7-Benzothiazolecarboxaldehyde(9CI)

Into a 8 mL vial, was placed 6-[3-(3-aminocyclobutanecarbonyl)-3, 8- diazabicyclo[3.2. l]octan-8-yl]pyridine-3-carbonitrile (40 mg, 0.13 mmol, 1 eq), 1, 3- benzothiazole-7-carbaldehyde (21 mg, 0.13 mmol, 1 eq), Ti(Oi-Pr)4 (110 mg, 0.39 mmol, 3 eq), methanol (3 mL). The resulting solution was stirred for 1.5 h at 25C. Then NaBH4 (7.30 mg, 0.19 mmol, 1.5 eq) was placed into the vial. The resulting solution was stirred for 0.5 h at 25C. The reaction was then quenched by the addition of water. The solids were filtered out. The resulting mixture was concentrated and purified by Prep-HPLC. This resulted in 24.8 mg (42%) of 6-[3-(3- [[(l, 3-benzothiazol-7-yl)methyl]amino]cyclobutanecarbonyl)-3, 8-diazabicyclo[3.2. l]octan-8- yl]pyridine-3-carbonitrile as a white solid. LCMS : m/z = 459.4 [M+H]+.Into a 8 mL vial, was placed 6-[3-(3-aminopropanoyl)-3, 8- diazabicyclo[3.2. l]octan-8-yl]pyridine-3-carbonitrile (84 mg, 0.294 mmol, 1.2 eq), 1, 3- benzothiazole-7-carbaldehyde (40 mg, 0.25 mmol, 1 eq), Ti(Oi-Pr)4 (105 mg, 0.37 mmol, 1.5 eq), MeOH (2 mL). The resulting solution was stirred for 1.5 h at 25C. Then NaBH3CN (46 mg, 0.74 mmol, 3 eq) was placed into the vial. The resulting solution was stirred for 0.5 h at 25C. The reaction was then quenched by the addition of 1 mL of water. The solids were filtered out. The resulting mixture was concentrated. The crude product was purified by Prep-HPLC. This resulted in 40 mg (37%) of 6-[3-(3-[[(l, 3-benzothiazol-7-yl)methyl]amino]propanoyl)-3, 8- diazabicyclo[3.2. l]octan-8-yl]pyridine-3-carbonitrile as a yellow solid. LCMS: m/z = 433.3 (1048) [M+H]+; 1H NMR (Methanol-^) S 9.22 (s, 1H), 8.44 (d, J= 1.9 Hz, 1H), 7.98 (d, J= 8.0 Hz, 1H), 7.77 (dd, j= 9.0, 2.3 Hz, 1H), 7.55 (t, 1H), 7.48 (d, j= 7.2 Hz, 1H), 6.86 (d, j= 9.0 Hz, 1H), 4.73 (s, 2H), 4.25 (d, 7= 13.9 Hz, 1H), 4.11 (s, 2H), 3.71 (d, j= 12.6 Hz, 1H), 3.36 (s, 1H), 2.94 - 2.84 (m, 3H), 2.73 - 2.52 (m, 2H), 2.06 - 1.98 (m, 2H), 1.88 - 1.72 (m, 2H).A mixture of benzo[d|thiazole-7-carbaldehyde (4.2 g, 25.6 mmol), p-TsOH (100 mg) and ethane- 1 , 2-diol (3.0 mL) in toluene (50 mL) was refluxed overnight, cooled to rt and diluted with EtOAc (100 mL). The solution was washed with sat. NaHC03 and brine. Then the solution was dried, concentrated and purified by chromatography to give compound 7-(1 , 3-dioxolan-2- yl)benzo[a(lthiazole lnt-6-8(2S)-N-(3-(5-(3-(benzo [d]thiazol-7-yl)-1, 2, 4-oxadiazol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-2-aminopropanamide (Example 191) Example 191 Part A: Preparation of Part B: Preparation of benzo[d]thiazole-7-carbonitrile A mixture of

Molecular Weight:163.20
XLogP3:1.8
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:163.00918496
Monoisotopic Mass:163.00918496
Topological Polar Surface Area:58.2
Heavy Atom Count:11
Complexity:162
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes