Cyclobutane

The cyclobutane ring occupies a productive position in small-molecule medicinal chemistry, sitting between the high reactivity of cyclopropane and the relative inertness of cyclopentane and larger carbocycles. Important characteristics of the cyclobutane ring include its unique puckered structure, longer C-C bond lengths, increased C-C π-character, and relative chemical inertness for a highly strained carbocycle. This combination of moderate ring strain and conformational rigidity makes cyclobutane a versatile scaffold capable of projecting substituents in well-defined three-dimensional arrangements, reducing the entropic cost of binding and supporting productive target interactions. Cyclobutanes have been used to prevent cis/trans-isomerisation by replacing alkenes, replacing larger cyclic systems, increasing metabolic stability, directing key pharmacophore groups, inducing conformational restriction, reducing planarity, serving as an aryl isostere, and filling hydrophobic pockets.

In the broader context of the "escape from flatland" strategy, the sp³-rich character of cyclobutane addresses the lipophilicity and metabolic liabilities associated with highly aromatic lead series, without the synthetic challenges that can accompany more strained systems such as cyclopropane. The strained yet stable structure, coupled with advances in synthetic tractability, has led to broader application by medicinal chemists and inclusion in more than ten FDA-approved drugs. The scaffold has found application across oncology, CNS disorders, cardiovascular disease, and anti-infective programmes.

Ivosidenib (Tibsovo, Agios Pharmaceuticals) contains a difluorocyclobutyl moiety and was developed as an inhibitor of mutant isocitrate dehydrogenase 1 (IDH1). The fluorine atoms were found important for enzyme inhibitory activity, whilst the difluorocyclobutyl group conferred improved metabolic stability. Approved by the FDA in July 2018, ivosidenib was the first IDH1 inhibitor approved for adult patients with relapsed or refractory acute myeloid leukaemia with a susceptible IDH1 mutation. Abrocitinib (Cibinqo, Pfizer), approved by the FDA in January 2022, is a selective JAK1 inhibitor for the treatment of moderate-to-severe atopic dermatitis whose core scaffold is a 1,3-disubstituted cyclobutane, with the ring directing the pyrrolopyrimidine pharmacophore and sulfonamide group into the geometry required for selective JAK1 engagement.

Our range of cyclobutanes features novel substitutions and the incorporation of synthetically tractable functional groups such as boronic acids and esters, amines, carboxylic acids, ketones, hydroxyls and halogens to enable expedient synthetic strategies.

Please examine a selection of cyclobutanes in our catalogue. The full range can be found using the substructure feature of our Search tools.