Nitration of 2,4,5-trifluoro-3-methylbenzoic acid (I) with H2SO4 and HNO3 provides nitrobenzoic acid derivative (II), which is then converted into the nitrobenzoyl chloride derivative (III) by reaction with oxalyl chloride in CH2Cl2 in the presence of DMF. Condensation of (III) with diethyl malonate (IV) by means of Mg in EtOH in the presence of CCl4 yields diethyl (2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)malonate (V), which is then treated with p-toluene sulfonic acid in refluxing H2O to furnish ethyl acetate derivative (VI). Reaction of (VI) with ethyl orthoformate and acetic anhydride at reflux affords ethyl acrylate derivative (VII), which is then treated with cyclopropylamine (VIII) in EtOH to give compound (IX). Cyclization of (IX) is then induced either by treatment with NaH in 1,4-dioxane or with 18-crown-6-ether and K2CO3 in THF to provide quinolone derivative (X), whose nitro group is reduced by hydrogenation over Ni Raney in HOAc to give amino derivative (XI). Hydrolysis of the ethyl ester moiety of (XI) is performed by refluxing with HCl/HOAc to furnish carboxylic acid (XII), which is then treated with boron trifluoride etherate to give boron chelate (XIII). Finally, condensation of (XIII) with (S)-7-trifluoroacetylamino-5-azaspiro[2.4]heptane hydrochloride (XIV) by means of Et3N in DMSO, followed by deprotection with KOH in H2O and treatment with MeSO3H affords the desired compound. Alternatively, the target product can also be synthesized from the Boc protected derivative (XVI) obtained either by coupling of boron chelate (XIII) with (S)-7-Boc-amino-5-azaspiro[2.4]heptane hydrochloride (XIV) by means of DIEA in DMSO (or Et3N in MeOH) or by reaction between carboxylic acid (XII) and compound (XV) by heating in DMSO. Finally, the Boc protecting group of (XVI) is removed with HCl and the corresponding methanesulfonate salt formed by treatment with MeSO3H.

Nitration of 2,4,5-trifluoro-3-methylbenzoic acid (I) with H2SO4 and HNO3 provides nitrobenzoic acid derivative (II), which is then converted into the nitrobenzoyl chloride derivative (III) by reaction with oxalyl chloride in CH2Cl2 in the presence of DMF. Condensation of (III) with diethyl malonate (IV) by means of Mg in EtOH in the presence of CCl4 yields diethyl (2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)malonate (V), which is then treated with p-toluene sulfonic acid in refluxing H2O to furnish ethyl acetate derivative (VI). Reaction of (VI) with ethyl orthoformate and acetic anhydride at reflux affords ethyl acrylate derivative (VII), which is then treated with cyclopropylamine (VIII) in EtOH to give compound (IX). Cyclization of (IX) is then induced either by treatment with NaH in 1,4-dioxane or with 18-crown-6-ether and K2CO3 in THF to provide quinolone derivative (X), whose nitro group is reduced by hydrogenation over Ni Raney in HOAc to give amino derivative (XI). Hydrolysis of the ethyl ester moiety of (XI) is performed by refluxing with HCl/HOAc to furnish carboxylic acid (XII), which is then treated with boron trifluoride etherate to give boron chelate (XIII). Finally, condensation of (XIII) with (S)-7-trifluoroacetylamino-5-azaspiro[2.4]heptane hydrochloride (XIV) by means of Et3N in DMSO, followed by deprotection with KOH in H2O and treatment with MeSO3H affords the desired compound. Alternatively, the target product can also be synthesized from the Boc protected derivative (XVI) obtained either by coupling of boron chelate (XIII) with (S)-7-Boc-amino-5-azaspiro[2.4]heptane hydrochloride (XIV) by means of DIEA in DMSO (or Et3N in MeOH) or by reaction between carboxylic acid (XII) and compound (XV) by heating in DMSO. Finally, the Boc protecting group of (XVI) is removed with HCl and the corresponding methanesulfonate salt formed by treatment with MeSO3H.