Quinoline-carboxamide derivatives as P2Y12 antagonists

4-[(S)-4-Carboxy-2-({4-[2-(4-hydroxy-2-methoxycarbonyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

(i) 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid ethyl ester

To a solution of 15.5 g of m-Tolylamine in 130 ml of methanol, 24.6 g of but-2-ynedioic acid diethyl ester was added drop-wise over 30 min at 0° C. and stirred for 3 h at RT. Then, the solvents were removed under reduced pressure and the residue was dissolved in 70 ml of Dowtherm® and heated to 250° C. for 2 h. Then, the reaction mixture was allowed to cool to RT and 300 ml of n-heptane was added to precipitate the crude product, which was collected by filtration. The title compound was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 9.7 g.

As a second fraction the regioisomeric product 4-Hydroxy-5-methyl-quinoline-2-carboxylic acid ethyl ester was isolated. Yield: 8.6 g.

(ii) 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid

To a solution of 9.7 g of 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid ethyl ester in 200 ml of THF, 84 ml of a 1M aqueous sodium hydroxide solution was added and stirred for 16 h at RT. The reaction mixture was acidified with 1M hydrochloric acid to pH 1 to precipitate the product, which was then collected by filtration. The residue was co-distilled additional two times with toluene. After drying under reduced pressure the product was pure enough for the next reaction step. Yield: 7.7 g.

(iii) 4-((S)-2-Benzyloxycarbonylamino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester

To a solution of 15 g of (S)-2-Benzyloxycarbonylamino-pentanedioic acid 5-tert-butyl ester, 20.4 g of NEM and 14.5 g of TOTU in 75 ml of DMF, 7.4 g of Piperazine-1-carboxylic acid ethyl ester was added at RT and stirred for 16 h. The reaction mixture was then diluted with saturated aqueous sodium hydrogen carbonate solution and then extracted with 300 ml of ethyl acetate. The organic phase was washed with diluted saturated aqueous sodium hydrogen carbonate solution and dried over MgSO 4 . The solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with n-heptane/ethyl acetate (1/1). The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 20.6 g.

(iv) 4-((S)-2-Amino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester

A solution of 20.6 g of 4-((S)-2-Benzyloxycarbonylamino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester in 200 ml of ethanol was purged with argon. Then, 2 g of Pd/C (5-10%) was added and the mixture stirred under a hydrogen atmosphere (4 bar). After 16 h the reaction mixture was filtered through a pad of celite and the solvents were removed under reduced pressure. After drying under reduced pressure the product was pure enough for the next reaction step. Yield: 14.4 g.

(v) 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

To a solution of 4 g of 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid and 6.7 g of 4-((S)-2-Amino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester in 40 ml of DMF, 3 g of HOBT and 3.7 g of EDC was added and the reaction mixture was stirred for 2 h at RT. Then, the reaction mixture was diluted with water and extracted with DCM. The organic phase was dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 9.4 g.

(iiv) 4-[(S)-4-tert-Butoxycarbonyl-2-({4-[2-(4-hydroxy-2-methoxycarbonyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

To a solution of 100 mg 4-{(S)-4-Carboxy-2-[(4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester and 100 mg of 1-(2-Bromo-acetyl)-4-hydroxy-pyrrolidine-2-carboxylic acid methyl ester in 2 ml of DMF, 122 mg of cesium carbonate was added. The reaction mixture was heated to 80° C. for 5 h, then cooled to RT and diluted with water. After filtration through a chem Elut® cartridge by eluting with ethyl acetate the solvents were removed under reduced pressure. The isolated crude product was pure enough for the next reaction step.

(vi) 4-[(S)-4-Carboxy-2-({4-[2-(4-hydroxy-2-methoxycarbonyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

To a solution of 4-[(S)-4-tert-Butoxycarbonyl-2-({4-[2-(4-hydroxy-2-methoxycarbonyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester from the preceding reaction step (v) in 5 ml of DCM 1 ml of TFA was added at RT. After 3 h, 20 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. The product was obtained as its trifluoroacetate salt. Yield: 13 mg MS (ES+): m/e=658.

4-[(S)-4-Carboxy-2-({7-methyl-4-[2-oxo-2-(2-oxo-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

(i) 4-[(S)-4-tert-Butoxycarbonyl-2-({7-methyl-4-[2-oxo-2-(2-oxo-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

To a solution of 200 mg of 4-{(S)-4-Carboxy-2-[(4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 2.5 ml of DMF, 184 mg of cesium carbonate and 91 mg of 1-(2-Chloro-acetyl)-pyrrolidin-2-one was added and the reaction mixture was stirred for 3 days at RT. Then, the reaction mixture was diluted with water and filtered through a chem Elut® cartridge by eluting with ethyl acetate. The solvents were removed under reduced pressure and the isolated crude product was pure enough for the next reaction step.

(ii) 4-[(S)-4-Carboxy-2-({7-methyl-4-[2-oxo-2-(2-oxo-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

To a solution of 4-[(S)-4-tert-Butoxycarbonyl-2-({7-methyl-4-[2-oxo-2-(2-oxo-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester from the preceding reaction step (i) in 5 ml of DCM, 0.2 ml of TFA was added at RT. After 5 h, 20 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. The product was obtained as its trifluoroacetate salt. Yield: 108 mg MS (ES+): m/e=598.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

(i) (S)-2-Cyclopropylcarbamoyl-pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of 10 g of (S)-Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester in 953 ml of DMF, 9.2 g of HOBT, 11.5 g of EDC, 3.4 g of cyclopropylamine and 13.8 g of DIPEA was added and the reaction mixture was stirred for 16 h at RT. Then, the reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium hydrogen carbonate solution and water and dried over MgSO 4 . The solvents were removed under reduced pressure and the crude product was pure enough for the next reaction step.

(ii) (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride

The crude (S)-2-Cyclopropylcarbamoyl-pyrrolidine-1-carboxylic acid tert-butyl ester from the preceding reaction step was dissolved in 20 ml of saturated ethanolic hydrochloric acid and stirred for 2 h. Then, the reaction mixture was diluted with 200 ml of toluene and the solvents were removed under reduced pressure. The residue was co-distilled additional 3 times with toluene and then, triturated with ether. The obtained crystalline white solid was filtered and dried. Yield: 8.2 g.

(iii) 4-{(S)-2-[(4-Benzyloxycarbonylmethoxy-7-methyl-quinoline-2-carbonyl)-amino]-4-tert-butoxycarbonyl-butyryl}-piperazine-1-carboxylic acid ethyl ester

To a solution of 5 g of 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester (prepared analogously as in example 1) in 150 ml of DMF, 3.3 g of cesium carbonate and 2.4 g of Bromo-acetic acid benzyl ester was added and stirred for 2 h. Then, the reaction mixture was diluted with water and extracted with ethyl acetate (3×150 ml). The combined organic phases were dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was pure enough for the next reaction step. Yield: 5.4 g.

(iv) 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-carboxymethoxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

A solution of 5.4 g of 4-{(S)-2-[(4-Benzyloxycarbonylmethoxy-7-methyl-quinoline-2-carbonyl)-amino]-4-tert-butoxycarbonyl-butyryl}-piperazine-1-carboxylic acid ethyl ester in 30 ml of ethyl acetate was purged with argon. Then, 2 g of Pd/C (5-10%) was added and the mixture stirred under a hydrogen atmosphere (3 bar). After 16 h reaction the mixture was filtered through a pad of celite and the solvents were removed under reduced pressure. After drying under reduced pressure the product was pure enough for the next reaction step. Yield: 4.5 g.

(v) 4-[(S)-4-tert-Butoxycarbonyl-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

To a solution of 1 g of 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-carboxymethoxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 12 ml of DMF, 392 mg of EDC, 376 mg of pentafluorophenol and 392 mg of NEM was added and the reaction mixture was warmed to 50° C. for 2 h. Then, after cooling to RT, 334 mg of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 201 mg of NEM in 5 ml of DMF was added. After 1 h the reaction mixture was diluted with water and extracted with DCM (3×50 ml). The combined organic phases were dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was pure enough for the next reaction step. Yield: 1.2 g.

(vi) 4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

To a solution of 184 mg of 4-[(S)-4-tert-Butoxycarbonyl-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester in 2 ml of DCM, 0.2 ml of TFA was added at RT. After 4 h 20 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. The product was obtained as its trifluoroacetate salt. Yield: 104 mg MS (ES+): m/e=667.

4-[(S)-4-Carboxy-2-({7-methyl-4-[2-oxo-2-(3-oxo-piperazin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that Piperazin-2-one was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=613.

4-[(S)-4-Carboxy-2-({4-[2-(3-carboxy-azetidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that Azetidine-3-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=614.

4-[(S)-4-Carboxy-2-({4-[2-((2S,3S)-2-carboxy-3-hydroxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (2S,3S)-3-Hydroxy-pyrrolidine-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=644.

4-[(S)-4-Carboxy-2-({4-[2-((2S,4R)-2-ethoxycarbonyl-4-hydroxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (2S,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid ethyl ester was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=672.

4-[(S)-4-Carboxy-2-({4-[2-((R)-3-hydroxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (R)-Pyrrolidin-3-ol was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=600.

4-[(S)-4-Carboxy-2-({4-[2-((S)-3-hydroxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidin-3-ol was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=600.

4-[(S)-4-Carboxy-2-({4-[2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that Piperidin-4-ol was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=614.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-ethoxycarbonyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid ethyl ester was used instead of (5)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=656.

4-[(S)-4-Carboxy-2-({4-[2-((2R,4R)-2-carboxy-4-hydroxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (2R,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=644.

4-[(S)-4-Carboxy-2-({4-[2-(3-hydroxy-azetidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that Azetidin-3-ol was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=586.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-methoxycarbonyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid methyl ester was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=642.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-carboxy-azetidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (5)-Azetidine-2-carboxylic acid was used instead of (5)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=614.

4-[(S)-4-Ethoxycarbonyl-2-({7-methyl-4-[2-oxo-2-(2-oxo-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

To 10 ml of a saturated ethanolic solution of hydrochloric acid 100 mg of 4-[(S)-4-Carboxy-2-({7-methyl-4-[2-oxo-2-(2-oxo-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester was added and the mixture was stirred for 1 h. Then, 30 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. The product was obtained as its trifluoroacetate salt. Yield: 47 mg MS (ES + ): m/e=626.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-carboxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=628.

4-[(S)-4-Carboxy-2-({4-[2-(3-methanesulfonyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that 3-Methanesulfonyl-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=662.

4-[(S)-4-Carboxy-2-({4-[2-(3-carboxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that Pyrrolidine-3-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=628.

4-[(S)-4-Carboxy-2-({4-[2-((3S,4S)-3,4-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (3S,4S)-Pyrrolidine-3,4-diol was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=616.

4-[(S)-4-Carboxy-2-({7-methyl-4-[2-oxo-2-(2-oxo-oxazolidin-3-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that Oxazolidin-2-one was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=600.

4-[(S)-4-Carboxy-2-({4-[2-(3-cyclopropylcarbamoyl-azetidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that Azetidine-3-carboxylic acid cyclopropylamide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=653.

4-[(S)-4-Carboxy-2-({4-[2-((R)-2-cyclopropylcarbamoyl-azetidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (R)-Azetidine-2-carboxylic acid cyclopropylamide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=653.

4-[(S)-2-({4-[2-((S)-2-Cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-ethoxycarbonyl-butyryl]-piperazine-1-carboxylic acid ethyl ester

To 15 ml of a saturated solution of hydrochloric acid in ethanol 100 mg of 4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]piperazine-1-carboxylic acid ethyl ester was added and the mixture was stirred for 1 h. Then, 30 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. The product was obtained as its trifluoroacetate salt. Yield: 72 mg MS (ES + ): m/e=695.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-ethylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid ethylamide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=655.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-1,1-dimethyl-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that 2-Bromo-2-methyl-propionic acid benzyl ester was used instead of Bromo-acetic acid benzyl ester. MS (ES + ): m/e=695.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-dimethylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid dimethylamide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=655.

4-[(S)-2-({4-[2-((S)-2-Carbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-carboxy-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid amide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=627.

4-[(S)-4-Carboxy-2-({4-[2-((S)-3-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-3-carboxylic acid cyclopropylamide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=667.

4-[(S)-4-Carboxy-2-({4-[2-((R)-3-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (R)-Pyrrolidine-3-carboxylic acid cyclopropylamide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=667.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-1-Pyrrolidin-2-yl-methanol was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=614.

4-{(S)-4-Carboxy-2-[(7-methyl-4-{2-oxo-2-[(S)-2-(2,2,2-trifluoro-ethylcarbamoyl)-pyrrolidin-1-yl]-ethoxyl}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid (2,2,2-trifluoro-ethyl)-amide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=709.

4-[(S)-4-Carboxy-2-({4-[2-(4-methoxy-piperidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that 4-Methoxy-piperidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=628.

4-[(S)-4-Carboxy-2-({7-methyl-4-[2-oxo-2-(3-oxo-pyrazolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that Pyrazolidin-3-one was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=599.

4-[(S)-4-Carboxy-2-({4-[2-(2-hydroxymethyl-morpholin-4-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that Morpholin-2-yl-methanol was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=630.

4-[(S)-4-Carboxy-2-({7-methyl-4-[2-oxo-2-((1S,5R)-3-oxo-8-aza-bicyclo[3.2.1]oct-8-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (1S,5R)-8-Aza-bicyclo[3.2.1]octan-3-one was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=638.

4-[(S)-4-Carboxy-2-({7-methyl-4-[2-oxo-2-(5-oxo-[1,4]diazepan-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that [1,4]Diazepan-5-one was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=627.

4-[(S)-4-Carboxy-2-({4-[2-(4-ethoxycarbonyl-piperidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that Piperidine-4-carboxylic acid ethyl ester was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=670.

4-[(S)-4-Carboxy-2-({4-[2-(4-ethoxy-piperidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that 4-Ethoxy-piperidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=642.

4-((S)-4-Carboxy-2-{[7-methyl-4-(2-morpholin-4-yl-2-oxo-ethoxy)-quinoline-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that Morpholine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=600.

4-[(S)-4-Carboxy-2-({4-[2-(3-hydroxy-piperidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that Piperidin-3-ol was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=614.

4-[(S)-4-Carboxy-2-({4-[2-(4-carboxy-piperidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that Piperidine-4-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=642.

4-[(S)-4-Carboxy-2-({4-[2-((R)-3-hydroxy-piperidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (R)-Piperidin-3-ol was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=614.

4-[(S)-4-Carboxy-2-({4-[2-(2,2-dimethyl-3-oxo-piperazin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that 3,3-Dimethyl-piperazin-2-one was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=641.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-carboxy-piperidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Piperidine-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=642.

4-[(S)-4-Carboxy-2-({4-[2-((R)-2-carboxy-piperidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (R)-Piperidine-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=642.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-methoxymethyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-2-Methoxymethyl-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=628.

4-[(S)-4-Carboxy-2-({4-[2-(4-cyclopropylcarbamoyl-piperidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that Piperidine-4-carboxylic acid cyclopropylamide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=681.

4-[(S)-4-Carboxy-2-({4-[2-((R)-2-cyclopropylcarbamoyl-piperidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (R)-Piperidine-2-carboxylic acid cyclopropylamide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=681.

4-[(S)-4-Carboxy-2-({4-[2-((S)-3-hydroxymethyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-1-Pyrrolidin-3-yl-methanol was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=614.

4-[(S)-4-Carboxy-2-({4-[2-((R)-3-hydroxymethyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (R)-1-Pyrrolidin-3-yl-methanol was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=614.

4-[(S)-4-Carboxy-2-({4-[2-(2-carboxy-4,4-difluoro-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that 4,4-Difluoro-pyrrolidine-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=664.

4-[(S)-4-Carboxy-2-({7-methyl-4-[2-oxo-2-(3-oxo-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that Pyrrolidin-3-one was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=598.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclopropylcarbamoyl-piperidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Piperidine-2-carboxylic acid cyclopropylamide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=681.

4-[(S)-4-Carboxy-2-({4-[2-(3-cyclopropylcarbamoyl-piperidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that Piperidine-3-carboxylic acid cyclopropylamide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=681.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-5,7-dimethyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

(i) (S)-1-(2-Bromo-acetyl)-pyrrolidine-2-carboxylic acid cyclopropylamide

To a solution of 1.2 g of bromo-acetyl bromide in 30 ml of DCM a solution of 1 g of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride, 0.6 g of triethylamine and 7 mg of DMAP in 10 ml of DCM was added drop-wise at 0° C. After 1 h the reaction mixture was diluted with ethyl acetate and the solids were filtered off. The organic phase was evaporated under reduced pressure and the residue was filtered over silica gel eluting with ethyl acetate/heptane (8/2). After evaporation of the solvent the obtained product was pure enough for the subsequent reaction step. Yield: 1.3 g.

(ii) 4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-5,7-dimethyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

To a solution of 100 mg of (S)-1-(2-Bromo-acetyl)-pyrrolidine-2-carboxylic acid cyclopropylamide and 98 mg of 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-hydroxy-5,7-dimethyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester [prepared by adapting the procedures described in example 3 using 4-Hydroxy-5,7-dimethyl-quinoline-2-carboxylic acid] in 2 ml of DMF, 118 mg of cesium carbonate was added and the reaction mixture was heated to 80° C. for 5 h. Then, the reaction mixture was diluted with water and filtered through a chem Elut® cartridge by eluting with ethyl acetate. The solvents were removed under reduced pressure and the residue was dissolved in 1 ml of DCM and 0.2 ml of TFA. After 16 h at RT 10 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. The product was obtained as its trifluoroacetate salt. Yield: 10 mg MS (ES+): m/e=681.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

(i) (S)-2-Cyclobutylcarbamoyl-pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of 1.5 g of (S)-Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester in 30 ml of DMF, 948 mg of HOAT, 1.3 g of EDC and 495 mg of cyclobutylamine was added and the reaction mixture was stirred for 16 h at RT. Then, water was added and the reaction mixture was extracted with DCM. The organic phase was dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was pure enough for the next reaction step.

(ii) (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide

The crude (S)-2-Cyclobutylcarbamoyl-pyrrolidine-1-carboxylic acid tert-butyl ester from the preceding reaction step was dissolved in 10 ml of DCM and 5 ml of TFA and stirred for 3 h. Then, the reaction mixture was diluted with 70 ml of toluene and the solvents were removed under reduced pressure. The residue was co-distilled additional three times with toluene. The product was obtained as its trifluoroacetate. Yield: 2 g.

(iii) 4-{(S)-2-[(4-Benzyloxycarbonylmethoxy-7-methyl-quinoline-2-carbonyl)-amino]-4-tert-butoxycarbonyl-butyryl}-piperazine-1-carboxylic acid ethyl ester

To a solution of 26.4 g of 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester (prepared analogously as in example 1) in 150 ml of DMF, 18 g of cesium carbonate and 12.7 g of Bromo-acetic acid benzyl ester was added and stirred for 16 h. Then, the reaction mixture was diluted with water and extracted with ethyl acetate (3×300 ml). The combined organic phases were dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 23.6 g.

(iv) 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-carboxymethoxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

A solution of 23.6 g of 4-{(S)-2-[(4-Benzyloxycarbonylmethoxy-7-methyl-quinoline-2-carbonyl)-amino]-4-tert-butoxycarbonyl-butyryl}-piperazine-1-carboxylic acid ethyl ester in 200 ml of ethyl acetate was purged with argon. Then, 2.4 g of Pd/C (5-10%) was added and the mixture stirred under a hydrogen atmosphere (3 bar). After 16 h the reaction mixture was filtered through a pad of celite and the solvents were removed under reduced pressure. After drying under reduced pressure the product was pure enough for the next reaction step. Yield: 19.8 g.

(v) 4-[(S)-4-tert-Butoxycarbonyl-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

To a solution of 3.5 g of 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-carboxymethoxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 30 ml of DMF, 1.1 g of EDC, 1.1 g of pentafluorophenol and 1.8 g of NEM was added and the reaction mixture was warmed to 40° C. for 4 h. Then, after cooling to RT 2.6 g of (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide trifluoroacetate and 1 g of NEM in 10 ml of DMF was added. After 4 h the reaction mixture was diluted with water and extracted with DCM (3×150 ml). The combined organic phases were dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.8 g.

(vi) 4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

To a solution of 1.3 g of 4-[(S)-4-tert-Butoxycarbonyl-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester in 10 ml of DCM, 2.1 ml of TFA was added at RT. After 16 h 20 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. The product was obtained as its trifluoroacetate salt. Yield: 2.1 g MS (ES+): m/e=681.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-ethoxycarbonyl-butyryl]-piperazine-1-carboxylic acid ethyl ester

To 100 ml of a saturated solution of hydrochloric acid in ethanol 2.5 g of 4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester was added and the mixture was stirred for 3 h. Then, 30 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. The product was dissolved in DCM and washed with saturated aqueous sodium hydrogen carbonate solution and water. The organic phase dried over MgSO 4 . The solvents were removed under reduced pressure to yield the product as a white solid. Yield: 1.2 g MS (ES + ): m/e=709.

Alternatively the product was prepared by the following procedure:

To 100 ml of a saturated solution of hydrochloric acid in ethanol 5 g of 4-[(S)-4-tert-Butoxycarbonyl-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester was added and the mixture was stirred for 2 h. Then, 30 ml of toluene was added and the solvents were removed under reduced pressure. The residue was filtered through a plug of silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. The residue was purified by re-crystallisation from n-heptane/ethyl acetate and dried under reduced pressure. Yield: 3.8 g MS (ES + ): m/e=709.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-6-fluoro-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 56 with the difference that 4-{(S)-4-tert-Butoxycarbonyl-2-[(6-fluoro-4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester was used instead of 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-hydroxy-5,7-dimethyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester. MS (ES + ): m/e=685.

4-[(S)-4-Carboxy-2-({4-[2-((R)-2-ethoxycarbonyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (R)-Pyrrolidine-2-carboxylic acid ethyl ester was used instead of (5)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=656.

4-[(S)-2-({4-[2-((R)-2-Carbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-carboxy-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (R)-Pyrrolidine-2-carboxylic acid amide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=627.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-carboxy-2-methyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-2-Methyl-pyrrolidine-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=642.

4-{(S)-4-Carboxy-2-[(4-{2-[(S)-2-(cyclopropylmethyl-carbamoyl)-pyrrolidin-1-yl]-2-oxo-ethoxy}-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid cyclopropylmethyl-amide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=681.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-isopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid isopropylamide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=669.

