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Janus kinases inhibitors, compositions thereof and use thereof

A compound, alkyl technology, used in drug combinations, anti-inflammatory agents, non-central analgesics, etc., can solve problems such as signal transduction inactivation

Active Publication Date: 2018-08-03
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the common gamma chain is capable of activating JAK3, JAK1 has been shown to be superior to JAK3, and inhibition of JAK1 is sufficient to inactivate signaling through the common gamma chain regardless of whether JAK3 is active (Haan et al., 2011, Chem. Biol. 18(3) :314-323)

Method used

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  • Janus kinases inhibitors, compositions thereof and use thereof
  • Janus kinases inhibitors, compositions thereof and use thereof
  • Janus kinases inhibitors, compositions thereof and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0455]

[0456] N-(3-(2-(Difluoromethoxy)-5-(methylthio)phenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3- Formamide

[0457] To a solution of 4-bromo-2-iodophenol (282 g, 943.447 mmol) in N,N-dimethylformamide (2000 mL) and water (500 mL) was added sodium 2-chloro-2,2-difluoroacetate ( 216g, 1.417mol), Cs 2 CO 3 (617g, 1.894mol). The resulting mixture was stirred overnight at 120°C, allowed to cool to room temperature, and poured into ice water (3000ml). The resulting solution was extracted with ethyl acetate (3 x 1500ml), and the organic layers were combined. The ethyl acetate extract was washed with brine (1000ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with ethyl acetate / petroleum ether (1:10), to obtain 300 g (91%) of 4-bromo-1-(difluoromethoxy)-2-iodobenzene as Yellow oil. 1 H NMR (300MHz, CDCl 3 )δ: (ppm) 7.96 (dd, J = 5.7Hz, 2.4Hz, 1H), 7.45 (dd, J = 8.7Hz, 2.4H...

Embodiment 5

[0490]

[0491] N-(3-(2-(difluoromethoxy)-5-(methylthio)phenyl)-1-(2-(4-morpholinopiperidin-1-yl)-2-oxo Ethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0492] In nitrogen atmosphere, to 2-[3-[2-(difluoromethoxy)-5-(methylsulfanyl)phenyl]-4-[pyrazolo[1,5-a]pyrimidine- 3-amino]-1H-pyrazol-1-yl]acetic acid (700mg, 1.48mmol), N,N-dimethylformamide (20mL) solution was added EDC.HCl (564mg, 2.94mmol), HOBt ( 400 mg, 2.96 mmol), DIPEA (762 mg, 5.90 mmol) and 4-(piperidin-4-yl)morpholine (502 mg, 2.95 mmol). The resulting solution was stirred overnight at room temperature. Additional amounts of EDC.HCl (564 mg, 2.94 mmol), HOBt (400 mg, 2.96 mmol) and DIPEA (762 mg, 5.90 mmol) were added. The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was applied to a silica gel column and eluted with dichloromethane / methanol (20 / 1-5 / 1). The appropriate fractions were combined and concentrated in vacuo. The residue was ...

Embodiment 11

[0494]

[0495] (R)-N-(3-(2-(Difluoromethoxy)-5-(methylthio)phenyl)-1-(2-((tetrahydrofuran-3-yl)amino)ethyl)- 1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0496] Into a 500-mL round bottom flask flushed with nitrogen and maintained inert environment was added N-[3-[2-(difluoromethoxy)-5-(methylsulfanyl)phenyl]-1H-pyrazole- 4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (5.00g, 12.0mmol), tetrahydrofuran (150ml), Cs 2 CO 3 (15.7g, 48.2mmol,), 1,2-dibromoethane (45.0g, 240mmol). The reaction mixture was stirred at 80 °C for 2 h, cooled to room temperature and concentrated in vacuo. The crude product was recrystallized in a 3 / 1 mixed solvent of hexane / ethyl acetate. The solid was collected by filtration. 5.80 g (92%) of N-[1-(2-bromoethyl)-3-[2-(difluoromethoxy)-5-(methylsulfanyl)phenyl]-1H-pyridine were obtained Azol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as light yellow solid. LCMS (Method A, ESI): [M+H] + =525.1,R T =1.48min.

[0497] Add CH to a ...

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Abstract

Compounds of Formula (00A) and salts thereof, wherein R1, R2 R3, R4 and n are defined herein, are useful as inhibitors of one or more Janus kinases. Also provided are pharmaceutical compositions thatinclude a compound of Formula (00A) and a pharmaceutically acceptable carrier, adjuvant or vehicle, and methods of treating or lessening the severity of a disease or condition responsive to the inhibition of a Janus kinase activity in a patient.

Description

[0001] Cross-References to Related Applications [0002] This application claims the benefit of International Application No. PCT / CN2015 / 095310, filed November 23, 2015, and International Application No. PCT / CN / 2015 / 095423, filed November 24, 2015, each of which is incorporated in its entirety This application is incorporated by reference. technical field [0003] The present invention relates to compounds of formula (00A), which are inhibitors of Janus kinases such as JAK1, and to compositions comprising these compounds and methods of use, including but not limited to the diagnosis or treatment of patients with conditions responsive to inhibition of JAK kinases . Background technique [0004] Cytokine pathways mediate a wide range of biological functions, including many aspects of inflammation and immunity. Janus kinases (JAKs) (including JAK1, JAK2, JAK3, and TYK2) are cytoplasmic protein kinases that associate with type I and type II cytokine receptors and regulate cyto...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/519A61P11/06A61P29/00
CPCC07D487/04C07D519/00A61P11/06A61P29/00A61P43/00
Inventor Y-X·成P·吉伯恩斯T·凯勒W·李R·蒙顿卡P·源M·E·扎克L·张
Owner F HOFFMANN LA ROCHE & CO AG
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