Pharmaceutical compounds

Abstract

This invention relates to compounds of the formula (1): X1-L-X2 or a salt or tautomer thereof; wherein X1 and X2 are independently selected from formulae (2A), (2B), (2C) and (2D), wherein * indicates the point of attachment to group L, provided that at least one of X1 and X2 is of formula (2A). The compounds increase mitochondrial function and the invention therefore also provides pharmaceutical compositions containing the compounds and the therapeutic uses of the compounds, in particular in diseases caused or affected by mitochondrial dysfunction.

Description

PHARMACEUTICAL COMPOUNDSThis invention relates to compounds that increase mitochondrial function, pharmaceutical compositions containing the compounds and the therapeutic uses of the compounds, in particular in the treatment of diseases caused or affected by mitochondrial dysfunction.Background of the InventionMitochondria are complex intracellular organelles that play a critical role in cell homeostasis. Responsible for orchestrating cellular energy production, mitochondria are central to the maintenance of life [Osellame 2012], Chemical energy is produced by mitochondria through the process of oxidative phosphorylation (OXPHOS) and is stored in the form of adenosine triphosphate (ATP). ATP is produced by mitochondria through a number of chemical reactions collectively known as the Krebs cycle, also known as the tricarboxylic acid (TCA) cycle. This set of complex cellular reactions is powered by a proton gradient across the mitochondrial inner membrane [Papa 2012], In addition to supplying energy, mitochondria are involved in a number of other processes such as cell signaling, cellular differentiation as well as regulation of cell death [Finkel et al., Circulation Research. 2015;116:1810-1819; McBride 2006],Oxidative phosphorylation (OXPHOS) is the metabolic pathway responsible for the generation of the majority of cellular energy. The human mitochondrial genome contains genetic coding information for 13 proteins, all of which encode essential components of OXPHOS. The OXPHOS system consists of five multiprotein complexes, the individual subunits of which are encoded either by the mitochondrial or by the nuclear genome [Smeitink 2001], This complex series of biochemical reactions convert transmembrane electrochemical proton gradient energy into mechanical energy through ATP synthase, ultimately catalysing the chemical bond energy between ADP and phosphate (P) to form ATP [Friedman 2014],Free radical molecules produced during ATP synthesis can cause DNA damage and therefore DNA within mitochondria are more susceptible to damage than DNA in other cells. Mitochondria also do not possess some of the protective mechanisms which are responsible for preventing DNA damage in other cellular systems. In addition, genetic mutations can result in a reduction in mitochondria production. All of these factors can lead to a reduction in mitochondrial activity. Mitochondrial abnormalities, characterized by a decline in mitochondrial function and the accumulation of damaged mitochondria,have been observed in various cell types and tissues. Some diseases may be caused by mutations or deletions in the mitochondrial genome, while others may be caused by impairment of the mitochondrial respiratory system or other damage of the mitochondrial function [Wallace 1999. In patients with mtDNA mutations, inheritance and clinical presentation are further complicated by the presence of multiple mtDNA genomes in an individual cell leading to a mixture of mutated and wild-type genomes (heteroplasmy) in the same cell or tissue [Stewart 2015]Mitochondrial disorders are common genetic diseases of energy metabolism that affect one in every 5000 people, that are often incurable, genetically and clinically heterogeneous diseases [DiMauro 2008], This heterogeneous group of disorders can manifest as child- or adulthood encephalopathies, myopathies or multi-organsyndromes. They are characterized by deficient activity of one, or more, of the mitochondrial respiratory chain (RC) complexes [complex I (Cl) to V] involved in OXPHOS and / or reductions in steady-state levels of the OXPHOS complexes resulting in diminished ATP production [Nsiah-Sefaa 2016], Most often, they are caused by inherited mutations in the mitochondrial or nuclear genome with clinical heterogeneity and phenotypic variability, which share a defective OXPHOS and disruption of ATP synthesis. Furthermore, the presence of mtDNA in all human tissues means that dysfunction occurs in multiple organ systems. The most commonly affected organ systems are the nervous, muscular, cardiac, and endocrine systems. Regardless of the phenotypic representations, all mitochondrial disorders can be considered as deficiencies in energy metabolism and cell function [Schaefer 2004],Mitochondrial myopathies are clinically heterogeneous disorders that can affect multiple systems besides skeletal muscle and are usually defined by morphological abnormalities of muscle mitochondria. These represent the largest subset of primary mitochondrial diseases, making them the most common inborn error of metabolism [DiMauro 2008], Mitochondrial myopathies that have been found to be associated with functional disruption of mitochondrial output include: mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), one of the most common maternally inherited mitochondrial diseases [Lin 2014]; myoclonic epilepsy and ragged-red fibers (MERRF) in which 80-90% of the patients harbor a mutation in the tRNALys gene of mtDNA resulting in inefficient generation of ATP [Wu 2010]; mitochondrial DNA- associated Leigh syndrome and NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa), part of a continuum of progressive neurodegenerative disorderscaused by abnormalities of mitochondrial energy generation [Thorburn 2017]; Leigh syndrome, a devastating neurodegenerative disease with numerous causative mutations in mitochondrial and nuclear genes encoding components of OXPHOS [Baertling 2014]; mitochondrial dysfunction in fatty acid oxidation disorders such as Long-chain 3- hydroxyacyl-CoA dehydrogenase (LCHAD) [Olpin 2005, Wajner 2016]; Maple syrup urine disease (MSUD) an inborn error of metabolism which results in accumulation of DNA damage and corresponding mitochondrial dysfunction [Strand 2014]; Luft disease which is characterized clinically by hypermetabolism and is caused by extensive uncoupling of mitochondrial respiration in skeletal muscle tissue [Luft 1994]; Chronic progressive external ophthalmoplegia (CPEO), also known as progressive external ophthalmoplegia (PEO), a disorder characterized by slowly progressive paralysis of the extraocular muscles [Luft 1994, Man 2005]; Charcot-Marie-Tooth disease type 2 (CMT2) in which mutations of the mitofusin 2 gene (MFN2) may account for at least a third of the cases and reduced efficacy of oxidative phosphorylation in MFN2-related CMT2 may contribute to the pathophysiology of the axonal neuropathy [Zuchner 2004, Loiseau 2007]; Leber hereditary optic neuropathy (LHON), a primary mtDNA disorder characterised by visual loss in young adults [Luft 1994]; inherited conditions such as Kearns-Sayre syndrome (KSS) [Pieczenik 2007], myoneurogenic gastrointestinal encephalopathy (MNGIE) [Pieczenik 2007] and Barth syndrome, an X chromosome-linked cardiomyopathy caused by tafazzin mutations, [Gonzalvez 2013] have all been implicated with mitochondrial dysfunction. In addition, mitochondrial DNA (mtDNA) depletion syndromes (MDS) are a genetically and clinically heterogeneous group of autosomal recessive disorders that are characterized by a severe reduction in mtDNA content leading to impaired energy production in affected tissues and organs, these disorders include TK2-related and POLG-related disorders [El-Hattab 2013],Furthermore, mitochondrial mutations have been linked to mitochondrial dysfunction in: Maternally inherited epilepsy I mito tubulointerstitial kidney disease (MITKD) [Connor 2017]; Mitochondrial deafness (DEAF) [Kototas 2007]; Ataxia, myoclonus and deafness (AMDF) [Park 2014]; hypertrophic cardiomyopathy HCM [Lucas 2003]; Diabetes Mellitus & Deafness DMDF [Hutchin 200]; Maternally Inherited Diabetes and Deafness (MIDD) [Tsang 2018]; Mitochondrial syndromic sensorineural hearing loss (SNHL) [Forli 2007]; Focal segmental glomerulosclerosis associated with mitochondrial disease (FSGS) [Lim 2017]; Autism Spectrum Disorders (ASD)

[2012] ; Progressive encephalopathy (PEM) [Kollberg 2006]; Bilateral striatal necrosis (BSN) [Solano 2003]; Leber hereditary optic neuropathy and dystonia (LDYT)

[2021] ; Maternally inherited cardiomyopathy (MICM)[Casali 1999]; Motor neuron disease (MND)

[2020] ; Myoclonus epilepsy I myoclonic epilepsy [Lamperti 2016]; Mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA)

[2014] ; Familial Bilateral Striatal Necrosis (FBSN) [Thyagarajan 1995]; Epilepsy, stroke, optic atrophy, and cognitive decline (ESOC)

[2001] ,Mitochondrial dysfunction is not only a hallmark of rare inherited mitochondrial disorders but also implicated in age-related diseases: including neurodegenerative diseases such as Parkinson's disease; Huntington's disease; amyotrophic lateral sclerosis; and Alzheimer's disease [Johri 2021]; metabolic disorders such as Type 2 Diabetes [Lowell 2005]; Steatosis and non-alcoholic steatohepatitis (NASH) [Begriche 2006]; and obesity [Bournat 2010], In addition, cardiac disease such as ischemia reperfusion; ischemic preconditioning; cardiomyopathy and heart failure [Lesnefsky 2001]; and muscular dystrophies [Ryu 2016] and aging [Cui 2012] have all been implicated with mitochondrial dysfunction.Cellular energy deficiency resulting from mitochondrial dysfunction is a hallmark of mitochondrial diseases. This raises the possibility of pharmacologically increasing the mitochondrial content of the cell, in order to increase mitochondrial ATP output, just as occurs in response to exercise [Komen 2014], A potential therapeutic avenue to overcome maladaptive mitochondrial biogenesis is to efficiently boost mitochondrial biogenesis via pharmacological means to compensate for the OXPHOS deficit associated with mitochondrial respiratory dysfunction, with the objective to enrich the wild-type mitochondrial population [Wenz 2010, Moraes 2009], Therefore, strategies aimed at improving mitochondrial function could provide an efficacious therapy for patients with mitochondrial diseases. Pharmacological stimulation of several proteins has been demonstrated to improve mitochondrial biogenesis and function, for example pharmacological activation of the transcriptional co-activator Peroxisome proliferator- activated receptor gamma coactivator 1 -alpha (PGC-1a) [Sandoval-Acuna 2014]; agonist activation of Peroxisome proliferator-activated receptor (PPAR) in combination with deoxyribonucleosides (dNs) has been shown to increases mtDNA Copy Number and mitochondrial mass resulting in an improvement of mitochondrial respiratory function in cellular MELAS models [Burgin 2020]; AMPK-activating compounds have been shown to promote mitochondrial function by increasing the expression of genes involved in mitochondrial biogenesis [Herzig 2018], Compounds such as nicotinamide riboside have been demonstrated to increase mitochondrial biogenesis and whole-body metabolism [Kahn 2014] and nicotinamide mononucleotide has been demonstrated to improve age-related phenotypes in mice, including changes in energy metabolism and increased physical activity, through elevation of NAD+ levels [Mills 2016], Furthermore, NAD- boosting compounds such as PARP inhibitors [Felici 2014] and CD38 inhibitors [Escande 2013] and NAD(P)H:quinone oxidoreductase 1 (NQO1) interacting compounds have also been demonstrated to improve mitochondrial mass and OXPHOS in cellular models of mitochondrial dysfunction [Seo, Kang-Sik 2018], These findings in cellular and murine models of diverse mitochondrial defects support a strategy to ameliorate conditions characterized by abnormal mitochondrial biology through increased mitochondrial mass.It would therefore be beneficial to develop compounds that have the ability to increase mitochondrial activity of cells, for example through the increase of mitochondrial mass.The InventionThe present invention provides compounds selected from compounds that can be used for improving mitochondrial activity and / or increasing mitochondrial mass.Accordingly, in a first embodiment (Embodiment 1.1) of the invention, there is provided a compound of the formula (1):X1-L-X2(1) or a salt or tautomer thereof; whereinX1and X2are independently selected from formulae (2A), (2B), (2C) and (2D):wherein * indicates the point of attachment to group L, provided that at least one of X1and X2is of formula (2A);R2is selected from hydrogen, a C1-4 hydrocarbyl group optionally substituted with a hydroxyl group, and a 5-6 membered cyclic aromatic group or a 3-6 membered cyclic non-aromatic group, wherein the cyclic aromatic and cyclic non-aromatic groups are optionally substituted with one or more substituents selected from halogen, C1-4 alkyl, hydroxyl, C1-4 alkoxy and C1-4 alkanoyl; and one of R3and R4is selected from hydrogen and a C1-4 hydrocarbyl group optionally substituted with a 5-6 membered cyclic aromatic group, wherein the cyclic aromatic group is optionally substituted with one or more substituents selected from halogen, cyano, hydroxy, C1-4 alkyl and C1-4 alkoxy; and the other of R3and R4is hydrogen; L is an optionally substituted cyclic or acyclic linker group having a chain length between X1and X2of 2 to 8 carbon atoms wherein one of the carbon atoms may optionally be replaced with a heteroatom selected from O, N, S and oxidized formsthereof, provided that there are always at least two carbon atoms between the heteroatom when present and each of X1and X2.Particular and preferred compounds of the formula (1) are defined in the Embodiments1.2 to 1.95 below.1.2 A compound according to Embodiment 1.1 wherein X1and X2are the same.1.3 A compound according to Embodiment 1.1 wherein X1and X2are different.1.4 A compound according to Embodiment 1.1 wherein X1has the formula (2A).1.5 A compound according to Embodiment 1.4 wherein X2has the formula (2A).1.6 A compound according to Embodiment 1.4 wherein X2has the formula (2B).1.7 A compound according to Embodiment 1.4 wherein X2has the formula (2C).1.8 A compound according to Embodiment 1.4 wherein X2has the formula (2D).1.9 A compound according to any one of Embodiments 1.1 to 1.3 wherein L has a chain length of from 2 to 6 carbon atoms, wherein one of the carbon atoms may optionally be replaced with a heteroatom selected from O, N, S, S(O) and SO2, provided that there are always at least two carbon atoms between the heteroatom when present and each of X1and X2.1.10 A compound according to Embodiment 1.9 wherein L has a chain length of from 2 to 6 carbon atoms, wherein one of the carbon atoms may optionally be replaced with a heteroatom selected from O, N and S, provided that there are always at least two carbon atoms between the heteroatom when present and each of X1and X2.1.11 A compound according to Embodiment 1.9 wherein L has a chain length of from 2 to 5 carbon atoms, wherein one of the carbon atoms may optionally be replaced with a heteroatom selected from O, N, S, S(O) and SO2, provided that there are always at least two carbon atoms between the heteroatom when present and each of X1and X2.1.12 A compound according to Embodiment 1.11 wherein L has a chain length of from 2 to 5 carbon atoms, wherein one of the carbon atoms may optionally be replaced with a heteroatom selected from O, N and S, provided that there are always at least two carbon atoms between the heteroatom when present and each of X1and X2.1.13 A compound according to any one of embodiments 1.1 to 1.3 wherein L has a chain length of from 2 to 6 carbon atoms, wherein none of the carbon atoms are replaced with a heteroatom.1.14 A compound according to any one of embodiments 1.13 wherein L has a chain length of from 2 to 5 carbon atoms, wherein none of the carbon atoms are replaced with a heteroatom.1.15 A compound according to any one of Embodiments 1.1 to 1.13 wherein L has the formula A1-B-A2wherein:A1and A2are independently selected from a bond and a C1-4 hydrocarbyl linker optionally substituted with one or more hydroxy or halogen;B is selected from a bond, C(Rb)2, N(Rb), O, S, S(O), SO2, a 3 to 6 membered cyclic non-aromatic group and a 5- or 6-membered cyclic aromatic group wherein the cyclic non-aromatic group and the cyclic aromatic group are optionally substituted with one or more groups Rb; andRbis selected from hydrogen, halogen, hydroxyl, C1-6 hydrocarbyl and -O-C1-6 hydrocarbyl, wherein each hydrocarbyl group may optionally be substituted with one or more substituents selected from hydroxy and halogen.1.16 A compound according to any one of Embodiments 1.1 to 1.15 wherein A1and A2are the same.1.17 A compound according to any one of Embodiments 1 .1 and 1 .3 to 1 .16 wherein A1and A2are different.1.18 A compound according to any one of Embodiments 1.1 to 1.17 wherein A1is a bond.1.19 A compound according to any one of Embodiments 1.1 to 1.18 wherein A2is a bond.1 .20 A compound according to any one of Embodiments 1 .15 to 1 .17 wherein A1and A2are independently selected from a C1-4 hydrocarbyl linker (e.g. a C1-4 saturated hydrocarbyl linker) optionally substituted with one or more hydroxy or halogen.1.21 A compound according to any one of Embodiments 1.15 to 1.17 wherein A1and A2are independently selected from a C1-3 hydrocarbyl linker (e.g. a C1-3 saturated hydrocarbyl linker) optionally substituted with one or more hydroxy or halogen.1.22 A compound according to any one of Embodiments 1.15 to 1.17 wherein A1and A2are independently selected from a C1-4 hydrocarbyl linker (e.g. a C1-4 saturated hydrocarbyl linker) optionally substituted with one hydroxy or halogen substituent.1.23 A compound according to any one of Embodiments 1.15 to 1.17 wherein A1and A2are independently selected from a C1-3 hydrocarbyl linker (e.g. a C1-3 saturated hydrocarbyl linker).1.24 A compound according to any one of Embodiments 1.15 to 1.23 wherein A1and A2are independently selected from a methylene or ethylene group.1.25 A compound according to any one of Embodiments 1.15 to 1.24 wherein B is selected from a bond, C(Rb)2, N(Rb), O, S, S(O), SO2, a 