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Therapeutic compounds and compositions, and methods of use thereof

A compound, alkyl technology, applied in the field of therapeutic compounds and compositions and their use, capable of solving problems such as defects

Active Publication Date: 2020-01-10
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Consistent with this, primary cells derived from TYK2-deficient humans are defective in type I interferon, IL-6, IL-10, IL-12, and IL-23 signaling

Method used

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  • Therapeutic compounds and compositions, and methods of use thereof
  • Therapeutic compounds and compositions, and methods of use thereof
  • Therapeutic compounds and compositions, and methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0348] General Experimental Details

[0349] All solvents and commercially available reagents were used as received unless otherwise stated. When purifying the product by silica gel chromatography, use a glass column (Kieselgel 60, 220-440 mesh, 35-75 μm) manually packed with silica gel or SPE SiII column. 'Isolute SPE Si column' means a prepacked polypropylene column comprising unbonded reactive silica and an average size of 50 μm with a nominal porosity of irregular particles. when using SCX-2 column, SCX-2 column' means a pre-packed polypropylene column comprising a non-endcapped propanesulfonic acid functionalized silica gel strong cation exchange sorbent.

[0350] Procedure and LCMS conditions

[0351] Method A

[0352] Equipped with a C18 reversed-phase column (50x3mm Xtimate TM -C18, 2.2 μm particle size) SHIMADZU 20A HPLC, elution solvent A: water + 0.05% trifluoroacetic acid; solvent B: acetonitrile + 0.05% trifluoroacetic acid. gradient:

[0353]

[...

Embodiment 5

[0496]

[0497] N-(3-(2-(Difluoromethoxy)-5-((trifluoromethyl)sulfanyl)phenyl)-1H-pyrazol-4-yl)pyrazolo[1,5- a] pyrimidine-3-carboxamide

[0498] N-[5-[2-(difluoromethoxy)-5-[[tri(prop-2-yl)silyl]sulfanyl]phenyl]-1-[ [2-(Trimethylsilyl)ethoxy]methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (140mg, 0.203mmol) To a solution of TBAF (75 mg, 85%, 0.244 mmol) in DMA (1 mL) was added to a solution of DMA (2.5 mL). The mixture was stirred at 0 °C for 5 min, then 1-(trifluoromethyl)-3H-1-λ-3,2-benziodaoxol-3-one (85.0 mg, 0.269 mmol) in DMA (1 mL) was added dropwise . The mixture was allowed to warm to room temperature and stirred for 20 minutes. The reaction was repeated once on the same scale and the products of both reactions were combined for purification. The mixture was diluted with ethyl acetate (50 mL), washed with water (2x) and brine (2x), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography ...

Embodiment 22

[0501]

[0502] N-(3-(2-(difluoromethoxy)-5-((1,3-difluoroprop-2-yl)sulfanyl)phenyl)-1-(2-hydroxyethyl)- 1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0503] N-[3-[5-bromo-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (500mg, 1.11mmol), (2-bromoethoxy)(tert-butyl)dimethylsilane (292mg, 1.22mmol) and Cs 2 CO 3 (725 mg, 2.22 mmol) in N,N-dimethylformamide (15 mL) was heated at 60° C. under nitrogen for 2 hours and then allowed to cool to room temperature. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (60 mL). The organic phase was washed with brine (2x), 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 / 1). The appropriate fractions were combined and concentrated under reduced pressure to give 433 mg (64%) of N-[3-[5-bromo-2-(difluoromethoxy)phenyl]-1-[2-[(tert-butyldi ...

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Abstract

Compounds and salts thereof that are useful as JAK kinase inhibitors are described herein. Also provided are pharmaceutical compositions that include such a JAK inhibitor 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 priority to U.S. Patent Application Serial No. 62 / 644,784, filed March 19, 2018, and International Patent Application No. PCT / CN2017 / 085277, filed May 22, 2017, the disclosures of which are incorporated by reference in their entirety This article. [0003] field of invention [0004] The present invention relates to compounds that are inhibitors of Janus kinases, such as JAK1, as well as compositions comprising these compounds and methods of use, including, but not limited to, diagnosing or treating patients with conditions responsive to inhibition of JAK kinases. [0005] Background of the invention [0006] Cytokine pathways mediate many biological functions, including many aspects of inflammation and immunity. Janus kinases (JAKs), including JAK1, JAK2, JAK3 and TYK2, are cytoplasmic protein kinases associated with type I and type II cytokine receptors and regulate cytokine signal transduction...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/519A61P11/00
CPCC07D487/04A61P11/00C07D498/04
Inventor M·扎克F·A·罗梅罗Y-X·成李伟
Owner F HOFFMANN LA ROCHE & CO AG
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