P4250

Example 174

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To a solution of 2-Fluoro-4-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-benzylamine hydrochloride (2) (30.00 mg; 0.08 mmol; 1.00 eq.) in methanol (2 mL) was added 3,4-Difluoro-benzaldehyde (8.39 μl; 0.08 mmol; 1.00 eq.) and TEA (31.74 μl; 0.23 mmol; 3.00 eq.), The reaction mixture was heated to 60° C. and stirred overnight.

LCMS at 20 hr indicated the reaction was complete. The reaction mixture was poured into saturated NaHCO3 (10 mL) and was extracted with ethyl acetate (2×10 mL). The combined organic phases were concentrated. The crude product was purified by prep HPLC (Interchim P4250; 30×150 mm C-18 column; 0.1% formic acid modified mobile phases (A=water, B=ACN); gradient 60% B over 15 min at 60 mL/min). The product fractions were combined and lyophilized to provide 3 mg (9%) of N-(3,4-difluorobenzyl)-1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl)phenyl)methanamine as a white solid. HPLC: 92% purity. MS: 449 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d4): δ 8.36 (bs, 2H), 8.21 (s, 1H), 7.89 (bs, 2H), 7.64 (t, 1H), 7.43 (bs, 1H), 7.35 (t, 1H), 7.30-7.16 (m, 2H), 4.03 (s, 3H), 3.93 (s, 2H), 3.83 (s, 2H).

Example 177

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To a solution of 2-Fluoro-4-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-benzylamine hydrochloride (2) (30.00 mg; 0.08 mmol; 1.00 eq.) in DMF (2 mL) was added DIPEA (39.66 μl; 0.23 mmol; 3.00 eq.) and (1-Cyanomethyl-cyclopropyl)-methanesulfonyl chloride (22.05 mg; 0.11 mmol; 1.50 eq.), The reaction mixture was stirred at room temperature.

LCMS at 2 hr indicated the reaction was complete. The reaction was partially concentrated and purified directly via prep HPLC (Interchim P4250; 30×150 mm C-18 column; 0.1% formic acid modified mobile phases (A=water, B=ACN); gradient 10-50% B over 10 min at 60 mL/min). The product fractions were combined and lyophilized to provide 23 mg (63%) of 1-(1-(cyanomethyl)cyclopropyl)-N-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl)benzyl)methanesulfonamide as a white solid. HPLC: 100% purity. MS: 480 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 13.41 (s, 1H), 8.47 (s, 1H), 8.31 (d, 2H), 8.21 (d, 1H), 8.16 (s, 1H), 7.89 (bs, 1H), 7.64 (t, 1H), 7.57 (bs, 1H), 4.32 (s, 2H), 3.97 (s, 3H), 3.22 (s, 2H), 2.85 (s, 2H), 0.82 (s, 2H), 0.71 (s, 2H).

Example 150

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Into a 20-mL reaction vial was added 3-tert-butyl-[1,2,4]oxadiazole-5-carboxylic acid 4-(2,3-diamino-pyridin-4-yl)-2-fluoro-benzylamide (150.00 mg; 0.39 mmol; 1.00 eq.), pyridine-4-carbaldehyde (52.24 mg; 0.49 mmol; 1.25 eq.), and DMF (3.00 ml; 38.77 mmol; 99.34 eq.). The resulting solution was placed under nitrogen atmosphere and stirred overnight at 130 degrees Celsius. After 20 hr the reaction was then quenched by the addition of water (20 mL). The resulting solution was extracted with dichloromethane (3×25 mL) and the organic layers were combined. The DCM was concentrated and the residue was dissolved in DMSO (2.0 mL) and purified directly via prep HPLC (Interchim P4250; 30×150 mm C-18 column: 0.1% formic acid modified mobile phases (A=water, B=ACN); gradient 20-55% B over 15 min at 60 mL/min). The product eluted at 45% ACN. The product fractions were combined and lyophilized to yield 5 mg (3%) of 3-(tert-butyl)-N-(2-fluoro-4-(2-(pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-7-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide as a white solid. HPLC: 100% purity. MS: 472 [M+H]⁺ ion. ¹H NMR (400 MHz, DMSO-d6) δ 9.95 (t, 1H), 8.80 (d, 2H), 8.47 (d, 1H), 8.29 (d, 1H), 8.22 (d, 3H), 7.63 (m, 2H), 4.63 (s, 2H), 1.39 (s, 9H).

Example 150

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Into a 20-mL reaction vial was added 3-tert-butyl-[1,2,4]oxadiazole-5-carboxylic acid 4-(2,3-diamino-pyridin-4-yl)-2-fluoro-benzylamide (150.00 mg; 0.39 mmol; 1.00 eq.), pyridine-4-carbaldehyde (52.24 mg; 0.49 mmol; 1.25 eq.), and DMF (3.00 ml; 38.77 mmol; 99.34 eq.). The resulting solution was placed under nitrogen atmosphere and stirred overnight at 130 degrees Celsius. After 20 hr the reaction was then quenched by the addition of water (20 mL). The resulting solution was extracted with dichloromethane (3×25 mL) and the organic layers were combined. The DCM was concentrated and the residue was dissolved in DMSO (2.0 mL) and purified directly via prep HPLC (Interchim P4250; 30×150 mm C-18 column; 0.1% formic acid modified mobile phases (A=water, B=ACN); gradient 20-55% B over 15 min at 60 mL/min). The product eluted at 45% ACN. The product fractions were combined and lyophilized to yield 5 mg (3%) of 3-(tert-butyl)-N-(2-fluoro-4-(2-(pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-7-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide as a white solid. HPLC: 100% purity. MS: 472 [M+H]⁺ ion. ¹H NMR (400 MHz, DMSO-d6) δ 9.95 (t, 1H), 8.80 (d, 2H), 8.47 (d, 1H), 8.29 (d, 1H), 8.22 (d, 3H), 7.63 (m, 2H), 4.63 (s, 2H), 1.39 (s, 9H).