3 to 6 membered cyclic nonaromatic group and a 5- or 6-membered cyclic aromatic group wherein the cyclic nonaromatic group and the cyclic aromatic group are optionally substituted with one or more groups Rb.1.26 A compound according to any one of Embodiments 1.15 to 1.25 wherein B is selected from a bond, O, SO2 and a 3 to 6 membered cyclic non-aromatic group optionally substituted with one or more groups Rb.1.27 A compound according to any one of Embodiments 1.15 to 1.26 wherein B is selected from a bond, O, SO2 and a 3 to 6 membered carbocyclic non-aromatic group optionally substituted with one or more groups Rb.1.28 A compound according any one of Embodiments 1.15 to 1.24 wherein B is a bond.1.29 A compound according any one of Embodiments 1.15 to 1.24 wherein C(Rb)2 is a bond.1.30 A compound according any one of Embodiments 1.15 to 1.24 wherein B is N(Rb).1.31 A compound according any one of Embodiments 1.15 to 1.24 wherein B is O.1.32 A compound according any one of Embodiments 1.15 to 1.24 wherein B is S.1.33 A compound according any one of Embodiments 1.15 to 1.24 wherein B is S(O).1.34 A compound according any one of Embodiments 1.15 to 1.24 wherein B is SO2.1.35 A compound according any one of Embodiments 1.15 to 1.24 wherein B is a 3 to6 membered cyclic non-aromatic group and a 5- or 6-membered cyclic aromatic group wherein the cyclic non-aromatic group and the cyclic aromatic group are optionally substituted with one or more groups Rb.1.36 A compound according to Embodiment 1.35 wherein B is a 3 to 6 membered carbocyclic or heterocyclic non-aromatic group optionally substituted with one or more groups Rb.1.37 A compound according to Embodiment 1.36 wherein B is a 3 to 6 membered carbocyclic non-aromatic group optionally substituted with one or more groups Rb.1.38 A compound according to Embodiment 1.36 wherein B is a 4 to 6 membered carbocyclic non-aromatic group optionally substituted with one or more groups Rb.1.39 A compound according to Embodiment 1.38 wherein the carbocyclic non-aromatic group is selected from cyclohexyl, cyclopentyl and cyclobutyl.1.40 A compound according to Embodiment 1.39 wherein the carbocyclic non-aromatic group is cyclohexyl.1.41 A compound according to Embodiment 1.40 wherein L has the following formula(3):wherein * indicates the point of attachment to any one of X1or X2, provided that in formula (3) there is one point of attatchment to X1and one point of attatchment to X2.1.42 A compound according to Embodiment 1.39 wherein the carbocyclic non-aromatic group is cyclopentyl.1.43 A compound according to Embodiment 1.39 wherein the carbocyclic non-aromatic group is cyclobutyl.1.44 A compound according to any one of Embodiments 1.15 to 1.43 wherein Rbis selected from hydrogen, halogen, hydroxyl, C1-4 hydrocarbyl and -O-C1-4 hydrocarbyl, wherein each hydrocarbyl group may saturated and may optionally be substituted with one or more substituents selected from hydroxy, halogen and cyano.1.45 A compound according to any one of Embodiments 1.15 to 1.44 wherein Rbis selected from hydrogen, halogen, hydroxyl, C1-2 hydrocarbyl and -O-C1-2 hydrocarbyl, wherein each hydrocarbyl group may saturated and may optionally be substituted with one or more substituents selected from hydroxy and halogen.1.46 A compound according to any one of Embodiments 1.15 to 1.44 wherein Rbis selected from hydrogen, fluorine, hydroxyl, C1-2 hydrocarbyl and -O-C1-2 hydrocarbyl.1.47 A compound according to Embodiment 1.46 wherein Rbis hydrogen.1.48 A compound according to Embodiment 1.46 wherein Rbis fluorine.1.49 A compound according to any one of Embodiments 1.1 to 1.48 wherein L is a C2-6 hydrocarbyl linker (e.g. has the formula (CH2)n wherein n is from 2 to 6).1.50 A compound according to any one of Embodiments 1.1 to 1.49 wherein L is a C2-5 hydrocarbyl linker (e.g. has the formula (CH2)n wherein n is from 2 to 5).1.51 A compound according to any one of Embodiments 1.1 to 1.50 wherein L is a C2-4 hydrocarbyl linker (e.g. has the formula (CH2)n wherein n is from 2 to 4).1.52 A compound according to any one of Embodiments 1.1 to 1.51 wherein L is a C2-3 hydrocarbyl linker (e.g. has the formula (CH2)n wherein n is from 2 to 3).1.53 A compound according to any one of Embodiments 1.49 to 1.52 wherein the hydrocarbyl linker is a saturated hydrocarbyl linker.1.54 A compound according to any one of Embodiments 1.1 to 1.52 wherein L contains up to 15 non-hydrogen atoms.1.55 A compound according to any one of Embodiments 1.1 to 1.54 wherein L contains up to 10 non-hydrogen atoms.1.56 A compound according to any one of Embodiments 1.1 to 1.55 wherein L contains up to 8 non-hydrogen atoms.1.57 A compound according to any one of Embodiments 1.1 to 1.56 wherein L contains up to 6 non-hydrogen atoms.1.58 A compound according to any one of Embodiments 1.1 to 1.57 wherein L contains up to 5 non-hydrogen atoms.1.59 A compound according to any one of Embodiments 1.1 to 1.58 wherein L contains up to 4 non-hydrogen atoms.1.60 A compound according to any one of Embodiments 1.1 to 1.59 wherein L contains up to 3 non-hydrogen atoms.1.61 A compound according to any one of Embodiments 1.1 to 1.60 wherein L contains up to 3 atoms other than carbon and hydrogen.1.62 A compound according to any one of Embodiments 1.1 to 1.61 wherein L contains 0, 1 or 2 atoms other than carbon and hydrogen.1.63 A compound according to any one of Embodiments 1.1 to 1.62 wherein L contains 0 or 1 atom other than carbon and hydrogen.1.64 A compound according to any one of Embodiments 1.1 to 1.63 wherein L contains 0 atoms other than carbon and hydrogen.1.65 A compound according to any one of Embodiments 1.1 to 1.64 wherein L contains 1 atom other than carbon and hydrogen.1.66 A compound according to any one of Embodiments 1.1 to 1.65 wherein L contains 2 atoms other than carbon and hydrogen.1.67 A compound according to any one of Embodiments 1.1 to 1.66 wherein R2is selected from hydrogen, a C1-4 saturated hydrocabyl group and a 5-6 membered cyclic aromatic group optionally substituted with one or more substituents selected from halogen, C1-4 alkyl, hydroxyl, C1-4 alkoxy and C1-4 alkanoyl.1.68 A compound according to any one of Embodiments 1.1 to 1.67 wherein R2is hydrogen, a C1-4 alkyl group and a phenyl group optionally substituted with one or more substituents selected from halogen, C1-4 alkyl, hydroxyl, C1-4 alkoxy and C1-4 alkanoyl.1.69 A compound according to any one of Embodiments 1.1 to 1.67 wherein R2is selected from hydrogen, a C1-4 alkyl group and a 5-6 membered cyclic aromatic group.1.70 A compound according to any one of Embodiments 1.1 to 1.69 wherein R2is selected from hydrogen, a C1-4 alkyl group and an unsubstituted phenyl group.1.71 A compound according to any one of Embodiments 1.1 to 1.70 wherein R2is selected from hydrogen, methyl, ethyl and phenyl.1.72 A compound according to any one of Embodiments 1.1 to 1.70 wherein R2is selected from hydrogen and a C1-4 alkyl group.1.73 A compound according to any one of Embodiments 1.1 to 1.70 wherein R2is selected from hydrogen and a C1-3 alkyl group.1.74 A compound according to any one of Embodiments 1.1 to 1.71 wherein R2is selected from hydrogen, methyl and ethyl.1.75 A compound according to any one of Embodiments 1.1 to 1.74 wherein R2is hydrogen.1.76 A compound according to any one of Embodiments 1.1 to 1.74 wherein R2is methyl.1.77 A compound according to any one of Embodiments 1.1 to 1.74 wherein R2is phenyl.1.78 A compound according to any one of Embodiments 1.1 to 1.77 wherein R4is hydrogen.1.79 A compound according to any one of Embodiments 1.1 to 1.78 wherein R3is selected from hydrogen and a C1-4 hydrocarbyl group optionally substituted with a 5-6 membered cyclic aromatic group, wherein the cyclic aromatic group is optionally substituted with one or more substituents selected from halogen, cyano, hydroxy, C1-4 alkyl and C1-4 alkoxy.1.80 A compound according to any one of Embodiments 1.1 to 1.79 wherein R3is selected from hydrogen and a C1-3 hydrocarbyl group optionally substituted with a 5-6 membered cyclic aromatic group, wherein the cyclic aromatic group is optionally substituted with one or more substituents selected from halogen, cyano, hydroxy, C1-4 alkyl and C1-4 alkoxy.1.81 A compound according to any one of Embodiments 1.1 to 1.80 wherein R3is selected from hydrogen and a C1-3 hydrocarbyl group optionally substituted with a 5-6 membered cyclic aromatic group, wherein the cyclic aromatic group is optionally substituted with one or more substituents selected from cyano, C1-2 alkyl and C1-2 alkoxy.1.82 A compound according to any one of Embodiments 1.1 to 1.81 wherein R3is selected from hydrogen and a C1-3 hydrocarbyl group optionally substituted with a phenyl or pyridyl group, wherein the phenyl or pyridyl group is optionally substituted with one or more substituents selected from cyano and methoxy.1.83 A compound according to any one of Embodiments 1.1 to 1.82 wherein R3is selected from hydrogen and a C1-3 hydrocarbyl group optionally substituted with a phenyl or pyridyl group, wherein the phenyl or pyridyl group is optionally substituted with one or more substituents selected from cyano, C1-2 alkyl and C1-2 alkoxy.1.84 A compound according to any one of Embodiments 1.1 to 1.83 wherein R3is selected from hydrogen and a C1-3 hydrocarbyl group optionally substituted with a phenyl or group, wherein the phenyl is optionally substituted with one or more substituents selected from cyano, C1-2 alkyl and C1-2 alkoxy.1.85 A compound according to any one of Embodiments 1.1 to 1.84 wherein R3is selected from hydrogen and a C1-3 hydrocarbyl group optionally substituted with a phenyl group, wherein the phenyl group is optionally substituted with one or more substituents selected from cyano and methoxy.1.86 A compound according to any one of Embodiments 1.1 to 1.79 wherein R3is selected from hydrogen and a C1-4 hydrocarbyl group.1.87 A compound according to Embodiment 1.86 wherein R3is selected from hydrogen and an acyclic C1-4 hydrocarbyl group. 1.88 A compound according to Embodiment 1.87 wherein R3is selected from hydrogen and an acyclic C1-3 hydrocarbyl group.1.89 A compound according to any one of Embodiments 1.79 to 1.88 wherein the hydrocarbyl group is a saturated hydrocarbyl group.1.90 A compound according to Embodiment 1.89 wherein R3is selected from hydrogen, methyl, ethyl, propyl, / so-propyl and prop-2-enyl.1.91 A compound according to Embodiment 1.90 wherein R3is hydrogen.1.92 A compound according to any one of Embodiments 1.1 to 1.91 wherein X1and / or X2have the following formula (2A-i):wherein R2, R3and R4are as defined in any one of Embodiments 1.1 to 1.91.1.93 A compound according to any one of Embodiments 1.1 to 1.91 wherein X1and / or X2have the following formula (2A-ii):wherein R2, R3and R4are as defined in any one of Embodiments 1.1 to 1.91.1.94. A compound according to any one of Embodiments 1.1 to 1.91 wherein X1and / or X2have the following formula (2A-iii):wherein R2, R3and R4are as defined in any one of Embodiments 1.1 to 1.91.1.95. A compound according to any one of Embodiments 1.1 to 1.91 wherein X1and / or X2have the following formula (2A-iv):wherein R2, R3and R4are as defined in any one of Embodiments 1.1 to 1.91.1.96 A compound according to any of Embodiments 1.1 to 1.91 wherein X1has the formula 2A-i and X2has the formula 2A-i. 1.97 A compound according to any of Embodiments 1.1 to 1.92 wherein X1has the formula 2A-iii and X2has the formula 2A-iii.1.98 A compound according to any one of Embodiments 1.1 to 1.3 wherein X1and / or X2are selected from groups AA to Al in Table 1 below, wherein the asterisk marks the point of connection to L:1.99 A compound according to Embodiment 1.98 wherein X1and / or X2have the following formula (AE):wherein * indicates the point of attachment to group L.1.100 A compound according to any one of Embodiments 1.1 to 1.3 wherein L is selected from groups BA to CC in Table 2 below, wherein the asterisks mark the point of connection to X1and X2:1.101 A compound selected from the title compounds of Examples 1 to 56 herein.1.102 A compound having the following structural formula (1A):1.103 A compound having the following structural formula (1 B):1.104 A compound according to any one of Embodiments 1.1 to 1.103 which is in the form of a salt.1.105 A compound according to Embodiment 1.104 wherein the salt is an acid addition salt.1.106 A compound according to Embodiment 1.104 or Embodiment 1.105 wherein the salt is a pharmaceutically acceptable salt.1.107 A compound according to any one of Embodiments 1.1 to 1.103 which is in the form of a non-salt (e.g. free base).1.108 A compound according to any one of Embodiments 1.1 to 1.107 which is in the form of a solvate.1.109 A compound according to Embodiment 1.108 wherein the solvate is a hydrate.DefinitionsReferences to “carbocyclic” and “heterocyclic” groups as used herein shall, unless the context indicates otherwise, include both aromatic and non-aromatic ring systems. Thus, for example, the term “carbocyclic and heterocyclic groups” includes within its scope aromatic, non-aromatic, unsaturated, partially saturated and fully saturated carbocyclic and heterocyclic ring systems.The carbocyclic or heterocyclic groups can be aryl or heteroaryl groups. The aryl or heteroaryl groups can be monocyclic or bicyclic groups, as defined herein. The term “aryl” as used herein refers to a carbocyclic group having aromatic character and the term “heteroaryl” is used herein to denote a heterocyclic group having aromatic character. Where the context permits, the terms “aryl” and “heteroaryl” may embrace bicyclic ring systems wherein both rings are aromatic or one ring is non-aromatic and the other is aromatic. In such bicyclic systems containing one aromatic and one non-aromatic group, the group may be attached by the aromatic ring, or by the non-aromatic ring.The term “non-aromatic group” refers to unsaturated ring systems without aromatic character, partially saturated and fully saturated carbocyclic and heterocyclic ring systems. The terms “unsaturated” and “partially saturated” refer to rings wherein the ring structure(s) contains atoms sharing more than one valence bond e.g. the ring contains at least one multiple bond e.g. a C=C N=C bond. The term “saturated” refers to rings where there are no multiple bonds between ring atoms. Saturated carbocyclic groups include the cycloalkyl groups cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Partially saturated carbocyclic groups include the cycloalkenyl groups cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Non-aromatic heterocyclic groups include azetidine, pyrrolidine, piperidine, azepane, piperazine, morpholine, thiomorpholine, thiomorpholine S-oxide and S,S-dioxide, pyran (2H-pyran or 4H-pyran), dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran, tetrahydrothiopyran, S-oxide, S-S dioxide, imidazoline, imidazolidinone, oxazoline, thiazoline, pyrazoline and pyrazolidine.The term “hydrocarbyl” as used herein refers to aliphatic, alicyclic and aromatic and acyclic groups having an all-carbon backbone and consisting of carbon and hydrogen atoms, except where otherwise stated. Examples of hydrocarbyl groups include alkyl, cycloalkyl, cycloalkenyl, carbocyclic aryl, alkenyl, alkynyl, cycloalkylalkyl, cycloalkenylalkyl, and carbocyclic aralkyl, aralkenyl and aralkynyl groups. Such groups can be unsubstituted or, where stated, substituted by one or more substituents as defined herein. In certain cases, as defined herein, one or more, but not all, of the carbon atoms of the hydrocarbyl group may be replaced by another atom or group of atoms. The hydrocarbyl group may be saturated or unsaturated.In formula (1), L is a linker group having a chain length between X1and X2of 2 to 8 carbon atoms.The term “chain length” as used herein refers to the number of atoms (e.g. carbon atoms) extending in a line between two specified points (e.g. between X1and X2), excluding any atoms branching from the chain. Thus, for example, a group -(CH2)3-C(CH3)2-CH2- has a chain length of 5 carbon atoms.When the chain includes a ring structure, the chain length is based on the smallest number of carbon atoms (or other atoms) needed to traverse the ring. For example, in the linker group:the chain length consists of the two carbon atoms in the methylene groups plus four intervening carbon atoms in the cyclohexane ring, giving a total chain length of 6 carbon atoms.For some compounds disclosed herein the stereochemistry at the point of attachment of X1to L and the point of attachment X2to L is displayed. For other compounds disclosed herein the stereochemistry at the point of attachment of X1to L and the point of attachment X2to L is not displayed. It should be understood that if the stereochemistry at the point of attachment is not disclosed, it may take either form.When the term Cx-yhydrocarbyl linker is used, the integers x and y refer to the number of carbon atoms in the hydrocarbyl linker (rather than the chain length of the linker).The claims of this application should be understood to cover only compounds which are stable. The claims are not intended to cover any combinations of groups which lead to unstable compounds. For example, if the claimed definition were to cover a compound having an 0-0 or an 0-N bond, it should be understood that this compound is not intended to be claimed because it is not a stable compound.SaltsThe compounds of the invention as defined in Embodiments 1.1 to 1.109 may be presented in the form of salts.The salts referred to above (and also defined in embodiments 1.104, 1.105 and 1.106) are typically acid addition salts.The salts can be synthesized from the parent compound by conventional chemical methods such as methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. Generally, such salts can be prepared by reacting the free base form of the compound with the acid in water or in an organic solvent, or in amixture of the two; generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.Alternatively, the salts can be formed during the synthesis and subsequent isolation of the compound of formulae (1) or (2).Acid addition salts (as defined in Embodiment 1.105) may be formed with a wide variety of acids, both inorganic and organic. Examples of acid addition salts include salts formed with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L-ascorbic), L-aspartic, benzenesulphonic, benzoic, 