Iscartrelvir

Iscartrelvir

CAS 2921711-74-0

MF 2921711-74-0, 526.4 g/mol

N-{(1S,2R)-2-[4-bromo-2-(methylcarbamoyl)-6-nitroanilino]cyclohexyl}isoquinoline-4-carboxamide
antiviral, WU-04, WU 04, W2LTV65R5E

Iscartrelvir is an investigational new drug developed by the Westlake University for the treatment of COVID-19. It targets the SARS-CoV-2 3CL protease, which is crucial for the replication of the virus responsible for COVID-19.^[1][2]

Iscartrelvir is a small molecule drug. The usage of the INN stem ‘-trelvir’ in the name indicates that Iscartrelvir is a antiviral 3CL protease inhibitor. Iscartrelvir has a monoisotopic molecular weight of 525.1 Da.

PAT

WO2022150962A1

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2022150962&_cid=P11-MJKTXT-76321-1

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=CN331401594&_cid=P11-MJKTO7-65334-1

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2024243841&_cid=P11-MJKTO7-65334-1

N-((1S,2R)-2-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)isoquinoline-4-carboxamide, and its structure is as follows:

Example 1: Preparation of Compound 1 

[0189]A free, amorphous compound 1, a yellow solid, was prepared according to the method disclosed in paragraphs [00121]-[00128] of WO2022150962A1, and was used in the following examples. The specific synthetic steps are shown in steps a to d:

The reagents and conditions for steps a to d are further described below: (a) 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), N,N-diisopropylethylamine (DIPEA), CH₂Cl₂ 

_or 

_{dichloromethane} (DCM), 0°C, 2 h; (b) DIPEA, dimethylformamide (DMF), 80°C, 16 h; (c) 3M ethyl hydrochloride (HCl·EA), CH₂Cl₂ , ₁ 

_h ; (d ) HATU, DIPEA, DMF, room temperature, 12 h. 

[0191]Step a: Synthesis of N-methyl-5-bromo-2-fluoro-3-nitrobenzamide (I-1) 

[0192]A solution of 5-bromo-2-fluoro-3-nitrobenzoic acid (0.8 g, 3.80 mmol) in dichloromethane (20 mL) was stirred at 0 °C. Then, HATU (2.0 g, 5.25 mmol), DIPEA (1.88 mL, 11.4 mmol), and methylamine hydrochloride (0.31 g, 4.5 mmol) were added to the reaction mixture. The mixture was stirred at 0 °C for 2 hours until it became clear. The mixture was extracted three times with dichloromethane, and the combined organic layers were washed with a saturated brine solution. The organic phase was then dried over anhydrous Na₂SO₄ and _concentrated 

_under vacuum. Finally, the mixture was purified by chromatography to give compound I-1 (0.8 g, 76% yield) as a yellow solid.

[0193]Step b: Synthesis of tert-butyl 2-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)carbamate (I-2) 

[0194]A solution of compound I-1 (0.8 g, 2.9 mmol) in 15 mL of DMF was stirred at room temperature. Then, tert-butyl ((1S,2R)-2-aminocyclohexyl)carbamate (0.75 g, 3.5 mmol) (the corresponding stereoisomer of this reagent can be used to synthesize the stereoisomer of compound I-2) and DIPEA (1.44 mL, 8.7 mmol) were added to the reaction mixture. The mixture was heated to 80 °C and stirred for 16 hours. The mixture was extracted three times with ethyl acetate, and the combined organic layers were washed with saturated salt solution. The organic phase was then dried over anhydrous Na₂SO₄ and _{concentrated under vacuum to give compound} 

_I -2 as a yellow solid, requiring no further purification.

Step c: Synthesis of 2-(2-aminocyclohexyl)amino)-5-bromo-N-methyl-3-nitrobenzamide hydrochloride (I-3) 

[0196]A solution of compound I-2 (90 mg, 0.19 mmol) (or the corresponding stereoisomer) in anhydrous dichloromethane (6 mL) was stirred at room temperature. Then, HCl (4 mL, 3 M in ethyl acetate) was added. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under vacuum to give compound I-3 as a yellow solid, requiring no further purification. 