4-{(S)-4-Carboxy-2-[(4-{2-[(S)-2-(2,2-difluoro-ethylcarbamoyl)-pyrrolidin-1-yl]-2-oxo-ethoxy}-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid (2,2-difluoro-ethyl)-amide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=691.

4-{(S)-4-Carboxy-2-[(4-{2-[(S)-2-(2-fluoro-ethylcarbamoyl)-pyrrolidin-1-yl]-2-oxo-ethoxy}-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid (2-fluoro-ethyl)-amide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=673.

4-[(S)-4-Carboxy-2-({4-[2-((R)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (R)-Pyrrolidine-2-carboxylic acid cyclopropylamide was used instead of (5)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=667.

4-[(S)-4-Carboxy-2-({4-[2-(4,4-dimethyl-oxazolidin-3-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that 4,4-Dimethyl-oxazolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=614.

4-[(S)-4-Ethoxycarbonyl-2-({4-[2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

To 10 ml of a saturated solution of hydrochloric acid in ethanol 178 mg of 4-[(S)-4-tert-Butoxycarbonyl-2-({4-[2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester was added and the mixture was stirred for 2 h. Then, 30 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. The product was obtained as its trifluoroacetate salt. Yield: 105 mg MS (ES + ): m/e=642.

4-[(S)-4-Carboxy-2-({7-methyl-4-[2-oxo-2-((S)-2-propylcarbamoyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid propylamide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=669.

4-[(S)-4-Carboxy-2-({4-[2-(4-hydroxy-2-methoxycarbonyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 1 with the difference that 4-Hydroxy-quinoline-2-carboxylic acid was used instead of 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=644.

4-[(S)-4-Carboxy-2-({4-[2-oxo-2-(2-oxo-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 2 with the difference that 4-Hydroxy-quinoline-2-carboxylic acid was used instead of 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=584.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

(i) (S)-2-Cyclopropylcarbamoyl-pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of 10 g of (S)-Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester in 953 ml of DMF, 9.2 g of HOBT, 11.5 g of EDC, 3.4 g of cyclopropylamine and 13.8 g of DIPEA was added and the reaction mixture was stirred for 16 h at RT. Then, the reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium hydrogen carbonate solution and water and dried over MgSO 4 . The solvents were removed under reduced pressure and the crude product was pure enough for the next reaction step.

(ii) (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride

The crude (S)-2-Cyclopropylcarbamoyl-pyrrolidine-1-carboxylic acid tert-butyl ester from the preceding reaction step was dissolved in 20 ml of saturated ethanolic hydrochloric acid and stirred for 2 h. Then, the reaction mixture was diluted with 200 ml of toluene and the solvents were removed under reduced pressure. The residue was co-distilled additional 3 times with toluene and then, triturated with ether. The obtained crystalline white solid was filtered and dried. Yield: 8.2 g.

(iii) 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-hydroxy-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

To a solution of 2.7 g 4-Hydroxy-quinoline-2-carboxylic acid and 5 g of 4-((S)-2-Amino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester in 25 ml of DMF, 2.2 g of HOBT and 2.8 g of EDC was added and the reaction mixture was stirred for 3 h at RT. Then, the reaction mixture was diluted with water and extracted with DCM. The organic phase was dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was purified by re-crystallisation from n-heptane/ethyl acetate and dried under reduced pressure. Yield: 7.2 g.

(iv) 4-{(S)-2-[(4-Benzyloxycarbonylmethoxy-quinoline-2-carbonyl)-amino]-4-tert-butoxycarbonyl-butyryl}-piperazine-1-carboxylic acid ethyl ester

To a solution of 6.2 g of 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-hydroxy-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester 80 ml of DMF, 4.3 g of cesium carbonate and 2.5 g of Bromo-acetic acid benzyl ester was added and stirred for 2 h. Then, the reaction mixture was diluted with water and extracted with ethyl acetate (3×150 ml). The combined organic phases were dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 4.4 g.

(v) 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-carboxymethoxy-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

A solution of 4.4 g of 4-{(S)-2-[(4-Benzyloxycarbonylmethoxy-quinoline-2-carbonyl)-amino]-4-tert-butoxycarbonyl-butyryl}-piperazine-1-carboxylic acid ethyl ester in 30 ml of ethyl acetate was purged with argon. Then, 2 g of Pd/C (5-10%) was added and the mixture stirred under a hydrogen atmosphere (3 bar). After 16 h reaction the mixture was filtered through a pad of celite and the solvents were removed under reduced pressure. After drying under reduced pressure the product was pure enough for the next reaction step. Yield: 3.9 g.

(vi) 4-[(S)-4-tert-Butoxycarbonyl-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

To a solution of 2.2 g of 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-carboxymethoxy-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 30 ml of DMF, 883 mg of EDC, 848 mg of pentafluorophenol and 885 mg of NEM was added and the reaction mixture was stirred for 2 h at RT. Then, 732 mg of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 442 mg of NEM in 5 ml of DMF was added. After 2 h the reaction mixture was diluted with water and extracted with DCM (3×50 ml). The combined organic phases were dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was pure enough for the next reaction step. Yield: 2.9 g.

(vii) 4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]piperazine-1-carboxylic acid ethyl ester

To a solution of 80 mg of 4-[(S)-4-tert-Butoxycarbonyl-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester in 2 ml of DCM, 0.1 ml of TFA was added at RT. After 4 h 20 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. The product was obtained as its trifluoroacetate salt. Yield: 41 mg MS (ES+): m/e=653.

4-[(S)-4-Carboxy-2-({4-[2-((R)-3-hydroxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference (R)-Pyrrolidin-3-ol was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=586.

4-[(S)-4-Carboxy-2-({4-[2-((2S,4R)-2-ethoxycarbonyl-4-hydroxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (2S,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid ethyl ester was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=658.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-carboxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (S)-Pyrrolidine-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=614.

4-[(S)-4-Carboxy-2-({4-[2-((2S,4R)-2-carboxy-4-hydroxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (2S,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=630.

4-[(S)-4-Carboxy-2-({4-[2-((2S,3S)-2-carboxy-3-hydroxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (2S,3S)-3-Hydroxy-pyrrolidine-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=630.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-carboxy-azetidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (S)-Azetidine-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=600.

4-[(S)-4-Carboxy-2-({4-[2-(2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-8-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 1,3,8-Triaza-spiro[4.5]decane-2,4-dione was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=668.

4-[(S)-2-({4-[2-(3-Acetylamino-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-4-carboxy-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that N-Pyrrolidin-3-yl-acetamide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=627.

4-(2-{2-[(S)-3-Carboxy-1-(4-ethoxycarbonyl-piperazine-1-carbonyl)-propylcarbamoyl]-quinolin-4-yloxy}-acetyl)-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that Piperazine-1-carboxylic acid ethyl ester was used instead of (5)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=657.

4-[(S)-4-Carboxy-2-({4-[2-(4-ethyl-piperazin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 1-Ethyl-piperazine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=613.

4-[(S)-4-Carboxy-2-({4-[2-((2S,4S)-2-carboxy-4-hydroxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (2S,4S)-4-Hydroxy-pyrrolidine-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=630.

4-[(S)-4-Carboxy-2-({4-[2-(3-methanesulfonyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 3-Methanesulfonyl-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=648.

4-[(S)-4-Carboxy-2-({4-[2-oxo-2-(3-oxo-piperazin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that Piperazin-2-one was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=599.

4-{(S)-4-Carboxy-2-[(4-{2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-2-oxo-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2-Piperazin-1-yl-ethanol was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=629.

4-[(S)-2-({4-[2-(4-Acetyl-piperazin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-4-carboxy-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 1-Piperazin-1-yl-ethanone was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=627.

4-[(S)-4-Carboxy-2-({4-[2-((2R,4R)-2-carboxy-4-hydroxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (2R,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=630.

4-[(S)-2-({4-[2-(3-Amino-azetidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-4-carboxy-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that Azetidin-3-ylamine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=571.

4-[(S)-4-Carboxy-2-({4-[2-(3-hydroxy-azetidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that Azetidin-3-ol was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=572.

4-[(S)-4-Carboxy-2-({4-[2-((2S,4R)-4-hydroxy-2-methoxycarbonyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (2S,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid methyl ester was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=644.

4-[(S)-4-Carboxy-2-({4-[2-(3-carboxy-azetidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that Azetidine-3-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=600.

3-(2-{2-[(S)-3-Carboxy-1-(4-ethoxycarbonyl-piperazine-1-carbonyl)-propylcarbamoyl]-quinolin-4-yloxy}-acetyl)-3-aza-bicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 3-Aza-bicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=654.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-ethoxycarbonyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (S)-Pyrrolidine-2-carboxylic acid ethyl ester was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=642.

4-[(S)-4-Carboxy-2-({4-[2-(4-carboxymethyl-piperazin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that Piperazin-1-yl-acetic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=643.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-methoxycarbonyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (S)-Pyrrolidine-2-carboxylic acid methyl ester was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=628.

4-[(S)-4-Carboxy-2-({4-[2-(3-methoxycarbonylmethanesulfonyl-azetidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (Azetidine-3-sulfonyl)-acetic acid methyl ester was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=692.

4-[(S)-4-Carboxy-2-({4-[2-((3R,4R)-3,4-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (3R,4R)-Pyrrolidine-3,4-diol was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=602.

4-[(S)-4-Carboxy-2-({4-[2-((3S,4S)-3,4-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (3S,4S)-Pyrrolidine-3,4-diol was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=602.

4-[(S)-4-Carboxy-2-({4-[2-((S)-3-hydroxy-2-oxo-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (S)-3-Hydroxy-pyrrolidin-2-one was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=600.

4-[(S)-4-Carboxy-2-({4-[2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that Piperidin-4-ol was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=600.

4-[(S)-4-Carboxy-2-({4-[2-(3-carboxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that Pyrrolidine-3-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=614.

4-[(S)-4-Carboxy-2-({4-[2-((S)-3-hydroxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (S)-Pyrrolidin-3-ol was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=586.

4-[(S)-4-Carboxy-2-({4-[2-((2S,4S)-4-hydroxy-2-methoxycarbonyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (2S,4S)-4-Hydroxy-pyrrolidine-2-carboxylic acid methyl ester was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=644.

4-[(S)-4-Ethoxycarbonyl-2-({4-[2-oxo-2-(2-oxo-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

To 10 ml of a saturated solution of hydrochloric acid in ethanol 100 mg of 4-[(S)-4-Carboxy-2-({4-[2-oxo-2-(2-oxo-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester was added and the mixture was stirred for 1 h. Then, 30 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. The product was obtained as its trifluoroacetate salt. Yield: 38 mg MS (ES + ): m/e=612.

4-[(S)-2-({4-[2-((S)-2-Cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-4-ethoxycarbonyl-butyryl]-piperazine-1-carboxylic acid ethyl ester

To 150 ml of a saturated solution of hydrochloric acid in ethanol 4.1 g of 4-[(S)-4-tert-Butoxycarbonyl-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester was added and the mixture was stirred for 1 h. Then, 200 ml of toluene was added and the solvents were removed under reduced pressure. The residue was co-distilled twice with toluene and then purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. The product was obtained as its trifluoroacetate salt. Yield: 1 g MS (ES + ): m/e=681.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-dimethylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (S)-Pyrrolidine-2-carboxylic acid dimethylamide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=641.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-ethylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (S)-Pyrrolidine-2-carboxylic acid ethylamide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=641.

4-[(S)-2-({4-[2-((S)-2-Carbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-4-carboxy-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (S)-Pyrrolidine-2-carboxylic acid amide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=613.

4-[(S)-4-Carboxy-2-({4-[2-(3-cyclopropylcarbamoyl-azetidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that Azetidine-3-carboxylic acid cyclopropylamide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=639.

4-[(S)-4-Carboxy-2-({4-[2-((S)-3-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (S)-Pyrrolidine-3-carboxylic acid cyclopropylamide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=653.

4-[(S)-4-Carboxy-2-({4-[2-((R)-3-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (R)-Pyrrolidine-3-carboxylic acid cyclopropylamide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=653.

4-{(S)-4-Carboxy-2-[(4-{2-[(S)-2-(2,2-difluoro-ethylcarbamoyl)-pyrrolidin-1-yl]-2-oxo-ethoxyl}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (5)-Pyrrolidine-2-carboxylic acid (2,2-difluoro-ethyl)-amide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=677.

4-{(S)-4-Carboxy-2-[(4-{2-[(S)-2-(2-fluoro-ethylcarbamoyl)-pyrrolidin-1-yl]-2-oxo-ethoxyl}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (S)-Pyrrolidine-2-carboxylic acid (2-fluoro-ethyl)-amide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=659.

4-[(S)-4-Carboxy-2-({4-[2-oxo-2-((1S,5R)-3-oxo-8-aza-bicyclo[3.2.1]oct-8-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (1S,5R)-8-Aza-bicyclo[3.2.1]octan-3-one was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=624.

4-[(S)-4-Carboxy-2-({4-[2-(2-hydroxymethyl-morpholin-4-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that Morpholin-2-yl-methanol was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=616.

4-[(S)-4-Carboxy-2-({4-[2-((R)-3-hydroxy-piperidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (R)-Piperidin-3-ol was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=600.

4-[(S)-4-Carboxy-2-({4-[2-oxo-2-(3-oxo-pyrazolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that Pyrazolidin-3-one was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=585.

4-[(S)-4-Carboxy-2-({4-[2-(4-methoxy-piperidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 4-Methoxy-piperidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=614.

4-{(S)-4-Carboxy-2-[(4-{2-oxo-2-[(S)-2-(2,2,2-trifluoro-ethylcarbamoyl)-pyrrolidin-1-yl]-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (S)-Pyrrolidine-2-carboxylic acid (2,2,2-trifluoro-ethyl)-amide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=695.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (S)-1-Pyrrolidin-2-yl-methanol was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=600.

4-[(S)-4-Carboxy-2-({4-[2-(4-cyclopropylcarbamoyl-piperidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that Piperidine-4-carboxylic acid cyclopropylamide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=667.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclopropylcarbamoyl-piperidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (S)-Piperidine-2-carboxylic acid cyclopropylamide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=667.

4-[(S)-4-Carboxy-2-({4-[2-((S)-3-hydroxymethyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (S)-1-Pyrrolidin-3-yl-methanol was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=600.

4-[(S)-4-Carboxy-2-({4-[2-((R)-3-hydroxymethyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (R)-1-Pyrrolidin-3-yl-methanol was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=600.

4-((S)-4-Carboxy-2-{[4-(2-morpholin-4-yl-2-oxo-ethoxy)-quinoline-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that Morpholine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=586.

4-[(S)-4-Carboxy-2-({4-[2-(4-ethoxy-piperidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 4-Ethoxy-piperidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=628.

4-[(S)-4-Carboxy-2-({4-[2-(4-carboxy-piperidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that Piperidine-4-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=628.

4-[(S)-4-Carboxy-2-({4-[2-(4-ethoxycarbonyl-piperidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that Piperidine-4-carboxylic acid ethyl ester was used instead of (5)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=656.

4-[(S)-4-Carboxy-2-({4-[2-oxo-2-(5-oxo-[1,4]diazepan-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that [1,4]Diazepan-5-one was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=613.

4-[(S)-4-Carboxy-2-({4-[2-(3-cyclopropylcarbamoyl-piperidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that Piperidine-3-carboxylic acid cyclopropylamide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=667.

4-[(S)-4-Carboxy-2-({4-[2-((R)-2-cyclopropylcarbamoyl-piperidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (R)-Piperidine-2-carboxylic acid cyclopropylamide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=667.

4-[(S)-4-Carboxy-2-({4-[2-oxo-2-(3-oxo-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that Pyrrolidin-3-one was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=584.

4-[(S)-4-Carboxy-2-({4-[2-(2-carboxy-4,4-difluoro-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 4,4-Difluoro-pyrrolidine-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=650.

4-[(S)-4-Carboxy-2-({4-[2-(3-hydroxy-piperidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that Piperidin-3-ol was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=600.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-carboxy-piperidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (S)-Piperidine-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=628.

4-[(S)-4-Carboxy-2-({4-[2-((R)-2-carboxy-piperidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (R)-Piperidine-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=628.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-methoxymethyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (S)-2-Methoxymethyl-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=614.

4-[(S)-4-Carboxy-2-({6-chloro-4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 56 with the difference that 4-{(S)-4-tert-Butoxycarbonyl-2-[(6-chloro-4-hydroxy-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester was used instead of 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-hydroxy-5,7-dimethyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester. MS (ES + ): m/e=687.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-6-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 56 with the difference that 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-hydroxy-6-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester was used instead of 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-hydroxy-5,7-dimethyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester. MS (ES + ): m/e=667.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-5-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 56 with the difference that 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-hydroxy-5-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester was used instead of 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-hydroxy-5,7-dimethyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester. MS (ES + ): m/e=667.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=667.

4-[(S)-4-Carboxy-2-({4-[2-((R)-2-ethoxycarbonyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (R)-Pyrrolidine-2-carboxylic acid ethyl ester was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=642.

4-[(S)-2-({4-[2-((R)-2-Carbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-4-carboxy-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (R)-Pyrrolidine-2-carboxylic acid amide was used instead of (5)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=613.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-carboxy-2-methyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (S)-2-Methyl-pyrrolidine-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=628.

4-{(S)-4-Carboxy-2-[(4-{2-[(S)-2-(cyclopropylmethyl-carbamoyl)-pyrrolidin-1-yl]-2-oxo-ethoxyl}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (S)-Pyrrolidine-2-carboxylic acid cyclopropylmethyl-amide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=667.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-isopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (S)-Pyrrolidine-2-carboxylic acid isopropylamide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=655.

4-[(S)-4-Carboxy-2-({4-[2-((R)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (R)-Pyrrolidine-2-carboxylic acid cyclopropylamide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=653.

4-[(S)-4-Carboxy-2-({4-[2-(4,4-dimethyl-oxazolidin-3-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 4,4-Dimethyl-oxazolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=600.

4-[(S)-4-Carboxy-2-({4-[2-oxo-2-((S)-2-propylcarbamoyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (S)-Pyrrolidine-2-carboxylic acid propylamide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=655.

4-[(S)-4-Carboxy-2-({4-[2-((R)-2-hydroxymethyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (R)-1-Pyrrolidin-2-yl-methanol was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=600.

4-((S)-4-Carboxy-2-{[4-(3-carboxy-azetidine-1-carbonyl)-quinoline-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester

(i) 2-Furan-2-yl-quinoline-4-carboxylic acid ethyl ester

To 40 ml of a saturated solution of hydrochloric acid in ethanol 2 g of 2-Furan-2-yl-quinoline-4-carboxylic acid was added and the mixture was heated to reflux for 3 h. Then, after cooling to RT, 30 ml of toluene was added and the solvents were removed under reduced pressure. The obtained crude product was pure enough for the next reaction step. Yield: 2.5 g.

(ii) Quinoline-2,4-dicarboxylic acid 4-ethyl ester

To a vigorously stirred of 8 g of sodium periodate and 20 mg of ruthenium trichloride in 37 ml of tetrachloro-methane, 37 ml of acteonitrile and 54 ml of water 2.5 g of 2-Furan-2-yl-quinoline-4-carboxylic acid ethyl ester was added at RT. Then, after 4 h additional 8 g of sodium periodate and 10 mg of ruthenium trichloride was added and the reaction mixture was stirred for an additional hour. Then, the reaction mixture was diluted with water and extracted with DCM (3×150 ml). The combined organic phases were dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was used in the next reaction step without further purification. Yield: 2.0 g.

(iii) 2-[(S)-3-tert-Butoxycarbonyl-1-(4-ethoxycarbonyl-piperazine-1-carbonyl)-propylcarbamoyl]-quinoline-4-carboxylic acid ethyl ester

To a solution of 2 g of Quinoline-2,4-dicarboxylic acid 4-ethyl ester and 2.8 g of 4-((S)-2-Amino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester in 21 ml of DMF, 1.3 g of HOBT and 1.6 g of EDC was added and the reaction mixture was stirred for 16 h at RT. Then, the reaction mixture was diluted with water and extracted with DCM. The organic phase was dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.1 g.

(iv) 2-[(S)-3-tert-Butoxycarbonyl-1-(4-ethoxycarbonyl-piperazine-1-carbonyl)-propylcarbamoyl]-quinoline-4-carboxylic acid

To a solution of 1.1 g of 2-[(S)-3-tert-Butoxycarbonyl-1-(4-ethoxycarbonyl-piperazine-1-carbonyl)-propylcarbamoyl]-quinoline-4-carboxylic acid ethyl ester in 10 ml of THF, 2 ml of a 1 M aqueous NaOH solution was added. After stirring for 5 h at RT additional 1 ml of a 1 M aqueous NaOH solution was added and allowed to stir upon completion of the reaction. Then, the reaction was acidified to pH 1 with diluted aqueous hydrochloric acid and extracted with DCM (3×100 ml). The combined organic phases were dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was used in the next reaction step without further purification. Yield: 1.0 g.

(v) 4-((S)-4-tert-Butoxycarbonyl-2-{[4-(3-carboxy-azetidine-1-carbonyl)-quinoline-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester

To a solution of 80 mg of 2-[(S)-3-tert-Butoxycarbonyl-1-(4-ethoxycarbonyl-piperazine-1-carbonyl)-propylcarbamoyl]-quinoline-4-carboxylic acid 68 mg of NEM and 53 mg of TOTU in 2 ml of DMF, 30 mg of Azetidine-3-carboxylic acid was added at RT and stirred for 16 h. Then, the reaction mixture was diluted with water and filtered through a chem Elut® cartridge by eluting with DCM. The solvents were removed and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. The product was obtained as its trifluoroacetate salt. Yield: 8 mg.

(vi) 4-((S)-4-Carboxy-2-{[4-(3-carboxy-azetidine-1-carbonyl)-quinoline-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester

To a solution of 8 mg of 4-((S)-4-tert-Butoxycarbonyl-2-{[4-(3-carboxy-azetidine-1-carbonyl)-quinoline-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester in 1 ml of DCM, 0.4 ml of TFA was added at RT. After 16 h 10 ml of toluene was added and the solvents were removed under reduced pressure. The residue was dissolved in 5 ml of water and lyophilized to yield a white solid. The product was obtained as its trifluoroacetate salt. Yield: 5 mg. MS (ES + ): m/e=570.

4-((S)-2-{[4-(Azetidine-1-carbonyl)-quinoline-2-carbonyl]-amino}-4-carboxy-butyryl)-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 153 with the difference that Azetidine was used instead of Azetidine-3-carboxylic acid. MS (ES + ): m/e=526.