4- acetamidobenzoic, butanoic, (+) camphoric, camphor-sulphonic, (+)-(1S)-camphor-10- sulphonic, capric, caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulphuric, ethane- 1 ,2-disulphonic, ethanesulphonic, 2-hydroxyethanesulphonic, formic, fumaric, galactaric, gentisic, glucoheptonic, D-gluconic, glucuronic (e.g. D-glucuronic), glutamic (e.g. L- glutamic), a-oxoglutaric, glycolic, hippuric, hydrobromic, hydrochloric, hydriodic, isethionic, (+)-L-lactic, (±)-DL-lactic, lactobionic, maleic, malic, (-)-L-malic, malonic, (±)- DL-mandelic, methanesulphonic, naphthalene-2-sulphonic, naphthalene-1,5-disulphonic, 1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, L-pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulphuric, tannic, (+)-L-tartaric, thiocyanic, p-toluenesulphonic, undecylenic and valeric acids, as well as acylated amino acids and cation exchange resins.The salt forms of the compounds of the invention are typically pharmaceutically acceptable salts (Embodiment 1.106), and examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, “Pharmaceutically Acceptable Salts,” J. Pharm. Sci., Vol. 66, pp. 1-19. However, salts that are not pharmaceutically acceptable may also be prepared as intermediate forms which may then be converted into pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salts forms, which may be useful, for example, in the purification or separation of the compounds of the invention, also form part of the invention.The ability of a given compound of the invention to form a stable acid addition salt will depend in part upon the basicity of the free base form of the compound and the acidity of the acid. It is preferred, although not necessarily essential, that there is a difference of at least two pKa units between the pKa of the acid and the pKa of the conjugate acid of the base. The acid may be selected from one which has a pKa of 3.5 or lower, for example 3.0 or lower. Accordingly, in further embodiments, the invention provides:1.110 A compound according to any one of Embodiments 1.1 to 1.106, 1.108 and 1.109 which is in the form of an acid addition salt formed with an acid having a pKa of 3.5 or lower (e.g. -7.0 to +3.5).1.111 A compound according to any one of Embodiments 1.1 to 1.106, 1.108 and 1.109 which is in the form of an acid addition salt formed with an acid having a pKa of 3.0 or lower.1.112 A compound according to Embodiment 1.110 or Embodiment 1.111 wherein the acid from which the acid addition salt is formed is selected from hydrochloric, sulphuric, phosphoric, methanesulphonic, ethanesulphonic, benzenesulphonic, toluene sulphonic, naphthalene sulphonic, malonic, maleic, and fumaric acids.1.113 A compound according to Embodiment 1.112 wherein the acid from which the acid addition salt is formed is selected from hydrochloric, sulphuric and methanesulphonic acids.Crystalline FormsThe hydrochloric acid salt of compounds of formula (1) can exist in an amorphous form or a crystalline form, as described in Example 1 herein, and it is envisaged that other salt forms of the compound will also exist in an amorphous form as well as a crystalline form.Accordingly, in a further embodiment (Embodiment 1.114), the invention provides an acid addition salt of a compound of formula (1) in substantially crystalline form.The term “substantially crystalline” refers to forms of the compound of formula (1) in which it is from 50% to 100% crystalline. Within this range, the compound of formula (1) may be at least 55% crystalline, or at least 60% crystalline, or at least 70% crystalline, or at least 80% crystalline, or at least 90% crystalline, or at least 95% crystalline, or at least 98% crystalline, or at least 99% crystalline, or at least 99.5% crystalline, or at least 99.9% crystalline.Accordingly, in further embodiments (Embodiments 1.115 to 1.118), the invention provides:1.115 An acid addition salt of a compound of formula (1) in substantially crystalline form which is at least 90% crystalline.1.116 An acid addition salt of a compound of formula (1) in substantially crystalline form which is at least 95% crystalline.1.117 An acid addition salt of a compound of formula (1) in substantially crystalline form which is at least 99% crystalline.1.118 An acid addition salt of a compound of formula (1) in substantially crystalline form which is at least 99.9% crystalline.The crystalline forms of the compound of the invention may be solvated (e.g. hydrated) or non-solvated (e.g. anhydrous).The term “anhydrous” as used herein does not exclude the possibility of the presence of some water on or in the compound (e.g. a crystal of the compound). For example, there may be some water present on the surface of the compound (e.g. crystal), or minor amounts within the body of the compound (e.g. crystal). Typically, an anhydrous form contains fewer than 0.4 molecules of water per molecule of compound, and more preferably contains fewer than 0.1 molecules of water per molecule of compound, for example 0 molecules of water.Where the crystalline forms are hydrated, they can contain, for example, up to three molecules of water of crystallisation, more usually up to two molecules of water, e.g. one molecule of water or two molecules of water. Non-stoichiometric hydrates may also be formed in which the number of molecules of water present is less than one or is otherwise a non-integer. For example, where there is less than one molecule of water present, there may be for example 0.4, or 0.5, or 0.6, or 0.7, or 0.8, or 0.9 molecules of water present per molecule of compound (1).The crystalline forms can be characterised using a number of techniques including, X-ray powder diffraction (XRPD), single crystal X-ray diffraction (see Example 1), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). The behaviour of the crystals under conditions of varying humidity can be analysed by gravimetric vapour sorption studies (such as dynamic vapour sorption (DVS)).The crystalline structure of a compound can be analysed by the solid-state technique of X-ray Powder Diffraction (XRPD). XRPD can be carried out according to conventional methods such as those described herein (see the Examples below) and in “Introduction to X-ray Powder Diffraction”, Ron Jenkins and Robert L. Snyder (John Wiley & Sons, NewYork, 1996). The presence of defined peaks (as opposed to random background noise) in an XRPD diffractogram indicates that the compound has a degree of crystallinity.A compound’s X-ray powder pattern is characterised by the diffraction angle (20) and interplanar spacing (d) parameters of an X-ray diffraction spectrum. These are related by Bragg’s equation, nA=2d Sin 0, (where n=1; A=wavelength of the X-ray radiation; d=interplanar spacing; and 0=diffraction angle).Alternatively, or additionally, the crystalline structure of the salt form of compound (1) can be analysed by single crystal X-ray diffraction methods, as described in Example 1 below. Single crystal X-ray diffraction studies have been used to determine the absolute stereochemical configuration of the compound of formula (1).Geometric isomers and tautomersThe compounds of the invention may exist in a number of different geometric isomeric, and tautomeric forms and references to the compounds of formulae (1) and (2) as defined in Embodiments 1.1 to 1.118 include all such forms.The optical isomers may be characterised and identified by their optical activity (i.e. as + and - isomers, or d and I isomers) or they may be characterised in terms of their absolute stereochemistry using the “R and S” nomenclature developed by Cahn, Ingold and Prelog, see Advanced Organic Chemistry by Jerry March, 6thEdition, John Wiley & Sons, New Jersey, 2007, pages 155-158, and see also Cahn, Ingold & Prelog, Angew. Chem. Int. Ed. Engl., 1966, 5, 385-415.Optical isomers can be separated by a number of techniques including chiral chromatography (chromatography on a chiral support) and such techniques are well known to the person skilled in the art.As an alternative to chiral chromatography, optical isomers can be separated by forming diastereoisomeric salts with chiral acids such as (+)-tartaric acid, (-)-pyroglutamic acid, (-)-di-toluoyl-L-tartaric acid, (+)-mandelic acid, (-)-malic acid and (-)-camphorsulphonic, or chiral amines such as (+)-1 -phenylethylamine or (+)-1-(1-naphthyl)ethylamine and separating the diastereoisomers by preferential crystallisation, and then dissociating the salts to give the individual enantiomer of the free base.In each of Embodiments 1.1 to 1.118, the compounds of formulae (1) and (2) are substantially optically pure; i.e. have an enantiomeric excess (e.e.) of at least 80% over any other optical isomers of the compounds of formulae (1) and (2).The term “enantiomeric excess” as used herein is used in its conventional sense to mean the percentage excess of the enantiomer of interest (compound (1) or compound (2)). Where the enantiomeric excess is 80%, this corresponds to a composition of matter containing 90% desired enantiomer + 10% other enantiomers = 100% (as 90%-10% = 80%) . More usually, the compounds of formulae (1) and (2) have optical purities (enantiomeric excesses) of at least 82%, or at least 84%, or at least 86%, or at least 88%, or at least 90%, or at least 92%, or at least 94%, or at least 96%, or at least 98%, or at least 99%, or 100%.Accordingly, further embodiments (Embodiments 1.119 to 1.122), the invention provides:1.119 A compound as defined in any one of Embodiments 1.1 to 1.118 wherein the compound of formula (1) or (2), as the case may be, has an optical purity of:(i) at least 80%; or(ii) at least 82%; or(iii) at least 84%, or(iv) at least 86%; or(v) at least 88%; or(vi) at least 90%; or(vii) at least 92%; or(viii) at least 94%; or(ix) at least 96%; or(x) at least 98%; or(xi) at least 99%; or(xii) 100%.1.120 A compound according to Embodiment 1.119 wherein the compound of formula (1) or (2), as the case may be has, an optical purity of at least 98%.1.121 A compound according to Embodiment 1.119 wherein the compound of formula (1) or (2), as the case may be has, an optical purity of at least 99%.1.122 A compound according to Embodiment 1.119 wherein the compound of formula (1) or (2), as the case may be has, an optical purity of 100%.IsotopesIn one embodiment, the compounds of the invention as defined in any one of Embodiments 1.1 to 1.122 are enriched in one or more positions with deuterium.Methods of deuterating organic compounds are known to the person skilled in the art (see for example, “Deuterium Discover and Applications in Organic Chemistry”, Jaemoon Yang, 2016, Elsevier and “The Organic Chemistry of Isotopic Labelling”, James R Hanson, 2019, RSC Publishing).When the compounds of Embodiments 1.1 to 1.122 are deuterated, the percentage of the total hydrogen atoms in the compounds of the invention that are deuterium atoms is less than 2%, more typically less than 1%, more usually less than 0.1%, preferably less than 0.05% and most preferably no more than 0.02%.SolvatesCompounds as defined in any one of Embodiments 1.1 to 1.122 can be solvated or unsolvated.Preferred solvates are solvates formed by the incorporation into the solid state structure (e.g. crystal structure) of the compounds of the invention of molecules of a non-toxic pharmaceutically acceptable solvent (referred to below as the solvating solvent).Examples of such solvents include water, alcohols (such as ethanol, isopropanol and butanol) and dimethylsulphoxide. Solvates can be prepared by recrystallising the compounds of the invention with a solvent or mixture of solvents containing the solvating solvent. Whether or not a solvate has been formed in any given instance can be determined by subjecting crystals of the compound to analysis using well known and standard techniques such as thermogravimetric analysis (TGE), differential scanning calorimetry (DSC) and X-ray crystallography.The solvates can be stoichiometric or non-stoichiometric solvates.Particularly preferred solvates are hydrates, and examples of hydrates include hemihydrates, monohydrates and dihydrates.For a more detailed discussion of solvates and the methods used to make and characterise them, see Bryn et al., Solid-State Chemistry of Drugs, Second Edition, published by SSCI, Inc of West Lafayette, IN, USA, 1999, ISBN 0-967-06710-3.Complexes and clathratesIn one embodiment, the compounds of any one of Embodiments 1.1 to 1.122 are complexes (e.g. inclusion complexes or clathrates with compounds such as cyclodextrins, or complexes with metals) of the compounds.Biological ActivityCompounds as defined in any one of Embodiments 1.1 to 1.122 can be used to to enhance energy production in mitochondria. The compounds can be used to improve mitochondrial activity in vivo or ex vivo.The compounds can be used in the prevention (to reduce the likelihood of developing) or treatment of disorders or diseases having a component relating to mitochondrial dysfunction or aberrant activity.For example, the compounds may be useful in preventing or treating disease states and conditions in which mitochondrial activity is reduced. This reduction in activity may be caused by a reduction in the number of mitochondria produced by the body or as a result of the mitochondria produced having a reduced mitochondrial activity.The term “treatment” as used herein in a general sense to denote a beneficial therapeutic intervention. The treatment may suppress symptoms caused by an underlying disease state, even in instances where the underlying disease state remains, e.g., the treatment may reduce or alleviate the symptoms of the disease thereby making them more manageable by the patient.The term “preventing” as used herein is used in a general sense to denote a therapeutic intervention where the emergence of symptoms of a mitochondrial disease may be prevented altogether, or slowed down, even in cases where the underlying cause of the disease (e.g. an inherited mutation) remains.Accordingly, in further embodiments (Embodiments 2.1 to 2.21), the invention provides:2.1 A compound as defined in any one of Embodiments 1.1 to 1.122 for use in medicine or therapy.2.2 A compound as defined in any one of Embodiments 1.1 to 1.122 for use in preventing or treating a mitochondrial disease.2.3 A compound as defined in any one of Embodiments 1.1 to 1.122 for use in preventing or treating a disease characterised by reduced mitochondrial activity.2.4 The use of a compound as defined in any one of Embodiment 1.1 to 1.122 for the treatment or prevention of a mitochondrial disease.2.5 The use of a compound as defined in any one of Embodiment 1.1 to 1.122 for the treatment or prevention of a disease characterised by reduced mitochondrial activity.2.6 A method of treating a mitochondrial disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound as defined in any one of Embodiments 1.1 to 1.122.2.7 A method of treating a disease characterised by reduced mitochondrial activity in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound as defined in any one of Embodiments 1 .1 to 1 .122.The mitochondrial disease may be a mitochondrial myopathy. Nerve cells present in the brain and muscles utilize a significant amount of chemical energy and therefore mitochondrial dysfunction can give rise to a number of neuromuscular diseases.Examples of such disorders and diseases include Kearns-Sayre syndrome (KSS), Leigh syndrome, maternally inherited Leigh syndrome (MILS), Mitochondrial DNA depletion syndrome (MDS), Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), Myoclonus epilepsy with ragged red fibers (MERRF), Neuropathy ataxia and retinitis pigmentosa (NARP), Pearson syndrome, or Progressive external ophthalmoplegia (PEO), CPEO Charcot-Marie-Tooth disease type 2 (CMT2), fatty acid oxidation disorders, Long- chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), Maple syrup urine disease (MSUD), Luft disease and Leber hereditary optic neuropathy (LHON), Maternally inherited epilepsy I mito tubulointerstitial kidney disease (MITKD), Mitochondrial deafness (DEAF), Ataxia,myoclonus and deafness (AMDF), hypertrophic cardiomyopathy (HCM), Diabetes Mellitus & Deafness (DMDF), Maternally Inherited Diabetes and Deafness (MIDD), Mitochondrial syndromic sensorineural hearing loss (SNHL), Focal segmental glomerulosclerosis associated with mitochondrial disease (FSGS), Autism Spectrum Disorders (ASD), Progressive encephalopathy (PEM), Bilateral striatal necrosis (BSN), Leber hereditary optic neuropathy and dystonia (LDYT), Maternally inherited cardiomyopathy (MICM), Motor neuron disease (MND), Myoclonus epilepsy I myoclonic epilepsy, Mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA), Familial Bilateral Striatal Necrosis (FBSN), Epilepsy, stroke, optic atrophy, and cognitive decline (ESOC).The mitochondrial disease may also be Diabetes mellitus or deafness (DAD) and type 2 diabetes.In addition to the diseases mentioned above, there are also a number of acquired conditions in which it is thought that mitochondrial dysfunction is involved. These include:• Huntington’s disease• cancer• Alzheimer’s disease• Parkinson’s disease• bipolar disorder• schizophrenia• aging and senescence• anxiety disorders• cardiovascular disease• sarcopenia• chronic fatigue syndrome• amyotrophic lateral sclerosis• steatosis and non-alcoholic steatohepatitis (NASH)• obesity• ischemia reperfusion• ischemic preconditioning• cardiomyopathy• heart failure• muscular dystrophies.Accordingly, in further embodiments (Embodiments 2.8 to 2.17), the invention provides:2.8 A compound as defined in any one of Embodiments 1.1 to 1.122 for use in preventing or treating a mitochondrial myopathy.2.9 The use of a compound as defined in any one of Embodiments 1.1 to 1.122 for the treatment or prevention of a mitochondrial myopathy.2.10 A method of treating a mitochondrial myopathy in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound as defined in any one of Embodiments 1.1 to 1.122.2.11 A compound for use according to Embodiment 2.8, the use of a compound according to Embodiment 2.9 or a method according to Embodiment 2.10 wherein the mitochondrial myopathy is selected from Kearns-Sayre syndrome (KSS), Leigh syndrome, maternally inherited Leigh syndrome (MILS), Mitochondrial DNA depletion syndrome (MDS), Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), Myoclonus epilepsy with ragged red fibers (MERRF), Neuropathy