1,1-dioxo-1,3-thiazolidine-4-carboxamide;hydrochloride

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In analogy to the procedure described in Example 127 e), 6-(cyclopropylmethoxy)-5-(1-fluorocyclobutyl)pyridine-2-carboxylic acid (Example 130 f) was reacted with 1,1-dioxo-1,3-thiazolidine-4-carboxamide hydrochloride (Example 127 d) to give the title compound as yellow oil, MS (EI): m/e=412.13 [MH+].

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In analogy to the procedure described in Example 127 e), 6-(cyclopropylmethoxy)-5-(1-hydroxycyclobutyl)pyridine-2-carboxylic acid (CAN 1415899-53-4, 50 mg, 190 μmol) was reacted with 1,1-dioxo-1,3-thiazolidine-4-carboxamide hydrochloride (Example 127 d, 45.7 mg, 228 μmol) to give the title compound (7 mg, 8%) as colorless oil, MS (EI): m/e=410.5 [MH+].

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In analogy to the procedure described in Example 127 e), 6-(cyclopropylmethoxy)-5-(1-hydroxycyclobutyl)pyridine-2-carboxylic acid (CAN 1415899-53-4, 50 mg, 190 μmol) was reacted with 1,1-dioxo-1,3-thiazolidine-4-carboxamide hydrochloride (Example 127 d, 45.7 mg, 228 μmol) to give the title compound (7 mg, 8%) as colorless oil, MS (EI): m/e=410.5 [MH+].

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In analogy to the procedure described in Example 127 e), 6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxylic acid (Example 128 a, 30 mg, 108 μmol) was reacted with 1,1-dioxo-1,3-thiazolidine-4-carboxamide hydrochloride (Example 127 d, 26.0 mg, 129 μmol) to give the title compound (15 mg, 33%) as off-white solid, MS (EI): m/e=425.5 [MH+].

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b, 200 mg, 704 μmol), 1,1-dioxo-1,3-thiazolidine-4-carboxamide hydrochloride (Example 127 d, 169 mg, 844 μmol), 2-bromo-1-ethylpyridinium tetrafluoroborate (212 mg, 774 μmol) and DIEA (273 mg, 361 μL, 2.11 mmol) in THF (20 mL) was stirred for 24 h at ambient temperature. The solvent was removed under reduced pressure, ice/sat. aqueous NaHCO3 (75 mL) and EtOAc (75 mL) were added and the layers were separated. The aqueous layer was extracted with EtOAc (75 mL). The combined extracts were washed with ice/0.1N HCl (75 mL) and ice/brine (75 mL), dried over Na2SO4 and filtered. The solvent was removed under reduced pressure to give a yellow solid which was recrystallized from EtOAc (3 mL). The crude product was purified by chiral HPLC (Reprosil Chiral NR, EtOH/heptane 40%/60%) to give the title compound (63 mg, 21%) as colorless oil, MS (EI): m/e=431.3 [MH+]. was stirred for 24 h at ambient temperature The solvent was removed under reduced pressure, ice/ aqueous NaHCO3 (75 mL) and EtOAc (75 mL) were added the layers were separated The aqueous layer was extracted with EtOAc (75 mL) The combined extracts were washed with ice/0.1N HCl (75 mL) and ice/brine (75 mL) dried over Na2SO4 filtered The solvent was removed under reduced pressure to give a yellow solid which was recrystallized from EtOAc (3 mL) The crude product was purified by chiral HPLC (Reprosil Chiral NR, EtOH/heptane 40%/60%)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b, 200 mg, 704 μmol), 1,1-dioxo-1,3-thiazolidine-4-carboxamide hydrochloride (Example 127 d, 169 mg, 844 μmol), 2-bromo-1-ethylpyridinium tetrafluoroborate (212 mg, 774 μmol) and DIEA (273 mg, 361 μL, 2.11 mmol) in THF (20 mL) was stirred for 24 h at ambient temperature. The solvent was removed under reduced pressure, ice/sat. aqueous NaHCO3 (75 mL) and EtOAc (75 mL) were added and the layers were separated. The aqueous layer was extracted with EtOAc (75 mL). The combined extracts were washed with ice/0.1N HCl (75 mL) and ice/brine (75 mL), dried over Na2SO4 and filtered. The solvent was removed under reduced pressure to give a yellow solid which was recrystallized from EtOAc (3 mL). The crude product was purified by chiral HPLC (Reprosil Chiral NR, EtOH/heptane 40%/60%) to give the title compound (63 mg, 21%) as colorless oil, MS (EI): m/e=431.3 [MH+]. was stirred for 24 h at ambient temperature The solvent was removed under reduced pressure, ice/ aqueous NaHCO3 (75 mL) and EtOAc (75 mL) were added the layers were separated The aqueous layer was extracted with EtOAc (75 mL) The combined extracts were washed with ice/0.1N HCl (75 mL) and ice/brine (75 mL) dried over Na2SO4 filtered The solvent was removed under reduced pressure to give a yellow solid which was recrystallized from EtOAc (3 mL) The crude product was purified by chiral HPLC (Reprosil Chiral NR, EtOH/heptane 40%/60%)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: An ice cold 4 M solution of HCl in dioxane (4.73 mL, 18.9 mmol) was added to a solution of tert-butyl 4-carbamoyl-1,1-dioxo-1,3-thiazolidine-3-carboxylate (Example 127 c, 500 mg, 1.89 mmol) in dichloromethane (10.2 mL). The mixture was stirred for 4 d at ambient temperature. Removal of the solvent in vacuo yielded the title compound (388 mg, quant.) as white solid which was used in the next step without further purification, MS (ESI) m/e=198.99 [M−H−]. Removal of the solvent in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In analogy to the procedure described in Example 127 e), 6-(cyclopropylmethoxy)-5-(1-fluorocyclobutyl)pyridine-2-carboxylic acid (Example 130 f) was reacted with 1,1-dioxo-1,3-thiazolidine-4-carboxamide hydrochloride (Example 127 d) to give the title compound as yellow oil, MS (EI): m/e=412.13 [MH+].

