WO 2010038165 Imidazo[1,5]naphthyridine compounds, their pharmaceutical use and compositions

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Scaffold: 1,5-naphthyridine

Biological target:

Phosphoinositide 3-kinase alpha: PI3-Kα 

Mammalian target of rapamycin protein kinase: mTOR 

Activity:

Dual inhibitors

Steps Conditions Reactions
a EtOH Secondary amine synthesis (Nucleophilic substitution)
b Ph2O Cyclisation
c POCl3 Chlorination
Steps Conditions Reactions
a Pd(PPH3)4 / K2CO3 / toluene Suzuki reaction
b K2CO3 / DMA Secondary amine synthesis (Aromatic substitution)
c LIOH / MeOH / THF  Carboxylic acid synthesis (Ester hydrolysis)
d DPPA / Et3N / DMF Curtius rearrangement / Cyclisation
e MeI / NaH / DMF N-Methylation
f TMSI / CHCl3 CBz deprotection
Steps Conditions Reactions
a
HCHO / HCOOH
N-Methylation
b
CH3COCl / Et3N /DMSO
Acetylation
Steps Conditions Reactions
a
2-hydroxyacetic acid / HATU / NMM / DMF
Amide synthesis (HATU coupling)
b
2-chloroacetamide / Et3N /DMSO
Tertiary amine synthesis (Nucleophilic substitution)
c
Methyl isocyanate / Et3N / THF
Urea synthesis
Steps Conditions Reactions
a
Et3N  / DCM
Carbamate synthesis
b NH3 / DMSO

Urea synthesis

Steps Conditions Reactions
a
Et3N  / DCM
Amide synthesis
b NH3 / DMSO Hydroxyl synthesis (Ester hydrolysis)