Fanregratinib

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Fanregratinib

CAS 1628537-44-9

MF C27H33ClN6O2, 509.0 g/mol

4-chloro-3-[2-[2-[4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]anilino]pyrimidin-5-yl]ethyl]-5-methoxy-N-methylbenzamide

fibroblast growth factor receptor tyrosine kinase inhibitor, antineoplastic, 8RWL2B2CLS

OriginatorHutchison MediPharma
DeveloperHutchison MediPharma; HUTCHMED
ClassAntineoplastics; Small molecules
Mechanism of ActionType 1 fibroblast growth factor receptor antagonists; Type 3 fibroblast growth factor receptor antagonists; Type-2 fibroblast growth factor receptor antagonists
PreregistrationCholangiocarcinoma
Phase IIMesothelioma
Phase I/IISolid tumours
29 Dec 2025Preregistration for Cholangiocarcinoma (Late-stage disease, Metastatic disease, Second-line therapy or greater, Inoperable/Unresectable) in China (PO)
29 Dec 2025Updated efficacy data from a phase II trial in Cholangiocarcinoma released by HUTCHMED
03 Nov 2025HUTCHMED announces intention to submit new drug application to NMPA for Cholangiocarcinoma in first half of 2026

FANREGRATINIB is a small molecule drug with a maximum clinical trial phase of II and has 1 investigational indication.
Fanregratinib is a small molecule drug. The usage of the INN stem ‘-gratinib’ in the name indicates that Fanregratinib is a fibroblast growth factor receptor (FGFR) inhibitor. Fanregratinib has a monoisotopic molecular weight of 508.24 Da.

Fanregratinib is an orally bioavailable inhibitor of the fibroblast growth factor receptor (FGFR) types 1, 2, and 3 (FGFR1/2/3), with potential antineoplastic activity. Upon administration, fanregratinib binds to and inhibits FGFR1/2/3, which may result in the inhibition of FGFR1/2/3-related signal transduction pathways. This inhibits proliferation in FGFR1/2/3-overexpressing tumor cells. FGFR, a family of receptor tyrosine kinases (RTKs) upregulated in many tumor cell types, plays a key role in cellular proliferation, migration and survival.

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=US159751913&_cid=P10-MKQ98D-55657-1

Example 9

Synthesis of Compounds 79-91, 146-155

Compound 79

4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide

(C) 4-chloro-3-(2-(2-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenylamino)pyrimidin-5-yl)ethyl)-5-methoxy-N-methylbenzamide

A mixture of 4-chloro-3-((E)-2-(2-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenylamino)pyrimidin-5-yl)vinyl)-5-methoxy-N-methylbenzamide (120 mg, 0.237 mmol), 4-methylbenzenesulfonohydrazide (528 mg, 2.84 mmol) and sodium acetate (233 mg, 2.84 mmol) in THF (6 mL) and water (6 mL) was stirred overnight at 100° C. under nitrogen atmosphere. The resulting mixture was concentrated. The residue was partitioned between 2N HCl (15 mL) and EA (15 mL). The aqueous layer was then adjusted to pH=8 with 30% NaOH and extracted with DCM (2*15 mL). The combined extracts were concentrated and the residue was purified via ISCO (eluted with MeOH in H ₂O 0˜100%) to afford the title compound as a yellow solid (50 mg, 41.5% yield). MS (m/z): 509.0 (M+H) ⁺. ¹H NMR (400 MHz, CD ₃OD) δ 8.11 (s, 2H), 7.44 (d, J=9.1 Hz, 2H), 7.37 (d, J=2.0 Hz, 1H), 7.30 (d, J=2.0 Hz, 1H), 6.95 (d, J=9.1 Hz, 2H), 3.93 (s, 3H), 3.53-3.44 (m, 2H), 3.10-2.99 (m, 4H), 2.90 (s, 3H), 2.82 (t, J=7.6 Hz, 2H), 2.25 (t, J=7.5 Hz, 2H), 1.16 (d, J=6.4 Hz, 6H).

