Pyrrolo [1,2,f] [1,2,4] triazines useful for treating respiratory syncitial virus infections

Abstract

Provided herein are formulations, methods and substituted tetrahydrofuranyl- pyrrolo[1,2-f][1,2,4]triazine-4-amine compounds of Formula (I) for treating Pneumovirinae virus infections, including respiratory syncytial virus infections, as well as methods and intermediates for synthesis of tetrahydrofuranyl-pyrrolo[1,2-fj[i,2,4]triazine-4-amine compounds.

Description

technical field

[0001] Provided herein are substituted tetrahydrofuranyl-pyrrolo[1,2-f][1,2,4]triazine- 4-Amine compounds, processes and pharmaceutical formulations, and processes and intermediates useful in the preparation of said compounds. Background technique

[0002] Pneumovirinae viruses are negative-sense, single-stranded RNA viruses that are responsible for many prevalent human and animal diseases. The pneumovirinae subfamily of viruses is part of the Paramyxoviridae family and includes the human respiratory syncytial virus (HRSV). Almost all children experience HRSV infection by their second birthday. HRSV is a leading cause of lower respiratory tract infections in infants and children, with 0.5% to 2% of those infected requiring hospitalization. Older adults and adults with chronic heart disease, lung disease, or those who are immunosuppressed are also at high risk for developing severe HRSV disease (http: / / www.cdc.gov / rsv / index.html). There is currently no vac...

Examples

Embodiment

[0343] Example 1-(2R,3S,4R,5S)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-3,4-dihydroxy -2-(Hydroxymethyl)tetrahydrofuran-2-carbonitrile.

[0344] To a solution of crude intermediate lo in methanol (1 mL) was added methylamine (40% in water, 0.3 mL) at room temperature. After 2.5 hours, the reaction mixture was concentrated under reduced pressure and analyzed by preparative HPLC (Phenominex Luna 5u C18 100 x 30 mm column, 5-15% acetonitrile / water gradient, 25 min) for direct purification. Fractions containing the desired product and the 4' anomer were combined and concentrated under reduced pressure. Then by preparative HPLC (Phenominex Luna 5u C18 100 x 30 mm column, 5-15% acetonitrile / water gradient, 25 min) to separate the 4' anomer. Fractions containing the desired product were combined and lyophilized to give Example 1.

[0345] 1 H NMR (400MHz, CD 3 OD)δ7.79(s,1H),6.85(d,J=4.5Hz,1H),6.76(d,J=4.5Hz,1H),5.45(d,J=5.9Hz,1H),4.59(t , J=5.7Hz, 1H), 4.40 (d, J=...

Embodiment 3

[0476] Example 3-(2R,3R,4R,5S)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-4-fluoro-3- Hydroxy-2-(hydroxymethyl)tetrahydrofuran-2-carbonitrile.

[0477] at 0°C and N 2 To a solution of intermediate 3d (100 mg, 0.191 mmol) / THF (2 mL) in a polypropylene tube was added 70% HF·pyridine / pyridine (60 μL, 0.478 mmol) under atmosphere. The reaction was checked after 20 minutes; no reaction so additional 70% HF·pyridine / pyridine (150 μL) was added and the cooling bath removed. After 1 h 50 min additional 70% HF·pyridine / pyridine (150 μL) was added. Additional 70% HF-pyridine / pyridine (300 [mu]L) was added after a further 2 hours. Additional 70% HF-pyridine / pyridine (1 mL) was added after a further 2 hours and 15 minutes. The reaction became clear and homogeneous on this last addition of 70% HF·pyridine / pyridine. The reaction was stirred overnight. The next day the reaction was complete. Cool the reaction in an ice bath and wash with H 2 O and a small amount of saturated NaHCO ...

Embodiment 4

[0555] Example 4-(2R,3S,4R,5S)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-2-(hydroxymethyl )-2-Methyltetrahydrofuran-3,4-diol

[0556] Intermediate 4r (23 mg, 0.042 mmol) was dissolved in formic acid / MeOH solution (1:9, 10 mL). Palladium black was added and stirred at 60°C for 90 minutes. Cool to room temperature and filter through celite. The filtrate was concentrated under reduced pressure. Purified by preparative HPLC. Concentrate under reduced pressure. dissolved in NaHCO 3(水溶液) and purified by HPLC under neutral conditions to obtain Example 4.

[0557] Prep HPLC system: Gilson 215 Liquid Handler; Phenomenex Gemini, C 18 4u, 100x30.0mm

[0558] Buffer A: 0.1% TFA / water; Buffer B: 0.1% TFA / acetonitrile; 5-100% Buffer B for 13 minutes, 20 mL / min.

[0559] 1 H NMR (400MHz, CDCl 3 ):δ8.01(s,1H),7.41(d,J=4.8Hz,1H),7.02(d,J=4.8Hz,1H),5.33(d,J=8Hz,1H),4.53-4.49( m, 1H), 4.15 (d, J=5.6Hz, 1H), 3.50 (m, 2H), 1.27 (s, 3H).

