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Sevabertinib
Sevabertinib
CAS 2521285-05-0
MF C24H25ClN4O5, 484.9 g/mol
3-(3-chloro-2-methoxyanilino)-2-[3-[[(2S)-1,4-dioxan-2-yl]methoxy]-4-pyridinyl]-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one
11/19/2025, FDA 2025, APPROVALS 2025, Hyrnuo, 2A7VPM5RWH, BAY-2927088, BAY 2927088
To treat locally advanced or metastatic non-squamous non-small cell lung cancer with tumors that have activating HER2 tyrosine kinase domain activating mutations in patients who received a systemic therapy
Sevabertinib, sold under the brand name Hyrnuo, is an anti-cancer medication used for the treatment of non-small cell lung cancer.[1] Sevabertinib is a kinase inhibitor.[1] It is taken by mouth.[1]
Sevabertinib was approved for medical use in the United States in November 2025.[2]
SYN
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020216781&_cid=P22-MICIVF-33261-1
Intermediate 3-1
1-chloro-3-isothiocyanato-2-methoxybenzene
3-chloro-2-methoxyaniline (CAS 511 14-68-2, 8.4 ml, 63 mmol) was solved in DCM (100 ml) and sat. sodium bicarbonate solution (100 ml) was added. To the ice cooled mixture was slowly added thiophosgene (5.4 ml, 70 mmol). The reaction was stirred at 0°C for 2 h. At RT the DCM layer was separated and washed with sat. sodium bicarbonate solution, filtered through a hydrophobic filter and concentrated under reduced pressure to give the title compound (12.97 g, 100 % yield) which was used directly in the next step.
1H-NMR (400MHz, DMSO-de): d [ppm]= 7.51 (dd, 1 H), 7.35 (dd, 1 H), 7.20 (t, 1 H), 3.85 -3.91 (m, 3H).
Intermediate 4-1
tert- butyl 5-[(3-chloro-2-methoxyphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2/-/)-carboxylate
To an ice-cooled solution of 1-chloro-3-isothiocyanato-2-methoxybenzene (intermediate 3-1 , 4.00 g, 20.0 mmol) and tert- butyl 2,4-dioxopiperidine-1-carboxylate (CAS 845267-78-9, 4.27 g, 20.0 mmol) in acetonitrile (92 ml) was added dropwise DBU (4.5 ml, 30 mmol). The reaction was stirred at RT overnight. To the reaction mixture was added ice-water (200 ml_) and cone. HCI (2 ml_). The mixture was stirred for 20 min. and extracted with DCM. The organic phase was filtered over a water-repellent filter, conentrated under reduced pressure and purified by flash chromatography (silica, hexane / EtOAc gradient 0-50 %) to give 6.54 g of the title compound (71 % yield).
1H-NMR (400MHz, DMSO-de): d [ppm]= 13.36 (br s, 1 H), 7.73 (d, 1 H), 7.47 (dd, 1 H), 7.22 (t, 1 H), 3.76 – 3.82 (m, 5H), 2.88 (t, 2H), 1.48 (s, 9H).
LC-MS (method 1): Rt = 1.49 min; MS (ESIpos): m/z = 413.1 [M+H]+
Intermediate 5-1
A/-(3-chloro-2-methoxyphenyl)-4-hydroxy-2-oxo-1 ,2,5,6-tetrahydropyridine-3-carbothioamide
To a solution of tert- butyl 5-[(3-chloro-2-methoxyphenyl)carbamothioyl]-4-hydroxy-6-oxo-3,6-dihydropyridine-1 (2/-/)-carboxylate (intermediate 4-1 , 6.54 g, 15.8 mmol) in dichloromethane (94 ml) was added TFA (12 ml, 160 mmol) and the mixture was stirred 1.5 h at RT. The reaction mixture was concentrated under reduced pressure and the residue was solved in EtOAc and washed with sat. sodium bicarbonate solution and brine. The organic layer was filtered through a hydrophobic filter and the filtrate was dried to dryness. The residue was purified by flash chromatography (silica, hexane / EtOAc gradient 20-100 %) to give 4.06 g of the title compound (78 % yield).
1H-NMR (400 MHz, DMSO-de): d [ppm]= 16.45 (d, 1 H), 14.69 (s, 1 H), 14.33 (s, 1 H), 9.37 (br s, 1 H), 8.18 (br s, 1 H), 7.76 – 7.87 (m, 1 H), 7.37 – 7.45 (m, 1 H), 7.15 – 7.23 (m, 1 H), 3.73 – 3.76 (m, 3H), 3.43 (td, 1 H), 3.27 – 3.32 (m, 1 H), 2.79 (t, 1 H), 2.59 – 2.69 (m, 1 H).
LC-MS (method 1): Rt = 1.19 min; MS (ESIpos): m/z = 313 [M+H]+
ntermediate 6-2
A/-(3-chloro-2-methoxyphenyl)-4-{[(3-{[(2S)-1 ,4-dioxan-2-yl]methoxy}pyridin-4-yl)methyl]amino}-2-oxo-1 ,2,5,6-tetrahydropyridine-3-carbothioamide
A mixture of A/-(3-chloro-2-methoxyphenyl)-4-hydroxy-2-oxo-1 ,2,5,6-tetrahydropyridine-3-carbothioa ide (intermediate 5-1 , 866 mg, 2.77 mmol) and 1-(3-{[(2S)-1 ,4-dioxan-2-yl]methoxy}pyridin-4-yl)methanamine (intermediate 2-8, 776 mg, 80% purity, 2.77 mmol) in ACN (22 ml) was treated with A/,0-bis(trimethylsilyl)acetamide (2.05 ml, 8.6 mmol, CAS 10416-59-8) and stirred at 80°C for 4 h. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography (silica, DCM / EtOH gradient 0-20%) to give 1.23 g (95% purity, 81 % yield) of the title compound.
1H-NMR (400MHz, DMSO-d6): d [ppm]= 2.78 (t, 2H), 3.16 (td, 2H), 3.40 – 3.54 (m, 3H), 3.59 – 3.69 (m, 2H), 3.71 (s, 3H), 3.73 – 3.79 (m, 1 H), 3.83 – 3.95 (m, 2H), 4.16 (t, 2H), 4.67 (d, 2H), 7.11 (t, 1 H), 7.27 – 7.33 (m, 2H), 7.73 (br s, 1 H), 7.81 (dd, 1 H), 8.24 (d, 1 H), 8.39 (s, 1 H), 13.69 (s, 1 H), 14.79 (s, 1 H).
LC-MS (method 2): Rt = 1.09 min; MS (ESIpos): m/z = 519 [M+H]+
Example 2
3-(3-chloro-2-methoxyanilino)-2-(3-{[(2S)-1 ,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1 ,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (Stereoisomer 1)
The title compound from example 1 (140 mg) was separated into enantiomers by preparative chiral HPLC to give title compound (enantiomer 1 , 27 mg at Rt = 14.0 – 17.0 min) and enantiomer 2 (25 mg at Rt = 20.0 – 24.8 min, see example 3).
Preparative chiral HPLC method:
Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241 , Labcol Vario 4000; column: Cellulose SB 5m, 250×30 mm; eluent A: hexane + 0.1 vol. % diethylamine (99 %); eluent B: 2-propanol; isocratic: 50 % A + 50 % B; flow 50 ml/min; UV: 254 nm.
Analytical chiral HPLC method:
Instrument: Agilent HPLC 1260; column: Cellulose SB 3m, 100×4.6 mm; eluent A: hexane + 0.1 vol. % diethylamine (99 %); eluent B: 2-propanol; isocratic: 50 % A + 50 % B, flow 1.4 ml/min; temperature: 25°C; UV: 254 nm
Analytical chiral HPLC: Rt = 4.49 min.
Optical rotation:[a]D = 1.7° +/- 0.98° (c = 3.6 mg/2 ml, methanol)
Enantioselective synthesis confirmed the title compound as 3-(3-chloro-2-methoxyanilino)-2-(3-{[(2S)-1 ,4-dioxan-2-yl]methoxy}pyridin-4-yl)-1 ,5,6,7-tetrahydro-4/-/-pyrrolo[3,2-c]pyridin-4-one. 872 mg (95% purity, 72% yield) of the title compound were prepared in analogy to example 1 using A/-(3-chloro-2-methoxyphenyl)-4-{[(3-{[(2S)-1 ,4-dioxan-2-yl]methoxy}pyridin-4-yl)methyl]amino}-2-oxo-1 ,2,5,6-tetrahydropyridine-3-carbothioamide (intermediate 6-2, 1.23 g, 2.36 mmol) as starting material, followed by purification with preparative HPLC (method 10, gradient: 0.00-0.50 min 15% B, 0.50-6.00 min 15-55% B).
1H-NMR (400MHz, DMSO-d6): d [ppm]= 2.86 (t, 2H), 3.38 – 3.47 (m, 3H), 3.53 (td, 1 H), 3.69
– 3.78 (m, 2H), 3.83 (dd, 1 H), 3.88 (s, 3H), 3.90 (m, 1 H), 3.98 – 4.08 (m, 1 H), 4.12 – 4.18 (m, 1 H), 4.28 (dd, 1 H), 6.12 – 6.17 (quin, 1 H), 6.66 – 6.71 (m, 2H), 7.16 (s, 1 H), 7.28 (d, 1 H),
7.52 (s, 1 H), 8.04 (d, 1 H), 8.39 (s, 1 H), 11.07 (s, 1 H).
Analytical chiral HPLC: Rt = 4.46 min.
Optical rotation:[a]D = -12.5° +/- 0.52° (c = 5.6 mg/ l, chloroform)
PAT
- 4H-pyrrolo[3,2-c]pyridin-4-one compoundPublication Number: CN-114127064-BPriority Date: 2019-04-24Grant Date: 2023-12-26
- 4H-Pyrrolo[3,2-c]pyridin-4-one compoundsPublication Number: CN-117946100-APriority Date: 2019-04-24
- 4H-pyrrolo [3,2-c ] pyridin-4-one compoundsPublication Number: CN-117986251-APriority Date: 2019-04-24
- 4h-pyrrolo[3,2-c]pyridin-4-one compoundsPublication Number: TW-I849114-BPriority Date: 2019-04-24Grant Date: 2024-07-21
- 4H-pyrrolo[3,2-c]pyridin-4-one compoundPublication Number: KR-20220004103-APriority Date: 2019-04-24
- 4H-PYRROLO[3,2-C]PYRIDIN-4-ONE COMPOUNDSPublication Number: PE-20220254-A1Priority Date: 2019-04-24
- 4H-Pyrrolo [3,2-C] Pyridine-4-one CompoundPublication Number: JP-2022532850-APriority Date: 2019-04-24
- 4h-pyrrolo[3,2-c]pyridin-4-one compoundsPublication Number: US-2022298157-A1Priority Date: 2019-04-24
- 4H-PYRROL[3,2-C]PYRIDIN-4-ONE, ITS USES, PHARMACEUTICAL COMPOSITION, AND KIT OF PARTSPublication Number: BR-112021019998-B1Priority Date: 2019-04-24
- 4h-pyrrolo[3,2-c]pyridin-4-one compoundsPublication Number: WO-2020216781-A1Priority Date: 2019-04-24
- 4h-pyrrolo[3,2-c]pyridin-4-one compoundsPublication Number: TW-202106683-APriority Date: 2019-04-24
- 4H-pyrrolo(3,2-c)pyridin-4-one compoundsPublication Number: AU-2020262221-A1Priority Date: 2019-04-24
- 4H-pyrrolo [3,2-c ] pyridin-4-one compoundsPublication Number: CN-114127064-APriority Date: 2019-04-24
- 4h-pyrrolo[3,2-c]pyridin-4-one compoundsPublication Number: EP-3959211-A1Priority Date: 2019-04-24
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Medical uses
Sevabertinib is indicated for the treatment of adults with locally advanced or metastatic non-squamous non-small cell lung cancer whose tumors have HER2 (ERBB2) tyrosine kinase domain activating mutations.[1][2]
Adverse effects
The US prescribing information includes warnings and precautions for diarrhea, hepatotoxicity, interstitial lung disease/pneumonitis, ocular toxicity, pancreatic enzyme elevation, and embryo-fetal toxicity.[2]
History
Efficacy was evaluated in people with unresectable or metastatic, non-squamous non-small cell lung cancer with HER2 (ERBB2) tyrosine kinase domain activating mutations who had received prior systemic therapy and received sevabertinib in SOHO-01 (NCT05099172), an open-label, single-arm, multi-center, multi-cohort clinical trial.[2] HER2 (ERBB2) activating mutations were determined in tumor tissue or plasma by local laboratories prior to enrollment.[2]
The US Food and Drug Administration granted the application for sevabertinib priority review, breakthrough therapy, and orphan drug designations.[2]
Society and culture
Legal status
Sevabertinib was approved for medical use in the United States in November 2025.[3][4]
Names
Sevabertinib is the international nonproprietary name.[5]
Sevabertinib is sold under the brand name Hyrnuo.[1][3]
References
- “HYRNUO (sevabertinib) tablets, for oral use” (PDF). Bayer HealthCare Pharmaceuticals Inc. U.S. Food and Drug Administration.
- “FDA grants accelerated approval to sevabertinib for non-squamous non-small cell lung cancer”. U.S. Food and Drug Administration (FDA). 19 November 2025. Retrieved 21 November 2025.
This article incorporates text from this source, which is in the public domain. - “U.S. FDA Approves Hyrnuo (sevabertinib) for Previously Treated Patients with HER2-Mutated Locally Advanced or Metastatic Non-Squamous Non-Small Cell Lung Cancer” (Press release). Bayer. 20 November 2025. Retrieved 21 November 2025 – via Business Wire.
- “U.S. FDA grants accelerated approval to Bayer’s Hyrnuo (sevabertinib) for patients with previously treated advanced HER2-mutant non-small cell lung cancer”. Bayer (Press release). 20 November 2025. Retrieved 21 November 2025.
- World Health Organization (2025). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 93”. WHO Drug Information. 39 (1). hdl:10665/381075.
