WO2010010184 [1,2,4]triazolo[1,5-A]pyridines as JAK inhibitors

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Scaffold: Triazolopyridine

Biological target:

Janus kinase: JAK 

Activity:

Inhibitor

Steps Conditions Reactions
a DCM Thiourea synthesis
b NH2-OH / DIEA / EtOH:MeOH (1:1) Cyclisation
c PdCl2dppf / K2CO3 / dioxane:H2O (5:1) Suzuki reaction
d Pd(AcO)2 / BINAP / Cs2CO3 / dioxane Buchwald -Hartwig amination
e

1. SnCl2 / EtOH

2. Ac2O / THF

Primary amine synthesis (nitro reduction) / Acylation
Steps Conditions Reactions
a PdCl2dppf / K2CO3 / dioxane:H2O (5:1) Suzuki reaction 
b Pd(AcO)2 / BINAP / Cs2CO3 / dioxane Buchwald-Hartwig amination
c

1. LiOH / Acetone

2.CH3-NH2 / EDCI / HOBt / Et3N / DMF

Carboxylic acid synthesis (Ester hydrolysis) / Amide synthesis (EDCI coupling)
Steps Conditions Reactions
a TMS-diazomethane / THF Ester synthesis (Esterification)
b MeMgBr / THF Grignard reaction
c Bis(pinacolato)diboron / Pd(dppf)Cl2 / AcOK / dioxane Boronic ester synthesis
Steps Conditions Reactions
a CSCl2 / DCM Thioisocyanide synthesis 
b THF Thiourea synthesis
c

1. CH3I / NaH / THF

2. NH2OH.HCl / DIEA / EtOH

S-Methylation / Imine synthesis 
d TFA / THF Cyclisation
Steps Conditions Reactions
a NaH / NMP Nucleophilic susbtitution
b Bis(pinacolato)diboron / Pd(dppf)Cl2 / AcOK / dioxane Boronic ester synthesis
Steps Conditions Reactions
a Titanium tetraisoproxide / (R)-t-butyl sulfinamide / THF Imine substitution
b MeMgBr / DCM Grignard reaction
c HCl 4N / dioxane / MeOH Primary amine synthesis
d 2-chloroethyl ether / K2CO3 / DMF Morpholine synthesis (nucleophilic substitution)
e Bis(pinacolato)diboron / Pd(dppf)Cl2 / AcOK / dioxane  Boronic ester synthesis
Steps Conditions Reactions
a

1. Ti(Oi-Pr)4 / EtMgBr / Et2O

2. BF3.Et2O

Cyclopropyl synthesis
b 1-bromo-2-(2-bromo-ethoxy)-ethane / DIPEA / DMF Morpholine synthesis (nucleophilic substitution)
c Bis(pinacolato)diboron / Pd(dppf)Cl2 / AcOK / dioxane Boronic ester synthesis
Steps Conditions Reactions
a

1. Ti(Oi-Pr)4 / EtMgBr / Et2O

2. BF3.Et2O

Cyclopropyl synthesis
b Divinyl sulfone / Na2CO3 / isopropanol / H2O Nucleophilic substitution
c Bis(pinacolato)diboron / Pd(dppf)Cl2 / AcOK / Dioxane Boronic ester synthesis
Steps Conditions Reactions
a CHCl3 / NaOH / Acetone
b

1. SOCl2.

2.NH3 aq

Primary amide synthesis
c Bis(pinacolato)diboron / Pd(dppf)Cl2 / AcOK / dioxane Boronic ester synthesis
Steps Conditions Reactions
a

1. MeLi / CeCl3 / THF

2. Boc2O


b 1-bromo-2-(2-bromo-ethoxy)-ethane / DIPEA / DMF Morpholine synthesis (nucleophilic substitution)
c Bis(pinacolato)diboron / Pd(dppf)Cl2 / AcOK / Dioxane Boronic ester synthesis
Steps Conditions Reactions
a DBU / DMF Nucleophilic substitution

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