Engasertib

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Engasertib

CAS 1313439-71-2

MF C25H25N3O3 MW415.5 g/mol

1H-Pyrido[2,3-b][1,4]oxazin-2(3H)-one, 6-[4-(cis-1-amino-3-hydroxycyclobutyl)phenyl]-1-ethyl-7-phenyl-

6-[4-(1-amino-3-hydroxycyclobutyl)phenyl]-1-ethyl-7-phenylpyrido[2,3-b][1,4]oxazin-2-one

6-{4-[(1S,3S)-1-amino-3-hydroxycyclobutyl]phenyl}-1-ethyl-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one
serine/threonine kinase inhibitor, ALM-301, VAD-044, ALM 301, VAD 044, Orphan Drug, K2US8HW4TQ

Engasertib is an oral, once-daily AKT inhibitor developed by Vaderis Therapeutics, primarily investigated as a targeted therapy for Hereditary Hemorrhagic Telangiectasia (HHT). Clinical trials show it safely reduces the frequency and duration of bleeding episodes without an FDA-approved equivalent currently available

Core Information

Mechanism of Action: Engasertib is a highly selective inhibitor of AKT1 and AKT2. In HHT, mutations in the ALK1 pathway lead to abnormal blood vessel growth driven by an excess of the AKT protein. By inhibiting AKT, the drug promotes vascular stability and reduces vessel fragility.
Target Indication: Hereditary Hemorrhagic Telangiectasia (HHT) — a rare, severe genetic disorder causing vascular abnormalities and frequent, heavy bleeding, particularly nosebleeds (epistaxis)

Clinical Efficacy & Safety

Proof-of-Concept Trial: A 12-week, placebo-controlled study with 75 HHT patients evaluated daily doses of 30 mg and 40 mg.
- The 40 mg cohort demonstrated a 41% reduction in mean bleeding duration and a 28% reduction in bleeding frequency, compared to 24% and 18% in the placebo group.
- 61% of patients in the 40 mg group rated their clinical condition as “Much Better”.
Extended Efficacy: In long-term open-label extensions, benefits were sustained and amplified over 12 months, resulting in a 66% reduction in mean bleeding duration and a 55% reduction in bleeding frequency.
Side Effects: Generally well-tolerated. The most common side effects (reversible and manageable with supportive care) were mild-to-moderate rash and hyperglycemia

OriginatorAlmac Discovery
DeveloperVaderis Therapeutics
ClassAntineoplastics; Small molecules; Vascular disorder therapies
Mechanism of ActionProto-oncogene protein c-akt inhibitors
Orphan Drug StatusYes – Hereditary haemorrhagic telangiectasia
Phase IVascular disorders
PreclinicalBreast cancer; Prostate cancer
No development reportedHereditary haemorrhagic telangiectasia
28 Dec 2025No recent reports of development identified for phase-I development in Hereditary haemorrhagic telangiectasia in Belgium (PO, Capsule)
28 Dec 2025No recent reports of development identified for phase-I development in Hereditary haemorrhagic telangiectasia in France (PO, Capsule)
28 Dec 2025No recent reports of development identified for phase-I development in Hereditary haemorrhagic telangiectasia in Italy (PO, Capsule)

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2011077098&_cid=P11-MP96JJ-17609-1

Example 139: 6-(4-((1s.3s)-1-amino-3-hydroxycyclobutyl)phenyl)-1-ethyl-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one

Step 1: tert-butyl ((1s.3s)-1-(4-(1-ethyl-2-oxo-7-phenyl-2.3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)-3-hydroxycyclobutyl)carbamate

