Abstract
Here we describe the synthesis of N-(6-chloro-3-nitropyridin-2-yl)5-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-amine via a three-step procedure including a Buchwald–Hartwig arylamination with benzophenone imine and a highly regioselective nucleophilic aromatic substitution. The title compound was analyzed by nuclear magnetic resonance spectroscopy (1H, 13C, HSQC, HMBC, COSY, DEPT90 and NOESY), high resolution mass spectrometry (ESI-TOF-HRMS) and infrared spectroscopy (ATR-IR) and its structure was confirmed by single crystal X-ray diffraction. The inhibitory potency of the title compound was evaluated for selected kinases harboring a rare cysteine in the hinge region (MPS1, MAPKAPK2 and p70S6Kβ/S6K2).
Highlights
The monopolar spindle 1 (MPS1) kinase, known as threonine and tyrosine kinase (TTK) [1], is a potential therapeutic target for the treatment of various malignancies such as triple negative breast cancer [2]
The structure was derived from N-(2,4-dimethoxyphenyl)-5-(1-methylpyrazol-4-yl)isoquinolin3-amine (2), a potent reversible MPS1 inhibitor reported by Innocenti et al [4]
We established a synthesis for N-(6-chloro-3-nitropyridin-2-yl)-5-(1methyl-1H-pyrazol-4-yl)isoquinolin-3-amine (1)
Summary
The monopolar spindle 1 (MPS1) kinase, known as threonine and tyrosine kinase (TTK) [1], is a potential therapeutic target for the treatment of various malignancies such as triple negative breast cancer [2]. The structure was derived from N-(2,4-dimethoxyphenyl)-5-(1-methylpyrazol-4-yl)isoquinolin3-amine (2), a potent reversible MPS1 inhibitor reported by Innocenti et al [4] The latter compound forms a crucial dual hydrogen bond between the 3-aminoisoquinoline core and the backbone of Gly605 located in the hinge region of the kinase [4]. The adjacent hinge residue in MPS1 is a poorly conserved cysteine (Cys604), which might be exploited in the development of selective targeted covalent inhibitors (TCIs) [5,6]. To address this rare cysteine, we sought to employ nucleophilic aromatic substitution (SN Ar) chemistry as a non-generic design approach [7]. We combined the 5-(1-methyl-1H-pyrazol-4-yl)isoquinoline scaffold with an electrophilic
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