ataxia and retinitis pigmentosa (NARP), Pearson syndrome, or Progressive external ophthalmoplegia (PEO), CPEO Charcot-Marie-Tooth disease type 2 (CMT2), fatty acid oxidation disorders, Long- chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), Maple syrup urine disease (MSUD), Luft disease and Leber hereditary optic neuropathy (LHON), Maternally inherited epilepsy I mito tubulointerstitial kidney disease (MITKD), Mitochondrial deafness (DEAF), Ataxia, myoclonus and deafness (AMDF), hypertrophic cardiomyopathy (HCM), Diabetes Mellitus & Deafness (DMDF), Maternally Inherited Diabetes and Deafness (MIDD), Mitochondrial syndromic sensorineural hearing loss (SNHL), Focal segmental glomerulosclerosis associated with mitochondrial disease (FSGS), Autism Spectrum Disorders (ASD), Progressive encephalopathy (PEM), Bilateral striatal necrosis (BSN), Leber hereditary optic neuropathy and dystonia (LDYT), Maternally inherited cardiomyopathy (MICM), Motor neuron disease (MND), Myoclonus epilepsy I myoclonic epilepsy, Mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA), Familial Bilateral Striatal Necrosis (FBSN), Epilepsy, stroke, optic atrophy, and cognitive decline (ESOC).2.12 A compound as defined in any one of Embodiments 1.1 to 1.122 for use in preventing or treating Diabetes mellitus or deafness (DAD) and type 2 diabetes.2.13 The use of a compound as defined in any one of Embodiments 1.1 to 1.122 for the treatment or prevention of Diabetes mellitus or deafness (DAD) and type 2 diabetes.2.14 A method of treating Diabetes mellitus or deafness (DAD) and type 2 diabetes in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound as defined in any one of Embodiments 1.1 to 1.122.2.15 A compound as defined in any one of Embodiments 1.1 to 1.122 for use in preventing or treating a disease selected from Huntington’s disease, cancer, Alzheimer’s disease, Parkinson’s disease, bipolar disorder, schizophrenia, aging and senescence, anxiety disorders, cardiovascular disease, sarcopenia, chronic fatigue syndrome, amyotrophic lateral sclerosis, steatosis and non-alcoholic steatohepatitis (NASH), obesity, ischemia reperfusion, ischemic preconditioning, cardiomyopathy, heart failure and muscular dystrophies.2.16 The use of a compound as defined in any one of Embodiment 1.1 to 1.122 for the treatment or prevention of a disease selected from Huntington’s disease, cancer, Alzheimer’s disease, Parkinson’s disease, bipolar disorder, schizophrenia, aging and senescence, anxiety disorders, cardiovascular disease, sarcopenia, chronic fatigue syndrome, amyotrophic lateral sclerosis, steatosis and non-alcoholic steatohepatitis (NASH), obesity, ischemia reperfusion, ischemic preconditioning, cardiomyopathy, heart failure and muscular dystrophies.2.17 A method of treating a disease selected from Huntington’s disease, cancer, Alzheimer’s disease, Parkinson’s disease, bipolar disorder, schizophrenia, aging and senescence, anxiety disorders, cardiovascular disease, sarcopenia, chronic fatigue syndrome, amyotrophic lateral sclerosis, steatosis and non-alcoholic steatohepatitis (NASH), obesity, ischemia reperfusion, ischemic preconditioning, cardiomyopathy, heart failure and muscular dystrophies in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound as defined in any one of Embodiments 1.1 to 1.122.2.18 A method of treating a subject who has been diagnosed and has been found to be suffering from a disease or condition characterised by reduced mitochondrial activity, which method comprises administering to the subject an effective amount of a compound as defined in any one of Embodiments 1.1 to 1.122.2.19 A method for the diagnosis and treatment of a disease state or condition characterised by reduced mitochondrial activity which method comprises (i) screening a patient to determine whether a disease or condition from which the patient is or may be suffering is one which would be susceptible to treatment with a compound that increases mitochondrial activity; and (ii) where it is indicated that the disease or condition from which the patient is thus susceptible, thereafter administering to the patient a compound as defined in any one of Embodiments 1.1 to 1.122.2.20 The use of a compound as defined in any one of Embodiments 1.1 to 1.122 for the manufacture of a medicament for the treatment or prophylaxis of a disease state or condition in a patient who has been screened and has been determined as suffering from, or being at risk of suffering from, a disease or condition which would be susceptible to treatment with a compound that increases mitochondrial activity.2.21 A compound as defined in any one of Embodiments 1.1 to 1.122 for use in the treatment or prophylaxis of a disease state or condition in a patient who has been screened and has been determined as suffering from, or being at risk of suffering from, a disease or condition which would be susceptible to treatment with a compound that increases mitochondrial activity.The diagnostic methods used to determine whether a particular cancer is susceptible to treatment with the compounds of the invention can be as described below in the section headed “Methods of Diagnosis”.Determination of biological propertiesThe ability of the compounds of Embodiments 1.1 to 1.122 to increase mitochondrial activity can also be determined using the protocols set out in the Examples section below.Cell-based in vitro functional and phenotypic assays can be used to simultaneously profile mitochondrial parameters and hence obtain a more global footprint of the activity of a compound on mitochondria. The mitochondrial membrane potential (AipM) can be assessed using dyes that accumulate inside mitochondria without having any impact on mitochondrial respiration. These include, but are not limited to, Acridine Orange 10-Nonyl Bromide (NAO), MitoTracker™ Green FM, MITO-ID® Green and MitoView™ Green. These dyes are widely used to image mitochondria, to assess their localisation within the cell and to quantify mitochondrial abundance and thereby provide a proxy formitochondrial biogenesis and efficiency [Kitami 2012], To assess mitochondrial biomass at the cellular level, reporter cell lines, transfected with mitochondrially targeted green fluorescent protein (GFP), can be used to quantify the expression of the respiratory complex subunits, such as the cytochrome c oxidase subunit IV (COXVIII) in live cells [Wang 2012, Nilsson 2015], Furthermore, the development of oxygen-dependent fluorescence quenching systems and High-Resolution Respirometry (HRR) enable the direct quantification of mitochondrial respiration in a high throughput format. By combining the results of several tests for all compounds, it is possible to define a comprehensive set of mitochondrial signatures that enable the clustering of novel chemical entities according to their footprint on mitochondrial function [Andreux 2016],Preferred compounds of Embodiments 1.1 to 1.122 are those having a mitochondrial size activity (measured using a method described above, for example in a Mitotracker Assay or a COX8 MTS reporter assay) of 102% or greater, preferably 105% of greater.Accordingly, in further embodiments (Embodiments 2.22 to 2.26), the invention provides:2.22 A compound according to any one of Embodiments 1.1 to 1.122 having a mitochondrial size activity of 102% or greater.2.23 A compound according to any one of Embodiments 1.1 to 1.122 having a mitochondrial size activity of 103% or greater.2.24 A compound according to any one of Embodiments 1.1 to 1.122 having a mitochondrial size activity of 104% or greater.2.25 A compound according to any one of Embodiments 1.1 to 1.122 having a mitochondrial size activity of 105% or greater.2.26 A compound according to any one of Embodiments 1.1 to 1.122 for use in a therapy, treatment, method or use according to any one of Embodiments 2.1 to 2.25.Methods for the Preparation of Compounds of the InventionThe invention also provides methods for the preparation of a compound according to any one of Embodiments 1.1 to 1.122.Compounds of formula (1) can be prepared according to the following scheme below, by reacting a first carboxylic acid derivative of general formula (4) one equivalent of a bis-hydroxy compound of general formula (5), optionally separating out the mono-substituted product (5A) and then subsequently reacting the compound of formula (5A) with one equivalent of a second carboxylic acid derivative of general formula (6):wherein Y is defined as having one of the following structural formulae (7A), (7B), (70) or(7D):(7A) (7B) (70) (7D) wherein * indicates the point of attachment to the leaving group LG. Accordingly, in a further embodiment (Embodiment 3.1) there is provided a method of preparing a compound as defined in any one of Embodiments 1.1 to 1.122, comprising:(a) reacting one equivalent of a first carboxylic acid derivative of general formula (4) with one equivalent of a b / s- hydroxy compound of general formula (5) to form a monosubstituted product having the formula (5A):(b) reacting the mono-substituted product (5) with one equivalent of a second carboxylic acid derivative of general formula (6); wherein L is as defined in any one of Embodiments 1.1 to 1.122, LG is a suitable leaving group and Y is selected from (7A), (7B), (70) or (7D):(7A) (7B) (70) (7D) wherein * indicates the point of attachment to the leaving group LG.The mono-substituted product may be isolated after step (a) and prior to step (b).Preferably, the reaction takes place in an aprotic solvent at room temperate and in the presence of a coupling agent. If the structures of the first and second carboxylic acid derivative are not the same (i.e. if structure 4 and structure 6 are different), it is also preferable that one of the hydroxyl groups on the b / s-hydroxy compound are provided with a suitable protecting group in step (a). Alternatively, if the structures of the first and second carboxylic acid derivatives are the same (i.e. if structure 4 and structure 6 are the same), the reaction may take place in one step, wherein one equivalent of each of the first and second carboxylic acid derivatives (which are the same) are reacted with one equivalent of the b / s-hydroxyl compound in a single step.Further embodiments (Embodiments 3.2 to 3.13) are provided below:3.2 A method according to Embodiment 3.1 wherein LG is selected from OH, a halide, tosylate, mesylate, besylate, OR or OC(O)R wherein R is a C1-3 alkyl group.3.3 A method according to Embodiment 3.2 is selected from OH and Cl.3.4 A method according to Embodiment 3.3 wherein LG is OH.3.4 A method according to any one of Embodiments 3.1 to 3.4 wherein the reaction is carried out in an aprotic solvent.3.5 A method according to Embodiment 3.3 wherein the aprotic solvent is tetrahydrofuran (THF) or dioxane.3.6 A method according to any one of Embodiments 3.1 to 3.5 where the reaction is conducted in the presence of a non-nucleophilic base.3.7 A method according to Embodiment 3.6. herein the non-nucleophilic base is DMAP.3.8 A method according to any one of Embodiments 3.1 to 3.7 wherein the reaction takes place at room temperature.3.9 A method according to any one of Embodiments 3.1 to 3.8 wherein the reaction takes place in the presence of a coupling agent.3.10 A method according to Embodiment 3.9 wherein the coupling agent is dicyclohexylcarbodiimide (DCC) or diisopropylcarbodiimide (DIC).3.11 A method according to any one of Embodiments 3.1 to 3.10 wherein the compound of formula (4) and the compound of formula (6) are the same.3.12 A method according to Embodiment 3.11 wherein step (a) and step (b) take place at the same time.3.13 A method according to any one of Embodiments 3.1 to 3.10 wherein the compound of formula (4) and the compound of formula (6) are different.3.14 A method according to Embodiment 3.13 wherein the method further comprises addition of a protecting group to one of the hydroxyl groups on the b / s-hydroxy compound before step (a) and removal of the protecting group before step (b).Compounds of formulae (4) or (6) in which LG is OH (referred herein as compounds of formula (8)), can be prepared according to the scheme below, by reacting a compound of the formula (9), wherein PG is a suitable nitrogen protecting group, with an acid in a polar solvent in order to remove the N-Boc protecting group.Accordingly, in a further embodiment (Embodiment 3.15) there is provided a method of preparing a compound of formula (4) or formula (6) as defined above, in which LG is OH, which method comprises: (a) removing protecting group, PG, from a compound of formula (9):to form a compound of formula (8);Further embodiments are provided below: 3.16 A method according to Embodiment 3.15 wherein PG has the formula C(O)ORN, wherein RNis an optionally substituted C1-4 hydrocarbyl group.3.17 A method according to Embodiment 3.16 wherein RNis tert-butyl.3.18 A method according to any one of Embodiments 3.15 to 3.17 wherein step (a) is carried out in the presence of an acid.3.19 A method according to Embodiment 3.18 wherein the acid is selected from trifluoroacetic acid and hydrochloric acid.3.20 A method according to any one of Embodiments 3.15 to 3.19 wherein step (a) is carried out in a polar, aprotic solvent.3.26 A method according to any one of Embodiments 3.20 to 3.25 wherein step (a) is carried out in dichloromethane or diethyl ether.Protecting GroupsIn the methods described above, it may be necessary to protect one or more groups to prevent reaction from taking place at an undesirable location on the molecule. Examples of protecting groups, and methods of protecting and deprotecting functional groups, can be found in Protective Groups in Organic Synthesis (P. Wuts; 5thEdition; Wiley, 2014).A hydroxy group may be protected, for example, as an ether (-OR) or an ester (- OC(=O)R), for example, as: a t-butyl ether; a tetrahydropyranyl (THP) ether; a benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl or t-butyldi methylsilyl ether; or an acetyl ester (-OC(=O)CH3, -OAc).An aldehyde or ketone group may be protected, for example, as an acetal (R-CH(OR)2) or ketal (R2C(OR)2), respectively, in which the carbonyl group (>C=O) is converted to a diether (>C(OR)2), by reaction with, for example, a primary alcohol. The aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.An amine group may be protected, for example, as an amide (-NRCO-R) or a urethane (- NRCO-OR), for example, as: a methyl amide (-NHCO-CH3); a benzyloxy amide (-NHCO- OCH2C6H5, -NH-Cbz or NH-Z); as a t-butoxy amide (-NHCO-OC(CH3)3, -NH-Boc); a 2- biphenyl-2-propoxy amide (-NHCO-OC(CH3)2C6H4C6Hs, -NH-Bpoc), as a 9- fluorenylmethoxy amide (-NH-Fmoc), as a 6-nitroveratryloxy amide (-NH-Nvoc), as a 2- trimethylsilylethyloxy amide (-NH-Teoc), as a 2,2,2-trichloroethyloxy amide (-NH-Troc), as an allyloxy amide (-NH-Alloc), or as a 2(-phenylsulphonyl)ethyloxy amide (-NH-Psec).Other protecting groups for amines, such as cyclic amines and heterocyclic N-H groups, include toluenesulphonyl (tosyl) and methanesulphonyl (mesyl) groups, benzyl groups such as a para-methoxybenzyl (PMB) group and tetrahydropyranyl (THP) groups.A carboxylic acid group may be protected as an ester for example, as: an C1-7 alkyl ester (e.g., a methyl ester; a t-butyl ester); a Ci-y haloalkyl ester (e.g., a C1-7 trihaloalkyl ester); a triCi-7 alkylsilyl-Ci-7alkyl ester; or a Cs-2o aryl-Ci-7 alkyl ester (e.g., a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as a methyl amide. A thiol group may be protected, for example, as a thioether (-SR), for example, as: a benzyl thioether; an acetamidomethyl ether (-S-CH2NHC(=O)CH3).Pharmaceutical FormulationsThe compounds of the invention are typically administered to patients in the form of a pharmaceutical composition. Accordingly, in another Embodiment of the invention (Embodiment 4.1), the invention provides a pharmaceutical composition comprising a compound according to any one of Embodiments 1.1 to 1.122 and a pharmaceutically acceptable excipient.In further embodiments, there are provided:4.2 A pharmaceutical composition according to Embodiment 4.1 which comprises from approximately 1 % (w / w) to approximately 95% (w / w) of a compound of any one of Embodiments 1.1 to 1.122 and from 99% (w / w) to 5% (w / w) of a pharmaceutically acceptable excipient or combination of excipients and optionally one or more further therapeutically active ingredients.4.3 A pharmaceutical composition according to Embodiment 4.2 which comprises from approximately 5% (w / w) to approximately 90% (w / w) of a compound of any one of Embodiments 1.1 to 1.122 and from 95% (w / w) to 10% of a pharmaceutically acceptable excipient or combination of excipients and optionally one or more further therapeutically active ingredients.4.4 A pharmaceutical composition according to Embodiment 4.3 which comprises from approximately 10% (w / w) to approximately 90% (w / w) of a compound of any one of Embodiments 1.1 to 1.122 and from 90% (w / w) to 10% of a pharmaceutically acceptable excipient or combination of excipients.4.5 A pharmaceutical composition according to Embodiment 4.4 which comprises from approximately 20% (w / w) to approximately 90% (w / w) of a compound of any one of Embodiments 1.1 to 1.122 and from 80% (w / w) to 10% of a pharmaceutically acceptable excipient or combination of excipients.4.6 A pharmaceutical composition according to Embodiment 4.5 which comprises from approximately 25% (w / w) to approximately 80% (w / w) of a compound of any one of Embodiments 1.1 to 1.122 and from 75% (w / w) to 20% of a pharmaceutically acceptable excipient or combination of excipients.The pharmaceutical compositions of the invention can be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, ophthalmic, otic, rectal, intra-vaginal, or transdermal administration. Where the compositions are intended for parenteral administration, they can be formulated for intravenous, intramuscular, intraperitoneal or subcutaneous administration, or for direct delivery into a target organ or tissue by injection, infusion or other means of delivery.Pharmaceutical dosage forms suitable for oral administration include tablets, capsules, caplets, pills, lozenges, syrups, solutions, sprays, powders, granules, elixirs and suspensions, sublingual tablets, sprays, wafers or patches and buccal patches.Pharmaceutical compositions (e.g. as defined in Embodiment 4.1) containing a