b]pyridin‐6‐yl)‐ propanecarbo (s, 1H), 7.07 - 3‐methyl‐5‐ nyl]piperidine 7.02 (m, 1H), (trifluoromethyl) (Intermediate5.01 - 4.76 (m,phenol 118) and 3-1H), 4.61 - 4.11methyl-2- (m, 2H), 3.55 - (4,4,5,5- 2.83 (m, 3H), tetramethyl- 2.10 (s, 3H), 2.37 1,3,2-- 1.76 (m, 6H)dioxaborolan- 2-yl)-5- (trifluorometh yl)phenol (Intermediate 5)71 3‐methyl‐2‐{2‐4‐{6‐chloro‐ M / Z:1H NMR (400 [1‐(1‐ 2H‐ 459.3 MHz, DMSO-d6) methylcycloprop pyrazolo[3,4‐ [M+H]+,δ = 10.10 (s, 1H),anecarbonyl)pip b]pyridin‐2‐ ESI+, RT = 8.58 (s, 1H), 8.23 eridin‐4‐yl]‐2H‐ yl}‐1‐(1‐ 0.93(d, J = 8.5 Hz,pyrazolo[3,4‐ methylcyclopr (S1)1H), 7.18 – 7.01b]pyridin‐6‐yl}‐ opanecarbony (m, 3H), 4.855‐ l)piperidine(ddt, J = 11.4, 8.2,(trifluoromethyl) (Intermediate 4.0 Hz, 1H), 4.45 phenol 119) and 3-(d, J = 13.4 Hz,methyl-2- 2H), 3.09 (s, 2H), (4,4,5,5-2.22 (d, J = 12.3tetramethyl- Hz, 2H), 2.13 – 1,3,2- 1.94 (m, 5H), dioxaborolan- 1.29 (s, 3H), 0.86 2-yl)-5-(q, J = 4.2 Hz,(trifluorometh2H), 0.66 – 0.51yl)phenol (m, 2H). (Intermediate 5) 72 rac-2‐{2‐[1‐(2,2‐ rac-4‐{6‐ M / Z:1H NMR (400 difluoro‐1‐ chloro‐2H‐ 495.3 MHz, DMSO-d6) methylcycloprop pyrazolo[3,4‐ [M+H]+,δ = 10.16 (s, 1H),anecarbonyl)pip b]pyridin‐2‐ ESI+, RT =8.57 (d, J = 7.2eridin‐4‐yl]‐2H‐ yl}‐1‐(2,2‐ 0.97 Hz, 1H), 8.23 (d, pyrazolo[3,4‐ difluoro‐1‐ (S1)J = 8.5 Hz, 1H),b]pyridin‐6‐yl}‐ methylcyclopr7.15 – 6.98 (m,3‐methyl‐5‐ opanecarbony3H), 4.96 – 4.80(trifluoromethyl) l)piperidine (m, 1H), 4.60 – phenol (Intermediate 4.39 (m, 1H), 120) and 3- 4.01 – 3.87 (m,methyl-2-1H), 3.60 – 3.35(4,4,5,5- (m, 1H), 2.95 (t, J tetramethyl- = 12.6 Hz, 1H), 1,3,2-2.33 – 2.15 (m,dioxaborolan- 2H), 2.10 (s, 3H), 2-yl)-5-2.07 – 1.73 (m,(trifluorometh3H), 1.70 – 1.55yl)phenol (m, 1H), 1.43 (d, (IntermediateJ = 13.8 Hz, 3H).5)73 rac-ethyl 3‐{6‐rac-ethyl 3‐ M / Z:1H NMR (400 [2‐hydroxy‐6‐ {6‐chloro‐2H‐ 408.2 MHz, DMSO-d6) methyl‐4‐ pyrazolo[3,4‐ [M+H]+,δ = 10.14 (br. s.,(trifluoromethyl) b]pyridin‐2‐ ESI+, RT = 1H), 8.53 (s, 1H), phenyl]‐2H‐ yl}butanoate1.11 (S1). 8.21 (d, J = 8.4pyrazolo[3,4‐ (Intermediate Hz, 1H), 7.10 (s, b]pyridin‐2‐106) and 3-1H), 7.07 (s, 1H), yl}butanoate methyl-2-7.04 (d, J = 8.4(4,4,5,5- Hz, 1H), 5.19 - tetramethyl- 5.05 (m, 1H), 1,3,2-4.06 - 3.94 (m,dioxaborolan-2H), 3.21 - 3.112-yl)-5- (m, 1H), 3.08 - (trifluorometh 2.96 (m, 1H), yl)phenol 2.09 (s, 3H), 1.59 (Intermediate(d, J = 6.7 Hz,5)3H), 1.08 (t, J =7.0 Hz, 3H)74 3‐methyl‐2‐(2‐(3S)‐3‐({6‐ M / Z:1H NMR (400 {[(3S)‐1‐ chloro‐2H‐ 433.4 MHz, DMSO-d6) (oxetan‐3‐ pyrazolo[3,4‐ [M+H]+,δ = 10.59 - 9.88yl)pyrrolidin‐3‐ b]pyridin‐2‐ ESI+, RT = (m, 1H), 8.52 (s, yl]methyl}‐2H‐ yl}methyl)‐1‐ 0.761H), 8.21 (d, J =pyrazolo[3,4‐ (oxetan‐3‐ (S2) 8.4 Hz, 1H), 7.21 b]pyridin‐6‐yl)‐ yl)pyrrolidine- 6.89 (m, 3H),5‐ (Intermediate4.59 - 4.49 (m,(trifluoromethyl)109) and 3- 2H), 4.48 - 4.35phenol methyl-2- (m, 4H), 3.55 (4,4,5,5-(quin, J = 6.2 Hz,tetramethyl-1H), 2.92 - 2.791,3,2- (m, 1H), 2.62 - dioxaborolan- 2.38 (m, 2H), 2-yl)-5-2.48 - 2.30 (m,(trifluorometh 2H), 2.09 (s, 3H),yl)phenol1.97 - 1.83 (m,(Intermediate1H), 1.63 - 1.515) (m, 1H)75 3‐methyl‐2‐(2‐(3R)‐3‐({6‐ M / Z:1H NMR (400 {[(3R)‐1‐ chloro‐2H‐ 433.4 MHz, DMSO-d6) (oxetan‐3‐ pyrazolo[3,4‐ [M+H]+,δ = 10.21 (s, 1H),yl)pyrrolidin‐3‐ b]pyridin‐2‐ ESI+, RT = 8.53 (s, 1H), 8.23 yl]methyl}‐2H‐ yl}methyl)‐1‐ 0.76(d, J = 8.5 Hz,pyrazolo[3,4‐ (oxetan‐3‐ (S2)1H), 7.13 – 7.02b]pyridin‐6‐yl)‐ yl)pyrrolidine (m, 3H), 4.56 (t, J 5‐ (Intermediate = 6.5 Hz, 2H), (trifluoromethyl)110) and 3- 4.45 (dd, J = 6.5,phenol methyl-2- 4.6 Hz, 4H), 3.62 (4,4,5,5-– 3.51 (m, 1H),tetramethyl-2.93 – 2.79 (m,1,3,2-1H), 2.63 – 2.53dioxaborolan- (m, 2H), 2.48 – 2-yl)-5- 2.40 (m, 1H), (trifluorometh2.39 – 2.32 (m,yl)phenol 1H), 2.10 (s, 3H), (Intermediate1.98 – 1.85 (m,5)1H), 1.59 (dq, J =13.3, 6.6 Hz, 1H).76 2‐(2‐{[(3S)‐1‐(3S)‐3‐({6‐ M / Z:1H NMR (400 [(3‐ chloro‐2H‐ 465.3 MHz, DMSO-d6) fluorooxetan‐3‐ pyrazolo[3,4‐ [M+H]+,δ = 10.16 (br. s.,yl)methyl]pyrrol b]pyridin‐2‐ ESI+, RT = 1H), 8.49 (s, 1H), idin‐3‐ yl}methyl)‐1‐ 0.828.22 (d, J = 8.4yl]methyl}‐2H‐ [(3‐ (S2) Hz, 1H), 7.11 (s, pyrazolo[3,4‐ fluorooxetan‐ 1H), 7.07 (s, 1H), b]pyridin‐6‐yl)‐ 3‐7.04 (d, J = 8.63‐methyl‐5‐ yl)methyl]pyr Hz, 1H), 4.66 - rolidine 4.49 (m, 4H),(trifluoromethyl) (Intermediate4.42 (d, J = 7.5phenol111) and 3-Hz, 2H), 2.94 (d, methyl-2-J = 25.5 Hz, 2H),(4,4,5,5-2.88 - 2.76 (m,tetramethyl-1H), 2.50 (td, J =1,3,2- 1.7, 3.5 Hz, 4H), dioxaborolan- 2.09 (s, 3H), 1.95 2-yl)-5-- 1.80 (m, 1H),(trifluorometh1.64 - 1.50 (m,yl)phenol 1H) (Intermediate 5)77 2‐(2‐{[(3R)‐1‐(3R)‐3‐({6‐ M / Z:1H NMR (400 [(3‐ chloro‐2H‐ 465.3 MHz, DMSO-d6) fluorooxetan‐3‐ pyrazolo[3,4‐ [M+H]+,δ = 10.14 (s, 1H),yl)methyl]pyrrol b]pyridin‐2‐ ESI+, RT = 8.50 (s, 1H), 8.22 idin‐3‐ yl}methyl)‐1‐ 0.79(d, J = 8.5 Hz,yl]methyl}‐2H‐ [(3‐ (S2)1H), 7.13 – 7.01pyrazolo[3,4‐ fluorooxetan‐ (m, 3H), 4.73 – b]pyridin‐6‐yl)‐ 3‐ 4.48 (m, 4H), 3‐methyl‐5‐ yl)methyl]pyr4.42 (d, J = 7.5(trifluoromethyl) rolidine Hz, 2H), 3.00 – phenol (Intermediate 2.91 (m, 2H), 115) and 3- 2.88 – 2.75 (m,methyl-2-1H), 2.73 – 2.50(4,4,5,5- (m, 4H), 2.09 (s, tetramethyl-3H), 1.93 – 1.801,3,2- (m, 1H), 1.62 – dioxaborolan- 1.50 (m, 1H). 2-yl)-5- (trifluorometh yl)phenol(Intermediate 5)78 2‐(2‐{[(3S)‐1‐((3S)‐3‐({6‐ M / Z:1H NMR (400 [(1‐ chloro‐2H‐ 499.2 MHz, DMSO-d6) fluorocycloprop pyrazolo[3,4‐ [M+H]+,δ = 10.10 (br. s.,yl)methyl]pyrrol b]pyridin‐2‐ ESI+, RT = 1H), 8.53 (s, 1H), idin‐3‐ yl}methyl)‐1‐ 0.708.25 (d, J = 8.5yl]methyl}‐2H‐ [(1‐ (S1) Hz, 1H), 7.23 – pyrazolo[3,4‐ fluorocyclopr 6.96 (m, 3H), b]pyridin‐6‐yl)‐ opyl)methyl]p4.57 - 4.35 (m,3‐methyl‐5‐ yrrolidine2H), 2.93 - 2.81(trifluoromethyl) (Intermediate (m, 1H), 3.20- phenol 114) 2.75 (m, 6H), and 3-methyl-2.10 (s, 3H), 2.00 2-(4,4,5,5-– 1.90 (m, 1H)tetramethyl-1.80 - 1.72 (m,1,3,2-1H), 1.15 - 0.90dioxaborolan- (m, 2H), 0.88 - 2-yl)-5- 0.65 (m, 2H) (trifluorometh yl)phenol (Intermediate 5)79 2‐(2‐{[(3R)‐1‐(3R)‐3‐({6‐ M / Z:1H NMR (400 [(1‐ chloro‐2H‐ 499.3 MHz, DMSO-d6) fluorocycloprop pyrazolo[3,4‐ [M+H]+,δ = 10.02 (br s,yl)methyl]pyrrol b]pyridin‐2‐ ESI+, RT = 1H), 8.51 (s, 1H), idin‐3‐ yl}methyl)‐1‐ 0.878.22 (d, J = 8.6yl]methyl}‐2H‐ [(1‐ (S2) Hz, 1H), 7.19 - pyrazolo[3,4‐ fluorocyclopr 6.96 (m, 3H), b]pyridin‐6‐yl)‐ opyl)methyl]p4.57 - 4.35 (m,3‐methyl‐5‐ yrrolidine2H), 2.93 - 2.81(trifluoromethyl) (Intermediate (m, 1H), 2.75 (d, phenol113) and 3- J = 22.7 Hz, 2H),methyl-2-2.73 - 2.53 (m,(4,4,5,5- 4H), 2.09 (s, 3H), tetramethyl-1.97 - 1.80 (m,1,3,2-1H), 1.57 (qd, J =dioxaborolan- 6.4, 13.1 Hz, 1H), 2-yl)-5-1.05 - 0.87 (m,(trifluorometh2H), 0.71 - 0.55yl)phenol (m, 2H) (Intermediate 5) 80 butyl 3‐({6‐[2‐butyl 3‐({6‐ M / Z:1H NMR (400 hydroxy‐6‐ chloro‐2H‐ 464.2 MHz, DMSO-d6) methyl‐4‐ pyrazolo[3,4‐ [M+H]+,δ =10.10 (br. s.,(trifluoromethyl) b]pyridin‐2‐ ESI+, RT = 1H), 8.50 (s, 1H), phenyl]‐2H‐ yl}methyl)oxe 1.178.23 (d, J = 8.4pyrazolo[3,4‐ tane‐3‐ (S1) Hz, 1H), 7.11 (s, b]pyridin‐2‐ carboxylate 1H), 7.07 (s, 1H), yl}methyl)oxeta (Intermediate7.05 (d, J = 8.6ne‐3‐carboxylate121) and 3-Hz, 1H), 5.10 (s, methyl-2-2H), 4.85 - 4.75(4,4,5,5- (m, 4H), 4.06 (t, J tetramethyl- = 6.5 Hz, 2H), 1,3,2- 2.08 (s, 3H), 1.50 dioxaborolan-- 1.38 (m, 2H),2-yl)-5-1.15 (qd, J = 7.4,(trifluorometh 14.9 Hz, 2H), yl)phenol0.76 (t, J = 7.4(Intermediate Hz, 3H) 5)Example compound in Table 36 was synthesised according to the general route 44 asexemplified by Example 2 using the corresponding starting materials / intermediates.Table 36 ExamStructure Name StartingLCMS1H NMR ple materials data 81 2‐(2‐{[3‐butyl 3‐({6‐ M / Z:1H NMR (400 (hydroxymethy [2‐hydroxy‐6‐ 394.1 MHz, DMSO-d6) l)oxetan‐3‐ methyl‐4‐ [M+H]+,δ = 10.52 - 9.75yl]methyl}‐2H‐ (trifluorometh ESI+, RT = (m, 1H), 8.48 (s, pyrazolo[3,4‐ yl)phenyl]‐ 0.88 (S1).1H), 8.24 (d, J =b]pyridin‐6‐yl)‐ 2H‐ 8.4 Hz, 1H), 7.15 3‐methyl‐5‐ pyrazolo[3,4‐- 6.98 (m, 3H),(trifluoromethy b]pyridin‐2‐5.17 - 5.04 (m,l)phenol yl}methyl)oxe 1H), 4.76 (s, 2H), tane‐3‐4.62 (d, J = 6.1carboxylate Hz, 2H), 4.37 (d, J= 6.1 Hz, 2H),3.49 (br d, J = 3.8Hz, 2H), 2.09 (s, 3H) Scheme for route 51:Example 82: 2‐(2‐{[1‐(hydroxymethyl)cyclopropyl]methyl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl)‐3‐methyl‐5‐(trifluoromethyl)phenolExample 82Ethyl 1‐({6‐[2‐hydroxy‐6‐methyl‐4‐(trifluoromethyl)phenyl]‐2H‐pyrazolo[3,4‐b]pyridin‐2‐ yl}methyl)cyclopropane‐1‐carboxylate (Example 48, 100 mg, 0.24 mmol) was dissolved inDCM (20 mL) at 0 °C, then 1M DIBAL-H in THF (480 µL, 0.48 mmol) was added. The mixturewas stirred 5h at r.t. The mixture was then diluted with a saturated aqueous solution of NH4Cl and water and extracted with EtOAc. The organic phases were then filtered through a phase separator and concentrated in vacuo. The crude material was purified by reverse chromatography on C18 cartridge (0-70 % of ACN+0.1% HCOOH in H2O+0.1% HCOOH) tothe yield title compound (10 mg, 0.026 mmol, 11% yield) as a white solid.1H NMR (400 MHz, MeOD-d4) δ = 8.39 (s, 1H), 8.30 (d, J = 8.5 Hz, 1H), 7.17 (d, J = 8.5 Hz,1H), 7.12 – 7.08 (m, 1H), 7.04 (d, J = 1.7 Hz, 1H), 4.54 (s, 2H), 3.37 (s, 2H), 2.19 (s, 3H), 0.89– 0.81 (m, 2H), 0.71 – 0.57 (m, 2H). M / Z: 378.3 [M+H]+, ESI+, RT = 0.92 (S1).Example compound in Table 37 was synthesised according to the general route 51 asexemplified by Example 82 using the corresponding starting materials / intermediates.Table 37 ExamStructure Name StartingLCMS 1H NMR ple materials data 83 rac-2‐[2‐(4‐rac-ethy1N l 3‐ M / Z: H NMR (400 NNOH hydroxybutan‐2‐ {6‐[2‐ 366.2 MHz, DMSO-d6) F C OH yl)‐2H‐ hydroxy‐6‐ [M+H]+,δ = 10.19 (br. s.,pyrazolo[3,4‐ methyl‐4‐ ESI+, RT = 1H), 8.48 (s, 1H), b]pyridin‐6‐yl]‐ (trifluorometh0.92 (S1) 8.20 (d, J = 8.43‐methyl‐5‐ yl)phenyl]‐ Hz, 1H), 7.09 (br. (trifluoromethyl) 2H‐ s., 1H), 7.06 (s, phenol pyrazolo[3,4‐1H), 7.04 (d, J =b]pyridin‐2‐ 8.4 Hz, 1H), 4.92 yl}butanoate- 4.80 (m, 1H),(Example 73)4.59 (br. t., J =4.5 Hz, 1H), 3.31 (s, 1H), 3.26 - 3.14 (m, 1H), 2.17 (tdd, J = 5.7,8.3, 13.9 Hz, 1H), 2.10 (s, 3H), 2.06 -1.95 (m, 1H),1.58 (d, J = 6.7Hz, 3H)Example 84: 3‐methyl‐2‐{2‐[(1‐methylazetidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐1 M LiAlH4 in THF (0.22 mL, 0.22 mmol) was added to a solution of tert‐butyl 3‐({6‐[2‐ hydroxy‐6‐methyl‐4‐(trifluoromethyl)phenyl]‐2H‐pyrazolo[3,4‐b]pyridin‐2‐yl}methyl)azetidine‐1‐carboxylate (Intermediate 125, 50 mg, 0.11 mmol) in THF (2.5 mL). Themixture was heated at 70 °C for 1.5 h. The mixture was cooled to r.t., diluted with 2 M NaOHand extracted with EtOAc (3x). Organic phases were dried and evaporated in vacuo, the residuewas purified by chromatography on NH-silica gel (20-80 % EtOAc / EtOH 3 / 1 in cHex) to yieldthe title compound (7.5 mg, 0.02 mmol, 18% yield). 