Submission Details
Molecule(s):
C=CC(=O)N1CCN(S(=O)(=O)c2c(F)cccc2OCCCNc2ccc(C#N)cn2)CC1
C=CC(=O)N1CCN(S(=O)(=O)c2ccccc2-c2ccc(Nc3ccc(C#N)cn3)cc2)CC1
C=CC(=O)N1C[C@H]2CN(S(=O)(=O)c3c(F)cccc3OCCCNc3ccc(C#N)cn3)C[C@H]2C1
C=CC(=O)N1C[C@H]2CN(S(=O)(=O)c3ccccc3-c3ccc(Nc4ccc(C#N)cn4)cc3)C[C@H]2C1
C=CC(=O)N1CC(NS(=O)(=O)c2ccccc2-c2ccc(Nc3ccc(C#N)cn3)cc2)C1
C=CC(=O)NC1CN(S(=O)(=O)c2ccccc2-c2ccc(Nc3ccc(C#N)cn3)cc2)C1
C=CC(=O)NC1CN(S(=O)(=O)c2c(F)cccc2OCCCNc2ccc(C#N)cn2)C1
C=CC(=O)N1CC(NS(=O)(=O)c2c(F)cccc2OCCCNc2ccc(C#N)cn2)C1
C=CC(=O)N1CCN(CC2=CNC3C=CC(C#N)=CC23)CC1
C=CC(=O)N1CC(NCC2=CNC3C=CC(C#N)=CC23)C1
C=CC(=O)NC1CN(CC2=CNC3C=CC(C#N)=CC23)C1
C=CC(=O)N1C[C@@H]2CN(CC3=CNC4C=CC(C#N)=CC34)C[C@@H]2C1
C=CC(=O)N(C)CCN(C)CC1=CNC2C=CC(C#N)=CC12
Design Rationale:
Screening of piperazine isosteres to see if the acrylamide can bind as well as the corresponding chloroacetamides, which are too prone to hydrolysis imo. Priopiolamides should also be considered for all proposed acrylamides. I'm not able to dock these molecules but measured distances (and angles) should make irreversible inhibition possible. X0305_0 as non-covalent scaffold for both series. X0755_0 for first series, X0692_0 for second.
Other Notes:
All necessary building blocks are commercially available: piperazine isosteres CAS nr. : 102065-89-4 , 250275-15-1 First series: 60230-36-6 (2,6-Difluorobenzenesulfonyl chloride) SnAr on the resulting sulfonamide 33252-28-7 (6-Chloro-3-pyridinecarbonitrile) SnAr substrate Biphenyl via Suzuki: several options available Second series indole building block for reductive amination: 17380-18-6