compound according to any one of Embodiments 1.1 to 1.122 of the invention can be formulated in accordance with known techniques, see for example, Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.Thus, tablet compositions can contain a unit dosage of active compound together with an inert diluent or carrier such as a sugar or sugar alcohol, e.g.; lactose, sucrose, sorbitol or mannitol; and / or a non-sugar derived diluent such as sodium carbonate, calcium phosphate, talc, calcium carbonate, or a cellulose or derivative thereof such as methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starches such as corn starch. Tablets may also contain such standard ingredients as binding and granulating agents such as polyvinylpyrrolidone, disintegrants (e.g. swellable crosslinked polymers such as crosslinked carboxymethylcellulose), lubricating agents (e.g. stearates), preservatives (e.g. parabens), antioxidants (e.g. BHT), buffering agents (for example phosphate or citrate buffers), and effervescent agents such as citrate / bicarbonate mixtures. Such excipients are well known and do not need to be discussed in detail here.Capsule formulations may be of the hard gelatin or soft gelatin variety and can contain the active component in solid, semi-solid, or liquid form. Gelatin capsules can be formed from animal gelatin or synthetic or plant derived equivalents thereof.The solid dosage forms (e.g.: tablets, capsules etc.) can be coated or un-coated, but typically have a coating, for example a protective film coating (e.g. a wax or varnish) or a release controlling coating. The coating (e.g. a Eudragit ™ type polymer) can be designed to release the active component at a desired location within the gastro-intestinal tract. Thus, the coating can be selected so as to degrade under certain pH conditions within the gastrointestinal tract, thereby selectively releasing the compound in the stomach or in the ileum or duodenum.Instead of, or in addition to, a coating, the drug can be presented in a solid matrix comprising a release controlling agent, for example a release delaying agent which may be adapted to selectively release the compound under conditions of varying acidity or alkalinity in the gastrointestinal tract. Alternatively, the matrix material or release retarding coating can take the form of an erodible polymer (e.g. a maleic anhydride polymer) which is substantially continuously eroded as the dosage form passes through the gastrointestinal tract.In one particular embodiment , the pharmaceutical composition of Embodiments 4.1 is an enterically coated solid dosage form such as a tablet or capsule having a coating which is selected so as to withstand acidic conditions and degrade under pH conditions prevailing within the duodenum or ileum thereby selectively releasing the compound in the duodenum or ileum.Compositions for topical use include ointments, creams, sprays, patches, gels, liquid drops and inserts (for example intraocular inserts). Such compositions can be formulated in accordance with known methods.Compositions for parenteral administration are typically presented as sterile aqueous or oily solutions or fine suspensions, or may be provided in finely divided sterile powder form for making up extemporaneously with sterile water for injection.Examples of formulations for rectal or intra-vaginal administration include pessaries and suppositories which may be, for example, formed from a shaped mouldable or waxy material containing the active compound.Compositions for administration by inhalation may take the form of inhalable powder compositions or liquid or powder sprays, and can be administrated in standard form using powder inhaler devices or aerosol dispensing devices. Such devices are well known. Foradministration by inhalation, the powdered formulations typically comprise the active compound together with an inert solid powdered diluent such as lactose.The compounds of the inventions will generally be presented in unit dosage form and, as such, will typically contain sufficient compound to provide a desired level of biological activity. For example, according to Embodiment 4.1, a composition intended for oral administration may contain from 2 milligrams to 200 milligrams of active ingredient, more usually from 10 milligrams to 100 milligrams, for example, 12.5 milligrams, 25 milligrams or 50 milligrams.Combination TherapyIt is envisaged that the compounds of Embodiments 1.1 to 1.122 will be useful either as sole therapeutic agents or in combination with other therapeutic agents.The compounds of the present invention which are designed to enhance mitochondrial bioenergetics through increasing OXPHOS capacity would be expected to work in combination with:• Agents that replenish NAD+ pools;• Inhibitors of pathways that use up cellular and mitochondrial NAD+ pools;• Modulators of mitochondrial biogenesis;• Activators of the retinoid X receptor-a(RXRa);• AMPK agonists;• SI RT1 -activating compounds (STACs);• Mitochondria-targeted protective compounds that reduce the production of toxic reactive oxygen species;• Antioxidants;• Vitamins and supplements; and• Behavioural interventions.The compounds of the invention as defined in any one of the Embodiments 1.1 to 1.122 may be administered over a prolonged term to maintain beneficial therapeutic effects or may be administered for a short period only. Alternatively, they may be administered in a pulsatile or continuous manner.The compounds of the invention will be administered in an effective amount, i.e. an amount which is effective to bring about the desired therapeutic effect. For example, the “effective amount” can be a quantity of compound which, when administered to a subject, ameliorates the symptoms of a disease and / or increases longevity of the subject.The amount of compound of the invention administered to the subject will depend on the type and severity of the disease or condition and on the characteristics of the subject, such as general health, age, sex, body weight and tolerance to drugs. The skilled person will be able to determine appropriate dosages depending on these and other factors.The compounds are generally administered to a subject in need of such administration, for example a human or animal subject (patient), preferably a human.Ultimately, the quantity of compound administered and the type of composition used will be commensurate with the nature of the disease or physiological condition being treated and will be at the discretion of the physician.Methods of DiagnosisPrior to administration of a compound of any one of Embodiments 1.1 to 1.122, a patient may be screened to determine whether a disease or condition from which the patient is or may be suffering is one which would be susceptible to treatment with a compound which can increase mitochondrial activity. Such patient can then be treated according to the methods described above.For example, a biological sample taken from a patient may be analysed to determine whether a condition or disease that the patient is or may be suffering from is one which is characterised by a genetic abnormality which leads to mitochondrial dysfunction. The term mitochondrial dysfunction covers the reduced production of mitochondria and also the production of mitochondria with reduced mitochondrial activity.Mitochondrial dysfunction can be caused by exposure to certain environmental factors such as occupational chemical mutagens, air pollution and cigarette smoke or genetic abnormalities of both mitochondrial (mtDNA) and nuclear DNA (nDNA). Mitochondrial dysfunction can affect any organ system and appear at any age.The diagnosis of mitochondrial myopathies from patient tissue, skin or blood serum samples includes techniques such as histological and immunohistochemical analysis:such as staining of skeletal muscle cryosections with modified Gomori Trichrome, indicating the presence of ragged-red fibers (RRF); succinate dehydrogenase (SDH, complex II) histochemistry, to detect mitochondrial aggregates as a result of mitochondrial OXPHOS dysfunction; and sequential COX / SDH histochemistry, which can be used to detect cytochrome c oxidase (COX, complex IV)-negative fibers. Biochemical enzymatic analysis by spectrophotometric evaluation of the OXPHOS complexes, such as NADH:ubiquinone oxidoreductase for complex I; succinate:cytochrome c oxidase oxidoreductase for complex II; ubiquinol cytochrome c oxidoreductase for complex III, cytochrome c oxidase for complex IV, and the blue native acrylamide PAGE (BN-PAGE can be used to detect mitochondrial dysfunction from patient tissue, skin or blood serum. Mutations causing mitochondrial myopathy can be found in either the mtDNA or nDNA and these can be detected through next-generation sequencing (NGS), whole exome sequencing (WES), whole genome sequencing (WGS) or a targeted multigene panel of candidate genes by NGS. For some patients with mitochondrial myopathy, it is helpful to determine mtDNA copy number in muscle tissue using real-time PCR, or long-range PCR may be used to detect large-scale mtDNA deletion or multiple mtDNA deletions, and NGS, real-time PCR, pyrosequencing, and long-range PCR can be used for determination of mtDNA heteroplasmy and deletions.In particular mutations in mtDNA have been identified and linked to mitochondrial dysfunctuion in the the following diseases:Other diagnostic tests for mitochondrial myopathy include: the determination of lactate concentrations at rest or following exercise; blood serum Fibroblast growth factor 21 (FGF-21); blood serum growth differentiation factor 15 (GDF-15). The intergartion of information from these tests allows for the diagnosis in the majority of pateinets with mitochondrial myopathies [Ahmed 2018],Ex Vivo UsesAs described above, the compounds of Embodiment 1.1 to 1.122 can be used for improving mitochondrial activity of cells ex vivo. Such ex vivo methods are envisaged to be useful in a wide variety of therapies, which involve removing cells from a subject, modifying the cells and then reintroducing cells into the subject. Examples of such therapies include CAR-T and CAR-NK therapy.Accordingly, there is also provided an ex vivo method of improving the mitochondrial activity of a cell, said method comprising bringing an effective amount of a compound of any one of Embodiments 1.1 to 1.122 into contact with the cell.EXAMPLESEXAMPLES 1 TO 56The compounds of Examples 1 to 56 in Table 3 below are illustrative of the invention.The following examples are provided solely to illustrate the present invention and are not intended to limit the scope of the invention, as described herein.For convenience, the following common abbreviations are used herein:- ACN for acetonitrileBoc for tert-butyloxycarbonylCDI for 1 ,T-carbonyldiimidazoleDCC for dicyclohexylcarbodiimideDCM for dichloromethaneDMAP for 4-(dimethylamino) pyridineDMF for / V, / V-dimethylformamideDMSO for dimethylsulfoxide.EDC for 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide h for hoursHPLC for High Pressure Liquid Chromatography.LCMS for Liquid Chromatography-Mass SpectrometryMin for minutesMTBE for methyl tert-butyl etherNMR for Nuclear Magnetic ResonanceRT for Retention TimeSFC for supercritical fluid chromatographyTFA for trifluoroacetic acidTHF for tetrahydrofuranTBDMS for tert-butyldi(methyl)silylGeneral Methods:Analytical MethodsLiquid Chromatography-Mass SpectrometryLCMS-Method 1LC-MS was performed on an Agilent 1260 Infinity II LC / MSD system with a DAD\ELSD Alltech 3300 or Agilent DAD\ELSD G7102A 1290 Infinity II and an Agilent LC\MSD G6120B mass-spectrometer using an Agilent Poroshell 120 SB-C182.7 pm 4.6x30mm column, maintained at a temperature of 60°C, the column being initially held at 1% acetonitrile (LC-MS grade) in high purity water (Milli-Q) with 0.1% (v / v) formic acid for 0.01 minutes, followed by a linear gradient of 1-100% acetonitrile in 1.5 minutes and then held at 100% acetonitrile for 2.2 minutes at a flow rate of 3 mL / min.LCMS-Method 2LC-MS was performed on an Agilent 1260 Infinity II LC / MSD system with a DAD\ELSD Alltech 3300 or Agilent DAD\ELSD G7102A 1290 Infinity II and an Agilent LCWISD G6120B mass-spectrometer using an Agilent Poroshell 120 SB-C182.7 pm 4.6x30mm column, maintained at a temperature of 60°C, the column being initially held at 1% acetonitrile (LC-MS grade) in high purity water (Milli-Q) with 0.1% (v / v) formic acid for 0.01 minutes, followed by a linear gradient of 1-100% acetonitrile in 5 minutes and then held at 100% acetonitrile for 5.99 minutes at a flow rate of 1.5 mL / min.LCMS-Method 3LC-MS was performed on an Agilent 1290 series with UV detector, ELSD 1290 detector and Agilent 6120 detector using a Waters Atlantis T3 (4.6 x 100 mm; 3 pm) column, the column being initially held at 100% high purity water (Milli-Q) with 0.05% (v / v) trifluoroacetic acid for 2 minutes, followed by a linear gradient of 0-90% acetonitrile (LC- MS grade) in 3 minutes, and then held at 90% acetonitrile for 4 minutes at a flow rate of 1.0 mL / min.LCMS-Method 4LC-MS was performed on an UPLC-ESI-MS instrument equipped with a UV-VIS (Nexera UHPLC system LC40) and a MS detector (LCMS8045 triple quadrupole Shimadzu) using a reverse phase column (Zorbax XBD C18®, C18, 3.5 pm, 50 x 4.6 mm), maintained at atemperature of 40°C, the column being initially held at 5% acetonitrile (LC-MS grade) in high purity water (Milli-Q) with 0.1% (v / v) formic acid for 1 minute, followed by a linear gradient of 5-95% acetonitrile in 2.5 minutes and then held isocratically at 95% acetonitrile for 1.5 minutes at a flow rate of 0.7 mL / min.NMR1H Nuclear magnetic resonance (NMR) spectroscopy was carried out using a Bruker, Varian or Agilent Resonance instrument operating at 400 MHz, 500 MHz or 600 MHz using the stated solvent at around room temperature unless otherwise stated. In all cases, NMR data were consistent with the proposed structures. Characteristic chemical shifts (5) are given in parts-per-million using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; m, multiplet; br, broad.Purification MethodsPreparative Reverse-Phase HPLC conditionsPreparative HPLC purification was performed by High Pressure Liquid Chromatography (HPLC) using Agilent Technologies 1260 Infinity LC / MSD system. The standard HPLC method used a Chromatorex C18 (19mm x 100mm, 5pm) column, 25 °C column temperature; flow rate of 30 mL / min (loading pump 4 mL / min). Appropriate focused gradients were selected based on acetonitrile and methanol solvent systems under either acidic or basic conditions. The modifiers used under acidic / basic conditions were trifluoroacetic acid or HCI or NH3 32% solution (0.3% V / V) respectively.Typical gradient is:Samples were loaded with the ACD, analyzed by with DAD\ELSD Alltech 3300 at 210- 400 nm and Agilent and LCWISD G6120B mass-spectrometer in SIM and TIC mode and collected by Agilent 1200 Series HPLC G1364B Prep Scale Fraction Collector. Fractionswith target ion were concentrated under reduced pressure, transferred to pre-weighted flasks, lyophilized and analyzed using LCMS and NMR techniques.HPLC conditions 1: mobile phase 5-5-25%, 0-1-5 min H2O / ACN / 0.1% TFA; column Phenyl SMB100-5 100x19 mm 5pm.HPLC conditions 2: mobile phase 50-75%, 0-5 min H2O / ACN; column Chromatorex 18 SMB100-5T 100x19 mm 5pmHPLC conditions 3: mobile phase 5-30%, 0-5 min H2O / ACN / 0.1% TFA; column Phenyl SMB100-5 100x19 mm 5pmHPLC conditions 4: mobile phase 5-5-20%, 0-2-5 min H2O / ACN / 0.1% TFA; column Chromatorex 18 SMB100-5T 100x19 mm 5pmSynthesisSeveral methods for the chemical synthesis of azabicyclic dimer compounds of the present application are described herein. These and / or other well-known methods may be modified and / or adapted in various ways in order to facilitate the synthesis of additional compounds within the scope of the present application and claims. Such alternative methods and modifications should be understood as being within the spirit and scope of this application and claims. Accordingly, it should be understood that the methods set forth in the following descriptions, schemes and examples are intended for illustrative purposes and are not to be construed as limiting the scope of the disclosure.Starting 2-(tert-butoxycarbonyl)-2-azabicyclo[2. 1. 1]hexane-5-carboxylic acids (l-VII).I II III2-(fert-butoxycarbonyl)- (1 R,4S,5S)-2-(fert-butoxycarbonyl)- (1 S,4R,5R)-2-(fert-butoxycarbonyl)- 2-azabicyclo[2.1 .1 ]hexane- 2-azabicyclo[2.1 .1 ]hexane- 2-azabicyclo[2.1 .1 ]hexane- 5-carboxylic acid 5-carboxylic acid 5-carboxylic acid CAS 1279894-35-72-(fert-butoxycarbonyl)- (1 R,4S,5S)-2-(fert-butoxycarbonyl)- 4-methyl-2-azabicyclo[2.1 .1 ]hexane- 4-methyl-2-azabicyclo[2.1 .1 ]hexane- 5-carboxylic acid 5-carboxylic acidVI VII(1 S,4R,5R)-2-(fert-butoxycarbonyl)- 2-(fert-butoxycarbonyl)-4- 4-methyl-2-azabicyclo[2.1 .1 ]hexane- phenyl-2-azabicyclo[2.1 .1 ]hexane- 5-carboxylic acid 5-carboxylic acidIntermediate IL (1F?,4S,5S)-2-(tert-Butoxycarbonyl)-2-azabicvclof2.1.1]hexane-5- carboxylic acidTo a stirred solution of 2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (CAS 1279894-35-7, 81.7 g, 0.35 mol) in THF (2000 mL) was added R--(+)-1- phenylethylamine (47 mL, 0.37 mol, 1.05 eq.) over 0.1 h. After this time, the mixture was filtered and the solid was collected and re-crystalised from THF. The resulting materialwas further recrystalised from ACN to give a solid. The solid was suspended in ethyl acetate (200 mL) and 2 / V hydrochloric acid (200 mL) was added. The organic phase was separated, dried (Na2SO4) and concentrated under reduced pressure to afford the title compound (20g, 49% yield) as a pale-yellow oil. Chiral SFC (Method 1) RT 3.28 min (99% e.e.).1H NMR (400 MHz, CDCI3): δ 4.60 (d, 1 H), 3.60 (d, 1 H), 3.30 (d, 1 H), 3.32 - 3.29 (m, 1 H), 2.82 - 2.80 (m, 1 H), 1.81 - 1.78 (m, 1 H), 1.42 (d, 9H), 1.38 (m, 1 H).Intermediate HL (7S,4 / R,5 / R)-2-(tert-Butoxycarbonyl)-2-azabicvclor2.1.1lhexane-5- carboxylic acidTo a stirring solution of 2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (CAS 1279894-35-7, 290 g, 1.28 mol) in THF (1500 mL) was added S-(-)-1- phenylethylamine (75 g, 0.62 mol, 0.5 eq.) After stirring for 18 h at room temperature, the mixture was filtered and the solid re-crystalised from THF and then ACN. The obtained solid was added to ethyl acetate (600 mL) and 2 / V aqueous HCI (600 mL) was added. The organic phase was separated, dried (Na2SO44 and concentrated under reduced pressure to afford (7S,4FR,5R)-2-(tert-Butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5- carboxylic acid (42 g, 28% yield) as a yellow oil. Chiral SFC (Method 1) RT 4.06 min (99% e.e.).1H NMR (400 MHz, CDCI3): δ 4.60 (d, 1 H), 3.60 (d, 1 H), 3.30 (d, 1 H), 3.30 - 3.26 (m, 1 H), 2.85 - 2.74 (m, 1 H), 1.83 - 1 .79 (m, 1 H), 1 .42 (d, 9H), 1.40 - 1 .37 (m, 1 H), exchangeable proton not observed.Intermediate IV. 2-(tert-Butoxycarbonyl)-4-methyl-2-azabicyclor2.1 ,1]hexane-5- carboxylic acidSTEP ASynthesis of (3E)-4-f(2-methylprop-2-en-1-yl)amino1but-3-en-2-oneTo a solution of 2-methylprop-2-en-1 -amine (20 g, 281 mmol, 1.05 eq.) in THF (500 mL) was added (3E)-4-methoxybut-3-en-2-one (27 g, 268 mmol). After stirring for 18 h at room temperature, the reaction mixture was concentrated under reduced pressure to afford (3E)-4-[(2-methylprop-2-en-1-yl)amino]but-3-en-2-one (40 g, 97% yield) as a pale yellow oil that was used in the next step without further purification. LCMS (Method 1) RT = 0.85 min, m / z: [ESP] 140.2 (M+H)+.1H NMR (400 MHz, CDCI3): δ 9.78 (br s, 1 H), 9.78 (m, 1 H), 6.58 - 6.53 (m, 1H), 4.98 - 4.96 (m, 1H), 4.83 (s, 2H), 3.63 (d, 2H), 2.01 (s, 3H), 1.68 (s, 3H), exchangeable proton not observed.STEP BSynthesis of tert-butyl / V-(2-methylprop-2-en-1-yl)- / \ / -r(1E)-3-oxobut-1-en-1-yl1carbamateTo a 0 °C solution of (3E)-4-[(2-methylprop-2-en-1-yl)amino]but-3-en-2-one (40 g, 287 mmol) in THF (1000 mL) was added sodium tert-butoxide (27 g, 284 mmol, 1.1 eq.). After this time, di-tert-butyl dicarbonate (56 g, 258 mmol, 1.0 eq.) was added and the mixture was stirred for a further 3 h. After this time, the solvent was removed under reduced pressure, MTBE (400 mL) was added and the organic layers were washed with brine. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography to afford tert-butyl / V-(2-methylprop-2-en-1-yl)- / \ / -[(7E)-3-oxobut-1-en-1-yl]carbamate (52 g, 84% yield) as a pale yellow oil. LCMS (Method 1) RT = 1.29 min, m / z: [ESP] 140.2 (M+H-56)+.1H NMR (400 MHz, CDCI3): δ 8.18 - 8.16 (m, 1H), 5.48 - 5.45 (m, 1 H), 4.88 (s, 1 H), 4.69 (s, 1H), 4.09 (s, 2H), 2.23 (s, 3H), 1.71 (s, 3H), 1.53 (s, 9H).STEP CSynthesis of tert-butyl-5-acetyl-4-methyl-2-azabicyclof2.1.11hexane-2-carboxylate tert-Butyl / V-(2-methylprop-2-en-1-yl)- / \ / -[(1E)-3-oxobut-1-en-1-yl]carbamate (10.0 g, 42 mmol) was dissolved in ACN (1000 mL) and irradiated by UV-lamp (350 nm) in a flowreactor with a flow speed of 2.5 mL / min for 3.3 h. After this time, the reaction mixture was concentrated under reduced pressure and purified by flash column chromatography to afford tert-butyl-5-acetyl-4-methyl-2-azabicyclo[2.1.1]hexane-2-carboxylate (4.0 g, 47% yield) as a pale yellow oil.1H NMR (400 MHz, CDCI3): δ 4.57 - 4.55 (m, 1 H), 3.27 - 3.25 (m, 1 H), 3.02 - 2.97 (m, 1 H), 2.40 (s, 1 H), 2.05 (s, 3H), 1.49 - 1.45 (m, 2H), 1.43 (s, 9H), 1.37 (s, 3H).STEP DSynthesis of 2-r(tert-butoxy)carbonyl1-4-methyl-2-azabicyclof2.1.11hexane-5-carboxylic acidTo a 0 °C stirred solution of sodium hydroxide (836 mg, 21 mmol, 10.0 eq.) in water (4 mL) was added bromine (1.67 g, 10 mmol, 5.0 eq.). The reaction mixture was stirred for 0.5 h, then a solution of tert-butyl-5-acetyl-4-methyl-2-azabicyclo[2.1.1]hexane-2- carboxylate (500 mg, 2.1 mmol) in dioxane (2 mL) was added. The mixture was stirred at room temperature for 4 h. After this time, the reaction mixture was quenched with a sodium sulfite solution and the resulting mixture was washed twice with diethyl ether. The organic layers were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to afford 2-[(tert-butoxy)carbonyl]-4-methyl-2-azabicyclo[2.1.1]hexane-5- carboxylic acid (400 mg, 93% yield) as a colourless solid. LCMS (Method 1) RT = 1.15 min, m / z: [ESI-] 240.2 (M-H)'.1H NMR (400 MHz, CDCI3): δ 4.50 (br s, 1 H), 3.39 - 3.36 (m, 1 H), 3.07 - 3.05 (m, 1 H), 2.48 (s, 1 H), 1.58 - 1 .55 (m, 1 H), 1.43 (s, 9H), 1.44 - 1.41 (m, 1 H), 1.35 (s, 3H), exchangeable proton not observed.Intermediate V. (1R ,4S,5S)-2-(tert-Butoxycarbonyl)-4-methyl-2- azabicyclof2.1.1]hexane-5-carboxylic acidTo a refluxing stirred suspension of 2-(tert-butoxycarbonyl)-4-methyl-2- azabicyclo[2.1.1]hexane-5-carboxylic acid (302 g, 0.68 mol) in ACN (2 L), was added a solution of (S)-phenylglycinol (94 g, 0.69 mol, 1.01 eq.) in ACN (2 L). The reaction was stirred at reflux for 0.5 h and then allowed to cool to room temperature. The resulting suspension was filtered, the filter cake washed with ACN and dried under reduced pressure to afford (1R,4S,5S)-2-(tert-butoxycarbonyl)-4-methyl-2- azabicyclo[2.1.1]hexane-5-carboxylic acid as the phenylglycinol salt (110 g, 85% yield). Chiral HPLC: 99.4% e.e..To a stirred suspension of (1R,4S,5S)-2-(tert-butoxycarbonyl)-4-methyl-2- azabicyclo[2.1.1]hexane-5-carboxylic acid phenylglycinol salt (51 g, 0.13 mol) in DCM (1L) was added an aqueous solution of potassium hydrogen sulfate (21 g, 0.15 mol, 500 mL, 1.1 eq). The biphasic mixture was stirred for 0.2 h and then the phases were separated. The aqueous layer was extracted with DCM and the combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure to afford (1R,4S,5S)-2-(ferf-butoxycarbonyl)-4-methyl-2-azabicyclo[2.1.1]hexane-5-carboxylic acid as an off-white solid (30 g, 90% yield). LCMS (Method 3) RT = 1.65 min, m / z: [ESP] 242.2 (M+H)+.Intermediate VL (1S,4 / R,5 / R)-2-(tert-Butoxycarbonyl)-4-methyl-2- azabicvclo[2.1.1]hexane-5-carboxylic acidTo a refluxing, stirred solution of the mother liquor of the resolution of (1R,4S,5S)-2-(tert- butoxycarbonyl)-4-methyl-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (14.7 g, 0.03 mol) in ACN (100 mL) was added a solution of (R)-(-)-2-phenylglycinol (3.85 g, 0.03 mol, 1 eq.) in ACN (100 mL) over 1 h. After complete addition, the reaction was stirred at reflux for 0.5 h, cooled to room temperature and stirred overnight. The reaction mixture was cooled in an ice bath for 1 h, the resulting suspension was filtered. The filter cake was washed with ACN and dried under reduced pressure to afford (1 S,4R,5R)-2-(tert- butoxycarbonyl)-4-methyl-2-azabicyclo[2.1.1]hexane-5-carboxylic acid as the phenylglycinol salt (6.32 g, quant.). Chiral HPLC: 99.9% e.e..To a stirred suspension of (1S,4R,5R)-2-(ferf-butoxycarbonyl)-4-methyl-2- azabicyclo[2.1.1]hexane-5-carboxylic acid phenylglycinol salt (6.32 g, 0.02 mol) in DCM (120 mL) was added an aqueous solution of potassium hydrogen sulfate (2.5 g, 0.02 mol, 73 mL, 1.1 eq.). The biphasic mixture was stirred for 0.2 h and then the phases were separated. The aqueous layer was extracted with DCM, the combined organic layers were dried (Na2SC>4), filtered and concentrated under reduced pressure to afford (7S,4R,5R)-2-(tert-butoxycarbonyl)-4-methyl-2-azabicyclo[2.1.1]hexane-5-carboxylic acid as an off-white solid (3.59 g, 90% yield). Chiral HPLC: 100% e.e.. LCMS (Method 3) RT = 1.64 min, m / z: [ESP] 242.2 (M+H)+.1H NMR (400 MHz, CDCI3): δ 4.452 (br s, 1 H), 3.40 -3.37 (m, 1 H), 3.07 - 3.05 (m, 1 H), 2.50 (s, 1 H), 1.58 - 1.56 (m, 1 H), 1.45 (s, 9H), 1.45 - 1.41 (m, 1H), 1.37 (s, 3H), exchangeable proton not observed.Intermediate VII: 2-(tert-butoxycarbonyl)-4-phenyl-2-azabicvclor2.1.1]hexane-5- carboxylic acidSTEP A is of (E)-4-< :-3-en-2-oneTo a 0 °C stirred solution of 2-phenylprop-2-en-1 -amine (1.23 g, 9.2 mmol) in diethyl ether (30 mL) was added (E)-4-methoxybut-3-en-2-one (0.93 mL, 9.2 mmol, 1.0 eq.). The resulting mixture was stirred at room temperature for 16 h. After this time, the mixture was cooled to 0 °C and further (E)-4-methoxybut-3-en-2-one (0.46 mL, 4.6 mmol, 0.5 eq.) was added. The resulting mixture was stirred at room temperature for 20 h. The mixture was concentrated under reduced pressure to afford (E)-4-((2-phenylallyl)amino)but-3-en-2-one as a yellow oil which was used directly in the next step.STEP B is of tert-\ ;-oxobut-1-en-1-To a 0 °C stirred solution of (E)-4-((2-phenylallyl)amino)but-3-en-2-one (1.87 g, 9.2 mmol) in DCM (30 mL) was added di-tert-butyl dicarbonate (2.33 mL, 10.2 mmol, 1.1 eq.) and DMAP (56 mg, 0.05 mmol, 0.05 eq.). The resulting mixture was stirred at room temperature for 16 h. After this time, the reaction mixture was concentrated under reduced pressure and directly purified by flash column chromatography to afford tert-butyl (E)-(3-oxobut-1-en-1-yl)(2-phenylallyl)carbamate as a yellow oil (1.15 g, 42% yield over 2 steps).1H NMR (400 MHz, CDCI3) δ 8.20 (d, J = 14.5 Hz, 1H), 7.39 - 7.27 (m, 5H), 5.53 (d, J = 14.5 Hz, 1H), 5.36 (t, J = 1.7 Hz, 1 H), 4.94 (t, J = 1.9 Hz, 1 H), 4.55 (t, J = 1.8 Hz, 2H), 2.21 (s, 3H), 1.52 (s, 9H).STEP S is of tert-l 5-, l-4-i I-2-; ,1.1lhexane-2-itert-Butyl (E)-(3-oxobut-1-en-1-yl)(2-phenylallyl)carbamate (380 mg, 1.26 mmol, 1.00 eq.) was dissolved in acetonitrile (12 mL). [lr(dF(CF3)ppy)2(dtbbpy)][PFe] (3.2 mg, 0.033 mmol, 0.01 eq.) was weighed in a photoreactor vial. To the photoreactor vial was added 3.2 mL of the ACN solution prepared above and the mixture was sparged with N2 for 5 min. This operation was repeated 4 times to give 4 batches. The 4 vials were sealed, placed in the photoreactor with fan cooling and irradiated with blue LEDs at 456 nm for 5 h. After complete consumption of starting material the vials were combined and the mixture was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography to afford tert-butyl 5-acetyl-4-phenyl-2- azabicyclo[2.1.1]hexane-2-carboxylate as a yellow oil (115 mg, 30% yield).1H NMR (400 MHz, CDCI3) δ 7.39 - 7.30 (m, 3H), 7.25 - 2.22 (m, 2H), 4.59 (d, J = 2.1 Hz, 1 H), 3.84 (dd, J = 8.9, 1.7 Hz, 1 H), 3.50 (d, J = 8.9 Hz, 1 H), 3.22 (d, J = 7.4 Hz, 1 H), 2.99 (dt, J = 7.7, 1.9 Hz, 1 H), 1.88 (t, J = 7.6 Hz, 1 H), 1.78 (s, 3H), 1.49 (s, 9H).STEP DSynthesis of 2-(tert-butoxycarbonyl)-4-phenyl-2-azabicyclo[2.1.11hexane-5-carboxylic acid IY1To a 0 °C stirred solution of sodium hydroxide (84 mg, 2.10 mmol, 10.0 eq.) in water (1.3 mL) was added bromine (43 pL, 0.84 mmol, 4.0 eq.), followed by a solution of tert-butyl 5- acetyl-4-phenyl-2-azabicyclo[2.1.1]hexane-2-carboxylate (63 mg, 0.20 mmol) in 1 ,4- dioxane (0.4 mL). The resulting mixture was stirred and warmed to room temperature over 16 hours. The reaction mixture was diluted with water, washed with diethyl ether, acidified to pH = 2-3 using aqueous hydrochloric acid and extracted with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure to afford 2-(tert-butoxycarbonyl)-4-phenyl-2-azabicyclo[2.1.1]hexane-5- carboxylic acid as an off-white solid (diastereomeric mixture, 45 mg, 71% yield).1H NMR (400 MHz, DMSO-d6) δ 12.31 (br s, 1 H), 7.40 - 7.24 (m, 5H), 4.37 - 4.36 (m, 1 H), 3.65 - 3.63 (m, 1 H), 3.25 - 3.21 (m, 1 H), 3.04 - 3.00 (m, 2H), 1.92 - 1.88 (m, 1 H), 1.43 (s, 9H).1 ,1'-sulfonylbis(2-methylpropan-2-ol)STEP ASynthesis of methyl 2-l(2-methoxy-2-oxoethyl)sulfanyl1acetateTo a stirred solution of 2-[(carboxymethyl)sulfanyl]acetic acid (1.0 g, 6.66 mmol) in methanol at -5°C thionyl chloride (2.38 g, 19.9 mmol, 3.0 eq.) was added dropwise. The mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure and the residue was diluted with MTBE (200 mL). The organic layer was washed with sodium carbonate and brine, dried (Na2SO4) and concentrated under reduced pressure to afford methyl 2-[(2-methoxy-2-oxoethyl)sulfanyl]acetate (2.6 g, 73% yield) as a colorless oil.1H NMR (500 MHz, CDCI3) δ 3.75 (s, 6H), 3.41 (s, 4H).STEP BSynthesis of 14(2-hydroxy-2-methylpropyl)sulfanyl1-2-methylpropan-2-olTo a stirred solution of chloro(methyl)magnesium (8.73 g, 116.7 mmol, 8.0 eq.) in THF (250 mL) at -5°C was added a solution of methyl 2-[(2-methoxy-2-oxoethyl)sulfanyl]acetate (2.6 g, 14.6 mmol) in THF (20 mL) over 30 minutes. The resulting mixture was stir at room temperature overnight. Then, a saturated aqueous solution of ammonium chloride was added to the mixture and the organic phase was separated. The aqueous layer was extracted with fresh THF and the combined organic layer was concentrated under reduced pressure. The residue was dissolved in hexanes (100 mL), dried (Na2SO4), concentrated under reduced pressure and purified by preparative HPLC to afford 1-[(2-hydroxy-2- methylpropyl)sulfanyl]-2-methylpropan-2-ol (396 mg, 15.2% yield) as a yellow oil.1H NMR (500 MHz, CDCI3) δ 2.28 (s, 4H), 1.26 (s, 12H), exchangeable protons not observed.STEP CSynthesis of 1 -(2-hydroxy-2-methylpropanesulfonyl)-2-methylpropan-2-olTo a stirred solution of 1-[(2-hydroxy-2-methylpropyl)sulfanyl]-2-methylpropan-2-ol 3 (396 mg, 5.05 mmol) in DCM (15 mL) at 0 °C was added 3-chlorobenzene-1-carboperoxoic acid (1.74 g, 10.1 mmol, 2 eq.). The resulting mixture was stirred overnight at room temperature. After this time, the mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC to afford 1-(2-hydroxy-2-methylpropanesulfonyl)-2- methylpropan-2-ol (225 mg, 21.2% yield) as a colorless oil.1H NMR (500 MHz, CDCI3) δ 2.47 (s, 4H), 1.48 (s, 12H), exchangeable protons not observed.Scheme 1

[0020] In one approach (Scheme 1), compounds were prepared by the reaction of a carboxylic acid derivative of general formula (20) with a b / s- hydroxy compound of general formula (21) in a Steglich esterification reaction with a coupling agent such as DCC or DIG (N,I\T- diisopropylcarbodiimide) in a polar aprotic solvent such as THF or dioxane in the presence of a nucleophilic base such as DMAP. The reaction is generally conducted at room temperature. After reaction work up, typically by liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse phase preparative HPLC, or re-crystallisation. Compounds of general formula (22) are subsequently prepared by general / V-Boc deprotection step such reaction with TFA or HCI in a polar solvent such as DCM or diethyl ether. After reaction work-up typically by ion exchange purification or liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse phase preparative HPLC, or re-crystallisation.EXAMPLE 1 : Propane-1, 3-diyl bis(2-azabicyclo[2.1.11hexane-5-carboxylate) trifluoroacetateSTEP ASynthesis of 2,2'-di-tert-butyl 5, 5’-(propane-1 , 3-diyl) bis(2-azabicyclo[2.1.11hexane-2,5- dicarboxylate)To a stirred solution of 2-[(tert-butoxy)carbonyl]-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (1.50 g, 6.6 mmol, 2.2 eq.), A / . / V-dicyclohexylmethanediimine (2.04 g, 9.90 mmol, 3.3 eq.) and / V, / V-dimethylpyridin-4-amine (161 mg, 1.32 mmol, 0.44 eq.) in THF (15 mL) was added propane-1 , 3-diol (226 mg, 2.97 mmol, 1.0 eq.) and the mixture was stirred at roomtemperature for 18 h. After this time, the solvent was concentrated under reduced pressure and hexane (50 mL) was added to the residue. The resulting suspension was filtered and the filtrate was washed with aqueous citric acid solution, aqueous sodium bicarbonate solution and brine. The combined organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (conditions 2) to afford 2,2'-di-tert-butyl 5,5’-(propane-1 , 3-diyl) bis(2- azabicyclo[2.1.1]hexane-2,5-dicarboxylate) as a colourless oil (0.32 g 22% yield).STEP BSynthesis of propane-1 , 3-diyl 6 / s(2-azabicyclo[2.1.11hexane-5-carboxylate) trifluoroacetate2,2'-D / -tert-butyl 5,5’-(propane-1 , 3-diyl) bis(2-azabicyclo[2.1.1]hexane-2,5-dicarboxylate) (0.32 g, 0.66 mmol) was dissolved in TFA (3 mL) and the solution was stirred at room temperature for 0.25 h. After this time, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in water (10 mL), washed with DCM and concentrated under reduced pressure. The residue was purified by preparative HPLC (conditions 1) to afford propane-1, 3-diyl bis(2-azabicyclo[2.1.1]hexane-5- carboxylate) trifluoroacetate as an off-white solid (0.17 g, 50% yield). LCMS (Method 2) RT = 0.37 min, m / z: [ESI-] 295.16 (M+H)+.1H NMR (400 MHz, D2O) δ 4.32 (dt, J = 5.9, 1.7 Hz, 2H), 4.16 - 4.02 (m, 4H), 3.43 - 3.30 (m, 4H), 3.21 - 3.10 (m, 4H), 2.05 - 1.98 (m, 2H), 1.95 - 1.88 (m, 2H), 1.32 (dd, J = 9.4, 1.1 Hz, 2H), exchangeable protons not observed.Scheme 2. General scheme for.1.1lhexane-5- carboxylates).STEP A2-(tert-Butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5-carboxylic acids (l-VII) (2.4 mmol, 2.2 eq.), DCC (595 mg, 2.88 mmol, 2.7 eq.) and DMAP (587 mg, 4.81 mmol, 4.5 eq.) were dissolved in THF (10 mL) at room temperature. After 5 min of stirring, the corresponding diol (1.1 mmol, 1.0 eq.) was added and the reaction mixture was stirred at room temperature for 18 hours. The solvent was concentrated under reduced pressure and diethyl ether (50 mL) was added to the residue. The resulting suspension was filtered. The filtrate was washed with aqueous citric acid, aqueous NaHCCh solution and brine, dried (Na2SO4), filtered and concentrated under reduced pressure. All intermediates were isolated by preparative HPLC. STEP BEach intermediate (1.0 eq.) was dissolved in DCM (1mL / mmol) and cooled to 0 °C, then TFA (5.0 eq.) was added dropwise. The solution was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure and the residue was purified using preparative HPLC to afford the final product as TFA salt.The following compounds were made according to Scheme 1 in the method above:EXAMPLE 35. (1-Methylazetidine-3,3-diyl)bis(methylene) bis(2- azabicyclof2.1.11hexane-5-carboxylate) trifluoroacetateSTEP ASynthesis of benzyl 3, 3-bis(hydroxymethyl)-azetidine-1 -carboxylateTo a stirred 0 °C solution of [3-(hydroxymethyl)azetidin-3-yl]methanol hydrochloride (492 mg, 3.2 mmol) in water / THF (5 mL / 10 mL), was added potassium carbonate (1.11 g, 8.01 mmol, 2.5 eq.). The reaction mixture was stirred for 10 minutes before a solution of benzyl chloroformate (574 mg, 3.36 mmol, 1.05 eq.) in THF (6 mL) was added. The resulting mixture was then stirred at room temperature for 4 h. After this time, the mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4), filtered, concentrated under reduced pressure and purified by preparative HPLC to afford benzyl 3,3-b / s(hydroxymethyl)-azetidine-1- carboxylate as a colourless oil (600 mg, 99% yield). LCMS (Method 1) RT = 0.86 min, m / z: [ESI+] 252.12 (M+H)+.STEP BSynthesis of 5,5'-f{1-r(benzyloxy)carbonyl1azetidine-3,3-diyl}bis(methylene)1 2,2'-di-tert- butyl di(2-azabicyclof2.1.11hexane-2,5-dicarboxylate)To a stirred 0 °C solution of 2-[(tert-butoxy)carbonyl]-2-azabicyclo[2.1.1]hexane-5- carboxylic acid (1.50 g, 6.6 mmol), / V, / V'-dicyclohexylmethanediimine (3.54 g, 17.2 mmol, 2.6 eq.) and / V, / V-dimethyl-pyridin-4-amine (8.0 mg, 0.07 mmol, 0.01 eq.) in anhydrous THF (200 mL), was added benzyl 3,3-b / s(hydroxymethyl)azetidine-1-carboxylate (829 mg, 3.3 mmol, 0.5 eq.). The reaction mixture was stirred at room temperature overnight. The resulting precipitate was filtered and the organic phase was concentrated under reduced pressure. The residue was purified by flash column chromatography to afford 5,5'-[{1-[(benzyloxy)carbonyl]azetidine-3,3-diyl}bis(methylene)] 2,2'-di-tert-butyl di(2-azabicyclo[2.1.1]hexane-2,5-dicarboxylate) as an off-white solid (1.1 g, 28% yield). LCMS (Method 1) RT = 1.59 min, m / z: [ESP] 570.30 (M-100+H)+.STEP C-D of 2,2'-di-tert-butyl 5,5'-[(1-methylazetidine-3,3-diyl)bis(methylene)l di(2- azabicyclor2.1.1lhexane-2,5-dicarboxylate)To a stirred solution of 5,5'-[{1-[(benzyloxy)carbonyl]azetidine-3,3-diyl}bis(methylene)] 2,2'-di-tert-butyl di(2-azabicyclo[2.1.1]hexane-2,5-dicarboxylate) (500 mg, 0.75 mmol) in methanol (30 mL) was added 10% Pd / C (8 mg) and formaldehyde (22.4 mg, 0.75 mmol, 1 eq.). The resulting mixture was hydrogenated (50 atm) at 50 °C and stirred for 24 h in an autoclave. The catalyst was filtered and the solvent was concentrated under reduced pressure to afford crude 2,2'-di-tert-butyl 5,5'-[(1-methylazetidine-3,3-diyl)bis(methylene)] di(2-azabicyclo[2.1.1]hexane-2,5-dicarboxylate) as a yellow oil that was used in the next step without further purification (490 mg). LCMS (Method 2) RT = 0.86 min, m / z: [ESP] 550.31 (M+H)+.STEP E bis(2-azabicyclo[2.1.1]hexane-5-See Scheme 2, step B. The crude material was purified by preparative HPLC (Method 4) to afford (1-methylazetidine-3,3-diyl)bis(methylene) bis(2-azabicyclo[2.1.1]hexane-5- carboxylate) trifluoroacetate as a yellow oil (298 mg, 47% yield over two steps). LCMS (Method 2) RT = 0.11 min, m / z: [ESP] 350.20 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1 H), 9.50 (br s, 2H), 9.00 (br s, 2H), 4.46 (d, J = 6.1 Hz, 2H), 4.30 - 4.05 (m, 6H), 3.92 (d, J = 14.4 Hz, 2H), 3.43 - 3.22 (m, 6H), 3.18 - 3.07 (m, 2H), 2.85 (d, J = 4.1 Hz, 3H), 1.97 (q, J = 8.7, 8.2 Hz, 2H), 1.31 (d, J = 8.6 Hz, 2H).EXAMPLE 36. (1,1-dioxo-1A6-thiane-4,4-diyl)bis(methylene) di(2- azabicyclof2.1.11hexane-5-carboxylate) trifluoroacetateSTEP ASynthesis of (thiane-4,4-diyl)dimethanolTo a stirred 0 °C solution of 4-[(tert-butoxy)carbonyl]thiane-4-carboxylic acid (1.00 g, 4.06 mmol) in THF (20 mL) was added lithium aluminium hydride (689 mg, 20.3 mmol, 5 eq.). The mixture was stirred at room temperature for 16 h. After this time, the reaction mixture was cooled to 0°C and a solution of NaOH (275 mg) in water (2.7 mL) was added. The resulting precipitate was filtered and the solvent was concentrated under reduced pressure. The residue was dissolved in DCM (30 mL), washed with water, dried (Na2SO4) and filtered. The solvent was concentrated under reduced pressure to afford (thiane-4,4- diyl)dimethanol as a yellow oil (500 mg, 76% yield).1H NMR (400 MHz, CDCI3) δ 3.65 (d, J = 5.5 Hz, 2H), 3.61 (s, 4H), 2.61 - 2.49 (m, 4H), 1.74 - 1.68 (m, 4H).STEP BSynthesis of 2-di-tert-butyl 5,5’-fthiane-4,4-diylbis(methylene)1 bis(2- azabicvclof2.1.11hexane-2,5-dicarboxylate)To a stirred 0 °C solution of (thiane-4,4-diyl)dimethanol (195 mg, 1.2 mmol) and 2-[(tert- butoxy)carbonyl]-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (600 mg, 2.64 mmol, 2.2 eq.) in dry DCM (25 mL) was added / V, / V'-dicyclohexyl-methanediimine (594 mg, 2.88 mmol, 2.4 eq.) and / V, / V-dimethylpyridin-4-amine (88 mg, 0.72 mmol, 0.6 eq.). The reaction mixture was stirred overnight at room temperature. After this time, the resulting precipitate was filtered. The organic phase was washed with water, dried (Na2SO4) and filtered. The solvent was concentrated under reduced pressure, and the residue was purified by preparative HPLC to afford 2-di-tert-butyl 5,5’-[thiane-4,4-diylbis(methylene)] bis(2-azabicyclo[2.1.1]hexane-2,5-dicarboxylate) as a yellow oil (188 mg, 31% yield). LCMS (Method 2) RT = 1.53 min, m / z: [ESI+] 581.33 (M+H)+.STEP CSynthesis of 2,2'-di-tert-butyl 5,5'-f(1 ,1-dioxo-1A6-thiane-4,4-diyl)bis(methylene)1 di(2- azabicvclof2.1.11hexane-2,5-dicarboxylate)To a stirred 0 °C solution of 2-di-tert-butyl 5,5’-[thiane-4,4-diylbis(methylene)] bis(2- azabicyclo[2.1.1]hexane-2,5-dicarboxylate) (188 mg, 0.32 mmol) in DCM (10 mL) was added 3-chlorobenzene-1-carboperoxoic acid (123 mg, 0.71 mmol, 2.2 eq.). The reaction mixture was stirred overnight at room temperature. After this time, the solution was washed with saturated aqueous sodium bicarbonate solution and brine. The combiner organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure toafford 2,2'-di-tert-butyl 5,5'-[(1,1-dioxo-1A6-thiane-4,4-diyl)bis(methylene)] di(2- azabicyclo[2.1 ,1]hexane-2,5-dicarboxylate)as a beige oil that was used in the next step without further purification (175 mg, 99% yield). LCMS (Method 2) RT = 1.00 min, m / z: [ESP] 613.27 (M+H)+.STEP DSynthesis of (1,1-dioxo-1A6-thiane-4,4-diyl)bis(methylene) di(2-azabicyclo(2.1.11hexane- 5-carboxylate) trifluoroacetateThe title compound was prepared analogously to the procedure outlined in scheme 2, step B. The crude material was purified by preparative HPLC (Method 3) to afford (1,1- dioxo-1λ6-thiane-4,4-diyl)bis(methylene) di(2-azabicyclo[2.1.1]hexane-5-carboxylate) trifluoroacetate as a beige oil (88 mg, 48% yield). LCMS (Method 2) RT = 0.20 min, m / z: [ESP] 413.17 (M+H)+.1H NMR (400 MHz, CD3OD) δ 4.42 (dt, J = 6.1, 1.7 Hz, 2H), 4.21 - 4.16 (m, 4H), 3.59 - 3.47 (m, 2H), 3.43 (d, J = 10.1 Hz, 2H), 3.31 - 3.23 (m, 4H), 3.13 (t, J = 6.1 Hz, 4H), 2.23 - 1.98 (m, 6H), 1.44 (d, J = 9.2 Hz, 2H), exchangeable protons not observed.EXAMPLE 37. Ethane-1,2-diyl bisr(1R,4S,5S)-2-azabicyclor2.1.1]hexane-5- carboxylate] hydrochlorideSTEP ASynthesis of 2,2'-d / -tert-butyl 5,5’-ethane-1,2-diyl bis[(1 R,4S,5S)-2- azabicyclo(2.1.11hexane-2,5-dicarboxylate1To a stirred solution of 1 ,1'-carbonyldiimidazole (8.0 g, 49.2 mmol, 2.2 eq.) in DMF (50 mL), was added a solution of (7R,4S,5S)-2-(tert-butoxycarbonyl)-2- azabicyclo[2.1.1]hexane-5-carboxylic acid (11.0 g, 48.2 mmol, 2.2 eq.) in DMF (55 mL), The reaction mixture was stirred at room temperature for 1 hour. After this time, ethane- 1 ,2-diol (1.4 g, 22.4 mmol, 1 eq.) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (7.8 g, 51.4 mmol , 2.3 eq.) were added to the reaction mixture. The resulting mixture was then stirred overnight at room temperature. After this time the mixture was diluted with water (105 mL) and extracted with MTBE. The organic layers were combined, dried(Na2SC>4), filtered, concentrated under reduced pressure. The crude residue was purified by flash column chromatography to afford 2,2'-d / -tert-butyl 5,5’-ethane-1 ,2-diyl bis[(1 R,4S,5S)-2-azabicyclo[2.1.1]hexane-2,5-dicarboxylate] as a colourless solid (6.65 g, 62% yield). LCMS (Method 3) RT = 2.25 min, m / z: [ESP] 481.40 (M+H)+.STEP BSynthesis of ethane-1 ,2-diyl bisf(1 R,4S,5S)-2-azabicyclof2.1.11hexane-5-carboxylate1 hydrochlorideTo a stirred solution of 2,2'-d / -tert-butyl 5,5’-ethane-1 ,2-diyl bis[(1 R,4S,5S)-2- azabicyclo[2.1.1]hexane-2,5-dicarboxylate] (6.65 g, 14 mmol) in isopropyl alcohol (150 mL) was added a solution of 5 M HCI in isopropyl alcohol (48 mL, 17.5 eq.). The reaction was stirred at room temperature overnight. After this time, the reaction mixture was poured into MTBE (220 mL) and stirred for 1 hour. The resulting precipitate was filtered, transferred to a round bottom flask, azeotroped with MTBE and methanol, filtered and air dried to afford ethane-1 ,2-diyl bis[(1 R,4S,5S)-2-azabicyclo[2.1.1]hexane-5-carboxylate] hydrochloride as an off-white solid (2.9 g, 61 % yield). LCMS (Method 3) RT = 5.23 min, m / z: [ESP] 281.1 (M+H)+.1H NMR (300 MHz, DMSO-d6): δ 10.06 (br s, 2H), 8.94 (br s, 2H), 4.39 - 4.36 (m, 2H), 4.32 - 4.23 (m, 4H), 3.29 - 3.21 (m, 6H), 3.11 - 3.06 (m, 2H), 1.96 - 1.93 (m, 2H), 1.41 - 1.38 (m, 2H).EXAMPLE 38. ethane-1,2-diyl bisr(1R,4S,5S)-2-azabicyclor2J J]hexane-5- carboxylate] hydrochlorideSTEP ASynthesis of 2,2'-d / -tert-butyl 5,5’-(1S,4S)-cyclohexane-1 ,4-diyl bisf(1 R,4S,5S)-4-methyl-2-azabicyclof2.1.11hexane-2,5-dicarboxylate1To a stirred solution of (7R,4S,5S)-2-(ferf-butoxycarbonyl)-4-methyl-2- azabicyclo[2.1.1]hexane-5-carboxylic acid (9.0 g, 37 mmol, 2.2 eq.) and trans-1,4- cyclohexanediol (2.0 g , 17 mmol) in DCM (200 mL), was added DMAP (2.1 g, 17 mmol, 1.0 eq.) and 3-(((ethylimino)methylene)amino)- / \ / , / \ / -dimethylpropan-1-amine hydrochloride (7.8 g, 41 mmol, 2.4 eq.). The reaction was stirred at room temperature for 16 h. After this time, the reaction mixture was diluted with DCM (200 mL), washed with water (200 mL), aqueous 0.5 N HCI solution (200 mL), aqueous sodium bicarbonate solution (200 mL), and water (200 mL). The organic layer was dried (Na2SO4), filtered, concentrated under reduced pressure and purified by flash column chromatography eluting with mixtures of ethyl acetate and heptane to afford 2,2'-d / -tert-butyl 5,5’-(7S,4S)- cyclohexane-1 ,4-diyl bis[( 1 R,4S,5S)-4-methyl-2-azabicyclo[2.1.1]hexane-2,5- dicarboxylate] as a colourless syrup (7.4 g, 78% yield). LCMS (Method 3) RT= 2.68 min, m / z: [ESP] 463.40 (M-100+H)+.STEP BSynthesis of (1S,4S)-cyclohexane-1,4-diyl bis[(1 R,4S,5S)-4-methyl-2- azabicyclo[2.1.11hexane-5-carboxylate1 hydrochlorideTo a stirred solution of 2,2'-d / -tert-butyl 5,5’-(7S,4S)-cyclohexane-1,4-diyl bis[(1R,4S,5S)- 4-methyl-2-azabicyclo[2.1.1]hexane-2,5-dicarboxylate] (7.4 g, 13.1 mmol) in cyclopentyl methyl ether (100 mL) was added a solution of aqueous HCI in cyclopentyl methyl ether (3.0 M, 100 mL). The solution was stirred at room temperature for 16 h. After this time, the reaction mixture was concentrated under reduced pressure and the residue was triturated from pentane (100 mL). The precipitate was filtered, washed with pentane and air dried to afford (7S,4S)-cyclohexane-1,4-diyl bis[(1 R,4S,5S)-4-methyl-2- azabicyclo[2.1.1]hexane-5-carboxylate] hydrochloride as an off-white solid (4.1 g, 72% yield). LCMS (Method 3) RT= 4.77 min, m / z: [ESP] 363.2 (M+H)+.1H NMR (400 MHz, DMSO-d6): δ 10.21 (br s, 2H), 8.66 (br s, 2H), 4.78 (s, 2H), 4.28 (s, 2H), 3.11 (m, 2H), 3.03 (m, 2H), 2.96 (s, 2H), 1.89 (t, J = 3.1 Hz, 4H), 1.75 (d, J = 8.0 Hz, 2H), 1.61 - 1.49 (m, 6H), 1.34 (s, 6H).EXAMPLE 39. Propane-1, 3-diyl bisr(1R,4S,5S)-4-methyl-2-azabicvclor2.1.1]hexane- 5-carboxylate] hydrochlorideSTEP ASynthesis of 2,2'-d / '-tert-butyl 5,5’-(propane-1 ,3-diyl) bis[(1 R,4S,5S)-4-methyl-2- azabicyclof2.1.11hexane-2,5-dicarboxylate1To a stirred solution of (7R,4S,5S)-2-(ferf-butoxycarbonyl)-4-methyl-2- azabicyclo[2.1.1]hexane-5-carboxylic acid (9.0 g, 37 mmol, 2.2 eq.) and propane-1 , 3-diol (1.3 g , 17 mmol) in DCM (200 mL) was added DMAP (2.1 g, 17 mmol, 1.0 eq.) and 3- (((ethylimino)methylene)amino)- / \ / , / \ / -dimethylpropan-1 -amine hydrochloride (7.8 g, 41 mmol, 2.4 eq.). The reaction was stirred at room temperature for 80 h. After this time, the reaction mixture was diluted with DCM (200 mL), washed with water (100 mL), aqueous HCI solution (0.5 A / , 100 mL), aqueous sodium bicarbonate solution (100 mL), and water (50 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to afford 2,2'-d / -tert-butyl 5,5’-(propane-1 ,3-diyl) bis[(1R,4S,5S)-4-methyl-2- azabicyclo[2.1.1]hexane-2,5-dicarboxylate] (8.5 g, crude) which was used in the next step without further purification. LCMS (Method 3) RT= 2.46 min, m / z: [ESP] 523.40 (M+H)+.STEP BSynthesis of propane- 1 ,3-diyl bis[(1 R,4S,5S)-4-methyl-2-azabicyclo[2.1.1]hexane-5- carboxylate] hydrochlorideTo a stirred solution of 2,2'-d / -tert-butyl 5,5’-(propane-1,3-diyl) bis[(1 R,4S,5S)-4-methyl-2- azabicyclo[2.1.1]hexane-2,5-dicarboxylate] (8.5 g, 16 mmol) in cyclopentyl methyl ether (100 mL) was added a solution of HCI in cyclopentyl methyl ether (3.0 M, 100 mL). The mixture was stirred at room temperature for 80 h. After this time, the reaction mixture was concentrated under reduced pressure. The residue was solubilised in DCM and concentrated to dryness to afford propane-1, 3-diyl bis[(1R,4S,5S)-4-methyl-2- azabicyclo[2.1.1]hexane-5-carboxylate] hydrochloride as a brown solid (5.5 g, 70% yield over two steps). LCMS (Method 3) RT= 4.68 min, m / z: [ESP] 323.2 (M+H)+.1H-NMR (400 MHz, DMSO-d6): δ 10.22 (br s, 2H), 8.85 (br s, 2H), 4.30 (s, 2H), 4.15 (m, 2H), 4.10 (m, 2H), 3.09 (br s, 4H), 2.98 (s, 2H), 1.95 (t, J = 6.3 Hz, 2H), 1.76 (d, J = 8.0 Hz, 2H), 1.54 (d, J = 8.7 Hz, 2H), 1.34 (s, 6H).Scheme 3To a stirred solution of GDI (2.2 eq.) in DMF (0.05 M) was added the corresponding 2- (tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5-carboxylic acids (II or V) (2.2 eq.) in DMF (0.05 M). After 2 h, 1,8-diazabicyclo[5.4.0]undec-7-ene (2.3 eq.) and the corresponding diol (1.0 eq.) were added, and the reaction mixture was stirred at room temperature overnight. After this time, MTBE and water were added, the phases were separated and the organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure. Compounds of general formula (30) were prepared by general / V-Boc deprotection step such as reaction with TFA, 3M HCI in cyclopentyl methyl ether or formic acid in DCM. The mixture was stirred at room temperature for the desired time. The volatiles were concentrated under reduced pressure and the residue was dissolved in water. The aqueous layer was extracted with DCM and the crude product was dried using centrifugal evaporation.EXAMPLE 40. 2,2-dimethylpropane-1,3-diyl bisf(1R,4S,5S)-2- azabicyclof2.1.11hexane-5-carboxylate1 trifluoroacetateSTEP ASynthesis of 2,2'-di-tert-butyl 5,5’-(2,2-dimethylpropane-1,3-diyl) bis[(1 R,4S,5S)-2- azabicyclo[2.1.1]hexane-2,5-dicarboxylate]To a stirred solution of (1R,,4S,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5- carboxylic acid (504 mg, 2.22 mmol, 2.2 eq.) in DMF (44 mL) was added a solution of CDI (360 mg, 2.22 mmol, 2.2 eq.) in DMF (44 mL). The mixture was stirred for 0.5 h at room temperature, then neopentyl glycol (105 mg, 1.0 mmol, 1.0 eq.) and 1 ,8- diazabicyclo[5.4.0]undec-7-ene (353 mg, 2.32 mmol, 2.3 eq.) were added. The mixture was stirred at room temperature overnight. After this time, MTBE and water were added and the mixture stirred. The phases were separated and the organic phase was dried(Na2SC>4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with mixtures of cyclohexane and ethyl acetate to afford 2,2'-d / -tert-butyl 5,5’-(2,2-dimethylpropane-1 ,3-diyl) bis[(1 R,4S,5S)-2- azabicyclo[2.1.1]hexane-2,5-dicarboxylate] as a colourless solid (158 mg, 30% yield).1H NMR (400 MHz, CDCI3) δ 4.59 - 4.53 (m, 2H), 3.95 - 3.48 (m, 4H), 3.32 - 3.25 (m, 2H), 3.04 (brs, 2H), 2.80 (brs, 2H), 1.82 - 1.77 (m, 2H), 1.45 (s, 18H), 1.35- 1.30 (m, 2H), 0.93 - 0.88 (m, 8H).STEP BSynthesis of 2,2-dimethylpropane-1 ,3-diyl bis[(1 R,4S,5S)-2-azabicyclo[2.1.1]hexane-5- ca rboxylatel trifluoroacetate2,2'-D / -tert-butyl 5,5’-(2,2-dimethylpropane-1 ,3-diyl) bis[(1 R,4S,5S)-2- azabicyclo[2.1.1]hexane-2,5-dicarboxylate] (85 mg, 0.16 mmol) was dissolved in TFA (2 mL) and the mixture was stirred at room temperature for 0.25 h. After this time, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, the aqueous layer was washed with DCM and the crude product was freeze-dried to afford 2,2-dimethylpropane-1 ,3-diyl bis[(1 R,4S,5S)-2-azabicyclo[2.1.1]hexane-5- carboxylate] as a colourless oil (93 mg, quant, yield). LCMS (Method 4) RT= 0.87 min, m / z: [ESP] 323.1 (M+H)+.1H NMR (400 MHz, D2O) δ 4.46 (dd, J = 4.7, 2.6 Hz, 2H), 4.06 - 3.90 (m, 4H), 3.48 (s, 4H), 3.30 (d, J = 6.7 Hz, 4H), 2.13 (d, J = 8.8 Hz, 2H), 1.45 (d, J = 9.5 Hz, 2H), 0.98 (s, 6H), exchangeable protons not observed.The following compounds were made according to Scheme 3 in the method above:EXAMPLE 51. 2-azidopropane-1 ,3-diyl bisr(1R,4S,5S)-2-azabicyclor2.1.1]hexane-5- carboxylate] trifluoroacetateSTEP ASynthesis of 2,2’-di-tert-butyl 5,5’-(2-hvdroxypropane-1,3-diyl) bisf(1R,4S,5S)-2- azabicyclof2.1.11hexane-2,5-dicarboxylate1To a stirred solution of (7R,4S,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5- carboxylic acid (1083 mg, 4.77 mmol, 2.2 eq.) in DMF (95 mL) was added a solution of GDI (774 mg, 4.77 mmol, 2.2 eq.) in DMF (95 mL). The mixture was stirred for 0.5 h at room temperature, then propane-1, 2, 3-triol (200 mg, 2.17 mmol, 1 eq.) and 1,8- diazabicyclo[5.4.0]undec-7-ene (760 mg, 4.99 mmol, 2.3 eq.) were added. The mixture was stirred at room temperature overnight. After this time, MTBE and water were added and the mixture rapidly stirred. The phases were separated and the organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with mixtures of cyclohexane and ethyl acetate to afford O5-[3-[(1R,4S)-2-tert-butoxycarbonyl-2-azabicyclo[2.1.1]hexane-5- carbonyl]oxy-2-hydroxy-propyl] O2-tert-butyl (1R,4S)-2-azabicyclo[2.1.1]hexane-2,5- dicarboxylate as a colourless oil (296 mg, 27% yield).1H NMR (400 MHz, CDCh) δ 4.58 (s, 2H), 4.35 - 4.18 (m, 1H), 4.05 - 4.01 (m, 2H), 3.62 - 3.57 (m, 3H), 3.36 - 3.18 (m, 3H), 3.05 (dd, J = 6.7, 3.0 Hz, 2H), 2.81 (dd, J = 7.4, 4.7 Hz, 2H), 1.81 - 1.77 (m, 2H), 1.46 (d, J = 2.Q Hz, 18H), 1.38 - 1.31 (m, 2H).STEP BSynthesis of 5,5’-(2-azidopropane-1 ,3-diyl) 2,2'-d / -tert-butyl bisf(1 R,4S,5S)-2- azabicyclof2.1.11hexane-2,5-dicarboxylate1To a stirred solution of 2,2'-d / -tert-butyl 5,5’-(2-hydroxypropane-1,3-diyl) bis[(1 R,4S,5S)- 2-azabicyclo[2.1.1]hexane-2,5-dicarboxylate] (296 mg, 0.58 mmol) in THF (7 mL) was added triphenylphosphine (306 mg, 1.17 mmol, 2.0 eq.), followed by diisopropylazodicarboxylate (252 pL, 1.17 mmol, 2.0 eq.) and diphenylphosphoryl azide (85 pL, 0.39 mmol, 2.0 eq.). The resulting mixture was stirred at room temperature overnight. After this time, the reaction mixture was concentrated under reduced pressure, filtered and the solid washed with ethyl acetate. The filtrate was concentrated under reduced pressure and purified by flash column chromatography eluting with mixtures of ethyl acetate and cyclohexane, to afford 5,5’-(2-azidopropane-1,3-diyl) 2,2'-d / -tert-butyl bis[(1R,4S,5S)-2- azabicyclo[2.1.1]hexane-2,5-dicarboxylate] as a colourless oil (209 mg, 67% yield).1H NMR (CDCI3, 400 MHz) δ 4.57 (s, 2H), 4.21 - 4.11 (m, 3H), 4.03 (dd, J = 11.6, 6.5 Hz, 1 H), 3.89 - 3.76 (m, 1 H), 3.55 (s, 2H), 3.27 (d, J = 8.8 Hz, 2H), 3.17 - 2.97 (m, 2H), 2.90 - 2.75 (m, 2H), 1.83 - 1.81 (m, 2H), 1.46 (d, J = 0.5 Hz, 18H), 1.34 (dd, J = 7.6, 1.1 Hz, 2H).STEP CSynthesis of 2-azidopropane-1,3-diyl bisf(1 R,4S,5S)-2-azabicyclof2.1.11hexane-5- carboxylatel trifluoroacetate5,5’-(2-azidopropane-1 ,3-diyl) 2,2'-cf / -te / Y-butyl bis[( 1 R,4S,5S)-2- azabicyclo[2.1 ,1 ]hexane-2,5-dicarboxylate] (100 mg, 0.19 mmol) was dissolved in TFA (2.5 m L) and the mixture was stirred at room temperature for 0.25 h. After this time, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in water. The aqueous layer was washed with DCM and the crude aqueous layer was freeze-dried to afford 2-azidopropane-1 ,3-diyl bis[(1 R,4S,5S)-2-azabicyclo[2.1.1 ]hexane-5-carboxylate] trifluoroacetate as a colourless oil (100 mg, 95% yield). LCMS (Method 4) RT = 1.13 min, m / z: [ESI+] 335 (M+H)+.1H NMR (D2O, 400 MHz) 5 4.49 - 4.46 (m, 2H), 4.42 - 4.33 (m, 2H), 4.30 - 4.22 (m, 2H), 4.19 - 4.15 (m, 1 H), 3.56 - 3.45 (m, 4H), 3.36 - 3.26 (m, 4H), 2.20 - 2.09 (m, 2H), 1 .49 - 1 .42 (m, 2H), exchangeable protons not observed.EXAMPLE 52. (2R,3R)-Butane-2,3-diyl bisr(1R,4S,5S)-4-methyl-2- azabicyclof2.1.11hexane-5-carboxylate1 hydrochlorideSTEP ASynthesis of 2-(tert-butyl) 5-((2R3R)-3-hydroxybutan-2-yl) (1F?,4S,5S)-4-methyl-2- azabicyclof2.1.11hexane-2,5-dicarboxylateTo a stirred solution of (7F?,4S,5S)-2-(ferf-butoxycarbonyl)-4-methyl-2- azabicyclo[2.1.1]hexane-5-carboxylic acid (206 mg, 0.85 mmol, 2.2 eq.) in DMF (17 mL) was added a solution of GDI (139 mg, 0.85 mmol, 2.2 eq.) in DMF (17 mL). The mixture was stirred at room temperature for 0.5 h. After this time, (2F?,3F?)