1H NMR (400 MHz, DMSO-d6) δ = 10.08(br s, 1H), 8.49 (s, 1H), 8.22 (d, J = 8.6 Hz, 1H), 7.12 (s, 1H), 7.07 (s, 1H), 7.04 (d, J = 8.4 Hz,1H), 4.65 (d, J = 7.2 Hz, 2H), 3.23 (t, J = 7.1 Hz, 2H), 3.04 - 2.98 (m, 2H), 2.98 - 2.86 (m, 1H),2.20 (s, 3H), 2.09 (s, 3H). M / Z: 377.2 [M+H]+, ESI+, RT = 0.65 (S1)Scheme for route 53:Example 85: 3‐methyl‐2‐[5‐methyl‐2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl]‐5‐(trifluoromethyl)phenolA suspension of 2‐[2‐(3,6‐dihydro‐2H‐pyran‐4‐yl)‐5‐methyl‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl]‐3‐methyl‐5‐(trifluoromethyl)phenol (Intermediate 131, 50 mg, 0.13 mmol) 10% Pd / C (14 mg,0.13 mmol) in EtOH (5 mL) was stirred at r.t. under H2 atmosphere for 3h. The mixture wasfiltered over a pad of celite® washing with EtOH. The solution was dried in vacuo, the residuewas purified by chromatography on silica gel (0-90 % EtOAc in cHex) to yield the titlecompound (23 mg, 0.06 mmol, 46 % yield) as pale yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 10.43 (s, 1H), 8.81 (s, 1H), 7.13 (d, J = 35.1 Hz, 2H), 4.84 (tt, J = 10.6, 5.1 Hz, 1H),4.05 (dt, J = 11.7, 3.4 Hz, 2H), 3.56 (td, J = 11.2, 3.2 Hz, 2H), 2.33 (s, 3H), 2.26 – 2.08 (m,4H), 2.02 (s, 3H). M / Z:393.2 [M+H]+, ESI+, RT = 0.97 (S1).Example 86 and Example 87Regioisomeric mixture 5‐(difluoromethyl)‐3‐methyl‐2‐[2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl]phenol and 3‐(difluoromethyl)‐5‐methyl‐2‐[2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]phenol was synthesised according to the general route 49 asexemplified by Example 11 starting from 6‐chloro‐2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridine(Intermediate 25, 40 mg, 0.17 mmol) and 2:1 mixture of 5‐(difluoromethyl)‐3‐methyl‐2‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)phenol and 3‐(difluoromethyl)‐5‐methyl‐2‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)phenol (Intermediate 90 , 57 mg, 0.20 mmol). Itwas separated by preparative HPLC to yield single regioisomers: MDAP Waters with mass spectrometry detection (MS:ZQ2000). Column: CSH C18 (30x100 mm, 5 µm).Conditions: [A1: Water + 0.1% HCOOH]; [B1: ACN]. Preparative HPLC protocol Gradient: from 37.0% B1 to 42.0% B1 in 10 min (flow:40.00 mL / min). Detection: UV / V is detection range 210 nmto 350 nm MS(ES+ / ES-) Scan range 100 to 1000 AMUEx Structure Name Characterisation86 5‐M / Z:360.0 [M+H]+, ESI+, RT = 0.88 (S1) (difluoromethy l)‐3‐methyl‐2‐[2‐(oxan‐4‐yl)‐1H NMR (400 MHz, DMSO-d6) δ = 9.852H‐(br. s., 1H), 8.53 (s, 1H), 8.20 (d, J = 8.4 Hz,pyrazolo[3,4‐1H), 7.04 (d, J = 8.4 Hz, 1H), 6.97 - 6.93b]pyridin‐6‐(m, 2H), 6.96 (t, J = 56.3 Hz, 1H), 4.87 -yl]phenol4.74 (m, 1H), 4.03 (b.r dd., J = 3.0, 10.4 Hz,2H), 3.55 (dt, J = 2.9, 11.4 Hz, 2H), 2.24 -2.09 (m, 4H), 2.08 (s, 3H) 87 3‐M / Z:360.1 [M+H]+, ESI+, RT = 0.92 (S1) (difluoromethy l)‐5‐methyl‐2‐1H NMR (400 MHz, DMSO-d6) δ = 9.85 (s,[2‐(oxan‐4‐yl)‐1H), 8.54 (s, 1H), 8.19 (d, J = 8.6 Hz, 1H),2H‐7.14 (d, J = 8.4 Hz, 1H), 7.01 (s, 1H), 6.93pyrazolo[3,4‐(s, 1H), 6.84 (t, J = 55.7 Hz, 1H), 4.87 - 4.70b]pyridin‐6‐(m, 1H), 4.03 (br. dd., J = 2.8, 10.4 Hz, 2H),yl]phenol3.54 (dt, J = 2.9, 11.4 Hz, 2H), 2.35 (s, 3H),2.24 - 2.07 (m, 4H)Example 88 and Example 89: Rac-2‐{2‐[(1‐ethyl‐3‐fluoropiperidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐5‐(trifluoromethyl)phenol (Example 6) was separated into the single enantiomers bypreparative chiral HPLC to yield single enantiomers: Column Chiralpak IG (25 x 2.0 cm), 5µm, Mobil phase n-Preparative chiral Hexane / Ethanol 60 / 40 % v / v, Flow rate 17 mL / min, UVchromatography protocoldetection 220 nm, Loop 2000 μLEx Structure Name Characterization88 Enantiomer 1:RT= 6.7 min, 100% ee 2-(2-{[(3R)-1- M / Z: 437.2 [M+H]+, ESI+, RT = 0.69 (S1) ethyl-3- fluoropiperidin-1H NMR (400 MHz, DMSO-d6) δ = 10.173-yl]methyl}-(br. s., 1H), 8.40 (s, 1H), 8.25 (d, J = 8.6 Hz,2H-1H), 7.12 (s, 1H), 7.10 - 7.03 (m, 2H), 4.87pyrazolo[3,4-- 4.71 (m, 2H), 2.60 - 2.43 (m, 2H), 2.43 -b]pyridin-6-yl)-3-methyl-5-2.28 (m, 4H), 2.10 (s, 3H), 1.73 - 1.45 (m,(trifluoromethyl4H), 0.98 (t, J = 7.1 Hz, 3H))phenol (stereochemistr y arbitrarily assigned as 3R) 89 Enantiomer 2:RT= 11.9 min, 99% ee 2-(2-{[(3S)-1- M / Z: 437.2 [M+H]+, ESI+, RT = 0.69 (S1) ethyl-3- fluoropiperidin-1H NMR (400 MHz, DMSO-d6) δ = 10.173-yl]methyl}-(br. s., 1H), 8.40 (s, 1H), 8.25 (d, J = 8.6 Hz,2H-1H), 7.12 (s, 1H), 7.10 - 7.03 (m, 2H), 4.87pyrazolo[3,4-- 4.71 (m, 2H), 2.60 - 2.43 (m, 2H), 2.43 -b]pyridin-6-yl)-2.28 (m, 4H), 2.10 (s, 3H), 1.73 - 1.45 (m,3-methyl-5-4H), 0.98 (t, J = 7.1 Hz, 3H)(trifluoromethyl )phenol (stereochemistr y arbitrarily assigned as 3S) Example 90 and Example 91: Rac-2‐{2‐[(4,4‐difluoro‐1‐methylpiperidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐5‐(trifluoromethyl)phenol (Example 23) was separated into the single enantiomers bypreparative chiral HPLC to yield single enantiomers: Column Chiralpak AD-H (25 x 2.0 cm), 5µm, Mobil phase Preparative chiral n-Hexane / Ethanol 50 / 50 % v / v, Flow rate 17 mL / min, UV chromatography protocol detection 220 nm, Loop 800 μLEx Structure Name Characterization90 Enantiomer 1:RT= 4.4 min, 100% ee 2-(2-{[(3S)- M / Z: 441.1 [M+H]+, ESI+, RT = 0.90 (S2) 4,4-difluoro-1- methylpiperidi1H NMR (400 MHz, DMSO-d6) δ = 10.14n-3-(br. s, 1H), 8.53 (s, 1H), 8.23 (d, J = 8.5 Hz,yl]methyl}-1H), 7.13 – 7.03 (m, 3H), 4.76 (dd, J = 13.7,2H-4.5 Hz, 1H), 4.52 (dd, J = 13.7, 9.2 Hz, 1H),pyrazolo[3,4-2.86 (ddd, J = 18.5, 9.6, 4.9 Hz, 1H), 2.74 –b]pyridin-6-2.64 (m, 1H), 2.25 (d, J = 11.7 Hz, 1H), 2.14yl)-3-methyl-(d, J = 29.5 Hz, 10H).5- (trifluorometh yl)phenol (stereochemist ry arbitrarily assigned as 3S) 91 Enantiomer 2:RT= 5.8 min, 100% ee 2-(2-{[(3R)- M / Z: 441.1 [M+H]+, ESI+, RT = 0.90 (S2) 4,4-difluoro-1- methylpiperidi1H NMR (400 MHz, DMSO-d6) δ = 10.14n-3-(br. s, 1H), 8.53 (s, 1H), 8.23 (d, J = 8.5 Hz,yl]methyl}-1H), 7.13 – 7.03 (m, 3H), 4.76 (dd, J = 13.7,2H-4.5 Hz, 1H), 4.52 (dd, J = 13.7, 9.2 Hz, 1H),pyrazolo[3,4-2.86 (ddd, J = 18.5, 9.6, 4.9 Hz, 1H), 2.74 –b]pyridin-6-2.64 (m, 1H), 2.25 (d, J = 11.7 Hz, 1H), 2.14yl)-3-methyl-(d, J = 29.5 Hz, 10H).5- (trifluorometh yl)phenol (stereochemist ry arbitrarily assigned as 3R) Example 92 and Example 93:Rac-3‐methyl‐2‐[2‐(oxepan‐4‐yl)‐2H-pyrazolo[3,4‐b]pyridin‐6‐yl]‐5-(trifluoromethyl)phenol(Example 62) was separated into the single enantiomers by preparative chiral HPLC to yieldsingle enantiomers: Column Chiralpak IC (25 x 2.0 cm), 5µm, Modifier Preparative chiral Methanol 20 % v / v, Flow rate 45 mL / min, Pressure 120 bar, chromatography protocol Temperature 40 °C, UV detection 220 nm, Loop 850 μLEx Structure Name Characterization92 Enantiomer 1: RT= 7.7 min, 100% ee 3‐methyl‐2‐{2‐ M / Z: 392.2 [M+H]+, ESI+, RT = 1.03 (S1) [(4R)‐oxepan‐ 4‐yl]‐2H‐1H NMR (400 MHz, DMSO-d6) δ = 10.18pyrazolo[3,4‐(br. S., 1H), 8.52 (s, 1H), 8.20 (d, J = 8.4b]pyridin‐6‐ Hz, 1H), 7.10 (s, 1H), 7.06 (s, 1H), 7.04 (d, yl}‐5‐J = 8.4 Hz, 1H), 4.89 - 4.79 (m, 1H), 3.88 -trifluoromethyl3.76 (m, 2H), 3.75 - 3.64 (m, 2H), 2.43 -)phenol2.32 (m, 1H), 2.33 - 2.19 (m, 2H), 2.15 (td,(stereochemistJ = 4.4, 8.7 Hz, 1H), 2.10 (s, 3H), 1.92 - 1.79ry arbitrarily (m, 2H) assigned as 4R) 93 Enantiomer 2:RT= 9.8 min, 99.5% ee 3‐methyl‐2‐{2‐ M / Z: 392.2 [M+H]+, ESI+, RT = 1.03 (S1) [(4S)‐oxepan‐ 4‐yl]‐2H‐1H NMR (400 MHz, DMSO-d6) δ = 10.18pyrazolo[3,4‐(br. s., 1H), 8.52 (s, 1H), 8.20 (d, J = 8.4 Hz,b]pyridin‐6‐1H), 7.10 (s, 1H), 7.06 (s, 1H), 7.04 (d, J =yl}‐5‐8.4 Hz, 1H), 4.89 - 4.79 (m, 1H), 3.88 - 3.76trifluoromethyl(m, 2H), 3.75 - 3.64 (m, 2H), 2.43 - 2.32 (m,)phenol1H), 2.33 - 2.19 (m, 2H), 2.15 (td, J = 4.4,(stereochemist8.7 Hz, 1H), 2.10 (s, 3H), 1.92 - 1.79 (m,ry arbitrarily 2H) assigned as 4S)Example 94 and Example 95:Rac-2‐{2‐[(1‐ethyl‐4,4‐difluoropiperidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐5‐(trifluoromethyl)phenol (Example 59) was separated into the single enantiomers bypreparative chiral HPLC to yield single enantiomers: Column Chiralpak IG (25 x 2.0 cm), 5µm, Mobil phase n- Preparative chiral Hexane / Ethanol 60 / 40 % v / v, Flow rate 17 mL / min, UV chromatography protocol detection 220 nm, Loop 700 μLEx Structure Name Characterization94 Enantiomer 1: RT= 5.7 min, 100% ee 2‐(2‐{[(3S)‐1‐ M / Z: 455.2 [M+H]+, ESI+, RT = 0.73 (S1) ethyl‐4,4‐ difluoropiperid1H NMR (400 MHz, DMSO-d6) δ = 10.10in‐3‐(br. s., 1H), 8.53 (s, 1H), 8.24 (d, J = 8.6 Hz,yl]methyl}‐1H), 7.17 - 7.03 (m, 3H), 4.76 (dd, J = 4.6,2H‐13.7 Hz, 1H), 4.53 (dd, J = 9.1, 13.6 Hz,pyrazolo[3,4‐1H), 2.93 - 2.79 (m, 1H), 2.41 - 2.31 (m,b]pyridin‐6‐2H), 2.78 - 2.16 (m, 4H), 2.10 (s, 3H), 2.22yl)‐3‐methyl‐- 1.88 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H)5‐ (trifluorometh yl)phenol (stereochemist ry arbitrarily assigned as 3S) 95 Enantiomer 2:RT= 8.2 min, 100% ee 2‐(2‐{[(3R)‐1‐ M / Z: 455.2 [M+H]+, ESI+, RT = 0.73 (S1) ethyl‐4,4‐ difluoropiperidin‐3‐1H NMR (400 MHz, DMSO-d6) δ = 10.10yl]methyl}‐(br. s., 1H), 8.53 (s, 1H), 8.24 (d, J = 8.6 Hz,2H‐1H), 7.17 - 7.03 (m, 3H), 4.76 (dd, J = 4.6,pyrazolo[3,4‐13.7 Hz, 1H), 4.53 (dd, J = 9.1, 13.6 Hz,b]pyridin‐6‐1H), 2.93 - 2.79 (m, 1H), 2.41 - 2.31 (m,yl)‐3‐methyl‐2H), 2.78 - 2.16 (m, 4H), 2.10 (s, 3H), 2.225‐- 1.88 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H)(trifluorometh yl)phenol (stereochemist ry arbitrarily assigned as 3R) Example 96 and Example 97Isomeric mixture of 2‐{2‐[(3‐hydroxycyclobutyl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐5‐(trifluoromethyl)phenol was synthesised according to the general route 