Synthesis of intermediate (IX): Iodination of 4-amino-1-tosylindole (I) by reaction with NaNO2 and HCl in H2O followed by reaction with KI in H2O yields iodoindole (II), whose tosyl group is removed by treatment with NaOH in refluxing MeOH to provide 4-Iodoindole (III). Subsequent protection of (III) with tert-butyldimethylsilyl chloride (TBS-Cl) in THF in the presence of NaH affords compound (IV). 1-Methoxyindole (V) is first treated with n-BuLi in THF and then with triethylboran in hexane to give borane (VI), which is coupled with compound (IV) by means of PdCl2(Ph3P)2 in refluxing THF to provide substituted bisindole (VII). Deprotection of (VII) is performed by treatment with tetrabutyl ammonium fluoride (TBAF) to yield derivative (VIII), which is finally hydrogenated over Pd/C in MeOH to give diindole intermediate (IX). Alternatively, intermediate (IX) can be obtained as follows: Treatment of 1-methoxyindole (V) with BuLi in THF provides lithium salt (X), which is converted into bisindole (XII) by first condensation with tetrahydroindolone derivative (XI) in either THF or THF/HCl, followed by oxidation with DDQ in benzene. Removal of the tosyl group of (XII) is accomplished by treatment with NaOH in refluxing MeOH to furnish derivative (XIII), which is then hydrogenated over Pd/C in MeOH to afford intermediate (IX). Conversion of (XII) into (IX) can also be directly performed by treatment of (XII) with Mg in refluxing MeOH. Synthesis of EN 285030: Finally, reaction of intermediate (IX) with methylmagnesium iodide in THF (or with methylmagnesium bromide) followed by condensation with N-(tert-butyldimethylsilyl)-2,3-dibromomaleimide (XIV) in refluxing toluene provides the target compound. Alternatively, if benzene is used as a solvent in the last reaction (condensation with (XIV)), a protected derivative (XV) is isolated, which is converted into the final product by removal of the TBDMS group by treatment with TBAF in THF.

Synthesis of intermediate (IX): Iodination of 4-amino-1-tosylindole (I) by reaction with NaNO2 and HCl in H2O followed by reaction with KI in H2O yields iodoindole (II), whose tosyl group is removed by treatment with NaOH in refluxing MeOH to provide 4-Iodoindole (III). Subsequent protection of (III) with tert-butyldimethylsilyl chloride (TBS-Cl) in THF in the presence of NaH affords compound (IV). 1-Methoxyindole (V) is first treated with n-BuLi in THF and then with triethylboran in hexane to give borane (VI), which is coupled with compound (IV) by means of PdCl2(Ph3P)2 in refluxing THF to provide substituted bisindole (VII). Deprotection of (VII) is performed by treatment with tetrabutyl ammonium fluoride (TBAF) to yield derivative (VIII), which is finally hydrogenated over Pd/C in MeOH to give diindole intermediate (IX). Alternatively, intermediate (IX) can be obtained as follows: Treatment of 1-methoxyindole (V) with BuLi in THF provides lithium salt (X), which is converted into bisindole (XII) by first condensation with tetrahydroindolone derivative (XI) in either THF or THF/HCl, followed by oxidation with DDQ in benzene. Removal of the tosyl group of (XII) is accomplished by treatment with NaOH in refluxing MeOH to furnish derivative (XIII), which is then hydrogenated over Pd/C in MeOH to afford intermediate (IX). Conversion of (XII) into (IX) can also be directly performed by treatment of (XII) with Mg in refluxing MeOH. Synthesis of EN 285030: Finally, reaction of intermediate (IX) with methylmagnesium iodide in THF (or with methylmagnesium bromide) followed by condensation with N-(tert-butyldimethylsilyl)-2,3-dibromomaleimide (XIV) in refluxing toluene provides the target compound. Alternatively, if benzene is used as a solvent in the last reaction (condensation with (XIV)), a protected derivative (XV) is isolated, which is converted into the final product by removal of the TBDMS group by treatment with TBAF in THF.