Discovery and Optimization of Potent, Selective, and Brain-Penetrant 1-Heteroaryl-1H-Indazole LRRK2 Kinase Inhibitors for the Treatment of Parkinson's Disease.

Inhibition of leucine-rich repeat kinase 2 (LRRK2) kinase activity represents a genetically supported, chemically tractable, and potentially disease-modifying mechanism to treat Parkinson's disease. Herein, we describe the optimization of a novel series of potent, selective, central nervous system (CNS)-penetrant 1-heteroaryl-1H-indazole type I (ATP competitive) LRRK2 inhibitors. Type I ATP-competitive kinase physicochemical properties were integrated with CNS drug-like properties through a combination of structure-based drug design and parallel medicinal chemistry enabled by sp3-sp2 cross-coupling technologies. This resulted in the discovery of a unique sp3-rich spirocarbonitrile motif that imparted extraordinary potency, pharmacokinetics, and favorable CNS drug-like properties. The lead compound, 25, demonstrated exceptional on-target potency in human peripheral blood mononuclear cells, excellent off-target kinase selectivity, and good brain exposure in rat, culminating in a low projected human dose and a pre-clinical safety profile that warranted advancement toward pre-clinical candidate enabling studies.

Structure-Guided Discovery of Aminoquinazolines as Brain-Penetrant and Selective LRRK2 Inhibitors.

The leucine-rich repeat kinase 2 (LRRK2) protein has been genetically and functionally linked to Parkinson's disease (PD), a disabling and progressive neurodegenerative disorder whose current therapies are limited in scope and efficacy. In this report, we describe a rigorous hit-to-lead optimization campaign supported by structural enablement, which culminated in the discovery of brain-penetrant, candidate-quality molecules as represented by compounds 22 and 24. These compounds exhibit remarkable selectivity against the kinome and offer good oral bioavailability and low projected human doses. Furthermore, they showcase the implementation of stereochemical design elements that serve to enable a potency- and selectivity-enhancing increase in polarity and hydrogen bond donor (HBD) count while maintaining a central nervous system-friendly profile typified by low levels of transporter-mediated efflux and encouraging brain penetration in preclinical models.

Optimization of brain-penetrant picolinamide derived leucine-rich repeat kinase 2 (LRRK2) inhibitors.

The discovery of potent, kinome selective, brain penetrant LRRK2 inhibitors is the focus of extensive research seeking new, disease-modifying treatments for Parkinson's disease (PD). Herein, we describe the discovery and evolution of a picolinamide-derived lead series. Our initial optimization efforts aimed at improving the potency and CLK2 off-target selectivity of compound 1 by modifying the heteroaryl C-H hinge and linker regions. This resulted in compound 12 which advanced deep into our research operating plan (ROP) before heteroaryl aniline metabolite 14 was characterized as Ames mutagenic, halting its progression. Strategic modifications to our ROP were made to enable early de-risking of putative aniline metabolites or hydrolysis products for mutagenicity in Ames. This led to the discovery of 3,5-diaminopyridine 15 and 4,6-diaminopyrimidine 16 as low risk for mutagenicity (defined by a 3-strain Ames negative result). Analysis of key matched molecular pairs 17 and 18 led to the prioritization of the 3,5-diaminopyridine sub-series for further optimization due to enhanced rodent brain penetration. These efforts culminated in the discovery of ethyl trifluoromethyl pyrazole 23 with excellent LRRK2 potency and expanded selectivity versus off-target CLK2.

Discovery of Amino-cyclobutarene-derived Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitors for Cancer Immunotherapy.

Checkpoint inhibitors have demonstrated unprecedented efficacy and are evolving to become standard of care for certain types of cancers. However, low overall response rates often hamper the broad utility and potential of these breakthrough therapies. Combination therapy strategies are currently under intensive investigation in the clinic, including the combination of PD-1/PD-L1 agents with IDO1 inhibitors. Here, we report the discovery of a class of IDO1 heme-binding inhibitors featuring a unique amino-cyclobutarene motif, which was discovered through SBDD from a known and weakly active inhibitor. Subsequent optimization efforts focused on improving metabolic stability and were greatly accelerated by utilizing a robust SNAr reaction of a facile nitro-furazan intermediate to quickly explore different polar side chains. As a culmination of these efforts, compound 16 was identified and demonstrated a favorable overall profile with superior potency and selectivity. Extensive studies confirmed the chemical stability and drug-like properties of compound 16, rendering it a potential drug candidate.

Surprising Reactivity in NiXantphos/Palladium-Catalyzed α-Arylation of Substituted Cyclopropyl Nitriles.

α-Arylations of cyclopropyl and related nitriles provide access to important synthetic intermediates and pharmacophores for biologically active molecules. However, robust methods for coupling of sterically encumbered partners have remained elusive. Through optimization using high-throughput experimentation (HTE), the NiXantphos ligand was found to be effective in the coupling of sterically hindered ß-substituted cyclopropyl nitriles with a number of aryl groups and heterocycles, including those containing acidic N-H and O-H bonds.

Branched/linear selectivity in palladium-catalyzed allyl-allyl cross-couplings: The role of ligands.

While Pd-catalyzed allyl-allyl cross-couplings in the presence of small-bite-angle bidentate ligands reliably furnish the branched regioisomer with high levels of selectivity, cross-couplings in the presence of large-bite-angle bidentate ligands give varying, often unpredictable, levels of selectivity. In a combined computational and experimental study, we probe the underlying features that govern the regioselectivity in these metal-catalyzed cross-couplings.

Congested C-C bonds by Pd-catalyzed enantioselective allyl-allyl cross-coupling, a mechanism-guided solution.

Under the influence of a chiral bidentate diphosphine ligand, the Pd-catalyzed asymmetric cross-coupling of allylboron reagents and allylic electrophiles establishes 1,5-dienes with adjacent stereocenters in high regio- and stereoselectivity. A mechanistic study of the coupling utilizing reaction calorimetry and density functional theory analysis suggests that the reaction operates through an inner-sphere 3,3'-reductive elimination pathway, which is both rate-defining and stereodefining. Coupled with optimized reaction conditions, this mechanistic detail is used to expand the scope of allyl-allyl couplings to allow the generation of 1,5-dienes with tertiary centers adjacent to quaternary centers as well as a unique set of cyclic structures.

Stereocontrol in Palladium-Catalyzed Propargylic Substitutions: Kinetic Resolution to give Enantioenriched 1,5-Enynes and Propargyl Acetates.

Kinetic resolution during the catalytic allyl-propargyl cross-coupling with chiral starting materials can be accomplished with a chiral Palladium catalyst. These reactions offer ready access to enantiomerically enriched enyne products from simple readily available starting materials.

Construction of 1,5-enynes by stereospecific Pd-catalyzed allyl-propargyl cross-couplings.

The palladium-catalyzed cross-coupling of chiral propargyl acetates and allyl boronates delivers chiral 1,5-enynes with excellent levels of chirality transfer and can be applied across a broad range of substrates.

Diastereocontrol in asymmetric allyl-allyl cross-coupling: stereocontrolled reaction of prochiral allylboronates with prochiral allyl chlorides.

Palladium-catalyzed allyl-allyl cross-coupling was investigated with substituted prochiral allylic boronates. These reactions deliver products bearing adjacent stereocenters, and the issue of diastereocontrol is therefore paramount. Under appropriately modified conditions, this allyl-allyl coupling strategy was found to apply to a range of substrates, generally occurring with high enantioselectivity (92:8 to >99:1 er) and good diastereoselection (4:1 to 14:1 dr).