Navlimetostat

CAS 2630904-45-7

ALSO 2630904-44-6

MF C23H18ClFN6O2 MW464.9 g/mol

• Benzonitrile, 2-(4-(4-(aminomethyl)-1,2-dihydro-1-oxo-6-phthalazinyl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-(cyclopropyloxy)-3-fluoro-, (2S)-
• (M)-27
• 2-[4-[4-(aminomethyl)-1-oxo-2H-phthalazin-6-yl]-2-methylpyrazol-3-yl]-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile

(2M)-2-{4-[4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl] -1-methyl-1H-pyrazol-5-yl}-4-chloro-6-(cyclopropyloxy)-3-fluorobenzonitrile
antineoplastic, MRTX-1719, BMS-986504, MRTX 1719, BMS 986504

Navlimetostat (also known as MRTX-1719 or BMS-986504) is an investigational, first-in-class oral targeted cancer therapy being developed by Bristol-Myers Squibb. It works by selectively binding to the PRMT5-MTA complex, exploiting synthetic lethality to kill cancer cells with MTAP gene deletions while sparing healthy cells.

Navlimetostat is currently in Phase 1/2 clinical trials for advanced solid tumors, including MTAP-deficient non-small cell lung cancer (NSCLC), pancreatic cancer, and glioblastoma.

Key highlights and ongoing research:

• Mechanism: In MTAP-deleted cancer cells, a metabolite called MTA accumulates and binds to PRMT5. Navlimetostat targets and inhibits this specific PRMT5-MTA complex, leading to tumor cell death.
• Clinical Trials: It is currently being investigated as a monotherapy (e.g., in MTAP-deleted advanced solid tumors) and in combination with other agents like pumitamig

• OriginatorMirati Therapeutics
• DeveloperBristol-Myers Squibb; Mirati Therapeutics
• ClassAntineoplastics; Small molecules
• Mechanism of ActionPRMT5 protein inhibitors
• Phase II/IIIAdenocarcinoma; Non-small cell lung cancer
• Phase I/IIMesothelioma; Neurilemmoma; Pancreatic cancer; Solid tumours
• 22 May 2026University of Southampton in collaboration with Bristol-Myers Squibb plans a phase II SELECTmeso1 trial for Malignant mesothelioma (Second-line therapy or greater) in United Kingdom in May 2026 (PO, Tablet) (NCT07602946)
• 13 May 2026Northwestern University plans a phase Ib/II trial for Solid tumours (Metastatic disease, Second-line therapy or greater, Combination therapy) in USA(PO) in December 2027 (NCT07594626)
• 12 May 2026M.D. Anderson Cancer Center plans a phase I/II trial for Non-small cell lung cancer (Combination therapy, Late-stage disease, Metastatic disease, Second-line therapy or greater) in USA (PO), in November 2026 (NCT07579221)

PRMT5 Inhibitor BMS-986504 is an orally bioavailable methylthioadenosine (MTA)-selective inhibitor of the protein arginine methyltransferase 5 (PRMT5), with potential antineoplastic activity. Upon oral administration, PRMT5 inhibitor BMS-986504 targets, binds to and inhibits PRMT5 that is bound to MTA, a complex that is elevated in methylthioadenosine phosphorylase (MTAP)-deleted cancer cells, thereby specifically inhibiting the function of PRMT5 solely within MTAP-deleted cancer cells and not in normal, healthy cells. By inhibiting the methyltransferase activity of PRMT5, levels of both monomethylated and dimethylated arginine residues in histones H2A, H3 and H4 are decreased. This modulates the expression of genes involved in several cellular processes, including cellular proliferation. This may increase the expression of antiproliferative genes and/or decrease the expression of genes that promote cell proliferation, which may lead to decreased growth of rapidly proliferating cancer cells. BMS-986504 also causes dysregulated RNA splicing and decreased retinoblastoma protein (pRb). Together, this decreases proliferation and increases apoptosis specifically in MTAP-deleted cancer cells. PRMT5, a type II methyltransferase that catalyzes the formation of both omega-N monomethylarginine (MMA) and symmetric dimethylarginine (sDMA) on histones and a variety of other protein substrates involved in signal transduction and cellular transcription, is essential for the viability of cancer and normal cells. It is overexpressed in several neoplasms. Elevated levels are associated with decreased patient survival. MTAP is deleted in certain cancer cells leading to an accumulation of the metabolite MTA; MTA binds to and partially inhibits the activity of PRMT5.

