1557244-40-2

Upstream product

• 50675-19-9 4-thianylcarbaldehyde 
• 100-58-3 phenylmagnesium bromide 

Downstream Products

• 1557245-00-7 4-nitro-1-[phenyl(tetrahydro-2H-thiopyran-4-yl)methyl]-1H-pyrazole 
• 1557235-41-2 (1S)-N-(1-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(phenyl)methyl)-1H-pyrazol-4-yl)-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide 
• 1557244-97-9 4-((4-amino-1H-pyrazol-1-yl)(phenyl)methyl)tetrahydro-2H-thiopyran-1-oxide 
• 1557244-37-7 4-[(4-amino-1H-pyrazol-1-yl)(phenyl)methyl]-1λ⁶-thiane-1,1-dione 

Relevant academic research and scientific papers

Tetrahydroindazoles as interleukin-2 inducible T-cell kinase inhibitors. Part II. Second-generation analogues with enhanced potency, selectivity, and pharmacodynamic modulation in vivo

The medicinal chemistry community has directed considerable efforts toward the discovery of selective inhibitors of interleukin-2 inducible T-cell kinase (ITK), given its role in T-cell signaling downstream of the T-cell receptor (TCR) and the implications of this target for inflammatory disorders such as asthma. We have previously disclosed a structure- and property-guided lead optimization effort which resulted in the discovery of a new series of tetrahydroindazole-containing selective ITK inhibitors. Herein we disclose further optimization of this series that resulted in further potency improvements, reduced off-target receptor binding liabilities, and reduced cytotoxicity. Specifically, we have identified a correlation between the basicity of solubilizing elements in the ITK inhibitors and off-target antiproliferative effects, which was exploited to reduce cytotoxicity while maintaining kinase selectivity. Optimized analogues were shown to reduce IL-2 and IL-13 production in vivo following oral or intraperitoneal dosing in mice.

PYRAZOLE CARBOXAMIDE COMPOUNDS, COMPOSITIONS AND METHODS OF USE

Provided herein are compounds of formula (AA): N N H HN O N N R R 6 A (R a ) p, (AA) stereoisomers or a pharmaceutically acceptable salt thereof, wherein A, R a, p, R and R 6 are defined herein, compositions including the compounds and methods of manufacturing and using the compounds for the treatment of diseases.