This Letter details our efforts to develop new M4 PAM scaffolds with improved pharmacological properties. This endeavor involved replacing the 3,4-dimethylpyridazine core with two novel cores: a 2,3-dimethyl-2H-indazole-5-carboxamide core or a 1-methyl-1H-benzo[d][1,2,3]triazole-6-carboxamide core. Due to shallow SAR, these cores were further evolved into two unique tricyclic cores: an 8,9-dimethyl-8H-pyrazolo[3,4-h]quinazoline core and an 1-methyl-1H-[1,2,3]triazolo[4,5-h]quinazoline core. Both tricyclic cores displayed low nanomolar potency against both human and rat M4.

中文翻译：

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发现结构上不同的三环M4阳性变构调节剂（PAM）化学型。

这封信详细介绍了我们为开发具有改善药理特性的新型M4 PAM支架所做的努力。这项工作涉及用两个新的核取代3,4-二甲基哒嗪核：2,3-二甲基-2H-吲唑-5-羧酰胺核或1-甲基-1H-苯并[d] [1,2,3]三唑-6-羧酰胺核心。由于SAR较浅，这些核进一步演化为两个独特的三环核：8,9-二甲基-8H-吡唑并[3,4-h]喹唑啉核和1-甲基-1H- [1,2,3]三唑并[4,5-h]喹唑啉核心。两个三环核心均对人和大鼠M4均表现出较低的纳摩尔浓度。