Soxataltinib

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Soxataltinib

CAS 2546116-88-3

MF C29H30N8O2 MW 522.60

6-(3-hydroxy-3-methylazetidin-1-yl)-4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl}pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

Pyrazolo[1,5-a]pyridine-3-carbonitrile, 6-(3-hydroxy-3-methyl-1-azetidinyl)-4-[6-[6-[(6-methoxy-3-pyridinyl)methyl]-3,6-diazabicyclo[3.1.1]hept-3-yl]-3-pyridinyl]-

6-(3-hydroxy-3-methylazetidin-1-yl)-4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl}pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
RET-kinase inhibitor, antineoplastic, HS-10365, HS 10365, AZ4Q643U3D

Soxataltinib (example 7) is a potent inhibitor of RET-kinase , with the IC ₅₀of 0.601 nM. Soxataltinib plays an important role in
cancer research.

Discovery and Development

Soxataltinib corresponds to Example 114 in a patent [WO2020228756]describing pyrazolo[1,5-a]pyridine carbonitrile RET inhibitors.
It is believed to correspond to HS-10365, a RET inhibitor developed by Hansoh Pharma (structure disclosed via patent).

Drug class comparison:

Drug	Company	Type
Selpercatinib	Eli Lilly	1st-gen selective RET inhibitor
Pralsetinib	Blueprint	selective RET inhibitor
Soxataltinib	Hansoh	next-gen RET inhibitor

Patent Family (Major Members)

Typical family members include:

Patent	Jurisdiction
WO2020228756	WIPO
CN112209925	China
US continuation filings	USA
EP equivalents	Europe

One Chinese patent describes the preparation of piperazine-containing pyrazolopyridine RET inhibitors, including Soxataltinib analogues

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CN112209925

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US20230322769,

https://patentscope.wipo.int/search/en/detail.jsf?docId=US410559026&_cid=P11-MMSKPK-66512-1

Example 32

To a 25 mL sealed tube were added successively 49 (52 mg, 0.1 mmol), Pd ₂(dba) ₃(5.5 mg, 0.006 mmol), t-BuXPhos (8.4 mg, 0.02 mmol), 3-methyl-3-azetidinol (26 mg, 0.3 mmol), Cs ₂CO ₃(65 mg, 0.2 mmol), 1,4-dioxane (3 mL) and DMF (1 mL). The mixture was stirred at 80° C. overnight under Ar, and TLC monitoring showed no starting material 49 remained. The mixture was cooled to room temperature, and 10 mL of water was added. The mixture was stirred for 10 min, and a yellow solid precipitated. The solid was collected by filtration, dried and purified by column chromatography to give product 86 (34 mg, 65% yield).

¹H NMR (400 MHz, CDCl ₃) δ 8.37 (d, J=2.3 Hz, 1H), 8.15 (s, 1H), 8.10 (d, J=2.0 Hz, 1H), 7.78 (dd, J=8.8, 2.5 Hz, 1H), 7.72 (d, J=1.9 Hz, 1H), 7.65 (dd, J=8.5, 2.2 Hz, 1H), 6.77-6.66 (m, 3H), 4.12-3.98 (m, 1H), 3.92 (s, 3H), 3.91 (s, 2H), 3.87-3.74 (m, 6H), 3.62-3.58 (m, 4H), 2.73-2.67 (m, 1H), 1.67 (s, 3H). LC-MS [M+H] ⁺ 522.6.

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https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020228756&_cid=P11-MMSKHR-61501-1

Example 114

[1913]6-(3-hydroxy-3-methylacetidin-1-yl)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile

Using 3-methylacetidin-3-ol as a raw material, in the first step of Reference Example 110, 6-(3-hydroxy-3-methylacetidin-1-yl)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile was obtained.

[1916]MS m/z(ESI):523.3[M+H]

⁺ .

[1917]

¹H NMR(400MHz,CDCl ₃)δ8.40(s,1H),8.15(s,3H),7.82(d,J＝7.4Hz,1H),7.74(s,1H),6.80(d,J＝8.4Hz,1H),6.75(d,J＝1.7Hz,1H),6.72(d,J＝8.8Hz,1H),4.21(s,2H),4.01(s,2H),3.93-3.92(m,7H),3.84(d,J＝7.3Hz,4H),1.68(s,3H).

PAT