In a 15 mL reaction tube was added 6-bromo-1-ethyl-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (50 mg, 0.150 mmol), tert-butyl ((1s,3s)-3-hydroxy-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)carbamate (49 mg, 0.125 mmol) and cesium carbonate (204 mg, 0.625 mmol) in a mixture of 1,4-dioxane (2.3 ml) and water (0.8 ml) to give a colourless solution. This was degassed by bubbling nitrogen for 15 minutes, followed by the addition of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (20 mg, 0.025 mmol) and degassing for a further 5 minutes. The reaction mixture was heated to 50°C under a nitrogen atmosphere for one hour then allowed to cool to room temperature, diluted with water (5 ml) and extracted into ethyl acetate (3 x 5 ml). The combined organic phases were dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. The residue was purified by Biotage chromatography (cyclohexane:ethyl acetate, gradient elution from 90:10 to 0:100) to give the desired product as an off-white solid (45 mg, 70% yleld). Ή-NMR (500 MHz, CDCl₃) δ 7.29-7.35 (5H, m), 7.28 (1H, s), 7.18-7.24 (4H, m), 4.96 (1H, br s), 4.88 (2H, s), 4.05 (1H, br s), 4.01 (2H, q), 2.98 (2H, br s), 2.75 (2H, br s), 1.20-1.51 (9H, br m), 1.32 (3H, t). LCMS (Method D) RT = 1.25 min, M+H⁺ = 516.20.

Step 2: 6-(4-((1s,3s)-1-amino-3-hydroxycyclobutyl)phenyl)-1-ethyl-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one

tert-butyl ((1s,3s)-1-(4-(1-ethyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)-3-hydroxycyclobutyl)carbamate (45 mg, 0.087 mmol) was dissolved in TFA (1 mL) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (~3 mL) and concentrated to dryness under reduced pressure three times. The residue was then slurried in diethyl ether (3 mL) and after settling the supernatant solvent removed by pipette. This was repeated three times. The remaining solvent was removed by freeze drylng overnight to give the desired compound as an off-white solid (33 mg, 71% yleld).

¹H-NMR (500 MHz, MeOD) δ 7.55 (1H, s), 7.39-7.42 (4H, m), 7.27-7.31 (3H, m), 7.20-7.24 (2H, m), 4.93 (2H, s), 4.01-4.11 (3H, m), 3.03-3.11 (2H, m), 2.42-2.50 (2H, m), 1.28 (3H, t). LCMS (Method D) RT = 0.74 min, M+H⁺ = 416.20.

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2022069552&_cid=P11-MP969X-06022-1

EXAMPLES

Example 1: Synthesis of 6-(4-(l-amino-3-hvdroxycvclobutyl)phenyl)-l-ethyl-7-phenyl-lH-pyrido[2,3-b][l,4]oxazin-2(3H)-one

6-(4-(l-amino-3-hydroxycyclobutyl)phenyl)-l-ethyl-7-phenyl-lH-pyrido[2,3-b][l,4]oxazin-2(3H)-one (referred to herein as “VAD044 free base”) was synthesized in accordance with the protocol as set out in W02011077098 – see in particular Examples 97, 113 and 139 (reproduced below):

Synthesis of 6-(4-((ls,3s)-l-amino-3-hvdroxycvclobutyl)phenyl)-l-ethyl-7-phenyl-lH-pyrido[2,3-bHl,41oxazin-2(3H)-one: from WO2Q11077098 Example 139:

Step 1: tert-butyl((ls,3s)-l-(4-(l-ethyl-2-oxo-7-phenyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-6-yl)phenyl)-3-hvdroxycvclobutyl)carbamate

In a 15 mL reaction tube was added 6-bromo-l-ethyl-7-phenyl-lH-pyrido[2,3-b][l,4]oxazin-2(3H)-one* (50 mg, 0.150 mmol), tert-butyl((ls,3s)-3-hydroxy-l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)carbamate** (49 mg, 0.125 mmol) and cesium carbonate (204 mg, 0.625 mmol) in a mixture of 1,4-dioxane (2.3 ml) and water (0.8 ml) to give a colourless solution. This was degassed by bubbling nitrogen for 15 minutes, followed by the addition of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) dichloromethane adduct (20 mg, 0.025 mmol) and degassing for a further 5 minutes. The reaction mixture was heated to 50°C under a nitrogen atmosphere for one hour then allowed to cool to room temperature, diluted with water (5 ml) and extracted into ethyl acetate (3 x 5 ml). The combined organic phases were dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. The residue was purified by Biotage chromatography (cyclohexane:ethyl acetate, gradient elution from 90:10 to 0:100) to give the desired product as an off- white solid (45 mg, 70% yield). ¹H-NMR (500 MHz, CDCI₃) 6 7.29-7.35 (5H, m), 7.28 (1H, s), 7.18-7.24 (4H, m), 4.96 (1H, br s), 4.88 (2H, s), 4.05 (1H, br s), 4.01 (2H, q), 2.98 (2H, br s), 2.75 (2H, br s), 1.20-1.51 (9H, br m), 1.32 (3H, t). LCMS (Method D) RT = 1.25 min, M+H⁺ = 516.20.