Further reading
- Le X, Kim TM, Loong HH, Prelaj A, Goh BC, Li L, et al. (November 2025). “Sevabertinib in Advanced HER2-Mutant Non-Small-Cell Lung Cancer”. The New England Journal of Medicine. 393 (18): 1819–1832. doi:10.1056/NEJMoa2511065. PMID 41104928.
- Siegel F, Siegel S, Kotýnková K, Karsli Uzunbas G, Korr D, Tomono H, et al. (October 2025). “Sevabertinib, a Reversible HER2 Inhibitor with Activity in Lung Cancer”. Cancer Discovery: OF1 – OF14. doi:10.1158/2159-8290.CD-25-0605. PMID 41090369.
External links
- “Sevabertinib”. NCI Drug Dictionary.
- “Sevabertinib ( Code – C185187 )”. EVS Explore.
- Clinical trial number NCT05099172 for “First in Human Study of BAY2927088 in Participants Who Have Advanced Non-small Cell Lung Cancer (NSCLC) With Mutations in the Genes of Epidermal Growth Factor Receptor (EGFR) and/or Human Epidermal Growth Factor Receptor 2 (HER2)” at ClinicalTrials.gov
| Clinical data | |
|---|---|
| Trade names | Hyrnuo |
| Other names | BAY2927088, sevabertinib hydrate (JAN JP) |
| License data | US DailyMed: Sevabertinib |
| Routes of administration | By mouth |
| Drug class | Antineoplastic |
| ATC code | None |
| Legal status | |
| Legal status | US: ℞-only[1] |
| Identifiers | |
| CAS Number | 2521285-05-0 |
| PubChem CID | 155234713 |
| DrugBank | DB21667 |
| ChemSpider | 129786615 |
| UNII | 2A7VPM5RWH |
| KEGG | D13098 |
| Chemical and physical data | |
| Formula | C24H25ClN4O5 |
| Molar mass | 484.94 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| SMILES | |
| InChI | |
/////sevabertinib, FDA 2025, APPROVALS 2025, Hyrnuo, 2A7VPM5RWH, BAY-2927088, BAY 2927088
Plozasiran
Plozasiran
CAS 2379776-40-4
2379776-41-5 SODIUM SALT
RNA, ([1′-de(6-amino-9H-purin-9-yl)]dA-(5′→5′)-sp-Am-Cm-Gm-Gm-Gm-Am-Cm-Am-(2′-deoxy-2′-fluoro)G-(2′-deoxy-2′-fluoro)U-(2′-deoxy-2′-fluoro)A-Um-Um-Cm-Um-Cm-Am-Gm-Um-Im-Am-(3′→3′)-sp-[1′-de(6-amino-9H-purin-9-yl)]dA), 3′-[O-[cis-4-[(3S,8S)-17-[[2-(acetylamino)-2-deoxy-β-D-galactopyranosyl]oxy]-3,8-bis[[[2-[2-[[2-(acetylamino)-2-deoxy-β-D-galactopyranosyl]oxy]ethoxy]ethyl]amino]carbonyl]-1,6,11-trioxo-15-oxa-2,7,12-triazaheptadec-1-yl]cyclohexyl] hydrogen phosphorothioate], complex with RNA (Um-sp-(2′-deoxy-2′-fluoro)C-sp-Am-sp-(2′-deoxy-2′-fluoro)C-Um-(2′-deoxy-2′-fluoro)G-Am-Gm-Am-Am-Um-(2′-deoxy-2′-fluoro)A-Cm-(2′-deoxy-2′-fluoro)U-Gm-(2′-deoxy-2′-fluoro)U-Cm-(2′-deoxy-2′-fluoro)C-Cm-(2′-deoxy-2′-fluoro)G-sp-Um) (1:1
FDA 2025, 11/18/2025, APPROVALS 2025, Redemplo, ARO-APOC3, VSA001, ARO-APOC3, VSA 001, ADS 005, XG9ARL6P25
To reduce triglycerides in adults with familial chylomicronemia syndrome
Plozasiran, sold under the brand name Redemplo, is a medication usd for the treatment of familial chylomicronemia syndrome.[1] Plozasiran is an apolipoprotein C-III (apoC-III)-directed small interfering ribonucleic acid (siRNA).[1] It is given by injection under the skin (subcutaneously).[1]
Plozasiran was approved for medical use in the United States in November 2025.[2]
Plozasiran is under investigation in clinical trial NCT05089084 (Study of ARO-APOC3 (Plozasiran) in Adults With Familial Chylomicronemia Syndrome (FCS)).
Plozasiran (ARO-APOC3) is an investigational RNAi therapeutic targeting apolipoprotein C-III (APOC3). It received an Orphan Drug designation by the FDA for the treatment of familial chylomicronemia syndrome.1
Plozasiran, a novel therapeutic agent, is a small interfering RNA (siRNA) developed by Silence Therapeutics. This innovative medication targets proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein involved in cholesterol metabolism, and is specifically indicated for the treatment of hypercholesterolemia, a condition characterized by elevated levels of low-density lipoprotein cholesterol (LDL-C) in the blood. Hypercholesterolemia is a significant risk factor for cardiovascular diseases, making effective treatments crucial for patient health.
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Medical uses
Plozasiran is indicated as an adjunct to diet to reduce triglycerides in adults with familial chylomicronemia syndrome.[1]
Familial chylomicronemia syndrome is a rare genetic disorder that affects the body’s ability to break down fats (triglycerides) in the bloodstream.[2] This leads to abnormally high levels of chylomicrons, which are particles that carry triglycerides.[2] Normal triglyceride levels are less than 150 mg/dL; levels above 500 mg/dL are considered severely high (severe hypertriglyceridemia).[2] People with familial chylomicronemia syndrome can have triglyceride levels in the thousands.[2] These high triglyceride levels can cause severe abdominal pain, inflammation of the pancreas (acute pancreatitis), and fatty deposits in the skin (xanthomas).[2] Some of these symptoms, specifically acute pancreatitis, can be life-threatening.[2]
Side effects
The most common side effects include hyperglycemia (high blood sugar), headache, nausea, and injection site reaction.[2]
History
The efficacy of plozasiran was demonstrated in a randomized, placebo-controlled, double-blind trial (NCT05089084) in adults with genetically confirmed or clinically diagnosed familial chylomicronemia syndrome maintained on a low-fat diet (≤20 grams fat per day).[2] Participants were randomly assigned to receive four total doses of plozasiran 25 mg or matching placebo, injected subcutaneously (under the skin) once every three months over a twelve-month treatment period.[2] The primary endpoint was percent change in fasting triglycerides from baseline to month ten.[2] The median percent change in triglycerides from baseline to month ten in the plozasiran treatment group was -59% compared to the placebo group.[2]
The US Food and Drug Administration granted the application for plozasiran breakthrough therapy, orphan drug, and fast track designations.[2]
Society and culture
Legal status
Plozasiran was approved for medical use in the United States in November 2025.[3]
Names
Plozasiran is the international nonproprietary name.[4]
Plozasiran is sold under the brand name Redemplo.[2][3]
References
- https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/219947s000lbl.pdf
- “FDA approves drug to reduce triglycerides in adults with familial chylomicronemia syndrome”. U.S. Food and Drug Administration. 18 November 2025. Retrieved 21 November 2025. This article incorporates text from this source, which is in the public domain.
- “Arrowhead Pharmaceuticals Announces FDA Approval of Redemplo (plozasiran) to Reduce Triglycerides in Adults with Familial Chylomicronemia Syndrome (FCS)” (Press release). Arrowhead Pharmaceuticals. 18 November 2025. Retrieved 21 November 2025 – via Business Wire.
- World Health Organization (2024). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 92”. WHO Drug Information. 38 (3). hdl:10665/379650.
Further reading
- Alla SS, Shah DJ, Meyur S, Agarwal P, Alla D, Moraboina SL, et al. (2025). “Small Interfering RNA (siRNA) in Dyslipidemia: A Systematic Review on Safety and Efficacy of siRNA”. Journal of Experimental Pharmacology. 17: 249–267. doi:10.2147/JEP.S521579. PMC 12126973. PMID 40453040.
- Olatunji G, Ogieuhi IJ, Kokori E, Oluwatomiwa AV, Ajimotokan OI, Odukudu GO, et al. (November 2024). “Olezarsen and Plozasiran in Dyslipidemia Management: A Narrative Review of Clinical Trials”. High Blood Pressure & Cardiovascular Prevention. 31 (6): 567–576. doi:10.1007/s40292-024-00677-7. PMID 39352667.
- Pan Z, Zaman MA, Kalsoom S, Zhang Y (November 2024). “Messenger interference RNA therapies targeting apolipoprotein C-III and angiopoietin-like protein 3 for mixed hyperlipidemia: the future of plozasiran and zodasiran”. Expert Review of Clinical Pharmacology. 17 (11): 1017–1023. doi:10.1080/17512433.2024.2423724. PMID 39469883.
- Sydhom P, Al-Quraishi B, Gohar A, El-Shawaf M, Shehata N, Ataya M, et al. (November 2025). “The Efficacy and Safety of Plozasiran on Lipid Profile in Dyslipidemic Disorders: A Systematic Review and Meta-Analysis”. Cardiovascular Drugs and Therapy. doi:10.1007/s10557-025-07798-8. PMID 41251855.
External links
- Clinical trial number NCT05089084 for “Study of ARO-APOC3 (Plozasiran) in Adults With Familial Chylomicronemia Syndrome (FCS) (PALISADE)” at ClinicalTrials.gov
| Clinical data | |
|---|---|
| Trade names | Redemplo |
| Other names | ARO-APOC3 |
| AHFS/Drugs.com | Redemplo |
| License data | US DailyMed: Plozasiran |
| Routes of administration | Subcutaneous |
| ATC code | None |
| Legal status | |
| Legal status | US: ℞-only[1] |
| Identifiers | |
| CAS Number | 2379776-40-4 |
| DrugBank | DB18997 |
| UNII | |
//////////Plozasiran, FDA 2025, APPROVALS 2025, Redemplo, ARO-APOC3, VSA001, ARO-APOC3, VSA 001, ADS 005, XG9ARL6P25
Ziftomenib
Ziftomenib
CAS 2134675-36-6
4MOD1F4ENC, KO 539
717.9 g/mol, C33H42F3N9O2S2
APPROVALS 2025, FDA 2025, 11/13/2025, Komzifti
4-methyl-5-[[4-[[2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]piperidin-1-yl]methyl]-1-[(2S)-2-(4-methylsulfonylpiperazin-1-yl)propyl]indole-2-carbonitrile
To treat adults with relapsed or refractory acute myeloid leukemia with a susceptible nucleophosmin 1 mutation who have no satisfactory alternative treatment options
Ziftomenib, sold under the brand name Komzifti, is an anti-cancer medication used for the treatment of acute myeloid leukemia.[1] Ziftomenib is a menin inhibitor.[1] It is taken by mouth.[1]
Ziftomenib blocks the interaction between two proteins, menin (MEN1) and KMT2A (also known as mixed lineage leukemia protein, MLL).[2][3]
Ziftomenib was approved for medical use in the United States in November 2025.[4][5]
Ziftomenib, also known as KO539, is an orally bioavailable inhibitor of the menin-mixed lineage leukemia (MLL; myeloid/lymphoid leukemia; KMT2A) fusion protein, with potential antineoplastic activity. Upon oral administration, ziftomenib prevents the interaction between the two proteins menin and MLL, and thus the formation of the menin-MLL complex. This reduces the expression of downstream target genes and results in an inhibition of the proliferation of MLL-rearranged leukemic cells. The menin-MLL complex plays a key role in the survival, growth and proliferation of certain kinds of leukemia cells
SYN
syn
WO2022086986
above similar not same
pat
WO2020069027
WO2018175746
WO2017161028
WO2018106820
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=US239825810&_cid=P20-MI88RV-91969-1
PAT
- Inhibitors of the myst family of lysine acetyl transferasesPublication Number: US-2025051343-A1
- Small molecule inhibitors of dyrk/clk and uses thereofPublication Number: US-2025051325-A1
- VCP/p97 INHIBITOR FOR THE TREATMENT OF CANCERPublication Number: US-2025049800-A1
- RNAi agents for inhibiting expression of HIF-2 alpha (EPAS1), compositions thereof, and methods of usePublication Number: US-12221610-B2Grant Date: 2025-02-11
- Inhibitors of the myst family of lysine acetyl transferasesPublication Number: US-2025051343-A1
- Small molecule inhibitors of dyrk/clk and uses thereofPublication Number: US-2025051325-A1
- VCP/p97 INHIBITOR FOR THE TREATMENT OF CANCERPublication Number: US-2025049800-A1
- RNAi agents for inhibiting expression of HIF-2 alpha (EPAS1), compositions thereof, and methods of usePublication Number: US-12221610-B2Grant Date: 2025-02-11
- N-(3-hydroxy-4-piperidinyl)benzamide derivatives and pharmaceutical compositionsPublication Number: NZ-201856-APriority Date: 1981-10-01
- Novel n-(3-hydroxy-4-piperidinyl)benzamide derivativesPublication Number: EP-0076530-B1Priority Date: 1981-10-01Grant Date: 1985-12-11
- Novel N-(3-hydroxy-4-piperidinyl)benzamide derivativesPublication Number: EP-0076530-A2Priority Date: 1981-10-01
- Boron-containing polyphosphonates for the treatment of calcogenic tumorsPublication Number: JP-S5817120-APriority Date: 1981-06-30
- Novel n-aryl-piperazinealkanamidesPublication Number: IE-53465-B1Priority Date: 1981-06-23
- Novel((bis(aryl)methylene)-1-piperidinyl)-alkyl-pyrimidinonesPublication Number: IE-56180-B1Priority Date: 1982-11-01
- Novel ((bis(aryl)methylene)-1-piperidinyl)alkyl-pyrimidinonesPublication Number: EP-0110435-B1Priority Date: 1982-11-01Grant Date: 1989-01-04
- Novel ((bis(aryl)methylene)-1-piperidinyl)alkyl-pyrimidinonesPublication Number: EP-0110435-A1Priority Date: 1982-11-01
- NEW // BIS (ARYL) METHYLENE / -1-PIPERIDINYL / -ALKYL-PyrimidinonesPublication Number: BG-60538-B2Priority Date: 1982-11-01
- Process for preparing n-(3-hydroxy-4-piperidinyl)benzamide derivativesPublication Number: KR-860001584-B1Priority Date: 1982-07-30Grant Date: 1986-10-10
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Medical uses
Ziftomenib is indicated for the treatment of adults with relapsed or refractory acute myeloid leukemia with a susceptible nucleophosmin 1 mutation who have no satisfactory alternative treatment options.[1]
Adverse effects
The US prescribing information includes warnings and precautions for differentiation syndrome, QTc interval prolongation, and embryo-fetal toxicity.[4]
History
Efficacy was evaluated in KO-MEN-001 (NCT04067336), an open-label, single, arm, multi-center trial in 112 adults with relapsed or refractory acute myeloid leukemia with an nucleophosmin 1 mutation identified using next-generation sequencing or polymerase chain reaction.[4] Participants with nucleophosmin 1 mutations, including type A, B, and D mutations and other nucleophosmin 1 mutations likely to result in cytoplasmic localization of the nucleophosmin 1 protein, were enrolled.[4]
The US Food and Drug Administration granted the application for ziftomenib priority review, breakthrough therapy, and orphan drug designations.[4]
Society and culture
Legal status
Ziftomenib was approved for medical use in the United States in November 2025.[6]
Names
Ziftomenib is the international nonproprietary name.[7][8]
Ziftomenib is sold under the brand name Komzifti.[6]
References
- https://kuraoncology.com/wp-content/uploads/prescribinginformation.pdf
- “Ziftomenib”. NCI Cancer Dictionary. National Cancer Institute.
