Conformational Studies and Atropisomerism Kinetics of the ALK Clinical Candidate Lorlatinib (PF‐06463922) and Desmethyl Congeners

Abstract

Lorlatinib (PF-06463922) is an ALK/ROS1 inhibitor and is in clinical trials for the treatment of ALK positive or ROS1 positive NSCLC (i.e. specific subsets of NSCLC). One of the laboratory objectives for this molecule indicated that it would be desirable to advance a molecule which was CNS penetrant in order to treat brain metastases. From this perspective, a macrocyclic template was attractive for a number of reasons. In particular, this template reduces the number of rotatable bonds, provides the potential to shield polar surface area and reinforces binding through a restricted conformation. All of these features led to better permeability for the molecules of interest and thus increased the chance for better blood brain barrier penetration. With a CNS penetrant molecule, kinase selectivity is a key consideration particularly with regard to proteins such as TrkB, which are believed to influence cognitive function. Removal of the chiral benzylic methyl substituent from lorlatinib was perceived as not only a means to simplify synthetic complexity, but also as a strategy to further truncate the molecule of interest. Examination of the NMR of the desmethyl analogues revealed that the compound existed as a mixture of atropisomers, which proved separable by chiral SFC. The individual atropisomers were evaluated through a series of in vitro assays, and shown to have a favorable selectivity profile when compared to lorlatinib. The challenge to develop such a molecule lies in the rate at which the atropisomers interchange dictated by the energy barrier required to do this. Here, we describe the synthesis of the desmethyl macrocycles, conformational studies on the atropisomers, and the kinetics of the interconversion. In addition, the corresponding conformational studies on lorlatinib are reported providing a hypothesis for why a single diastereomer is observed when the chiral benzylic methyl group is introduced.

Synthesis and preliminary PET imaging of 11C and 18F isotopologues of the ROS1/ALK inhibitor lorlatinib

“…A common site of metastases in non-small cell lung cancer (NSCLC) patients is in the brain where previous generation ALK inhibitors have limited effectiveness, and may be attributed to poor blood–brain barrier (BBB) penetration or active transport out of the brain by efflux pumps111213. Lorlatinib was specifically designed to address this unmet clinical need for robust brain penetration and activity against TKI-resistant ALK mutants, including the crizotinib-, alectinib- and ceritinib-resistant fusion of echinoderm microtubule-associated protein-like 4 ( EML-4 ) -ALK Gly1202Arg mutant14. This drug is presently undergoing Phase I/II clinical trial investigations (http://clinicaltrials.gov/ct2/show/NCT01970865) in ROS1 and ALK fusion-positive NSCLC patients1315161718192021.…”

Medium‐Ring Nitrogen Heterocycles through Migratory Ring Expansion of Metalated Ureas

“…[5] Larger heterocyclic rings are likewise prevalent in biologically active macrolides [6] and cyclic peptides. [7] Recent exploration of drug candidates containing medium-ring nitrogen heterocycles [8] has highlighted the importance of conformational constraints in these structures. [9] Methods enabling the straightforward synthesis of classes of nitrogen heterocycles with ring sizes of eight or more would prove particularly valuable for exploring this less-charted area of chemical space.…”

Metabolism-based structure optimization: Discovery of a potent and orally available tyrosine kinase ALK inhibitor bearing the tetracyclic benzo[b]carbazolone core

“…In addition, a nµMber of other small molecules, including brigatinib (4) [16][17][18] , lorlatinib (5) 16,19,20 , and entrectinib (6) 21 are also under extensive clinical trials with high potency against both ALK and its active mutants.…”