Design, synthesis and biological evaluation of novel 1H-1,2,4-triazole, benzothiazole and indazole-based derivatives as potent FGFR1 inhibitors viafragment-based virtual screening

Figures & data

Figure 1. Structure of representative FGFR inhibitors.

Figure 2. (a) Binding model of AZD4547 and NVP-BGJ398 to the FGFR1 kinase domain (PDB ID: 4V05, 3TTO). (b) The fragment-based virtual screening protocol.

Scheme 1. Synthesis of indazole derivatives. Reagents and conditions: (a) K₂CO₃, DMSO, 120 °C, 85–90%; (b) NaOH, MeOH, H₂O, 80 °C, 93–96%; (c) HATU, K₂CO₃, DMF, rt, 62–70%; (d) hydrazine hydrate, n-butanol, 120 °C, 86%; (e) Boc₂O, DMAP, THF, 89%; (f) NaH, THF, 60 °C, 52–61%; (g) TFA, CH₂Cl₂, 0 °C, 70%; (h) R-B(OH)₂, Cs₂CO₃, Pd(dppf)Cl₂, dioxane, 120 °C, 30–48%.

Scheme 2. Synthesis of benzothiazole derivatives. Reagents and conditions: (a) 4, NaH, THF, 60 °C, 51–62%; (b) R-B(OH)₂, Cs₂CO₃, Pd(dppf)Cl₂, dioxane, 120 °C, 47–53%.

Scheme 3. Synthesis of 1H-1,2,4-triazole derivatives. Reagents and conditions: (a) propanedioic acid, pyridine, piperidine, 105 °C, 77–82%; (b) Pd/C, H₂, EtOH, 88–93%; (c) SO₂Cl₂, reflux; (d) amino guanidine hydrochloride, 140 °C, 49–53%; (f) 4, NaH, THF, 60 °C, 54–62%; (g) TFA, CH₂Cl₂, 0 °C, 70%.

Table 1. Structures and activities of various derivatives 9a-d, 12a-d, and 18a-c.

Table 2. Structures and activities of indazole derivatives 9e–t.

Table 3. Structures and activities of indazole derivatives 9 u–z.

Table 4. Selectivity of 9 u in a panel of kinases.

Tyrosine kinase	IC50 (nM)	Tyrosine kinase	IC50 (nM)
FGFR1	3.3	Flt-1	>100
FGFR2	5.2	RET	>100
FGFR3	12.2	c-Src	>100
FGFR4	>1000	IGF1R	>1000
ALK	>1000	c-Met	>1000
Bcr-Abl	>1000	EGFR	>1000
EPH-A2	>1000	ErbB2	>1000

Figure 3. The docking mode of compound 9d (a), 12a (b), and 18 b (c). (d) Superposed docking poses of 9e (white), 9f (yellow), and 9 g (green).