Zongertinib

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Zongertinib

CAS No. : 2728667-27-2,
BI-1810631, BI1810631

Molecular Weight	535.60
Formula	C₂₉H₂₉N₉O₂

FDA 8/8/2025, Hernexeos, To treat adults with unresectable or metastatic non-squamous non-small cell lung cancer whose tumors have HER2 tyrosine kinase domain activating mutations, as detected by an FDA-approved test, and who have received prior systemic therapy

N-(1-(8-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)piperidin-4-yl)acrylamide
N-(1-(8-((3-methyl-4-((1-methyl-1H-benzo(d)imidazol-5-yl)oxy)phenyl)amino)pyrimido(5,4-d)pyrimidin-2-yl)piperidin-4-yl)acrylamide
884-819-6

Zongertinib is an orally bioavailable inhibitor of the receptor tyrosine kinase human epidermal growth factor receptor 2 (HER2; ErbB2; HER-2), with potential antineoplastic activity. Upon oral administration, zongertinib covalently binds to and inhibits the activity of both wild-type and HER2 mutants, including HER2 mutants with exon 20 insertion (ex20ins) mutations. This prevents HER2-mediated signaling and may lead to cell death in HER2-expressing tumor cells. HER2, a receptor tyrosine kinase overexpressed on a variety of tumor cell types, plays an important role in tumor cell proliferation and tumor vascularization.

REF

https://aacrjournals.org/cancerdiscovery/article/15/1/119/750858/Zongertinib-BI-1810631-an-Irreversible-HER2-TKI

Synthesis of zongertinib (N-(1-(8-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-
548 yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)piperidin-4-yl)acrylamide)

Methods

Synthesis of Zongertinib (N-(1-(8-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)piperidin-4-yl)acrylamide)

An overview of the synthetic routes to zongertinib and BI-3999 is shown in Supplementary Fig. S1, and graphical NMR spectra are shown in Supplementary Fig. S2.

3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)aniline (500 mg, 1.97 mmol) and 8-chloro-2-(methylthio)pyrimido[5,4-d]pyrimidine hydrochloride (492 mg, 1.97 mmol) were suspended in isopropanol, and the resulting reaction mixture stirred at 50°C for 3 hours, at which time high-performance liquid chromatography–mass spectrometry (HPLC-MS) indicated full conversion. The reaction mixture was concentrated under reduced pressure, and the crude product was redissolved in dichloromethane and washed with aqueous NaHCO₃. The organic layer was dried over Na₂SO₄ and concentrated, and the resulting crude product was purified by column chromatography (SiO₂, gradient of 0%–15% methanol in dichloromethane) to afford the product (840 mg).

N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-6-(methylthio)pyrimido[5,4-d]pyrimidin-4-amine (860 mg, 90%, 1.80 mmol) was suspended in dichloromethane (30 mL), and the resulting mixture was cooled to 0°C to 5°C. mCPBA (3-chloroperbenzoic acid, 444 mg, 77%, 1.98 mmol) was added portionwise over 1 hour, and the resulting reaction mixture was stirred at room temperature overnight, at which time HPLC-MS indicated full conversion. The reaction mixture was diluted with dichloromethane and washed with aqueous NaHCO₃. The organic layer was dried over Na₂SO₄ and concentrated, and the resulting crude product which was used directly in the next step (767 mg, crude).

N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-6-(methylsulfinyl)pyrimido[5,4-d]pyrimidin-4-amine (5.42 g, 80%, 9.73 mmol) was dissolved in N,N-dimethyl formamide (DMF, 50 mL) and diisopropylethylamine (2.8 mL, 16 mmol). 4-Boc-amino-1-piperidine (2.39 g, 11.9 mmol) was added, and the reaction was stirred at 60°C overnight. Then, the reaction mixture was concentrated, and the crude product was used directly in the next step (5.66 g, crude).