- Rausch J, Dzama MM, Dolgikh N, Stiller HL, Bohl SR, Lahrmann C, et al. (October 2023). “Menin inhibitor ziftomenib (KO-539) synergizes with drugs targeting chromatin regulation or apoptosis and sensitizes acute myeloid leukemia with MLL rearrangement or NPM1 mutation to venetoclax”. Haematologica. 108 (10): 2837–2843. doi:10.3324/haematol.2022.282160. PMC 10543165. PMID 37102614.
- “FDA approves ziftomenib for relapsed or refractory acute myeloid leukemia with a NPM1 mutation”. U.S. Food and Drug Administration (FDA). 13 November 2025. Retrieved 14 November 2025. This article incorporates text from this source, which is in the public domain.
- “Novel Drug Approvals for 2025”. U.S. Food and Drug Administration (FDA). 13 November 2025. Retrieved 14 November 2025.
- “Kura Oncology and Kyowa Kirin Announce FDA Approval of Komzifti (ziftomenib), the First and Only Once-Daily Targeted Therapy for Adults with Relapsed or Refractory NPM1-Mutated Acute Myeloid Leukemia” (Press release). Kura Oncology. 13 November 2025. Retrieved 14 November 2025 – via GlobeNewswire News Room.
- World Health Organization (2022). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 87”. WHO Drug Information. 36 (1). hdl:10665/352794.
- World Health Organization (2022). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 88”. WHO Drug Information. 36 (3). hdl:10665/363551.
Further reading
- Wang ES, Issa GC, Erba HP, Altman JK, Montesinos P, DeBotton S, et al. (October 2024). “Ziftomenib in relapsed or refractory acute myeloid leukaemia (KOMET-001): a multicentre, open-label, multi-cohort, phase 1 trial”. The Lancet. Oncology. 25 (10): 1310–1324. doi:10.1016/S1470-2045(24)00386-3. PMID 39362248.
External links
- Clinical trial number NCT04067336 for “First in Human Study of Ziftomenib in Relapsed or Refractory Acute Myeloid Leukemia” at ClinicalTrials.gov
| Clinical data | |
|---|---|
| Trade names | Komzifti |
| Other names | KO-539; KO539 |
| AHFS/Drugs.com | Komzifti |
| License data | US DailyMed: Ziftomenib |
| Routes of administration | By mouth |
| Drug class | Antineoplastic |
| ATC code | None |
| Legal status | |
| Legal status | US: ℞-only[1] |
| Identifiers | |
| IUPAC name | |
| CAS Number | 2134675-36-6 |
| PubChem CID | 138497449 |
| IUPHAR/BPS | 11680 |
| DrugBank | DB17171 |
| ChemSpider | 115009296 |
| UNII | 4MOD1F4ENC |
| KEGG | D12419 |
| ChEMBL | ChEMBL5095038 |
| PDB ligand | K5O (PDBe, RCSB PDB) |
| Chemical and physical data | |
| Formula | C33H42F3N9O2S2 |
| Molar mass | 717.88 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| SMILES | |
| InChI | |
////////Ziftomenib, APPROVALS 2025, FDA 2025, 4MOD1F4ENC, Komzifti
Elinzanetant
Elinzanetant
CAS 929046-33-3
MW 668.6 g/mol MF C33H35F7N4O3
N-[6-[(7S,9aS)-7-(hydroxymethyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-2-[3,5-bis(trifluoromethyl)phenyl]-N,2-dimethylpropanamide
FDA 10/24/2025, Lynkuet, To treat moderate-to-severe vasomotor symptoms due to menopause
BAY-3427080; GSK-1144814; NT-814, UNII-NZW2BOW35N
Elinzanetant, sold under the brand name Lynkuet, is a medication used for the treatment of moderate to severe vasomotor symptoms due to menopause.[4] It is an neurokinin 1 and neurokinin 3 receptor antagonist.[4] It was developed by Bayer Healthcare.[4] It is taken by mouth.[4]
Elinzanetant is a non-hormonal, selective, neurokinin 1 (NK-1) and neurokinin 3 (NK-3) receptor antagonist.[5] By blocking NK-1 and NK-3 receptors signaling, elinzanetant is postulated to normalize neuronal activity involved in thermo- and sleep regulation in the hypothalamus.[5]
Elinzanetant is an orally bioavailable neurokinin/tachykinin 1 receptor (NK1-receptor; NK1R; NK-1R) and NK3 receptor (NK-3R; NK3R) antagonist, that may be used to treat vasomotor symptoms in menopausal woman. Upon oral administration, elinzanetant targets, competitively binds to and blocks the activity of the NK1R and NK3R in the central nervous system (CNS), thereby inhibiting the binding of the endogenous ligands and neuropeptides substance P (SP; neurokinin-1; NK1) and neurokinin B (NKB). This inhibits NK1R/NK3R-mediated signal transduction and may prevent certain menopausal symptoms such as hot flashes. Neurokinin-mediated signaling may increase during hormone deficiency and may cause hot flashes.
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021094247&_cid=P20-MHLSZY-53200-1
“Compound A” refers to 2-[3,5-Bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[(7S,9aS)-7-(hydroxymethyl)hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl]-3-pyridi-nyl}-N,2-dimethylpropanamide, and has the chemical structure depicted below.
(Compound A).
Example 8
2-[3.5-Bis(trifluoromethyl¾phenyl1-N-{4-(4-fluoro-2-methylphenyl¾-6-[(7S.9aS¾-7-(hvdroxymethyl¾hexa-hvdropyrazino[2,l-c1[l,41oxazin-8(lH)-yl1-3-pyridinyl}-N, 2-dimethyl propanamide as anhydrous crys talline form (Compound A)
Example 7 (2-[3,5-Bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[(7S,9aS)-7-(hy-droxymethyl)hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl]-3-pyridinyl}-N,2-dimethylpropanamide dihydrochloride salt mono-isopropanol solvate (Compound XII)) (3.4 kg), methyl-f-butyl ether (from now on, MTBE) (15.0 L/kg of Example 7) and NaOH 2.5N (4.9 L/kg of Example 7) were loaded, heated to 40QC and stirred for 10 to 30 min. The layers were settled for not less than 30 min at 40QC and the bottom aqueous layer discarded.
An aqueous solution of L-cysteine 9 wt% (5.0 L water per kg of Example 7+ 0.5 w/w L-cysteine per Ex ample 7) was added over the organic layer and stirred at 40QC for not less than 60 min. The layers were settled for not less than 30 min at 40QC and the bottom aqueous layer discarded.
Water (5.0 L/kg of Example 7) was added over the organic layer and stirred at 40QC for not less than 15 min. The layers were settled for not less than 60 min at 40QC and the bottom aqueous layer dis carded.
Water (5.0 L/kg of Example 7) was added over the organic layer and stirred at 40QC for not less than 15 min. The layers were settled for not less than 60 min at 40QC and the bottom aqueous layer dis carded.
The organic layer was concentrated at atmospheric pressure to 2.5 L/kg of Example 7. Iso-octane (8.3 L/kg of Example 7) was added at 50/55QC in not less than lh and the solution distilled under light vac uum to 4.0 L/kg of Example 7. A sample was taken for controlling the water and MTBE removal.
Isopropanol (0.8 L/kg of Example 7) was added and stirred at 65/75QC until total dissolution. The solu tion was cooled down to 45/55QC and filtered to remove any foreign matters. Iso-octane (4.5 L/kg of Example 7) was added and the batch heated to 70QC for not less than 30 min. The solution was cooled down to 50QC and seeded with a slurry of 2-[3,5-Bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[(7S,9aS)-7-(hydroxymethyl)hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl]-3-pyridi-nyl}-N,2-dimethylpropanamide(0.008% w/w of Example 7) in iso-octane (0.07 L/kg of Example 7) and isopropanol (0.01 L/kg of Example 7). The seeds were aged at 50QC for not less than 3h and additional iso-octane (4.2 L/kg of Example 7) was added in not less than 3h keeping the temperature at 50/55QC. The slurry was held at 50QC for not less than 8h, cooled down to 0QC in not less than 5h and aged for not less than 3h before proceeding with the centrifugation step.
The slurry was centrifuged and the cake washed with iso-octane (2 x 3.3 L/kg of Example 7).
The wet product was dried under vacuum at 50QC to obtain 2.34 kg of the title compound (yield = 82.7%). This product was sieved for delumping to obtain 2.26kg of the title compound with a 99.8% purity as a white powder.
NMR spectrometer: Varian Agilent Mercury Vx 400 (16 scans, sw 6400 Hz, 25 °C).
*H NMR (400 MHz, DMSO-ds): d 8.02 (s, 1 H), 7.85 (s, 1 H), 7.74 (bd, 2 H), 7.22-6.92 (m, 3 H), 6.61 (s, 1 H), 4.70 (m, 1 H), 4.21 (bd, 1 H), 4.09 (bd, 1 H), 3.75 (m, 3 H), 3.55 (td, 11.3 Hz, 2.2 Hz, 1 H), 3.40 (bd, 1 H), 3.15 (t, 10.5 Hz, 1 H), 3.02 (d, 11.3 Hz, 1 H), 2.63 (d, 11.3 Hz, 1 H), ca. 2.5 (bd, 2 H), 2.31-2.00 (m, 7 H), 1.58-1.10 (m, 6 H).
SYN
- WO2007028654
- https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2007028654&_cid=P20-MHLT4M-58180-1
Example 34
2-[3,5-Bis(trifluoromethyl)phenyl]-yV-{4-(4-fluoro-2-methylphenyl)-6-[(7S,9aS)-7-(hydroxymethyl)hexahydropyrazino[2,1 -c][1 ,4]oxazin-8(1 H)-yl]-3-pyridinyl}-A/,2-dimethylpropanamide (E34)
2-[3,5-bis(trifluoromethyl)phenyl]-Λ/-[6-[(7S,9aS)-7-({[(1 , 1 -dimethylethyl)(dimethyl)silyl]oxy}methyl)hexahydropyrazino[2,1-c][1 ,4]oxazin-8(1H)-yl]-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-Λ/,2-dimethylpropanamide (D24) (390 mg, 0.498 mmol) was dissolved 17 ml. of methanol. To this solution was added concentrated HCI (0.9 mL) at 00C, and stirring was continued at room temperature for 3h (complete conversion). The reaction mixture was loaded on a SCX cartridge and washed with MeOH. The product was eluted with 0.5 M methanolic ammonia. The product-containing fractions were evaporated, leaving the target compound as a white solid: 310 mg, 0.464 mmol, 93%.
UPLC/MS: m/z= 669 (M+1 ).
1H-NMR (DMSO-d6): δ (ppm) 8.07-7.97 (s, 1 H), 7.88-7.81 (s, 1 H), 7.79-7.69 (br. s, 2H), 7.19-7.11 (d, 1 H), 7.14-7.06 (br. s, 2H) 6.64-6.56 (s, 1 H), 4.75-4.65 (m, 1 H), 4.31-4.13 (br. S, 1 H), 4.15-4.01 (br. s, 1 H), 3.80-3.68 (m, 3H), 3.58-3.49 (t, 1 H); 3.43-3.34 (m, 1 H); 3.18-3.09 (t, 1 H); 3.04-2.98 (d, 1 H); 2.68-2.58 (d, 1 H); 2.51-2.45 (s, 3H); 2.20-2.13 (s, 3H); 2.29-2.00 (m, 4H); 1.54-1.39 (s, 3H); 1.39-1.28 (s, 3H).
SYN
Crystalline forms of a pyridine derivative
Publication Number: WO-2010015626-A1
Priority Date: 2008-08-05
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2010015626&_cid=P20-MHLT79-60873-1
ntermediate 7
2-r3.5-bis(trifluoromethyl)phenvn-Λ/-f4-(4-fluoro-2-methylphenyl)-6-r(7S,9aS)-7-(hvdroxymethyl)hexahvdro-pyrazinoF2,1-c1f1 ,41oxazin-8(1/-/)-vn-3-pyridinyl}-Λ/.2-dimethylpropanamide
16.90 g of bis(trifluoromethyl)phenyl]-Λ/-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]- Λ/,2-dimethylpropanamide (WO 2005/002577) 4.58 g sodium tert-butoxide and 2.1O g Bis-(tri-terf-butylphposphine-palladium(O) catalyst was loaded into the vessel under nitrogen.