Example 184

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To a 20-mL reaction vial was added 3-tert-Butyl-[1,2,4]oxadiazole-5-carboxylic acid 4-(2,3-diamino-pyridin-4-yl)-2-fluoro-benzylamide (75.00 mg; 0.20 mmol; 1.00 eq.), 2-methyl-propionaldehyde (14.07 mg; 0.20 mmol; 1.00 eq.), and DMF (2.00 ml; 25.84 mmol; 132.46 eq.). The resulting solution was placed under nitrogen atmosphere and stirred overnight at 130 degrees Celsius. LCMS at 22 hr showed minor amounts of starting material. The reaction was cooled to room temperature and then quenched by the addition of water (10 mL). The mixture was extracted with ethyl acetate (3×20 mL) and the combined organic layer was dried over Na₂SO₄, filtered, and concentrated. The crude material was dissolved in DMSO (2 mL) and purified via prep HPLC (Interchim P4250; 30×150 mm C-18 column; 0.1% formic acid modified mobile phases (A=water, B=ACN); gradient 10-60% B over 15 min at 60 mL/min). The product fractions were combined and lyophilized to yield 17 mg (20%) of 3-tert-butyl-[1,2,4]oxadiazole-5-carboxylic acid 2-fluoro-4-(2-isopropyl-3H-imidazo[4,5-b]pyridine-7-yl)-benzyl as an off white solid. HPLC: 90% purity. MS: 437 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 12.96 (s, 1H), 8.30 (d, 1H), 8.26 (dd, 1H), 8.15 (dd, 1H), 7.57 (t, 2H), 7.53 (d, 1H), 4.59 (d, 2H), 1.39 (d, 6H), 1.38 (s, 9H), 1.27 (s, 1H).

Example 177

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To a solution of 2-Fluoro-4-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]-benzylamine hydrochloride (2) (30.00 mg; 0.08 mmol; 1.00 eq.) in DMF (2 mL) was added DIPEA (39.66 μl; 0.23 mmol; 3.00 eq.) and (1-Cyanomethyl-cyclopropyl)-methanesulfonyl chloride (22.05 mg; 0.11 mmol; 1.50 eq.). The reaction mixture was stirred at room temperature.

LCMS at 2 hr indicated the reaction was complete. The reaction was partially concentrated and purified directly via prep HPLC (Interchim P4250; 30×150 mm C-18 column; 0.1% formic acid modified mobile phases (A=water, B=ACN); gradient 10-50% B over 10 min at 60 mL/min). The product fractions were combined and lyophilized to provide 23 mg (63%) of 1-(1-(cyanomethyl)cyclopropyl)-N-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl)benzyl)methanesulfonamide as a white solid. HPLC: 100% purity. MS: 480 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 13.41 (s, 1H), 8.47 (s, 1H), 8.31 (d, 2H), 8.21 (d, 1H), 8.16 (s, 1H), 7.89 (bs, 1H), 7.64 (t, 1H), 7.57 (bs, 1H), 4.32 (s, 2H), 3.97 (s, 3H), 3.22 (s, 2H), 2.85 (s, 2H), 0.82 (s, 2H), 0.71 (s, 2H).

Example 152

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Into a 20-mL reaction vial was added 3-tert-butyl-[1,2,4]oxadiazole-5-carboxylic acid 4-(2,3-diamino-pyridin-4-yl)-2-fluoro-benzylamide (150.00 mg; 0.39 mmol; 1.00 eq.), 3-methoxy-pyridine-2-carbaldehyde (66.89 mg; 0.49 mmol; 1.25 eq.), and DMF (3.00 ml; 38.77 mmol; 99.34 eq.). The resulting solution was placed under nitrogen atmosphere and stirred overnight at 130 degrees Celsius. After 20 hr the reaction was then quenched by the addition of water (20 mL). The resulting solution was extracted with dichloromethane (3×25 mL) and the organic layers were combined. The DCM was concentrated and the residue was dissolved in DMSO (2.0 mL) and purified directly via prep HPLC (Interchim P4250; 30×150 mm C-18 column; 0.1% formic acid modified mobile phases (A=water, B=ACN); gradient 20-55% B over 15 min at 60 mL/min). The product eluted with 47% ACN. The product fractions were combined and lyophilized to yield 36 mg (18%) of 3-(tert-butyl)-N-(2-fluoro-4-(2-(3-methoxypyridin-2-yl)-3H-imidazo[4,5-b]pyridin-7-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide as a white solid. HPLC: 94% purity. MS: 502 [M+H]⁺ ion. ¹H NMR (400 MHz, DMSO-d6) δ 13.40 (s, 1H), 9.93 (t, 1H), 8.46 (m, 2H), 8.38 (bs, 1H), 8.22 (d, 1H), 7.75 (d, 1H), 7.66 (bs, 1H), 7.56 (m, 2H), 4.61 (d, 2H), 3.98 (s, 3H), 1.38 (s, 9H).

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