SYN

[WO2014139465]

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014139465&_cid=P10-MKQ9F3-62190-1

Example 9: Synthesis of Compounds 78-103

Compound 78

4-chloro-3-(2-(2-((4-((3S,5/f)-3,5-dimethylpiperazin-l-yl)phenyl)amino)pyrimidin-5

-yl)ethyl)-5-methoxy-N-methylbenzamide

(A) Methyl 4-chloro-3-((_JE)-2-(2-(4-((3S,5R)-3,5-dimethylpiperazin-l-yl)

phenylamino)pyrimidin-5-yl)vinyl)-5-methoxybenzoate

A mixture of (E)-methyl 4-chloro-3-(2-(2-chloropyrimidin-5-yl)vinyl)-5-methoxy benzoate (150mg, 0.442 mmol), 4-((35′,5i?)-3,5-dimethylpiperazin-l-yl)aniline (109 mg, 0.531 mmol) and TFA (0.1 mL, 1.326 mmol) in propan~2-oi (5 mL) was stirred at 150 ^°C for 1 h under microwave. The resulting mixture was concentrated, basified with ammonia water, purified via ISCO (DCM/MeOH) to afford the title compound as a

yellow solid (130 mg, 57.9% yield). MS (m/z): 508.2(M+H)⁺.

(B) 4-chloro-3-((£)-2-(2-(4-((3S,5R)-3,5-dimethylpiperazin-l-yl)phenylamino)pyrim idin-5-yl)vinyl)-5-methoxy-N-methylbenzamide

A mixture of methyl 4-chloro-3-((E)-2-(2-(4-((35′,5i?)-3,5-dimethylpiperazin-l-yl) phenylamino)pyrimidin-5-yl)vinyl)-5-methoxybenzoate (250 mg, 0.492 mmol) and methylamine (6 mL, 35% solution in ethanol) was stirred at 145 ^°C for 22 min under microwave. The resulting mixture was concentrated, purified via ISCO (DCM/MeOH) to afford the title compound as a yellow solid (145 mg, 58.1%> yield). MS (m/z):

506.9(M+H)⁺.

(C) 4-chloro-3-(2-(2-(4-((3S,5R)-3,5-dimethylpiperazin-l-yl)phenylamino)pyrimidin -5-yl)ethyl)-5-methoxy-N-methylbenzamide

A mixture of 4-chloro-3-((E)-2-(2-(4-((35^*,5i?)-3,5-dimethylpiperazin-l-yl)

phenylamino)pyrimidin-5-yl)vinyl)-5-methoxy-N-methylbenzamide (120 mg, 0.237 mmol), 4-methylbenzenesulfonohydrazide (528 mg, 2.84 mmol) and sodium acetate (233 mg, 2.84 mmol) in THF (6mL) and water (6mL) was stirred overnight at 100 ^°C under nitrogen atmosphere. The resulting mixture was concentrated. The residue was partitioned between 2N HC1 (15 mL) and EA (15 mL). The aqueous layer was then adjusted to pH=8 with 30% NaOH and extracted with DCM (2* 15 mL). The combined extracts were concentrated and the residue was purified via ISCO (eluted with MeOH in H₂0 0-100%) to afford the title compound as a yellow solid (50 mg, 41.5% yield). MS (m/z): 509.0(M+H)⁺. 1H NM (400 MHz, CD₃OD) δ 8.1 1 (s, 2H), 7.44 (d, J = 9.1 Hz, 2H), 7.37 (d, J = 2.0 Hz, 1H), 7.30 (d, J = 2.0 Hz, 1H), 6.95 (d, J = 9.1 Hz, 2H), 3.93 (s, 3H), 3.53 – 3.44 (m, 2H), 3.10 – 2.99 (m, 4H), 2.90 (s, 3H), 2.82 (t, J = 7.6 Hz, 2H), 2.25 (t, J = 7.5 Hz, 2H), 1.16 (d, J = 6.4 Hz, 6H).

PAT