tert-butyl((ls,3s)-l-(4-(l-ethyl-2-oxo-7-phenyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-6-yl)phenyl)-3- hydroxycyclobutyl)carbamate (45 mg, 0.087 mmol) was dissolved in TFA (1 mL) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (~3 mL) and concentrated to dryness under reduced pressure three times. The residue was then slurried in diethyl ether (3 mL) and after settling the supernatant solvent removed by pipette. This was repeated three times. The remaining solvent was removed by freeze drying overnight to give the desired compound as an off-white solid (33 mg, 71% yield). ¹H-NMR (500 MHz, MeOD) 6 7.55 (1H, s), 7.39- 7.42 (4H, m), 7.27-7.31 (3H, m), 7.20- 7.24 (2H, m), 4.93 (2H, s), 4.01-4.11 (3H, m), 3.03-3.1 1 (2H, m), 2.42-2.50 (2H, m), 1.28 (3H, t). LCMS (Method D) RT = 0.74 min, M+H⁺ = 416.20.

To a suspension of sodium hydride (5.31 g, 133 mmol) in 1,4-dioxane (250 ml), ethyl glycolate (12.56 ml,

133 mmol) was added drop wise over a period of 30 minutes ensuring that the temperature was maintained below 30°C. The resulting thick suspension was stirred at room temperature for 15 minutes.

In a separate II round- bottomed flask was added 5-bromo-2-chloro-3-nitropyridine (21 g, 88 mmol) in

1,4-dioxane (150 ml) to give a brown solution. The suspension of sodium hydride and ethyl glycolate was added drop wise over a period of 30 minutes at 0°C. The resulting reaction mixture was heated to 80°C overnight.

The reaction mixture was concentrated under reduced pressure and the crude residue was purified by

Biotage silica chromatography (gradient 0% to 10% ethyl acetate in n-hexanes) to give the title compound

(1 ,8g, 44%).¹H NMR (500 MHz, CDCI₃) 6 8.48 (1H, s), 8.42 (1H, s), 5.07 (2H, s), 4.28-4.24 (2H, q), 1.31-1.28

(3H, t).

In a II round-bottomed flask was added ethyl 2-(5-bromo-3-nitropyridin-2-yloxy)acetate (18.33 g, 60.1 mmol), phenylboronic acid (10.99 g, 90 mmol), triphenylphosphine (4.73 g, 18.02 mmol) and cesium fluoride (45.6 g, 300 mmol) in 1,2-dimethoxyethane (300 ml) to give a yellow solution. The reaction mixture was degassed by bubbling nitrogen for 30 minutes. Pallad ium (II ) acetate (2.023 g, 9.01 mmol) was added and the mixture was heated to 75°C under a nitrogen atmosphere overnight. The reaction mixture was allowed to cool to room temperature and concentrated to dryness under reduced pressure to give a brown solid. This was re-dissolved in dichloromethane, filtered and concentrated to dryness under reduced pressure to give a brown solid The crude residue was purified via Biotage chromatography (gradient 5% to 60% ethyl acetate in n-hexanes) to give the title compound (6.9g, 38%). 1H NMR (500 MHz, CDCI₃) 6 8.58 (1H, s), 8.56 (1H, s), 7.59-7.52 (2H, m), 7.48-7.46 (2H, m), 7.45-7.43 (1H, m), 5.13 (2H, s), 4.30-4.26 (2H, q), 1.33-1.30 (3H, t).

