Dezecapavir

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Dezecapavir

CAS 2570323-59-8

MF C37H29ClF9N9O5S MW918.19

1H-Cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-acetamide, N-[(1S)-1-[(3S)-3-[4-chloro-1-methyl-3-[(methylsulfonyl)amino]-1H-indazol-7-yl]-3,4-dihydro-4-oxo-7-(3,3,3-trifluoropropoxy)pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-, (3bS,4aR)-

N-[(1S)-1-[(3P)-3-[4-chloro-3-(methanesulfonamido)-1-methyl-1H-indazol-7-yl]-4-oxo-7-(3,3,3-
trifluoropropoxy)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(3bS,4aR)-3-
(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1Hcyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-
yl]acetamide
inhibitor of viral replication, antiviral, SEK9LN2LSM, VH 4011499, VH4011499, VH-4011499, VH 499, GSK2838232, GSK 2838232

Dezecapavir is a potent experimental antiviral compound, specifically a novel HIV-1 capsid inhibitor, developed to block HIV replication by targeting the virus’s capsid protein, showing high effectiveness in lab settings (low nM range EC50) and representing a new class of drugs for HIV treatment, potentially for long-acting injectable therapies. It’s a complex molecule with a unique structure designed to disrupt the HIV capsid assembly, halting the virus’s life cycle early on.

Key Characteristics:

Mechanism: Inhibits HIV-1 capsid assembly, a crucial step in the viral lifecycle.
Potency: Very effective in cell cultures, with a low nanomolar EC50 (effective concentration).
Class: Belongs to a new class of antivirals, distinct from integrase or reverse transcriptase inhibitors, offering a novel approach to HIV treatment.
Development: Under investigation, often mentioned as a potential candidate for long-acting injectable (LAI) treatments due to its potency.

What it does:
Dezecapavir binds to the HIV capsid, preventing the virus from uncoating and maturing, thereby stopping new infections from forming.

Significance:
It represents a promising new option for HIV treatment, especially in the context of growing resistance to existing drugs, and could be part of future long-acting regimens.

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020254985&_cid=P20-MKHOOT-76990-1

Preparation of Example 1: N-((S)-l-((3P)-3-(4-chloro-l-methyl-3-(methylsulfonamido)-lH- indazol-7-yl)-4-oxo-7-(3,3,3-trifluoropropoxy)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5- difluorophenyl)ethyl)-2-((3bS_r4aR)-3-(difluoromethyl)-5_r5-difluoro-3b_r4_r4a_r5-tetrahydro-lH- cyciopropa[3, 4]cydopenta[ l,2-c]pyrazoi-l-yi)acetamide

A solution of diisopropyl (E)-diazene-l,2-dicarboxylate (“DIAD”, 0.125 ml, 0.637 mmol) in THF (0.2 mL) was added dropwise to a mixture of N-(l-((3P)-3-(4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-l-methyl-lH-indazol-7-yl)-7-hydroxy-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-lH-cyclopropa[3,4]cyclopenta[l,2-c]pyrazol-l-yl)acetamide (0.2 g, 0.212 mmol)), 3,3,3-trifluoropropan-l-ol (0.073 g, 0.637 mmol) and triphenylphosphine (0.178 g, 0.679 mmol) in Tetrahydrofuran (2.1 mL) at rt. The reaction mixture was stirred for 18 h at rt and then was concentrated in vacuo. The residue was purified on silica gel (24 g RediSep Gold column) using a gradient of 0-60 % ethyl acetate in hexanes over 15 CV, and then holding at 60 % ethyl acetate in hexanes for 5 CV. Fractions containing the pure product were pooled and then concentrated to give a yellow solid. This solid was taken up in DCM (1 mL):TFA (0.5 mL); the solution was cooled to 0 °C; and to the solution was added triflic acid (0.057 mL, 0.637 mmol). The mixture was stirred for 1 h and then concentrated in vacuo. The residue was taken up in ethyl acetate; washed with 1 N