10.00 g intermediate 6 dissolved in 338 mL toluene was charged to afford a dark brown solution. The solution was heated to 800C and stirred for at least 16 h (thin suspension obtained).
The reaction mixture was cooled down to 20-25°C and 16.90 g celite was added to give a brown suspension. The suspension was filtered over 16.90 g celite and washed with 33.8 mL toluene. 338 mL sat. sodium bicarbonate solution was added and the biphasic system was stirred for 5 min. at 20-250C. After phase separation, the aqueous layer was extracted twice with 118 mL toluene. The combined organic layers were treated with 90 mL of a 10% aqueous cysteine solution and stirred for 1 h at 25°C. After phase separation the organic layer was treated again with 90 mL of a 10% cysteine-solution and stirred for a further 1 h at 25°C. After phase separation , the organic layer was washed with 85 mL half saturated sodium bicarbonate solution then solvent exchanged to dioxane. The dioxane solution was cooled down to 10-150C. 63.5 mL of 4M hydrogen chloride in dioxane was added at 10-150C over at least 10 min. The solution was warmed to 20-25°C and stirred for 2 h.
Dioxane was concentrated down to 85 mL at 45°C under reduced pressure. 85 mL water and 254 mL dichloromethane were added to the residue to give a thin suspension. The biphasic system was stirred for 5 min. at 20-250C. The layers were separated and the organic phase was washed with 33.8 mL saturated sodium bicarbonate solution at 20-25°C (pH adjusted to 7-8). The biphasic system was stirred for 5 min. at 20-250C and the organic layer separated and concentrated under reduced pressure at 500C to afford crude title compound as a pale brown solid. 8.00 g of the title compound (78.8% a/a HPLC) was dissolved in 16 mL ethyl acetate. The filter was loaded with 80 to 104 g silica gel and conditioned with ethyl acetate. The product solution was loaded on top of the column and chromatography was started using ethyl acetate as solvent. The product fractions were combined and partially concentrated at 45-50°C under reduced pressure. To the mixture was added 2.64 g to 4.00 g silicycle (Si-Thiol, 1.2 mmol/g) at rt and stirred for 2 h. Filtration over 8.00 g celite and washing with 32 mL ethyl acetate gave the filtrate which was concentrated to dryness at 45°C afford the title compound as a light brown solid. ( Weight yield 72%) 1H-NMR [ppm, CDCI3]: 8.04-7.91 , (m, 1 H); 7.77, (s, 1 H); 7.72-7.60, (m, 2H); 7.59-7.16, (m, 1H); 7.06-6.74, (m, 2H); 6.44, (s, 1 H); 4.64-4.43, (m, 1 H); 4.38-4.18, (m, 1 H); 4.07-3.96, (m, 2H); 3.95-3.76, (m, 3H); 3.76-3.61 , (m, 1 H); 3.37-3.27, (m, 1 H); 3.16-2.98, (m, 2H); 2.84-2.70, (m, 1 H); 2.67-2.51 , (m, 2H); 2.49-2.22, (m, 5H); 2.19-2.06, (m, 2H); 1.64-1.31 , (m, 5H), OH broad and not observed
LIT
- Elinzanetant: a phase III therapy for postmenopausal patients with vasomotor symptomsPublication Name: Expert Opinion on Investigational DrugsPublication Date: 2024-01-02PMID: 38224099DOI: 10.1080/13543784.2024.2305122
- Elinzanetant (NT-814), a Neurokinin 1,3 Receptor Antagonist, Reduces Estradiol and Progesterone in Healthy WomenPublication Name: The Journal of clinical endocrinology and metabolismPublication Date: 2021-02-24PMCID: PMC8277204PMID: 33624806DOI: 10.1210/clinem/dgab108
- Pleiotypic responses of regenerating liverPublication Name: Advances in Enzyme RegulationPublication Date: 1976PMID: 9791DOI: 10.1016/0065-2571(76)90023-6
PAT
Pyridine Derivatives and Their Use in the Treatment of Psychotic Disorders
Publication Number: US-2008269208-A1
Priority Date: 2005-06-06
- Pyridine Derivatives And Their Use In The Treatment Of Psychotic DisordersPublication Number: US-2011190276-A1Priority Date: 2005-09-09
- Pyridine derivatives and their use in the treatment of psychotic disordersPublication Number: US-7683056-B2Priority Date: 2005-09-09Grant Date: 2010-03-23
- Pyridine derivatives and their use in the treatment of psychotic disordersPublication Number: US-7919491-B2Priority Date: 2005-09-09Grant Date: 2011-04-05
- Pyridine derivatives and their use in the treatment of psychotic disordersPublication Number: US-8097618-B2Priority Date: 2005-09-09Grant Date: 2012-01-17
- Pyridine derivatives and their use in the treatment of psychotic disordersPublication Number: WO-2007028654-A1Priority Date: 2005-09-09
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Medical uses
Elinzanetant is indicated for the treatment of moderate to severe vasomotor symptoms associated with menopause.[4]
Society and culture
Legal status
In September 2025, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Lynkuet, intended for the treatment of moderate to severe vasomotor symptoms (hot flushes).[5] The applicant for this medicinal product is Bayer AG.[5]
Lynkuet was approved for medical use in the United States in October 2025.[6]
Names
Elinzanetant is the international nonproprietary name.[7]
Elinzanetant is sold under the brand name Lynkuet.[8]
References
- “Details for: Lynkuet”. Drug and Health Products Portal. 23 July 2025. Retrieved 28 September 2025.
- “Lynkuet product information”. Lynkuet. 23 July 2025. Retrieved 28 September 2025.
- “MHRA approves elinzanetant to treat moderate to severe vasomotor symptoms (hot flushes) caused by menopause”. Medicines and Healthcare products Regulatory Agency (Press release). 8 July 2025. Retrieved 28 September 2025.
- https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/219469s000lbl.pdf
- “Lynkuet EPAR”. European Medicines Agency (EMA). 19 September 2025. Retrieved 27 September 2025. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
- “Novel Drug Approvals for 2025”. U.S. Food and Drug Administration (FDA). 24 October 2025. Retrieved 29 October 2025.
- World Health Organization (2020). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 84”. WHO Drug Information. 34 (3). hdl:10665/340680.
- “Bayer’s Lynkuet (elinzanetant), the First and Only Neurokinin 1 and Neurokinin 3 Receptor Antagonist, Receives FDA Approval for Moderate to Severe Hot Flashes Due to Menopause” (Press release). Bayer. 24 October 2025. Retrieved 29 October 2025 – via Business Wire.
External links
- Clinical trial number NCT05042362 for “A Study to Learn More About How Well Elinzanetant Works and How Safe it is for the Treatment of Vasomotor Symptoms (Hot Flashes) That Are Caused by Hormonal Changes Over 26 Weeks in Women Who Have Been Through the Menopause (OASIS-1)” at ClinicalTrials.gov
- Clinical trial number NCT05099159 for “A Study to Learn More About How Well Elinzanetant Works and How Safe it is for the Treatment of Vasomotor Symptoms (Hot Flashes) That Are Caused by Hormonal Changes Over 26 Weeks in Women Who Have Been Through the Menopause (OASIS-2)” at ClinicalTrials.gov
| Clinical data | |
|---|---|
| Trade names | Lynkuet |
| Other names | BAY-3427080; GSK-1144814; NT-814 |
| License data | US DailyMed: Elinzanetant |
| Routes of administration | By mouth |
| ATC code | None |
| Legal status | |
| Legal status | CA: ℞-only[1][2]UK: POM (Prescription only)[3]US: ℞-only[4] |
| Identifiers | |
| IUPAC name | |
| CAS Number | 929046-33-3 |
| PubChem CID | 16063568 |
| ChemSpider | 17223178 |
| UNII | NZW2BOW35N |
| KEGG | D12123 |
| CompTox Dashboard (EPA) | DTXSID101337049 |
| Chemical and physical data | |
| Formula | C33H35F7N4O3 |
| Molar mass | 668.657 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| SMILES | |
| InChI | |
///////elinzanetant, Lynkuet, FDA 2025, APPROVALS 2025, BAY 3427080, GSK 1144814, NT 814
Remibrutinib
Remibrutinib
CAS 1787294-07-8
N-[3-[6-amino-5-[2-[methyl(prop-2-enoyl)amino]ethoxy]pyrimidin-4-yl]-5-fluoro-2-methylphenyl]-4-cyclopropyl-2-fluorobenzamide
MW 507.5 g/mol, MF C27H27F2N5O3
- LOU064
- NVP-LOU064-NXA
- LOU064-NXA
- I7MVZ8HDNU
- WHO 11062
APPROVALS 2025, FDA 2025, 9/30/2025, To treat chronic spontaneous urticaria in adults who remain symptomatic despite H1 antihistamine treatment
Remibrutinib, sold under the brand name Rhapsido, is a medication used for the treatment of chronic spontaneous urticaria.[1] Remibrutinib is an oral, small molecule kinase inhibitor that inhibits Bruton’s tyrosine kinase (BTK).[1] It is taken by mouth.[1]
SYN
Discovery of LOU064 (Remibrutinib), a Potent and Highly Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase
https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b01916
SYN
- WO2015079417
- https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015079417&_cid=P12-MH1R14-25744-1
Example 6
N-(3-(6-Amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2- methylphenyl)-4-cyclopropyl-2-fluorobenzamide
(1) tert-Butyl (2-((4-amino-6-chloropyrimidin-5-yl)oxy)ethyl)(methyl)carbamate, INT 8
To a solution of 4-amino-6-chloropyrimidin-5-ol (content 90%, 2.00 g, 12.37 mmol) in THF (120 mL) was added N-Boc-N-methyl-2-hydroxyethylamine (6.07 g, 34.64 mmol) followed by SMOPEX-301 (1 mmol/g, 30.90 g, 30.90 mmol). Then, a solution of DIAD (6.01 mL, 30.52 mmol) in THF (20 mL) was added slowly. The reaction mixture was stirred at 60 °C for 3 hr. The mixture was filtered through a pad of Celite. The filtrate was concentrated to afford an oil which was triturated with EtOAc and a white precipitate was formed. The solid was filtered off to afford INT 8. The mother liquor was concentrated and the residue was purified by flash chromatography (silica; DCM/EtOAc gradient, 0- 100%) to afford more INT 8 as a beige solid.
UPLC-MS: MS (ESI): [M+H]+ 303.1, rt = 0.86 min. 1H NMR (DMSO-d6): δ (ppm) 7.97 (s, 1H), 7.26 (s, br, 2H), 4.02-3.93 (m, 2H), 3.54 (t, 2H), 2.89 (s, br, 3H), 1.39 (s, 9H).
(2) tert-Butyl (2-((4-amino-6-(3-(4-cyclopropyl-2-fluorobenzamido)-5-fluoro-2- methylphenyl)pyrimidin-5-yl)oxy)ethyl)(methyl)carbamate, INT 9
To a solution of INT 8 (447 mg, 1.48 mmol) in DME (7.0 mL) and water (1.0 mL) was added INT 5 (638 mg, 1.54 mmol) followed by aqueous sodium carbonate solution (1 M, 4.21 mL, 4.21 mmol). The mixture was degassed with argon for 10 min and bis(triphenylphosphine)palladium(II) dichloride (49.2 mg, 0.070 mmol) was added. The reaction mixture was stirred at 110 °C for 10 min in a microwave reactor. More INT 5 (232 mg, 0.56 mmol) was added and the reaction mixture was stirred at 110 °C for an additional 15 min in a microwave reactor. The mixture was partitioned between saturated aqueous sodium hydrogen carbonate solution and EtOAc. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica; DCM/EtOAc gradient, 0-100%) to afford INT 9 as an off-white solid.
UPLC-MS: MS (ESI): [M+H]+ 554.3, rt = 1.21 min. 1H NMR (DMSO-d6): δ (ppm) rotamers 9.76 (s, 1H), 8.19 (s, 1H), 7.74-7.53 (m, 2H) 7.20-6.85 (m, 5H), 3.57-3.48 (m, 2H), 3.29- 3.15 (m, 2H), 2.58 (s, 3H), 2.08-1.99 (overlapping s, 3H and m, 1H), 1.34 and 1.28 (s, 9H), 1.10-1.02 (m, 2H), 0.84-0.77 (m, 2H).
(3) N-(3-(6-Amino-5-(2-(methylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2- methylphenyl)-4-cyclopropyl-2-fluorobenzamide, INT 10
To a solution of INT 9 (335 mg, 0.61 mmol) in DCM (5.0 mL) was added TFA (0.47 mL, 6.05 mmol). The reaction mixture was stirred at RT for 15 hr. The mixture was concentrated under reduced pressure. The residue was dried in vacuum to afford INT 10 as theTFA salt as a brown oil.
UPLC-MS: MS (ESI): [M+H]+ 454.3, rt = 0.73 min. 1H NMR (DMSO-d6): δ (ppm) 10.02 (s, 1H), 9.07-8.13 (s, v br, number of H cannot be assigned), 8.58 (s, 1H), 8.51 (s, br, 2H), 7.71-7.61 (m, 2H), 7.29-7.22 (m, 1H), 7.14-7.05 (m, 2H), 3.75-3.65 (m, 2H), 3.16-3.07 (m, 2H), 2.48 (s, 3H, overlapping with solvent peak), 2.12 (s, 3H), 2.10-1.99 (m, 1H), 1.11-1.03 (m, 2H), 0.83-0.76 (m, 2H).
(4) N-(3-(6-Amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide
To a solution of acrylic acid (62 mg, 0.87 mmol) in DMF (4.0 mL) was added DIPEA (0.302 mL, 1.73 mmol) followed by T3P solution (50% in DMF) (0.438 mL, 0.750 mmol). The mixture was stirred at RT for 30 min. To a solution of INT 10 (containing 3.0 eq TFA, content 90%, 510 mg, 0.577 mmol) and DIPEA (0.302 mL, 1.731 mmol) in DMF (2.0 mL) at 0 °C was added dropwise the above solution. The reaction mixture was stirred at 0 °C for 30 min. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water (2x) and brine (2x), dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica;
DCM/(MeOH with 2% aqueous ammonium hydroxide) gradient, 0-9%) to afford the title compound Example 6 as a white solid.
