Submission Details

Molecule(s):
O=C(Cc1cccc(Cl)c1)N(C(=O)C(F)(F)F)c1cncc2ccccc12

JOH-UNI-a38a7bdd-1

O=C(Cc1cccc(Cl)c1)N(C(=O)C(F)(F)F)c1cncc2ccccc12

3-aminopyridine-like Check Availability on Manifold View
O=C(Cc1cccc(Cl)c1)N(CC(F)(F)F)c1cncc2ccccc12

JOH-UNI-a38a7bdd-2

O=C(Cc1cccc(Cl)c1)N(CC(F)(F)F)c1cncc2ccccc12

3-aminopyridine-like Check Availability on Manifold View
Cc1ccncc1N(C(=O)Cc1cccc(Cl)c1)C(=O)C(F)(F)F

JOH-UNI-a38a7bdd-3

Cc1ccncc1N(C(=O)Cc1cccc(Cl)c1)C(=O)C(F)(F)F

3-aminopyridine-like Check Availability on Manifold View
Cc1ccncc1N(CC(F)(F)F)C(=O)Cc1cccc(Cl)c1

JOH-UNI-a38a7bdd-4

Cc1ccncc1N(CC(F)(F)F)C(=O)Cc1cccc(Cl)c1

3-aminopyridine-like Check Availability on Manifold View
O=C(Cc1cccc(Cl)c1)N(C(=O)C1CC1F)c1cncc2ccccc12

JOH-UNI-a38a7bdd-5

O=C(Cc1cccc(Cl)c1)N(C(=O)C1CC1F)c1cncc2ccccc12

3-aminopyridine-like Check Availability on Manifold View
O=C(Cc1cccc(Cl)c1)N(C(=O)C1CC1C(F)(F)F)c1cncc2ccccc12

JOH-UNI-a38a7bdd-6

O=C(Cc1cccc(Cl)c1)N(C(=O)C1CC1C(F)(F)F)c1cncc2ccccc12

3-aminopyridine-like Check Availability on Manifold View
Cc1ccncc1N(C(=O)Cc1cccc(Cl)c1)C(=O)C1CC1C(F)(F)F

JOH-UNI-a38a7bdd-7

Cc1ccncc1N(C(=O)Cc1cccc(Cl)c1)C(=O)C1CC1C(F)(F)F

3-aminopyridine-like Check Availability on Manifold View
Cc1ccncc1N(CC1CC1C(F)(F)F)C(=O)Cc1cccc(Cl)c1

JOH-UNI-a38a7bdd-8

Cc1ccncc1N(CC1CC1C(F)(F)F)C(=O)Cc1cccc(Cl)c1

3-aminopyridine-like Check Availability on Manifold View
Cc1ccncc1N(CC1CC1F)C(=O)Cc1cccc(Cl)c1

JOH-UNI-a38a7bdd-9

Cc1ccncc1N(CC1CC1F)C(=O)Cc1cccc(Cl)c1

3-aminopyridine-like Check Availability on Manifold View

Design Rationale:

Inspired by DAR-DIA-076fb6ea; rather than a covalent bond to Cys, can we have a more subtle electrostatic SH------F interaction to aid potency? CF3 had best balance of binding with 220CySH in p53-Y220C binding in an earlier study of ours and lowest desolvation penalties so gave most potent binder. See Spencer et al. DOI: 10.1021/acschembio.6b00315; ACS Chem. Biol. 2016, 11, 2265−2274.

Other Notes:

As pointed out earlier; CH2FCH2-N can give FCH2CO2H...... after oxid metabolism. Adding a CF3CH2 group to an amine can be problematic; we've observed loss of HF and formation of an iodoalkene with CF3CH2I !!! CF3CH2OTs was a good alkylating agent!

Discussion: