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. Author manuscript; available in PMC: 2019 Nov 9.
Published in final edited form as: J Med Chem. 2018 Jun 29;61(13):5623–5642. doi: 10.1021/acs.jmedchem.8b00375

Table 3.

Optimization/SAR of 3,4-disubstituted amides.c

graphic file with name nihms-1057822-t0036.jpg
F R1 R2 R3 FPA Ki (μM)a LEb
5a -CH2-c-Pr graphic file with name nihms-1057822-t0037.jpg 3-OMe 1.46 0.25
5b -CH2-c-Pr graphic file with name nihms-1057822-t0038.jpg 2-OMe 0.148 0.29
5c -CH2-c-Pr graphic file with name nihms-1057822-t0039.jpg 2-OEt 0.0425 0.31
5d -CH2-c-Pr graphic file with name nihms-1057822-t0040.jpg 2-O-i-Pr 0.0276 0.30
5e H graphic file with name nihms-1057822-t0041.jpg 2-O-i-Pr 0.0761 0.32
5f -CH2-c-Pr graphic file with name nihms-1057822-t0042.jpg 2-O-c-Bu 0.0228 0.30
5g H graphic file with name nihms-1057822-t0043.jpg 2-O-c-Bu 0.105 0.31
5h H graphic file with name nihms-1057822-t0044.jpg 2-N(CH3)2 0.185 0.32
5i H graphic file with name nihms-1057822-t0045.jpg 2-N(CH3)2 0.0519 0.33
5j H graphic file with name nihms-1057822-t0046.jpg graphic file with name nihms-1057822-t0047.jpg
(1,2)		 0.0207 0.32
5k H graphic file with name nihms-1057822-t0048.jpg 2-O-i-Pr 0.00989 0.35
5l -CH2-c-Pr graphic file with name nihms-1057822-t0049.jpg 2-O-i-Pr 0.0131 0.31
5m H graphic file with name nihms-1057822-t0050.jpg 2-O-c-Bu 0.00282 0.37
5n -CH2-c-Pr graphic file with name nihms-1057822-t0051.jpg 2-O-c-Bu 0.0289 0.29
5o -CH2-c-Pr graphic file with name nihms-1057822-t0052.jpg 2-O-c-Bu 0.00353 0.32
5p H graphic file with name nihms-1057822-t0053.jpg 2-O-c-Bu 0.0164 0.33
a

Ki values represent the average of two or more independent determinations conducted in replicate (CV < 0.3).

b

Ligand efficiency index, LE = 1.4*pKi / HAC.

c

c-Pr = cyclopropyl, i-Pr = isopropyl, c-Bu = cyclobutyl.