Table 1.

Synthesis and SAR of substituted 3-arylindazoles.

Compound	R1	R2	MEK4-p38, IC50, µM [95% CI]	Compound	R1	R2	MEK4-p38, IC50, µM [95% CI]
6a	H	3’-CO2H	0.64 [0.53, 0.77]	6q	5-CH3	4’-OH	0.59 [0.46, 0.75]
6bb	4-CH3	4’-OH	4.0 [3.3, 4.8]	6r	5-CH3	4’-CONH2	0.56 [0.40, 0.77]
6c	4-Cl	3’,4’-(OCH2O)	4.5 [3.9, 5.2]	6s	5-CH3	4’-CO2H	0.15 [0.10, 0.23]
6d	4-Cl	4’-CONH2	4.4 [3.9, 5.0]	6t	5-CH3	3’-pyridyl	1.6 [1.1, 2.3]
6e	4-Cl	3’-pyridyl	> 22	6u	5-CH3	3’-CH2OH	1.4 [1.2, 1.8]
6f	4-Cl	3’-CH2OH	7.2 [6.0, 8.6]	6v	5-CH3	3’-CONH2	0.97 [0.74, 1.3]
6g	4-Cl	3’-C(CH3)OH	> 22	6w	5-CH3	4’-CH2OH	1.3 [1.1, 1.5]
6h	4-Cl	3’-CONH2	1.3 [1.0, 1.6]	6x	6-CF3	3’,4’-(OCH2O)	6.1 [4.9, 7.7]
6i	4-Cl	4’-CH2OH	8.1 [7.2, 9.1]	6y	6-CF3	4’-CO2CH3	> 20
6j	5-CF3	4’-OH	0.76 [0.67, 0.86]	6z	6-CF3	4’-CO2H	0.72 [0.56, 0.92]
6kc	5-CF3	4’-OH	> 20	6aa	6-Cl	3’,4’-(OCH2O)	0.46 [0.30, 0.71]
6lc	5-CF3	3’-CONH2	9.9 [7.3, 14]	6bb	6-Cl	4’-CO2CH3	2.2 [1.7, 2.9]
6m	5-CF3	4’-CONH2	1.1 [0.99, 1.3]	6cc	6-Cl	4’-CO2H	0.12 [0.10, 0.14]
6n	5-CF3	4’-CO2H	0.47 [0.39, 0.55]	6dd	6-F	4’-CO2CH3	0.42 [0.35, 0.51]
6ob	5-CH3	3’-CH2OH, 4’-F	1.0 [0.69, 1.5]	6ee	6-F	3’,4’-(OCH2O)	0.063 [0.029, 0.14]
6p	5-CH3	3’,4’-(OCH2O)	0.41 [0.36, 0.48]	6ff	6-F	4’-CO2H	0.041 [0.034, 0.049]

^[a]Reagents and Conditions: (a) i. NaOH, I₂, MeOH, rt, 24 h, 90–95%; ii. Boc₂O, rt, 16 h.; (b) Ar-B(OH)₂, PdCl₂(dppf)·DCM, K₃PO₄, H₂O, 1,4-Dioxane, 90 °C, 1.5 h., 50–70%.

^[b]Compounds were purchased from ChemBridge.

^[c]Compound has a Boc-group on the indazole N-1 position.