4-((S)-4-Carboxy-2-{[4-(morpholine-4-carbonyl)-quinoline-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 153 with the difference that Morpholine was used instead of Azetidine-3-carboxylic acid. MS (ES + ): m/e=556.

4-((S)-4-Carboxy-2-{[4-((S)-2-carboxy-azetidine-1-carbonyl)-quinoline-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 153 with the difference that (S)-Azetidine-2-carboxylic acid was used instead of Azetidine-3-carboxylic acid. MS (ES + ): m/e=570.

4-((S)-4-Carboxy-2-{[4-(2-carboxy-pyrrolidine-1-carbonyl)-quinoline-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 153 with the difference that Pyrrolidine-2-carboxylic acid was used instead of Azetidine-3-carboxylic acid. MS (ES + ): m/e=584.

4-((S)-4-Carboxy-2-{[4-(3-hydroxy-azetidine-1-carbonyl)-quinoline-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 153 with the difference that Azetidin-3-ol was used instead of Azetidine-3-carboxylic acid. MS (ES + ): m/e=542.

4-((S)-4-Carboxy-2-{[4-(2-methoxycarbonyl-aziridine-1-carbonyl)-quinoline-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 153 with the difference that Aziridine-2-carboxylic acid methyl ester was used instead of Azetidine-3-carboxylic acid. MS (ES + ): m/e=570.

4-[(S)-4-Carboxy-2-({4-[2-(2-carboxy-4-hydroxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

To a solution of 40 mg of 4-[(S)-4-Carboxy-2-({4-[2-(4-hydroxy-2-methoxycarbonyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester in 1 ml of THF/MeOH (3/1), 4 mg of lithium hydroxide was added at 0° C. and stirred for 1 h. Then, the reaction mixture was neutralized with amberlite IR-120. After filtration the solvents were removed under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. The product was obtained as its trifluoroacetate salt. Yield: 10 mg MS (ES + ): m/e=630.

4-[(S)-4-Carboxy-2-({7-fluoro-4-[2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that Piperidin-4-ol and 7-Fluoro-4-hydroxy-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=618.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-8-fluoro-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide and 8-Fluoro-4-hydroxy-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=685.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-fluoro-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide and 7-Fluoro-4-hydroxy-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=685.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-ethylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-fluoro-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid ethylamide and 7-Fluoro-4-hydroxy-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=685.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-azetidin-1-yl)-2-oxo-ethoxy]-7-fluoro-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Azetidine-2-carboxylic acid cyclobutylamide and 7-Fluoro-4-hydroxy-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=671.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-fluoro-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference and 7-Fluoro-4-hydroxy-quinoline-2-carboxylic acid was used instead 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=671.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-azetidin-1-yl)-2-oxo-ethoxy]-8-fluoro-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Azetidine-2-carboxylic acid cyclobutylamide and 8-Fluoro-4-hydroxy-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=671.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-ethylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-8-fluoro-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid ethylamide and 8-Fluoro-4-hydroxy-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=659.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-8-fluoro-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that 8-Fluoro-4-hydroxy-quinoline-2-carboxylic acid was used instead of 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=671.

4-[(S)-4-Carboxy-2-({8-fluoro-4-[2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that Piperidin-4-ol and 8-Fluoro-4-hydroxy-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=618.

4-[(S)-4-Carboxy-2-({6-fluoro-4-[2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that Piperidin-4-ol and 6-Fluoro-4-hydroxy-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=618.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-ethylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-6-fluoro-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid ethylamide and 6-Fluoro-4-hydroxy-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=659.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-5-fluoro-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that 5-Fluoro-4-hydroxy-quinoline-2-carboxylic acid was used instead of 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=671.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-5-fluoro-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide and 5-Fluoro-4-hydroxy-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=685.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-6-fluoro-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that 6-Fluoro-4-hydroxy-quinoline-2-carboxylic acid was used instead of 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=671.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-6-fluoro-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide and 6-Fluoro-4-hydroxy-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=685.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-azetidin-1-yl)-2-oxo-ethoxy]-6-fluoro-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Azetidine-2-carboxylic acid cyclobutylamide and 6-Fluoro-4-hydroxy-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=671.

4-[(S)-4-Carboxy-2-({5-fluoro-4-[2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that Piperidin-4-ol and 5-Fluoro-4-hydroxy-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=618.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-ethylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-5-fluoro-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid ethylamide and 5-Fluoro-4-hydroxy-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=659.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-azetidin-1-yl)-2-oxo-ethoxy]-5-fluoro-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Azetidine-2-carboxylic acid cyclobutylamide and 5-Fluoro-4-hydroxy-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=671.

4-{(S)-2-[(4-{2-[(S)-2-(Azetidine-1-carbonyl)-pyrrolidin-1-yl]-2-oxo-ethoxy}-7-methyl-quinoline-2-carbonyl)-amino]-4-carboxy-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that Azetidin-1-yl-(S)-pyrrolidin-2-yl-methanone was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=667.

4-{(S)-4-Carboxy-2-[(7-methyl-4-{2-oxo-2-[(S)-2-(pyrrolidine-1-carbonyl)-pyrrolidin-1-yl]ethoxyl}-quinoline-2-carbonyl)-amino]butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidin-2-yl-pyrrolidin-1-yl-methanone was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide. MS (ES + ): m/e=681.

4-{(S)-4-Carboxy-2-[(7-methyl-4-{2-oxo-2-[(S)-2-(piperidine-1-carbonyl)-pyrrolidin-1-yl]-ethoxyl}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that Piperidin-1-yl-(S)-pyrrolidin-2-yl-methanone was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide. MS (ES + ): m/e=695.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclopentylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid cyclopentylamide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide. MS (ES + ): m/e=695.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7,8,9,10-tetrahydro-benzo[h]quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 56 with the difference that 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-hydroxy-7,8,9,10-tetrahydro-benzo[h]quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester was used instead of 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-hydroxy-5,7-dimethyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester. MS (ES + ): m/e=707.

4-[(S)-3-Carboxy-2-({4-[(S)-2-((S)-2-cyclopentylcarbamoyl-pyrrolidin-1-yl)-1-methyl-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester

(i) 4-((S)-2-{[4-((S)-1-Benzyloxycarbonyl-ethoxy)-7-methyl-quinoline-2-carbonyl]-amino}-3-tert-butoxycarbonyl-propionyl)-piperazine-1-carboxylic acid ethyl ester

To a solution of 1 g of 4-{(S)-3-tert-Butoxycarbonyl-2-[(4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-propionyl}-piperazine-1-carboxylic acid ethyl ester and 350 mg of (R)-2-Hydroxy-propionic acid benzyl ester in 20 ml of THF, 764 mg of Triphenyl-phosphane and 507 mg of Diethyl azodicarboxylate was added and stirred for 2 h. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.3 g.

(ii) 4-((S)-3-tert-Butoxycarbonyl-2-{[4-((S)-1-carboxy-ethoxy)-7-methyl-quinoline-2-carbonyl]-amino}-propionyl)-piperazine-1-carboxylic acid ethyl ester

A solution of 1.3 g of 4-((S)-2-{[4-((S)-1-Benzyloxycarbonyl-ethoxy)-7-methyl-quinoline-2-carbonyl]-amino}-3-tert-butoxycarbonyl-propionyl)-piperazine-1-carboxylic acid ethyl ester in 20 ml of ethyl acetate was purged with argon. Then, 200 mg of Pd/C (5-10%) was added and the mixture was stirred under a hydrogen atmosphere (3 bar). After 16 h the reaction mixture was filtered through a pad of celite and the solvents were removed under reduced pressure. After drying under reduced pressure the product was pure enough for the next reaction step. Yield: 1.2 g.

(iii) 4-[(S)-3-tert-Butoxycarbonyl-2-({4-[(S)-2-((S)-2-cyclopentylcarbamoyl-pyrrolidin-1-yl)-1-methyl-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester

To a solution of 146 mg of 4-((S)-3-tert-Butoxycarbonyl-2-{[4-((S)-1-carboxy-ethoxy)-7-methyl-quinoline-2-carbonyl]-amino}-propionyl)-piperazine-1-carboxylic acid ethyl ester in 1 ml of DMF, 52 mg of EDC, 34 mg of pentafluorophenol and 24 mg of NEM was added and the reaction mixture was stirred for 2 h. Then, 62 mg of (S)-Pyrrolidine-2-carboxylic acid cyclopentylamide trifluoroacetate and 20 mg of NEM in 2 ml of DMF was added. After 1 h the reaction mixture was diluted with water. After filtration through a chem Elut® cartridge by eluting with ethyl acetate the solvents were removed under reduced pressure. The isolated crude product was pure enough for the next reaction step.

(iv) 4-[(S)-3-Carboxy-2-({4-[(S)-2-((S)-2-cyclopentylcarbamoyl-pyrrolidin-1-yl)-1-methyl-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester

To a solution of the 4-[(S)-3-tert-Butoxycarbonyl-2-({4-[(S)-2-((S)-2-cyclopentylcarbamoyl-pyrrolidin-1-yl)-1-methyl-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester obtained by the preceding reaction step in 1 ml of DCM, 2 ml of TFA was added at RT. After 1 h 20 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. The product was obtained as its trifluoroacetate salt. Yield: 5 mg MS (ES+): m/e=695.

4-[(S)-3-Carboxy-2-({4-[(S)-2-((S)-2-cyclopentylcarbamoyl-azetidin-1-yl)-1-methyl-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 185 with the difference that (S)-Azetidine-2-carboxylic acid cyclopentylamide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopentylamide. MS (ES + ): m/e=681.

4-[(S)-3-Carboxy-2-({4-[(S)-2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-1-methyl-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 185 with the difference that (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopentylamide. MS (ES + ): m/e=667.

4-[(S)-3-Carboxy-2-({4-[(S)-2-((S)-2-ethylcarbamoyl-pyrrolidin-1-yl)-1-methyl-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 185 with the difference that (S)-Pyrrolidine-2-carboxylic acid ethylamide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopentylamide. MS (ES + ): m/e=655.

4-[(S)-3-Carboxy-2-({4-[(S)-2-(4-hydroxy-piperidin-1-yl)-1-methyl-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 185 with the difference that Piperidin-4-ol was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopentylamide. MS (ES + ): m/e=614.

4-[(S)-3-Carboxy-2-({4-[(S)-2-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-1-methyl-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 185 with the difference that (S)-1-Pyrrolidin-2-yl-methanol was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopentylamide. MS (ES + ): m/e=614.

4-[(S)-3-Carboxy-2-({4-[(S)-2-((S)-3-hydroxymethyl-pyrrolidin-1-yl)-1-methyl-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 185 with the difference that (S)-1-Pyrrolidin-3-yl-methanol was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopentylamide. MS (ES + ): m/e=614.

4-[(S)-3-Carboxy-2-({4-[(S)-2-((S)-2-cyclobutylcarbamoyl-azetidin-1-yl)-1-methyl-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 185 with the difference that (S)-Azetidine-2-carboxylic acid cyclobutylamide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopentylamide. MS (ES + ): m/e=667.

4-[(S)-3-Carboxy-2-({4-[(S)-2-((S)-2-isopropylcarbamoyl-pyrrolidin-1-yl)-1-methyl-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 185 with the difference that (S)-Pyrrolidine-2-carboxylic acid isopropylamide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopentylamide. MS (ES + ): m/e=669.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclopentylcarbamoyl-azetidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Azetidine-2-carboxylic acid cyclopentylamide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=681.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-ethylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-6,7-difluoro-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid ethylamide and 6,7-Difluoro-4-hydroxy-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=677.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-6,7-difluoro-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide and 6,7-Difluoro-4-hydroxy-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=703.

4-[(S)-3-Carboxy-2-({4-[2-((S)-2-ethylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester

(i) 4-((S)-2-Benzyloxycarbonylamino-3-tert-butoxycarbonyl-propionyl)-piperazine-1-carboxylic acid ethyl ester

To a solution of 25 g of (S)-2-Benzyloxycarbonylamino-succinic acid 4-tert-butyl ester, 35.6 g of NEM and 25.3 g of TOTU in 125 ml of DMF, 12.9 g of Piperazine-1-carboxylic acid ethyl ester was added at RT and stirred for 3 h. The reaction mixture was diluted saturated aqueous sodium hydrogen carbonate solution and extracted with 400 ml of ethyl acetate. The organic phase was washed with diluted saturated aqueous sodium hydrogen carbonate solution and dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with n-heptane/ethyl acetate (1/1). The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 35.4 g.

(ii) 4-((S)-2-Amino-3-tert-butoxycarbonyl-propionyl)-piperazine-1-carboxylic acid ethyl ester

A solution of 20.6 g of 4-((S)-2-Benzyloxycarbonylamino-3-tert-butoxycarbonyl-propionyl)-piperazine-1-carboxylic acid ethyl ester in 200 ml of ethanol was purged with argon. Then, 3.5 g of Pd/C (5-10%) was added and the mixture stirred under a hydrogen atmosphere (4 bar). After 16 h the reaction mixture was filtered through a pad of celite and the solvents were removed under reduced pressure. After drying under reduced pressure the product was pure enough for the next reaction step. Yield: 24.5 g.

(iii) 4-{(S)-3-tert-Butoxycarbonyl-2-[(4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-propionyl}-piperazine-1-carboxylic acid ethyl ester

To a solution of 4 g of 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid and 6.4 g of 4-((S)-2-Amino-3-tert-butoxycarbonyl-propionyl)-piperazine-1-carboxylic acid ethyl ester in 37 ml of DMF, 3.0 g of HOBT and 3.7 g of EDC was added and the reaction mixture was stirred for 2 h at RT. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was purified by crystallization from ethyl acetate/heptane. Yield: 5.4 g.

(iv) 4-{(S)-2-[(4-Benzyloxycarbonylmethoxy-7-methyl-quinoline-2-carbonyl)-amino]-3-tert-butoxycarbonyl-propionyl}-piperazine-1-carboxylic acid ethyl ester

To a solution of 3 g of 4-{(S)-3-tert-Butoxycarbonyl-2-[(4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-propionyl}-piperazine-1-carboxylic acid ethyl ester and 1.5 g of Bromo-acetic acid benzyl ester in 38 ml of DMF, 2 g of cesium carbonate was added. The reaction mixture was stirred for 4 h at RT, diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 2.8 g.

(v) 4-{(S)-3-tert-Butoxycarbonyl-2-[(4-carboxymethoxy-7-methyl-quinoline-2-carbonyl)-amino]-propionyl}-piperazine-1-carboxylic acid ethyl ester

A solution of 2.8 g of 4-{(S)-2-[(4-Benzyloxycarbonylmethoxy-7-methyl-quinoline-2-carbonyl)-amino]-3-tert-butoxycarbonyl-propionyl}-piperazine-1-carboxylic acid ethyl ester in 30 ml of ethyl acetate was purged with argon. Then, 280 mg of Pd/C (5-10%) was added and the mixture stirred under a hydrogen atmosphere (3 bar). After 4 h the reaction mixture was filtered through a pad of celite and the solvents were removed under reduced pressure. After drying under reduced pressure the product was pure enough for the next reaction step. Yield: 2.2 g.

(vi) 4-[(S)-3-tert-Butoxycarbonyl-2-({4-[2-((S)-2-ethylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester

To a solution of 80 mg of 4-{(S)-3-tert-Butoxycarbonyl-2-[(4-carboxymethoxy-7-methyl-quinoline-2-carbonyl)-amino]-propionyl}-piperazine-1-carboxylic acid ethyl ester in 8 ml of DMF, 33 mg of EDC, 32 mg of pentafluorophenol and 24 mg of NEM was added and the reaction mixture was stirred for 2 h. Then, 39 mg of (S)-Pyrrolidine-2-carboxylic acid ethylamide trifluoroacetate and 20 mg of NEM in 5 ml of DMF was added. After 1 h the reaction mixture was diluted with water. After filtration through a chem Elut® cartridge by eluting with ethyl acetate the solvents were removed under reduced pressure. The isolated crude product was pure enough for the next reaction step.

(vii) 4-[(S)-3-Carboxy-2-({4-[2-((S)-2-ethylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester

To a solution of 184 mg of 4-[(S)-3-tert-Butoxycarbonyl-2-({4-[2-((S)-2-ethylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester in 1 ml of DCM, 2 ml of TFA was added at RT. After 1 h 20 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. The product was obtained as its trifluoroacetate salt. Yield: 19 mg MS (ES+): m/e=641.

4-[(S)-3-Carboxy-2-({4-[2-((S)-2-isopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 197 with the difference that (S)-Pyrrolidine-2-carboxylic acid isopropylamide was used instead of (S)-Pyrrolidine-2-carboxylic acid ethylamide. MS (ES + ): m/e=655.

4-[(S)-3-Carboxy-2-({4-[2-((S)-2-cyclopentylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 197 with the difference that (S)-Pyrrolidine-2-carboxylic acid cyclopentylamide was used instead of (S)-Pyrrolidine-2-carboxylic acid ethylamide. MS (ES + ): m/e=681.

4-{(S)-3-Carboxy-2-[(4-{2-[(S)-2-(cyclopropylmethyl-carbamoyl)-pyrrolidin-1-yl]-2-oxo-ethoxy}-7-methyl-quinoline-2-carbonyl)-amino]-propionyl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 197 with the difference that (S)-Pyrrolidine-2-carboxylic acid cyclopropylmethyl-amide was used instead of (S)-Pyrrolidine-2-carboxylic acid ethylamide. MS (ES + ): m/e=667.

4-[(S)-3-Carboxy-2-({4-[2-((S)-2-cyclopentylcarbamoyl-azetidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 197 with the difference that (S)-Azetidine-2-carboxylic acid cyclopentylamide was used instead of (S)-Pyrrolidine-2-carboxylic acid ethylamide. MS (ES + ): m/e=667.

4-[(S)-3-Carboxy-2-({4-[2-((S)-2-cyclopentylcarbamoyl-azetidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 197 with the difference that (S)-Azetidine-2-carboxylic acid cyclopentylamide and 4-Hydroxy-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid ethylamide and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=653.

4-[(S)-3-Carboxy-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 197 with the difference that 4-{(S)-3-tert-Butoxycarbonyl-2-[(4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-propionyl}-piperazine-1-carboxylic acid ethyl ester was used instead of 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-hydroxy-5,7-dimethyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester. MS (ES + ): m/e=653.

4-[(S)-3-Carboxy-2-({7-methyl-4-[2-oxo-2-((S)-2-propylcarbamoyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 197 with the difference that (S)-Pyrrolidine-2-carboxylic acid propylamide was used instead of (S)-Pyrrolidine-2-carboxylic acid ethylamide. MS (ES + ): m/e=655.

4-[(S)-3-Carboxy-2-({4-[2-((S)-2-cyclopentylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 197 with the difference that (S)-Pyrrolidine-2-carboxylic acid cyclopentylamide and 4-Hydroxy-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid ethylamide and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=667.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-ethylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methoxy-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid ethylamide and 4-Hydroxy-7-methoxy-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=657.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methoxy-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide and 4-Hydroxy-7-methoxy-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=697.

4-[(S)-4-Carboxy-2-({7-ethyl-4-[2-((S)-2-ethylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid ethylamide and 7-Ethyl-4-hydroxy-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=669.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-ethyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide and 7-Ethyl-4-hydroxy-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=695.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-ethyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that 7-Ethyl-4-hydroxy-quinoline-2-carboxylic acid was used instead of 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=681.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-ethylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-6-fluoro-5-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid ethylamide and 6-Fluoro-4-hydroxy-5-methyl-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=673.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-6-fluoro-5-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide and 6-Fluoro-4-hydroxy-5-methyl-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=699.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-6-ethoxy-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that 6-Ethoxy-4-hydroxy-quinoline-2-carboxylic acid was used instead of 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=697.

4-[(S)-4-Carboxy-2-({6-ethoxy-4-[2-((S)-2-ethylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid ethylamide and 6-Ethoxy-4-hydroxy-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=685.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-6-ethoxy-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide and 6-Ethoxy-4-hydroxy-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=711.

4-[(S)-4-Carbamoyl-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

To 10 ml of a saturated solution of ammonia in methanol (7M) 43 mg of 4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-ethoxycarbonyl-butyryl]-piperazine-1-carboxylic acid ethyl ester and 10 mg of sodium cyanide was added and the reaction was stirred at 40° C. for two days. Then, 20 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. The product was obtained as its trifluoroacetate salt. Yield: 12 mg MS (ES + ): m/e=680.

4-{(S)-4-Carboxy-2-[(6-fluoro-7-methyl-4-{2-oxo-2-[(S)-2-(pyrrolidine-1-carbonyl)-pyrrolidin-1-yl]-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (5)-pyrrolidin-2-yl-pyrrolidin-1-yl-methanone and 6-Fluoro-4-hydroxy-7-methyl-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=699.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-ethylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-6-fluoro-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid ethylamide and 6-Fluoro-4-hydroxy-7-methyl-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=673.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-6-fluoro-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide and 6-Fluoro-4-hydroxy-7-methyl-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=699.

4-{(S)-4-Carboxy-2-[(7-fluoro-4-{2-oxo-2-[(S)-2-(pyrrolidine-1-carbonyl)-pyrrolidin-1-yl]-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-pyrrolidin-2-yl-pyrrolidin-1-yl-methanone and 7-Fluoro-4-hydroxy-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=685.

4-[(S)-4-Carboxy-2-({7-fluoro-4-[2-oxo-2-((S)-2-propylcarbamoyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid propylamide and 7-Fluoro-4-hydroxy-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=673.

4-[(S)-4-Ethoxycarbonyl-2-({7-fluoro-4-[2-oxo-2-((S)-2-propylcarbamoyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

To a solution of 31 mg of 4-[(S)-4-Carboxy-2-({7-fluoro-4-[2-oxo-2-((S)-2-propylcarbamoyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester in 0.2 ml of ethanol, 1 ml of a saturated solution of hydrochloric acid in ethanol was added and the mixture was stirred for 16 h at RT. Then, 5 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. The product was obtained as its trifluoroacetate salt. Yield: 10 mg MS (ES + ): m/e=701.

4-[(S)-4-Ethoxycarbonyl-2-({4-[2-((S)-2-ethylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-fluoro-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedure described in example 222 with the difference that 4-[(S)-4-Carboxy-2-({4-[2-((S)-2-ethylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-fluoro-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester was used instead of 4-[(S)-4-Carboxy-2-({7-fluoro-4-[2-oxo-2-((S)-2-propylcarbamoyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester. MS (ES + ): m/e=687.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-fluoro-quinoline-2-carbonyl}-amino)-4-ethoxycarbonyl-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedure described in example 222 with the difference that 4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-fluoro-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester was used instead of 4-[(S)-4-Carboxy-2-({7-fluoro-4-[2-oxo-2-((S)-2-propylcarbamoyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester. MS (ES + ): m/e=713.

