The M1 receptor has long been investigated as a promising CNS drug target, yet further research is essential to fully elucidate compound's Pharmacodynamic (PD) as well as Toxicokinetic (TK) effects. In this context, the development of structurally diverse and high-profile M1 PAM tool compounds remains highly valuable, as existing advanced tools exhibit notable structural similarity. One approach that can be considered during scaffold hopping exercise and can improve drug-like properties is to introduce additional sp3 carbon atoms and increase Fsp3 values; the fraction of sp3 hybridized carbons. Determining the correct location to incorporate sp3 carbon atoms can be challenging, but once the right position is identified, it often leads to novel optimization opportunities. Reported herein is the discovery of a novel sp3-rich M1 positive allosteric modulator series utilizing a N-cyclopentyl pyrazole core. Also, an iterative library synthesis approach provided an enhanced understanding of the minimum pharmacophore. Several compounds within the series showed favorable on-target potencies and DMPK properties. In conclusion, the reported sp3-rich N-cyclopentyl pyrazole-based M1 PAM scaffold offers a promising structure-activity relationship starting point to discover structurally distinct M1 PAM chemotypes.

Disclosed herein are tricyclic compounds, including pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine-8-amine, pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine-4-amine, pyrazino[2′,3′:4,5]thieno[3,2-d]pyrimidin-4-amine, pyrido[3′,2′:4,5]furo[3, 2-d]pyrimidin-4-amine, and pyrimido[4′,5′:4,5]furo[2,3-c]pyridazin-8-amine compounds, which may be useful as positive allosteric modulators of the muscarinic acetylcholine receptor M 4 (mAChR M 4 ). Also disclosed herein are methods of making the compounds, pharmaceutical compositions comprising the compounds, and methods of treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction using the compounds and compositions.

En este documento se divulgan compuestos triciclicos, incluyendo los compuestos pirimido[4',5':4,5]tieno[2,3-c]piridazin-8-amina, pirido[3',2':4,5]tieno[3,2-d]pirimidin-4-amina, pirazino[2',3':4,5]tieno[3,2-d]pirimidin-4-amina, pirido[3',2':4,5]furo[3,2-d]pirimidin-4-amina y pirimido[4',5':4,5]furo[2,3-c]piridazin-8-amina, que pueden ser utiles como moduladores alostericos positivos del receptor muscarinico de acetilcolina M4 (mAChR M4). En este documento tambien se divulgan metodos de preparacion de los compuestos, composiciones farmaceuticas que comprenden los compuestos y metodos de tratamiento de trastornos neurologicos y psiquiatricos asociados con el mal funcionamiento del receptor muscarinico de acetilcolina usando los compuestos y composiciones.