Synthesis and biological evaluation of new pyrimidine-4-yl-ethanol derivatives as ROS1 kinase inhibitors

Figures & data

Figure 1. Structure of the lead compounds KIST301072 and KIST301080.

Scheme 1. Synthesis of target compounds: (i) LHMDS, 2,4-dichloro-6-methylpyrimidine, THF, N₂, rt, 24 h, 81%; (ii) THF, various amine, 80 °C, 3 h; (iii) 3-pyridineboronic acid, Pd(PPh₃)₂Cl₂, K₂CO₃, N₂, THF/CH₃CN/H₂O (2:1:1), 90 °C, 3 h; (iv) BF₃· S(CH₃)₂, dichloromethane, N₂, rt, 12 h; and (v) NaBH₄, ethanol, N₂, 0 → rt, 12 h.

Table 1. The IC₅₀ values of the target compounds against ROS1 kinase.

Compound no.	ROS1 (IC50, μM)	Compound no.	ROS1 (IC50, μM)
4a	>20	6a	13.7
4b	4.6	6b	12.6
4c	>20	6c	>20
4d	>20	6d	>20
4e	>20	6e	13.5
4f	>20	6f	8.1
5a	No inhibition	7a	9.1
5b	No inhibition	7b	>20
5c	15.6	7c	>20
5d	>20	7d	>20
5e	17.7	7e	5.8
5f	>20	7f	4.9

Figure 2. Binding mode of crizotinib in ROS1 active pocket in 2D and 3D, respectively.

Figure 3. Overlay of crizotinib (green stick) and KIST301072 (element colored stick) bound to ROS1 active site.

Figure 4. Overlay of KIST301072 (yellow stick) and compound 7a (orange stick) bound to ROS1 active site.