UPLC-MS: MS (ESI): [M+H]+ 508.3, rt = 0.95 min. 1H NMR (DMSO-d6): δ (ppm) rotamers 9.77 and 9.56 (s, total 1H), 8.25-8.14 (m, 1H), 7.79-7.50 (m, 2H), 7.17-6.93 (m, 5H), 6.70-6.55 (m, 1H), 6.06 (t, 1H), 5.59 (d, 1H), 3.63-3.40 (m, 4H), 2.80 and 2.49 (s, total 3H, peak at 2.49 overlapping with solvent peak), 2.09-1.93 (m, 4H), 1.11-1.00 (m, 2H), 0.85-0.76 (m, 2H).
PAT
- US9512084,
- https://patentscope.wipo.int/search/en/detail.jsf?docId=US133778840&_cid=P12-MH1R60-30520-1
SYN
Publication Date: 2020
Publication Name: Synfacts
PAT
- Amino Pyrimidine DerivativesPublication Number: US-2023312483-A1Priority Date: 2013-11-29
- A complex of bisphenol and a phosphorus compound and heat-developable image-recording material containing the samePublication Number: DE-60121375-T2Priority Date: 2000-01-11Grant Date: 2007-07-05
- Photothermographic materialPublication Number: DE-60011207-T2Priority Date: 1999-10-26Grant Date: 2005-06-23
- CD19 binding molecules and uses thereofPublication Number: US-12221481-B2Grant Date: 2025-02-11
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Medical uses
Remibrutinib is indicated for the treatment of chronic spontaneous urticaria in adults who remain symptomatic despite H1 antihistamine treatment[1]
Society and culture
Legal status
Remibrutinib was approved for medical use in the United States in September 2025.[2]
Names
Remibrutinib is the international nonproprietary name.[3]
Remibrutinib is sold under the brand name Rhapsido.[2]
References
- https://www.novartis.com/us-en/sites/novartis_us/files/rhapsido.pdf
- “Novartis receives FDA approval for Rhapsido (remibrutinib), the only oral, targeted BTKi treatment for chronic spontaneous urticaria (CSU)” (Press release). Novartis Pharmaceuticals. 30 September 2025. Retrieved 1 October 2025 – via PR Newswire.
- World Health Organization (2020). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 83”. WHO Drug Information. 34 (1). hdl:10665/339768.
Further reading
- Maurer, Marcus; Berger, William; Giménez-Arnau, Ana; Hayama, Koremasa; Jain, Vipul; Reich, Adam; et al. (December 2022). “Remibrutinib, a novel BTK inhibitor, demonstrates promising efficacy and safety in chronic spontaneous urticaria”. The Journal of Allergy and Clinical Immunology. 150 (6): 1498–1506.e2. doi:10.1016/j.jaci.2022.08.027. hdl:10230/55511. ISSN 1097-6825. PMID 36096203.
- Maurer, Marcus; Giménez-Arnau, Ana; Jain, Vipul; Tillinghast, Jeffrey; Tolcachier, Alberto; Nigen, Simon; et al. (February 2022). “Remibrutinib Treatment Improves Quality of Life in Patients with Chronic Spontaneous Urticaria”. Journal of Allergy and Clinical Immunology. 149 (2): AB179. doi:10.1016/j.jaci.2021.12.589. S2CID 246522006.
External links
- Clinical trial number NCT05030311 for “A Phase 3 Study of Efficacy and Safety of Remibrutinib in the Treatment of CSU in Adults Inadequately Controlled by H1 Antihistamines (REMIX-1)” at ClinicalTrials.gov
- Clinical trial number NCT05032157 for “A Phase 3 Study of Efficacy and Safety of Remibrutinib in the Treatment of CSU in Adults Inadequately Controlled by H1-antihistamines (REMIX-2)” at ClinicalTrials.gov
| Clinical data | |
|---|---|
| Trade names | Rhapsido |
| License data | US DailyMed: Remibrutinib |
| Routes of administration | By mouth |
| ATC code | L04AA60 (WHO) |
| Legal status | |
| Legal status | US: ℞-only[1] |
| Identifiers | |
| IUPAC name | |
| CAS Number | 1787294-07-8 |
| PubChem CID | 118107483 |
| IUPHAR/BPS | 10457 |
| DrugBank | DB16852 |
| ChemSpider | 78317000 |
| UNII | I7MVZ8HDNU |
| KEGG | D12285 |
| ChEMBL | ChEMBL4483575 |
| PDB ligand | N6Z (PDBe, RCSB PDB) |
| Chemical and physical data | |
| Formula | C27H27F2N5O3 |
| Molar mass | 507.542 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| SMILES | |
| InChI | |
- Maurer M, Berger W, Gimenez-Arnau A, Hayama K, Jain V, Reich A, Haemmerle S, Lheritier K, Walsh P, Xia S, Storim J: Remibrutinib, a novel BTK inhibitor, demonstrates promising efficacy and safety in chronic spontaneous urticaria. J Allergy Clin Immunol. 2022 Dec;150(6):1498-1506.e2. doi: 10.1016/j.jaci.2022.08.027. Epub 2022 Sep 9. [Article]
- Nuesslein-Hildesheim B, Ferrero E, Schmid C, Huck C, Smith P, Tisserand S, Rubert J, Bornancin F, Eichlisberger D, Cenni B: Remibrutinib (LOU064) inhibits neuroinflammation driven by B cells and myeloid cells in preclinical models of multiple sclerosis. J Neuroinflammation. 2023 Aug 26;20(1):194. doi: 10.1186/s12974-023-02877-9. [Article]
- Bozek A, Reich A: Evaluating remibrutinib in the treatment of chronic spontaneous urticaria. Immunotherapy. 2025 May;17(7):479-484. doi: 10.1080/1750743X.2025.2510892. Epub 2025 Jun 2. [Article]
- Kaul M, End P, Cabanski M, Schuhler C, Jakab A, Kistowska M, Kinhikar A, Maiolica A, Sinn A, Fuhr R, Cenni B: Remibrutinib (LOU064): A selective potent oral BTK inhibitor with promising clinical safety and pharmacodynamics in a randomized phase I trial. Clin Transl Sci. 2021 Sep;14(5):1756-1768. doi: 10.1111/cts.13005. Epub 2021 Apr 9. [Article]
- Gimeno R, Ribas-Llaurado C, Pesque D, Andrades E, Cenni B, Ambros B, Pujol R, Gimenez-Arnau AM: Remibrutinib inhibits hives effector cells stimulated by serum from chronic urticaria patients independently of FcepsilonR1 expression level and omalizumab clinical response. Clin Transl Allergy. 2023 Mar;13(3):e12227. doi: 10.1002/clt2.12227. [Article]
- Dorner T, Kaul M, Szanto A, Tseng JC, Papas AS, Pylvaenaeinen I, Hanser M, Abdallah N, Grioni A, Santos Da Costa A, Ferrero E, Gergely P, Hillenbrand R, Avrameas A, Cenni B, Siegel RM: Efficacy and safety of remibrutinib, a selective potent oral BTK inhibitor, in Sjogren’s syndrome: results from a randomised, double-blind, placebo-controlled phase 2 trial. Ann Rheum Dis. 2024 Feb 15;83(3):360-371. doi: 10.1136/ard-2023-224691. [Article]
- FDA Approved Drug Products: RHAPSIDO (remibrutinib) tablets, for oral use [Link]
- Novartis: Novartis receives FDA approval for Rhapsido® (remibrutinib), the only oral, targeted BTKi treatment for chronic spontaneous urticaria (CSU) [Link]
//////////Remibrutinib, APPROVALS 2025, FDA 2025, Rhapsido, LOU064, NVP-LOU064-NXA, LOU064-NXA, I7MVZ8HDNU, WHO 11062
Fovinaciclib
Fovinaciclib
CAS 2146171-49-3
MF C29H40N8OS
Exact Mass: 548.3046
Molecular Weight: 548.75
7-cyclopentyl-N,N-dimethyl-2-({5-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]pyridin-2-yl}amino) thieno[3,2-d]pyrimidine-6-carboxamide
7-cyclopentyl-N,N-dimethyl-2-((5-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-2-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide
7-cyclopentyl-N, N-dimethyl-2- ( (5- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) pyridin-2-yl) amino) thieno [3, 2-d] pyrimidine-6-carboxamide
7-Cyclopentyl-N,N-dimethyl-2-((5-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)pyridin-2-yl)amino Thieno[3,2-d]pyrimidine-6-carboxamide
cyclin dependent kinase inhibitor, antineoplastic, Fovinaciclibum, LPW3H579X8, inzhou Aohong Pharmaceutical Co
- OriginatorChongqing Fochon Pharmaceutical
- DeveloperAhon Pharmaceutical; Chongqing Fochon Pharmaceutical; Shanghai Fosun Pharmaceutical
- Class2 ring heterocyclic compounds; Amides; Amines; Antineoplastics; Cyclopentanes; Piperazines; Piperidines; Pyridines; Pyrimidines; Small molecules; Thiophenes
- Mechanism of ActionCyclin-dependent kinase 4 inhibitors; Cyclin-dependent kinase 6 inhibitors
- MarketedHER2 negative breast cancer
- No development reportedSolid tumours
- 04 Sep 2025Chemical structure information added.
- 02 Sep 2025Launched for HER2-negative-breast-cancer (Late-stage disease, Second-line therapy or greater) in China (PO) (Shanghai Henlius Biotech pipeline, September 2025)
- 26 Aug 2025Registered for HER2-negative-breast-cancer (Late-stage disease, Second-line therapy or greater) in China (PO) prior to August 2025
Fovinaciclib is an orally bioavailable inhibitor of cyclin-dependent kinase (CDK) types 4 (CDK4) and 6 (CDK6), with potential antineoplastic activity. Upon administration, fovinaciclib selectively inhibits CDK4 and CDK6, which inhibits the phosphorylation of retinoblastoma protein (Rb) early in the G1 phase, prevents CDK-mediated G1/S transition and leads to cell cycle arrest. This suppresses DNA replication and decreases tumor cell proliferation. CDK4 and 6 are serine/threonine kinases that are upregulated in many tumor cell types and play key roles in the regulation of both cell cycle progression from the G1-phase into the S-phase and cell proliferation.
On May 29, 2025, China’s National Medical Products Administration (NMPA) approved the Class 1 innovative drug Fovinaciclib (CDK4&6 inhibitor), developed by Jinzhou Aohong Pharmaceutical Co., Ltd. This medication, in combination with fulvestrant, is indicated for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative recurrent or metastatic breast cancer, who have experienced disease progression following prior endocrine therapy.
Notably, Fovinaciclib represents an excellent example of scaffold hopping—its design replaces the pyrrolo-pyrimidine core of Ribociclib (first approved on March 13, 2017) with a thieno-pyrimidine ring.
PAT
https://patentscope.wipo.int/search/en/detail.jsf?docId=CN236278427&_cid=P21-MGRD95-18783-1
| Example 3 |
| 7-Cyclopentyl-N,N-dimethyl-2-((5-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)pyridin-2-yl)amino Thieno[3,2-d]pyrimidine-6-carboxamide (3) |
According to the synthesis method of Example 2, CH
3 CHO replaced by CH
2 O, to prepare the title compound 7-cyclopentyl-N,N-dimethyl-2-((5-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)pyridin-2-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide (3). MS-ESI (m/z): 549 [M+1] + .
PAT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017193872&_cid=P21-MGRDEF-24321-1
[0266]
7-cyclopentyl-N, N-dimethyl-2- ( (5- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) pyridi n-2-yl) amino) thieno [3, 2-d] pyrimidine-6-carboxamide (5)
[0267]
To a solution of 7-cyclopentyl-N, N-dimethyl-2- ( (5- (4- (piperazin-1-yl) piperidin-1-yl) pyridin-2-yl) amino) thieno [3, 2-d] pyrimidine-6-carboxamide (4) (1.5 g, 2.8 mmol) in DCM (45 mL) was added NaBH (OAc) 3(3.56 mg, 16.8 mmol) followed by CH 2O (40％in water, 252 mg, 3.4 mmol) . The mixture was stirred at r.t. for 30 min. The mixture was diluted with saturated aqueous NaHCO 3(100 mL) and extracted with DCM (2 × 30 mL) . The extracts were dried over Na 2SO 4. Solvents were evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 96: 3: 1 DCM/methanol/ammonia to give 7-cyclopentyl-N, N-dimethyl-2- ( (5- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) pyridin-2-yl) amino) thieno [3, 2-d] pyrimidine-6-carboxamide (5) . MS-ESI (m/z) : 549 [M + 1] +.