In a 500 ml round-bottomed flask was added ethyl 2-(3-nitro-5-phenylpyridin-2-yloxy)acetate (4.6 g, 15.22 mmol) in hydrochloric acid, 37% (40 ml) to give a yellow suspension. The mixture was cooled to 0-5°C followed by the portion wise addition of tin powder (9.94 g, 84 mmol). The addition proved to be exothermic. Caution should be taken while adding. The mixture was then stirred at room temperature for further 30 minutes until all foaming ceased. The reaction mixture was heated to 80°C under a nitrogen atmosphere for 3 hours. The reaction mixture cooled to room temperature and diluted with water (800ml). The white precipitate was isolated by filtration, washed with water (100 ml) and sucked dry to give a white solid. The solid was azeotroped with toluene (3 x 30 ml) to give a white solid as the title compound (2.6g, 77%). ^XH NMR (500 MHz, (CD₃)₂SO) 6 10.41 (1H, s), 8.10 (1H, s), 7.59 (2H, d), 7.49-7.42 (2H, t), 7.39-7-38 (1H, d), 4.83 (2H, s).

Step 4: 6-bromo-7-phenyl-lH-pyrido[2,3-b][l,4]oxazin-2(3H)-one

In a 10ml microwave vial was 7-phenyl-l H-pyrido[2,3-b][l ,4]oxazin-2(3H)-one (50 mg, 0.221 mmol) and N-bromosuccinimide (78.6 mg, 0.441 mmol) in dimethylformamide (1 ml). The reaction mixture was heated to 80°C under microwave irradiation for 30 minutes. The reaction mixture was cooled to room

temperature and diluted with ethyl acetate (10ml). The organic solution was washed with water (2x10ml) and brine (2x10ml). The organic phase was dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The crude residue was purified via Biotage chromatography (gradient 0% to 5% methanol in dichloromethane) to give the title compound as a yellow solid (61 mg, 90%). ¹H NMR (500 MHz, CD3OD) 6 7.48-7.32 (5H, m), 7.12 (1 H, s), 4.82 (2H, s).

In a 15 mL reaction tube was added 6-bromo-7-phenyl-lH-pyrido[2,3-b][l,4]oxazin-2(3H)-one (300 mg, 0.983 mmol), iodoethane (0.095 mL, 1.180 mmol) and potassium carbonate (408 mg, 2.95 mmol) in anhydrous N,N-dimethylformamide (1 mL) to give a brown suspension. This was stirred at 50 °C under a nitrogen atmosphere for 60 minutes. The reaction mixture was diluted with saturated sodium bicarbonate solution (5 mL) and extracted into ethyl acetate (3 x 5 mL). The combined organic phases were washed with 50:50 water.brine (3 x 5 mL), dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure to give a brown solid. This was purified by Biotage chromatography (25g silica cartridge, cyclohexane:ethyl acetate, gradient elution from 90:10 to 20:80) to give the title compound as a beige solid (160 mg, 48.8 % yield). ^XH NMR (500 MHz, CDCI₃) 6 7.58-7.37 (5H, m), 7.21 (1H, s), 4.86 (2H, s), 3.96 (2H, q), 1.27 (3H, t). LCMS (Method D) RT 1.293 min, M+l= 334.

n a 40 mL reaction tube was added tert-butyl(ls,3s)-l-(4-bromophenyl)-3- hydroxycyclobutylcarbamate*** (0.25 g, 0.731 mmol) in anhydrous tetrahydrofuran (14 ml) to give a colourless solution. This was degassed by bubbling nitrogen for 20 minutes, followed by the addition of [l,l’-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) dichloromethane adduct (60 mg, 0.073 mmol). After bubbling nitrogen for a further 15 minutes, potassium acetate (143 mg, 1.461 mmol) and bis(pinacolato)diboron (223 mg, 0.877 mmol) were added. The reaction mixture was heated to reflux overnight then concentrated to dryness under reduced pressure and purified by Biotage chromatography (cyclohexane:ethyl acetate, gradient elution from 88:12 to 0:100) to give the desired product as a colourless oil that solidified upon standing (240 mg, 84% yield). ¹H-NMR (500 MHz, CDCI₃) 6 7.71 (2H, d), 7.44 (2H, d), 4.15 (1H, br s), 2.87-2.98 (2H, m), 2.27-2.44 (2H, m), 1.22-1.49 (21H, br m).

(*** synthesis described in WO2009148887 and WO2009148916)

ADVT

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