Lunbotinib

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Lunbotinib

CAS 2479961-46-9

MF C28H28FN11 MW537.6 g/mol

2-[6-(6-{[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]methyl}-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl]-6-methyl-N-(5-methyl1H-pyrazol-3-yl)pyrimidin-4-amine
tyrosine kinase inhibitor, antineoplastic, KL3T9ZU6HQ

2-(6-(6-((6-(4-fluoropyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo(3.1.1)heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine
2-[6-[6-[[6-(4-fluoropyrazol-1-yl)pyridin-3-yl]methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]pyridin-3-yl]-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine

Lunbotinib is an orally bioavailable selective inhibitor of the proto-oncogene receptor tyrosine kinase rearranged during transfection (RET), with potential antineoplastic activity. Upon oral administration, lunbotinib selectively binds to various RET fusions and mutations, including solvent front resistance mutations, and inhibits the activity of RET. This results in an inhibition of cell growth of tumors that exhibit increased RET activity due to these fusions and mutations. RET overexpression, activating mutations, and fusions result in the upregulation and/or overactivation of RET tyrosine kinase activity in various cancer cell types. Dysregulated RET activity plays a key role in the development and progression of certain cancers. Lunbotinib is able to penetrate the blood-brain barrier (BBB) and may also be able to overcome resistance mechanisms to first generation selective RET inhibitors (SRIs).

SYN

WO2020168939

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020168939&_cid=P12-MHKH7H-14851-1

Example 6: 2-(6-(6-((6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 17)

Step 1: Preparation of 6-(4-fluoro-1H-pyrazol-1-yl)nicotinaldehyde (compound 17a)

[0396]Compound 8c (2.0 g), 91a hydrochloride (1.58 g), and potassium carbonate (4.45 g) were sequentially added to DMF (15 mL), and the mixture was heated to 80 °C and stirred for 14 h. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with DCM (50 mL x 2). The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA = 10:1) to give compound 17a (0.81 g). MS m/z (ESI): 192.1 [M+H]

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[0397]Step 2: Preparation of 2-(6-(6-((6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 17)

[0398]1 g of trifluoroacetate (22.82 mg) and compound 17a (27.47 mg) were added to methanol (1.0 mL), followed by the sequential addition of triethylamine (4.45 mg) and sodium cyanoborohydride (13.86 mg), and the reaction was carried out at room temperature for 14 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain compound 17 (7.0 mg). MS m/z (ESI): 538.3 [M+H]

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[0399]

¹H NMR(400MHz,DMSO-d ₆)δ11.98(s,1H),9.66(s,1H),9.12(d,J＝2.16Hz,1H),8.67(dd,J＝4.54,0.64Hz,1H),8.43(dd,J＝8.94,2.28Hz,1H),8.41(d,J＝1.68,1H),7.98(dd,J＝8.48Hz,2.12 1H),7.92(d,J＝4.28,1H),7.87(d,J＝8.4,1H),6.78(d,J＝9.0Hz,2H),6.31(br,1H),3.78-3.71(m,4H),3.68-3.52(m,4H),2.59-2.52(m,1H),2.33(s,3H),2.25(s,3H),1.60(d,J＝8.36Hz,1H).

PAT