Envonalkib

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Envonalkib

CAS 1621519-26-3
QB7KTQ7VW9
5-((1R)-1-(2,6-Dichloro-3-fluorophenyl)ethoxy)-4′-methoxy-6′-((2S)-2-methyl-1-piperazinyl)(3,3′-bipyridin)-6-amine
506.4 g/mol, C₂₄H₂₆Cl₂FN₅O₂

TQ-B3139, Chia Tai Tianqing, Anluoqing, cancer

ENVONALKIB is a small molecule drug with a maximum clinical trial phase of II and has 1 investigational indication.

SYN

WO2014117718

https://patentscope.wipo.int/search/en/WO2014117718

Example 27: 5-[(2,6-dichloro-3-fluorophenyl)ethoxy-4′-methoxy-6′ …

Step 1: 5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4′-methoxy-6′-((S)-2-methyl-4-tert-butoxycarbonylpiperazin-1-yl)-3,3′-bipyridin-6-amine

To dioxane (10 mL) and water (1.5 mL) were added tert-butyl (S)-4-(5-bromo-4-methoxypyridin-2-yl)-3-methylpiperidin-1-carboxylate (106 mg, 0.275 mmol), (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-aminopyridine (140 mg, 0.33 mmol), tetrakis(triphenylphosphine)palladium (32 mg, 0.0275 mmol) and cesium carbonate (179 mg, 0.55 mmol), the atmosphere was replaced with nitrogen, and the reaction was carried out at 100 ° C. overnight. After cooling, the mixture was separated by silica gel column chromatography to give 5-(2,6-dichloro-3-fluorophenyl)ethoxy)-4′-methoxy-6-(5-(2-methyl-4-tert-butoxycarbonylpiperidin-1-yl)-3,3′-bipyridin-6-amine) (70 mg) in a yield of 42%. MS m/z [ESI]: 606.2 [M+1].

Step 2: 5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4′-methoxy-6′-((S)-2-methylpiperazin-1-yl)-3,3′-bipyridin-6-amine

To a stirred dichloromethane solution (10 mL) of 5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4′-methoxy-6′-((S)-2-methyl-4-tert-butoxycarbonylpiperidin-1-yl)-3,3′-bipyridin-6-amine (67 mg, 0.11 mmol) was added trifluoroacetic acid (1 mL) and stirred for 1 hour. The pH was adjusted to greater than 13 with sodium hydroxide solution, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The product was separated and purified by column chromatography (with dichloromethane:methanol = 8:1 as eluent) to give 5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4′-methoxy-6′-((S)-2-methylpiperidin-1-yl)-3,3′-bipyridin-6-amine (30 mg). Yield: 55%, MS m/z [ESI]: 506.1[M+1]. 1H-NM (400 MHz, CDC1 ₃ ):5= 7.94(1H, s), 7.71(1H, s), 7.28-7.32(lH, m), 7.07(1H, t, J=8.4Hz), 6.97(1H, s), 6.04-6.13(2H, m), 4.86 (2H _: s), 4.57-4.59(lH, m), 4.03 (1H, d, J=14Hz), 3.76(3H, s), 3.07-3.33(4H, m), 2.88-3.00(lH, m), 1.84(3H, d, J=6.8Hz), 1.34 (3H, d, J=6.8Hz).

SYN

CN107949560

SYN

US9708295, 27

https://patentscope.wipo.int/search/en/detail.jsf?docId=US154015806&_cid=P11-MEF9W1-27198-1

Example 27: 5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4′-methoxy-6′-((S)-2-methylpiperazin-1-yl)-[3,3′-bipyridin]-6-amine

General Synthetic Methods:

Step 1: (S)-tert-butyl 4-(6′-amino-5′-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4-methoxy-[3,3′-bipyridin]-6-yl)-3-methylpiperazine-1-carboxylate

(S)-tert-butyl 4-(5-bromo-4-methoxypyridin-2-yl)-3-methylpiperazine-1-carboxylate (106 mg, 0.275 mmol), (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-am ine (140 mg, 0.33 mmol), Pd(PPh ₃) ₄(32 mg, 0.0275 mmol), and Cs ₂CO ₃(179 mg, 0.55 mmol) were dissolved in 1,4-dioxane (10 mL) and water (1.5 mL), purged with nitrogen, and the resultant was stirred at 100° C. overnight. After the resultant was cooled, it was purified by silica gel column chromatography to give (S)-tert-butyl 4-(6′-amino-5′-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4-methoxy-[3,3′-bipyridin]-6-yl)-3-methylpiperazine-1-carboxylate (70 mg, 42% yield). MS m/z [ESI]: 606.2 [M+1].

