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. Author manuscript; available in PMC: 2019 Feb 8.
Published in final edited form as: J Med Chem. 2018 Jan 5;61(3):1182–1203. doi: 10.1021/acs.jmedchem.7b01654

Table 5.

SAR of ortho- and para-aniline ring substitutions

graphic file with name nihms967105u6.jpg
Compound R1 R2 R3 R4 Tb IC50,b μM Hs IC50,c μM Tb427 EC50,d μM
7 H Cl H Cl 3.7 (3.3–4.1) 27% at 180 5.6 (4.5–7.1)
62 H Cl F Cl 1.5 (1.4–1.8) 160 (135–191) 4.8 (3.3–7)
63 H Br F Br 1.6 (1.3–1.8) 43% at 180 4.6 (3.6–5.9)
64 H Cl Cl Cl 11 (8.8–13) >63 4.5 (3.4–5.9)
65 H Cl Me Cl 20 (17–24) >63 4.4 (4.2–4.8)
66 H Cl OPh Cl 38% at 180 >180 1.1 (0.97–1.3)
67 H Cl OH Cl 33% at 180 >180 13 (10–16)
68 H Cl OCHF2 Cl >63 >63 4.5 (3.7–5.4)
69 H Cl NMe2 Cl >180 >180 5.8 (4.2–7.9)
70 H Cl N-morpholino Cl >180 >180 18 (14–24)
71 H Cl N-piperidino Cl >180 >180 2.1 (1.3–3.2)
72 OH Cl H Cl 37 (29–46) >180 26% at 100
73 F Cl F Cl 2.2 (2.0–2.6) >63 10 (8.5–12)
74 Cl H H Cl 115 (89–150) >180 23% at 25
75 Cl Cl H H 137 (95–198) >180 27% at 25
76 Cl H Cl H >180 >180 28% at 25
77 Me H H H >180 >180 >25
78 SMe H H H >180 >180 >25
79 Br H H H >180 >180 >25
80 Me Cl H H >180 >180 29% at 25
81 Me H H Cl >180 >180 28% at 25
82 Me H Cl H >180 >180 >25
83 F H Br H >180 >180 25% at 25
84 Cl H H CF3 199 (164–240) >180 28% at 25
85 H H Cl H >180 >180 28% at 25
86 H H Et H >180 >180 19 (17–22)
87 H H iPr H >180 >180 11 (8.5–15)
88 H H CF3 H >180 >180 15 (13–17)
89 H H 3,5-Cl2Ph H >180 >180 1.0 (0.88–1.2)
90 H F F H 33% at 180 >180 25% at 25

All compounds have pKa(N1)a of 7.3 except 67 (pKa(N1)= 7.0); 72 (pKa(N1)= 7.1); 73, 74, and 83 (pKa(N1)= 7.2).

a, b, c, d

See footnotes for Table 1.