Table 1. Impact of Covalent Reactive Group Selection on Compound Pharmacology^a.

				IC50c (nM)				kinact/Kid (1/(M·s))
compd	X	Y	ωb	BTK WT	BTK C481S	EGFR	SRC	BTK WTe	EGFRf	BTK T1/2e,g (h)	THLE IC50 (μM)
1			0.83	0.1	3.4	18	38	226 000	45 040	>24	11
9a			0.44	1.5	43	16 800	1 630	123 900	56	6	137
9b	H	H	0.83	0.25	17	26	4 030	206 500	25 110	>24	15
9c	CH3	H	0.48	247	176	>20 000	3 350	<1h	i	i	i
9d	H	CH3	0.60	61	66	>20 000	3 410	4 910	i	>24	149
9e	F	H	0.69	5.3	170	570	6 480	35 300	435	>24	67
9f	H	CH2OH	0.61	2.3	33	2 910	4 610	26 650	213	>24	43
9g	H	CH2F	0.65	2.7	90	2 180	3 140	85 770	332	>24	49
9h	H	CHF2	0.81	0.41	115	274	5 840	80 500	i	>24	8
9i	H	CH2NMe2	0.59	3.7	65	149	370	19 180	514	>24	15

^aAll values are the mean of two or more independent assays.

^bElectrophilicity index calculated using DMol3 at PBE/TNP/COSMO level of theory in water with LowModeMD.

^cLanthascreen assay, [ATP] = K_m.

^dFor reversible inhibitors, the analogous second-order rate constant is given.

^eTR-FRET binding assay.

^fCaliper enzymatic assay.

^gApparent dissociation rate.

^hKinetics consistent with reversible inhibition; time dependence not observed.

ⁱNot determined.