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In analogy to the procedure described in Example 127 e), 6-(cyclopropylmethoxy)-5-(1-hydroxycyclobutyl)pyridine-2-carboxylic acid (CAN 1415899-53-4, 50 mg, 190 μmol) was reacted with 1,1-dioxo-1,3-thiazolidine-4-carboxamide hydrochloride (Example 127 d, 45.7 mg, 228 μmol) to give the title compound (7 mg, 8%) as colorless oil, MS (EI): m/e=410.5 [MH+].

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In analogy to the procedure described in Example 127 e), 6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxylic acid (Example 128 a, 30 mg, 108 μmol) was reacted with 1,1-dioxo-1,3-thiazolidine-4-carboxamide hydrochloride (Example 127 d, 26.0 mg, 129 μmol) to give the title compound (15 mg, 33%) as off-white solid, MS (EI): m/e=425.5 [MH+].

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b, 200 mg, 704 μmol), 1,1-dioxo-1,3-thiazolidine-4-carboxamide hydrochloride (Example 127 d, 169 mg, 844 μmol), 2-bromo-1-ethylpyridinium tetrafluoroborate (212 mg, 774 μmol) and DIEA (273 mg, 361 μL, 2.11 mmol) in THF (20 mL) was stirred for 24 h at ambient temperature. The solvent was removed under reduced pressure, ice/sat. aqueous NaHCO3 (75 mL) and EtOAc (75 mL) were added and the layers were separated. The aqueous layer was extracted with EtOAc (75 mL). The combined extracts were washed with ice/0.1N HCl (75 mL) and ice/brine (75 mL), dried over Na2SO4 and filtered. The solvent was removed under reduced pressure to give a yellow solid which was recrystallized from EtOAc (3 mL). The crude product was purified by chiral HPLC (Reprosil Chiral NR, EtOH/heptane 40%/60%) to give the title compound (63 mg, 21%) as colorless oil, MS (EI): m/e=431.3 [MH+]. was stirred for 24 h at ambient temperature The solvent was removed under reduced pressure, ice/ aqueous NaHCO3 (75 mL) and EtOAc (75 mL) were added the layers were separated The aqueous layer was extracted with EtOAc (75 mL) The combined extracts were washed with ice/0.1N HCl (75 mL) and ice/brine (75 mL) dried over Na2SO4 filtered The solvent was removed under reduced pressure to give a yellow solid which was recrystallized from EtOAc (3 mL) The crude product was purified by chiral HPLC (Reprosil Chiral NR, EtOH/heptane 40%/60%)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: An ice cold 4 M solution of HCl in dioxane (4.73 mL, 18.9 mmol) was added to a solution of tert-butyl 4-carbamoyl-1,1-dioxo-1,3-thiazolidine-3-carboxylate (Example 127 c, 500 mg, 1.89 mmol) in dichloromethane (10.2 mL). The mixture was stirred for 4 d at ambient temperature. Removal of the solvent in vacuo yielded the title compound (388 mg, quant.) as white solid which was used in the next step without further purification, MS (ESI) m/e=198.99 [M−H−]. Removal of the solvent in vacuo