Scientists from GlaxoSmithKline’s Stevenage site have an excellent article in J. Med. Chem. showing that cyclopropyl pyran (CPP) groups can serve as viable isosteres to N-pyrimidyl morpholines thanks in part to favorable cyclopropane σ -> aryl π interactions.

N-aryl morpholines are privileged motifs in drug discovery, and suitable hydrogen-bond accepting isosteres are scarce.  This is in part due to the typical co-planarity of the morpholine ring with the N-aryl substituent thanks to hyperconjugation.  The tetrahydropyran (THP) group looks nice on paper but the lack of hyperconjugation results in a very different ground state conformation from N-aryl morpholines due to sterics (Figure 1).  The dihydropyran (DHP) group, which maintains a co-planar ground state, occasionally appears in the literature but is generally unattractive as a morpholine isostere due to its potential reactivity and lower solubility profile.

Conformational differences between morpholines and potential morpholine isosteres
Figure 1. N-Aryl morpholines (e.g. A) have a ground state conformation very different from that of tetrahydropyrans such as C. Dihydropyrans such as B mimic morpholine conformations but are unattractive as drug molecules. Images modified from J. Med. Chem. 2019, 62, 6972-6984

Heather Hobbs and colleagues from GlaxoSmithKline (Stevenage, UK) have a very nice article in J. Med. Chem.1 showing that cyclopropyl pyran (CPP) groups can serve as viable morpholine isosteres in N-aryl morpholines.  They demonstrate this using mTOR inhibitors as a proof of concept, since the morpholine unit of these inhibitors is critical to activity as it binds to the hinge region of the kinase with strict conformational requirements.  An impressive example from their article is shown below (Figure 2), in which the replacement of a methyl morpholine group with a CPP group results in a compound with similar potency, lipophilic efficiency, and solubility, but with improved selectivity against a similar kinase, PI3Kσ.  The relative lipophilic efficiency and solubility of the CPP compound are remarkable given the removal of a nitrogen atom!

Comparison of a morpholine analog to a morpholine isostere compound
Figure 2. A cyclopropyl pyran (CPP) mTOR inhibitor has comparable properties to a methyl morpholine mTOR inhibitor.

In contrast, in similar molecules, tetrahydropyran (THP) derivatives were significantly less active, likely due to the disconnect between the ground state THP conformation from the conformation needed for kinase binding.  The authors generated dihedral scanning plots for various pyrimidine fragments using DFT calculations demonstrating that a co-planar arrangements are energetic minima for N-aryl morpholines, aryl dihydropyrans (DHP), and aryl cyclopropyl pyran (CPP) groups, but not for aryl THPs (Figure 3).  The conformational landscape for the CPP derivative is proposed to be driven by favorable cyclopropane C-C σ -> aryl π interactions.

Conformational analysis of potential morpholine isosteres
Figure 3. Dihedral scanning plots for the bolded dihedral in four potential aryl morpholine isosteres. The CPP analog has a similar conformational landscape to the morpholine in contrast to the THP compound. Image copied from J. Med. Chem. 2019, 62, 6972-6984.

The existence of a co-planar ground state for N-pyrimidyl CPP compounds is experimentally supported by a recently deposited crystal structure by the GSK team (CSD entry COKFEQ, Figure 4). 

3D conformation of cyclopropyl pyran morpholine isostere compound
Figure 4. Crystal structure of an aryl cyclopropyl pyran (CPP) compound providing evidence for ground-state co-planarity of the CPP ring with a pyrimidine arene. 2

The authors also outline a few synthetic routes to these interesting morpholine isostere compounds, with a convenient general route from a common intermediate shown below (Scheme 1).

Synthesis of morpholine isotere CPP cyclopropyl pyranyl compounds
Scheme 1. A synthetic route to aryl CPP derivatives featuring cyclopropanation of a boronic ester and sp<sup>3</sup>-sp<sub>2</sub> cross coupling.

Overall this was a very thorough and well-put together piece of scientific work, and I look forward to seeing the second CPP manuscript in preparation by the team at GSK. For context on the use of cyclopropanes as conformational tools in drug design, Gilles Ouvry has a nice post here.

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  1. Hobbs, H. et al., J. Med. Chem. 2019, 62, 6972-6984.
  2. CSD Entry COKFEQ