PAT
- Certain protein kinase inhibitorsPublication Number: JP-2019516790-APriority Date: 2016-05-07
- Certain protein kinase inhibitorsPublication Number: US-2019209566-A1Priority Date: 2016-05-07
- Certain protein kinase inhibitorsPublication Number: WO-2017193872-A1Priority Date: 2016-05-07
- Certain protein kinase inhibitorsPublication Number: US-10835535-B2Priority Date: 2016-05-07Grant Date: 2020-11-17
- A class of protein kinase inhibitorsPublication Number: CN-109153686-BPriority Date: 2016-05-07Grant Date: 2021-04-30
- specific protein kinase inhibitorsPublication Number: KR-102374033-B1Priority Date: 2016-05-07Grant Date: 2022-03-14
- Certain protein kinase inhibitorsPublication Number: EP-3452484-B1Priority Date: 2016-05-07Grant Date: 2023-07-05
- Certain protein kinase inhibitorsPublication Number: ES-2954148-T3Priority Date: 2016-05-07Grant Date: 2023-11-20
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//////////Fovinaciclib, CHINA 2025, APPROVALS 2025, cyclin dependent kinase inhibitor, antineoplastic, Fovinaciclibum, LPW3H579X8, inzhou Aohong Pharmaceutical Co
Imlunestrant
Imlunestrant
CAS 2408840-26-4
as tosylate: 2408840-41-3
(5R)-5-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinolin-2-ol
- (5r)-5-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-8-(trifluoromethyl)-5h-(1)benzopyrano(4,3-c)quinolin-2-ol
- 5h-(1)benzopyrano(4,3-c)quinolin-2-ol, 5-(4-(2-(3-(fluoromethyl)-1-azetidinyl)ethoxy)phenyl)-8-(trifluoromethyl)-, (5r)-
MF C29H24F4N2O3 MW 524.516
FDA 9/25/2025, Inluriyo, LY3484356, LY-3484356, To treat estrogen receptor-positive, human epidermal growth factor receptor 2-negative, estrogen receptor-1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy
Imlunestrant, sold under the brand name Inluriyo, is an anti-cancer medication used for the treatment of breast cancer.[1] It is an is an estrogen receptor antagonist.[1] It is used as the salt, imlunestrant tosylate.[2] It is taken by mouth.[1] It was developed by Eli Lilly and Company.[2]
The most common adverse events and laboratory abnormalities include decreased hemoglobin, musculoskeletal pain, decreased calcium, decreased neutrophils, increased AST, fatigue, diarrhea, increased ALT, increased triglycerides, nausea, decreased platelets, constipation, increased cholesterol, and abdominal pain.[2]
Imlunestrant was approved for medical use in the United States in September 2025.[2]
SYN
- Imlunestrant with or without Abemaciclib in Advanced Breast CancerPublication Name: The New England journal of medicinePublication Date: 2025-03-27PMID: 39660834DOI: 10.1056/nejmoa2410858
- Targeting the Estrogen Receptor for the Treatment of Breast Cancer: Recent Advances and ChallengesPublication Name: Journal of Medicinal ChemistryPublication Date: 2023-06-28PMID: 37377342DOI: 10.1021/acs.jmedchem.3c00136
- Novel endocrine therapies: What is next in estrogen receptor positive, HER2 negative breast cancer?Publication Name: Cancer Treatment ReviewsPublication Date: 2023-06PMID: 37146385DOI: 10.1016/j.ctrv.2023.102569
- Oral Selective Estrogen Receptor Degraders (SERDs) as a Novel Breast Cancer Therapy: Present and Future from a Clinical PerspectivePublication Name: International Journal of Molecular SciencesPublication Date: 2021-07-22PMCID: PMC8345926PMID: 34360578DOI: 10.3390/ijms22157812
PAT
https://patentscope.wipo.int/search/en/detail.jsf?docId=US281655517&_cid=P12-MG7DCV-14904-1
Example 1A
5-(4-{2-[3-(Fluoromethyl)azetidin-1-yl]ethoxy}phenyl)-8-(trifluoromethyl)-5H-[1]benzopyrano[4,3-c]quinolin-2-ol, Isomer 1Separate the two enantiomers of 5-(4-{2-[3-(fluoromethyl)azetidin-1-yl]ethoxy}phenyl)-8-(trifluoromethyl)-5H-[1]benzopyrano[4,3-c]quinolin-2-ol by chiral SFC with the following conditions: Column: LUX® Cellulose-1, 5×25 cm; eluting with a mobile phase of 30% iPrOH (with 0.5% DMEA) in CO 2; column temperature: 40° C.; flow rate: 300 g/minute; UV detection wavelength: 270 nm to give Example 1A as the first eluting enantiomer (Isomer 1). ES/MS (m/z): 525.2 (M+H). Confirm enantiomeric enrichment of Isomer 1 by chiral analytical SFC, >99% ee, t (R): 1.30 minutes; column: CHIRALCEL® OD-H, 4.6×150 mm; eluting with a mobile phase of 30% MeOH (0.2% IPA) in CO 2; column temperature: 40° C.; flow rate: 5 mL/minute; UV detection wavelength: 225 nm. Isolate the title compound of Example 1B to give the second eluting enantiomer (Isomer 2). ES/MS (m/z): 525.2 (M+H). Confirm enantiomeric enrichment of Isomer 2 by chiral analytical SFC, 98% ee, t (R): 2.03 minutes; column: CHIRALCEL® OD-H, 4.6×150 mm; eluting with a mobile phase of 30% MeOH (0.2% IPA) in CO 2; column temperature: 40° C.; flow rate: 5 mL/minute; UV detection wavelength: 225 nm.
Alternate Preparation Example 1B
Crystalline 5-(4-{2-[3-(Fluoromethyl)azetidin-1-yl]ethoxy}phenyl)-8-(trifluoromethyl)-5H-[1]benzopyrano[4,3-c]quinolin-2-ol, Isomer 2
PAT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020014435&_cid=P12-MG7DHN-18354-1
EXAMPLE 1
Racemic 5-(4-{2-[3-(Fluoromethyl)azetidin-l-yl]ethoxy}phenyl)-8-(trifluoromethyl)-5H- [ 1 ]benzopyrano[4,3 -c]quinolin-2-ol
Cool a solution of (4-{2-[3-(fluoromethyl)azetidin-l-yl]ethoxy}phenyl){3-[2-fluoro-4-(trifluoromethyl)phenyl]-7-hydroxyquinolin-4-yl}methanone (5.27 g, 9.71 mmol) in 1,4-dioxane (100 mL) to 5 °C. Add lithium triethylborohydride (1 M in THF, 30.0 mL, 30.0 mmol). Remove the cooling bath and stir for 1.5 hours at room temperature. Quench the mixture with water. Add saturated NH4Cl solution and EtOAc. Separate the layers and extract the aqueous layer with EtOAc. Combine the organic extracts, dry over anhydrous MgS04, filter, and concentrate the filtrate. Dissolve the crude residue in THF (100 mL).
Add sodium hydride (60% in mineral oil, 1.94 g, 48.5 mmol). Reflux the solution for 1.5 hours. Add additional sodium hydride (60% in mineral oil, 1.94 g, 48.5 mmol), then reflux for an additional 30 minutes. Cool the solution to room temperature and quench with water. Add EtOAc and saturated NH4Cl solution. Separate the layers and extract the aqueous layer with EtOAc. Combine the organic extract, dry over anhydrous MgS04, filter, and concentrate the filtrate. Purify the residue by silica gel column chromatography eluting with a gradient of 5-7% MeOH in DCM to give the title compound (3.70 g, 72%) as a light yellow foam. ES/MS (m/z): 525.2 (M+H).
Prepare the following compounds in a manner essentially analogous to the method of Example 1, with the following variations in procedure. For the reduction, use 3 to 5 equivalents of lithium triethylborohydride with reaction times from 30 minutes to one hour and drying of the organic layers over magnesium sulfate or sodium sulfate. ETse the crude residue directly or purify by silica gel column chromatography eluting with a gradient of 0-5-7.5-10% MeOH in DCM before cyclization. Complete the cyclization by refluxing in THF for up to 16 hours, or in DMF, from 2 hours at room temperature for Ex 2, to 2 hours at 85 °C for Ex 8. Extract with DCM or EtOAc and dry organic layers over magnesium sulfate or sodium sulfate. Purify by silica gel column chromatography using up to 10% (MeOH or 7 M ammoniated MeOH) in DCM (Ex 2: gradient 0-10% MeOH in DCM; Ex 5: gradient 4-10% 7 M ammoniated MeOH in DCM; Ex 8: gradient 5-7.5% 7 M ammoniated MeOH in DCM) or by high pH reversed phase HPLC as noted.
EXAMPLE 1A
-(4-{2-[3-(Fluoromethyl)azetidin-l-yl]ethoxy}phenyl)-8-(trifluoromethyl)-5H- [l]benzopyrano[4,3-c]quinolin-2-ol, Isomer 1
and
EXAMPLE 1B
5-(4-{2-[3-(Fluoromethyl)azetidin-l-yl]ethoxy}phenyl)-8-(trifluoromethyl)-5H- [l]benzopyrano[4,3-c]quinolin-2-ol, Isomer 2
Separate the two enantiomers of 5-(4-{2-[3-(fluoromethyl)azetidin-l-yl]ethoxy}phenyl)-8-(trifluoromethyl)-5H-[l]benzopyrano[4,3-c]quinolin-2-ol by chiral SFC with the following conditions: Column: LUX® Cellulose-l, 5 x 25 cm; eluting with a mobile phase of 30% iPrOH (with 0.5% DMEA) in C02; column temperature: 40 °C; flow rate: 300 g/minute; UV detection wavelength: 270 nm to give Example 1 A as the first eluting enantiomer (Isomer 1). ES/MS (m/z): 525.2 (M+H). Confirm enantiomeric enrichment of Isomer 1 by chiral analytical SFC, >99% ee, /(R>: 1.30 minutes; column: CHFRALCEL® OD-H, 4.6 x 150 mm; eluting with a mobile phase of 30% MeOH (0.2% IP A) in C02; column temperature: 40 °C; flow rate: 5 mL/minute; UV detection wavelength: 225 nm. Isolate the title compound of Example 1B to give the second eluting enantiomer (Isomer 2). ES/MS (m/z): 525.2 (M+H). Confirm enantiomeric enrichment of Isomer 2 by chiral analytical SFC, 98% ee, /(R>: 2.03 minutes; column: CHIRALCEL® OD-H, 4.6 x 150 mm; eluting with a mobile phase of 30% MeOH (0.2% IP A) in C02; column temperature: 40 °C; flow rate: 5 mL/minute; UV detection wavelength: 225 nm.
Alternate Preparation EXAMPLE 1B
Crystalline 5-(4-{2-[3-(Fluoromethyl)azetidin-l-yl]ethoxy}phenyl)-8-(trifluoromethyl)-5H- [l]benzopyrano[4,3-c]quinolin-2-ol, Isomer 2
Stir 5-(4-{2-[3-(fluoromethyl)azetidin-l-yl]ethoxy}phenyl)-8-(trifluoromethyl)-5H-[l]benzopyrano[4,3-c]quinolin-2-ol, 4-methylbenzenesulfonic acid, Isomer 2 (23.8 g, 0.034 mol) in water (250 mL) at 1000 rpm. Add NaOH (76 pL) and stir the solution for 2 hours. Add DCM (600 mL). Separate the mixture, dry the DCM extract with magnesium sulfate, filter the material through a syringe filter (0.45 pm), and concentrate to dryness. Allow the material to sit under a N2 stream over a weekend. Add 1 : 1 EtOH/water (80 mL) and stir the mixture with sonication. Collect a tan solid by filtration on a nylon membrane to give the title compound (10.47 g, 0.02 mol, 59%).
PAT
- Selective estrogen receptor degradersPublication Number: US-2023234960-A1Priority Date: 2018-07-12
- Selective estrogen receptor degraderPublication Number: CN-112424205-BPriority Date: 2018-07-12Grant Date: 2023-10-31
- selective estrogen receptor degraderPublication Number: CN-117379428-APriority Date: 2018-07-12
- Selective estrogen receptor degradersPublication Number: US-11993608-B2Priority Date: 2018-07-12Grant Date: 2024-05-28
- Selective estrogen receptor degradersPublication Number: US-12128040-B2Priority Date: 2018-07-12Grant Date: 2024-10-29
PAT
https://patents.google.com/patent/US11926634B2/en
Selective estrogen receptor degraders (SERDs) bind to the estrogen receptor (ER) and downregulate ER-mediated transcriptional activity. The degradation and downregulation caused by SERDs can be useful in the treatment of various proliferative immune mediated disorders, cell proliferation disorders, including cancers such as breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, gastric cancer, and lung cancer as well as mutations due to emerging resistance. Some small molecule examples of SERDs have been disclosed in the literature (see, e.g., WO2005073204, WO2014205136, and WO2016097071). Nonetheless, there is a need for new SERDs to treat ER-positive cancers, such as breast cancer, gastric cancer, and/or lung cancer.
As described in U.S. Pat. No. 10,654,866 (the ‘866 patent) a series of SERDs of the following formula have been discovered, along with pharmaceutically acceptable salts thereof:
wherein one of R1 and R2 are independently Cl, F, —CF3, or —CH3, and the other is H.
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……
| Clinical data | |
|---|---|
| Trade names | Inluriyo |
| Other names | LY3484356, LY-3484356 |
| AHFS/Drugs.com | Inluriyo |
| License data | US DailyMed: Imlunestrant |
| Routes of administration | By mouth |
| Drug class | Estrogen receptor antagonist |
| ATC code | None |
| Legal status | |
| Legal status | US: ℞-only[1] |
| Identifiers | |
| IUPAC name | |
| CAS Number | 2408840-26-4as tosylate: 2408840-41-3 |
| PubChem CID | 146603228 |
| DrugBank | DB19043 |
| ChemSpider | 115010421 |
| UNII | 9CXQ3PF69Uas tosylate: F7UDT90EW5 |
| KEGG | D12216as tosylate: D12217 |
| ChEMBL | ChEMBL5095183 |
| Chemical and physical data | |
| Formula | C29H24F4N2O3 |
| Molar mass | 524.516 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| SMILES | |
| InChI | |
References
- https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/218881s000lbl.pdf
- “FDA approves imlunestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer”. U.S. Food and Drug Administration (FDA). 25 September 2025. Retrieved 27 September 2025. This article incorporates text from this source, which is in the public domain.
- “U.S. FDA approves Inluriyo (imlunestrant) for adults with ER+, HER2-, ESR1-mutated advanced or metastatic breast cancer” (Press release). Eli Lilly. 25 September 2025. Retrieved 27 September 2025 – via PR Newswire.
- World Health Organization (2022). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 88”. WHO Drug Information. 36 (3). hdl:10665/363551.
Further reading
- Jhaveri, Komal L.; Jeselsohn, Rinath; Lim, Elgene; Hamilton, Erika P.; Yonemori, Kan; Beck, J. Thaddeus; et al. (June 2022). “A phase 1a/b trial of imlunestrant (LY3484356), an oral selective estrogen receptor degrader (SERD) in ER-positive (ER+) advanced breast cancer (aBC) and endometrial endometrioid cancer (EEC): Monotherapy results from EMBER”. Journal of Clinical Oncology. 40 (16_suppl): 1021. doi:10.1200/JCO.2022.40.16_suppl.1021. S2CID 249445691.