4-{(S)-4-Carboxy-2-[(4-{2-[(S)-2-(ethyl-methyl-carbamoyl)-pyrrolidin-1-yl]-2-oxo-ethoxy}-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid ethyl-methyl-amide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=669.

4-[(S)-3-Carboxy-2-({4-[(R)-2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-1-methyl-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester

(i) 4-((S)-2-{[4-((R)-1-Benzyloxycarbonyl-ethoxy)-7-methyl-quinoline-2-carbonyl]-amino}-3-carboxy-propionyl)-piperazine-1-carboxylic acid ethyl ester

To a solution of 1 g of 4-{(S)-3-tert-Butoxycarbonyl-2-[(4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-propionyl}-piperazine-1-carboxylic acid ethyl ester and 350 mg of (S)-2-Hydroxy-propionic acid benzyl ester in 20 ml of THF, 764 mg of Triphenyl-phosphane and 507 mg of Diethyl azodicarboxylate was added and stirred for 2 h. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.0 g.

(ii) 4-((S)-3-tert-Butoxycarbonyl-2-{[4-((R)-1-carboxy-ethoxy)-7-methyl-quinoline-2-carbonyl]-amino}-propionyl)-piperazine-1-carboxylic acid ethyl ester

A solution of 1.3 g of 4-((S)-2-{[4-((R)-1-Benzyloxycarbonyl-ethoxy)-7-methyl-quinoline-2-carbonyl]-amino}-3-carboxy-propionyl)-piperazine-1-carboxylic acid ethyl ester in 20 ml of ethyl acetate was purged with argon. Then, 120 mg of Pd/C (5-10%) was added and the mixture stirred under a hydrogen atmosphere (3 bar). After 16 h the reaction mixture was filtered through a pad of celite and the solvents were removed under reduced pressure. After drying under reduced pressure the product was pure enough for the next reaction step. Yield: 850 mg.

(iii) (S)-2-Cyclobutylcarbamoyl-pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of 1.5 g of (S)-Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester in 30 ml of DMF 948 mg of HOAT, 1.3 g of EDC and 495 mg of cyclobutylamine was added and the reaction mixture was stirred for 16 h at RT. Then, water was added and the reaction mixture was extracted with DCM. The organic phase was dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was pure enough for the next reaction step.

(iv) (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide

The crude (S)-2-Cyclobutylcarbamoyl-pyrrolidine-1-carboxylic acid tert-butyl ester from the preceding reaction step was dissolved in 10 ml of DCM and 5 ml of TFA and stirred for 3 h. Then, the reaction mixture was diluted with 70 ml of toluene and the solvents were removed under reduced pressure. The residue was co-distilled additional 3 times with toluene. The product was obtained as its trifluoroacetate. Yield: 2 g.

(iii) 4-[(S)-3-tert-Butoxycarbonyl-2-({4-[(R)-2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-1-methyl-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester

To a solution of 121 mg of 4-((S)-3-tert-Butoxycarbonyl-2-{[4-((R)-1-carboxy-ethoxy)-7-methyl-quinoline-2-carbonyl]-amino}-propionyl)-piperazine-1-carboxylic acid ethyl ester in 1 ml of DCM, 43 mg of EDC, 43 mg of pentafluorophenol and 27 mg of NEM was added and the reaction mixture was stirred for 2 h. Then, 67 mg of (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide trifluoroacetate and 20 mg of NEM in 2 ml of DCM was added. After 1 h the reaction mixture was diluted with water. After filtration through a chem Elut® cartridge by eluting with ethyl acetate the solvents were removed under reduced pressure. The isolated crude product was pure enough for the next reaction step.

(iv) 4-[(S)-3-Carboxy-2-({4-[(R)-2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-1-methyl-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester

To a solution of the 4-[(S)-3-tert-Butoxycarbonyl-2-({4-[(R)-2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-1-methyl-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester obtained by the preceding reaction step in 1 ml of DCM, 2 ml of TFA was added at RT. After 1 h, 20 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. The product was obtained as its trifluoroacetate salt. Yield: 39 mg MS (ES+): m/e=681.

4-{(S)-3-Carboxy-2-[(7-methyl-4-{(R)-1-methyl-2-oxo-2-[(S)-2-(pyrrolidine-1-carbonyl)-pyrrolidin-1-yl]-ethoxy}-quinoline-2-carbonyl)-amino]-propionyl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 226 with the difference that (S)-Pyrrolidin-2-yl-pyrrolidin-1-yl-methanone was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide. MS (ES + ): m/e=681.

4-[(S)-3-Carboxy-2-({7-methyl-4-[(R)-1-methyl-2-oxo-2-((S)-2-propylcarbamoyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 226 with the difference that (S)-Pyrrolidine-2-carboxylic acid propylamide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide. MS (ES + ): m/e=669.

4-[(S)-3-Carboxy-2-({4-[(R)-2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-1-methyl-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 226 with the difference that (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide. MS (ES + ): m/e=667.

4-[(S)-3-Carboxy-2-({4-[(R)-2-((S)-2-cyclobutylcarbamoyl-azetidin-1-yl)-1-methyl-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 226 with the difference that (S)-Azetidine-2-carboxylic acid cyclobutylamide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide. MS (ES + ): m/e=667.

4-[(S)-3-Carboxy-2-({4-[(R)-2-((S)-3-hydroxymethyl-pyrrolidin-1-yl)-1-methyl-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 226 with the difference that (S)-1-Pyrrolidin-3-yl-methanol was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide. MS (ES + ): m/e=614.

4-[(S)-4-Ethoxycarbonyl-2-({4-[2-((S)-2-ethylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-6-fluoro-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedure described in example 222 with the difference that 4-[(S)-4-Carboxy-2-({4-[2-((S)-2-ethylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-6-fluoro-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester was used instead of 4-[(S)-4-Carboxy-2-({7-fluoro-4-[2-oxo-2-((S)-2-propylcarbamoyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester. MS (ES + ): m/e=701.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-ethylcarbamoyl-butyryl]-piperazine-1-carboxylic acid ethyl ester

To 11 mg of DMAP and 17 mg of EDC a solution of 50 mg of 4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester in 2 ml of DCM was added. Then, 24 mg of ethylamine was added and the reaction mixture was stirred for 16 h at RT. The solvents were removed under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. The product was obtained as its trifluoroacetate salt. Yield: 6 mg MS (ES+): m/e=708.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-dimethylcarbamoyl-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 233 with the difference that dimethyl-amine was used instead of ethylamine. MS (ES + ): m/e=708.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-methylcarbamoyl-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 233 with the difference that methylamine was used instead of ethylamine. MS (ES + ): m/e=694.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-cyclopropylcarbamoyl-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 233 with the difference that Cyclopropylamine was used instead of ethylamine. MS (ES + ): m/e=720.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-methoxycarbonyl-butyryl]-piperazine-1-carboxylic acid ethyl ester

To 11 mg of DMAP and 17 mg of EDC a solution of 50 mg of 4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester in 2 ml of DCM was added. Then, 12 mg of methanol was added and the reaction mixture was stirred for 16 h at RT. The solvents were removed under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. The product was obtained as its trifluoroacetate salt. Yield: 18 mg MS (ES+): m/e=695.

Alternatively 4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-methoxycarbonyl-butyryl]-piperazine-1-carboxylic acid ethyl ester was obtained by the following procedure.

To 10 ml of a saturated solution of hydrochloric acid in methanol 700 mg of 4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester was added and the mixture was stirred for 16 h. Then, 30 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. This solid was dissolved in 8 ml of a water/actonitrile mixture, 2 ml of a 1 M aqueous hydrochloric acid was added and the solution was again lyophilized to yield the product as its hydrochloride. Yield: 389 mg MS (ES + ): m/e=695.

4-[(S)-4-Butoxycarbonyl-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

To 165 mg of DMAP and 260 mg of EDC a solution of 900 mg of 4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester in 6 ml of DCM was added. Then, 420 mg of Butan-1-ol was added and the reaction mixture was stirred for 16 h at RT. The solvents were removed under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. The product was obtained as its trifluoroacetate salt. This solid was dissolved in 8 ml of a water/actonitrile mixture, 2 ml of a 1 M aqueous hydrochloric acid was added and the solution was again lyophilized to yield the product as its hydrochloride. Yield: 571 mg MS (ES+): m/e=737.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-pentyloxycarbonyl-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 237 with the difference that Pentan-1-ol was used instead of methanol. MS (ES + ): m/e=751.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-isopropoxycarbonyl-butyryl]-piperazine-1-carboxylic acid ethyl ester

To 10 ml of a saturated solution of hydrochloric acid in 2-propanol 400 mg of 4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester was added and the mixture was stirred for 16 h. Then, 30 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. This solid was dissolved in 8 ml of a water/actonitrile mixture, 2 ml of a 1 M aqueous hydrochloric acid was added and the solution was again lyophilized to yield the product as its hydrochloride. Yield: 371 mg MS (ES + ): m/e=723.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-(1-ethyl-propoxycarbonyl)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 237 with the difference that Pentan-3-ol was used instead of methanol. MS (ES + ): m/e=751.

4-[(S)-4-Cyclobutoxycarbonyl-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 237 with the difference that Cyclobutanol was used instead of methanol. MS (ES + ): m/e=735.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-cyclopentyloxycarbonyl-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 237 with the difference that cyclopentanol was used instead of methanol. MS (ES + ): m/e=749.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-cyclopropylmethoxycarbonyl-butyryl]-piperazine-1-carboxylic acid ethyl ester

To 165 mg of DMAP and 260 mg of EDC a solution of 900 mg of 4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester in 6 ml of DCM was added. Then, 408 mg of Cyclopropyl-methanol was added and the reaction mixture was stirred for 16 h at RT. The solvents were removed under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. The product was obtained as its trifluoroacetate salt. This solid was dissolved in 8 ml of a water/actonitrile mixture, 2 ml of a 1 M aqueous hydrochloric acid was added and the solution was again lyophilized to yield the product as its hydrochloride. Yield: 507 mg MS (ES+): m/e=735.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-(indan-5-yloxycarbonyl)-butyryl]-piperazine-1-carboxylic acid ethyl ester

To 92 mg of DMAP and 144 mg of EDC a solution of 500 mg of 4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester in 6 ml of DCM was added. Then, 422 mg of Indan-5-ol was added and the reaction mixture was stirred for 16 h at RT. The solvents were removed under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. The product was obtained as its trifluoroacetate salt. This solid was dissolved in 8 ml of a water/actonitrile mixture, 2 ml of a 1 M aqueous hydrochloric acid was added and the solution was again lyophilized to yield the product as its hydrochloride. Yield: 296 mg MS (ES+): m/e=797.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-cyclopentylmethoxycarbonyl-butyryl]-piperazine-1-carboxylic acid ethyl ester

To 161 mg of DMAP and 253 mg of EDC a solution of 750 mg of 4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester in 6 ml of DCM was added. Then, 552 mg of Cyclopentyl-methanol was added and the reaction mixture was stirred for 16 h at RT. The solvents were removed under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. The product was obtained as its trifluoroacetate salt. This solid was dissolved in 8 ml of a water/actonitrile mixture, 2 ml of a 1 M aqueous hydrochloric acid was added and the solution was again lyophilized to yield the product as its hydrochloride. Yield: 570 mg MS (ES+): m/e=763.

4-[(S)-2-({4-[2-((S)-2-Cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-fluoro-quinoline-2-carbonyl}-amino)-4-ethoxycarbonyl-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedure described in example 222 with the difference that 4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-fluoro-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester was used instead of 4-[(S)-4-Carboxy-2-({7-fluoro-4-[2-oxo-2-((S)-2-propylcarbamoyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester. MS (ES + ): m/e=699.

4-{(S)-4-Ethoxycarbonyl-2-[(7-fluoro-4-{2-oxo-2-[(S)-2-(pyrrolidine-1-carbonyl)-pyrrolidin-1-yl]-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedure described in example 222 with the difference that 4-{(S)-4-Carboxy-2-[(7-fluoro-4-{2-oxo-2-[(S)-2-(pyrrolidine-1-carbonyl)-pyrrolidin-1-yl]-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester was used instead of 4-[(S)-4-Carboxy-2-({7-fluoro-4-[2-oxo-2-((S)-2-propylcarbamoyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester. MS (ES + ): m/e=713.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-(2-morpholin-4-yl-ethoxycarbonyl)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 237 with the difference that 2-Morpholin-4-yl-ethanol was used instead of methanol. MS (ES + ): m/e=794.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-(1-morpholin-4-ylmethyl-propoxycarbonyl)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 237 with the difference that 1-Morpholin-4-yl-butan-2-ol was used instead of methanol. MS (ES + ): m/e=822.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-cyclohexyloxycarbonyl-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 237 with the difference that Cyclohexanol was used instead of methanol. MS (ES + ): m/e=763.

4-[(S)-4-Benzyloxycarbonyl-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

To 161 mg of DMAP and 253 mg of EDC a solution of 750 mg of 4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester in 6 ml of DCM was added. Then, 596 mg of Phenyl-methanol was added and the reaction mixture was stirred for 16 h at RT. The solvents were removed under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. The product was obtained as its trifluoroacetate salt. This solid was dissolved in 8 ml of a water/actonitrile mixture, 2 ml of a 1 M aqueous hydrochloric acid was added and the solution was again lyophilized to yield the product as its hydrochloride. Yield: 555 mg MS (ES+): m/e=771.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-isobutoxycarbonyl-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 237 with the difference that 2-Methyl-propan-1-ol was used instead of methanol. MS (ES + ): m/e=737.

4-[(S)-2-({4-[2-((S)-2-Cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-6-fluoro-7-methyl-quinoline-2-carbonyl}-amino)-4-ethoxycarbonyl-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedure described in example 222 with the difference that 4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-6-fluoro-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester was used instead of 4-[(S)-4-Carboxy-2-({7-fluoro-4-[2-oxo-2-((S)-2-propylcarbamoyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester. MS (ES+): m/e=713.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-6-fluoro-7-methyl-quinoline-2-carbonyl}-amino)-4-ethoxycarbonyl-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedure described in example 222 with the difference that 4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-6-fluoro-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester was used instead of 4-[(S)-4-Carboxy-2-({7-fluoro-4-[2-oxo-2-((S)-2-propylcarbamoyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester. MS (ES+): m/e=727.

4-{(S)-4-Ethoxycarbonyl-2-[(6-fluoro-7-methyl-4-{2-oxo-2-[(S)-2-(pyrrolidine-1-carbonyl)-pyrrolidin-1-yl]-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedure described in example 222 with the difference that 4-{(S)-4-Carboxy-2-[(6-fluoro-7-methyl-4-{2-oxo-2-[(S)-2-(pyrrolidine-1-carbonyl)-pyrrolidin-1-yl]-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester was used instead of 4-[(S)-4-Carboxy-2-({7-fluoro-4-[2-oxo-2-((S)-2-propylcarbamoyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester. MS (ES+): m/e=727.

4-{(S)-4-Ethoxycarbonyl-2-[(7-methyl-4-{2-oxo-2-[(S)-2-(pyrrolidine-1-carbonyl)-pyrrolidin-1-yl]-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedure described in example 222 with the difference that 4-{(S)-4-Carboxy-2-[(7-methyl-4-{2-oxo-2-[(S)-2-(pyrrolidine-1-carbonyl)-pyrrolidin-1-yl]-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester was used instead of 4-[(S)-4-Carboxy-2-({7-fluoro-4-[2-oxo-2-((S)-2-propylcarbamoyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester. MS (ES+): m/e=709.

4-[(S)-3-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-5-fluoro-quinoline-2-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 197 with the difference that 5-Fluoro-4-hydroxy-quinoline-2-carboxylic acid and (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide was used instead of 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid and (S)-Pyrrolidine-2-carboxylic acid ethylamide. MS (ES + ): m/e=671.

4-[(S)-3-Carboxy-2-({5-fluoro-4-[2-oxo-2-((S)-2-propylcarbamoyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 197 with the difference that 5-Fluoro-4-hydroxy-quinoline-2-carboxylic acid and (S)-Pyrrolidine-2-carboxylic acid propylamide was used instead of 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid and (S)-Pyrrolidine-2-carboxylic acid ethylamide. MS (ES + ): m/e=659.

4-[(S)-4-Carboxy-2-({5-fluoro-7-methyl-4-[2-oxo-2-((S)-2-propylcarbamoyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid propylamide and 5-Fluoro-4-hydroxy-7-methyl-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=687.

4-{(S)-4-Carboxy-2-[(5-fluoro-7-methyl-4-{2-oxo-2-[(S)-2-(pyrrolidine-1-carbonyl)-pyrrolidin-1-yl]-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidin-2-yl-pyrrolidin-1-yl-methanone and 5-Fluoro-4-hydroxy-7-methyl-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=699.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-5-fluoro-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide and 5-Fluoro-4-hydroxy-7-methyl-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=699.

4-{(S)-3-Carboxy-2-[(7-methyl-4-{2-oxo-2-[(S)-2-(pyrrolidine-1-carbonyl)-pyrrolidin-1-yl]-ethoxy}-quinoline-2-carbonyl)-amino]-propionyl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 197 with the difference that (S)-Pyrrolidin-2-yl-pyrrolidin-1-yl-methanone was used instead of (S)-Pyrrolidine-2-carboxylic acid ethylamide. MS (ES + ): m/e=667.

4-[(S)-2-({4-[2-((S)-2-Cyclopentylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-ethoxycarbonyl-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedure described in example 222 with the difference that 4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclopentylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester was used instead of 4-[(S)-4-Carboxy-2-({7-fluoro-4-[2-oxo-2-((S)-2-propylcarbamoyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester. MS (ES + ): m/e=723.

4-[(S)-3-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-fluoro-quinoline-2-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 197 with the difference that 7-Fluoro-4-hydroxy-quinoline-2-carboxylic acid and (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide was used instead of 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid and (S)-Pyrrolidine-2-carboxylic acid ethylamide. MS (ES + ): m/e=671.

4-[(S)-3-Carboxy-2-({5-fluoro-7-methyl-4-[2-oxo-2-((S)-2-propylcarbamoyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 197 with the difference that 5-Fluoro-4-hydroxy-7-methyl-quinoline-2-carboxylic acid and (S)-Pyrrolidine-2-carboxylic acid propylamide was used instead of 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid and (S)-Pyrrolidine-2-carboxylic acid ethylamide. MS (ES + ): m/e=673.

4-{(S)-3-Carboxy-2-[(5-fluoro-7-methyl-4-{2-oxo-2-[(S)-2-(pyrrolidine-1-carbonyl)-pyrrolidin-1-yl]-ethoxy}-quinoline-2-carbonyl)-amino]-propionyl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 197 with the difference that (S)-Pyrrolidin-2-yl-pyrrolidin-1-yl-methanone and 5-Fluoro-4-hydroxy-7-methyl-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid ethylamide and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=685.

4-[(S)-3-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-5-fluoro-7-methyl-quinoline-2-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 197 with the difference that 5-Fluoro-4-hydroxy-7-methyl-quinoline-2-carboxylic acid and (5)-Pyrrolidine-2-carboxylic acid cyclobutylamide was used instead of 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid and (S)-Pyrrolidine-2-carboxylic acid ethylamide. MS (ES + ): m/e=685.

4-{(S)-3-Carboxy-2-[(5-fluoro-4-{2-oxo-2-[(S)-2-(pyrrolidine-1-carbonyl)-pyrrolidin-1-yl]-ethoxy}-quinoline-2-carbonyl)-amino]-propionyl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 197 with the difference that 5-Fluoro-4-hydroxy-quinoline-2-carboxylic acid and (S)-Pyrrolidin-2-yl-pyrrolidin-1-yl-methanone was used instead of 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid and (S)-Pyrrolidine-2-carboxylic acid ethylamide. MS (ES + ): m/e=671.

4-[(S)-3-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-6-fluoro-7-methyl-quinoline-2-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 197 with the difference that 6-Fluoro-4-hydroxy-7-methyl-quinoline-2-carboxylic acid and (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide was used instead of 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid and (S)-Pyrrolidine-2-carboxylic acid ethylamide. MS (ES + ): m/e=685.

4-{(S)-4-Ethoxycarbonyl-2-[(5-fluoro-7-methyl-4-{2-oxo-2-[(S)-2-(pyrrolidine-1-carbonyl)-pyrrolidin-1-yl]-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedure described in example 222 with the difference that 4-{(S)-4-Carboxy-2-[(5-fluoro-7-methyl-4-{2-oxo-2-[(S)-2-(pyrrolidine-1-carbonyl)-pyrrolidin-1-yl]-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester was used instead of 4-[(S)-4-Carboxy-2-({7-fluoro-4-[2-oxo-2-((S)-2-propylcarbamoyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester. MS (ES+): m/e=727.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-5-fluoro-7-methyl-quinoline-2-carbonyl}-amino)-4-ethoxycarbonyl-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedure described in example 222 with the difference that 4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-5-fluoro-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester was used instead of 4-[(S)-4-Carboxy-2-({7-fluoro-4-[2-oxo-2-((S)-2-propylcarbamoyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester. MS (ES+): m/e=727.

4-{(S)-3-Carboxy-2-[(4-{2-[(S)-2-(ethyl-methyl-carbamoyl)-pyrrolidin-1-yl]-2-oxo-ethoxy}-7-methyl-quinoline-2-carbonyl)-amino]-propionyl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 197 with the difference that (S)-Pyrrolidine-2-carboxylic acid ethyl-methyl-amide was used instead of (S)-Pyrrolidine-2-carboxylic acid ethylamide. MS (ES + ): m/e=655.

4-[(S)-4-Carboxy-2-({4-[(R)-2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-1-methyl-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

(i) 4-((S)-2-{[4-((R)-1-Benzyloxycarbonyl-ethoxy)-7-methyl-quinoline-2-carbonyl]-amino}-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester

To a solution of 1 g of 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester and 341 mg of (S)-2-Hydroxy-propionic acid benzyl ester in 15 ml of THF, 744 mg of Triphenyl-phosphane and 494 mg of Diethyl azodicarboxylate was added and stirred for 2 h. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.0 g.