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021050915&_cid=P12-MR76CL-04796-1

[0186] Step 6: To a solution of 6-bromo-4-(chloromethyl)-2H-phthalazin-1-one 13c (148 g, crude) in DMF (1.5 L) was added (1,3-dioxoisoindolin-2-yl)potassium (121 g, 653 mmol). The reaction mixture was stirred at 90 °C for 2 hours and then cooled to 25 °C. The formed precipitate was filtered and washed with DMF (200 mL x 2) and the filter cake triturated with water (1.00 L), filtered and dried to give Intermediate F, 2-[(7-bromo-4-oxo-3H-phthalazin-1-yl)methyl]isoindoline-1,3-dione (162 g, 413 mmol, 76% yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) d = 12.59 (s, 1H), 8.43 (d, J = 1.2 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 8.07 (dd, J = 1.6, 8.4 Hz, 1H), 7.97 – 7.93 (m, 2H), 7.92 – 7.86 (m, 2H), 5.19 (s, 2H). LCMS [M+1]: 383.9.

[0327] Step 4: A mixture of 4-chloro-6-(cyclopropoxy)-3-fluoro-2-(2-methylpyrazol-3-yl)benzonitrile (180 mg, 0.617 mmol, 1.00 eq) and N-bromosuccinimide (220 mg, 1.23 mmol, 2.00 eq.) in acetonitrile (10 mL) was stirred at 40 °C for 2 hours under a nitrogen atmosphere. After such time the mixture was concentrated and the residue was purified by prep-TLC (SiO₂, petroleum ether: ethyl acetate 20%) to give 2-(4-bromo-2-methyl-pyrazol-3-yl)-4-chloro-6-(cyclopropoxy)-3-fluoro-benzonitrile (170 mg, 0.455 mmol, 74% yield) as a white solid. LCMS [M+1] ⁺ = 371.8; ¹H NMR (400 MHz, CDCl₃) d = 7.61 (s, 1H), 7.55 (d, J = 6.0 Hz, 1H), 3.93 – 3.85 (m, 1H), 3.80 (s, 4H), 0.97 – 0.94 (m, 4H).

EXAMPLE 16-7 and 16-8

[0590] Example 4-230, 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile (30 mg, 0.065 mmol) separated by SFC (DAICEL CHIRALPAK IC (250 mm × 30 mm x 10 mm); mobile phase:

[0.1% NH₃H₂O isopropanol]; B%: 40% isocratic, 4.1 min cycle; 120 min total ) to give example 16-7 (ee > 99%, 13 mg, 0.026 mmol, 25% yield) as a yellow solid and example 16-8 (8 mg, ee = 84% ). Example 16-8 was then then further separated by SFC (DAICEL CHIRALPAK IC (250 mm × 30 mm,10 mm); mobile phase: [0.1% NH₃H₂O EtOH]; B%: 60% isocratic, 3.1 min cycle; total 50 min) to give Example 16-8 (ee > 99%, 4 mg, 0.007 mmol, 7% yield) as a yellow gum. Spectra data for Example 16-7: LCMS [M+1] ⁺ = 465.1; ¹H NMR (400 MHz, DMSO-d₆) d = 12.59 – 12.44 (s, 1H), 8.29 (s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 6.0 Hz, 1H), 7.75 (s, 1H), 7.67 (br d, J = 7.6 Hz, 1H), 4.23 – 4.17 (m, 1H), 3.86 (br s, 2H), 3.78 (s, 3H), 0.94 – 0.88 (m, 2H), 0.84 – 0.79 (m, 2H). Spectra data for Example 16-8: LCMS [M+1] ⁺ = 465.1; ¹H NMR (400 MHz, DMSO-d₆) d = 12.49 – 12.37 (s, 1H), 8.26 (s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 6.0 Hz, 1H), 7.73 (d, J = 1.6 Hz, 1H), 7.72 – 7.68 (m, 1H), 4.19 (m, 1H), 3.80 (s, 2H), 3.77 (s, 3H), 0.93 – 0.87 (m, 2H), 0.83 – 0.78 (m, 2H).