Tert-butyl (1-(8-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)piperidin-4-yl)carbamate (5.66 g, 9.73 mmol) was dissolved in dichloromethane (100 mL) and methanol (30 mL). Four mol/L HCl in dioxane (11 mL, 44 mmol) was added, and the resulting reaction mixture was heated to 45°C for 7 hours. HPLC-MS indicated some remaining starting material; therefore, the reaction mixture was stirred at room temperature overnight. Four mol/L HCl in dioxane (1 mL, 0.40 mmol) was added, and the reaction mixture was reheated to 45°C for 4 hours, at which time HPLC-MS indicated full conversion. The reaction mixture was concentrated, and the resulting crude product was purified by column chromatography (SiO₂, gradient of 0%–20% methanol in dichloromethane) to afford the product (4.5 g, 70% purity).

1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazino[5,4-d]pyrimidin-2-yl]piperidin-4-amine (4.5 g, 70%, 6.9 mmol) was suspended in dichloromethane (150 mL) and triethyl amine (4 mL, 28 mmol), and dimethylaminopyridine (115 mg, 0.941 mmol) was added. Then, acroyloyl anhydride (1.36 g, 95%, 10.3 mmol) was added, and the resulting reaction mixture was stirred at room temperature for 1 hour, at which time HPLC-MS indicated full conversion. The reaction mixture was diluted with dichloromethane (50 mL) and washed with aqueous NaHCO₃ and brine. The organic layer was dried over Na₂SO₄ and concentrated, and the resulting crude product was purified by column chromatography (SiO₂, gradient of 0%–20% methanol in dichloromethane) to afford the product (2.49 g).

¹H NMR (DMSO-d₆, 500 MHz) δ 9.58 (s, 1H), 9.08 (s, 1H), 8.39 (s, 1H), 8.19 (s, 1H), 8.10 (d, 1H, J = 7.6 Hz), 7.84 (d, 1H, J = 2.2 Hz), 7.77 (dd, 1H, J = 8.8 Hz, J = 2.2 Hz), 7.57 (d, 1H, J = 8.8 Hz), 7.09 (d, 1H, J = 2.2 Hz), 7.00 (dd, 1H, J = 2.2, 8.5 Hz), 6.89 (d, 1H, J = 8.8 Hz), 6.20 (dd, 1H, J = 10.1, 17.0 Hz), 6.10 (dd, 1H, J = 2.2, 17.0 Hz), 5.6 (dd, 1H, J = 2.2, 9.8 Hz), 4.86 (m, 2H), 3.99 (m, 1H), 3.84 (s, 3H), 3.25 (m, 2H), 2.26 (s, 3H), 1.92 (m, 2H), and 1.43 (m, 2H).

Synthesis of BI-3999 (N-(1-(8-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)piperidin-4-yl)acetamide)

6-(4-aminopiperidin-1-yl)-N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)pyrimido[5,4-d]pyrimidin-4-amine (100 mg, 208 mmol) and 4-dimethylaminopyridine (2.5 mg, 0.02 mmol) were suspended in 5 mL dichloromethane. Acetic anhydride (25 μL, 0.23 mmol) was added, and the resulting reaction mixture was stirred at room temperature for one hour. Then, the reaction mixture was diluted with dichloromethane and washed with aqueous NaHCO₃ and brine. Then, the layers were separated, and the organic layer was dried over MgSO₄ and concentrated. The crude product was purified by column chromatography (SiO₂, gradient of 0%–10% methanol in dichloromethane) to afford the product (75 mg).

¹H NMR (DMSO-d₆, 400 MHz) δ 9.58 (s, 1H), 9.07 (s, 1H), 8.39 (s, 1H), 8.17 (s, 1H), 7.88 (d, 1H, J = 7.9 Hz), 7.84 (d, 1H, J = 2.5 Hz), 7.77 (dd, 1H, J = 2.7, 8.7 Hz), 7.57 (d, 1H, J = 8.9 Hz), 7.09 (d, 1H, J = 2.3 Hz), 7.00 (dd, 1H, J = 2.3, 8.6 Hz), 6.89 (d, 1H, J = 8.6 Hz), 4.85 (m, 2H), 3.90 (m, 1H), 3.84 (s, 3H), 3.23 (m, 2H), 2.26 (s, 3H), 1.88 (m, 2H), 1.82 (s, 3H), and 1.38 (m, 2H).