Eclitasertib

Eclitasertib

CAS 2125450-76-0

5-benzyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydropyrido[3,2-b][1,4]oxazepin-3-yl]-1H-1,2,4-triazole-3-carboxamide

• DNL-758
• SAR-443122
• Eclitasertib (DNL-758) is a potent receptor-interacting protein kinase 1 (RIPK1) inhibitor with an IC₅₀ of 0.0375 µΜ.
• UNII-975AT1P9J6

• OriginatorHarvard University
• DeveloperDenali Therapeutics Inc; Sanofi
• Class2 ring heterocyclic compounds; Amides; Anti-inflammatories; Antipsoriatics; Antirheumatics; Oxazepines; Pyridines; Skin disorder therapies; Small molecules; Triazoles
• Mechanism of ActionRIPK1 protein inhibitors

• Phase IIUlcerative colitis
• DiscontinuedCutaneous lupus erythematosus; Psoriasis; Rheumatoid arthritis; SARS-CoV-2 acute respiratory disease
• 12 Mar 2024Discontinued – Phase-I for Psoriasis (In volunteers) in USA (unspecified route) (Denali pipeline, February 2024)
• 12 Mar 2024Discontinued – Phase-I for Rheumatoid arthritis (In volunteers) in USA (unspecified route) (Denali pipeline, February 2024)
• 27 Feb 2024Efficacy and adverse events data from phase II trial in Cutaneous lupus erythematosus released by Sanofi

SAR443122, was investigated in several clinical trials to evaluate its safety and efficacy. NCT04469621 was studied in severe COVID-19 patients, while NCT05588843 is currently recruiting participants with ulcerative colitis. Additionally, NCT04781816, which was completed with results, focused on patients with cutaneous lupus erythematosus.

Eclitasertib is an orally bioavailable, small-molecule inhibitor of receptor-interacting serine/threonine-protein kinase 1 (RIPK1; receptor-interacting protein 1; RIP1), with potential anti-inflammatory and immunomodulatory activities. Upon oral administration, eclitasertib disrupts RIPK1-mediated signaling, and may attenuate inflammation and the resulting tissue damage. RIPK1, a signaling protein in the tumor necrosis factor (TNF) receptor pathway, plays a key role in inflammation and cell death in response to tissue damage and pathogen recognition.

SCHEME

SIDE CHAIN

MAIN

REF

WO2017136727 

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017136727&_cid=P22-MAYSGO-11421-1

Example 42: (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)- 4H-1,2,4-triazole-3-carboxamide

Step 1: Preparation oƒ (2S)-2-(((tert-butoxy)carbonyl)amino)-3-((2-nitropyridin-3-yl)oxy)propanoic acid

[0535] Sodium hydride (60%, 2 g, 50 mmol) was added into a stirring solution of (2S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (5 g, 25.0 mmol) in N,N-dimethylformamide (100 mL). The resulting mixture was stirred at 0 °C for 2 hours. 3-Fluoro-2-nitropyridine (3.6 g, 25.3 mmol) was added and the reaction mixture was stirred at room temperature for an additional 8 hours before quenching with hydrochloric acid (3 N, 5 mL). After adjusting the pH to 3-4 with hydrochloric acid (3 N, 20 mL), the resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reversed phase chromatography with a RP-C18 column (acetonitrile/water, 1/2) to afford the title compound (3.2 g, 39%) as a light yellow oil. LC-MS (Method C): m/z = 272.1 [M+H-(t-BuO)]⁺, 1.269 min.

Step 2: Preparation oƒ (2S)-3-((2-aminopyridin-3-yl)oxy)-2-(((tert-butoxy)carbonyl)amino)propanoic acid

[0536] (2S)-2-(((tert-butoxy)carbonyl)amino)-3-((2-nitropyridin-3-yl)oxy)propanoic acid (0.45 g, 1.4 mmol) in methanol (20 mL) was aged overnight at room temperature in the presence of palladium on carbon (10%, 0.5 g) under hydrogen atmosphere (2-3 atm). The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to afford the title compound (0.32 g, 78%) as a yellow oil. LC-MS (Method C): m/z = 298.1 [M+H]⁺, 0.982 min.