PAT

• MTA-synergistic PRMT5 inhibitorsPublication Number: CN-114728912-APriority Date: 2019-09-12
• Mta-cooperative prmt5 inhibitorsPublication Number: WO-2021050915-A1Priority Date: 2019-09-12
• MTA-Cooperative PRMT5 InhibitorsPublication Number: US-2021078994-A1Priority Date: 2019-09-12
• MTA-Cooperative PRMT5 InhibitorsPublication Number: US-2021079003-A1Priority Date: 2019-09-12

ADVERTISEMENT

ANAX LABORATORIES

WEBSITE https://www.anaxlab.com/

Discovery Solutions, Supporting the chemistry needs of clients in the Medical, Analytical and Bio Sciences

Development Solutions, Developing from Lab scale to PR&D, Kilo Scale-ups and Commercial Scales

SEE MORE………Integrated Solutions, Manufacturing Solutions, Products,
Can’t Find? Let’s Connect

Phone : +91 897704 2010 /  +91 9177075735, Email : info@anaxlab.com

#MedicinalChemistry, #DrugDiscovery, #OrganicSynthesis, #ChemicalLibrary, #BuildingBlocks, #SARStudies, #ChemistryInnovation, #medchem, #Drugdevelopment, #Biotech, #Biotechnology, #AnaxLaboratories, #Pharma

AS ON FEB2026 4.574 LAKHS VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT

join me on Linkedin

Anthony Melvin Crasto Ph.D – India | LinkedIn

join me on Researchgate

RESEARCHGATE

join me on Facebook

Anthony Melvin Crasto Dr. | Facebook

• Twitter
• FACEBOOK

join me on twitter

Anthony Melvin Crasto Dr. | twitter

+919321316780 call whatsaapp

EMAIL. amcrasto@gmail.com

References

• Dynamic Kinetic Resolution of Axially Chiral MRTX1719Publication Name: SynfactsPublication Date: 2022-10-18DOI: 10.1055/s-0041-1738738
• Design and evaluation of achiral, non-atropisomeric 4-(aminomethyl)phthalazin-1(2H)-one derivatives as novel PRMT5/MTA inhibitorsPublication Name: Bioorganic & Medicinal ChemistryPublication Date: 2022-10-01PMID: 35926325DOI: 10.1016/j.bmc.2022.116947
• Synthesis of MRTX1719Publication Name: SynfactsPublication Date: 2022-03-18DOI: 10.1055/s-0041-1737934
• Fragment-Based Discovery of MRTX1719, a Synthetic Lethal Inhibitor of the PRMT5•MTA Complex for the Treatment of MTAP -Deleted CancersPublication Name: Journal of Medicinal ChemistryPublication Date: 2022-01-18PMID: 35041419DOI: 10.1021/acs.jmedchem.1c01900
• Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5Publication Name: Science (New York, N.Y.)Publication Date: 2016-03-11PMID: 26912361DOI: 10.1126/science.aad5944
• Synthesis of MRTX1719DOI: 10.1055/s-0041-1737934Publication Date: 2022Publication Name: Synfacts
• Dynamic Kinetic Resolution of Axially Chiral MRTX1719DOI: 10.1055/s-0041-1738738Publication Date: 2022Publication Name: Synfacts

////////navlimetostat, anax labs, antineoplastic, MRTX-1719, BMS-986504, MRTX 1719, BMS 986504