(ii) 4-((S)-4-tert-Butoxycarbonyl-2-{[4-((R)-1-carboxy-ethoxy)-7-methyl-quinoline-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester

A solution of 1.4 g of 4-((S)-2-{[4-((R)-1-Benzyloxycarbonyl-ethoxy)-7-methyl-quinoline-2-carbonyl]-amino}-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester in 20 ml of ethyl acetate was purged with argon. Then, 140 mg of Pd/C (5-10%) was added and the mixture stirred under a hydrogen atmosphere (3 bar). After 16 h the reaction mixture was filtered through a pad of celite and the solvents were removed under reduced pressure. After drying under reduced pressure the product was pure enough for the next reaction step. Yield: 1.2 g.

(iii) (S)-2-Cyclobutylcarbamoyl-pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of 1.5 g of (S)-Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester in 30 ml of DMF 948 mg of HOAT, 1.3 g of EDC and 495 mg of cyclobutylamine was added and the reaction mixture was stirred for 16 h at RT. Then, water was added and the reaction mixture was extracted with DCM. The organic phase was dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was pure enough for the next reaction step.

(iv) (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide

The crude (S)-2-Cyclobutylcarbamoyl-pyrrolidine-1-carboxylic acid tert-butyl ester from the preceding reaction step was dissolved in 10 ml of DCM and 5 ml of TFA and stirred for 3 h. Then, the reaction mixture was diluted with 70 ml of toluene and the solvents were removed under reduced pressure. The residue was co-distilled additional 3 times with toluene. The product was obtained as its trifluoroacetate. Yield: 2 g.

(v) 4-[(S)-4-tert-Butoxycarbonyl-2-({4-[(R)-2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-1-methyl-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

To a solution of 250 mg of 4-((S)-4-tert-Butoxycarbonyl-2-{[4-((R)-1-carboxy-ethoxy)-7-methyl-quinoline-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester in 2.5 ml of DCM, 96 mg of EDC, 92 mg of pentafluorophenol was added and the reaction mixture was stirred for 2 h. Then, 117 mg of (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide trifluoroacetate and 192 mg of NEM in 2 ml of DCM was added. After 2 h the reaction mixture was diluted with water. After filtration through a chem Elut® cartridge by eluting with ethyl acetate the solvents were removed under reduced pressure. The isolated crude product was pure enough for the next reaction step.

(vi) 4-[(S)-4-Carboxy-2-({4-[(R)-2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-1-methyl-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

To a solution of the 4-((S)-4-tert-Butoxycarbonyl-2-{[4-((R)-1-carboxy-ethoxy)-7-methyl-quinoline-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester obtained by the preceding reaction step in 1.4 ml of DCM, 0.1 ml of TFA was added at RT. After 2 h, 20 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. The product was obtained as its trifluoroacetate salt. Yield: 17 mg MS (ES+): m/e=695.

4-[(S)-4-Ethoxycarbonyl-2-({5-fluoro-7-methyl-4-[2-oxo-2-((S)-2-propylcarbamoyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedure described in example 222 with the difference that 4-[(S)-4-Carboxy-2-({5-fluoro-7-methyl-4-[2-oxo-2-((S)-2-propylcarbamoyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester was used instead of 4-[(S)-4-Carboxy-2-({7-fluoro-4-[2-oxo-2-((S)-2-propylcarbamoyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester. MS (ES+): m/e=715.

4-{(S)-3-Carboxy-2-[(6-fluoro-7-methyl-4-{2-oxo-2-[(S)-2-(pyrrolidine-1-carbonyl)-pyrrolidin-1-yl]-ethoxy}-quinoline-2-carbonyl)-amino]-propionyl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 197 with the difference that 6-Fluoro-4-hydroxy-7-methyl-quinoline-2-carboxylic acid and (S)-Pyrrolidin-2-yl-pyrrolidin-1-yl-methanone was used instead of 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid and (S)-Pyrrolidine-2-carboxylic acid ethylamide. MS (ES + ): m/e=685.

4-[(S)-3-Carboxy-2-({4-[2-((S)-2-ethylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-fluoro-quinoline-2-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 197 with the difference that 7-Fluoro-4-hydroxy-quinoline-2-carboxylic acid was used instead of 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=645.

4-[(S)-3-Carboxy-2-({7-fluoro-4-[2-oxo-2-((S)-2-propylcarbamoyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 197 with the difference that 7-Fluoro-4-hydroxy-quinoline-2-carboxylic acid and (S)-Pyrrolidine-2-carboxylic acid propylamide was used instead of 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid and (S)-Pyrrolidine-2-carboxylic acid ethylamide. MS (ES + ): m/e=659.

4-[(S)-3-Carboxy-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-fluoro-quinoline-2-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 197 with the difference that 7-Fluoro-4-hydroxy-quinoline-2-carboxylic acid and (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide was used instead of 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid and (S)-Pyrrolidine-2-carboxylic acid ethylamide. MS (ES + ): m/e=657.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-naphthalene-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

(i) 2-Benzylidene-malonic acid diethyl ester

To a solution of 12.8 g sodium ethylate in 140 ml of ethanol, 10.0 g of benzaldehyde and 17.4 g of Malonic acid diethyl ester dissolved in 35 ml ethanol was added drop-wise over 1 h at 50° C. Then, the reaction mixture was heated to reflux for 12 h. After cooling to RT half of the solvent was evaporated under reduced pressure and diluted with 200 ml of water. The remaining reaction mixture was acidified to pH 1 by addition of concentrated hydrochloric acid and then extracted with ethyl acetate. The organic phase was dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was pure enough for the next reaction step.

(ii) 4-Acetoxy-naphthalene-2-carboxylic acid ethyl ester

To a solution of 24 g of 2-Benzylidene-malonic acid diethyl ester in 60 ml of acetic acid anhydride, 7.5 g sodium acetate was added and the reaction mixture was heated to reflux for 5 h. After cooling to RT the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed three times with saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was pure enough for the next reaction step.

(iii) 4-Hydroxy-naphthalene-2-carboxylic acid

To a solution of 18.5 g of 4-Acetoxy-naphthalene-2-carboxylic acid ethyl ester in 100 ml ethanol/water (9:1), 240 ml of a 1M NaOH was added and stirred for 2 days at RT. Then, the reaction mixture was acidified to pH 2 with diluted hydrochloric acid to precipitate the product. The product was then collected by filtration and dried reduced pressure. Yield: 13.7 g.

(iv) 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-hydroxy-naphthalene-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

To a solution of 630 mg of 4-Hydroxy-naphthalene-2-carboxylic acid and 1.1 g of 4-((S)-2-Amino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester in 3 ml of DMF, 512 mg of HOBT and 641 mg of EDC was added and the reaction mixture was stirred for 4 h at RT. Then, the reaction mixture was diluted with water and extracted with DCM. The organic phase was dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with n-heptane/ethyl acetate (1/2). The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 246 mg.

(v) 4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-naphthalene-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

To a solution of 100 mg of (S)-1-(2-Bromo-acetyl)-pyrrolidine-2-carboxylic acid cyclopropylamide and 93 mg of 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-hydroxy-naphthalene-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 2 ml of DMF, 118 mg of cesium carbonate was added and the reaction mixture was heated to 80° C. for 5 h. Then, the reaction mixture was diluted with water and filtered through a chem Elut® cartridge by eluting with ethyl acetate. The solvents were removed under reduced pressure and the residue was dissolved in 1 ml of DCM and 0.2 ml of TFA. After 16 h at RT 10 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. Yield: 40 mg MS (ES+): m/e=652.

4-{(S)-4-Carboxy-2-[(6,7-dimethyl-4-{2-oxo-2-[(S)-2-(pyrrolidine-1-carbonyl)-pyrrolidin-1-yl]-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidin-2-yl-pyrrolidin-1-yl-methanone and 4-Hydroxy-6,7-dimethyl-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=695.

4-{(S)-4-Ethoxycarbonyl-2-[(7-methyl-4-{2-oxo-2-[(S)-2-(2,2,2-trifluoro-ethylcarbamoyl)-pyrrolidin-1-yl]-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedure described in example 107 with the difference that 4-{(S)-4-tert-Butoxycarbonyl-2-[(7-methyl-4-{2-oxo-2-[(S)-2-(2,2,2-trifluoro-ethylcarbamoyl)-pyrrolidin-1-yl]-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester was used instead of 4-[(S)-4-tert-Butoxycarbonyl-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester. MS (ES+): m/e=737.

4-{(S)-2-[(4-{2-[(S)-2-(Cyclopropylmethyl-carbamoyl)-pyrrolidin-1-yl]-2-oxo-ethoxy}-7-methyl-quinoline-2-carbonyl)-amino]-4-ethoxycarbonyl-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedure described in example 107 with the difference that 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-{2-[(S)-2-(cyclopropylmethyl-carbamoyl)-pyrrolidin-1-yl]-2-oxo-ethoxy}-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester was used instead of 4-[(S)-4-tert-Butoxycarbonyl-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester. MS (ES+): m/e=709.

4-[(S)-4-Ethoxycarbonyl-2-({7-methyl-4-[2-oxo-2-((S)-2-propylcarbamoyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedure described in example 107 with the difference that 4-[(S)-4-tert-Butoxycarbonyl-2-({7-methyl-4-[2-oxo-2-((S)-2-propylcarbamoyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester was used instead of 4-[(S)-4-tert-Butoxycarbonyl-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester. MS (ES+): m/e=725.

4-[(S)-4-Carboxy-2-({6,7-dimethyl-4-[2-oxo-2-((S)-2-propylcarbamoyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid propylamide and 4-Hydroxy-6,7-dimethyl-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=683.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-5-fluoro-quinoline-2-carbonyl}-amino)-4-ethoxycarbonyl-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedure described in example 107 with the difference that 4-[(S)-4-tert-Butoxycarbonyl-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-5-fluoro-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester was used instead of 4-[(S)-4-tert-Butoxycarbonyl-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester. MS (ES+): m/e=713.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-6-fluoro-quinoline-2-carbonyl}-amino)-4-ethoxycarbonyl-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedure described in example 107 with the difference that 4-[(S)-4-tert-Butoxycarbonyl-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-6-fluoro-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester was used instead of 4-[(S)-4-tert-Butoxycarbonyl-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester. MS (ES+): m/e=713.

4-{(S)-4-Carboxy-2-[(5,6-difluoro-4-{2-oxo-2-[(S)-2-(pyrrolidine-1-carbonyl)-pyrrolidin-1-yl]-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid propylamide and 5,6-Difluoro-4-hydroxy-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=703.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-5,6-difluoro-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide and 5,6-Difluoro-4-hydroxy-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=703.

4-[(S)-4-Carboxy-2-({5,6-difluoro-4-[2-oxo-2-((S)-2-propylcarbamoyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid propylamide and 5,6-Difluoro-4-hydroxy-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=691.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-6,7-dimethyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 3 with the difference that (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide and 4-Hydroxy-6,7-dimethyl-quinoline-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid. MS (ES + ): m/e=695.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-6-fluoro-5-methyl-quinoline-2-carbonyl}-amino)-4-ethoxycarbonyl-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedure described in example 107 with the difference that 4-[(S)-4-tert-Butoxycarbonyl-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-6-fluoro-5-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester was used instead of 4-[(S)-4-tert-Butoxycarbonyl-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester. MS (ES+): m/e=727.

4-[(S)-2-({4-[(R)-2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-1-methyl-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-ethoxycarbonyl-butyryl]-piperazine-1-carboxylic acid ethyl ester

To 3 ml of a saturated solution of hydrochloric acid in ethanol 150 mg of 4-[(S)-4-tert-Butoxycarbonyl-2-({4-[(R)-2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-1-methyl-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester was added and the mixture was stirred for 2 h. Then, 20 ml of toluene was added and the solvents were removed under reduced pressure. The residue was co-distilled twice with toluene and then purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. This solid was dissolved in 8 ml of a water/actonitrile mixture, 2 ml of a 1 M aqueous hydrochloric acid was added and the solution was again lyophilized to yield the product as its hydrochloride. Yield: 135 mg MS (ES + ): m/e=723.

4-[(S)-4-Carboxy-2-({4-[(R)-2-((S)-2-cyclopentylcarbamoyl-pyrrolidin-1-yl)-1-methyl-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 274 with the difference that (S)-Pyrrolidine-2-carboxylic acid cyclopentylamide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide. MS (ES + ): m/e=709.

4-[(S)-2-({4-[(R)-2-((S)-2-Cyclopentylcarbamoyl-pyrrolidin-1-yl)-1-methyl-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-ethoxycarbonyl-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedure described in example 107 with the difference that 4-[(S)-4-tert-Butoxycarbonyl-2-({4-[(R)-2-((S)-2-cyclopentylcarbamoyl-pyrrolidin-1-yl)-1-methyl-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester was used instead of 4-[(S)-4-tert-Butoxycarbonyl-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester. MS (ES+): m/e=737.

4-{(S)-4-Carboxy-2-[(7-methyl-4-{(R)-1-methyl-2-oxo-2-[(S)-2-(piperidine-1-carbonyl)-pyrrolidin-1-yl]-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 274 with the difference that Piperidin-1-yl-(S)-pyrrolidin-2-yl-methanone was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide. MS (ES + ): m/e=709.

4-{(S)-4-Ethoxycarbonyl-2-[(7-methyl-4-{(R)-1-methyl-2-oxo-2-[(S)-2-(piperidine-1-carbonyl)-pyrrolidin-1-yl]-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedure described in example 107 with the difference that 4-{(S)-4-tert-Butoxycarbonyl-2-[(7-methyl-4-{(R)-1-methyl-2-oxo-2-[(S)-2-(piperidine-1-carbonyl)-pyrrolidin-1-yl]-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester was used instead of 4-[(S)-4-tert-Butoxycarbonyl-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester. MS (ES+): m/e=737.

4-[(S)-4-Carboxy-2-({7-methyl-4-[(R)-1-methyl-2-oxo-2-((S)-2-propylcarbamoyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 274 with the difference that Piperidin-1-yl-(S)-pyrrolidin-2-yl-methanone was used instead of (S)-Pyrrolidine-2-carboxylic acid propylamide. MS (ES + ): m/e=683.

4-[(S)-4-Ethoxycarbonyl-2-({7-methyl-4-[(R)-1-methyl-2-oxo-2-((S)-2-propylcarbamoyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedure described in example 107 with the difference that 4-[(S)-4-tert-Butoxycarbonyl-2-({7-methyl-4-[(R)-1-methyl-2-oxo-2-((S)-2-propylcarbamoyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester was used instead of 4-[(S)-4-tert-Butoxycarbonyl-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester. MS (ES+): m/e=711.

4-{(S)-4-Carboxy-2-[(4-{(R)-2-[(S)-2-(cyclopropylmethyl-carbamoyl)-pyrrolidin-1-yl]-1-methyl-2-oxo-ethoxy}-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 274 with the difference that (S)-Pyrrolidine-2-carboxylic acid cyclopropylmethyl-amide was used instead of (S)-Pyrrolidine-2-carboxylic acid propylamide. MS (ES + ): m/e=695.

4-{(S)-2-[(4-{(R)-2-[(S)-2-(Cyclopropylmethyl-carbamoyl)-pyrrolidin-1-yl]-1-methyl-2-oxo-ethoxy}-7-methyl-quinoline-2-carbonyl)-amino]-4-ethoxycarbonyl-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedure described in example 107 with the difference that 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-{(R)-2-[(S)-2-(cyclopropylmethyl-carbamoyl)-pyrrolidin-1-yl]-1-methyl-2-oxo-ethoxy}-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester was used instead of 4-[(S)-4-tert-Butoxycarbonyl-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester. MS (ES+): m/e=723.

4-{(S)-4-Carboxy-2-[(4-{2-[(S)-2-(4,4-difluoro-piperidine-1-carbonyl)-pyrrolidin-1-yl]-2-oxo-ethoxy}-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 57 with the difference that and (4,4-Difluoro-piperidin-1-yl)-(S)-pyrrolidin-2-yl-methanone was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide. MS (ES + ): m/e=731.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid butyl ester

(i) Piperazine-1,4-dicarboxylic acid butyl ester tert-butyl ester

To a solution of 15 g of Piperazine-1-carboxylic acid tert-butyl ester in 200 ml of DCM, 18 g of triethylamine was added and the mixture was cooled to 0° C. Then, 12.1 g of butyl chloroformate was slowly added. After the addition was completed the reaction mixture was allowed to warm to RT and to stir for 16 h. Then, 200 ml of DCM was added and the organic phase was washed two times with 0.1 M aqueous hydrochloric acid followed by saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was pure enough for the next reaction step. Yield: 21.9 g.

(ii) Piperazine-1-carboxylic acid butyl ester

To a solution of 21.9 g of Piperazine-1,4-dicarboxylic acid butyl ester tert-butyl ester from the preceding reaction step (i) in 20 ml of DCM, 30 ml of TFA was slowly added at RT. After 16 h, 200 ml of toluene was added and the solvents were removed under reduced pressure. The isolated crude product was obtained as its trifluoroacetate salt and was pure enough for the next reaction step. Yield: 23 g.

(iii) 4-((S)-2-Benzyloxycarbonylamino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid butyl ester

To a solution of 22.4 g of (S)-2-Benzyloxycarbonylamino-pentanedioic acid 5-tert-butyl ester, 30.7 g of NEM and 21.8 g of TOTU in 75 ml of DMF, 20 g of Piperazine-1-carboxylic acid butyl ester trifluoroacetate was added at RT and stirred for 16 h. The reaction mixture was then diluted with saturated aqueous sodium hydrogen carbonate solution and then extracted with 300 ml of ethyl acetate. The organic phase was washed with diluted saturated aqueous sodium hydrogen carbonate solution and dried over MgSO 4 . The solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with n-heptane/ethyl acetate (1/1). The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 33.4 g.

(iv) 4-((S)-2-Amino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid butyl ester

A solution of 33.4 g of 4-((S)-2-Benzyloxycarbonylamino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester in 130 ml of ethanol was purged with argon. Then, 3.3 g of Pd/C (5-10%) was added and the mixture stirred under a hydrogen atmosphere (3 bar). After 6 h the reaction mixture was filtered through a pad of celite and the solvents were removed under reduced pressure. After drying under reduced pressure the product was pure enough for the next reaction step. Yield: 17.3 g.

(v) 4-tert-Butoxycarbonylmethoxy-7-methyl-quinoline-2-carboxylic acid ethyl ester

To a solution of 3.0 g of 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid ethyl ester in 20 ml of DMF, 3.0 g of potassium carbonate and 3.8 g of Bromo-acetic acid tert-butyl ester was added and stirred for 16 h. Then, the reaction mixture was diluted with water and extracted with ethyl acetate (3×150 ml). The combined organic phases were dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was pure enough for the next reaction step. Yield: 4.9 g.

(vi) 4-Carboxymethoxy-7-methyl-quinoline-2-carboxylic acid ethyl ester

To a solution of 4.9 g of -tert-Butoxycarbonylmethoxy-7-methyl-quinoline-2-carboxylic acid ethyl ester from the preceding reaction step (v) in 50 ml of DCM 1.5 ml of TFA was added at RT. After 16 h, 20 ml of toluene was added and the solvents were removed under reduced pressure. The residue was co-distilled additional two times with toluene. After drying under reduced pressure the product was pure enough for the next reaction step. Yield: 3.8 g.

(vii) 4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carboxylic acid ethyl ester

To a solution of 2 g of 4-Carboxymethoxy-7-methyl-quinoline-2-carboxylic acid ethyl ester in 30 ml of DCM, 3.6 g of EDC, 3.4 g of pentafluorophenol, 2.2 g of NEM was added and the reaction mixture was stirred at RT for 2 h. Then, 5.3 g of (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide trifluoroacetate and 2.1 g of NEM in 10 ml of DCM was added. After 16 h the reaction mixture was diluted with water and extracted with DCM (3×150 ml). The combined organic phases were dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 2.5 g.

(viii) 4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carboxylic acid

To a solution of 2.5 g 4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carboxylic acid ethyl ester in 20 ml of THF, 5.7 ml of a 1M aqueous sodium hydroxide solution was added and stirred for 16 h at RT. The reaction mixture was acidified with 1M hydrochloric acid to pH 3 and the solvents were evaporated under reduced pressure. The residue was dissolved in a mixture of methanol/DCM and the solids were filtered off. The filtrate was evaporated under reduced pressure to yield the product which was pure enough for the next reaction step. Yield: 2.0 g.

(iix) 4-[(S)-4-tert-Butoxycarbonyl-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid butyl ester

To a solution of 500 mg of 4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carboxylic acid and 451 mg of 4-((S)-2-Amino-4-tert-butoxycarbonyl-butyryl)piperazine-1-carboxylic acid butyl ester in 5 ml of DMF, 186 mg of HOBT and 232 mg of EDC was added and the reaction mixture was stirred for 4 h at RT. Then, the reaction mixture was diluted with water and filtered through a chem Elut® cartridge by eluting with ethyl acetate. The solvents were removed under reduced pressure and the isolated crude product was pure enough for the next reaction step. Yield: 930 mg.

(ix) 4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid butyl ester

To a solution of 50 mg of 4-[(S)-4-tert-Butoxycarbonyl-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid butyl ester from the preceding reaction step (viii) in 2 ml of DCM 0.2 ml of TFA was added at RT. After 5 h, 20 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. The product was obtained as its trifluoroacetate salt. Yield: 6 mg MS (ES+): m/e=709.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-4-hydroxy-butyryl]-piperazine-1-carboxylic acid ethyl ester

(i) 4-((S)-4-Benzyloxy-2-tert-butoxycarbonylamino-butyryl)-piperazine-1-carboxylic acid ethyl ester

To a solution of 220 mg of (S)-4-Benzyloxy-2-tert-butoxycarbonylamino-butyric acid, 327 mg of NEM and 233 mg of TOTU in 1.6 ml of DMF, 112 mg of Piperazine-1-carboxylic acid ethyl ester was added at RT and stirred for 16 h. The reaction mixture was diluted saturated aqueous sodium hydrogen carbonate solution. After filtration through a chem Elut® cartridge by eluting with ethyl acetate the solvents were removed under reduced pressure. The isolated crude product was pure enough for the next reaction step.

(ii) 4-((S)-2-Amino-4-benzyloxy-butyryl)-piperazine-1-carboxylic acid ethyl ester

To a solution of 325 mg of 4-((S)-4-Benzyloxy-2-tert-butoxycarbonylamino-butyryl)-piperazine-1-carboxylic acid ethyl ester from the preceding reaction step (i) in 1.2 ml of DCM 0.6 ml of TFA was added at RT. After 16 h, 20 ml of toluene was added and the solvents were removed under reduced pressure. The isolated crude product was obtained as its trifluoroacetate salt and was pure enough for the next reaction step. Yield: 389 mg.

