Figure 1. Structures of dual VEGF-R2/TIE-2 inhibitors.

Figure 2. Design of dual VEGF-R2/TIE-2 inhibitors.

Scheme 1. Reagents and conditions: (a) i—(Z)-3-cyanoacrylic acid ethyl ester, YbBr₃, 80 °C, AcOH; ii—DDQ, CH₃CN; iii—Raney-Ni, DMF, MeOH, 50 psi, 27–30%; (b) i—Ac₂O, reflux; ii—hexamethylenetetramine, TFA, reflux, 79–88%; (c) i—NH₂OH·HCl or R²ONH₂·HCl, NMP, EtOH, reflux; ii—K₂CO₃, MeOH, reflux, 50–55%.

Scheme 2. Reagents and conditions: (a) i—acetyl chloride or isobutyryl chloride, AlCl₃, CH₂Cl₂, MeNO₂, rt; ii—Ac₂O, reflux, 71–80%; (b) i—NH₂OH·HCl or R²ONH₂·HCl, NMP, EtOH, reflux; ii—K₂CO₃, MeOH, reflux, 65–72%.

Scheme 3. Reagents and conditions: (a) i—(Z)-3-cyanoacrylic acid ethyl ester, YbBr₃, 80 °C, AcOH; ii—DDQ, CH₃CN, rt, 30–35%; (b) i—10 N NaOH, R11-I, acetone, reflux; ii—Raney-Ni, DMF, MeOH, 50 psi, 75–85%; (c) i—MeCOCl, AlCl₃, CH₂Cl₂, CH₃NO₂, rt; ii—Ac₂O, reflux, 50–55%; (d) i—NH₂OH·HCl or R²ONH₂·HCl, NMP, EtOH, reflux; ii—K₂CO₃, MeOH, reflux, 52–57%.

Scheme 4. Reagents and conditions: (a) i—(Z)-3-cyanoacrylic acid ethyl ester, YbBr₃, 80 °C, AcOH; ii—DDQ, CH₃CN, 30–35%; (b) i—10 N NaOH, 1-iodo-2-methylpropane, acetone, reflux; ii—Raney-Ni, DMF, MeOH, 50 psi, 82–85%; (c) i—MeCOCl, AlCl₃, CH₂Cl₂, CH₃NO₂, rt; ii—MeONH₂·HCl, Pyridine, 100 °C, 65–70%.

Figure 4. Hydrophobic surface map around compound 35 bound to the ATP site of TIE-2.

Figure 3. ORTEP drawing of the crystal structure of 35.

Figure 5. Anti-angiogenic activity of 35 in (A) VEGF-induced HUVEC capillary-tube formation and (B) ex vivo rat aortic ring explants. p < 0.05, ^**p < 0.01, ^***p < 0.0001.

Figure 6. Effects of oral administration of compound 35 on human melanoma xenografts.

SAR for R¹ and R²

ND, not determined.

SAR for R¹¹ and R²

ND, not determined.

Rat pharmacokinetic properties for 35 and 40