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Pyrazolopyrimidine compounds as jak inhibitors

A compound, C1-C6 technology, used in organic chemistry, drug combinations, medical preparations containing active ingredients, etc., can solve problems such as defective signal transduction

Pending Publication Date: 2020-08-25
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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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  • Pyrazolopyrimidine compounds as jak inhibitors
  • Pyrazolopyrimidine compounds as jak inhibitors
  • Pyrazolopyrimidine compounds as jak inhibitors

Examples

Experimental program
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Effect test

example

[0258] General Experimental Details

[0259] All solvents and commercially available reagents were used as received unless otherwise stated. In the case of product purification by silica gel chromatography, a glass column manually packed with silica gel (Kieselgel 60, 220-440 mesh, 35-75 μm) was used or A SPE Si II column was used for this operation. "Isolute SPE Si column" refers to the column containing 50μμm average particle size and nominal Prepacked polypropylene column of unbonded reactive silica with irregular particles of porosity. currently using In the case of the SCX-2 column, " "SCX-2 column" refers to a prepacked polypropylene column containing an unblocked propylsulfonic acid functionalized silica strong cation exchange sorbent.

[0260] LCMS conditions

[0261] Method A (LCMS15)

[0262] The experiment was carried out on SHIMADZU 20A HPLC, using C18 reverse phase column (50x 3mm Shim-Pack XR-ODS, 2.2μm particle size), the eluent was: solvent A: water ...

example 2

[0411] Example 2: First fraction, RT 1 =19.63min; 41.9mg white solid (S)-N-[3-[5-chloro-2-(difluoromethoxy)phenyl)-1-(1-methyl-2-oxopyrrolidine- 3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide; LC / MS (Method F, ESI): [M+H] + =502.2,R T =1.63min, 1 H NMR (400MHz, DMSO-d 6 ): δ(ppm)9.76(s,1H),9.36(dd,J=6.8,1.6Hz,1H),8.70–8.69(m,2H),8.43(s,1H),7.65(dd,J=8.8 ,2.4Hz,1H),7.59(d,J=2.4Hz,1H),7.46(d,J=8.8Hz,1H),7.31(dd,J=7.2,4.4Hz,1H),7.27(t,J =73.2Hz, 1H), 5.29–5.25(m, 1H), 3.54–3.51(m, 1H), 3.45–3.42(m, 1H), 2.83(s, 3H), 2.60–2.55(m, 2H).

example 3

[0412] Example 3: Second fraction, RT2 = 24.74min; 40.1 mg white solid (R)-N-[3-[5-chloro-2-(difluoromethoxy)phenyl)-1-(1-methan yl-2-oxopyrrolidin-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide; LC / MS (Method F, ESI): [M+H] + =502.2,R T = 1.61min, 1 H NMR (300MHz, DMSO-d 6 ): δ(ppm)9.76(s,1H),9.36(dd,J=6.8,1.6Hz,1H),8.70–8.69(m,2H),8.43(s,1H),7.65(dd,J=8.8 ,2.4Hz,1H),7.59(d,J=2.4Hz,1H),7.46(d,J=8.8Hz,1H),7.31(dd,J=7.2,4.4Hz,1H),7.27(t,J =73.2Hz, 1H), 5.29–5.25(m, 1H), 3.54–3.51(m, 1H), 3.45–3.42(m, 1H), 2.83(s, 3H), 2.60–2.55(m, 2H).

[0413] General Method 3: Examples 4 and 5

[0414]

[0415] N-(3-(5-chloro-2-(difluoromethoxy)phenyl)-1-(2-oxopyrrolidin-3-yl)-1H-pyrazol-4-yl)pyrazolo [1,5-a]pyrimidine-3-carboxamide (isomer 1) and

[0416] N-(3-(5-chloro-2-(difluoromethoxy)phenyl)-1-(2-oxopyrrolidin-3-yl)-1H-pyrazol-4-yl)pyrazolo [1,5-a]pyrimidine-3-carboxamide (isomer 2)

[0417] To a solution of Intermediate A (100 mg, 0.247 mmol) in DMF (10 mL) ...

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Abstract

Compounds and salts thereof that are useful as JAK kinse 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 patent application claims the benefit of priority from International Patent Application PCT / CN2018 / 072568 filed on January 15, 2018, the entire content of which is incorporated herein by reference. technical field [0003] The present invention relates to Janus kinase (such as JAK1) inhibitor compounds, compositions comprising these compounds, and methods of use including, but not limited to, diagnosing or treating a patient suffering from a condition responsive to inhibition of a JAK kinase. 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 cytokine signal transduction. Binding of cytokines to cognate receptors triggers activation of receptor-associated JAK...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61P37/00A61P11/06A61K31/519
CPCC07D487/04A61P37/00A61P11/06C07D519/00G06V20/53G06F3/147G06M11/00G08G1/005G08G1/04G09G2380/06H04N7/181H04N7/188
Inventor M·扎克P·吉本斯Y-X·程S·C·格达克里
Owner F HOFFMANN LA ROCHE & CO AG
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