49 asexemplified by Example 11 starting from 3‐({6‐chloro‐2H‐pyrazolo[3,4‐b]pyridin‐2‐yl}methyl)cyclobutan‐1‐ol (Intermediate 116, 90 mg, 0.38 mmol) and 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (Intermediate 5, 137 mg, 0.45mmol). It was separated by preparative chiral HPLC to yield single isomers:Column Chiralpak AD-H (25 x 2.0 cm), 5µm, Mobil phase Preparative chiral n-Hexane / Ethanol 70 / 30 % v / v, Flow rate 17 mL / min, UV chromatography protocol detection 220 nm, Loop 500 μLEx Structure Name Characterisation96 trans-2‐{2‐[(3‐ RT= 10.4 min, 100% a / a by UVhydroxycyclob M / Z:378.3 [M+H]+, ESI+, RT = 0.90 (S1) utyl)methyl]‐ 2H‐1H NMR (400 MHz, DMSO-d6) δ = 10.10pyrazolo[3,4‐(br. s., 1H), 8.44 (s, 1H), 8.22 (d, J = 8.4 Hz,b]pyridin‐6‐1H), 7.11 (s, 1H), 7.07 (s, 1H), 7.04 (d, J =yl}‐3‐methyl‐8.6 Hz, 1H), 5.06 (br. d., J = 6.0 Hz, 1H),5‐4.46 (d, J = 6.7 Hz, 2H), 4.04 - 3.89 (m, 1H),(trifluorometh2.40 - 2.22 (m, 3H), 2.09 (s, 3H), 1.76 - 1.62yl)phenol (m, 2H) 97 cis-2‐{2‐RT= 13.6 min, 98.9% a / a by UV [(3hydroxycyc M / Z:378.3 [M+H]+, ESI+, RT = 0.90 (S1) lobutyl)methyl ]‐2H‐1H NMR (400 MHz, DMSO-d6) δ = 10.10pyrazolo[3,4‐(br. s., 1H), 8.49 (s, 1H), 8.22 (d, J = 8.4 Hz,b]pyridin‐6‐1H), 7.11 (s, 1H), 7.07 (s, 1H), 7.04 (d, J =yl}‐3‐methyl‐8.4 Hz, 1H), 5.04 (d, J = 6.1 Hz, 1H), 4.505‐(d, J = 7.9 Hz, 2H), 4.28 (sxt, J = 6.7 Hz,(trifluorometh1H), 2.81 - 2.70 (m, 1H), 2.09 (s, 3H), 2.16yl)phenol- 2.07 (m, 2H), 2.01 - 1.90 (m, 2H)Example 98 and Example 99 Rac-2‐{2‐[(4,4‐difluoro‐1‐methylpiperidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3,5‐dimethylphenol was synthesised according to the general route 49 as exemplified byExample 11 starting from rac-3‐({6‐chloro‐2H‐pyrazolo[3,4‐b]pyridin‐2‐yl}methyl)‐4,4‐ difluoro‐1‐methylpiperidine (Intermediate 40, 300 mg, 0.94 mmol) and 3,5‐dimethyl‐2‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)phenol (Intermediate 88, 396 mg, 1.60 mmol). Itwas separated by preparative chiral HPLC to yield single isomers. Absoluteconfiguration was assigned after analysis by X-ray crystallography: Column Chiralpak AD-H (25 x 2.0 cm), 5µm, Preparative chiral chromatography Mobil phase n-Hexane / (Ethanol +0.1% protocol isopropylamine) 60 / 40 % v / v, Flow rate 17 mL / min, UV detection 220 nm, Loop 650 μLEx Structure Name Characterization98 2‐(2‐{[(3S)-4,4‐ RT= 7.9 min, 100% ee difluoro‐1‐ M / Z: 387.2 [M+H]+, ESI+, RT = methylpiperidin‐ 0.59 (S1) (S) 3‐yl]methyl}‐ 2H‐1H NMR (400 MHz, DMSO-d6) δ pyrazolo[3,4‐ = 9.51 (s, 1H), 8.50 (s, 1H), 8.17 b]pyridin‐6‐yl)‐(d, J = 8.5 Hz, 1H), 7.06 (d, J =3,5‐8.5 Hz, 1H), 6.59 (d, J = 8.7 Hz,dimethylphenol2H), 4.75 (dd, J = 13.7, 4.4 Hz,1H), 4.51 (dd, J = 13.7, 9.4 Hz,1H), 2.94 – 2.78 (m, 1H), 2.47-2.43 (m, 1H), 2.31-2.21 (m, 1H), 2.24 (s, 3H), 2.18(s, 3H), 2.16- 2.06 (m, 3H), 2.05 (s, 3H), 2.05- 1.96 (m, 1H) 99 2‐(2‐{[(3R)-4,4‐RT= 12.9 min, 100% ee difluoro‐1‐ M / Z: 387.2 [M+H]+, ESI+, RT = methylpiperidin‐ 0.59 (S1) 3‐yl]methyl}‐ 2H‐1H NMR (400 MHz, DMSO-d6) δ pyrazolo[3,4‐ = 9.51 (s, 1H), 8.50 (s, 1H), 8.17 b]pyridin‐6‐yl)‐(d, J = 8.5 Hz, 1H), 7.06 (d, J =3,5‐8.5 Hz, 1H), 6.59 (d, J = 8.7 Hz,dimethylphenol2H), 4.75 (dd, J = 13.7, 4.4 Hz,1H), 4.51 (dd, J = 13.7, 9.4 Hz,1H), 2.94 – 2.78 (m, 1H), 2.47-2.43 (m, 1H), 2.31-2.21 (m, 1H), 2.24 (s, 3H), 2.18(s, 3H), 2.16- 2.06 (m, 3H), 2.05 (s, 3H), 2.05- 1.96 (m, 1H) Example 100 and Example 101 Rac-2‐{2‐[(4,4‐difluoro‐1‐methylpiperidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐5‐methoxy‐3‐methylphenol was synthesised according to the general route 49 as exemplified byExample 11 starting from rac-3‐({6‐chloro‐2H‐pyrazolo[3,4‐b]pyridin‐2‐yl}methyl)‐4,4‐ difluoro‐1‐methylpiperidine (Intermediate 40, 240 mg, 0.80 mmol) and 5-methoxy-3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (Intermediate 7, 358 mg, 1.36 mmol). Itwas separated by preparative chiral HPLC to yield single isomers: Preparative chiral chromatographyColumn Chiralpak AD-H (25 x 2.0 cm), 5µm,protocol Mobil phase n-Hexane / (Ethanol +0.1%isopropylamine) 50 / 50 % v / v, Flow rate 17mL / min, UV detection 220 nm, Loop 1300 μLEx Structure Name Characterization100 Enantiomer 1: RT= 8.8 min, 100%2‐(2‐{[(3S)‐4,4‐difluoro‐1‐ ee methylpiperidin‐3‐ M / Z: 403.2 [M+H]+, yl]methyl}‐2H‐pyrazolo[3,4‐ESI+, RT = 0.56 (S1)b]pyridin‐6‐yl)‐5‐methoxy‐1H NMR (400 MHz, 3‐methylphenolDMSO-d6) δ = 9.94(stereochemistry arbitrarily (s, 1H), 8.49 (s, 1H), assigned as 3S)8.17 (d, J = 8.6 Hz,1H), 7.09 (d, J = 8.6Hz, 1H), 6.37 (s, 2H), 4.75 (dd, J = 13.7, 4.4Hz, 1H), 4.51 (dd, J =13.6, 9.3 Hz, 1H), 3.75 (s, 3H), 2.94 – 2.76 (m, 1H), 2.73- 2.63 (m, 1H), 2.45 (s, 1H),2.26 (t, J = 10.5Hz, 1H),2.18 (s, 3H), 2.15-2.05 (m, 5H), 2.05-1.96 (m, 1H). 101 Enantiomer 2: RT= 16.8 min, 100%2‐(2‐{[(3R)‐4,4‐difluoro‐1‐ ee methylpiperidin‐3‐ M / Z: 403.2 [M+H]+, yl]methyl}‐2H‐pyrazolo[3,4‐ ESI+, RT = 0.56 (S1) b]pyridin‐6‐yl)‐5‐methoxy‐1H NMR (400 MHz, 3‐methylphenolDMSO-d6) δ = 9.94(stereochemistry arbitrarily (s, 1H), 8.49 (s, 1H), assigned as 3R)8.17 (d, J = 8.6 Hz,1H), 7.09 (d, J = 8.6Hz, 1H), 6.37 (s, 2H),4.75 (dd, J = 13.7, 4.4Hz, 1H), 4.51 (dd, J =13.6, 9.3 Hz, 1H), 3.75 (s, 3H), 2.94 – 2.76 (m, 1H), 2.73- 2.63 (m, 1H), 2.45 (s, 1H),2.26 (t, J = 10.5Hz, 1H),2.18 (s, 3H), 2.15-2.05 (m, 5H), 2.05-1.96 (m, 1H).Example compounds in Table 38 were synthesised according to the general route 47 asexemplified by Example 5 using the corresponding starting materials / intermediates.Table 38 ExamStructure Name StartingLCMS1H NMR ple materials data 102 2‐{2‐[(4‐fluoro‐ 2‐{2‐[(4‐ M / Z:1H NMR (400 1‐ fluoropiperidi 423.3MHz, CDCl3) δ =methylpiperidin n‐4‐ [M+H]+, 11.33 (s, 1H), ‐4‐yl)methyl]‐ yl)methyl]‐ ESI+, RT =8.21 (d, J = 8.82H‐ 2H‐0.67 (S1).Hz, 1H), 8.12 (d, pyrazolo[3,4‐ pyrazolo[3,4‐J = 1.6 Hz, 1H),b]pyridin‐6‐ b]pyridin‐6‐7.34 (d, J = 8.7yl}‐3‐methyl‐5‐ yl}‐3‐methyl‐ Hz, 1H), 7.18 (d, (trifluoromethy 5‐J = 1.9 Hz, 1H),l)phenol (trifluorometh7.08 (d, J = 1.8yl)phenol Hz, 1H), 4.65 (d, (IntermediateJ = 21.6 Hz, 2H),156)2.69 (d, J = 12.0Hz, 2H), 2.55 (s, 3H), 2.32 (s, 5H),1.92 – 1.74 (m,4H).103 rac- 2‐{2‐[(5,5‐rac-2‐{2‐ M / Z:1H NMR (500 difluoro‐1‐ [(5,5‐ 441.2 MHz, DMSO-d6) methylpiperidin difluoropiperi [M+H]+,δ = 10.12 (br s,‐3‐yl)methyl]‐ din‐3‐ ESI+, RT = 1H), 8.47 (s, 1H), 2H‐ yl)methyl]‐ 0.72 (S1).8.24 (d, J = 8.4pyrazolo[3,4‐ 2H‐ Hz, 1H), 7.12 (s, b]pyridin‐6‐ pyrazolo[3,4‐ 1H), 7.08 (s, 1H), yl}‐3‐methyl‐5‐ b]pyridin‐6‐7.06 (d, J = 8.5(trifluoromethy yl}‐3‐methyl‐ Hz, 1H), 4.47 (d, l)phenol 5-J = 7.0 Hz, 2H),(trifluorometh2.87 (q, J = 9.1yl)phenol Hz, 1H), 2.59 (br (Intermediated, J = 12.2 Hz,157)1H), 2.56 - 2.51(m, 1H), 2.38 - 2.27 (m, 1H), 2.21 (s, 3H), 2.10 (s, 3H), 2.08 - 2.00 (m, J = 10.0Hz, 1H), 2.00 - 1.93 (m, 1H), 1.77 - 1.61 (m,1H)104 2‐{2‐[(3‐fluoro‐2‐{2‐[(3‐ M / Z:1H NMR (400 1‐ fluoroazetidin 395.1 MHz, DMSO-d6) methylazetidin‐ ‐3‐yl)methyl]‐ [M+H]+,δ = 10.22 – 10.173‐yl)methyl]‐ 2H‐ ESI+, RT = (bs, 1H), 8.47 (s, 2H‐ pyrazolo[3,4‐0.67 (S1). 1H), 8.23 (d, J =pyrazolo[3,4‐ b]pyridin‐6‐ 8.5 Hz, 1H), 7.14 b]pyridin‐6‐ yl}‐3‐methyl‐– 7.01 (m, 3H),yl}‐3‐methyl‐5‐ 5‐4.93 (d, J = 22.6(trifluorometh Hz, 2H), 3.72 –(trifluoromethy yl)phenol 3.62 (m, 2H), l)phenol (Intermediate3.20 – 3.05 (m,158) 2H), 2.33 (s, 3H), 2.09 (s, 3H).105 2‐(2‐{2‐[(2R)‐2‐(2‐{2‐[(2R)‐ M / Z:1H NMR (500 4,4‐difluoro‐1‐ 4,4‐ 441.3MHz, CDCl3) δ =methylpyrrolidi difluoropyrrol [M+H]+,11.80 - 11.17 (m,n‐2‐yl]ethyl}‐ idin‐2‐ ESI+, RT =1H), 8.20 (d, J =2H‐ yl]ethyl}‐2H‐0.71 (S1).8.8 Hz, 1H), 8.04 pyrazolo[3,4‐ pyrazolo[3,4‐ (s, 1H), 7.36 (d, J b]pyridin‐6‐yl)‐ b]pyridin‐6‐ = 8.8 Hz, 1H), 3‐methyl‐5‐ yl)‐3‐methyl‐ 7.19 (s, 1H), 7.09 (trifluoromethy 5‐ (s, 1H), 4.65 - l)phenol (trifluorometh 4.45 (m, 2H), yl)phenol3.40 (dt, J = 4.4,(Intermediate 12.0 Hz, 1H), 159)2.69 - 2.59 (m,2H), 2.57 (s, 3H), 2.56 - 2.48 (m,1H), 2.47 - 2.36(m, 1H), 2.33 (s, 3H), 2.26 - 2.15(m, 1H), 2.12 - 1.97 (m, 1H)Example compounds in Table 39 were synthesised according to the general route 53 asexemplified by Example 85 using the corresponding starting materials / intermediates.Table 39 ExamStructure Name StartingLCMS 1H NMR ple materials data106 3‐methyl‐2‐[2‐2‐[4‐ M / Z:1H NMR (400 (oxan‐4‐yl)‐4‐ cyclopropyl‐ 420.2MHz, CDCl3) δ =N O NNpropyl‐2H‐ 2‐(3,6‐ [M+H]+, 11.46 (br s, 1H), F3C OHpyrazolo[3,4‐ dihydro‐2H‐ ESI+, RT = 8.07 (s, 1H), 7.18 b]pyridin‐6‐yl]‐ pyran‐4‐yl)‐ 1.12 (S1). (s, 1H), 7.13 (s, 5‐ 2H‐ 1H), 7.08 (s, 1H), (trifluoromethyl) pyrazolo[3,4‐4.79 - 4.64 (m,phenol b]pyridin‐6‐1H), 4.27 - 4.15yl]‐3‐methyl‐ (m, 2H), 3.73 - 5‐ 3.56 (m, 2H), (trifluorometh2.93 (t, J = 7.6yl)phenol Hz, 2H), 2.56 (s, (Intermediate3H), 2.39 - 2.24173) (m, 4H), 1.85 (sxt, J = 7.4 Hz,2H), 1.04 (t, J =7.3 Hz, 3H)107 2‐[4‐(azetidin‐1‐2‐[4‐(azetidin‐ M / Z:1H NMR (500 N yl)‐2‐(oxan‐4‐ 1‐yl)‐2‐(3,6‐ 433.2 MHz, DMSO-d6) N O NNyl)‐2H‐ dihydro‐2H‐ [M+H]+,δ = 12.89 - 10.18F3C OH pyrazolo[3,4‐ pyran‐4‐yl)‐ ESI+, RT = (m, 1H), 8.54 (br b]pyridin‐6‐yl]‐ 2H‐ 0.69 (S1). s, 1H), 7.10 (s, 3‐methyl‐5‐ pyrazolo[3,4‐ 1H), 7.04 (s, 1H), (trifluoromethyl) b]pyridin‐6‐ 5.78 (br s, 1H), phenol yl]‐3‐methyl‐4.76 - 4.62 (m,5‐ 1H), 4.29 (br s, (trifluorometh4H), 4.07 - 3.93yl)phenol (m, 2H), 3.52 (dt, (IntermediateJ = 2.1, 11.8 Hz,174)2H), 2.49 - 2.42(m, 2H), 2.19 (s, 3H), 2.17 - 2.10(m, 2H), 2.09 - 2.01 (m, 2H)Example compounds in Table 40 were synthesised according to the general route 49 asexemplified by Example 11 using the corresponding starting materials / intermediates.Table 40 ExamStructure Name StartingLCMS 1H NMR ple materials data 108 N O 5‐(1,1‐6‐chloro‐2‐ M / Z:1H NMR (400 NNF difluoroethyl)‐3‐ (oxan‐4‐yl)‐ 374.2 MHz, CDCl3) δ = OH F methyl‐2‐[2‐ 2H‐ [M+H]+, 11.45 (s, 1H), (oxan‐4‐yl)‐2H‐ pyrazolo[3,4‐ ESI+, RT =8.19 (d, J = 8.8pyrazolo[3,4‐ b]pyridine 0.93 Hz, 1H), 8.07 (s, b]pyridin‐6‐ (Intermediate (S1)1H), 7.36 (d, J =yl]phenol25) and 5‐8.7 Hz, 1H), 7.12 (1,1‐– 7.05 (m, 1H),difluoroethyl)7.01 (dd, J = 1.9,‐3‐methyl‐2‐ 0.9 Hz, 1H), 4.80 (4,4,5,5‐– 4.68 (m, 1H),tetramethyl‐4.28 – 4.17 (m,1,3,2‐2H), 3.74 – 3.58dioxaborolan‐ (m, 2H), 2.56 (s, 2‐yl)phenol3H), 2.39 – 2.26(Intermediate (m, 4H), 1.96 (t, J 134) = 18.2 Hz, 3H). 