(iii) 4-Benzyloxycarbonylmethoxy-quinoline-2-carboxylic acid ethyl ester

To a solution of 10 g of 4-Hydroxy-quinoline-2-carboxylic acid ethyl ester in 300 ml of DMF, 10 g of potassium carbonate and 15.2 g of Bromo-acetic acid benzyl ester was added and stirred for 16 h. Then, the reaction mixture was diluted with water and extracted with ethyl acetate (3×150 ml). The combined organic phases were dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with n-heptane/ethyl acetate (2/8). The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 10.2 g.

(iv) 4-Carboxymethoxy-quinoline-2-carboxylic acid ethyl ester

A solution of 10.2 g of 4-Benzyloxycarbonylmethoxy-quinoline-2-carboxylic acid ethyl ester in 200 ml of ethyl acetate was purged with argon. Then, 2 g of Pd/C (5-10%) was added and the mixture stirred under a hydrogen atmosphere (4 bar). After 16 h the reaction mixture was filtered through a pad of celite washing with isopropanol, followed by acetonitrile and then DMF. The solvents were removed under reduced pressure. After drying under reduced pressure the product was pure enough for the next reaction step. Yield: 8.7 g.

(v) 4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carboxylic acid ethyl ester

To a solution of 2 g of 4-Carboxymethoxy-quinoline-2-carboxylic acid ethyl ester in 20 ml of DMF, 2.8 g of EDC, 2.7 g of pentafluorophenol was added and the reaction mixture was stirred at RT for 2 h. Then, 3.1 g of (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide trifluoroacetate and 1.7 g of NEM in 10 ml of DMF was added. After 16 h the reaction mixture was diluted with water and extracted with DCM (3×150 ml). The combined organic phases were dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.4 g.

(vi) 4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carboxylic acid

To a solution of 1.4 g 4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carboxylic acid ethyl ester in 20 ml of THF, 3.3 ml of a 1M aqueous sodium hydroxide solution was added and stirred for 16 h at RT. The reaction mixture was acidified with 1M hydrochloric acid to pH 1 to precipitate the product, which was then collected by filtration. The residue was co-distilled additional two times with toluene. After drying under reduced pressure the product was pure enough for the next reaction step. Yield: 945 mg.

(vii) 4-[(S)-4-Benzyloxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

To a solution of 200 mg of 4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carboxylic acid and 233 mg of 4-((S)-2-Amino-4-benzyloxy-butyryl)-piperazine-1-carboxylic acid ethyl ester trifluoroacetate in 4 ml of DMF, 77 mg of HOBT, 97 mg of EDC and 1 ml NEM was added and the reaction mixture was stirred for 16 h at RT. Then, the reaction mixture was diluted with water and filtered through a chem Elut® cartridge by eluting with ethyl acetate. The solvents were removed under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. The product was obtained as its trifluoroacetate salt. Yield: 448 mg MS (ES+): m/e=729.

(viii) 4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxyl]-quinoline-2-carbonyl}-amino)-4-hydroxy-butyryl]-piperazine-1-carboxylic acid ethyl ester

A solution of 580 mg of 4-[(S)-4-Benzyloxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester and 0.1 ml of acetic acid in 20 ml of ethanol was purged with argon. Then, 200 mg of Pd/C (5-10%) was added and the mixture was stirred under a hydrogen atmosphere (5 bar). After 16 h the reaction mixture was filtered through a pad of celite and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. The product was obtained as its trifluoroacetate salt. Yield: 206 mg MS (ES+): m/e=639.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-4-hydroxy-butyryl]-piperazine-1-carboxylic acid butyl ester

(i) 4-((S)-4-Benzyloxy-2-tert-butoxycarbonylamino-butyryl)-piperazine-1-carboxylic acid butyl ester

To a solution of 5 g of (S)-4-Benzyloxy-2-tert-butoxycarbonylamino-butyric acid, 7.4 g of NEM and 5.3 g of TOTU in 35 ml of DMF, 4.8 g of Piperazine-1-carboxylic acid butyl ester trifluoroacetate was added at RT and stirred for 16 h. The reaction mixture was diluted saturated aqueous sodium hydrogen carbonate solution and extracted with 250 ml of ethyl acetate. The organic phase was dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 6.3 g.

(ii) 4-((S)-2-Amino-4-benzyloxy-butyryl)-piperazine-1-carboxylic acid butyl ester

To a solution of 6.3 g of 4-((S)-4-Benzyloxy-2-tert-butoxycarbonylamino-butyryl)-piperazine-1-carboxylic acid butyl ester from the preceding reaction step (i) in 24 ml of DCM 5 ml of TFA was added at RT. After 5 h, 100 ml of toluene was added and the solvents were removed under reduced pressure. The residue was co-distilled with toluene additional two times and then dissolved in DCM and washed with water. The organic phase was dried over MgSO 4 and the solvents were removed under reduced pressure. The isolated crude product was obtained as its trifluoroacetate salt and was pure enough for the next reaction step. Yield: 6.1 g.

(iii) 4-{(S)-4-Benzyloxy-2-[(4-hydroxy-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid butyl ester

To a solution of 1 g of 4-Hydroxy-quinoline-2-carboxylic acid and 2.6 g of 4-((S)-2-Amino-4-benzyloxy-butyryl)-piperazine-1-carboxylic acid butyl ester trifluoroacetate in 12 ml of DMF, 0.8 g of HOBT, 1.0 g of EDC and 1.2 g of NEM was added and the reaction mixture was stirred for 16 h at RT. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was precipitated from a mixture of n-heptane and ethyl acetate. The precipitated product was collected by filtration and dried under reduced pressure. The isolated product was pure enough for the next reaction step. Yield: 900 mg.

(iv) 4-{(S)-4-Benzyloxy-2-[(4-tert-butoxycarbonylmethoxy-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid butyl ester

To a solution of 900 mg 4-{(S)-4-Benzyloxy-2-[(4-hydroxy-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid butyl ester in 6.7 ml of DMF, 587 mg of cesium carbonate and 351 mg of Bromo-acetic acid tert-butyl ester was added and the reaction mixture was stirred for 5 h at RT. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO 4 and the solvents were removed under reduced pressure. The isolated crude product was pure enough for the next reaction step. Yield: 1.1 g.

(v) 4-{(S)-4-Benzyloxy-2-[(4-carboxymethoxy-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid butyl ester

To a solution 1.1 g of 4-{(S)-4-Benzyloxy-2-[(4-tert-butoxycarbonylmethoxy-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid butyl ester from the preceding reaction step (iv) in 5 ml of DCM, 0.5 ml of TFA was added at RT. After 16 h, 20 ml of toluene was added and the solvents were removed under reduced pressure. The residue was dissolved in 100 ml of DCM and washed with water. The organic phase was dried over MgSO 4 and the solvents were removed under reduced pressure. The isolated crude product was obtained as its trifluoroacetate salt and was pure enough for the next reaction step. Yield: 990 mg.

(vi) 4-[(S)-4-Benzyloxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid butyl ester

To a solution of 990 mg of 4-{(S)-4-Benzyloxy-2-[(4-carboxymethoxy-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid butyl ester in 5 ml of DCM, 631 mg of EDC, 19 mg of NEM and 607 mg of pentafluorophenol was added and the reaction mixture was stirred at RT for 2 h. Then, 480 mg of (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide trifluoroacetate and 380 mg of NEM in 2 ml of DCM was added. After 3 h the reaction mixture was diluted with water and extracted with DCM (3×150 ml). The combined organic phases were dried over MgSO 4 and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. The product was obtained as its trifluoroacetate salt. Yield: 270 mg.

(vii) 4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-4-hydroxy-butyryl]-piperazine-1-carboxylic acid butyl ester

A solution of 270 mg of 4-[(S)-4-Benzyloxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid butyl ester and 0.1 ml of acetic acid in 10 ml of ethanol was purged with argon. Then, 100 mg of Pd/C (5-10%) was added and the mixture was stirred under a hydrogen atmosphere (5 bar). After 16 h the reaction mixture was filtered through a pad of celite and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. The product was obtained as its trifluoroacetate salt. Yield: 76 mg MS (ES+): m/e=667.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-hydroxy-butyryl]-piperazine-1-carboxylic acid ethyl ester

(i) 4-{(S)-4-Benzyloxy-2-[(4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

To a solution of 1 g of 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid and 1.7 g of 4-((S)-2-Amino-4-benzyloxy-butyryl)-piperazine-1-carboxylic acid ethyl ester trifluoroacetate in 15 ml of DMF, 566 mg of NEM, 753 mg of HOBT and 943 mg of EDC was added and the reaction mixture was stirred for 16 h at RT. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was precipitated from a mixture of n-heptane and ethyl acetate. The precipitated product was collected by filtration and dried under reduced pressure. The isolated product was pure enough for the next reaction step. Yield: 1.8 g.

(ii) 4-{(S)-4-Benzyloxy-2-[(4-tert-butoxycarbonylmethoxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

To a solution of 1.8 g of 4-{(S)-4-Benzyloxy-2-[(4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 20 ml of DMF, 1.2 g of cesium carbonate and 723 mg of Bromo-acetic acid tert-butyl ester was added and the reaction mixture was stirred for 2 h at RT. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.3 g.

(iii) 4-{(S)-4-Benzyloxy-2-[(4-carboxymethoxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

To a solution of 4-{(S)-4-Benzyloxy-2-[(4-tert-butoxycarbonylmethoxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester from the preceding reaction step (ii) in 10 ml of DCM 1.5 ml of TFA was added at RT. After 3 h, 20 ml of toluene was added and the solvents were removed under reduced pressure. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO 4 and the solvents were removed under reduced pressure. The product was obtained as its trifluoroacetate salt. Yield: 1.2 g.

(iv) 4-[(S)-4-Benzyloxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

To a solution of 1.2 g of 4-{(S)-4-Benzyloxy-2-[(4-carboxymethoxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 10 ml of DCM, 465 mg of EDC, 447 mg of pentafluorophenol and 466 mg of NEM was added and the reaction mixture was stirred for 2 h at RT. Then, 1.1 g of (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide trifluoroacetate and 466 mg of NEM in 4 ml of DCM was added. After 16 h the reaction mixture was diluted with water and extracted with DCM (3×150 ml). The combined organic phases were dried over MgSO 4 and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. The product was obtained as its trifluoroacetate salt. Yield: 2.5 g.

(v) 4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-hydroxy-butyryl]-piperazine-1-carboxylic acid ethyl ester

A solution of 600 mg of 4-[(S)-4-Benzyloxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester and 0.1 ml of acetic acid in 20 ml of ethanol was purged with argon. Then, 200 mg of Pd/C (5-10%) was added and the mixture was stirred under a hydrogen atmosphere (5 bar). After 16 h the reaction mixture was filtered through a pad of celite and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. This solid was dissolved in 5 ml of a water/actonitrile mixture, 2 ml of a 1 M aqueous hydrochloric acid was added and the solution was again lyophilized to yield the product as its hydrochloride. Yield: 441 mg MS (ES+): m/e=653.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-fluoro-quinoline-2-carbonyl}-amino)-4-ethoxycarbonyl-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedure described in example 107 with the difference that 4-[(S)-4-tert-Butoxycarbonyl-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-fluoro-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester was used instead of 4-[(S)-4-tert-Butoxycarbonyl-2-({4-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester. MS (ES+): m/e=713.

4-{(S)-4-Carboxy-2-[(4-{2-[(S)-2-(cyclobutylmethyl-carbamoyl)-pyrrolidin-1-yl]-2-oxo-ethoxy}-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 57 with the difference that and (S)-Pyrrolidine-2-carboxylic acid cyclobutylmethyl-amide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide. MS (ES + ): m/e=695.

4-[(S)-4-Carboxy-2-({4-[2-(3,3-difluoro-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 3,3-Difluoro-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=606.

4-[(S)-2-({4-[2-(2-Butyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-4-carboxy-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2-Butyl-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=626.

4-[(S)-4-Carboxy-2-({4-[2-(4-cyclohexyl-3-oxo-piperazin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 1-Cyclohexyl-piperazin-2-one was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=681.

4-[(S)-4-Carboxy-2-({4-[2-(2-methyl-3-oxo-piperazin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 3-Methyl-piperazin-2-one was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=613.

4-{(S)-4-Carboxy-2-[(4-{2-oxo-2-[4-(2-oxo-pyrrolidin-1-yl)-piperidin-1-yl]-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 1-Piperidin-4-yl-pyrrolidin-2-one was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=667.

4-[(S)-4-Carboxy-2-({4-[2-oxo-2-(3-oxo-4-phenyl-piperazin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 1-Phenyl-piperazin-2-one was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=675.

4-[(S)-4-Carboxy-2-({4-[2-(4-isobutoxy-piperidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 4-Isobutoxy-piperidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=656.

4-[(S)-4-Carboxy-2-({4-[2-(4-isopropoxy-piperidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 4-Isopropoxy-piperidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=642.

4-[(S)-4-Carboxy-2-({4-[2-(2-furan-2-yl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2-Furan-2-yl-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=636.

4-[(S)-4-Carboxy-2-({4-[2-((R)-2-cyano-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (R)-Pyrrolidine-2-carbonitrile was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=595.

4-{(S)-4-Carboxy-2-[(4-{2-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazin-1-yl]-2-oxo-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 1-Morpholin-4-yl-2-piperazin-1-yl-ethanone was used instead of (5)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=712.

4-[(S)-4-Carboxy-2-({4-[2-((2S,4R)-4-hydroxy-2-methoxycarbonyl-piperidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (2S,4R)-4-Hydroxy-piperidine-2-carboxylic acid methyl ester was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=658.

4-{(S)-4-Carboxy-2-[(4-{2-[2-(5-methyl-furan-2-yl)-pyrrolidin-1-yl]-2-oxo-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2-(5-Methyl-furan-2-yl)-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=650.

4-[(S)-4-Carboxy-2-({4-[2-(2-methoxymethyl-piperidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2-Methoxymethyl-piperidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=628.

4-[(S)-4-Carboxy-2-({4-[2-(4-morpholin-4-yl-piperidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 4-Piperidin-4-yl-morpholine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=669.

4-[(S)-4-Carboxy-2-({4-[2-(4-isopropyl-piperazin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 1-Isopropyl-piperazine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=627.

4-[(S)-4-Carboxy-2-({4-[2-(2-ethoxymethyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2-Ethoxymethyl-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=628.

4-[(S)-4-Carboxy-2-({4-[2-(4-cyclopropanecarbonyl-piperazin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that Cyclopropyl-piperazin-1-yl-methanone was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=653.

4-((S)-4-Carboxy-2-{[4-(2-oxo-2-piperazin-1-yl-ethoxy)-quinoline-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that Piperazine-1-carboxylic acid tert-butyl ester was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=585.

4-[(S)-4-Carboxy-2-({4-[2-(4-ethanesulfonyl-piperazin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 1-Ethanesulfonyl-piperazine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=677.

4-[(S)-4-Carboxy-2-({4-[2-oxo-2-((S)-2-trifluoromethyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (S)-2-Trifluoromethyl-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=638.

4-{(S)-4-Carboxy-2-[(4-{2-oxo-2-[2-(tetrahydro-furan-2-yl)-piperidin-1-yl]-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2-(Tetrahydro-furan-2-yl)-piperidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=654.

4-[(S)-4-Carboxy-2-({4-[2-(2-morpholin-4-ylmethyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 4-Pyrrolidin-2-ylmethyl-morpholine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=669.

4-[(S)-4-Carboxy-2-({4-[2-(2,2-dimethyl-3-oxo-piperazin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 3,3-Dimethyl-piperazin-2-one was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=627.

4-[(S)-4-Carboxy-2-({4-[2-(2-methylsulfanylmethyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2-Methylsulfanylmethyl-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=630.

4-[(S)-4-Carboxy-2-({4-[2-oxo-2-(2-phenyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2-Phenyl-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=646.

4-[(S)-4-Carboxy-2-({4-[2-oxo-2-(2-thiazol-2-yl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2-Pyrrolidin-2-yl-thiazole was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=653.

4-[(S)-4-Carboxy-2-({4-[2-(2-cyclopentyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2-Cyclopentyl-pyrrolidine was used instead of (5)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=638.

4-[(S)-4-Carboxy-2-({4-[2-(3-methoxy-3a,4,6,6a-tetrahydro-pyrrolo[3,4-d]isoxazol-5-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 3-Methoxy-4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]isoxazole was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=641.

4-[(S)-4-Carboxy-2-({4-[2-(4,4-difluoro-piperidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 4,4-Difluoro-piperidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=620.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyano-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (S)-Pyrrolidine-2-carbonitrile was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=595.

4-[(S)-4-Carboxy-2-({4-[2-oxo-2-(3-trifluoromethyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 3-Trifluoromethyl-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=638.

4-[(S)-4-Carboxy-2-({4-[2-oxo-2-(4-oxo-hexahydro-cyclopenta[c]pyrrol-2-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that Hexahydro-cyclopenta[c]pyrrol-4-one was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=624.

4-[(S)-4-Carboxy-2-({4-[2-oxo-2-(4-oxo-imidazolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that Imidazolidin-4-one was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=585.

(S)-4-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-5-[4-(3-methoxy-phenyl)-piperazin-1-yl]-5-oxo-pentanoic acid

(i) (S)-4-Benzyloxycarbonylamino-5-[4-(3-methoxy-phenyl)-piperazin-1-yl]-5-oxo-pentanoic acid tert-butyl ester

To a solution of 2 g of (S)-2-Benzyloxycarbonylamino-pentanedioic acid 5-tert-butyl ester 2.7 g of NEM and 1.9 g of TOTU in 10 ml of DMF, 1.1 g of 1-(3-Methoxy-phenyl)-piperazine was added at RT and stirred for 16 h. The reaction mixture was diluted with 150 ml of ethyl and subsequently extracted with aqueous LiCl (4% w/w), 0.1 M HCl and aqueous NaHCO 3 . The organic layer was dried over MgSO 4 and the solvent was removed under reduced pressure. The crude product thus obtained was pure enough for the further manipulations. Yield: 4 g.

(ii) (S)-4-Amino-5-[4-(3-methoxy-phenyl)-piperazin-1-yl]-5-oxo-pentanoic acid tert-butyl ester

A solution of 4 g of (S)-4-Benzyloxycarbonylamino-5-[4-(3-methoxy-phenyl)-piperazin-1-yl]-5-oxo-pentanoic acid tert-butyl ester in 60 ml of ethanol was purged with argon. Then, 0.7 g of Pd/C (5-10%) was added and the mixture stirred under a hydrogen atmosphere (3 bar). After 16 h the reaction mixture was filtered through a pad of celite and the solvents were removed under reduced pressure. After drying under reduced pressure the product was pure enough for the next reaction step. Yield: 2.9 g.

(iii) (S)-4-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-5-[4-(3-methoxy-phenyl)-piperazin-1-yl]-5-oxo-pentanoic acid

To a solution of 70 mg of 4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carboxylic acid and 66 mg (S)-4-Amino-5-[4-(3-methoxy-phenyl)-piperazin-1-yl]-5-oxo-pentanoic acid tert-butyl ester in 2 ml of DMF, 27 mg of HOBT, 27 mg of EDC and 0.5 ml NEM was added and the reaction mixture was stirred for 16 h at RT. Then, the reaction mixture was diluted with water and filtered through a chem Elut® cartridge by eluting with ethyl acetate. The solvents were removed under reduced pressure and the residue was dissolved in 1 ml of DCM and 0.6 ml of TFA. After 16 h at RT 10 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. The product was obtained as its trifluoroacetate salt. Yield: 65 mg MS (ES+): m/e=701.

4-[(S)-5-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-pentanoyl]-piperazine-1-carboxylic acid ethyl ester

(i) 4-((S)-2-Benzyloxycarbonylamino-5-tert-butoxycarbonyl-pentanoyl)-piperazine-1-carboxylic acid ethyl ester

To a solution of 2 g of (S)-2-Benzyloxycarbonylamino-hexanedioic acid 6-tert-butyl ester dicyclohexyl-ammonium salt, 1.7 g of NEM and 1.2 g of TOTU in 6 ml of DMF, 0.62 g of Piperazine-1-carboxylic acid ethyl ester was added at RT and stirred for 16 h. The reaction mixture was diluted saturated aqueous sodium hydrogen carbonate solution and extracted with 150 ml of ethyl acetate. The organic phase was dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 2.2 g.

(ii) 4-((S)-2-Amino-5-tert-butoxycarbonyl-pentanoyl)-piperazine-1-carboxylic acid ethyl ester

A solution of 2.3 g of 4-((S)-2-Benzyloxycarbonylamino-5-tert-butoxycarbonyl-pentanoyl)-piperazine-1-carboxylic acid ethyl ester in 50 ml of ethanol was purged with argon. Then, 50 mg of Pd/C (5-10%) was added and the mixture stirred under a hydrogen atmosphere (3 bar). After 4 h the reaction mixture was filtered through a pad of celite and the solvents were removed under reduced pressure. After drying under reduced pressure the product was pure enough for the next reaction step. Yield: 1.7 g.

(iii) 4-[(S)-5-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-pentanoyl]-piperazine-1-carboxylic acid ethyl ester

To a solution of 70 mg of 4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carboxylic acid and 63 mg of 4-((S)-2-Amino-5-tert-butoxycarbonyl-pentanoyl)-piperazine-1-carboxylic acid ethyl ester in 2 ml of DMF, 27 mg of HOBT, 27 mg of EDC and 0.5 ml NEM was added and the reaction mixture was stirred for 16 h at RT. Then, the reaction mixture was diluted with water and filtered through a chem Elut® cartridge by eluting with ethyl acetate. The solvents were removed under reduced pressure and the residue was dissolved in 1 ml of DCM and 0.6 ml of TFA. After 16 h at RT 10 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. The product was obtained as its trifluoroacetate salt. Yield: 33 mg MS (ES+): m/e=681.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-4-methanesulfonyl-butyryl]-piperazine-1-carboxylic acid ethyl ester

(i) 4-((S)-2-tert-Butoxycarbonylamino-4-methanesulfonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester

To a solution of 2 g of (S)-2-tert-Butoxycarbonylamino-4-methanesulfonyl-butyric acid, 3.2 g of NEM and 2.3 g of TOTU in 10 ml of DMF, 1.2 g of Piperazine-1-carboxylic acid ethyl ester was added at RT and stirred for 2 h. The reaction mixture was diluted saturated aqueous sodium hydrogen carbonate solution and extracted with 400 ml of ethyl acetate. The organic phase was washed with diluted saturated aqueous sodium hydrogen carbonate solution and dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.9 g.

