WO2010026122 Heterocyclic PIM-kinase inhibitors

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Biological target:

Proto-oncogene serine/threonine-protein kinase: Pim-1

Activity:

Inhibitor

Steps Conditions Reactions
a EtOH  Tertiary amine synthesis (Aromatic substitution)
b H2 / Pd-C / EtOH Primary amine synthesis (Nitro reduction)
Steps Conditions Reactions
a N-(benzyloxycarbonyloxy)succinimide / DIEA / DCM  Cbz protection
b DPPA / t-BuOH / DIEA   Curtius rearrangement
Steps Conditions Reactions
a DAST / DCM  Fluorination
Steps Conditions Reactions
a MsCl / Et3N / DCM  Mesyl synthesis
b Pyridine Cyclisation
c

Boc2O / Et3N / DMAP / DCM

Boc protection
Steps Conditions Reactions
a

1. NH4OH  / EtOH 

2. Boc2O / Et3N / DCM

Epoxide opening
Steps Conditions Reactions
a NaHMDS / Boc2O / THF  Boc protection
b H2 / Rh-C / PtO2 / AcOH Piperidine synthesis (Pyridine reduction)
Steps Conditions Reactions
a MeOH / EDCI / DMAP / DCM  Ester synthesis (Esterification)
b NaBH4 / LiCl / THF Hydroxyl synthesis (Ester reduction)
c

Perfluorobutanesulfonylfluoride / triethylamine.3HF / Et3N / THF

Fluorination
Steps Conditions Reactions
a Imidazole / DMAP / TBDMSCl / DCM  TBDMS protection
b H2 / Pd-C / EtOH:EtOAc 1:1  CBz deprotection
Steps Conditions Reactions
a Pd(dppf)Cl2-DCM / THF  Negishi coupling
Steps Conditions Reactions
a Pd(dppf)Cl2-DCM / DIPEA / Toluene:EtOH (1:1)  Suzuki reaction
b BBr3 / DCM Methoxy deprotection
c

1,1,1-trifluoro-N-Phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide / DIPEA / DCM

Triflyl synthesis
Steps Conditions Reactions
a Pd(OAc)2 / BINAP / Cs2CO3 / dioxane   Buchwald-hartwig amination

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