Step 3: Preparation oƒ tert-butyl N-((3S)-4-oxo-2H,3H,4H,5H-pyrido[3,2-b][1,4]oxazepin-3-yl)carbamate

[0537] N,N,N’,N’-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophospate (0.73 g, 1.92 mmol) and N,N-diisopropylethylamine (0.25 g, 1.93 mmol) were added to a stirring solution of (2S)-3-((2-aminopyridin-3-yl)oxy)-2-(((tert-butoxy)carbonyl)amino)propanoic acid (0.45 g, 1.51 mmol) in N,N-dimethylformamide (5 mL). After stirring for 6 hours at room temperature, the reaction mixture was quenched by the addition of water (20 mL), and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (methanol/dichloromethane, 1/10) to afford the title compound (0.11 g, 26%) as a white solid. LC-MS (Method C): m/z = 280.1 [M+H]⁺, 1.248 min.

tep 4: Preparation oƒ tert-butylN-((3S)-5-methyl-4-oxo-2H,3H,4H,5H-pyrido[3,2-b][1,4]oxazepin-3-yl)carbamate

[0538] Iodomethane (50 mg, 0.35 mmol) was added dropwise to a stirring solution of tert-butyl N-((3S)-4-oxo-2H,3H,4H,5H-pyrido[3,2-b][1,4]oxazepin-3-yl)carbamate (100 mg, 0.36 mmol) and cesium carbonate (120 mg, 0.36 mmol) in N,N-dimethylformamide (5 mL). After stirring for 3 hours at room temperature, the reaction mixture was diluted with water (20 mL), and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (methanol/dichloromethane, 1/10) to afford the title compound (90 mg, 86%) as a white solid. LC-MS (Method C): m/z = 294.1 [M+H]⁺, 1.333 min.

Step 5: Preparation oƒ (3S)-3-amino-5-methyl-2H,3H,4H,5H-pyrido-[3,2-b][1,4]oxazepin-4-one hydrochloride

[0539] tert-butyl N-((3S)-5-methyl-4-oxo-2H,3H,4H,5H-pyrido[3,2-b][1,4]oxazepin-3-yl)carbamate (90 mg, 0.31 mmol) was added to a solution of hydrogen chloride in dioxane (4 M, 10 mL). The reaction mixture was stirred for 3 hours at room temperature and concentrated under reduced pressure to afford the title compound (65 mg, 93%) as a white solid, which was used directly in the next step without further purification. LC-MS (Method C): m/z = 194.1 [M+H]⁺, 0.847 min.

Step 6: Preparation oƒ (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0540] A solution of (3S)-3-amino-5-methyl-2H,3H,4H,5H-pyrido-[3,2-b][1,4]oxazepin-4-one hydrochloride (55 mg, 0.24 mmol) in N,N-dimethylformamide (1 mL) was added to a stirring solution of 5-benzyl-2H-1,2,4-triazole-3-carboxylic acid (80 mg, 0.40 mmol), 1-hydroxy-benzotrizole (70 mg, 0.53 mmol), N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (100 mg, 0.52 mmol) and N,N-

diisopropylethylamine (160 mg, 1.21 mmol) in N,N-dimethylformamide (2 mL). After stirring for 8 hours at room temperature, the reaction mixture was quenched by the addition of water (20 mL), and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by Prep-HPLC with the following conditions: Column, XBridge Shield RP18 OBD Column, 5 μm, 19 x 150 mm; mobile phase, water (0.1% formic acid) and ACN (30.0% ACN to 60.0% over 7 min); Detector, UV 254 & 220 nm to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ 14.45 (s, 1H), 8.67 (d, J= 7.2 Hz, 1H), 8.37 (dd, J= 4.8, 1.8 Hz, 1H), 7.71 (dd, J= 7.8, 1.5 Hz, 1H), 7.37-7.21 (m, 6H), 4.92-4.82 (m, 1H), 4.73 (dd, J= 11.4, 9.6 Hz, 1H), 4.53 (dd, J= 9.6, 7.5 Hz, 1H), 4.14 (s, 2H), 3.37 (s, 3H). LC-MS (Method D): m/z = 379.1 [M+H]⁺, 1.611 min.

PATENT

• US9815850, Compound 42
• US9815850, Compound 169

WO2023182512

WO2023137035 

WO2022208262 

WO2021211919 

WO2021209740 

WO2021205298 

WO2021205296

, WO2017136727

PAPER

European Journal of Medicinal Chemistry (2021), 220, 113484

Structure-based bioisosterism design of thio-benzoxazepinones as novel necroptosis inhibitors

Publication Name: European Journal of Medicinal Chemistry

Publication Date: 2021-08-05

PMID: 33930803

DOI: 10.1016/j.ejmech.2021.113484

PATENT

WO2021203011

• [1]. Anthony A. ESTRADA, et al. Compounds, compositions and methods. WO2017136727A2.[2]. Darwish I, et al., Rip1k inhibitors. WO2021203011

//////////Eclitasertib, DNL-758, SAR-443122, DNL 758, SAR 443122, UNII-975AT1P9J6, Phase 2, Ulcerative colitis