- Jhaveri, Komal; O’Shaughnessy, Joyce; Andre, Fabrice; Goetz, Matthew P.; Harbeck, Nadia; Martín, Miguel; et al. (March 2023). “Abstract OT1-01-02: EMBER-4: A phase 3 adjuvant trial of imlunestrant vs standard endocrine therapy (ET) in patients with ER+, HER2- early breast cancer (EBC) with an increased risk of recurrence who have previously received 2 to 5 years of adjuvant ET”. Cancer Research. 83 (5_Supplement): OT1–01–02-OT1-01–02. doi:10.1158/1538-7445.SABCS22-OT1-01-02.
- Neven, P.; Stahl, N.; Losada, M.J. Vidal; Jimenez, M. Martin; Kaufman, P.A.; Harbeck, N.; et al. (October 2023). “273P A preoperative window-of-opportunity (WOO) study of imlunestrant in ER+, HER2- early breast cancer (EBC): Final analysis from EMBER-2”. Annals of Oncology. 34: S292 – S293. doi:10.1016/j.annonc.2023.09.470. S2CID 264385454.
External links
- Clinical trial number NCT04975308 for “A Study of Imlunestrant, Investigator’s Choice of Endocrine Therapy, and Imlunestrant Plus Abemaciclib in Participants With ER+, HER2- Advanced Breast Cancer (EMBER-3)” at ClinicalTrials.gov
/////////Imlunestrant, FDA 2025, APPROVALS 2025, Inluriyo, CANCER, LY3484356, LY 3484356, 9CXQ3PF69U
Brensocatib
Brensocatib
WeightAverage: 420.469
Monoisotopic: 420.179755269
Chemical FormulaC23H24N4O4
- AZD7986
- CAS 1802148-05-5
- INS1007
- AZD 7986
- WHO 11097
(2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-1,4-oxazepane-2-carboxamide
- 1,4-Oxazepine-2-carboxamide, N-((1S)-1-cyano-2-(4-(2,3-dihydro-3-methyl-2-oxo-5-benzoxazolyl)phenyl)ethyl)hexahydro-, (2S)-
- (2S)-N-((1S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide
- (2S)-N-{(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide
- Brensocatib [USAN]
- (S)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide
- UNII-25CG88L0BB
- (2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-1,4-oxazepane-2-carboxamide
FDA 8/12/2025. Brinsupri, To treat non-cystic fibrosis bronchiectasis
Brensocatib is an investigational new drug that is being evaluated to treat bronchiectasis.[1] It is a dipeptidyl-peptidase I (also known as cathepsin C) inhibitor.[2]
A phase 3 clinical trial, known as the ASPEN trial, was conducted to evaluate the safety and efficacy of brensocatib in patients with non-cystic fibrosis bronchiectasis.[3] Brensocatib tablets (Brinsupri) by Insmed Inc. was approved by the FDA in August 2025 after it received breakthrough therapy designation and was reviewed on a priority timeline.
Brensocatib is an orally bioavailable, small molecule, reversible inhibitor of dipeptidyl peptidase 1 (DPP1), with potential anti-inflammatory activity. Upon oral administration, brensocatib reversibly binds to and inhibits the activity of DPP1, thereby inhibiting the activation of neutrophil serine proteases (NSPs), including neutrophil elastase (NE), during neutrophil maturation. This inhibits the activity of NSPs, and may prevent lung inflammation and injury and improve lung function associated with NSPs-induced respiratory diseases. NSPs, serine proteases released by neutrophils during inflammation, is upregulated in a number of respiratory diseases.
SYN
J. Med. Chem. 2016, 59, 9457–9472, DOI: 10.1021/acs.jmedchem.6b01127
https://www.thieme-connect.com/products/ejournals/pdf/10.1055/s-0040-1719365.pdf
SYN
Brensocatib is now a clinical candidate to impair proteasedriven tissue degradation in COVID-19 (B. Korkmaz,
A. Lesner, S. Marchand-Adam, C. Moss, D. E. Jenne
J. Med. Chem. 2020, 63, 13258).
PAT
https://patents.google.com/patent/US9522894B2/en
A compound according to claim 1
which is (2S)—N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide
EXAMPLESExample 1(2S)—N-[(1S)-1-Cyano-2-(4′-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide
i) tert-Butyl(2S)-2-{[(1S)-1-cyano-2-(4′-cyanobiphenyl-4-yl)ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate
2-Pyridinol-1-oxide (0.155 g, 1.4 mmol), TEA (0.36 g, 3.6 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.268 g, 1.4 mmol) were added to a solution of (2S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid (Intermediate 3, 0.294 g, 1.2 mmol) in DCM (15 mL). After 20 min
4′-[(2S)-2-amino-2-cyanoethyl]biphenyl-4-carbonitrile (Intermediate 1, 0.296 g, 1.2 mmol) was added and the mixture was stirred for 3 h and allowed to stand at rt for 18 h. The mixture was heated at 40° C. for 4 h before water (15 mL) was added. After 10 min the DCM was dried (phase separating cartridge) and evaporated under reduced pressure. The resultant yellow oil was purified by silica gel column chromatography to give the subtitled compound (0.29 g, 52%). Used without further purification in the next step.ii) (2S)—N-[(1S)-1-Cyano-2-(4′-cyanobiphenyl-4-yl)ethyl]-1,4-oxazepane-2-carboxamide
Prepared according to procedure in Method A step ii) using tert-butyl(2S)-2-{[(1S)-1-cyano-2-(4′-cyanobiphenyl-4-yl)ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate to afford the title compound as a white solid (60 mg, 28%).
1H NMR (400 MHz, CDCl3): δ 7.77-7.65 (m, 4H), 7.62-7.57 (m, 2H), 7.40 (d, 2H), 7.11 (d, 1H), 5.18-5.11 (m, 1H), 4.19-4.14 (m, 1H), 4.06-3.96 (m, 2H), 3.75-3.69 (m, 1H), 3.56-3.48 (m, 2H), 3.18-3.05 (m, 3H), 2.95-2.90 (m, 1H), 2.70 (ddd, 1H) (1 exchangeable proton not observed).
LCMS (10 cm_ESCI_Formic_MeCN) tR 2.57 (min) m/z 375 (MH+).Example 2(2S)—N-{(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide
i) tert-Butyl(2S)-2-({(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (468 mg, 2.44 mmol) and 2-pyridinol 1-oxide (271 mg, 2.44 mmol) were added to a solution of (2S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid (Intermediate 3, 490 mg, 2.0 mmol) in DCM (15 mL). The reaction was stirred at rt for 30 min before the addition of (2S)-2-amino-3-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]propanenitrile (Intermediate 2, 586 mg, 2.0 mmol) and DiPEA (1.79 mL, 10 mmol). The reaction was stirred at rt for 18 h before transferring to a separating funnel. The mixture was washed with 2 M hydrochloric acid, saturated sodium hydrogen carbonate solution and brine. The organic extract was run through a hydrophobic frit/phase separator and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with 0-60% EtOAc in iso-hexane to afford the subtitled compound as an oil (457 mg, 44%). 1H NMR (400 MHz, CDCl3): δ 7.63-7.52 (m, 2H), 7.38 (d, 2H), 7.36-7.24 (m, 2H), 7.35-6.98 (m, 2H), 5.18 (t, 1H), 4.22-3.97 (m, 2H), 3.76-3.67 (m, 0.5H), 4.10-2.94 (m, 4.5H), 3.35-3.26 (m, 1H), 3.24-3.04 (m, 3H), 2.06-1.82 (m, 2H), 1.47 (s, 10H).ii) (2S)—N-{(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide
tert-Butyl(2S)-2-({(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate (457 mg, 0.85 mmol) was dissolved in formic acid (3 mL) and heated at 50° C. for 10 min on a pre-heated stirrer hotplate. After this time the reaction was concentrated under reduced pressure, dissolved in DCM and washed with saturated sodium hydrogen carbonate solution. The organic extract was run through a hydrophobic frit/phase separator and concentrated under reduced pressure. The resultant foam was purified by silica gel column chromatography eluting with 0-5% methanolic ammonia (7 N) in DCM to afford the title compound as solid material (230 mg, 64%).
1H NMR (400 MHz, CDCl3): δ 7.59-7.51 (m, 2H), 7.39 (dd, 2H), 7.33-7.23 (m, 3H), 7.14 (d, 1H), 5.23-5.12 (m, 1H), 4.12-4.06 (m, 1H), 4.05-3.95 (m, 1H), 3.81-3.71 (m, 1H), 3.46 (s, 3H), 3.34-3.26 (m, 1H), 3.19-3.00 (m, 3H), 2.99-2.82 (m, 2H), 1.92-1.77 (m, 2H) (one exchangeable proton not observed).
LCMS (10 cm_ESCI_Formic_MeCN) tR 2.48 (min) m/z 375 (MH+).Example 2Alternative Synthesis(2S)—N-{(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamidei) 5-Chloro-1,3-benzoxazol-2(3H)-one
To a solution of 2-amino-4-chlorophenol (400 g, 2.79 mol) in 2-MeTHF (6 L) was added CDI (497 g, 3.07 mol) under N2 (exotherm 11.0° C.-22.0° C.). The reaction mixture was heated at reflux for 1 h. The mixture was cooled to rt, washed with 2 M HCl(aq) (6 L), 8% NaHCO3(aq) (6 L) and brine (3 L). The organic layer was dried over MgSO4, filtered and evaporated. This gave the product as a pale brown solid (456.1 g, 97% yield, LC purity >99%).
1H NMR (270 MHz, DMSO-d6): δ 12.0-11.5 (br s, 1H), 7.31 (d, 1H), 7.12 (m, 2H).
LCMS (5 cm_ESCI, aq. formic acid_methanol) tR 3.87 (min) m/z 169.8 (MH+).ii) 5-Chloro-3-methyl-1,3-benzoxazol-2(3H)-one
To a solution of 5-chloro-1,3-benzoxazol-2(3H)-one (stage i) (1111.8 g, 6.56 mol) in DMF (4.12 L) was added Cs2CO3 (2136.4 g, 6.56 mol) maintaining the temperature between 0-5° C. MeI (450 ml, 7.21 mol) was then added slowly maintaining the temperature between 0-5° C. The reaction mixture was allowed to warm-up to rt and stirred overnight. The mixture was cooled to 0-5° C. and H2O (4.12 L) was added slowly. The reaction mixture was then warmed to rt and stirred for 15 min. The solids were filtered off and washed with water (4×980 ml). The filter cake was dried under vacuum at 55° C. overnight (1149.9 g, 96% yield, LC purity >99%, H2O: (Karl Fischer) 0.1%).
1H NMR (270 MHz, DMSO-d6): δ 7.45 (d, 1H), 7.35 (d, 1H), 7.15 (dd, 1H), 3.35 (s, 3H). LCMS (5 cm_ESCI_aq. formic acid_methanol) tR 4.13 (min) m/z 183.8 (M+).iii) 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazol-2(3H)-one
A solution of 5-chloro-3-methyl-1,3-benzoxazol-2(3H)-one (stage ii)) (350 g, 1.91 mol), B2pin2 (581.0 g, 2.29 mol) and KOAc (561.3 g, 5.72 mol) was vacuum degassed and purged with N2 (×3). Pd(OAc)2 (12.9 g, 57.2 mmol) and XPhos (54.6 g, 114 mmol) were added and the mixture was vacuum degassed and purged with N2 (×3). The mixture was heated to 75° C. A large exotherm was observed at ˜70° C. which warmed-up the mixture to reflux (100° C.). The reaction mixture was stirred for 1 h with no heating. HPLC analysis indicated 2.5% of the starting material remaining therefore the mixture was heated at 85° C. for 1 h. At this stage, no further change was observed. Additional portions of B2pin2 (14.6 g, 57.2 mmol), KOAc (5.7 g, 57.2 mmol), Pd(OAc)2 (12.9 g, 57.2 mmol) and XPhos (27.3 g, 57.2 mmol) were added and the mixture was stirred for 1 h at 75° C. HPLC analysis showed no starting material remaining. The mixture was cooled to rt, filtered through a pad of Celite (501 g) and the cake was washed with EtOAc (2240 ml). The filtrate was combined with two other batches prepared in the same way (2×350 g) and evaporated. This gave 1865.1 g of the product as a grey solid (97% yield, 90.0% pure by LC, 82±2% pure by 1H NMR (DMSO-d6) assay vs TCNB).
1H NMR (270 MHz, DMSO-d6): δ 7.40-7.50 (m, 2H), 7.30 (d, 1H), 3.40 (s, 3H), 1.30 (s, 12H).
LCMS (5 cm_ESCI_aq. formic acid_methanol_) tR 4.91 (min) m/z 276.1 (MH+).iv) Nα-(tert-Butoxycarbonyl)-4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-L-phenylalaninamide
To a suspension of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazol-2(3H)-one (stage iii)) (859 g, 700 g active, 2.544 mol) and tert-butyl (S)-1-carbamoyl-2-(4-iodophenypethylcarbamate (prepared according to the procedure in WO 2009/074829 p. 47), (903 g, 2.313 mol) in dioxane (4.1 L) was added 2 M K2CO3 (2.3 L). The suspension was vacuum degassed and purged with N2 (×3). Pd(dppf)Cl2.DCM (28.33 g, 0.0347 mol) was added and the reaction mixture was heated at 75° C. for 3 h. The mixture was cooled to rt and diluted with water (6.4 L). The suspension was stirred at rt overnight; the solid was filtered off and washed with water (3×1 L). The product was dried at 45° C. for 3 days (1269.1 g, yield 133%—by 1H NMR contains pinacol related impurity and dioxane, LC 94.3% pure, H2O: (Karl Fischer) 3.35%).
1H NMR (270 MHz, DMSO-d6): δ 7.62-7.34 (m, 7H), 7.04 (brs, 2H), 6.86 (d, 1H) 4.12 (m, 1H), 3.40 (s, 3H), 3.00 (dd, 1H), 2.78 (dd, 1H), 1.30 (s, 9H).
