WO2010063634 Pyrrolopyrazinyl urea kinase inhibitors

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Scaffold: pyrrolopyrazine

Biological target:

Janus kinase: JAK3

Activity:

Inhibitor

Steps Conditions Reactions
a

Pd(PPh3)2Cl2 / CuI / DIEA / THF

Sonogashira reaction
b

tBuOK / THF

Cyclisation (indole synthesis)
c SEM -Cl / NaH / DMF  SEM protection 
d Pd(OAc)2 / BINAP / Cs2CO3 / THF  Buchwald-hartwig amination 
e NH2-OH  / NaOAc / MeOH  Primary amine synthesis 
Steps Conditions Reactions
a

LiHMDS / allyl bromide / THF 

Nucleophilic substitution
b

sodium formate / Bu4NBr / Pd(OAc)2 / DMF

Cyclisation
Steps Conditions Reactions
a

LDA / CH3-I / THF

Nucleophilic substitution
b

Sodium triacetoxyborohydride / Benzylamine / DCM

Secondary amine synthesis (reductive amination)
c H2 / Pd(OH)2 / HCl 3N / EtOH  N-Benzyl deprotection 
Steps Conditions Reactions
a

H2SO4 / MeOH


b

1. Titanium tetraisopropoxide / EtMgBr / Et2O

2. APTS / Et2O

Cyclopropyl synthesis 
c

1. Benzylamine / benzene

2 .triacetoxyborohydride / AcOH / DCM

3. H2 / Pd(OH)2 / EtOH

Reductive amination / N-Benzyl deprotection
Steps Conditions Reactions
a

DIAD / PPh3 / THF

Mitsunobu reaction
b

HCl c / MeOH

TBDMS deprotection
c MsCl / DIEA / DCM  Mesyl synthesis 
d NaN3 / DMF  Azido synthesis 
e H2 / Pd-C / DCM / EtOH  Primary amine synthesis
Steps Conditions Reactions
a

BH3.Me2S / THF

Hydroxyl synthesis (Carboxylic acid reduction)
b

p-toluenesulfonyl chloride / Et3N / DMAP / DCM 

Tosyl synthesis
c Thiourea / EtOH    Nucleophilic substitution 
d Cl2 / H2O / THF  Chlorination 
Steps Conditions Reactions
a

SEM-Cl / NaH / DMF

SEM protection
b

1. benzophenone imine / Pd2(dba)3 / BINAP / sodium t-butoxide / toluene

2. Sodium acetate / NH2-OH / MeOH

Buchwald-Hartwig Amination
c DCM  Urea synthesis 
d TBAF / ethylene diamine / DMF  SEM deprotection 
Steps Conditions Reactions
a

Phosgene / DIEA / DCM

Urea synthesis
b

TBAF / ethylene diamine / DMF

SEM deprotection
Steps Conditions Reactions
a

NIS / Acetone 

Iodination
b

Cs2CO3 / Pd(dppf)Cl2.DCM / THF / H2O

Suzuki reaction
c H2 / Pd-C / MeOH  Alkene reduction 

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