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