[0560] LC / MS: t R =0.30min, MS m / z=281.3[M...

technical field

[0001] Provided herein are substituted tetrahydrofuranyl-pyrrolo[1,2-f][1,2,4]triazine- 4-Amine compounds, processes and pharmaceutical formulations, and processes and intermediates useful in the preparation of said compounds. Background technique

[0002] Pneumovirinae viruses are negative-sense, single-stranded RNA viruses that are responsible for many prevalent human and animal diseases. The pneumovirinae subfamily of viruses is part of the Paramyxoviridae family and includes the human respiratory syncytial virus (HRSV). Almost all children experience HRSV infection by their second birthday. HRSV is a leading cause of lower respiratory tract infections in infants and children, with 0.5% to 2% of those infected requiring hospitalization. Older adults and adults with chronic heart disease, lung disease, or those who are immunosuppressed are also at high risk for developing severe HRSV disease (http: / / www.cdc.gov / rsv / index.html). There is currently no vac...

Examples

Embodiment

[0343] Example 1-(2R,3S,4R,5S)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-3,4-dihydroxy -2-(Hydroxymethyl)tetrahydrofuran-2-carbonitrile.

[0344] To a solution of crude intermediate lo in methanol (1 mL) was added methylamine (40% in water, 0.3 mL) at room temperature. After 2.5 hours, the reaction mixture was concentrated under reduced pressure and analyzed by preparative HPLC (Phenominex Luna 5u C18 100 x 30 mm column, 5-15% acetonitrile / water gradient, 25 min) for direct purification. Fractions containing the desired product and the 4' anomer were combined and concentrated under reduced pressure. Then by preparative HPLC (Phenominex Luna 5u C18 100 x 30 mm column, 5-15% acetonitrile / water gradient, 25 min) to separate the 4' anomer. Fractions containing the desired product were combined and lyophilized to give Example 1.

[0345] 1 H NMR (400MHz, CD 3 OD)δ7.79(s,1H),6.85(d,J=4.5Hz,1H),6.76(d,J=4.5Hz,1H),5.45(d,J=5.9Hz,1H),4.59(t , J=5.7Hz, 1H), 4.40 (d, J=...

Embodiment 3

[0476] Example 3-(2R,3R,4R,5S)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-4-fluoro-3- Hydroxy-2-(hydroxymethyl)tetrahydrofuran-2-carbonitrile.

[0477] at 0°C and N 2 To a solution of intermediate 3d (100 mg, 0.191 mmol) / THF (2 mL) in a polypropylene tube was added 70% HF·pyridine / pyridine (60 μL, 0.478 mmol) under atmosphere. The reaction was checked after 20 minutes; no reaction so additional 70% HF·pyridine / pyridine (150 μL) was added and the cooling bath removed. After 1 h 50 min additional 70% HF·pyridine / pyridine (150 μL) was added. Additional 70% HF-pyridine / pyridine (300 [mu]L) was added after a further 2 hours. Additional 70% HF-pyridine / pyridine (1 mL) was added after a further 2 hours and 15 minutes. The reaction became clear and homogeneous on this last addition of 70% HF·pyridine / pyridine. The reaction was stirred overnight. The next day the reaction was complete. Cool the reaction in an ice bath and wash with H 2 O and a small amount of saturated NaHCO ...

Embodiment 4

[0555] Example 4-(2R,3S,4R,5S)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-2-(hydroxymethyl )-2-Methyltetrahydrofuran-3,4-diol

[0556] Intermediate 4r (23 mg, 0.042 mmol) was dissolved in formic acid / MeOH solution (1:9, 10 mL). Palladium black was added and stirred at 60°C for 90 minutes. Cool to room temperature and filter through celite. The filtrate was concentrated under reduced pressure. Purified by preparative HPLC. Concentrate under reduced pressure. dissolved in NaHCO 3(水溶液) and purified by HPLC under neutral conditions to obtain Example 4.

[0557] Prep HPLC system: Gilson 215 Liquid Handler; Phenomenex Gemini, C 18 4u, 100x30.0mm

[0558] Buffer A: 0.1% TFA / water; Buffer B: 0.1% TFA / acetonitrile; 5-100% Buffer B for 13 minutes, 20 mL / min.

[0559] 1 H NMR (400MHz, CDCl 3 ):δ8.01(s,1H),7.41(d,J=4.8Hz,1H),7.02(d,J=4.8Hz,1H),5.33(d,J=8Hz,1H),4.53-4.49( m, 1H), 4.15 (d, J=5.6Hz, 1H), 3.50 (m, 2H), 1.27 (s, 3H).

[0560] LC / MS: t R =0.30min, MS m / z=281.3[M...

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