LCMS (5 cm_ESI_Water_MeCN) tR 4.51 (min) m/z 312 (MH+).v) 4-(3-Methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-L-phenylalaninamide
To a very thick suspension of Nα-(tert-butoxycarbonyl)-4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-L-phenylalaninamide (stage iv)) (1269 g, active 952 g assumed 100% conversion at stage iv), 2.3138 mol) in DCM (2.1 L) under N2 was added dropwise 4.1 M HCl in dioxane (2.7 L, 11.06 mol) over 1 h maintaining the temperature at 15° C. (suspension became more mobile after addition of approx. 0.5 L of 4.1 M HCl dioxane). After 2 h, the mixture was diluted with water (5.6 L) and stirred for 30 min at rt. The mixture was then filtered through a pad of Celite (500 g) to remove undissolved material—very slow filtration; the Celite was checked for product by LC. The pad was washed with water (400 ml). The layers DCM/dioxane-water were separated. The aqueous layer was cooled to ˜5° C. and 35% NH3 (aq) (700 ml) was added slowly to achieve pH=9-10. The suspension was stirred overnight then the product was filtered off and washed with water (3×400 ml). The product was dried at 45° C. in vacuo for 2 days (off white solid, 489.4 g, 68% yield over two stages, 99.4% pure by LC, >99% EP, 98±2% pure by 1H NMR assay vs TCNB in DMSO, H2O: (Karl Fischer) 0.92%).
1H NMR (270 MHz, DMSO-d6): δ 7.59-7.30 (m, 7H), 6.98 (brs, 1H), 3.36 (m, 4H), 2.95 (dd, 1H), 2.67 (dd, 1H) 1.86 (brs, 2H).
LCMS (5 cm_ESI_Water_MeCN) tR 2.76 (min) m/z 312 (MH+).vi) tert-Butyl(2S)-2-({(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate
To a solution of 4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-L-phenylalaninamide (stage v)) (756 g, active 733 g, 2.354 mol) and (2S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid (577 g, 2.354) (Intermediate 3) in DMF (3 L) was added DiPEA (1230 ml, 7.062 mol) under N2. T3P in DMF (50% w/w, 1924 ml, 3.296 mol) was added dropwise over 1.5 h maintaining the temperature<25° C. After 30 min, LC completion check indicated completion of the coupling reaction. DiPEA (1230 ml, 7.062 mol) was then added and the reaction mixture was heated to 50° C. T3P in DMF (50% w/w, 3986 ml, 6.827 mol) was added portionwise over 1 h (no exotherm observed). The reaction mixture was stirred at 50° C. for 4 h and then at rt overnight. The mixture was cooled to 10° C., diluted with 2-MeTHF (4 L) and water (5.6 L, exothermic). The layers were separated and the aqueous layer was extracted with 2-MeTHF (2×4 L). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. This delivered the product as a pale brown solid in 98% yield (1242 g (active 1205 g), corrected yield 98%, LC purity 98.4%, 1H NMR assay vs TCNB 97±2%, main impurities by 1H NMR: 2-MeTHF 1.9%, DMF 0.6%).vii) (2S)—N-{(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide
A solution of tert-butyl(2S)-2-({(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate (stage vi)) (1776 g, active 1671 g, 3.210 mol) in formic acid/water (4.2 L/440 ml) was stirred on a buchi at 35-37° C. under reduced pressure (300-500 mbar). After 3 h, LCMS completion check indicated 93.95% of the product and 0.5% of the starting material. The mixture was concentrated (4 h) to give an oily residue. The residue was dissolved in water (4.4 L) and washed with TBME (2.2 L). The aqueous layer was vigorously stirred and treated with NH3(aq) (1.8 L) at <25° C. to achieve pH=9-10. The mixture was stirred at rt for 3 h. The solid was filtered off and washed with water (3×1 L). The filter cake was dried at 45° C. overnight. This gave the product as a pale brown solid (1498 g, active 1333 g, LC 91.5%, 1H NMR assay vs TCNB 89±2%, H2O: (Karl Fischer) 4.63%).
The crude product was re-crystallised from EtOH/H2O in two batches (2×747 g).
Batch A: The crude product (747 g) was dissolved in EtOH (8 L) at reflux under N2. Water (1.6 L) was added slowly. The mixture was hot filtered (65° C.) to remove black particles (filtrate temperature
50° C.) and then stirred at 40° C. overnight. The suspension was cooled to 10° C. over 4 h and held at that temperature for 3 h. The product was filtered off and washed with EtOH/H2O (8:2, 3×500 ml) then water (3×500 ml). The filter cake was dried at 45° C. overnight (473 g, 97.7% pure by LC, Pd level 71.4 ppm).
Batch B gave 436 g of the product (95.8% pure by LC, Pd level 65.8 ppm).
The liquors from both batches were combined and concentrated to ˜8 L. The liquors were left overnight at rt. The solids were filtered off and washed with EtOH/H2O (8:2, 3×400 ml) then water (3×400 ml). The product was dried at 45° C. overnight. This gave additional 88 g of the product (LC purity 95.0%).
The products (LC purity of the blend 95.69%) were re-crystallised from EtOH/H2O in two batches (Batch C: 520 g, Batch D: 520 g).
Batch C: The crude product (520 g) was dissolved in EtOH (6.24 L) at reflux under N2. Water (1248 ml) was added slowly. The mixture was allowed to cool down to 40° C. (3 h), seeded with 0.5 g of the title compound and stirred at 40° C. for 10 h. The mixture was then cooled to 26° C. over 7 h. The resulting suspension was cooled to 10° C. and stirred at that temperature for 6 h. The product was filtered off, washed with EtOH/water (8:2, 3×500 ml) and water (3×500 ml). The filter cake was dried at 45° C. for 2 d. The product was obtained as a grey solid (418 g, yield ˜56%, LCMS purity 97.5%, chiral LC
100%, 1H NMR (DMSO-d6) assay vs TCNB
100±2%).
Batch D: 418 g, yield 56%, LCMS purity 97.5%, chiral LC
100%, 1H NMR (DMSO-d6) assay vs TCNB
100±2%
The product was blended with the material from an intermediate scale reaction performed in the same way and re-analysed (968 g, LC purity 98.04%, chiral LC
100%, 1H NMR assay vs TCNB 99±2%, 0.35% EtOH by 1H NMR, H2O: (Karl Fischer) 4.58%, Pd 57.6 ppm, XRPD (X-ray powder diffraction) Form A.
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References
- “Brensocatib – Insmed”. AdisInsight. Springer Nature Switzerland AG.
- Chalmers JD, Usansky H, Rubino CM, Teper A, Fernandez C, Zou J, et al. (October 2022). “Pharmacokinetic/Pharmacodynamic Evaluation of the Dipeptidyl Peptidase 1 Inhibitor Brensocatib for Non-cystic Fibrosis Bronchiectasis”. Clinical Pharmacokinetics. 61 (10): 1457–1469. doi:10.1007/s40262-022-01147-w. PMC 9553789. PMID 35976570.
- Chalmers JD, Burgel PR, Daley CL, De Soyza A, Haworth CS, Mauger D, et al. (April 2025). “Phase 3 Trial of the DPP-1 Inhibitor Brensocatib in Bronchiectasis”. The New England Journal of Medicine. 392 (16): 1569–1581. doi:10.1056/NEJMoa2411664. PMID 40267423.
| Clinical data | |
|---|---|
| Other names | AZD7986; INS1007 |
| Identifiers | |
| IUPAC name | |
| CAS Number | 1802148-05-5 |
| PubChem CID | 118253852 |
| IUPHAR/BPS | 9412 |
| DrugBank | DB15638 |
| ChemSpider | 67896269 |
| UNII | 25CG88L0BB |
| KEGG | D12120 |
| ChEMBL | ChEMBL3900409 |
| Chemical and physical data | |
| Formula | C23H24N4O4 |
| Molar mass | 420.469 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| SMILES | |
| InChI | |
////////Brensocatib, APPROVALS 2025, FDA 2025, Brinsupri, non-cystic fibrosis, AZD7986, 1802148-05-5, INS1007, AZD 7986, WHO 11097
Dordaviprone
Dordaviprone
WeightAverage: 386.499
Monoisotopic: 386.210661473
Chemical FormulaC24H26N4O
- TIC10
- CAS 1616632-77-9
- Dordaviprone
- ONC201
- ONC 201
- 9U35A31JAI
- NSC-350625
11-benzyl-7-[(2-methylphenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),5-dien-8-one
Product Ingredients
| Ingredient | UNII | CAS | InChI Key |
|---|---|---|---|
| Dordaviprone dihydrochloride | 53VG71J90J | 1638178-82-1 | Not applicable |
- 11-benzyl-7-(o-tolylmethyl)-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),5-dien-8-one
- 11-benzyl-7-[(2-methylphenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.0(2,6)]trideca-1(9),5-dien-8-one
- 7-Benzyl-4-(2-methylbenzyl)-2,4,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(1H)-one
- 7-benzyl-4-[(2-methylphenyl)methyl]-2,4,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(1H)-one
FDA 8/6/2025, Modeyso, To treat diffuse midline glioma harboring an H3 K27M mutation with progressive disease following prior therapy
Dordaviprone, sold under the brand name Modeyso is an anti-cancer medication used for the treatment of diffuse midline glioma (a type of brain tumor).[1][2] Dordaviprone is a protease activator of the mitochondrial caseinolytic protease P.[1] It is dopamine receptor D2 antagonist and an allosteric activator of the mitochondrial caseinolytic protease P.[3]
Dordaviprone was approved for medical use in the United States in August 2025.[2] It is the first approval of a systemic therapy for H3 K27M-mutant diffuse midline glioma by the US Food and Drug Administration.[2]
Dordaviprone is an organic heterotricyclic compound that is 2,4,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(1H)-one substituted by 2-methylbenzyl and benzyl groups at positions 4 and 7, respectively. It is a selective antagonist of the dopamine receptor D2 and an allosteric agonist of mitochondrial protease caseinolytic protease P. It has a role as an antineoplastic agent, a dopamine receptor D2 antagonist and an apoptosis inducer. It is a member of toluenes, a member of benzenes and an organic heterotricyclic compound.
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References
- https://pp.jazzpharma.com/pi/modeyso.en.USPI.pdf [bare URL PDF]
- “FDA grants accelerated approval to dordaviprone for diffuse midline glioma”. U.S. Food and Drug Administration (FDA). 6 August 2025. Retrieved 7 August 2025. This article incorporates text from this source, which is in the public domain.
- Prabhu VV, Morrow S, Rahman Kawakibi A, Zhou L, Ralff M, Ray J, et al. (December 2020). “ONC201 and imipridones: Anti-cancer compounds with clinical efficacy”. Neoplasia. 22 (12). New York, N.Y.: 725–744. doi:10.1016/j.neo.2020.09.005. PMC 7588802. PMID 33142238.
- “Jazz Pharmaceuticals Announces U.S. FDA Approval of Modeyso (dordaviprone) as the First and Only Treatment for Recurrent H3 K27M-mutant Diffuse Midline Glioma” (Press release). Jazz Pharmaceuticals. 6 August 2025. Retrieved 10 August 2025 – via PR Newswire.
- World Health Organization (2023). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 89”. WHO Drug Information. 37 (1). hdl:10665/366661.
External links
- Clinical trial number NCT02525692 for “Oral ONC201 in Adult Recurrent Glioblastoma” at ClinicalTrials.gov
- Clinical trial number NCT03295396 for “ONC201 in Adults With Recurrent H3 K27M-mutant Glioma” at ClinicalTrials.gov
- Clinical trial number NCT03416530 for “ONC201 in Pediatric H3 K27M Gliomas” at ClinicalTrials.gov
- Clinical trial number NCT05392374 for “Expanded Access Use of ONC201 in a Patient With Diffuse Intrinsic Pontine Gliomas” at ClinicalTrials.gov
- Clinical trial number NCT03134131 for “Expanded Access to ONC201 for Patients With H3 K27M-mutant and/or Midline High Grade Gliomas” at ClinicalTrials.gov
| Clinical data | |
|---|---|
| Trade names | Modeyso |
| Other names | ONC201, ONC-201 |
| AHFS/Drugs.com | Modeyso |
| License data | US DailyMed: Dordaviprone |
| Routes of administration | By mouth |
| Drug class | Protease activator |
| ATC code | None |
| Legal status | |
| Legal status | US: ℞-only[1] |
| Identifiers | |
| IUPAC name | |
| CAS Number | 1616632-77-9as HCl: 1638178-82-1 |
| PubChem CID | 73777259 |
| DrugBank | DB14844as HCl: DBSALT003291 |
| ChemSpider | 30904994 |
| UNII | 9U35A31JAIas HCl: 53VG71J90J |
| KEGG | D12733as HCl: D12734 |
| ChEBI | CHEBI:232328 |
| ChEMBL | ChEMBL4297310 |
| Chemical and physical data | |
| Formula | C24H26N4O |
| Molar mass | 386.499 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| SMILES | |
| InChI | |
//////Dordaviprone, Modeyso, FDA 2025, APPROVALS 2025, TIC10, 1616632-77-9, Dordaviprone, ONC201, ONC 201, 9U35A31JAI, NSC 350625
Zongertinib
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
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).
A) 1H NMR spectrum of zongertinib
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021213800&_cid=P10-ME52KD-62836-1
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- [1]. WHO Drug Informat ion – World Health Organization (WHO).[2]. Wilding Birgit, et al. Synthesis of diazino-pyrimidines as anticancer agents: World Intellectual Property Organization, WO2021213800. 2021-10-28.[3]. Li S, et al. Emerging Targeted Therapies in Advanced Non-Small-Cell Lung Cancer. Cancers (Basel). 2023 May 24;15(11):2899. [Content Brief]
////////////Zongertinib, Hernexeos, APPROVALS 2025, FDA 2025, lung cancer, BI-1810631, BI1810631, DRH7R67UVL
New Drug Approvals 
