The intermediate 5-bromo-2-methoxy-6-(methylamino)pyridine-3-carboxylic acid (VII) has been obtained as follows: The reaction of 2,6-difluoropyridine (I) with BuLi and CO2 in THF gives 2,6-difluoropyridine-3-carboxylic acid (II), which is esterified with H2SO4 and methanol, yielding the methyl ester (III). The reaction of (III) with methylamine in ethanol affords 2-fluoro-6-(methylamino)pyridine-3-carboxylic acid ethyl ester (IV), which is treated with potassium tert-butoxide in refluxing methanol to provide 2-methoxy-6-(methylamino)pyridine-3-carboxylic acid methyl ester (V). The bromination of (V) with NBS in hot DMF gives the 5-bromo-2-methoxy-6-(methylamino)pyridine-3-carboxylic acid methyl ester (VI), which is finally hydrolyzed with NaOH in refluxing methanol/water to yield the target carboxylic acid intermediate (VII).

The reaction of N-methyl-N'-(3-methylbenzyl)ethylene-1,2-diamine (VIII) with (Boc)2O in chloroform gives N-(tert-butoxycarbonyl)-N-methyl-N'-(3-methylbenzyl)ethylene-1,2-diamine (IX), which is condensed with the chiral aziridine (X) by heating at 80 C to yield the diaminobutyric ester (XI). Selective elimination of the Boc protecting group of (XI) with HCl in methanol affords the methylamino intermediate (XII), which is treated with NaOH in ethanol/water to provide the carboxylic acid (XIII). The cyclization of (XIII) by means of DEC gives the perhydro-1,4-diazepin-5-one derivative (XIV), which is debenzylated by means of 1-chloroethyl chloroformate to yield the 6(S)-(benzyloxycarbonylamino)-4-methylperhydro-1,4-diazepin-5-one (XV). The reductive alkylation of (XV) with acetaldehyde, NaBH4 and TEA in methanol affords the 1-ethyl derivative (XVI), which is deprotected by means of conc. HBr to provide 6(S)-amino-1-ethyl-4-methylperhydro-1,4-diazepin-5-one (XVII). The reduction of (XVII) with BH3/THF gives 1-ethyl-4-methylperhydro-1,4-diazepin-6(R)-amine (XVIII), which is condensed with 5-bromo-2-methoxy-6-(methylamino)pyridine-3-carboxylic acid (VII) by means of ethyl chloroformate and TEA to yield the target amide (XIX). Finally, this compound is treated with fumaric acid (XX) in ethanol to afford the desired fumarate salt.

The protection of the NH2 group of L-serine (I) gives N-(benzyloxycarbonyl)-L-serine (II), which is converted into the N-methylamide (III). The reduction of the amide group of (III) affords the diaminopropanol (IV), which is N-protected to provide the Boc-protected compound (V). The mesylation of the OH group of (V) gives the mesylate (VI), which is treated with ethylamine to yield the triaminopropane (VII). Boc deprotection in (VII) with HCl affords intermediate (VIII), which is submitted to a reductive cyclization with glyoxal and BH3/TEA to provide the perhydro-1,4-diazepine (IX). Cbz deprotection in (IX) by hydrogenation with H2 over Pd/C gives the 1-ethyl-4-methylperhydro-1,4-diazepin-6(R)-amine (X), which is condensed with 5-bromo-2-methoxy-6-(methylamino)pyridine-3-carboxylic acid (XI) by means of ethyl chloroformate and TEA to yield the target amide (XII). Finally, this compound is treated with fumaric acid (XIII) in ethanol to afford the desired fumarate salt.

The protection of the NH2 group of L-serine (I) gives N-(benzyloxycarbonyl)-L-serine (II), which is converted into the N-methylamide (III). The reduction of the amide group of (III) affords the diaminopropanol (IV), which is N-protected to provide the Boc-protected compound (V). The mesylation of the OH group of (V) gives the mesylate (VI), which is treated with ethylamine to yield the triaminopropane (VII). The condensation of (VII) with ethyl bromoacetate (VIII) affords the aminoacetate (IX), which is selectively deprotected with HCl to provide the intermediate (X). The cyclization of (X) by means of NaOEt gives the perhydro-1,4-diazepin-2-one (XI), which is reduced with BH3/THF to yield the perhydro-1,4-diazepine (XII). Cbz deprotection in (XII) by hydrogenation with H2 over Pd/C gives the 1-ethyl-4-methylperhydro-1,4-diazepin-6(R)-amine (XIII), which is condensed with 5-bromo-2-methoxy-6-(methylamino)pyridine-3-carboxylic acid (XIV) by means of ethyl chloroformate and TEA to yield the target amide (XV). Finally, this compound is treated with fumaric acid (XVI) in ethanol to afford the desired fumarate salt.

The protection of the NH2 group of L-serine (I) with Ts-Cl and TEA gives N-tosyl-L-serine (II), which is converted into the N-methylamide (III). The cyclization of (III) by means of diisopropylazodicarboxylate (DIAD) yields the N-tosylaziridine (IV), which is treated with ethylamine (V) to afford the diaminopropionamide (VI). The reduction of the amide group of (VI) with LiAlH4 provides the triaminopropane (VII), which is submitted to a reductive cyclization with glyoxal and BH3/TEA to give the perhydro-1,4-diazepine (VIII). Ts deprotection in (VIII) by means of HBr affords the 1-ethyl-4-methylperhydro-1,4-diazepin-6(R)-amine (IX), which is condensed with 5-bromo-2-methoxy-6-(methylamino)pyridine-3-carboxylic acid (X) by means of ethyl chloroformate and TEA to yield the target amide (XI). Finally, this compound is treated with fumaric acid (XII) in ethanol to afford the desired fumarate salt.