[0197]Step d: Synthesis of N-((1S,2R)-2-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)isoquinoline-4-carboxamide 

[0198]At room temperature, a solution of the corresponding isoquinoline-4-carboxylic acid (1 equivalent) and HATU (1.5 equivalent) in anhydrous DMF (6 mL) was stirred. Then, compound I-3 and DIPEA (5.0 equivalent) were added. The mixture was stirred overnight at room temperature. The mixture was extracted three times with ethyl acetate, and the combined organic layers were washed with saturated brine. The organic phase was then dried over anhydrous Na₂SO₄ _and 

_concentrated under vacuum. Finally, the mixture was purified by chromatography to give compound 1 as a free amorphous solid in yellow form.

PAT

• Aromatic ring-containing pyridone amide compoundsPublication Number: CN-119100980-APriority Date: 2023-06-07
• Crystal of viral protease inhibitor and usePublication Number: WO-2024243841-A1Priority Date: 2023-05-31
• Protease inhibitors, their preparation and usePublication Number: CN-113072497-BPriority Date: 2021-01-12Grant Date: 2023-04-14
• Protease inhibitors, their preparation and usePublication Number: CN-113072497-APriority Date: 2021-01-12
• Protease inhibitors, their preparation and usePublication Number: CN-116751164-APriority Date: 2021-01-12

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Clinical data
Other names	WPV01; WU-04
Identifiers
IUPAC name
CAS Number	2921711-74-0
PubChem CID	156774920
ChemSpider	129307041
UNII	W2LTV65R5E
PDB ligand	J7R (PDBe, RCSB PDB)
Chemical and physical data
Formula	C24H24BrN5O4
Molar mass	526.391 g·mol−1
3D model (JSmol)	Interactive image
SMILES
InChI

References

1.  Yang L, Wang Z (September 2023). “Bench-to-bedside: Innovation of small molecule anti-SARS-CoV-2 drugs in China”. European Journal of Medicinal Chemistry. 257 115503. doi:10.1016/j.ejmech.2023.115503. PMC 10193775. PMID 37229831.
2.  Hou N, Shuai L, Zhang L, Xie X, Tang K, Zhu Y, et al. (February 2023). “Development of Highly Potent Noncovalent Inhibitors of SARS-CoV-2 3CLpro”. ACS Central Science. 9 (2): 217–227. doi:10.1021/acscentsci.2c01359. PMC 9885526. PMID 36844503.
3. Resistance mechanisms of SARS-CoV-2 3CLpro to the non-covalent inhibitor WU-04Publication Name: Cell DiscoveryPublication Date: 2024-04-09PMCID: PMC11003996PMID: 38594245DOI: 10.1038/s41421-024-00673-0
4. Identification of Ebselen derivatives as novel SARS-CoV-2 main protease inhibitors: Design, synthesis, biological evaluation, and structure-activity relationships explorationPublication Name: Bioorganic & Medicinal ChemistryPublication Date: 2023-12-15PMID: 37972434DOI: 10.1016/j.bmc.2023.117531
5. The molecular mechanism of non-covalent inhibitor WU-04 targeting SARS-CoV-2 3CLpro and computational evaluation of its effectiveness against mainstream coronavirusesPublication Name: Physical chemistry chemical physics : PCCPPublication Date: 2023-09-13PMID: 37655706DOI: 10.1039/d3cp03828a
6. Bench-to-bedside: Innovation of small molecule anti-SARS-CoV-2 drugs in ChinaPublication Name: European Journal of Medicinal ChemistryPublication Date: 2023-09-05PMCID: PMC10193775PMID: 37229831DOI: 10.1016/j.ejmech.2023.115503
7. Development of Highly Potent Noncovalent Inhibitors of SARS-CoV-2 3CLproPublication Name: ACS Central SciencePublication Date: 2023-01-25PMCID: PMC9885526PMID: 36844503DOI: 10.1021/acscentsci.2c01359

////////iscartrelvir, antiviral, WU-04, WU 04, W2LTV65R5E