(ii) 4-((S)-2-Amino-4-methanesulfonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester

To 1.9 g of 4-((S)-2-tert-Butoxycarbonylamino-4-methanesulfonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester, 20 ml of methanolic hydrochloric acid was added at RT and stirred for 3 h. Then, 100 ml of toluene was added and the solvents were removed under reduced pressure. The product was obtained as its hydrochloric acid salt. Yield: 1.9 g.

(iii) 4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-4-methanesulfonyl-butyryl]-piperazine-1-carboxylic acid ethyl ester

To a solution of 70 mg of 4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carboxylic acid and 57 mg of 4-((S)-2-Amino-4-methanesulfonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester in 2 ml of DMF, 27 mg of HOBT, 27 mg of EDC and 0.5 ml NEM was added and the reaction mixture was stirred for 16 h at RT. Then, the reaction mixture was diluted with water and filtered through a chem Elut® cartridge by eluting with ethyl acetate. The solvents were removed under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. The product was obtained as its trifluoroacetate salt. Yield: 120 mg MS (ES+): m/e=701.

4-[(S)-4-Carboxy-2-({4-[2-((S)-2-methyl-3-oxo-piperazin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (S)-3-Methyl-piperazin-2-one was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=613.

4-[(S)-4-Carboxy-2-({4-[2-oxo-2-(2-pyridin-3-yl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 3-Pyrrolidin-2-yl-pyridine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=647.

4-((S)-4-Carboxy-2-{[4-((1S,4S)-2-2,5-diaza-bicyclo[2.2.1]hept-2-yl-2-oxo-ethoxy)-quinoline-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=597.

4-[(S)-2-({4-[2-((S)-3-Amino-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-4-carboxy-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (S)-Pyrrolidin-3-yl-carbamic acid tert-butyl ester was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=585.

4-{(S)-4-Carboxy-2-[(4-{2-[2-(1-methyl-piperidin-2-yl)-pyrrolidin-1-yl]-2-oxo-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 1-Methyl-2-pyrrolidin-2-yl-piperidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=667.

4-[(S)-4-Carboxy-2-({4-[2-oxo-2-(3-pyridin-4-yl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 4-Pyrrolidin-3-yl-pyridine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=647.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-ethoxycarbonyl-butyryl]-piperazine-1-carboxylic acid butyl ester

To 5 ml of a saturated solution of hydrochloric acid in ethanol 200 mg of 4-[(S)-4-tert-Butoxycarbonyl-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]piperazine-1-carboxylic acid butyl ester was added and the mixture was stirred for 16 h. Then, 30 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. This solid was dissolved in 5 ml of a water/actonitrile mixture, 1 ml of a 1 M aqueous hydrochloric acid was added and the solution was again lyophilized to yield the product as its hydrochloride. Yield: 167 mg MS (ES + ): m/e=737.

4-[(S)-4-Carboxy-2-({4-[2-((R)-2-methoxymethyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (R)-2-Methoxymethyl-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=614.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-hydroxy-butyryl]-piperazine-1-carboxylic acid butyl ester

(i) 4-((S)-4-Benzyloxy-2-tert-butoxycarbonylamino-butyryl)-piperazine-1-carboxylic acid butyl ester

To a solution of 5 g of (S)-4-Benzyloxy-2-tert-butoxycarbonylamino-butyric acid, 7.4 g of NEM and 5.3 g of TOTU in 35 ml of DMF, 4.8 g of Piperazine-1-carboxylic acid butyl ester trifluoroacetate was added at RT and stirred for 16 h. The reaction mixture was diluted saturated aqueous sodium hydrogen carbonate solution and extracted with 250 ml of ethyl acetate. The organic phase was dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 6.3 g.

(ii) 4-((S)-2-Amino-4-benzyloxy-butyryl)-piperazine-1-carboxylic acid butyl ester

To a solution of 6.3 g of 4-((S)-4-Benzyloxy-2-tert-butoxycarbonylamino-butyryl)-piperazine-1-carboxylic acid butyl ester from the preceding reaction step (i) in 24 ml of DCM 5 ml of TFA was added at RT. After 5 h, 100 ml of toluene was added and the solvents were removed under reduced pressure. The residue was co-distilled with toluene additional two times and then dissolved in DCM and washed with water. The organic phase was dried over MgSO 4 and the solvents were removed under reduced pressure. The isolated crude product was obtained as its trifluoroacetate salt and was pure enough for the next reaction step. Yield: 6.1 g.

(iii) 4-{(S)-4-Benzyloxy-2-[(4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid butyl ester

To a solution of 1 g of 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid and 1.8 g of 4-((S)-2-Amino-4-benzyloxy-butyryl)-piperazine-1-carboxylic acid butyl ester trifluoroacetate in 12 ml of DMF, 566 mg of NEM, 1.1 g of HOBT and 1.4 g of EDC was added and the reaction mixture was stirred for 16 h at RT. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 650 mg.

(iv) 4-{(S)-4-Benzyloxy-2-[(4-tert-butoxycarbonylmethoxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid butyl ester

To a solution of 650 mg of 4-{(S)-4-Benzyloxy-2-[(4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid butyl ester in 7.7 ml of DMF, 414 mg of cesium carbonate and 248 mg of Bromo-acetic acid tert-butyl ester was added and the reaction mixture was stirred for 2 h at RT. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 590 mg.

(v) 4-{(S)-4-Benzyloxy-2-[(4-carboxymethoxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid butyl ester

To a solution of 4-{(S)-4-Benzyloxy-2-[(4-tert-butoxycarbonylmethoxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid butyl ester from the preceding reaction step (iv) in 10 ml of DCM 0.5 ml of TFA was added at RT. After 3 h, 20 ml of toluene was added and the solvents were removed under reduced pressure. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO 4 and the solvents were removed under reduced pressure. The product was obtained as its trifluoroacetate salt. Yield: 850 mg.

(vi) 4-[(S)-4-Benzyloxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid butyl ester

To a solution of 850 mg of 4-{(S)-4-Benzyloxy-2-[(4-carboxymethoxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid butyl ester in 10 ml of DCM, 524 mg of EDC and 504 mg of pentafluorophenol was added and the reaction mixture was stirred for 2 h at RT. Then, 772 mg of (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide trifluoroacetate and 315 mg of NEM in 2 ml of DCM was added. After 16 h the reaction mixture was diluted with water and filtered through a chem Elut® cartridge by eluting with ethyl acetate. Then, the solvents were removed under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. The product was obtained as its trifluoroacetate salt. Yield: 80 mg.

(vii) 4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-hydroxy-butyryl]-piperazine-1-carboxylic acid ethyl ester

A solution of 600 mg of 4-[(S)-4-Benzyloxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester and 0.1 ml of acetic acid in 5 ml of ethanol was purged with argon. Then, 100 mg of Pd/C (5-10%) was added and the mixture was stirred under a hydrogen atmosphere (5 bar). After 16 h the reaction mixture was filtered through a pad of celite and the solvents were removed under reduced pressure. The residue was co-distilled twice with toluene and then purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. This solid was dissolved in 8 ml of a water/actonitrile mixture, 1 ml of a 1 M aqueous hydrochloric acid was added and the solution was again lyophilized to yield the product as its hydrochloride. Yield: 55 mg MS (ES+): m/e=681.

4-[(S)-4-Carboxy-2-({4-[(R)-2-((S)-2-carboxy-pyrrolidin-1-yl)-1-methyl-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 274 with the difference that (S)-Pyrrolidine-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide. MS (ES + ): m/e=642.

4-[(S)-4-Carboxy-2-({7-methyl-4-[(R)-1-methyl-2-oxo-2-(2-phenyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 274 with the difference that 2-Phenyl-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide. MS (ES + ): m/e=674.

4-[(S)-4-Carboxy-2-({4-[2-oxo-2-(2-o-tolyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2-o-Tolyl-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=660.

4-[(S)-4-Carboxy-2-({4-[2-oxo-2-(3-phenyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 3-Phenyl-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=646.

4-[(S)-4-Carboxy-2-({4-[2-(2-hydroxymethyl-2,3-dihydro-indol-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (2,3-Dihydro-1H-indol-2-yl)-methanol was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=648.

4-[(S)-2-({4-[2-(5-Acetyl-2,3-dihydro-indol-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-4-carboxy-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 1-(2,3-Dihydro-1H-indol-5-yl)-ethanone was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=660.

(S)-1-(2-{2-[(S)-3-Carboxy-1-(4-ethoxycarbonyl-piperazine-1-carbonyl)-propylcarbamoyl]-quinolin-4-yloxyl}-acetyl)-2,3-dihydro-1H-indole-2-carboxylic acid

The title compound was prepared by adapting the procedures described in example 73 with the difference that (S)-2,3-Dihydro-1H-indole-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=662.

4-[(S)-4-Carboxy-2-({4-[2-(2-methyl-2,3-dihydro-indol-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2-Methyl-2,3-dihydro-1H-indole was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=632.

4-[(S)-4-Carboxy-2-({4-[2-(2,3-dihydro-indol-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2,3-Dihydro-1H-indole was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=618.

4-[(S)-4-Carboxy-2-({4-[2-((S)-3-hydroxymethyl-3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (S)-1-(1,2,3,4-Tetrahydro-isoquinolin-3-yl)-methanol was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=662.

4-[(S)-4-Carboxy-2-({4-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 1,2,3,4-Tetrahydro-isoquinoline was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=632.

4-[(S)-4-Carboxy-2-({4-[2-(6-methoxy-3,4-dihydro-2H-quinolin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 6-Methoxy-1,2,3,4-tetrahydro-quinoline was used instead of (5)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=662.

4-[(S)-4-Carboxy-2-({4-[2-(3,4-dihydro-2H-quinolin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 1,2,3,4-Tetrahydro-quinoline was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=632.

4-{(S)-4-Carboxy-2-[(4-{2-[2-(4-fluoro-phenyl)-pyrrolidin-1-yl]-2-oxo-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2-(4-Fluoro-phenyl)-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=664.

4-{(S)-4-Carboxy-2-[(4-{2-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-2-oxo-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2-(2-Chloro-phenyl)-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=680, chloro pattern.

4-[(S)-4-Carboxy-2-({4-[2-(4-methyl-3-oxo-piperazin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 1-Methyl-piperazin-2-one was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=613.

4-[(S)-4-Carboxy-2-({4-[2-(5-methyl-3-oxo-pyrazolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 5-Methyl-pyrazolidin-3-one was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=599.

4-[(S)-4-Carboxy-2-({4-[2-oxo-2-(2-pyridin-4-yl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 4-Pyrrolidin-2-yl-pyridine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=647.

4-[(S)-4-Carboxy-2-({4-[2-(2-methyl-4,6-dihydro-pyrrolo[3,4-d]thiazol-5-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2-Methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazole was used instead of (5)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=639.

4-[(S)-4-Carboxy-2-({4-[2-oxo-2-(3-pyridin-2-yl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2-Pyrrolidin-3-yl-pyridine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=647.

4-[(S)-4-Carboxy-2-({4-[2-oxo-2-((R)-2-phenylaminomethyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that Phenyl-(R)-1-pyrrolidin-2-ylmethyl-amine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=675.

4-[(S)-2-({4-[2-(2-Benzyloxymethyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-4-carboxy-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2-Benzyloxymethyl-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=690.

4-[(S)-4-Carboxy-2-({4-[2-(4,7-dihydro-5H-thieno[2,3-c]pyridin-6-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 4,5,6,7-Tetrahydro-thieno[2,3-c]pyridine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=638.

4-[(S)-4-Carboxy-2-({4-[2-(4-methyl-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 4-Methyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=652.

4-[(S)-4-Carboxy-2-({4-[2-oxo-2-(3-phenyl-6,7-dihydro-4H-isoxazolo[4,5-c]pyridin-5-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 3-Phenyl-4,5,6,7-tetrahydro-isoxazolo[4,5-c]pyridine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=699.

4-[(S)-2-({4-[2-(3-Benzyloxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-4-carboxy-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 3-Benzyloxy-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=676.

4-[(S)-4-Carboxy-2-({4-[2-oxo-2-(3-trifluoromethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 3-Trifluoromethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=690.

4-[(S)-4-Carboxy-2-({4-[2-(2-isopropyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2-Isopropyl-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=612.

4-[(S)-4-Carboxy-2-({4-[2-oxo-2-(2-m-tolyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2-m-Tolyl-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=660.

4-[(S)-4-Carboxy-2-({4-[2-oxo-2-((R)-3-phenyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (R)-3-Phenyl-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=646.

4-[(S)-4-Carboxy-2-({4-[2-(2-isopropyl-4-methyl-3-oxo-piperazin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 3-Isopropyl-1-methyl-piperazin-2-one was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=655.

4-[(S)-4-Carboxy-2-({4-[2-(2-ethyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2-Ethyl-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=598.

4-[(S)-4-Carboxy-2-({4-[2-oxo-2-(2-pyridin-2-yl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2-Pyrrolidin-2-yl-pyridine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=647.

4-[(S)-2-({4-[2-(2-tert-Butyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-4-carboxy-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2-tert-Butyl-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=626.

4-{(S)-2-[(4-{2-[2-(1H-Benzoimidazol-2-yl)-pyrrolidin-1-yl]-2-oxo-ethoxy}-quinoline-2-carbonyl)-amino]-4-carboxy-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2-Pyrrolidin-2-yl-1H-benzoimidazole was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=686.

4-[(S)-4-Carboxy-2-({4-[2-oxo-2-(3-phenylamino-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that Phenyl-pyrrolidin-3-yl-amine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=661.

4-((S)-2-{[4-(2-[1,3′]Bipyrrolidinyl-1′-yl-2-oxo-ethoxy)-quinoline-2-carbonyl]-amino}-4-carboxy-butyryl)-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that [1,3′]Bipyrrolidinyl was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=639.

4-{(S)-4-Carboxy-2-[(4-{2-oxo-2-[(S)-2-(1H-tetrazol-5-ylmethyl)-pyrrolidin-1-yl]-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 5-(S)-1-Pyrrolidin-2-ylmethyl-1H-tetrazole was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=652.

4-[(S)-4-Carboxy-2-({4-[2-oxo-2-(3-o-tolyloxy-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 3-o-Tolyloxy-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=676.

4-[(S)-4-Carboxy-2-({4-[2-(2-methyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2-Methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=653.

4-[(S)-2-({4-[2-(2-Butyl-4-methyl-3-oxo-piperazin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-4-carboxy-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 3-Butyl-1-methyl-piperazin-2-one was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=669.

4-{(S)-4-Carboxy-2-[(4-{2-[2-(3-methoxy-phenyl)-pyrrolidin-1-yl]-2-oxo-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2-(3-Methoxy-phenyl)-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=676.

4-[(S)-4-Carboxy-2-({4-[2-(6-methyl-octahydro-pyrrolo[3,4-b]pyridin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 6-Methyl-octahydro-pyrrolo[3,4-b]pyridine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=639.

4-{(S)-4-Carboxy-2-[(4-{2-[2-(2-methoxy-phenyl)-pyrrolidin-1-yl]-2-oxo-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2-(2-Methoxy-phenyl)-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=676.

4-[(S)-4-Carboxy-2-({4-[2-(3-diethylamino-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that Diethyl-pyrrolidin-3-yl-amine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=641.

4-[(S)-4-Carboxy-2-({4-[2-oxo-2-(3-o-tolyloxy-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 3-o-Tolyloxy-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=676.

4-{(S)-4-Carboxy-2-[(4-{2-[(S)-2-(cyclobutyl-methyl-carbamoyl)-pyrrolidin-1-yl]-2-oxo-ethoxy}-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 57 with the difference that (S)-Pyrrolidine-2-carboxylic acid cyclobutyl-methyl-amide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide. MS (ES + ): m/e=695.

4-{(S)-2-[(4-{2-[(S)-2-(Cyclobutyl-methyl-carbamoyl)-pyrrolidin-1-yl]-2-oxo-ethoxy}-7-methyl-quinoline-2-carbonyl)-amino]-4-ethoxycarbonyl-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 58 with the difference that (S)-Pyrrolidine-2-carboxylic acid cyclobutyl-methyl-amide was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide. MS (ES + ): m/e=723.

4-[(S)-4-Carboxy-2-({4-[2-oxo-2-((R)-2-phenyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (R)-2-Phenyl-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=646.

4-[(S)-4-Carboxy-2-({4-[2-oxo-2-((S)-2-phenyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (S)-2-Phenyl-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=646.

4-{(S)-4-Carboxy-2-[(4-{2-[2-(2-fluoro-phenyl)-pyrrolidin-1-yl]-2-oxo-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2-(2-Fluoro-phenyl)-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=664.

4-{(S)-4-Carboxy-2-[(4-{2-[3-(2-fluoro-phenyl)-pyrrolidin-1-yl]-2-oxo-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 3-(2-Fluoro-phenyl)-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=664.

4-{(S)-4-Carboxy-2-[(4-{2-[2-(2,4-dimethoxy-phenyl)-pyrrolidin-1-yl]-2-oxo-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2-(2,4-Dimethoxy-phenyl)-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=706.

4-[(S)-4-Carboxy-2-({4-[2-((2S,5R)-2-carboxy-5-phenyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (2S,5R)-5-Phenyl-pyrrolidine-2-carboxylic acid was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=690.

4-[(S)-4-Carboxy-2-({4-[2-oxo-2-(2-p-tolyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2-p-Tolyl-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=660.

4-{(S)-4-Carboxy-2-[(4-{2-[2-(3,4-difluoro-phenyl)-pyrrolidin-1-yl]-2-oxo-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2-(3,4-Difluoro-phenyl)-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=682.

4-{(S)-4-Carboxy-2-[(4-{2-[2-(3,4-dimethoxy-phenyl)-pyrrolidin-1-yl]-2-oxo-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2-(3,4-Dimethoxy-phenyl)-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=706.

4-[(S)-4-Carboxy-2-({4-[2-(2-ethyl-3-oxo-piperazin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 3-Ethyl-piperazin-2-one was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=627.

4-{(S)-4-Carboxy-2-[(4-{2-oxo-2-[3-(2-oxo-pyrrolidin-1-ylmethyl)-piperidin-1-yl]-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 1-Piperidin-3-ylmethyl-pyrrolidin-2-one was used instead of (5)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=681.

4-[(S)-4-Carboxy-2-({4-[2-oxo-2-(2-thiophen-2-yl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2-Thiophen-2-yl-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=652.

4-[(S)-4-Carboxy-2-({4-[2-oxo-2-(2-pyrimidin-4-yl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 4-Pyrrolidin-2-yl-pyrimidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=648.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-cyclohexylmethoxycarbonyl-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 237 with the difference that Cyclohexyl-methanol was used instead of methanol. MS (ES + ): m/e=777.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-cyclobutylmethoxycarbonyl-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 237 with the difference that Cyclobutyl-methanol was used instead of methanol. MS (ES + ): m/e=749.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-propoxycarbonyl-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 237 with the difference that Propan-1-ol was used instead of methanol. MS (ES + ): m/e=737.

4-[(S)-4-Cyclobutoxycarbonyl-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 237 with the difference that Cyclobutanol was used instead of methanol. MS (ES + ): m/e=735.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-cyclopentylmethoxycarbonyl-butyryl]-piperazine-1-carboxylic acid butyl ester

The title compound was prepared by adapting the procedures described in example 246 with the difference that 4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid butyl ester was used instead of 4-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester. MS (ES + ): m/e=791.

4-[(S)-4-Carboxy-2-({4-[2-oxo-2-(4-oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidin-6-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 5,6,7,8-Tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=650.

4-{(S)-4-Carboxy-2-[(4-{2-[2-(3-chloro-phenyl)-pyrrolidin-1-yl]-2-oxo-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2-(3-Chloro-phenyl)-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=681, chloro pattern.

4-{(S)-4-Carboxy-2-[(4-{2-[2-(2,4-difluoro-phenyl)-pyrrolidin-1-yl]-2-oxo-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2-(2,4-Difluoro-phenyl)-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=682.

3-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyrylamino]-azetidine-1-carboxylic acid butyl ester

(i) 3-Benzyloxycarbonylamino-azetidine-1-carboxylic acid butyl ester

To a solution of 2 g of Azetidin-3-yl-carbamic acid benzyl ester trifluoroacetate (prepared by standard protection and deprotection procedures from 3-Amino-azetidine-1-carboxylic acid tert-butyl ester) in 10 ml of DCM, 1.9 g of triethylamine was added and the mixture was cooled to 0° C. Then, 938 mg of butyl chloroformate was slowly added. After the addition was completed the reaction mixture was allowed to warm to RT and to stir for 1 h. Then, 200 ml of DCM was added and the organic phase was washed two times with 0.1M aqueous hydrochloric acid and the with saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.4 g.

(ii) 3-Amino-azetidine-1-carboxylic acid butyl ester

To a solution of 1.4 g 3-Benzyloxycarbonylamino-azetidine-1-carboxylic acid butyl ester in 50 ml ethyl acetate were added 150 mg Pd/C (10%) and the suspension stirred under an atmosphere of hydrogen (1 bar) for 5 h. The reaction mixture was filtrated over a plug of Celite®, washed with ethyl acetate and concentrated. Yield: 740 mg colorless solid

(iii) (S)-2-[(4-Hydroxy-quinoline-2-carbonyl)-amino]-pentanedioic acid 5-tert-butyl ester 1-methyl ester

To a solution of 5 g 4-Hydroxy-quinoline-2-carboxylic acid and 5 g of (S)-2-Amino-pentanedioic acid 5-tert-butyl ester 1-methyl ester hydrochloride in 50 ml of DMF, 4.0 g of HOBT, 5.1 g of EDC and 6 g of NEM was added and the reaction mixture was stirred for 16 h at RT. Then, the reaction mixture was diluted with water and extracted with DCM. The organic phase was dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was purified by re-crystallisation from ethyl acetate and dried under reduced pressure. Yield: 6.5 g.

(iv) (S)-2-[(4-Benzyloxycarbonylmethoxy-quinoline-2-carbonyl)-amino]-pentanedioic acid 5-tert-butyl ester 1-methyl ester

To a solution of 6.5 g of (S)-2-[(4-Hydroxy-quinoline-2-carbonyl)-amino]-pentanedioic acid 5-tert-butyl ester 1-methyl ester 50 ml of DMF, 6.5 g of cesium carbonate and 4.2 g of Bromo-acetic acid benzyl ester was added and stirred for 16 h. Then, the reaction mixture was diluted with water and extracted with DCM (3×150 ml). The combined organic phases were dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was used in the next reaction step. Yield: 8.9 g.

