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Inhibitors of activin receptor-like kinase

A technology of alkyl and heterocyclic groups, applied in the field of pharmaceutical compositions, can solve problems that hinder the identification of new treatment options

Active Publication Date: 2019-02-05
BLUEPRINT MEDICINES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Historically, a lack of understanding of the drivers of DIPG has hindered the identification of potential new treatment options

Method used

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  • Inhibitors of activin receptor-like kinase
  • Inhibitors of activin receptor-like kinase
  • Inhibitors of activin receptor-like kinase

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0549] Example 1. Synthesis of 6-bromopyrrolo[1,2-b]pyridazin-4-yl trifluoromethanesulfonate

[0550] Step 1: Synthesis of 1-(4-bromo-1H-pyrrol-2-yl)ethanone (Intermediate B)

[0551]

[0552] Amberlyst 15 (0.09 g / g-bulk-LR) was added to commercially available 1-(1H-pyrrol-2-yl)ethanone (70 g; 1.00 equiv; 641.45 mmol) in tetrahydrofuran (10 mL / g-bulk-LR; 9.71 moles; 700.00 mL; 700.00 g). Next, 1-bromopyrrolidine-2,5-dione (1 equivalent (molar); 641.45 mmol; 114.17 g) was added in portions at -30 to -20°C, and stirred for about 1 h until LCMS showed that the reaction was complete. The reaction mixture was then filtered, and the filtrate was washed with saturated Na 2 SO 3 The aqueous solution (350 mL) was quenched and extracted with DCM (700 mL x 2). The organic layer was concentrated, then diluted with MTBE (700 mL). The organic layers were combined, followed by saturated NaHCO 3 (350 mL x 2) washed, concentrated by rotary evaporator under reduced pressure to give 1...

Embodiment 2

[0577] Example 2. Synthesis of cyclopropyl (4-(6-(4-(piperazin-1-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piper azin-1-yl)methanone (Compound 127).

[0578] Step 1: Synthesis of (4-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)(cyclopropyl)methanone.

[0579]

[0580] 6-bromopyrrolo[1,2-b]pyridazin-4-yl trifluoromethanesulfonate (30g, 86.9mmol), cyclopropyl(piperazin-1-yl)methanone (16.0g, 104mmol ) and triethylamine (13.1 g, 130 mmol) in NMP (300 mL) was stirred at 100° C. for 30 min. The reaction mixture was cooled and diluted with EA. The organic layer was washed with water and brine, concentrated, and purified by silica gel column to give the title product (26.0 g, yield 86%) as a yellow solid. MS(ES+)C 15 h 17 BrN 4 O required value: 348, measured value: 349 [M+H] + .

[0581] Step 2: Synthesis of cyclopropyl(4-(6-(4-(piperazin-1-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl) Methanone (compound 127).

[0582]

[0583] (4-(6-Bromopyrrolo[1,2...

Embodiment 3

[0584] Example 3. Synthesis of cyclopropyl (4-(6-(4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)pyrrolo[1,2- b] pyridazin-4-yl)piperazin-1-yl)methanone (compound 274)

[0585]

[0586] Cyclopropyl (4-(6-(4-(piperazin-1-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)methanone ( A mixture of 100 mg, 232 μmol), 2-bromoethanol (57.9 mg, 464 μmol) and potassium carbonate (32 mg, 0.232 mmol) was stirred overnight (~12h) at 70°C. The reaction mixture was cooled and concentrated. The residue was purified by prep-HPLC to afford the title compound (10.5 mg, yield 9.5%) as a white solid. MS(ES+)C 27 h 34 N 6 o 2 , desired value: 474, measured value: 475 [M+H] + .

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Abstract

Described herein are compounds that inhibit ALK2 and its mutants, pharmaceutical compositions including such compounds, and methods of using such compounds and compositions.

Description

[0001] The present disclosure relates to activin receptor-like kinase-2 (ALK2) inhibitors. [0002] priority statement [0003] This application claims priority to U.S.S.N. 62 / 332,948, filed April 15, 2016, and U.S.S.N. 62 / 411,172, filed October 21, 2016, each of which is incorporated herein in its entirety. Background technique [0004] Activin receptor-like kinase-2 (ALK2) is encoded by the activin A receptor type I gene (ACVR1). ALK2 is a serine / threonine kinase in the bone morphogenetic protein (BMP) pathway (Shore et al., Nature Genetics 2006, 38:525-27). It binds to complexes containing bone morphogenetic proteins (BMPs) and is responsible for transducing BMP signals. Certain mutations in ALK2 result in a constitutively active kinase and are associated with various diseases. Fibrodysplasia ossificans progressiva (FOP) is a rare, severely debilitating genetic disorder characterized by progressive heterotopic ossification at extraskeletal sites. Individuals with the di...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D519/00A61K31/5025A61P19/00
CPCC07D487/04C07D519/00A61P19/00A61P25/00A61P35/00A61P43/00A61K31/5025A61K31/5377A61K31/5383
Inventor 娜塔莎·布鲁杰孟J·D·布鲁贝克M·克罗宁保罗·E·弗莱明B·L·霍道什J·L·基姆J·瓦特齐格B·威廉姆斯D·威尔逊K·J·威尔逊
Owner BLUEPRINT MEDICINES
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