Step 2: 5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4′-methoxy-6′-((S)-2-methylpiperazin-1-yl)-[3,3′-bipyridin]-6-amine

To a stirred solution of (S)-tert-butyl 4-(6′-amino-5′-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4-methoxy-[3,3′-bipyridin]-6-yl)-3-methylpiperazine-1-carboxylate (67 mg, 0.11 mmol) in CH ₂Cl ₂(10 mL), trifluoroacetate (1 mL) was added, and the mixture was then stirred for 1 hour. Concentrated NaOH was added to adjust the pH value to greater than 13, and the resultant was extracted by CH ₂Cl ₂. The extract was dried over anhydrous sodium sulphate, filtered, concentrated, and purified by silica gel column chromatography (CH ₂Cl ₂: methanol=8:1) to give 5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4′-methoxy-6′-((S)-2-methylpiperazin-1-yl)-[3,3′-bipyridin]-6-amine (55% yield). MS m/z[ESI]: 506.1 [M+1]. ¹H-NMR (400 MHz, CDCl ₃): δ=7.94 (1H, s), 7.71 (1H, s), 7.28-7.32 (1H, m), 7.07 (1H, t, J=8.4 Hz), 6.97 (1H, s), 6.04-6.13 (2H, m), 4.86 (2H, s), 4.57-4.59 (1H, m), 4.03 (1H, d, J=14 Hz), 3.76 (3H, s), 3.07-3.33 (4H, m), 2.88-3.00 (1H, m), 1.84 (3H, d, J=6.8 Hz), 1.34 (3H, d, J=6.8 Hz).

SYN

European Journal of Medicinal Chemistry 291 (2025) 117643

Envonalkib, also known as TQ-B3139, is a novel small-molecule TKI, developed by Chia Tai Tianqing Pharmaceutical Group. It targets ALK, ROS1, and c-Met kinases, exhibiting potent antitumor activity against cancers harboring these genetic alterations. In 2024, the NMPA approved Envonalkib under the brand name Anluoqing for the treatment of adult patients with ALK-positive locally advanced or metastatic NSCLC who have not received prior ALK inhibitor therapy [24]. Envonalkib exerts its therapeutic effects through selective inhibition of the kinase activities of ALK, ROS1, and c-Met, thereby interrupting the downstream signaling pathways that are crucial for tumor cell proliferation and survival [25]. The inhibition of these targets results in cell cycle arrest and apoptosis in cancer cells。The clinical efficacy of Envonalkib was evidenced in a Phase III randomized, open-label, multicenter clinical trial (NCT04009317), which compared Envonalkib with crizotinib in treatment-naïve patients with ALK-positive advanced NSCLC [25,26]. In the reported study, Envonalkib demonstrated a me dian PFS of 24.87 months, which was markedly superior to the 11.60 months achieved with crizotinib (hazard ratio [HR] = 0.47, p < 0.0001). Notably, in patients harboring brain metastases, Envonalkib exhibited a
central nervous system objective response rate (CNS-ORR) of 78.95 %, a substantial improvement over the 23.81 % observed with crizotinib. In terms of safety profile, Envonalkib was generally well-tolerated. Treat ment-related adverse events (TRAEs) of Grade ≥3 were noted in 55.73 % of patients receiving Envonalkib, contrasting with the 42.86 % incidence in the crizotinib cohort. The predominant TRAEs encompassed elevated liver enzymes, neutropenia, and gastrointestinal symptoms, all of which
were amenable to effective management through appropriate support ive care measures. The regulatory approval of Envonalkib thus in troduces a novel therapeutic modality for patients with ALK-positive NSCLC, effectively addressing a significant unmet medical need within this patient population [25].
The synthesis of Envonalkib, illustrated in Scheme 6, initiates with Mitsunobu coupling of Envo-001 and Envo-002, affording Envo-003 [27]. Sequential reduction and NBS-bromination converts Envo-003 to
Envo-005 via Envo-004. Miyaura borylation of Envo-005 constructs Envo-006, which undergoes Suzuki-Miyaura cross-coupling with Envo-007 followed by deprotection to deliver Envonalkib. In parallel,
Envo-009 reacts with Envo-010 through Buchwald-Hartwig cross coupling to form Envo-011. This intermediate is brominated to produce Envo-007, which is used in the Suzuki-Miyaura coupling with Envo-006

[24] X. Li, Y. Xia, C. Wang, S. Huang, Q. Chu, Efficacy of ALK inhibitors in Asian
patients with ALK inhibitor-naïve advanced ALK-Positive non-small cell lung
cancer: a systematic review and network meta-analysis, Transl. Lung Cancer Res.
13 (2024) 2015–2022.
[25] Y. Yang, J. Min, N. Yang, Q. Yu, Y. Cheng, Y. Zhao, M. Li, H. Chen, S. Ren, J. Zhou,
W. Zhuang, X. Qin, L. Cao, Y. Yu, J. Zhang, J. He, J. Feng, H. Yu, L. Zhang, W. Fang,
Envonalkib versus crizotinib for treatment-naive ALK-Positive non-small cell lung
cancer: a randomized, multicenter, open-label, phase III trial, Signal Transduct
Target Ther 8 (2023) 301.
[26] R. Garcia-Carbonero, A. Carnero, L. Paz-Ares, Inhibition of HSP90 molecular
chaperones: moving into the clinic, Lancet Oncol. 14 (2013) e358–e369.
[27] F. Gong, X. Li, R. Zhao, X. Zhang, X. Xu, X. Liu, D. Xiao, Y. Han, Process for
Preparation of Pyridine Substituted 2-aminopyridine Protein Kinase Inhibitor
Crystal, 2017. CN107949560B.