(v) (S)-2-[(4-Carboxymethoxy-quinoline-2-carbonyl)-amino]-pentanedioic acid 5-tert-butyl ester 1-methyl ester

A solution of 8.9 g of (S)-2-[(4-Benzyloxycarbonylmethoxy-quinoline-2-carbonyl)-amino]-pentanedioic acid 5-tert-butyl ester 1-methyl ester in 150 ml of ethanol was purged with argon. Then, 1 g of Pd/C (5-10%) was added and the mixture stirred under a hydrogen atmosphere (4 bar). After 16 h reaction the mixture was filtered through a pad of celite and the solvents were removed under reduced pressure. After drying under reduced pressure the product was pure enough for the next reaction step. Yield: 5.2 g.

(vi) (S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)pentanedioic acid 5-tert-butyl ester 1-methyl ester

To a solution of 4 g of (S)-2-[(4-Carboxymethoxy-quinoline-2-carbonyl)-amino]-pentanedioic acid 5-tert-butyl ester 1-methyl ester in 30 ml of DCM, 3.4 g of EDC and 3.2 g of pentafluorophenol was added and the reaction mixture was stirred for 2 h at RT. Then, 5 g of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide trifluoroacetate salt and 2 g of NEM in 10 ml of DCM was added. After 3 h the reaction mixture was diluted with water and extracted with DCM (3×150 ml). The combined organic phases were dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.8 g.

(vii) (S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-pentanedioic acid 5-tert-butyl ester

To a solution of 1.8 g of 4(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-pentanedioic acid 5-tert-butyl ester 1-methyl ester in 45 ml of THF, 4.5 ml of a 1M NaOH was added and stirred for 6 h at RT. Then, the reaction mixture was acidified to pH 2 with hydrochloric acid (1M), concentrated and extracted with DCM (3×150 ml). The combined organic phases were dried over MgSO 4 and the solvents were removed under reduced pressure. The product was used in the next reaction step without further purification. Yield: 1.4 g.

(viii) 3-[(S)-4-Carboxy-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyrylamino]-azetidine-1-carboxylic acid butyl ester

To a solution of 80 mg of (S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-pentanedioic acid 5-tert-butyl ester 23 mg 3-Amino-azetidine-1-carboxylic acid butyl ester in 1 ml of DMF, 21 mg of HOBT, 26 mg of EDC and 31 mg NEM was added and the reaction mixture was stirred for 16 h at RT. Then, the reaction mixture was diluted with water and filtered through a chem Elut® cartridge by eluting with ethyl acetate. The solvents were removed under reduced pressure and the residue was dissolved in 1 ml of DCM and 0.6 ml of TFA. After 16 h at RT 10 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. The product was obtained as its trifluoroacetate salt. Yield: 45 mg MS (ES+): m/e=681.

(S)-5-(4-Benzoyl-piperidin-1-yl)-4-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-5-oxo-pentanoic acid

The title compound was prepared by adapting the procedures described in example 424 with the difference that Phenyl-piperidin-4-yl-methanone was used instead of 3-Amino-azetidine-1-carboxylic acid butyl ester. MS (ES + ): m/e=698.

(S)-5-[4-(3-Chloro-benzoyl)-piperidin-1-yl]-4-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-5-oxo-pentanoic acid

The title compound was prepared by adapting the procedures described in example 424 with the difference that (3-Chloro-phenyl)-piperidin-4-yl-methanone was used instead of 3-Amino-azetidine-1-carboxylic acid butyl ester. MS (ES + ): m/e=733, chloro pattern.

(S)-5-(4-Benzoyl-piperazin-1-yl)-4-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-5-oxo-pentanoic acid

The title compound was prepared by adapting the procedures described in example 424 with the difference that Phenyl-piperazin-1-yl-methanone was used instead of 3-Amino-azetidine-1-carboxylic acid butyl ester. MS (ES + ): m/e=699.

4-[(S)-4-Carboxy-2-({4-[2-((2S,4R)-4-fluoro-2-methoxycarbonyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (2S,4R)-4-Fluoro-pyrrolidine-2-carboxylic acid methyl ester was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=646.

4-[(S)-4-Carboxy-2-({4-[2-(hexahydro-pyrrolo[3,4-b]pyrrol-5-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that Hexahydro-pyrrolo[3,4-b]pyrrole-1-carboxylic acid tert-butyl ester was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=611.

4-{(S)-2-[(4-{2-[2-(5-Bromo-pyridin-3-yl)-pyrrolidin-1-yl]-2-oxo-ethoxy}-quinoline-2-carbonyl)-amino]-4-carboxy-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 3-Bromo-5-pyrrolidin-2-yl-pyridine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=726.

(S)-5-(3-Butoxycarbonylamino-azetidin-1-yl)-4-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-5-oxo-pentanoic acid

(i) 3-tert-Butoxycarbonylamino-azetidine-1-carboxylic acid butyl ester

To a solution of 686 mg of Azetidin-3-yl-carbamic acid tert-butyl ester in 10 ml of DCM, 403 mg of triethylamine was added and the mixture was cooled to 0° C. Then, 598 mg of butyl chloroformate was slowly added. After the addition was completed the reaction mixture was allowed to warm to RT and to stir for 2 h. Then, 200 ml of DCM was added and the organic phase was washed two times with 0.1M aqueous hydrochloric acid and the with saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 910 mg.

(ii) 3-Amino-azetidine-1-carboxylic acid butyl ester

To a solution of 910 mg of 3-tert-Butoxycarbonylamino-azetidine-1-carboxylic acid butyl ester from the preceding reaction step (i) in 18 ml of DCM, 2.4 ml of TFA was slowly added at RT. After 4 h, 200 ml of toluene was added and the solvents were removed under reduced pressure. The isolated crude product was obtained as its trifluoroacetate salt and was pure enough for the next reaction step. Yield: 1.1 g.

(iii) (S)-5-(3-Butoxycarbonylamino-azetidin-1-yl)-4-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-5-oxo-pentanoic acid

The title compound was prepared by adapting the procedures described in example 424 with the difference that Azetidin-3-yl-carbamic acid butyl ester was used instead of 3-Amino-azetidine-1-carboxylic acid butyl ester. MS (ES + ): m/e=681.

4-{(S)-4-Carboxy-2-[(4-{2-[2-(3,4-dimethyl-phenyl)-pyrrolidin-1-yl]-2-oxo-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2-(3,4-Dimethyl-phenyl)-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=674.

4-{(S)-4-Carboxy-2-[(4-{2-[2-(3,5-dimethyl-phenyl)-pyrrolidin-1-yl]-2-oxo-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2-(3,5-Dimethyl-phenyl)-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=674.

4-{(S)-4-Carboxy-2-[(4-{2-[2-(2,4-dimethyl-phenyl)-pyrrolidin-1-yl]-2-oxo-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2-(2,4-Dimethyl-phenyl)-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=674.

4-[2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-acetyl]-piperazine-1-carboxylic acid butyl ester

(i) 4-(2-Benzyloxycarbonylamino-acetyl)-piperazine-1-carboxylic acid butyl ester

To a solution of 5.62 g Z-Gly-OH (Benzyloxycarbonylamino-acetic acid) in 100 ml DMF were added 13.7 ml N-ethylmorpholine, 8.8 g TOTU and 5.0 g Piperazine-1-carboxylic acid butyl ester. After stirring for 12 h, aqueous NaHCO 3 was added and the reaction mixture was diluted with ethyl acetate and washed with aqueous LiCl (4%) and 0.1 M HCl. The crude product obtained after evaporation of the solvent was purified by flash chromatography on silica using an ethyl acetate/heptane gradient. Yield: 6.34 g

(ii) 4-(2-Amino-acetyl)-piperazine-1-carboxylic acid butyl ester

To a solution of 6.34 g 4-(2-Benzyloxycarbonylamino-acetyl)-piperazine-1-carboxylic acid butyl ester in 120 ml ethanol were added 200 mg Pd/C (10%) and the suspension stirred under an atmosphere of hydrogen (3 bar) for 12 h. The reaction mixture was filtrated over a plug of Celite®, washed with ethanol and concentrated. Yield: 4.47 g colorless solid.

(iii) 4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carboxylic acid ethyl ester

To a solution of 2 g of 4-Carboxymethoxy-7-methyl-quinoline-2-carboxylic acid ethyl ester in 30 ml of DCM, 3.6 g of EDC, 3.4 g of pentafluorophenol, 2.2 g of NEM was added and the reaction mixture was stirred at RT for 2 h. Then, 5.3 g of (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide trifluoroacetate and 2.1 g of NEM in 10 ml of DCM was added. After 16 h the reaction mixture was diluted with water and extracted with DCM (3×150 ml). The combined organic phases were dried over MgSO 4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 2.5 g.

(iv) 4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carboxylic acid

To a solution of 2.5 g 4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carboxylic acid ethyl ester in 20 ml of THF, 5.7 ml of a 1M aqueous sodium hydroxide solution was added and stirred for 16 h at RT. The reaction mixture was acidified with 1M hydrochloric acid to pH 3 and the solvents were evaporated under reduced pressure. The residue was dissolved in a mixture of methanol/DCM and the solids were filtered off. The filtrate was evaporated under reduced pressure to yield the product which was pure enough for the next reaction step. Yield: 2.0 g.

(v) 4-[2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)acetyl]-piperazine-1-carboxylic acid butyl ester

To a solution of 1.0 g 4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carboxylic acid and 709 mg 4-(2-Amino-acetyl)-piperazine-1-carboxylic acid butyl ester in 10 ml DMF were added 1.2 ml NEM, 559 mg EDC and 446 mg HOBt and the mixture stirred for 16 h. The reaction mixture was concentrated then diluted with water and filtered through a chem Elut® cartridge by eluting DCM. The crude product obtained after evaporation of the solvent was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product as its trifluoroacetate salt. The latter one was dissolved in DCM, extracted once with each saturated aqueous NaHCO 3 and brine, followed by evaporation of the solvent to give the title compound. Yield: 472 mg MS(ES+): m/e=637.

Alternatively 4-[2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-acetyl]-piperazine-1-carboxylic acid butyl ester was obtained by the following procedure.

(i) 4-{2-[(4-Hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-acetyl}-piperazine-1-carboxylic acid butyl ester

To a solution of 4.0 g of 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid and 7 g of 4-(2-Amino-acetyl)-piperazine-1-carboxylic acid butyl ester in 40 ml of DMF, 3.3 g of HOBT and 4.1 g of EDC was added and the reaction mixture was stirred for 4 h at RT. Then, the reaction mixture was diluted with water and extracted with DCM. The combined organic phases were dried over MgSO 4 and the solvents were removed under reduced pressure. The isolated crude product was used in the next reaction step. Yield: 4.5 g.

(ii) 4-{2-[(4-Benzyloxycarbonyl methoxy-7-methyl-quinoline-2-carbonyl)-amino]-acetyl}-piperazine-1-carboxylic acid butyl ester

To a solution of 4.5 g 4-{2-[(4-Hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-acetyl}-piperazine-1-carboxylic acid butyl ester in 30 ml of DMF, 3.7 g of cesium carbonate and 2.6 g of Bromo-acetic acid benzyl ester were added and the reaction mixture was stirred for 16 h at RT. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO 4 and the solvents were removed under reduced pressure. The isolated crude product was purified by re-crystallising from ethyl acetate/heptane. Yield: 5 g.

(iii) 4-{2-[(4-Carboxymethoxy-7-methyl-quinoline-2-carbonyl)-amino]-acetyl}-piperazine-1-carboxylic acid butyl ester

To a solution of 5 g 4-{2-[(4-Benzyloxycarbonylmethoxy-7-methyl-quinoline-2-carbonyl)-amino]-acetyl}-piperazine-1-carboxylic acid butyl ester in 50 ml ethanol and 150 ml DMF were added under argon 732 mg Pd/C (10%) and the suspension was stirred under an atmosphere of hydrogen (5 bar) for 4 h. The suspension was filtered over a plug of Celite® and washed with ethanol and DMF. The crude product was obtained after evaporation of the solvent. Yield: 4.1 g.

(iv) 4-[2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-acetyl]-piperazine-1-carboxylic acid butyl ester

To a solution of 100 mg of 4-{2-[(4-Carboxymethoxy-7-methyl-quinoline-2-carbonyl)-amino]-acetyl}-piperazine-1-carboxylic acid butyl ester in 3 ml of DMF, 47 mg of EDC, 45 mg of pentafluorophenol was added and the reaction mixture was stirred for 2 h. Then, 62 mg of (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide hydrochloride and 70 mg of NEM in 3 ml of DMF was added. After 1 h the reaction mixture was diluted with water. After filtration through a chem Elut® cartridge by eluting with DCM the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product as its trifluoroacetate salt. Yield: 85 mg MS(ES+): m/e=637.

4-{(S)-4-Carboxy-2-[(4-{2-[2-(2,5-dimethyl-phenyl)-pyrrolidin-1-yl]-2-oxo-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2-(2,5-Dimethyl-phenyl)-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=674.

4-[(S)-4-Carboxy-2-({4-[2-(3-hydroxy-4,7-dihydro-5H-isoxazolo[5,4-c]pyridin-6-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 4,5,6,7-Tetrahydro-isoxazolo[5,4-c]pyridin-3-ol was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=639.

4-[(S)-4-Carboxy-2-({4-[2-oxo-2-(2-trifluoromethoxymethyl-pyrrolidin-1-yl)-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 2-Trifluoromethoxymethyl-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=668.

4-[(S)-4-Carboxy-2-({4-[2-(3-methoxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 3-Methoxy-pyrrolidine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=600.

4-[(S)-4-Carboxy-2-({4-[2-((2S,4S)-4-fluoro-2-methoxycarbonyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that (2S,4S)-4-Fluoro-pyrrolidine-2-carboxylic acid methyl ester was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=646.

4-[(S)-4-Carboxy-2-({4-[2-(4,6-dihydro-1H-pyrrolo[3,4-c]pyrazol-5-yl)-2-oxo-ethoxy]-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 1,4,5,6-Tetrahydro-pyrrolo[3,4-c]pyrazole was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=608.

4-{(S)-4-Carboxy-2-[(4-{2-[(S)-2-(5-methyl-pyridin-3-yl)-pyrrolidin-1-yl]-2-oxo-ethoxy}-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 73 with the difference that 3-Methyl-5-(S)-pyrrolidin-2-yl-pyridine was used instead of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride. MS (ES + ): m/e=661.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-5-hydroxy-pentanoyl]-piperazine-1-carboxylic acid butyl ester

(i) (S)-2-tert-Butoxycarbonylamino-5-hydroxy-pentanoic acid benzyl ester

To a solution of 7.0 g Boc-Glu-OBn in 100 ml THF were added dropwise under Argon at −10° C. 2.9 ml N-ethylmorpholine and 3.0 ml isobutyl chloroformate. The reaction mixture was stirred for 10 minutes before 2.4 g sodium borohydride were added. Methanol (400 ml) was added slowly over a period of 70 minutes at this temperature. It was stirred for additional 30 minutes at RT before being neutralized with 1 N HCl. The mixture was concentrated, dissolved in ethyl acetate and washed with 1 N HCl and brine. The crude product obtained after evaporation of the solvent was purified by flash chromatography on silica using an ethyl acetate/heptane gradient. Yield: 5.3 g.

(ii) (S)-2-tert-Butoxycarbonylamino-5-(tert-butyl-diphenyl-silanyloxy)-pentanoic acid benzyl ester

(S)-2-tert-Butoxycarbonylamino-5-hydroxy-pentanoic acid benzyl ester (2.5 g) was dissolved in 50 ml DMF and treated with 2.0 ml tert-butyldiphenylchlorosilane, 1.2 ml triethylamine and 95 mg DMAP. After stirring for 12 h equivalent portions of the reagents were added and the mixture stirred for additional 12 h. The mixture was concentrated, the residue was dissolved in ethyl acetate and washed with aqueous LiCl (4%), 0.1 M HCl and saturated aqueous NaHCO 3 . The crude product obtained after evaporation of the solvent was purified by flash chromatography on silica using an ethyl acetate/heptane gradient. Yield: 2.0 g.

(iii) (S)-2-tert-Butoxycarbonylamino-5-(tert-butyl-diphenyl-silanyloxy)-pentanoic acid

To a solution of 1.92 g (S)-2-tert-Butoxycarbonylamino-5-(tert-butyl-diphenyl-silanyloxy)-pentanoic acid benzyl ester in 40 ml ethyl acetate were added under argon 0.2 g Pd/C (10%) and the suspension was stirred under an atmosphere of hydrogen (3 bar) for 16 h. The suspension was filtered over a plug of Celite® and washed with ethyl acetate. The crude product was obtained after evaporation of the solvent. Yield: 1.61 g colorless oil.

(iv) 4-[(S)-2-tert-Butoxycarbonylamino-5-(tert-butyl-diphenyl-silanyloxy)-pentanoyl]-piperazine-1-carboxylic acid butyl ester

To a solution of 1.61 g (S)-2-tert-Butoxycarbonylamino-5-(tert-butyl-diphenyl-silanyloxy)-pentanoic acid in 8 ml DMF were added 1.02 g piperazine-1-carboxylic acid butyl ester hydrotrifluoroacetate, 1.7 ml N-ethylmorpholine and 1.1 g TOTU. After stirring for 12 h the solution was diluted with ethyl acetate and subsequently washed with aqueous LiCl (4%), 0.1 M HCl and saturated aqueous NaHCO 3 . The crude product obtained after evaporation of the solvent was used without further purification. Yield: 1.80 g.

(v) 4-[(S)-2-Amino-5-(tert-butyl-diphenyl-silanyloxy)-pentanoyl]-piperazine-1-carboxylic acid butyl ester hydrochloride

To a solution of 900 mg 4-[(S)-2-tert-Butoxycarbonylamino-5-(tert-butyl-diphenyl-silanyloxy)-pentanoyl]-piperazine-1-carboxylic acid butyl ester in 5 ml dioxane were added 5 ml HCl in dioxane (4 M). After 2.5 h conversion was complete and the reaction mixture was neutralized with basic ion exchange resin III (Merck), filtered and concentrated. Yield: 760 mg.

(vi) 4-[(S)-5-(tert-Butyl-diphenyl-silanyloxy)-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-pentanoyl]-piperazine-1-carboxylic acid butyl ester

To a solution of 385 mg 4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carboxylic acid in 10 ml DMF were added 215 mg HOBt, 270 mg EDC and 0.4 ml DIPEA. After 20 minutes 506 mg 4-[(S)-2-Amino-5-(tert-butyl-diphenyl-silanyloxy)-pentanoyl]-piperazine-1-carboxylic acid butyl ester hydrochloride were added and the mixture stirred for 12 h. The reaction mixture was concentrated, diluted with ethyl acetate and washed with aqueous LiCl (4%), 0.1 M HCl and saturated aqueous NaHCO 3 . The crude product thus obtained was pure enough for the following transformation. Yield: 850 mg.

(vii) 4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-5-hydroxy-pentanoyl]-piperazine-1-carboxylic acid butyl ester

To a solution of 700 mg 4-[(S)-5-(tert-Butyl-diphenyl-silanyloxy)-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-pentanoyl]-piperazine-1-carboxylic acid butyl ester in 70 ml THF were added 1.5 ml of TBAF (1 M in THF) and the mixture stirred at RT for 12 h. It was concentrated, the residue was dissolved in DCM and washed with water (3×). The solvent was removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product as its trifluoroacetate salt. Yield: 28 mg MS(ES+): m/e=695.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-(2-cyclopentyl-ethoxycarbonyl)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 237 with the difference that 2-Cyclopentyl-ethanol was used instead of methanol. MS (ES + ): m/e=777.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-(tetrahydro-furan-3-ylmethoxycarbonyl)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 237 with the difference that (Tetrahydro-furan-3-yl)-methanol was used instead of methanol. MS (ES + ): m/e=765.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-(3-methyl-oxetan-3-ylmethoxycarbonyl)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 237 with the difference that (3-Methyl-oxetan-3-yl)-methanol was used instead of methanol. MS (ES + ): m/e=765.

4-[(S)-4-((1R,4S)-1-Bicyclo[2.2.1]hept-2-ylmethoxycarbonyl)-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 237 with the difference that (1R,4S)-1-Bicyclo[2.2.1]hept-2-yl-methanol was used instead of methanol. MS (ES + ): m/e=789.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-(3-ethyl-oxetan-3-ylmethoxycarbonyl)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 237 with the difference that (3-Ethyl-oxetan-3-yl)-methanol was used instead of methanol. MS (ES + ): m/e=779.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-(tetrahydro-pyran-2-ylmethoxycarbonyl)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 237 with the difference that (Tetrahydro-pyran-2-yl)-methanol was used instead of methanol. MS (ES + ): m/e=779.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-(5-ethyl-[1,3]dioxan-5-ylmethoxycarbonyl)-butyryl]-piperazine-1-carboxylic acid ethyl

The title compound was prepared by adapting the procedures described in example 237 with the difference that (5-Ethyl-[1,3]dioxan-5-yl)methanol was used instead of methanol. MS (ES + ): m/e=809.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-(2-oxo-[1,3]dioxolan-4-ylmethoxycarbonyl)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 237 with the difference that 4-Hydroxymethyl-[1,3]dioxolan-2-one was used instead of methanol. MS (ES + ): m/e=781.

4-{(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-[2-(2-hydroxy-ethylamino)-ethoxycarbonyl]-butyryl}-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 237 with the difference that 2-(2-Hydroxy-ethylamino)-ethanol was used instead of methanol. MS (ES + ): m/e=768.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-(3-methoxy-butoxycarbonyl)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 237 with the difference that 3-Methoxy-butan-1-ol was used instead of methanol. MS (ES + ): m/e=767.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-(tetrahydro-furan-2-ylmethoxycarbonyl)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 237 with the difference that (Tetrahydro-furan-2-yl)-methanol was used instead of methanol. MS (ES + ): m/e=765.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-(3-dimethylamino-2,2-dimethyl-propoxycarbonyl)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 237 with the difference that 3-Dimethylamino-2,2-dimethyl-propan-1-ol was used instead of methanol. MS (ES + ): m/e=794.

4-[(S)-2-({4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-4-(2-dimethylamino-2-methyl-propoxycarbonyl)-butyryl]-piperazine-1-carboxylic acid ethyl ester

The title compound was prepared by adapting the procedures described in example 237 with the difference that 2-Dimethylamino-2-methyl-propan-1-ol was used instead of methanol. MS (ES + ): m/e=780.

4-[(