NaOH; washed with 0.5M citric acid; dried over Na2SC>4; filtered; and then was concentrated in vacuo. The residue was subjected to silica gel chromatography (24 g RediSep Gold column) using 0-60 % ethyl acetate in hexanes over 20 CV, then at 60 % ethyl acetate for 10 CV. Fractions containing the pure product were pooled and then concentrated in vacuoto give N-(l-((6P)-3-(4-chloro-l-methyl-3-(methylsulfonamido)-lH-indazol-7-yl)-4-oxo-7-(3,3,3-trifluoropropoxy)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-lH-cyclopropa[3,4]cyclopenta[l,2-c]pyrazol-l-yl)acetamide (0.078 g, 0.081 mmol, 38.0 % yield) as a brown solid. *H NMR (500 MHz, METHANOL-d^ d ppm 8.46 – 8.53 (m, 1 H) 7.28 – 7.34 (m, 1 H) 7.19 – 7.24 (m, 1 H) 7.03 – 7.09 (m, 1 H) 6.53 – 6.81 (m, 4 H) 4.80 (dd, J=5.96, 2.98Hz, 3 H) 4.49 – 4.62 (m, 2 H) 3.58 – 3.62 (m, 3 H) 3.40 – 3.49 (m, 1 H) 3.22 – 3.24 (m, 3 H) 3.06 – 3.14 (m, 1 H) 2.80 – 2.89 (m, 2 H) 2.37 – 2.44 (m, 2 H) 1.32 – 1.37 (m, 1 H) 0.96 – 1.01 (m, 1 H). LCMS Analysis Method: Column = Acquity UPLC BEH C18, 2.1 x 100 mm, 1.7 pm particles; Injection Volume = 5.00 pL; Flowrate = 0.80 mL/min; Solvent A = 95:5

WatenMeCN w/ 0.1% v/v formic acid; Solvent B = 5:95 WatenMeCN w/ 0.1% v/v formic acid;

Elution profile = Start %B: 0, End %B: 100, Gradient Time: 3.5 min. then hold at 100% B for 1 min.; Detection wavelength 1 = 220 nm, wavelength 2 = 254 nm. LCMS retention time = 3.097 min; m/z = 918.05 [M+l]⁺.

PAT

Pyrido[2,3-d]pyrimidine derivatives as inhibitors of human immunodeficiency virus replicationPublication Number: US-2021323967-A1Priority Date: 2019-06-19
Pyrido[2,3-d]pyrimidine derivatives as inhibitors of human immunodeficiency virus replicationPublication Number: US-2025019383-A1Priority Date: 2019-06-19
Pyrido[2,3-D]pyrimidine derivatives as inhibitors of human immunodeficiency virus replicationPublication Number: KR-20220024608-APriority Date: 2019-06-19
Pyrido[2,3-d]pyrimidine derivatives as inhibitors of human immunodeficiency virus replicationPublication Number: EP-3986561-A1Priority Date: 2019-06-19
Pyrido[2,3-d]pyrimidine derivatives as inhibitors of human immunodeficiency virus replicationPublication Number: EP-3986561-B1Priority Date: 2019-06-19Grant Date: 2024-02-14
Pyrido [2,3-d]pyrimidine derivatives as inhibitors of human immunodeficiency virus replicationPublication Number: US-12129255-B2Priority Date: 2019-06-19Grant Date: 2024-10-29
Pyrido[2,3-d]pyrimidine derivatives as inhibitors of human immunodeficiency virus replicationPublication Number: WO-2020254985-A1Priority Date: 2019-06-19
Inhibitors of human immunodeficiency virus replicationPublication Number: EP-4415685-A1Priority Date: 2021-10-13
Inhibitors of human immunodeficiency virus replicationPublication Number: WO-2023062559-A1Priority Date: 2021-10-13
Inhibitors of human immunodeficiency virus replicationPublication Number: US-2024423985-A1Priority Date: 2021-10-13
Inhibitors of human immunodeficiency virus replicationPublication Number: US-2023149408-A1Priority Date: 2020-04-15
Pharmaceutical compositions comprising cabotegravirPublication Number: US-2023045509-A1Priority Date: 2019-12-09

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