109 3‐methyl‐2‐(2‐(3S)‐3‐({6‐ M / Z:1H NMR (400 {[(3S)‐1‐ chloro‐2H‐ 447.2 MHz, CDCl3) δ = (oxetan‐3‐ pyrazolo[3,4‐ [M+H]+, 11.55 (s, 1H), yl)piperidin‐3‐ b]pyridin‐2‐ ESI+, RT =8.21 (d, J = 8.7yl]methyl}‐2H‐ yl}methyl)‐1‐ 0.65 Hz, 1H), 8.04 (s, pyrazolo[3,4‐ (oxetan‐3‐ (S1)1H), 7.37 (d, J =b]pyridin‐6‐yl)‐ yl)piperidine 8.7 Hz, 1H), 7.21 5‐ (Intermediate(d, J = 1.9 Hz,160) and 3- 1H), 7.11 (d, J =(trifluoromethyl) methyl-2- 1.9 Hz, 1H), 4.75 phenol (4,4,5,5-– 4.35 (m, 6H),tetramethyl-3.46 (p, J = 6.51,3,2- Hz, 1H), 2.59 (s, dioxaborolan-3H), 2.57 – 2.392-yl)-5- (m, 3H), 2.12 (s, (trifluorometh1H), 1.90 (t, J =yl)phenol 9.5 Hz, 1H), 1.85 (Intermediate– 1.63 (m, 4H),5)1.38 – 1.23 (m,1H)110 3‐methyl‐2‐(2‐(3R)‐3‐({6‐ M / Z:1H NMR (400 {[(3R)‐1‐ chloro‐2H‐ 447.2 MHz, CDCl3) δ = (oxetan‐3‐ pyrazolo[3,4‐ [M+H]+, 11.55 (s, 1H), yl)piperidin‐3‐ b]pyridin‐2‐ ESI+, RT =8.21 (d, J = 8.7yl]methyl}‐2H‐ yl}methyl)‐1‐ 0.65 Hz, 1H), 8.04 (s, pyrazolo[3,4‐ (oxetan‐3‐ (S1)1H), 7.37 (d, J =b]pyridin‐6‐yl)‐ yl)piperidine 8.7 Hz, 1H), 7.21 5‐ (Intermediate(d, J = 1.9 Hz,(trifluoromethyl)161) and 3- 1H), 7.11 (d, J =phenol methyl-2- 1.9 Hz, 1H), 4.75 (4,4,5,5-– 4.35 (m, 6H),tetramethyl-3.46 (p, J = 6.51,3,2- Hz, 1H), 2.59 (s, dioxaborolan-3H), 2.57 – 2.392-yl)-5- (m, 3H), 2.12 (s, (trifluorometh1H), 1.90 (t, J =yl)phenol 9.5 Hz, 1H), 1.85 (Intermediate– 1.63 (m, 4H),5)1.38 – 1.23 (m,1H)111 2‐(2‐{[(3S)‐1‐(3S)‐3‐({6‐ M / Z:1H NMR (400 [(1‐ chloro‐2H‐ 463.2 MHz, CDCl3) δ fluorocycloprop pyrazolo[3,4‐ [M+H]+,=8.20 (d, J = 8.7yl)methyl]piperi b]pyridin‐2‐ ESI+, RT = Hz, 1H), 8.04 (s, din‐3‐ yl}methyl)‐1‐ 0.691H), 7.36 (d, J =yl]methyl}‐2H‐ [(1‐ (S1) 8.7 Hz, 1H), 7.21 pyrazolo[3,4‐ fluorocyclopr(d, J = 1.9 Hz,b]pyridin‐6‐yl)‐ opyl)methyl]p1H), 7.10 (d, J =3‐methyl‐5‐ iperidine 1.8 Hz, 1H), 4.58 (trifluoromethyl) (Intermediate(dd, J = 13.2, 8.2phenol162) and 3-Hz, 1H), 4.44 (dd, methyl-2-J = 13.2, 6.5 Hz,(4,4,5,5-1H), 2.88 – 2.56tetramethyl- (m, 4H), 2.58 (s, 1,3,2-3H), 2.52 (q, J =dioxaborolan- 5.4 Hz, 1H), 2.44 2-yl)-5- (s, 1H), 2.31 – (trifluorometh 2.21 (m, 1H), yl)phenol1.83 – 1.67 (m,Intermediate 53H), 1.31 (dt, J =13.5, 8.5 Hz, 1H), 1.10 – 0.94 (m,2H), 0.64 – 0.51(m, 2H).112 2‐(2‐{[(3R)‐1‐(3R)‐3‐({6‐ M / Z:1H NMR (400 [(1‐ chloro‐2H‐ 463.2 MHz, CDCl3) δ = fluorocycloprop pyrazolo[3,4‐ [M+H]+,8.20 (d, J = 8.7yl)methyl]piperi b]pyridin‐2‐ ESI+, RT = Hz, 1H), 8.04 (s, din‐3‐ yl}methyl)‐1‐ 0.691H), 7.36 (d, J =yl]methyl}‐2H‐ [(1‐ (S1) 8.7 Hz, 1H), 7.21 pyrazolo[3,4‐ fluorocyclopr(d, J = 1.9 Hz,b]pyridin‐6‐yl)‐ opyl)methyl]p1H), 7.10 (d, J =3‐methyl‐5‐ iperidine 1.8 Hz, 1H), 4.58 (trifluoromethyl) (Intermediate(dd, J = 13.2, 8.2phenol163) and 3-Hz, 1H), 4.44 (dd, methyl-2-J = 13.2, 6.5 Hz,(4,4,5,5-1H), 2.88 – 2.56tetramethyl- (m, 4H), 2.58 (s, 1,3,2-3H), 2.52 (q, J =dioxaborolan- 5.4 Hz, 1H), 2.44 2-yl)-5- (s, 1H), 2.31 – (trifluorometh 2.21 (m, 1H), yl)phenol1.83 – 1.67 (m,(Intermediate3H), 1.31 (dt, J =5) 13.5, 8.5 Hz, 1H), 1.10 – 0.94 (m,2H), 0.64 – 0.51(m, 2H).113 2‐(2‐{[(3S)‐1‐(3S)‐3‐({6‐ M / Z:1H NMR (400 [(3‐ chloro‐2H‐ 479.2 MHz, CDCl3) δ = fluorooxetan‐3‐ pyrazolo[3,4‐ [M+H]+, 11.56 (s, 1H), yl)methyl]piperi b]pyridin‐2‐ ESI+, RT =8.21 (d, J = 8.7din‐3‐ yl}methyl)‐1‐ 0.67 Hz, 1H), 8.00 (s, yl]methyl}‐2H‐ [(3‐ (S1)1H), 7.37 (d, J =pyrazolo[3,4‐ fluorooxetan‐ 8.7 Hz, 1H), 7.21 b]pyridin‐6‐yl)‐ 3‐(d, J = 1.9 Hz,3‐methyl‐5‐ yl)methyl]pip1H), 7.11 (d, J =(trifluoromethyl) eridine 1.8 Hz, 1H), 4.74 phenol (Intermediate(dt, J = 19.4, 6.9164) and 3-Hz, 2H), 4.65 – methyl-2- 4.35 (m, 4H), (4,4,5,5-2.95 – 2.76 (m,tetramethyl-2H), 2.70 (d, J =1,3,2- 11.2 Hz, 2H), dioxaborolan- 2.59 (s, 3H), 2.50 2-yl)-5-(dt, J = 7.7, 4.1(trifluorometh Hz, 1H), 2.40 (t, J yl)phenol = 12.3 Hz, 1H), (Intermediate2.22 (dd, J = 11.2,5) 8.2 Hz, 1H), 1.81 –1.64 (m, 3H),1.30 – 1.15 (m,1H).114 2‐(2‐{[(3R)‐1‐(3R)‐3‐({6‐ M / Z:1H NMR (400 [(3‐ chloro‐2H‐ 479.2 MHz, CDCl3) δ = fluorooxetan‐3‐ pyrazolo[3,4‐ [M+H]+, 11.56 (s, 1H), yl)methyl]piperi b]pyridin‐2‐ ESI+, RT =8.21 (d, J = 8.7din‐3‐ yl}methyl)‐1‐ 0.67 Hz, 1H), 8.00 (s, yl]methyl}‐2H‐ [(3‐ (S1)1H), 7.37 (d, J =pyrazolo[3,4‐ fluorooxetan‐ 8.7 Hz, 1H), 7.21 b]pyridin‐6‐yl)‐ 3‐(d, J = 1.9 Hz,3‐methyl‐5‐ yl)methyl]pip1H), 7.11 (d, J =(trifluoromethyl) eridine 1.8 Hz, 1H), 4.74 phenol (Intermediate (dt, J = 19.4, 6.9 165) and 3-Hz, 2H), 4.65 – methyl-2- 4.35 (m, 4H), (4,4,5,5-2.95 – 2.76 (m,tetramethyl-2H), 2.70 (d, J =1,3,2- 11.2 Hz, 2H), dioxaborolan- 2.59 (s, 3H), 2.50 2-yl)-5-(dt, J = 7.7, 4.1(trifluorometh Hz, 1H), 2.40 (t, J yl)phenol = 12.3 Hz, 1H), (Intermediate2.22 (dd, J = 11.2,5) 8.2 Hz, 1H), 1.81 –1.64 (m, 3H),1.30 – 1.15 (m,1H).115 3‐methyl‐2‐[5‐6‐chloro‐5‐ M1N O / Z: H NMR (400 NNmethyl‐2‐(oxan‐ methyl‐2‐ 392.1 MHz, DMSO-d6) F3COH 4‐yl)‐2H‐ (oxan‐4‐yl)‐ [M+H]+,δ = 10.04 (br s,pyrazolo[3,4‐ 2H‐ ESI+, RT = 1H), 8.44 (s, 1H), b]pyridin‐6‐yl]‐ pyrazolo[3,4‐0.99 (S1).8.03 (s, 1H), 7.13 5‐b]pyridine and(s, 1H), 7.06 (s, 4‐chloro‐5‐1H), 4.83 - 4.71(trifluoromethyl) methyl‐2‐ (m, 1H), 4.03 (br phenol (oxan‐4‐yl)‐d, J = 11.0 Hz,2H‐2H), 3.60 - 3.48pyrazolo[3,4‐ (m, 2H), 2.04 (s, b]pyridine3H), 2.21 - 2.021:1 ratio (m, 4H), 1.95 (s, (Intermediate 3H) 149) and 3-methyl-2- (4,4,5,5- tetramethyl- 1,3,2- dioxaborolan- 2-yl)-5- (trifluorometh yl)phenol (Intermediate 5)116N3,5‐dimethyl‐2‐6‐chloro‐2‐ M / Z:1H NMR (500 N O NN[2‐(oxan‐4‐yl)‐ (oxan‐4‐yl)‐ 325.2 MHz, CDCl3) δ = OH 2H‐ 2H‐ [M+H]+, 10.49 (br s, 1H), pyrazolo[3,4‐ pyrazolo[3,4‐ ESI+, RT = 8.81 (s, 1H), 8.31 b]pyrazin‐6‐ b]pyrazine0.87 (S1).(s, 1H), 6.79 (s, yl]phenol (Intermediate 1H), 6.73 (s, 1H), 26) and 3,5‐ 4.74 (tt, J = 5.2,dimethyl‐2‐ 10.6 Hz, 1H), (4,4,5,5‐4.27 - 4.17 (m,tetramethyl‐2H), 3.65 (dt, J =1,3,2‐ 3.2, 11.4 Hz, 2H), dioxaborolan‐ 2.53 (s, 3H), 2.34 2‐yl)phenol (s, 3H), 2.38 - (Intermediate 2.26 (m, 4H) 88)117N Frac-2‐{2‐[(4,4‐ rac- 3‐({6‐M / Z:1H NMR (400 N F NNdifluoro‐1‐ chloro‐2H‐ 442.3 MHz, MeOD-d4) F3C OH Nmethylpiperidin‐ pyrazolo[3,4‐ [M+H]+, δ = 8.69 (s, 1H), 3‐yl)methyl]‐ b]pyrazin‐2‐ ESI+, RT = 8.61 (s, 1H), 7.14 2H‐ yl}methyl)‐0.66 (S1).(s, 1H), 7.07 (s, pyrazolo[3,4‐ 4,4‐difluoro‐1H), 4.94 (dd, J =b]pyrazin‐6‐yl}‐ 1‐ 4.6, 13.9 Hz, 1H), 3‐methyl‐5‐ methylpiperid4.61 (dd, J = 9.3,(trifluoromethyl) ine 13.8 Hz, 1H), phenol (Intermediate3.06 - 2.89 (m,126) and 3- 1H), 2.87 - 2.36methyl-2- (m, 2H), 2.31 - (4,4,5,5- 2.28 (m, 3H), tetramethyl-2.73 - 2.25 (m,1,3,2- 2H), 2.24 (s, 3H), dioxaborolan-2.21 - 2.00 (m,2-yl)-5- 2H) (trifluorometh yl)phenol (Intermediate 5)Example 118 and Example 119Rac- 2‐{2‐[(4,4‐difluoro‐1‐methylpiperidin‐3‐yl)methyl]‐3‐methyl‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐5‐(trifluoromethyl)phenol was synthesised according to the generalroute 49 as exemplified by Example 11 starting from rac-3‐({6‐chloro‐3‐methyl‐2H‐pyrazolo[3,4‐b]pyridin‐2‐yl}methyl)‐4,4‐difluoro‐1‐methylpiperidine (Intermediate 127, 150mg, 0.48 mmol) and 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (Intermediate 5, 173 mg, 0.57 mmol). It was separated by preparativechiral HPLC to yield single enantiomers: Column Chiralcel OD-H (25 x 2.0 cm), 5µm, Mobil Preparative chiral chromatography phase n-Hexane / Ethanol 85 / 15 % v / v, Flow rate 17protocol mL / min, UV detection 220 nm, Loop 800 μLEx Structure Name Characterization118 Enantiomer 1: RT= 8.5 min, 100% ee2‐(2‐{[(3S)‐4,4‐M / Z: 455.5 [M+H]+, ESI+,difluoro‐1‐RT = 0.70 (S1)methylpiperidin‐3‐ yl]methyl}‐3‐methyl‐1H NMR (400 MHz, DMSO- 2H‐pyrazolo[3,4‐d6) δ = 10.17 (br s, 1H), 8.21b]pyridin‐6‐yl)‐3‐(d, J = 8.3 Hz, 1H), 7.09 (brmethyl‐5‐ s, 1H), 7.06 (br s, 1H), 6.99 (trifluoromethyl)phenol(d, J = 8.4 Hz, 1H), 4.61 (dd,(stereochemistryJ = 4.2, 13.5 Hz, 1H), 4.42arbitrarily assigned as(br dd, J = 9.4, 13.8 Hz, 1H),3S)2.91 - 2.72 (m, 1H), 2.68 (s,3H), 2.19 (s, 3H), 2.09 (s, 3H), 2.72 - 1.96 (m, 6H)119 Enantiomer 2: RT= 10.1 min, 99.5% ee2‐(2‐{[(3R)‐4,4‐ M / Z: 455.5 [M+H]+, ESI+, difluoro‐1‐ RT = 0.70 (S1) methylpiperidin‐3‐ yl]methyl}‐3‐methyl‐1H NMR (400 MHz, DMSO- 2H‐pyrazolo[3,4‐d6) δ = 10.17 (br s, 1H), 8.21b]pyridin‐6‐yl)‐3‐(d, J = 8.3 Hz, 1H), 7.09 (brmethyl‐5‐ s, 1H), 7.06 (br s, 1H), 6.99 (trifluoromethyl)phenol(d, J = 8.4 Hz, 1H), 4.61 (dd,(stereochemistryJ = 4.2, 13.5 Hz, 1H), 4.42arbitrarily assigned as(br dd, J = 9.4, 13.8 Hz, 1H),3R)2.91 - 2.72 (m, 1H), 2.68 (s,3H), 2.19 (s, 3H), 2.09 (s, 3H), 2.72 - 1.96 (m, 6H)Example 120 and Example 121:Rac-2-{2-[(3-fluoro-1-methylpyrrolidin-3-yl)methyl]-2H-pyrazolo[3,4-b]pyrazin-6-yl}-3-methyl-5-(trifluoromethyl)phenol (Example 60) was separated into the single enantiomers bypreparative chiral HPLC to yield single enantiomers: Column Chiralpak AS-H (25 x 2.0 cm), 5µm, Mobil phase Preparative chiral n-Hexane / (Ethanol + 0.1% isopropylamine) 70 / 30% v / v, chromatography protocol Flow rate 17 mL / min, UV detection 220 nm, Loop 750 μLEx Structure Name Characterization120 Enantiomer 1:RT= 4.1 min, 98.6% ee 2‐(2‐{[(3R)‐3‐ M / Z: 410.1 [M+H]+, ESI+, RT = 0.63 (S1). fluoro‐1‐ methylpyrrolid1H NMR (400 MHz, MeOD-d4 ) δ = 8.70 –in‐3‐8.58 (m, 2H), 7.20 – 7.12 (m, 1H), 7.09 (d,yl]methyl}‐J = 1.7 Hz, 1H), 4.95 (dd, J = 20.5, 4.7 Hz,2H‐2H), 3.06 – 2.78 (m, 3H), 2.63 (ddd, J =pyrazolo[3,4‐ 10.0, 7.9, 6.2 Hz, 1H), 2.41 (s, 4H), 2.27 (s, b]pyrazin‐6‐3H), 2.15 (ddq, J = 28.2, 14.1, 7.4 Hz, 1H).yl)‐3‐methyl‐ 5‐ (trifluorometh yl)phenol (stereochemist ry arbitrarilyassigned as 3R) 121 Enantiomer 2: RT= 7.1 min, 100% ee2‐(2‐{[(3S)‐3‐ M / Z: 410.1 [M+H]+, ESI+, RT = 0.63 (S1). fluoro‐1‐ methylpyrrolid1H NMR (400 MHz, MeOD-d4 ) δ = 8.70 –in‐3‐8.58 (m, 2H), 7.20 – 7.12 (m, 1H), 7.09 (d,yl]methyl}‐J = 1.7 Hz, 1H), 4.95 (dd, J = 20.5, 4.7 Hz,2H‐2H), 3.06 – 2.78 (m, 3H), 2.63 (ddd, J =pyrazolo[3,4‐ 10.0, 7.9, 6.2 Hz, 1H), 2.41 (s, 4H), 2.27 (s, b]pyrazin‐6‐3H), 2.15 (ddq, J = 28.2, 14.1, 7.4 Hz, 1H).yl)‐3‐methyl‐5‐ (trifluorometh yl)phenol (stereochemist ry arbitrarily assigned as 3S)II. Biological assaysII. 1 THP1 IL-1β Release AssayThe purpose of this example was to evaluate the activity of example compounds synthesized in “Example I: Chemical Synthesis”.

