Synthesis of Intermediate (VII): Acylation of p-chloroaniline (I) with dimethylmalonic acid (A) and SOCl2 gives (II), which is then cyclized to quinolinedione (III) by means of P2O5 in CH3SO3H. Reduction of the carbonyl groups of (III) with LiAlH4 in THF/Et2O in presence of AlCl3 provides tetrahydroquinoline (IV), which is further sulfonated with pyridine/SO3, yielding derivative (V). Removal of the chloro substituent of (V) by hydrogenation in basic conditions (in the presence of either NaHCO3/H2O or Et3N in MeOH) affords sulfonic acid (VI), which is converted to the sulfonyl chloride (VII) by means of ultrasound in acetonitrile or 1,3-dimethylimidazolidin-2-one (DMID) followed by treatment with POCl3 in pyridine. This conversion can also be achieved by treatment with PPh3 in dichloromethane and sulfuryl chloride. Alternatively, (V) can be converted into (VII) by a first sulfonation to yield (VIII) followed by removal of the chloro substituent in the same conditions described above. Intermediate (VI) can also be obtained as follows: Bromination of quinolinone (IX) with Br2 in CHCl3 yields derivative (X), which is then reduced with LiAlH4/AlCl3 in THF/Et2O to give tetrahydroquinoline (XI). (XI) is then converted into (XII) by sulfonation with DMF/sulfur trioxide complex. Finally, hydrogenation of (XII) over Pd/C in the presence of NaHCO3 allows removal of the bromo substituent, providing (VI).

Alternatively, piperidine derivative (XV) can be protected as its acetic ester form (XXI) by reaction with AcOH and HCl gas. In this case: 1) Piperidine (XXI) is condensed with (XIV) in the presence of Et3N to yield (XXII). Finally, elimination of the protecting groups with NaOH/MeOH affords the desired product. 2) The coupling can be performed by reaction of nitro-protected L-arginine (XVIII) with isobutyl chloroformate in DMF in the presence of NMM, followed by reaction with protected piperidine derivative (XXI) to yield (XXIII). Removal of the Boc group of (XXIII) with HCl in AcOH or in dichloromethane/AcOH (2:1) and assembling to sulfonyl chloride intermediate (VII) with DIEA in DMF yields protected derivative (XXIV). Reductive cleavage of the nitro protecting group of (XXIV) with Pd/C, H2 in MeOH/AcOH/H2O (15:0.1:1), followed by elimination of the acetyl protecting group in the conditions described above, yields the desired product.

Synthesis of Intermediate (VII): Acylation of p-chloroaniline (I) with dimethylmalonic acid (A) and SOCl2 gives (II), which is then cyclized to quinolinedione (III) by means of P2O5 in CH3SO3H. Reduction of the carbonyl groups of (III) with LiAlH4 in THF/Et2O in presence of AlCl3 provides tetrahydroquinoline (IV), which is further sulfonated with pyridine/SO3, yielding derivative (V). Removal of the chloro substituent of (V) by hydrogenation in basic conditions (in the presence of either NaHCO3/H2O or Et3N in MeOH) affords sulfonic acid (VI), which is converted to the sulfonyl chloride (VII) by means of ultrasound in acetonitrile or 1,3-dimethylimidazolidin-2-one (DMID) followed by treatment with POCl3 in pyridine. This conversion can also be achieved by treatment with PPh3 in dichloromethane and sulfuryl chloride. Alternatively, (V) can be converted into (VII) by a first sulfonation to yield (VIII) followed by removal of the chloro substituent in the same conditions described above. Intermediate (VI) can also be obtained as follows: Bromination of quinolinone (IX) with Br2 in CHCl3 yields derivative (X), which is then reduced with LiAlH4/AlCl3 in THF/Et2O to give tetrahydroquinoline (XI). (XI) is then converted into (XII) by sulfonation with DMF/sulfur trioxide complex. Finally, hydrogenation of (XII) over Pd/C in the presence of NaHCO3 allows removal of the bromo substituent, providing (VI).

Coupling Method 1. Treatment of L-Arginine (XIII) with K2CO3 and assembling to intermediate (VII) affords derivative (XIV). After protection of the piperidine derivative (XV) as its tert-butyl ether (XVI) by means of isobutylene (B) in acidic media, (XVI) is condensed with (XIV) in the presence of Et3N to yield (XVII). Finally, elimination of the protecting groups with TFA, HBr gas or HCl in AcOH affords the desired product. 2. Alternatively, the coupling can be performed by reaction of nitro-protected L-arginine (XVIII) with isobutyl chloroformate in DMF in the presence of NMM, followed by reaction with protected piperidine derivative (XVI) to yield (XIX). Removal of the Boc group with HCl in AcOH or in dichloromethane/AcOH (2:1) and assembling to sulfonyl chloride intermediate (VII) with DIEA in DMF yields protected derivative (XX). Reductive cleavage of the nitro protecting group of (XX) with Pd/C, H2 in MeOH/AcOH/H2O (15:0.1:1), followed by elimination of the t-Bu protecting group in the conditions described above, yields the desired product.