Degraders of fibroblast growth factor receptor 2 (FGFR2)

A technology for growth factor receptors and fibroblasts, applied in the field of degradation agents of fibroblast growth factor receptor 2 (FGFR2), which can solve the problems of low survival rate

Pending Publication Date: 2021-12-03
丹娜-法伯癌症研究公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the 5.8-month survival rate is still unacceptably low, these results are significantly better than historical control data in patients with refractory advanced ICC
[0007] However, many challenges remain in translating this encouraging clinical signal into long-term clinical benefit
The first challenge is acquired resistance to adenosine triphosphate (ATP)-competitive FGFR inhibitors
The second challenge is to inhibit the on-target toxicity of different members of the FGFR family

Method used

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  • Degraders of fibroblast growth factor receptor 2 (FGFR2)
  • Degraders of fibroblast growth factor receptor 2 (FGFR2)
  • Degraders of fibroblast growth factor receptor 2 (FGFR2)

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0246] Example 1: Synthesis of Thalidomide-Based Intermediates.

[0247]

[0248] tert-Butyl 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetate

[0249] tert-Butyl bromoacetate (199 mg, 1.02 mmol) was added to 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione ( 200mg, 0.) 3mmol) and K 2 CO 3 (304 mg, 2.20 mmol) in a mixture in 3 mL of DMF. The mixture was stirred overnight, then quenched with water. The aqueous mixture was then extracted with 3 × 5 mL ethyl acetate, washed with brine, washed with Na 2 SO 4Dried and concentrated. Purification by silica gel chromatography provided tert-butyl 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetate (245 mg, 0.63 mmol, 86%) as a white crystalline solid. LC / MSm / z calculated as [M+2H–tBu] + 333.1, measured 333.1.

[0250]

[0251] 2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid

[0252] tert-butyl 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl...

Embodiment 2

[0263] Example 2: 2-(4-{4-[(6-{[(2,6-dichloro-3,5-dimethoxyphenyl)carbamoyl](methyl)amino}pyrimidine-4 -yl)amino]phenyl}piperazin-1-yl)-N-{2-[2-(2-{[3-(2,6-dioxypiperidin-3-yl)-2,4- Dioxo-3-azatricyclo[).3.1.0 5 , 13 Synthesis of ]trideca-1(12),5,),9(13),10-penten-)-yl]oxy}ethoxy)ethoxy]ethyl}acetamide (1)

[0264]

[0265] tert-butyl 4-(4-((6-chloropyrimidin-4-yl)amino)phenyl)piperazine-1-carboxylate

[0266] 4-(4-Aminophenyl)piperazine-1-carboxylate tert-butyl ester (2.0 g, .21 mmol) was added to 4 in DIEA (1.88 mL, 10.8 mmol) and isopropanol (15 mL), 6-dichloropyrimidine (1.61 g, 10.8 mmol). The purple solution was then stirred overnight at room temperature. The solvent was evaporated and the residue was purified by silica gel chromatography to give the title compound as a maroon solid (2.) 5 g, ).05 mmol, 98%). LC / MS m / z calculated as [M+H] + 390.16, measured 390.30.

[0267]

[0268] tert-Butyl 4-(4-((6-(methylamino)pyrimidin-4-yl)amino)phenyl)piperazine-1-c...

Embodiment 3

[0282] Example 3: 2-(4-{4-[(6-{[(2,6-dichloro-3,5-dimethoxyphenyl)carbamoyl](methyl)amino}pyrimidine-4 -yl)amino]phenyl}piperazin-1-yl)-N-(3-{[3-(2,6-dioxopiperidin-3-yl)-2,4-dioxo-3-nitrogen Heterotricyclic[).3.1.0 5 , 13 Synthesis of ]trideca-1(12),5,),9(13),10-penten-)-yl]oxy}propyl)acetamide (2)

[0283]

[0284] The synthesis method of bispecific compound 2 is similar to that of bispecific compound 1. LC / MS m / z calculated as [M+H] + 953.28, measured 953.53.

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Abstract

The present invention relates to bispecific compounds, compositions, and methods for treating diseases or conditions characterized or mediated by aberrant fibroblast growth factor receptor 2 (FGFR2) activity.

Description

[0001] Cross References to Related Applications [0002] Pursuant to 35 U.S.C. §119(e), this application claims the benefit of priority to U.S. Provisional Application No.: 62 / 831,952, filed April 10, 2019, and U.S. Provisional Application No.: 62 / 884,422, filed August 8, 2019, The entire contents of both applications are hereby incorporated by reference. [0003] government license [0004] This invention was made with government support under Grant P50 CA12)003 awarded by the National Institutes of Health. The government has certain rights in this invention. Background technique [0005] Biliary tract carcinoma (BTC) accounts for about 3% of all gastrointestinal (GI) malignancies and has a poor prognosis. The 5-year survival rate for all patients is less than 15%, dropping to 10% for stage III patients and nearly 0% for stage IV patients, despite best available chemotherapy. The incidence of BTC has been increasing for decades, mainly due to the increase in intrahepatic ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4045A61K39/395C07K16/28
CPCA61K31/506A61K31/519A61K31/426A61K31/403A61K31/473A61K47/55A61P35/00A61K47/555
Inventor 纳撒尼尔·格雷张庭湖杜广艳纳撒尼尔·亨宁姜杰
Owner 丹娜-法伯癌症研究公司
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