[0284] THP1 IL-1β Release Assay (HTRF): Example compounds were tested in LPS-primed THP1 cells to assess their pharmacological capability to inhibit NLRP3 activation with Nigericin and the release of IL-1β into the supernatant.

[0285] Day 1: THP1 cells were plated in 384-well Poly L-Lysine coated plates at adensity of 18.000 cells per well in differentiation medium containing RPMI 1640 Medium (noGlutamine & Phenol red), 10% FBS, 2 mM L-Glutamine, 50 µM 2-Mercaptoethanol and 200 ng / ml PMA and incubated for 24 h at 37 °C, 5% CO2.

[0286] Day 2: After 24 h, medium was exchanged to growth medium containing RPMI1640 Medium (no Glutamine & Phenol red), 10% FBS, 2 mM L-Glutamine, 50 µM 2-Mercaptoethanol and incubated for 24 h at 37 °C, 5% CO2.

[0287] Day 3: Example compounds were serially diluted in DMSO, spotted intointermediate plates and prediluted with serum-free growth medium (plate 1) or serum-free growth medium containing 50µM Nigericin (plate 2).

[0288] In addition to the example compound testing area, the plates also containedmultiples of High control (0.2% DMSO, 1µg / ml LPS, 50µM Nigericin final) and Low control(reference inhibitor MCC950 (sodium salt) at 10x IC50, 1µg / ml LPS, 50µM Nigericin final) forassay normalization purposes.

[0289] THP1 cells were washed with serum-free growth medium and 10µl examplecompounds from the intermediate plate 1 was added into 40µl serum-free medium in the assay plate. After 30 minutes incubation at 37 °C, 5% CO2, LPS in serum-free growth medium was added to a final concentration of 1µg / ml for priming followed by incubation for 2.5 h at 37°C, 5% CO2.

