Pruvonertinib

CAS 2064269-82-3

MF C27H32N8O2 MW500.6 g/mol

N-[2-[2-(dimethylamino)ethyl-methylamino]-4-methoxy-5-[[4-(8-methylimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl]amino]phenyl]prop-2-enamide

• 2-Propenamide, N-[2-[[2-(dimethylamino)ethyl]methylamino]-4-methoxy-5-[[4-(8-methylimidazo[1,2-a]pyridin-3-yl)-2-pyrimidinyl]amino]phenyl]-
• N-(2-{[2-(dimethylamino)ethyl](methyl)amino}-4-methoxy-5-{[4-(8-methylimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide

N-(2-{2-(dimethylamino)ethylamino}-4-methoxy-5-{[4-(8-methylimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)prop2-enamide
epidermal growth factor receptor tyrosine kinase inhibitor, antineoplastic, YK-029A, YK 029A, HXJ9459HFK

Pruvonertinib is an orally bioavailable, mutant-selective, third-generation epidermal growth factor receptor (EGFR) inhibitor, with potential antineoplastic activity. Upon oral administration, pruvonertinib targets, binds to and inhibits the activity of EGFR with exon 20 insertion (Ex20ins) activating mutations, the gatekeeper mutation T790M and some other rare mutations, thereby preventing EGFR-mediated signaling. This may both induce cell death and inhibit tumor growth in EGFR-overexpressing tumor cells. EGFR, a receptor tyrosine kinase mutated in many tumor cell types, plays a key role in tumor cell proliferation and tumor vascularization.

Pruvonertinib (also known by its development code YK-029A) is an investigational, orally bioavailable, mutant-selective, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. Developed by Puhe Pharmaceutical, it is designed as an antineoplastic agent primarily targeting advanced non-small cell lung cancer (NSCLC) with specific resistant mutations.

Mechanism of Action

• Target Specificity: Binds selectively to mutant forms of EGFR.
• Resistance Targeting: Inhibits the gatekeeper T790M mutation and exon 20 insertion (Ex20ins) mutations.
• Scaffold Lineage: Structurally derived as an analogue of the established oncology drug osimertinib.
• Tumour Regression: Blockades downstream EGFR-mediated signaling to induce cell death and stunt tumor vascularization.

Clinical Development & Indications

• Primary Indication: Treatment of advanced, metastatic, or biomarker-positive Non-Small Cell Lung Cancer (NSCLC).
• Development Status: Pre-commercial asset undergoing active clinical trial screening and testing evaluations.
• Regulatory Track: Listed under the World Health Organization (WHO) Proposed International Nonproprietary Names (INN) List 132.

SYN

Analogue 6

Discovery of YK-029A, a novel mutant EGFR inhibitor targeting both T790 M and exon 20 insertion mutations, as a treatment for NSCLC

Publication Name:European Journal of Medicinal Chemistry, Publication Date:2023-10-05

PMID:37406381DOI:10.1016/j.ejmech.2023.115590

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US298712718&_cid=P10-MSQW7F-15668-1

N-(2-methoxy-4-(N ¹,N ²,N ²-trimethyl-1,2-ethylenediamine-1-yl)-5-acrylamidephenyl)-4-(8-methylimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-amine (hereinafter referred to as “Compound 1”) is a novel EGFR inhibitor represented by Formula (I):

The above compound is described in Chinese Patent Application 201610679161.7, and the content of which can be used as a reference for the present application

Step 7: Preparation of Drug Substance H (i.e. Compound 1)

Intermediate F (1.01 kg, 2.26 mol) was added to a mixed solution of acetonitrile (4.73 kg) and water (1.52 kg), and the temperature was lowered to 0 to 5° C. 3-Chloropropionyl chloride (373 g, 2.94 mol) was added dropwise. After the addition, the mixture was stirred at 0˜5° C. for 0.5 h. The completion of the reaction was detected.

An aqueous solution of sodium hydroxide (sodium hydroxide: 290 g, 7.24 mol; purified water: 505 g) was added dropwise, and the reaction was heated to 65˜75° C. and stirred for 2˜3 h. The completion of the reaction was detected. The reaction system was cooled to 25-35° C., and purified water (4040 g) was added dropwise. Seed crystals were added and the mixture was stirred for 1˜2 h. Purified water (6060 g) was added dropwise. After the addition, the temperature was lowered to 5-10° C., and the mixture was stirred for 1˜2 h and filtered. The filter cake was rinsed with a mixed solvent of acetonitrile (1.6 kg) and purified water (4 kg), and then dried to give 900 g of the drug substance H with a purity of 97.8%. Yield: 79%.

LCMS, m/z (ES+)(M+H +) 501.2,

1HNMR (400 MHz, d 6-DMSO) δ 10.11 (s, 1H), 9.67 (d, J=5.8 Hz, 1H), 8.64 (s, 1H), 8.57 (s, 1H), 8.53 (s, 1H), 8.35 (d, J=5.4 Hz, 1H), 7.32 (d, J=5.4 Hz, 1H), 7.24 (d, J=6.9 Hz, 1H), 7.06 (s, 1H), 6.80 (t, J=6.9 Hz, 1H), 6.41 (dd, J=16.9, 10.1 Hz, 1H), 6.18 (dd, J=16.9, 1.9 Hz, 1H), 5.73 (dd, J=10.1, 1.9 Hz, 1H), 3.79 (s, 3H), 2.91 (t, J=5.7 Hz, 2H), 2.75 (s, 3H), 2.54 (s, 3H), 2.34 (t, J=5.8 Hz, 2H), 2.21 (s, 6H).

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