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Tetrazole-substituted pyrazolopyrimidine inhibitors of jak kinases and uses thereof

A medicinal salt and pyrrolidinyl technology, which is applied in tetrazole-substituted pyrazolopyrimidine JAK kinase inhibitors and its application field, can solve problems such as defective signal transduction, achieve the requirement of reducing the frequency of administration, dissolve Sex-enhancing, dose-reducing effects

Pending Publication Date: 2022-02-08
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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  • Tetrazole-substituted pyrazolopyrimidine inhibitors of jak kinases and uses thereof
  • Tetrazole-substituted pyrazolopyrimidine inhibitors of jak kinases and uses thereof
  • Tetrazole-substituted pyrazolopyrimidine inhibitors of jak kinases and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example

[0350] The following representative compounds of Table 1 were prepared using procedures similar to those described in the Schemes and Examples herein. The absolute stereochemistry of each of the following compounds may not have been drawn: thus, structures may occur more than once, each representing a single stereoisomer. Table 1 also shows the LC-MS method, retention time and m / z.

[0351] Table 1: Exemplary JAK Inhibitors

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369] Table 1

[0370] General Experiment Details

[0371] 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 ...

example 1

[0686]

[0687] N-(3-(5-chloro-2-(difluoromethoxy)phenyl)-1-((2-(2-hydroxyethyl)-2H-tetrazol-5-yl)methyl)- 1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0688] N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2H-1,2,3,4-tetrazol-5-ylmethyl)-1H-pyridine Azol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Intermediate 12, 200mg, 0.412mmol), 1,3-dioxolan-2-one (122mg, 1.38mmol , 3.35 equivalents), sodium hydroxide (44 mg, 1.10 mmol, 2.67 equivalents), N,N-dimethylformamide (30 mL) were placed in a 100 mL round bottom flask. The resulting solution was stirred in an oil bath at 120 °C for 4 h. The resulting mixture was concentrated under vacuum. The residue was applied on a silica gel column using dichloromethane / petroleum ether (11.5:1). The crude product was purified under the following conditions by chiral Prep-HPLC (Prep-HPLC-009): column, Phenomenex Lux 5u Cellulose-4XIAPacked, 2.12*25cm, 5um; mobile phase, Hex and ethanol (60.0% ethanol was maintained within 32m...

example 21

[0690] N-(3-(2,5-bis(difluoromethoxy)phenyl)-1-((2-(1-(2-(dimethylamino)ethyl)azetidine-3 -yl)-2H-tetrazol-5-yl)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0691]

[0692] Step 1: 3-(5-((3-(2,5-bis(difluoromethoxy)phenyl)-4-(pyrazolo[1,5-a]pyrimidine-3-carboxamido) Synthesis of tert-butyl -1H-pyrazol-1-yl)methyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate

[0693]

[0694] 1-Boc-3-iodoazetidine (2.42 g, 8.55 mmol) was added to N-[3-[2,5-bis(difluoromethoxy)phenyl]-1-(2H-tetra Azol-5-ylmethyl)pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Intermediate 1, 1.87g, 3.61mmol) and potassium carbonate (2.43g, 17.6 mmol) in a mixture in N,N-dimethylformamide (20 mL). The resulting solution was stirred at 60 °C for 3 h and at 75 °C overnight. The mixture was cooled to room temperature and filter. The filtrate was diluted with brine (120 mL). The resulting mixture was extracted with EA (3x50 mL) and the organic layers were combined. The organic l...

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Abstract

Compounds of formula (I) wherein R1, R2, R3, R4, R5 and R6 are as defined herein, 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 patent application claims priority to International Patent Application Serial No. PCT / CN2019 / 091709, filed June 18, 2019, and U.S. Provisional Patent Application No. 63 / 036,046, filed June 8, 2020, the disclosures of which are incorporated by reference Incorporated into this article. technical field [0003] The present invention relates to compounds that are inhibitors of Janus kinases (such as JAK1 and JAK2), compositions comprising these compounds, and methods of use including, but not limited to, the diagnosis or treatment of patients with JAK kinase-responsive Patients with depressive disorders. 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 cytokin...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/519A61K31/5377A61K31/538A61K45/06A61P35/00A61P9/10A61P3/10A61P1/16A61P9/00A61P25/28A61P37/02A61P17/06A61P19/02A61P1/00A61P11/06A61P37/06A61P29/00A61P25/00A61P31/00A61P37/08A61P31/12
CPCC07D487/04A61K45/06A61P35/00A61P9/10A61P3/10A61P1/16A61P9/00A61P25/28A61P37/02A61P17/06A61P19/02A61P1/00A61P11/06A61P37/06A61P29/00A61P25/00A61P31/00A61P37/08A61P31/12A61K31/519A61K31/5377A61P9/02A61K9/19A61K9/16A61K9/0075
Inventor M·E·扎克N·S·拉贾帕克萨Y-X·程J·M·格兰德纳D·G·M·肖尔F·A·罗梅罗M·C·布赖恩
Owner F HOFFMANN LA ROCHE & CO AG
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