[0290] After priming, cells were washed with serum-free growth medium containing50µM Nigericin and 10µl example compounds from the intermediate plate 2 as well as 40µl serum-free medium with Nigericin were added to the cells for activation and incubated for 2 h 37 °C, 5% CO2. Finally, the supernatant was removed and stored at -20°C.

[0291] Day 4: IL-1β in the supernatant was quantified by HTRF (homogenous timeresolved fluorescence) analysis using a human IL-1β Kit from Cisbio. Briefly, 8µl ofsupernatant as well as 2µl of pre-mixed anti-IL1β-Crypta antibody and anti-IL1β-XL antibody were added to a 384 well plate (Greiner BioOne), incubated for 24 h at r.t. and measured with the PHERAstar FSX Reader (BMG LabTech) at excitation 337 nm (donor) and emission 620 / 665 nm (acceptor).

[0292] The HTRF ratio between donor and acceptor signals was calculated andnormalized to High and Low controls to calculate IC50values (nM). NLRP3 inhibitors decrease LPS / Nigericin-induced IL-1β release which is indicated as a reduction in the HTRF ratio.

[0293] THP1 IL-1β release of the tested example compounds is provided in Table 41:

[0294] Table 41: NLRP3 inhibitory activityEx THP1 IL-1βRelease Assay (HTRF) IC50(µM) 10.0282 0.1173 0.0714 0.0515 0.1056 0.1627 0.1358 0.0689 0.91210 0.35511 0.07612 0.04913 0.28814 0.09315 0.03116 0.29517 0.33918 0.35519 0.14120 0.13821 0.12922 0.10723 0.02824 0.12925 0.3826 0.17827 0.2428 0.05829 0.15830 0.11531 0.01132 0.01733 0.11734 0.01835 0.10236 0.28237 0.23438 0.14539 0.09340 0.07641 0.1742 0.23443 0.11244 0.07145 0.32446 0.53747 0.75948 0.27549 1.09650 0.60351 0.05552 0.00853 0.08354 0.14555 0.02956 0.10757 0.03558 0.0159 0.08360 0.09161 0.09162 0.19563 0.58964 0.39865 0.21466 0.06967 0.168 0.41769 0.270 0.15571 0.17872 0.15873 0.15874 0.67675 0.12976 0.66177 0.07678 0.33179 0.04980 0.51381 0.33982 0.15583 0.18684 0.30285 0.70886 0.14187 0.07888 0.15189 0.16690 0.04791 0.06292 0.25793 0.20994 0.10795 0.08996 0.19197 0.13898 0.15899 0.191100 0.229101 0.245102 0.447104 0.355105 2.692106 0.245108 0.245109 0.229110 0.195111 0.676112 0.105114 0.437115 0.891116 0.158117 0.06118 0.2119 0.155120 0.148121 0.166

[0295] II. 2 SMN2 splicing assay (RT-qPCR):

[0296] Example compounds were tested in SMA Type I fibroblasts to assess theirpharmacological capability to modulate SMN2 splicing according to a protocol adapted fromPalacino et al., Nat Chem Biol 2015. A SMN2 modulator increases SMN2 full length anddecreases SNM2 ^7 transcript level.

[0297] Day 1: SMA Type I fibroblasts (Coriell) were plated in 96-well gelatine-coatedplates at a density of 100.000 cells per well in fibroblast culture medium (DMEM, high glucose,GlutaMAX™ Supplement, pyruvate, 10% FBS, 1x MEM NEAA, 50 µM 2-Mercaptoethanol)and incubated for 24 h at 37 °C, 5% CO2.

[0298] Day 2: After 24 h, example compounds and a reference molecule Branaplam(ChemScene) were serially diluted in DMSO, spotted into intermediate plates and prediluted with fibroblast culture medium. In addition to the example compound testing area, the plates also contained multiples of DMSO control for assay normalization purposes. For compound treatment, 20 µl of fibroblast culture medium was removed, 20 µl example compounds, reference and DMSO controls from the intermediate plate was added to the cells to a final volume of 200 µl and cells were incubated for 24 h at 37 °C, 5% CO2.

[0299] Day 3: After 24h, fibroblast culture medium was removed from compoundtreated SMA Type I fibroblasts, cells were washed with PBS, 150 µl lysis buffer (RLT buffer + β-Mercaptoethanol; RNeasy Mini 96 Kit from Qiagen) was added and samples were storedat -80 °C.

[0300] Day 4: RNA was isolated using the RNeasy Mini 96 Kit from Qiagen andtranscribed to cDNA using the SuperScript III First Strand kit from Invitrogen according tomanufacturer instructions. Samples were stored at -20 °C.

[0301] Day 5: SMN2 transcripts as well as reference gene GAPDH were quantified byRT-qPCR. The following forward and reverse primer combinations were used:

[0302] For a 10 µl reaction, 8 µl of a master mix containing 5 µl Roche SYBRGreenMastermix (2x), 0.5 µl Forward Primer (10 µM), 0.5 µl Reverse Primer (10 µM) and 2 µl H2O were added to a LightCycler® 480 Multiwell Plate 384 (white), covered with foil sealsand centrifuged for a few seconds. Then 2 µl cDNA sample per well was added into the 384well plate, sealed with LighCycler sealing foil (Roche) and centrifuged for a few seconds. RT-qPCR was run with the LightCycler 480 (Roche) with the following parameters: STEP # CYCLES TEMP TIMEDenaturation 1 95 °C 10 minAmplification 40 95 °C 5 seconds56 °C 5 seconds72 °C 5 seconds

[0303] Data analysis was performed by calculating ^Cq values of SNM2 full lengthand SMN2 ^7 versus GAPDH control. The ^Cq values were normalized to the mean of ^CqDMSO controls resulting in ^^Cq values that were indicated as fold change (2-^^Cq) in relation to DMSO control.

[0304] The SMN2 modulator Branaplam increased SMN2 full length transcript ordecreased SMN2 ^7 transcript up to 2 folds as compared to DMSO while tested examplecompounds did not affect SMN2 transcript level and were comparable to DMSO control up to10µM compound top concentration.

[0305] SMN2 splicing activity of the tested example compounds is provided in Table42. Table 42: SMN2 splicing activitySMN2 splicing Example EC50 1>10 µM4 >10 µM11 >10 µM15 >10 µM26 >10 µM28 >10 µM31 >10 µM43 >10 µM53 >10 µM65 >10 µM77 >10 µM79 >10 µM90 >10 µM91 >10 µM94 >10 µM95 >10 µM98 >10 µM99 >10 µMTable 42: SMN2 splicing activitySMN2 splicing Example EC50 116 >10 µMII. 3 In vitro investigation of Hepatic Clearance in Human Cryopreserved HepatocytesExperimental design:The objective of this study was to determine the metabolic stability of Test Items (Examplecompounds) in human cryopreserved hepatocytes. Testosterone and 7-OH coumarin (fromSigma-Aldrich) were tested in parallel with the incubation of Test items, as positive controlsfor metabolic stability.The test items were incubated at 0.5 µM. Methods and Procedures: Test system:Cryopreserved hepatocytes from human mixed gender donors (from BioIVT supplier) werestored in vapour phase of liquid nitrogen freezer until use. After thawing and prior to use, cell viability check was performed using Trypan Blue dye exclusion test. Incubations of examplecompounds and positive controls were carried out at the cell concentration of 0.5 x 106 cells / mLin William's medium E added with Glutamine 200 mM and HEPES 1 M. 0.495 mL of cellssuspension were dispensed to 48-well plate and pre-incubated at 37°C for at least 10 minutes.Test and Control Items Stock Solution PreparationsExample compounds and control items (Testosterone and 7-OH coumarin) were dissolved inDMSO to obtain a 10 mM, 50 mM and 5 mM stock solution for example compounds,testosterone and 7-OH-coumarin respectively. Stock solutions were further diluted in methanolto achieve a final dosing solution of 50 µM of example compounds, 1000µM of testosteroneand 500 µM of 7-OH-coumarin. All solutions were prepared immediately before the assay. Hepatocytes incubation5 µL of 50 µM example compounds (test item), 1000 µM testosterone and 500 µM 7-OH-coumarin were added to 0.495 mL of 0.5 x106cell suspensions to give final concentrations of 0.5 µM for test item, 10 µM for testosterone and 5 µM for 7-OH-coumarin. The incubationswere conducted manullay or with automated system at 37 °C with gentle orbital shaking at 600rpm in duplicate for test items and in single for positive controls. At each time point (0, 5, 10, 15, 20, 30, 45, 60, 90 and 120 min), 30 µL of incubation mixture from each well were added to30 µl of milliQ water and 180 µL of stop solution (acetonitrile containing 1% formic acid andRolipram as internal standard, IS) to precipitate protein. Samples were mixed thoroughly andcentrifuged at 3000 rpm at 4 °C for 10 min. Supernatant was collected (100 µL), diluted with18 % acetonitrile in Milli-Q water (200 µL) and then injected onto an HPLC MS / MS system tomonitor the test items to internal standard peak area ratios as representative of the examplecompounds or control items (testosterone and 7-OH coumarin) concentrations.Data AnalysisPeak areas for example compounds and control items were integrated using Integr...

Claims

Claims1. A compound of formula (I)or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1 is CN, C1-4 alkyl, O-C1-4 alkyl or halogen, wherein C1-4 alkyl and O-C1-4 alkyl areoptionally substituted with one or more F, and R1a is H, C1-4 alkyl or halogen;or R1and R1aare joined to form, together with the carbon atoms to which they are attached, a C4-6 cycloalkyl or an unsubstituted saturated 4- to 6-membered heterocycle;R2 is H, CH3, CH2CH3, CF3, CHF2, OCH3, Cl, CN or cyclopropyl and R3 is H or CH3,provided that not both, R2and R3, are H; X1is C(R4) or N; R4 is H, C1-4 alkyl, C3-5 cycloalkyl, unsubstituted saturated 4- to 6- memberedheterocyclyl, OCH3, CN, Cl or F, wherein C1-4 alkyl and C3-5 cycloalkyl are unsubstituted or substituted with one or more F; orR3 and R4 are joined to form -CH2-CH2-CH2- or -CH2-O-CH2-;R4a is H, CH3, OCH3 or CN;R5aand R5bare independently selected from the group consisting of H and CH3; and R5is R6; orR5is H and R5aand R5bare joined to form, together with the carbon atom to which they are attached, a ring T1; or R5, R5a, R5bare joined to form, together with the carbon atom to which they are attached, a bicyclic ring T2;T1 is C3-7 cycloalkyl, saturated 4- to 7-membered heterocyclyl containing one or twohetero ring atoms, which are independently selected from the group consisting of O,N(R7) and S(O)2 or saturated 7- to 12-membered heterobicyclyl containing one or twohetero ring atoms, which are independently selected from the group consisting of O,N(R7) and S(O)2, wherein T1 is optionally substituted with one or more R8, which arethe same or different; T2is bicyclo[1.1.1]pentanyl, wherein T2is substituted with one OH or one CH2OH;R6 is C1-6 alkyl, T3 or CH2T3, wherein C1-6 alkyl is substituted with one or more R6a,which are the same or different;R6a is OH, OC1-4 alkyl or C(O)OC1-4 alkyl;R7is C1-4alkyl, S(O)2-C1-4alkyl, C(O)CH2OCH3, S(O)2T4, C(O)T4, wherein each C1-4alkyl is independently unsubstituted or substituted with one OH; R8is oxo (=O), OH, CH2OH, F, CH3or OCH3;T3 is C3-7 cycloalkyl, bicyclo[1.1.1]pentanyl, saturated 4- to 7-membered heterocyclyl,or saturated 7- to 12-membered heterobicyclyl, wherein T3 is unsubstituted orsubstituted with one or more R9, which are the same or different;T4 is C3-7 cycloalkyl, bicyclo[1.1.1]pentanyl, saturated 4- to 7-membered heterocyclyl,saturated 7- to 12-membered heterobicyclyl, wherein T4 is unsubstituted or substitutedwith one or more R9a, which are the same or different;R9and R9aare independently selected from the group consisting of C1-4 alkyl, oxo (=O), OH, CH2OH, S(O)2-C1-4 alkyl, C(O)OC1-4 alkyl, T5, CH2T5 and F, wherein eachC1-4alkyl is independently unsubstituted or substituted with one or more F; T5 is saturated 4- to 7-membered heterocyclyl or C3-7 cycloalkyl, wherein T5 isunsubstituted or substituted with one or more F.

2. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of claim1, wherein R1 is CN, CH3, CF3, CHF2, OCH3, OCHF2, OCF3 or halogen and R1a is H.

3. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of claim1 or 2, wherein R1 is F, Cl or CF2CH3 and R1a is H.

4. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of claim1 or 2, wherein R1 is CF3 and R1a is H or R1 is CH3 and R1a is H.

5. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of anyone of claims 1 to 4, wherein R2is CH3, Cl or CHF2.

6. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of anyone of claims 1 to 5, wherein R2 is CH3.

7. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of anyone of claims 1 to 6, wherein R3is H.

8. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of anyone of claims 1 to 6, wherein R3is CH3.

9. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of anyone of claims 1, 2, 4 to 7, wherein R1 is CF3, R1a is H, R2 is CH3, and R3 is H or R1 isCH3, R1ais H, R2is CH3, and R3is H.

10. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of anyone of claims 1 to 9, wherein X1 is CH, C(CH3), C(CHF2) or C(OCH3).

11. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of anyone of claims 1 to 9, wherein X1 is C(CH2CH2CH3) or C(azetidin-1-yl).

12. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of anyone of claims 1 to 10, wherein X1 is CH.

13. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of anyone of claims 1 to 9, wherein X1 is N.

14. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of anyone of claims 1 to 13, wherein R4a is H or CH3.

15. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of anyone of claims 1 to 14, wherein R4ais H.

16. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of anyone of claims 1 to 15, wherein R5is H and R5aand R5bare joined to form, together with the carbon atom to which they are attached, a ring T1.

17. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of anyone of claims 1 to 16, wherein T1 is a saturated 4- to 7-membered heterocyclylcontaining one hetero ring atom, which is O, wherein T1is unsubstituted or substituted with one or two R8, which are the same or different;18. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of anyone of claims 1 to 17, wherein R8is methyl.

19. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of anyone of claims 1 to 18, wherein T1is oxan‐4‐yl, oxolan-3-yl, 5-oxaspiro[3.5]nonan-8- yl, 2,2-dimethyloxan‐4‐yl, or 2,6‐dimethyloxan‐4‐yl.

20. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of anyone of claims 1 to 18, wherein T1is oxepan‐4‐yl.

21. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of anyone of claims 1 to 16, wherein T1 is C3-7 cycloalkyl or saturated 4- to 7-memberedheterocyclyl containing one or two hetero ring atoms, which are N(R7), wherein T1is optionally substituted with one or two R8, which are the same or different.

22. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of claim21, wherein T1 is hydroxymethylcyclobutyl, hydroxycyclobutyl, 1‐(ethanesulfonyl)piperidin‐4‐yl, 1‐methanesulfonylpiperidin‐4‐yl, 1‐ cyclopropanecarbonylpiperidin‐4‐yl, 1‐(1‐methylpyrrolidine‐3‐carbonyl)piperidin‐4‐ yl, thiane-1,1-dioxo-4-yl, 1-cyclopropanecarbonylpiperidin-4-yl, 1‐(cyclobutanesulfonyl)piperidin‐4‐yl, 1-methoxymethylcarbonylpiperidin‐4‐yl, 1- (oxolane-3-carbonyl)piperidin-4-yl, 1-(1-methylpyrrolidine-3-carbonyl)piperidin-4-yl, 1‐(1‐fluorocyclopropanecarbonyl)piperidin‐4‐yl, 1‐[1‐ (trifluoromethyl)cyclopropanecarbonyl]piperidin‐4‐yl, or 1-(3,3‐difluoroazetidine‐1‐ carbonyl)piperidin‐4‐yl.

23. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of claim21, wherein T1 is 1‐(2,2‐difluorocyclopropanecarbonyl)piperidin‐4‐yl, 1‐(1‐methylcyclopropanecarbonyl)piperidin‐4‐yl, or 1‐(2,2‐difluoro‐1‐methylcyclopropanecarbonyl)piperidin‐4‐yl.

24. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of anyone of claims 1 to 15, wherein R5aand R5bare selected from the group consisting of H and CH3; and R5is R6.

25. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of anyone of claims 1 to 15, or 24, wherein R5aand R5bare H and R5is R6.

26. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of anyone of claims 24 or 25, wherein R6 is C1-6 alkyl, wherein C1-6 alkyl is substituted withone OH or OCH3.

27. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of claim26, wherein R6is C1-6 alkyl, wherein C1-6 alkyl is substituted with one OCH3.

28. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of anyone of claims 24 or 25, wherein R6 is C1-6 alkyl, wherein C1-6 alkyl is substituted withone C(O)OCH2CH3.

29. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of claim26 or 27, wherein R6 is hydroxyethyl, methoxyethyl, hydroxymethyl or 2‐hydroxy‐2‐methylpropyl.

30. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of claim28, wherein R6is ethyloxycarbonylethyl.

31. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of anyone of claims 1 to 15, 24 or 25, wherein R6 is T3 and T3 is a saturated 4- to 7-membered heterocyclyl, wherein T3is substituted with one, two or three R9, which are the same or different.

32. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of anyone of claims 1 to 15, 24, 25, 31, wherein R6 is T3 and T3 is 1-methylpiperidinyl, 1-ethylpiperidinyl, 1-methylpyrrolidinyl or 4-methylmorpholinyl, wherein T3is optionally further substituted with one or more R9.

33. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of anyone of claims 1 to 15, 24, 25, 31, wherein R6 is T3 and T3 is 1-methylazetidinyl,wherein T3is optionally further substituted with one or more R9.

34. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of anyone of claims 1 to 15, 24 to 33, wherein R9 and R9a are independently selected fromthe group consisting of C1-4 alkyl, oxo (=O), OH, CH2OH, S(O)2-C1-4 alkyl, C(O)OC1-4 alkyl and F, wherein each C1-4 alkyl is independently unsubstituted or substituted with one or more F.

35. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of anyone of claims 1 to 15, 24, 25, 31, 34, wherein R6 is 3‐fluoro‐1‐methylpiperidin‐3‐yl, 1‐ethyl‐3‐fluoropiperidin‐3‐yl, 1-methylpyrrolidin-2-oxo-3-yl, 1-methylpyrrolidin-2- oxo-4-yl, 3‐fluoro‐1‐methylpyrrolidin‐3‐yl, 4,4-difluoro‐1‐methylpiperidin‐3‐yl, 1- methylpyrrolidin-3-yl, 1-ethylpiperidin-3-yl, or 4‐methylmorpholin‐2‐yl.

36. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of anyone of claims 1 to 15, 24, 25, 31, 34, wherein R6 is 1‐ethyl‐4,4‐difluoropiperidin‐3‐yl,5,5-difluoro‐1‐methylpiperidin‐3‐yl; 4,4-difluoro-1-methylpyrrolidin-2-ylmethyl; 1- methyl-3-fluoro-pyrrolidin-3-yl or 4‐methylmorpholin‐3‐yl.

37. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of anyone of claims 1 to 15, 24, 25, 31, 34, wherein R6 is T3 and T3 is 1-(oxetan-3-yl)pyrrolidin-3-yl, 1‐[(3‐fluorooxetan‐3‐yl)methyl]pyrrolidin‐3‐yl, 1‐[(1‐fluorocyclopropyl)methyl]piperidin‐3‐yl, (3-fluorooxetan-3-yl)methylpiperidin-3-yl or1‐[(1‐fluorocyclopropyl)methyl]pyrrolidin‐3‐yl.

38. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of anyone of claims 1 to 15, 24, 25, 31 to 37, wherein R6 is T3 and T3 is substituted with atleast one F.

39. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of anyone of claims 1 to 15, 24, 25, 31 to 38, wherein R6is T3and T3is substituted with T5or CH2T5.

40. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of anyone of claims 1 to 15, 24, 25, 31, 34, 38 or 39, wherein R6 is T3 and T3 is oxan-4-yl oroxetan-3-yl, wherein T3 is unsubstituted or substituted with one R9.

41. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of anyone of claims 1 to 15, 24, 25, 31, 34, 38 to 40, wherein R6 is T3 and T3 is oxan-4-yl, 3-(butyloxycarbonyl)oxetan-3-yl or 3‐(hydroxymethyl)oxetan‐3‐yl.

42. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of anyone of claims 1 to 15, 24, 25, 31, 34, wherein R6 is thietane‐1,1‐dioxo-3-yl, 1-methanesulfonylazetidin-3-yl, or 1-ethoxycarbonylcycloprop-1-yl.

43. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of anyone of claims 1 to 15, 21, 24, 25, wherein R6 is 1-hydroxymethylcycloprop-1-yl or 3-hydroxycyclobut-1-yl.

44. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of anyone of claims 1 to 43, wherein the compound is selected from the group consisting of:2‐[2‐(3‐hydroxypropyl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐3‐methyl‐5‐ (trifluoromethyl)phenol; cis 2‐{2‐[3‐(hydroxymethyl)cyclobutyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐5‐(trifluoromethyl)phenol; trans 2‐{2‐[3‐(hydroxymethyl)cyclobutyl]‐2H-pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐ 5‐(trifluoromethyl)phenol; trans- 2‐[2‐(3‐hydroxycyclobutyl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐3‐methyl‐5‐(trifluoromethyl)phenol; rac-2‐{2‐[(3‐fluoro‐1‐methylpiperidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐ 3‐methyl‐5‐(trifluoromethyl)phenol; rac-2‐{2‐[(1‐ethyl‐3‐fluoropiperidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐ methyl‐5‐(trifluoromethyl)phenol; 2‐{2‐[1‐(ethanesulfonyl)piperidin‐4‐yl]‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl}‐3‐methyl‐5‐ (trifluoromethyl)phenol; 2‐[2‐(1‐methanesulfonylpiperidin‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl]‐3‐methyl‐5‐ (trifluoromethyl)phenol; 2‐[2‐(1‐cyclopropanecarbonylpiperidin‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl]‐3‐ methyl‐5‐(trifluoromethyl)phenol; rac-3‐methyl‐2‐{2‐[1‐(1‐methylpyrrolidine‐3‐carbonyl)piperidin‐4‐yl]‐2H‐ pyrazolo[3,4‐b]pyrazin‐6‐yl}‐5‐(trifluoromethyl)phenol; 3‐methyl‐2‐[2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐5‐(trifluoromethyl)phenol; 3‐methyl‐2‐[2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl]‐5‐ (trifluoromethyl)phenol;5‐methoxy‐3‐methyl‐2‐[2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]phenol; rac-3-methyl-2-[2-(oxolan-3-yl)-2H-pyrazolo[3,4-b]pyridin-6-yl]-5-(trifluoromethyl)phenol , 3R-, 3S-enantiomer;3-methyl-2-[4-methyl-2-(oxan-4-yl)-2H-pyrazolo[3,4-b]pyridin-6-yl]-5- (trifluoromethyl)phenol; 3‐methyl‐2‐[3‐methyl‐2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl]‐5‐ (trifluoromethyl)phenol; 3-methyl-2-[3-methyl-2-(oxan-4-yl)-2H-pyrazolo[3,4-b]pyridin-6-yl]-5- (trifluoromethyl)phenol; 4-{6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-2H-pyrazolo[3,4-b]pyridin-2- yl}-1λ⁶-thiane-1,1-dione; rac-3-({6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-2H-pyrazolo[3,4- b]pyrazin-2-yl}methyl)-1-methylpyrrolidin-2-one; rac-4-({6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-2H-pyrazolo[3,4- b]pyrazin-2-yl}methyl)-1-methylpyrrolidin-2-one; rac-3-methyl-2-(2-{5-oxaspiro[3.5]nonan-8-yl}-2H-pyrazolo[3,4-b]pyridin-6-yl)-5- (trifluoromethyl)phenol; rac-2‐{2‐[(3‐fluoro‐1‐methylpyrrolidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐ yl}‐3‐methyl‐5‐(trifluoromethyl)phenol; rac-2‐{2‐[(4,4‐difluoro‐1‐methylpiperidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐ yl}‐3‐methyl‐5‐(trifluoromethyl)phenol; 3‐({6‐[2‐hydroxy‐6‐methyl‐4‐(trifluoromethyl)phenyl]‐2H‐pyrazolo[3,4‐b]pyridin‐2‐ yl}methyl)‐1λ6‐thietane‐1,1‐dione; 2‐[2‐(3‐methoxypropyl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐3‐methyl‐5‐ (trifluoromethyl)phenol; 2‐[2‐(2‐hydroxyethyl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐3‐methyl‐5‐ (trifluoromethyl)phenol; 2‐[2‐(3‐hydroxy‐3‐methylbutyl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐3‐methyl‐5‐ (trifluoromethyl)phenol; 2‐[4‐(difluoromethyl)‐2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐3‐methyl‐5‐ (trifluoromethyl)phenol; 2‐[4‐methoxy‐2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐3‐methyl‐5‐ (trifluoromethyl)phenol;2-[2-(1-cyclopropanecarbonylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridin-6-yl]-3- methyl-5-(trifluoromethyl)phenol; rac-3-methyl-2-{2-[(1-methylpyrrolidin-3-yl)methyl]-2H-pyrazolo[3,4-b]pyrazin-6- yl}-5-(trifluoromethyl)phenol, 3-R, 3S-enantiomer; rac-3-methyl-2-{2-[(1-methylpyrrolidin-3-yl)methyl]-2H-pyrazolo[3,4-b]pyridin-6- yl}-5-(trifluoromethyl)phenol; 2-{2-[(1-methanesulfonylazetidin-3-yl)methyl]-2H-pyrazolo[3,4-b]pyridin-6-yl}-3- methyl-5-(trifluoromethyl)phenol; rac-2-{2-[(1-ethylpiperidin-3-yl)methyl]-2H-pyrazolo[3,4-b]pyridin-6-yl}-3-methyl- 5-(trifluoromethyl)phenol; 2-[2-(1-methanesulfonylpiperidin-4-yl)-2H-pyrazolo[3,4-b]pyridin-6-yl]-3-methyl-5- (trifluoromethyl)phenol; 2-{2-[1-(ethanesulfonyl)piperidin-4-yl]-2H-pyrazolo[3,4-b]pyridin-6-yl}-3-methyl-5- (trifluoromethyl)phenol; 2‐{2‐[1‐(cyclobutanesulfonyl)piperidin‐4‐yl]‐2H‐ pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐5‐(trifluoromethyl)phenol; 1‐(4‐{6‐[2‐hydroxy‐6‐methyl‐4‐(trifluoromethyl)phenyl]‐2H‐pyrazolo[3,4‐b]pyridin‐ 2‐yl}piperidin‐1‐yl)‐2‐methoxyethan‐1‐one; 1-(4-{6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-2H-pyrazolo[3,4-b]pyrazin- 2-yl}piperidin-1-yl)-2-methoxyethan-1-one; rac-3-methyl-2-{2-[1-(oxolane-3-carbonyl)piperidin-4-yl]-2H-pyrazolo[3,4-b]pyridin- 6-yl}-5-(trifluoromethyl)phenol, 3R-, 3S-enantiomer; rac-3-methyl-2-{2-[1-(1-methylpyrrolidine-3-carbonyl)piperidin-4-yl]-2H- pyrazolo[3,4-b]pyridin-6-yl}-5-(trifluoromethyl)phenol; 2‐{2‐[1‐(1‐fluorocyclopropanecarbonyl)piperidin‐4‐yl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐ yl}‐3‐methyl‐5‐(trifluoromethyl)phenol; 3‐methyl‐5‐(trifluoromethyl)‐2‐(2‐{1‐[1‐ (trifluoromethyl)cyclopropanecarbonyl]piperidin‐4‐yl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐ yl)phenol; 2‐{2‐[1‐(3,3‐difluoroazetidine‐1‐carbonyl)piperidin‐4‐yl]‐2H‐pyrazolo[3,4‐b]pyridin‐ 6‐yl}‐3‐methyl‐5‐(trifluoromethyl)phenol; rac-2‐[2‐(2,2‐dimethyloxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐3‐methyl‐5‐ (trifluoromethyl)phenol;3‐methyl‐2‐(2‐{[(2R)‐4‐methylmorpholin‐2‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐ yl)‐5‐(trifluoromethyl)phenol; 3‐methyl‐2‐(2‐{[(2S)‐4‐methylmorpholin‐2‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐ yl)‐5‐(trifluoromethyl)phenol; ethyl 1‐({6‐[2‐hydroxy‐6‐methyl‐4‐(trifluoromethyl)phenyl]‐2H‐pyrazolo[3,4‐ b]pyridin‐2‐yl}methyl)cyclopropane‐1‐carboxylate; 2‐{2‐[(2R,6S)‐2,6‐dimethyloxan‐4‐yl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐ 3‐methyl‐5‐ (trifluoromethyl)phenol; 3‐methyl‐2‐{2‐[(2R,4r,6S)‐2,6‐dimethyloxan‐4‐yl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐ 5‐(trifluoromethyl)phenol; 3‐methyl‐2‐{2‐[(2R,4s,6S)‐2,6‐dimethyloxan‐4‐yl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐ 5‐(trifluoromethyl)phenol; 2‐(2‐{[(3R)‐1‐ethylpiperidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl)‐3‐methyl‐ 5‐(trifluoromethyl)phenol; 2‐(2‐{[(3S)‐1‐ethylpiperidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl)‐3‐methyl‐ 5‐(trifluoromethyl)phenol; 3‐methyl‐2‐{2‐[(3R)‐oxolan‐3‐yl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐5‐ (trifluoromethyl)phenol; 3‐methyl‐2‐{2‐[(3S)‐oxolan‐3‐yl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐5‐ (trifluoromethyl)phenol; 3‐methyl‐2‐(2‐{1‐[(3R)‐oxolane‐3‐carbonyl]piperidin‐4‐yl}‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl)‐5‐(trifluoromethyl)phenol; 3‐methyl‐2‐(2‐{1‐[(3S)‐oxolane‐3‐carbonyl]piperidin‐4‐yl}‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl)‐5‐(trifluoromethyl)phenol; 3‐methyl‐2‐(2‐{[(3R)‐1‐methylpyrrolidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐ yl)‐5‐(trifluoromethyl)phenol; and3‐methyl‐2‐(2‐{[(3S)‐1‐methylpyrrolidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐ yl)‐5‐(trifluoromethyl)phenol.

45. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of any ofclaims 1 to 43, wherein the compound is selected from the group consisting of: rac-2-{2-[(4,4-difluoro-1-methylpiperidin-3-yl)methyl]-2H-pyrazolo[3,4-b]pyridin-6- yl}-3,5-dimethylphenol;2-(2-{[(3S)-4,4-difluoro-1-methylpiperidin-3-yl]methyl}-2H-pyrazolo[3,4-b]pyridin- 6-yl)-3,5-dimethylphenol; and 2‐(2‐{[(3R)‐4,4‐difluoro‐1‐methylpiperidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyridin‐ 6‐yl)‐3,5‐dimethylphenol.

46. The compound or a pharmaceutically acceptable salt or stereoisomer thereof of any oneof claims 1 to 43, wherein the compound is selected from the group consisting of:rac-2‐{2‐[(1‐ethyl‐4,4‐difluoropiperidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐ yl}‐3‐methyl‐5‐(trifluoromethyl)phenol; 2‐(2‐{[(3S)‐1‐ethyl‐4,4‐difluoropiperidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐ yl)‐3‐methyl‐5‐(trifluoromethyl)phenol; 2‐(2‐{[(3R)‐1‐ethyl‐4,4‐difluoropiperidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐ yl)‐3‐methyl‐5‐(trifluoromethyl)phenol; rac-2‐{2‐[(3‐fluoro‐1‐methylpyrrolidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐ yl}‐3‐methyl‐5‐(trifluoromethyl)phenol; cis- 2‐[2‐(3‐hydroxycyclobutyl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐3‐methyl‐5‐(trifluoromethyl)phenol; rac-3‐methyl‐2‐[2‐(oxepan‐4‐yl)‐2H-pyrazolo[3,4‐b]pyridin‐6‐yl]‐5- (trifluoromethyl)phenol; 3‐methyl‐2‐{2‐[(4R)‐oxepan‐4‐yl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐5‐ trifluoromethyl)phenol; 3‐methyl‐2‐{2‐[(4S)‐oxepan‐4‐yl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐5‐t rifluoromethyl)phenol; 3‐methyl‐2‐{2‐[(oxan‐4‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐5‐ (trifluoromethyl)phenol; 3‐methyl‐2‐(2‐{[(3R)‐4‐methylmorpholin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐ yl)‐5‐(trifluoromethyl)phenol; 3,5‐dimethyl‐2‐[2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]phenol; 5‐chloro‐3‐methyl‐2‐[2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]phenol; 3,5‐dichloro‐2‐[2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]phenol; 5‐fluoro‐3‐methyl‐2‐[2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]phenol; 2‐(2‐{1‐[(1S)‐2,2‐difluorocyclopropanecarbonyl]piperidin‐4‐yl}‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl)‐3‐methyl‐5‐(trifluoromethyl)phenol; 2‐(2‐{1‐[(1R)‐2,2‐difluorocyclopropanecarbonyl]piperidin‐4‐yl}‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl)‐3‐methyl‐5‐(trifluoromethyl)phenol;3‐methyl‐2‐{2‐[1‐(1‐methylcyclopropanecarbonyl)piperidin‐4‐yl]‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl}‐5‐(trifluoromethyl)phenol; rac-2‐{2‐[1‐(2,2‐difluoro‐1‐methylcyclopropanecarbonyl)piperidin‐4‐yl]‐2H‐ pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐5‐(trifluoromethyl)phenol; rac-ethyl 3‐{6‐[2‐hydroxy‐6‐methyl‐4‐(trifluoromethyl)phenyl]‐2H‐pyrazolo[3,4‐ b]pyridin‐2‐yl}butanoate; 3‐methyl‐2‐(2‐{[(3S)‐1‐(oxetan‐3‐yl)pyrrolidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl)‐5‐(trifluoromethyl)phenol; 3‐methyl‐2‐(2‐{[(3R)‐1‐(oxetan‐3‐yl)pyrrolidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl)‐5‐(trifluoromethyl)phenol; 2‐(2‐{[(3S)‐1‐[(3‐fluorooxetan‐3‐yl)methyl]pyrrolidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl)‐3‐methyl‐5‐(trifluoromethyl)phenol; 2‐(2‐{[(3R)‐1‐[(3‐fluorooxetan‐3‐yl)methyl]pyrrolidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl)‐3‐methyl‐5‐(trifluoromethyl)phenol; 2‐(2‐{[(3S)‐1‐[(1‐fluorocyclopropyl)methyl]pyrrolidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl)‐3‐methyl‐5‐(trifluoromethyl)phenol; 2‐(2‐{[(3R)‐1‐[(1‐fluorocyclopropyl)methyl]pyrrolidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl)‐3‐methyl‐5‐(trifluoromethyl)phenol; butyl 3‐({6‐[2‐hydroxy‐6‐methyl‐4‐(trifluoromethyl)phenyl]‐2H‐pyrazolo[3,4‐ b]pyridin‐2‐yl}methyl)oxetane‐3‐carboxylate; 2‐(2‐{[3‐(hydroxymethyl)oxetan‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl)‐3‐ methyl‐5‐(trifluoromethyl)phenol; 2‐(2‐{[1‐(hydroxymethyl)cyclopropyl]methyl}‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl)‐3‐ methyl‐5‐(trifluoromethyl)phenol; rac-2‐[2‐(4‐hydroxybutan‐2‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐3‐methyl‐5‐ (trifluoromethyl)phenol; 3‐methyl‐2‐{2‐[(1‐methylazetidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐5‐ (trifluoromethyl)phenol; 3‐methyl‐2‐[5‐methyl‐2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl]‐5‐ (trifluoromethyl)phenol; 5‐(difluoromethyl)‐3‐methyl‐2‐[2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]phenol; 3‐(difluoromethyl)‐5‐methyl‐2‐[2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]phenol; trans-2‐{2‐[(3‐hydroxycyclobutyl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐ 5‐(trifluoromethyl)phenol;cis-2‐{2‐[(3hydroxycyclobutyl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐5‐ (trifluoromethyl)phenol; 2-(2-{[(3R)-1-ethyl-3-fluoropiperidin-3-yl]methyl}-2H-pyrazolo[3,4-b]pyridin-6-yl)- 3-methyl-5-(trifluoromethyl)phenol; 2-(2-{[(3S)-1-ethyl-3-fluoropiperidin-3-yl]methyl}-2H-pyrazolo[3,4-b]pyridin-6-yl)- 3-methyl-5-(trifluoromethyl)phenol; 2-(2-{[(3S)-4,4-difluoro-1-methylpiperidin-3-yl]methyl}-2H-pyrazolo[3,4-b]pyridin- 6-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(2-{[(3R)-4,4-difluoro-1-methylpiperidin-3-yl]methyl}-2H-pyrazolo[3,4-b]pyridin- 6-yl)-3-methyl-5-(trifluoromethyl)phenol; rac-2‐{2‐[(4,4‐difluoro‐1‐methylpiperidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐ yl}‐5‐methoxy‐3‐methylphenol; 2‐(2‐{[(3S)‐4,4‐difluoro‐1‐methylpiperidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyridin‐ 6‐yl)‐5‐methoxy‐3‐methylphenol; 2‐(2‐{[(3R)‐4,4‐difluoro‐1‐methylpiperidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyridin‐ 6‐yl)‐5‐methoxy‐3‐methylphenol; 2‐{2‐[(4‐fluoro‐1‐methylpiperidin‐4‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐ methyl‐5‐(trifluoromethyl)phenol;rac- 2‐{2‐[(5,5‐difluoro‐1‐methylpiperidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐5‐(trifluoromethyl)phenol; 2‐{2‐[(3‐fluoro‐1‐methylazetidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐ methyl‐5‐(trifluoromethyl)phenol; 2‐(2‐{2‐[(2R)‐4,4‐difluoro‐1‐methylpyrrolidin‐2‐yl]ethyl}‐2H‐pyrazolo[3,4‐b]pyridin‐ 6‐yl)‐3‐methyl‐5‐(trifluoromethyl)phenol; 3‐methyl‐2‐[2‐(oxan‐4‐yl)‐4‐propyl‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐5‐ (trifluoromethyl)phenol; 2‐[4‐(azetidin‐1‐yl)‐2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐3‐methyl‐5‐ (trifluoromethyl)phenol; 5‐(1,1‐difluoroethyl)‐3‐methyl‐2‐[2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐ yl]phenol; 3‐methyl‐2‐(2‐{[(3S)‐1‐(oxetan‐3‐yl)piperidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl)‐5‐(trifluoromethyl)phenol;3‐methyl‐2‐(2‐{[(3R)‐1‐(oxetan‐3‐yl)piperidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl)‐5‐(trifluoromethyl)phenol; 2‐(2‐{[(3S)‐1‐[(1‐fluorocyclopropyl)methyl]piperidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl)‐3‐methyl‐5‐(trifluoromethyl)phenol; 2‐(2‐{[(3R)‐1‐[(1‐fluorocyclopropyl)methyl]piperidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl)‐3‐methyl‐5‐(trifluoromethyl)phenol; 2‐(2‐{[(3S)‐1‐[(3‐fluorooxetan‐3‐yl)methyl]piperidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl)‐3‐methyl‐5‐(trifluoromethyl)phenol; 2‐(2‐{[(3R)‐1‐[(3‐fluorooxetan‐3‐yl)methyl]piperidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl)‐3‐methyl‐5‐(trifluoromethyl)phenol; 3‐methyl‐2‐[5‐methyl‐2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl]‐5‐ (trifluoromethyl)phenol; 3,5‐dimethyl‐2‐[2‐(oxan‐4‐yl)‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐yl]phenol; rac-2‐{2‐[(4,4‐difluoro‐1‐methylpiperidin‐3‐yl)methyl]‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐ yl}‐3‐methyl‐5‐(trifluoromethyl)phenol; rac- 2‐{2‐[(4,4‐difluoro‐1‐methylpiperidin‐3‐yl)methyl]‐3‐methyl‐2H‐pyrazolo[3,4‐b]pyridin‐6‐yl}‐3‐methyl‐5‐(trifluoromethyl)phenol; 2‐(2‐{[(3S)‐4,4‐difluoro‐1‐methylpiperidin‐3‐yl]methyl}‐3‐methyl‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl)‐3‐methyl‐5‐(trifluoromethyl)phenol; 2‐(2‐{[(3R)‐4,4‐difluoro‐1‐methylpiperidin‐3‐yl]methyl}‐3‐methyl‐2H‐pyrazolo[3,4‐ b]pyridin‐6‐yl)‐3‐methyl‐5‐(trifluoromethyl)phenol; 2‐(2‐{[(3R)‐3‐fluoro‐1‐methylpyrrolidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐ yl)‐3‐methyl‐5‐(trifluoromethyl)phenol; and 2‐(2‐{[(3S)‐3‐fluoro‐1‐methylpyrrolidin‐3‐yl]methyl}‐2H‐pyrazolo[3,4‐b]pyrazin‐6‐ yl)‐3‐methyl‐5‐(trifluoromethyl)phenol.

47. A pharmaceutical composition comprising at least one compound or a pharmaceuticallyacceptable salt or stereoisomer thereof of any one of claims 1 to 46 together with apharmaceutically acceptable carrier, optionally in combination with one or more other bioactive compounds or pharmaceutical compositions.

48. A compound or a pharmaceutically acceptable salt or stereoisomer thereof of any oneof claims 1 to 46 for use as a medicament.

49. A compound or a pharmaceutically acceptable salt or stereoisomer thereof of any oneof claims 1 to 46 or a pharmaceutical composition of claim 47 for use in a method oftreating and / or preventing of one or more diseases, disorders or conditions associatedwith NLRP3.

50. A compound or a pharmaceutically acceptable salt or stereoisomer thereof of any oneof claims 1 to 46 or a pharmaceutical composition of claim 47 for use in a method oftreating and / or preventing one or more diseases, disorders or conditions associated withNLRP3-mediated inflammation.

51. The compound or composition for use of claim 49 or 50, wherein the one or morediseases, disorders or conditions are selected from the group consisting of cryopyrin-associated periodic syndromes (CAPS), familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS), and neonatal-onset multisystemautoinflammatory syndrome (NOMID).

52. The compound or composition for use of claim 49 or 50, wherein the disease, disorderor condition is selected from the group consisting of (a) chronic inflammatory diseases, (b) metabolic diseases, (c) neurological diseases, (d) diseases associated with inherited,autosomal dominant mutations in NLRP3 that promote NLRP3 inflammasome; (e) asthma and allergic airway inflammation; (f) hypertension; (g) myocardial infarction; (h) hyperinflammation following influenza and / or severe acute respiratory syndrome- coronavirus 2 (SARS CoV-2); (i) Graft-versus-host disease; (j) silicosis; (k) myelodysplastic syndrome; and (l) contact hypersensitivity and joint inflammation triggered by chikungunya virus.

53. The compound or composition for use of claim 52, wherein:(a) the chronic inflammatory disease is selected from the group consisting of gout, rheumatoid arthritis, inflammatory bowel disease (IBD), Crohn’s disease and ulcerative colitis; (b) the metabolic disease is selected from the group consisting of atherosclerosis, diabetes, metabolic syndrome, obesity, liver steatosis, nonalcoholicsteatohepatitis (NASH), and liver fibrosis; or(c) the neurological disease is selected from the group consisting of Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), Huntington’s disease (HD), Amyotrophic Lateral Sclerosis (ALS), Prion disease, Traumatic Brain Injury (TBI) and stroke.

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