WO2010026121 Bicyclic kinase inhibitors

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Biological target:

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

Activity:

Inhibitor

Steps Conditions Reactions
a Dimethylacetal dimethylformamide / DMF Enamine synthesis
b Sodium periodate / THF:H2O (1:1) Aldehyde synthesis
c TiCl4 / MeLi / Et2O Hydroxyl synthesis
d Dess-Martin periodinane / DCM Ketone synthesis
e Fe / AcOH Primary amine synthesis (Nitro reduction)
f Ns-Cl / Pyridine Nosyl protection
g LiOH 1M / THF:MeOH (1:1) Nosyl deprotection
h Dimethylformamidedimethylacetal / DIEA / DMF Cyclisation
Steps Conditions Reactions
a Boc2O / DMAP / DCM Boc protection
b

1. Pd(dppf)Cl2-DCM / Na2CO3 / DME

2. TFA / DCM 

Suzuki reaction / Boc deprotection
Steps Conditions Reactions
a 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)-methane sulfonamide / DIEA / DCM Mesyl synthesis
b DIEA / DCM Tertiary amine synthesis (Nucleophilic substitution)
c Bis(pinacolato)diboron / tricyclohexylphosphine / AcOK / Pd2(dba)3 / dioxane Ester boronic synthesis                  
Steps Conditions Reactions
a Pd(dppf)Cl2-DCM / THF
Negishi coupling
b Dioxane / H2O / HCl cc Methoxy deprotection
c 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide / DIEA / DCM  Triflate synthesis 
Steps Conditions Reactions
a

1. Pd(dppf)Cl2-DCM / Na2CO3 / DME

2. TFA / DCM

Suzuki reaction / Boc deprotection
Steps Conditions Reactions
a trimethylboroxine / Pd(PPh3)4 / K2CO3 / dioxane  Suzuki reaction
b Bis(pinacolato)diboron / tricyclohexylphosphine / AcOK / Pd2(dba)3 / dioxane
Ester boronic synthesis 
c Pd(dppf)Cl2-DCM / Na2CO3 / DME Suzuki reaction
d Bis(pinacolato)diboron / tricyclohexylphosphine / AcOK / Pd2(dba)3 / dioxane Ester boronic synthesis 
Steps Conditions Reactions
a 1-(Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) / ACN Fluorination
b Bis(pinacolato)diboron / tricyclohexylphosphine / AcOK / Pd2(dba)3 / dioxane
Ester boronic synthesis 
Steps Conditions Reactions
a

1. Pd(dppf)Cl2-DCM / Na2CO3 / DME

2. TFA / DCM

Suzuki reaction  / Boc deprotection
Steps Conditions Reactions
a DIEA / NMP Tertiary amine synthesis (Nucleophilic substitution)
b Bis(pinacolato)diboron / tricyclohexylphosphine / AcOK / Pd2(dba)3 / dioxane
Ester boronic synthesis
Steps Conditions Reactions
a Bn-OH / NaH / DMF O-Benzyl protection
b Bis(pinacolato)diboron / tricyclohexylphosphine / AcOK / Pd2(dba)3 / dioxane
Ester boronic synthesis
c Pd(dppf)Cl2-DCM / Na2CO3 / DME Suzuki reaction
d H2 / Pd-C / EtOH:EtOAc (1:1) O-Benzyl deprotection
e 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide / DIEA / DCM  Triflate synthesis
f

1. DIEA / iPrOH

2. TFA / DCM

Tertiary amine synthesis (Nucleophilic substitution) / Boc deprotection
Steps Conditions Reactions
a Bn-OH / NaH / THF O-benzyl protection
b Pd(dppf)Cl2-DCM / Na2CO3 / DME
Suzuki reaction
c H2 / Pd-C / EtOH:AcOEt (4:1) O-Benzyl deprotection
d 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide / DIEA / DCM 
Triflate synthesis
e

1. Pd(dppf)Cl2-DCM / THF

2. TFA / DCM

Negishi coupling

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