-butane-2,3-diol (35 mg, 0.39 mmol, 1 eq.) and 1 ,8-diazabicyclo[5.4.0]undec-7-ene (136 mg, 0.89 mmol, 2.3 eq.) were added. The mixture was stirred at room temperature overnight. Then, MTBE and water were added to the mixture and stirred, the phases were separated, and the organic phase was dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with mixtures of cyclohexane and ethyl acetate, to afford 2-(terf-butyl) 5-((2F?,3F?)-3-hydroxybutan-2-yl) (7F?,4S,5S)-4-methyl-2-azabicyclo[2.1.1]hexane-2,5-dicarboxylate as a yellow oil (122 mg, quant, yield).STEP BSynthesis of 5,5'-(2F?,3F?)-butane-2,3-diyl 2,2'-di-tert-butyl bis[(1F?,4S,5S)-4-methyl-2- azabicyclo[2.1.1]hexane-2,5-dicarboxylate]To a stirred solution of (7F?,4S,5S)-2-(ferf-butoxycarbonyl)-4-methyl-2- azabicyclo[2.1.1]hexane-5-carboxylic acid (169 mg, 0.70 mmol, 2.2 eq.) in DMF (14 mL) was added a solution of GDI (114 mg, 0.70 mmol, 2.2 eq.) in DMF (14 mL). The mixture was stirred at room temperature for 0.5 h. After this time, 2-(tert-butyl) 5-((2F?,3F?)-3- hydroxybutan-2-yl) (7F?,4S,5S)-4-methyl-2-azabicyclo[2.1.1]hexane-2,5-dicarboxylate (100 mg, 0.32 mmol, 1 eq.) and 1 ,8-diazabicyclo[5.4.0]undec-7-ene (112 mg, 0.73 mmol, 2.3 eq.) were added. The mixture was stirred at room temperature overnight. After thistime, MTBE and water were added to the mixture and stirred, the phases were separated and the organic phase was dried (Na2SC>4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with mixtures of cyclohexane and ethyl acetate, to afford 5,5'-(2R,3R)-butane-2,3-diyl 2,2'-di-tert-butyl bis[(1R,4S,5S)-4-methyl-2-azabicyclo[2.1.1]hexane-2,5-dicarboxylate] as a yellow oil (116 mg, 68% yield).1H NMR (400 MHz, CDCI3) δ 4.95 - 4.92 (m, 2H), 4.62 - 4.41 (m, 2H), 3.36 (s, 2H), 3.05 (d, J = 8.6 Hz, 2H), 2.47 (d, J = 8.4 Hz, 2H), 1.57 - 1.54 (m, 2H), 1.45 (s, 18H), 1.41 (dd, J = 7.3, 1.0 Hz, 2H), 1.37 (s, 6H), 1.19 - 1.11 (m, 6H).STEP C5,5'-(2R,3R)-butane-2,3-diyl 2,2'-di-tert-butyl bis[(1R,4S,5S)-4-methyl-2-.1. !-2,5-di (111 mg, 0.21 mmol, 1 .0 eq.) and HCI inCPME (3M, 0.83 mL) were stirred at room temperature overnight. After this time the solvent was concentrated under reduced pressure to afford (2R,3R)-butane-2,3-diyl bis[(1 R,4S,5S)-4-methyl-2-azabicyclo[2.1.1]hexane-5-carboxylate] hydrochloride as an off-white oil (84 mg, 99% yield). LCMS (Method 4) RT = 2.58 min, m / z: [ESI+] 337.1 (M+H)+.1H NMR (400 MHz, D2O) δ 5.12 - 5.05 (m, 2H), 4.40 (t, J = 1.6 Hz, 2H), 3.34 (dd, J = 10.2, 1.3 Hz, 2H), 3.28 (dd, J = 10.3, 2.2 Hz, 2H), 3.08 - 3.05 (m, 2H), 1.96 (dt, J = 9.4, 2.0 Hz, 2H), 1.59 (dd, J = 9.3, 1.2 Hz, 2H), 1.47 (s, 6H), 1.29 - 1.24 (m, 6H), exchangeable protons not observed.EXAMPLE 53. -cyclohexane-1,4-diyl bisr(1S,4R,5R)-4-methyl-2-azabicyclof2.1.11hexane-5-carboxylate1hydrochloridef 2,2'-di-tert-butyl 5,5’-((7R4R)-i,4R,5R)-4-To a stirred solution of (7S,4R,5R)-2-(tert-butoxycarbonyl)-4-methyl-2- azabicyclo[2.1.1]hexane-5-carboxylic acid (1.0 g, 4.14 mmol) and trans-1 ,4- cyclohexanediol (0.48 g, 4.14 mmol, 1.04 eq.) in DMF (22 mL) was added DMAP (0.51 g, 4.14 mmol, 1.0 eq.) and 3-(((ethylimino)methylene)amino)- / \ / , / \ / -dimethylpropan-1-amine hydrochloride (1.9 g, 9.9 mmol, 2.4 eq.). The reaction was stirred at room temperature for 16 h. After this time, the reaction mixture was diluted with DCM (35 mL), and washed with water (35 mL), aqueous 0.5 N HCI solution (35 mL), aqueous sodium bicarbonate solution (35 mL), and water again (35 mL). The organic layer was dried (Na2SO4), filtered, concentrated under reduced pressure and purified by flash column chromatography eluting with mixtures of ethyl acetate and heptane to afford 2,2'-di-tert-butyl 5,5’- ( -cyclohexane-1 ,4-diyl) bisf(1S,4R,5R)-4-methyl-2-azabicyclof2.1.11hexane-2,5-dicarboxylatel as an off-white solid (0.53 g, 23% yield). LCMS (Method 3) RT= 2.57 min, m / z: [ESI+] 463.40 (M-100+H)+.STEP BSynthesis of (7R,4R)-cyclohexane-1 ,4-diyl bis[(1S,4R,5R)-4-methyl-2- azabicyclo[2.1 .11hexane-5-carboxvlate1 hydrochlorideTo a stirred solution of 2,2'-di-tert-butyl 5,5’-((7R,4R)-cyclohexane-1 ,4-diyl) bis[(1S,4R,5R)-4-methyl-2-azabicyclo[2.1.1]hexane-2,5-dicarboxylate] (0.53 g, 0.95 mmol) in cyclopentyl methyl ether (8 mL) was added a solution of HCI in cyclopentyl methyl ether (3.0 M, 4.6 mL). The solution was stirred at room temperature for 16 h. After this time, additional HCI in cyclopentyl methyl ether (3.0 M, 1 mL) was added. The reaction was stirred for further 12 h. After this time, the reaction mixture was concentrated under reduced pressure and the residue diluted with pentane. The resulting precipitate was filtered, washed with pentane, and air-dried to afford (7R,4R)-cyclohexane-1 ,4-diyl bis[(1S,4R,5R)-4-methyl-2-azabicyclo[2.1.1]hexane-5-carboxylate] hydrochloride as an off-white solid (0.22 g, 55% yield). LCMS (Method 3) RT= 4.64 min, m / z: [ESI+] 363.2 (M+H)+.1H-NMR (400 MHz, CD3OD) δ 4.93 - 4.91 (m, 2H), 4.33 (t, J = 1.7 Hz, 2H), 3.24 - 3.22 (m, 4H), 2.98 - 2.96 (m, 2H), 2.03 - 1.99 (m, 4H), 1.93 - 1.91 (m, 2H), 1.63 - 1.61 (m, 4H), 1.57 - 1.54 (m, 2H), 1.44 (s, 6H), exchangeable protons not observed.EXAMPLE 54. Propane-1, 3-diyl bisr(1S,4R,5R)-4-methyl-2-azabicvclor2.1.1]hexane- 5-carboxylate] hydrochlorideSTEP ASynthesis of 2,2'-di-tert-butyl 5,5’-(propane-1,3-diyl) bis[(1S,4R,5R)-4-methyl-2- azabicyclo[2.1.1]hexane-2,5-dicarboxylate]To a stirred solution of (7S,4R,5R)-2-(ferf-butoxycarbonyl)-4-methyl-2- azabicyclo[2.1.1]hexane-5-carboxylic acid (1.0 g, 4.14 mmol) and propane-1, 3-diol (0.32 g , 4.14 mmol, 1 eq.) in DCM (22 mL) was added DMAP (0.51 g, 4.14 mmol, 1.0 eq.) and 3-(((ethylimino)methylene)amino)- / \ / , / \ / -dimethylpropan-1 -amine hydrochloride (1.9 g, 9.9 mmol, 2.4 eq.). The reaction was stirred at room temperature for 16 h. After this time, the reaction mixture was diluted with DCM (35 mL), and washed with water (35 mL), aqueous HCI solution (0.5 A / , 35 mL), aqueous sodium bicarbonate solution (35 mL), and water (35 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to afford 2,2'-di-tert-butyl 5,5’-(propane-1 ,3-diyl) bis[(1S,4R,5R)-4-methyl-2- azabicyclo[2.1.1]hexane-2,5-dicarboxylate] as an amber oil (0.8 g, 36% yield). LCMS (Method 3) RT= 2.43 min, m / z: [ESI+] 523.40 (M+H)+.STEP BSynthesis of Propane- 1 ,3-diyl bi s[( 1 S,4R,5R)-4-methyl-2-azabicyclo[2.1.1]hexane-5- ca rboxylatel hydrochlorideTo a stirred solution of 2,2'-di-tert-butyl 5,5’-(propane-1,3-diyl) bis[(1S,4R,5R)-4-methyl-2- azabicyclo[2.1.1]hexane-2,5-dicarboxylate] (0.8 g, 1.5 mmol) in cyclopentyl methyl ether (8 mL) was added a solution of HCI in cyclopentyl methyl ether (3.0 M, 7.5 mL). The mixture was stirred at room temperature for 16 h. After this time, the reaction mixture was concentrated under reduced pressure and purified by HPLC to afford Propane-1 , 3-diyl bis[(1S,4R,5R)-4-methyl-2-azabicyclo[2.1.1]hexane-5-carboxylate] hydrochloride as an off-white solid (0.5 g, 71% yield). LCMS (Method 3) RT= 4.57 min, m / z: [ESI+] 323.2 (M+H)+.1H-NMR (400 MHz, CD3OD): δ 4.31 - 4.26 (m, 2H), 4.24 - 4.21 (m, 2H), 4.17 - 4.11 (m, 2H), 3.28 - 3.21 (m, 4H), 2.95 - 2.93 (m, 2H), 2.02 - 1.95 (m, 2H), 1.8 - 1.85 (m, 2H), 1.54 - 1.52 (m, 2H), 1.40 (s, 6H), exchangeable protons not observed.EXAMPLE 55. (1S,4S)-4-(r(1 / ?,4S,5S)-2-azabicyclor2.1.1]hexane-5- carbonvUoxylcyclohexyl (1 / ?,4S,5S)-4-methyl-2-azabicvclor2.1.1]hexane-5- carboxylate hydrochlorideSTEP ASynthesis of (1r,4r)-4-((te / Y-butyldimethylsilyl)oxy)cyclohexan-1-olTo a stirred solution of trans-cyclohexanediol (25 g, 0.22 mol, 1.0 eq.) in THF (250 mL) was added tert-butyldimethylchlorosilane (32 g, 0.22 mol, 1.0 eq.) and imidazole (15 g, 0.22 mol, 1 eq.). The reaction mixture was stirred at room temperature overnight. After this time, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was triturated with chloroform (200 mL), the resulting solid was filtered and purified by flash column chromatography eluting with mixtures of ethyl acetate and heptane, to afford (7r,4r)-4-((tert-butyldimethylsilyl)oxy)cyclohexan-1-ol as a colourless syrup (12 g, 48% yield).STEP BSynthesis of 2-tert-butyl 54(1r,4S)-4-{ftert-butyldi(methyl)silyl1oxy}cyclohexyl1 (1R4S,5S)- 2-azabicyclof2.1.11hexane-2,5-dicarboxylateTo a solution of (1R,4S,5S)-2-[(tert-butoxy)carbonyl]-2-azabicyclo[2.1.1]hexane-5- carboxylic acid (6.5 g, 29 mmol, 1.1 eq.) in DCM (200 mL) was added (7r,4r)-4-((tert- butyldimethylsilyl)oxy)cyclohexan-1-ol (6.0 g, 26 mmol, 1 eq.), EDC (5.5 g, 29 mmol, 1.1 eq.) and DMAP (1.6 g, 13 mmol, 0.5 eq.). The reaction mixture was stirred at room temperature for 16 h. After this time, the mixture was washed sequentially with water (200 mL), aqueous 0.5 N HCI solution (200 mL), aqueous sodium bicarbonate solution (200 mL), and water (100 mL). The organic phase was dried (Na2SO4), filtered, concentrated under reduced pressure and purified by flash column chromatography eluting withmixtures of ethyl acetate and heptane, to afford 2-tert-butyl 5-[(1r,4S)-4-{[tert-To a stirred solution of 2-tert-butyl 5-[(1r,4S)-4-{[tert-butyldi(methyl)silyl]oxy}cyclohexyl] (1R,4S,5S)-2-azabicyclo[2.1.1]hexane-2,5-dicarboxylate (4.3 g, 10 mmol) in THF (100 mL) was added tetrabutyl ammonium fluoride (1.0 M in THF, 15 mL, 15 mmol, 1.5 eq.). The reaction mixture was stirred at 40 °C for 16 h. After this time, the mixture was poured into water (200 mL) and extracted with MTBE. The organic phase was washed with aqueous sodium bicarbonate solution (100 mL) then water (100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to afford 2-tert-butyl 5-[(7r,4S)-4- hydroxycyclohexyl] (7R,4S,5S)-2-azabicyclo[2.1.1]hexane-2,5-dicarboxylate which was directly used without further purification (3.4 g, quant).STEP Di-2-.1.2-tert-butyl (1 F?,4S,5S)-4-methyl-2-.1.To a stirred solution of 2-tert-butyl 5-[(7r,4S)-4-hydroxycyclohexyl] (1 R,4S,5S)-2- azabicyclo[2.1.1]hexane-2,5-dicarboxylate (3.4 g, 10 mmol) in DCM (100 mL) was added (7R,4S,5S)-2-(tert-butoxycarbonyl)-4-methyl-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (2.8 g, 11 mmol, 1.1 eq.) followed by EDCI (2.2 g, 11 mmol, 1.1 eq.) and DMAP (0.64 g, 5.2 mmol, 0.5 eq.). The reaction mixture was stirred at room temperature for 16 h. After this time, the mixture was washed sequentially with water (100 mL), aqueous 0.5 N HCI solution (50 mL), aqueous sodium bicarbonate solution (50 mL) and water (50 mL). The organic phase was dried (Na2SO4), concentrated under reduced pressure and purified by flash column chromatography eluting with mixtures of ethyl acetate and heptane to afford 5-[(1 S,4S)-4-{[(1R,4S,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5- carbonyl]oxy}cyclohexyl] 2-tert-butyl (1R,4S,5S)-4-methyl-2-azabicyclo[2.1.1]hexane-2,5-dicarboxylate as an off-white solid (3.0 g, 52% yield). LCMS (Method 3) RT= 6.71 min, m / z: [ESI+] 449.4 (M-100+H)+.STEP ESynthesis of (1 S,4S)-4-{[(1R,4S,5S)-2-azabicyclo[2.1.1lhexane-5-carbonylloxy}cyclohexy(1R,4S,5S)-4-methyl-2-azabicyclo[2.1.1]hexane-5-carboxylateTo a stirred solution of 5-[(1 S,4S)-4-{[(1R,4S,5S)-2-(tert-butoxycarbonyl)-2- azabicyclo[2.1 ,1]hexane-5-carbonyl]oxy}cyclohexyl] 2-tert-butyl (1R,4S,5S)-4-methyl-2- azabicyclo[2.1.1]hexane-2,5-dicarboxylate (3.0 g, 5.5 mmol) in diethyl ether (60 mL) was added a solution of HCI in cyclopentyl methyl ether (3.0 M; 40 mL, 120 mmol, 20 eq.). The reaction mixture was stirred at room temperature for 16 h. After this time, other solution of HCI in cyclopentyl methyl ether (10 mL) was added and the reaction was left stirring for further 6 h. After this time, the mixture was concentrated under reduced pressure to a solvent volume of ~40 mL then pentane (40 mL) was added. The resulting solid was isolated by filtration and dried under reduce pressure to afford (1 S,4S)-4- {[(1 R,4S,5S)-2-azabicyclo[2.1.1]hexane-5-carbonyl]oxy}cyclohexyl (1 R,4S,5S)-4-methyl- 2-azabicyclo[2.1.1]hexane-5-carboxylate as an off-white solid (1.8 g, 78% yield). LCMS (Method 3) RT= 4.48 min, m / z: [ESI+] 349.2 (M+H)+.1H NMR (400 MHz, DMSO-cfe) 6 10.36 - 10.28 (m, 2H), 8.78 - 8.71 (m, 2H), 4.73 (br s, 2H), 4.66 (br s, 2H), 4.34 (d, J = 5.9 Hz, 1 H), 4.27 (s, 1 H), 3.26 - 3.23 (m, 2H), 3.17 - 3.15 (m, 1 H), 3.12 - 2.98 (m, 3H), 2.95 (s, 1 H), 1.89 - 1 .83 (m, 4H), 1.74 (d, J = 7.7 Hz, 1 H), 1.61 - 1 .46 (m, 4H), 1.42 (d, J = 8.4 Hz, 1 H), 1.33 (s, 3H).EXAMPLE 56: S-RCyclopentanecarbonyDoxylpropyl 2-azabicyclor2.1.1]hexane-5- carboxylate trifluoroacetateTo a stirred 0 °C solution of 2-tert-butyl 5-(3-hydroxypropyl) 2-azabicyclo[2.1.1]hexane- 2,5-dicarboxylate (460 mg, 1.62 mmol) and cyclopentanecarboxylic acid (185 mg, 1.62 mmol, 1.0 eq.) anhydrous DCM, was slowly added DCC (401 mg, 1.95 mmol, 1.2 eq.) and DMAP (10 mg, 0.08 mmol). The mixture was stirred overnight at room temperature. After this time, the resulting precipitate was filtered. The organic phase was washed with water, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford 2-tert-butyl 5-{3- [(cyclopentanecarbonyl)oxy]propyl} 2-azabicyclo[2.1.1]hexane-2,5-dicarboxylate (242 mg, 43% yield). LCMS (Method 1) RT = 1.28 min, m / z: [ESP] 282.2 (M-100+H)+.STEP BSynthesis of 3-f(cyclopentanecarbonyl)oxylpropyl 2-azabicyclof2.1.11hexane-5- carboxylate trifluoroacetateTo a stirred 0 °C solution of 2-tert-butyl 5-{3-[(cyclopentanecarbonyl)oxy]propyl} 2- azabicyclo[2.1.1]hexane-2,5-dicarboxylate (242 mg, 0.64 mmol) in DCM, was added TFA (72 mg, 1.2 mmol). The solution was then stirred at room temperature overnight. After this time, the mixture was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to afford 3-[(cyclopentanecarbonyl)oxy]propyl 2- azabicyclo[2.1.1]hexane-5-carboxylate trifluoroacetate as a yellow oil (54 mg, 22% yield). LCMS (Method 1) RT = 0.92 min, m / z: [ESP] 282.19 (M+H)+.1H NMR (400 MHz, DMSO- cfe) δ 9.40 (s, 1 H), 8.62 (s, 1 H), 4.38 (d, J = 6.0 Hz, 1 H), 4.21 - 3.97 (m, 4H), 3.25 - 3.20 (m, 3H), 3.10 (dt, J = 6.1, 3.2 Hz, 1H), 2.73 - 2.70 (m, 1 H), 2.02 - 1.73 (m, 6H), 1.73 - 1.44 (m, 5H), 1.27 (d, J = 8.5 Hz, 1 H).EXAMPLE 57 - BIOLOGICAL ACTIVITYMitotracker Assay (MTR)25000 U937 cells per well are plated on Day 1 in a 96 well plate with the compound of interest, or DMSO control and incubated for 48 h at 37 °C, 5% CO2. On Day 3, Mitotracker Red CMXRos is added to each well at a final concentration of 200 nM, incubated for 1 h at 37 °C in CO2 incubator. After incubation, the fluorescence of the dye is acquired on the Quanteon for acquisition with the following parameters: Gain 300 for Yellow laser and PE-Cy5-H emission channel.The analysis of the data comprises PC5.5 median fluorescence of the live cells, % of live cells and cells / pL. All data point are normalised to the vehicle CTL.Reagents: RPMI (Gibco, ref. 61870-010), FBS (Gibco, Brazil origin, ref.10270- 106), Pen- Strep (Gibco™ 15140122), MitoTracker RedCMXRos (ThermoFisher Scientific, ref. M7512)Results are presented as minimum effective compound concentration giving 105% increase in MTR signal vs control (A = > 30 pM; B = between 29.9 pM and 15 pM; C = between 14.9 pM and 5 pM; D = < 4.9 pM).Fluorescent-labelled mitochondria protein Cox8 MTS reporter assayThe well described cytochrome oxidase subunit 8 (COX8) pre-sequence was fused to the N terminus of reporter fluorescent proteins (codon optimised Dasher, Twinkle and Rudolph (ATLIM Bio)) to allow the reporter fluorescent protein to be transported in the mitochondria. Such construct was cloned in a plasmid under the EF1a constitutive promoter, co-expressing the Puromycin resistance gene for mammalian cell selection. K562 cells were transfected and selected for stable expression of Cox8-dasherGFP. 25000 K562 Cox8-dasherGFP cells are plated per well on Day 1 in a 96 well plate with the compound of interest or DMSO control, and incubated for 48h at 37 °C, 5% CO2. On Day 3 the fluorescence of the reporter DasherGFP localised in the mitochondria is acquired on a NovoCyte Quanteon Flow Cytometer. The analysis of the data comprises median fluorescence of the live cells, % of live cells and cells / pL. All data point are normalised to the vehicle CTL. Results are presented as % increase in MTS signal vs control at the given test concentration (A = 101% - 104.9%; B = 105% - 108.9%; C = 109% - 112.9%; D = > 113%).High-Resolution Respirometry (HRR)Mitochondrial oxygen kinetics were measured by high-resolution respirometry OROBOROS Oxygraph-2k. 235000 LI937 cells per mL (grown RPMI / 10% FBS / PS) are plated in RPMI / 10% FBS / PS on Day 1 with the test compound or DMSO control, and incubated for 48 h at 37 °C, 5% CO2.1 . Before starting the experiment (RPMI / 10% FBS / PS) media is warmed to room temperature2. 70% ethanol is removed from the stoppers and chambers and rinsed three times with mQ water3. In each chamber 2.5 mL medium (RPMI / 10% FBS / PS) is added to rinse the stopper. The chamber is aspirated, and fresh 2.5 mL of medium is added4. Medium is removed from the chambers and replaced with 2.5 mL of medium (RPMI / 10% FBS / PS). Air calibration is performed on the instrument and the saved file is used for the calibration of sample runs5. Medium is removed from the chambers and replaced with 2.5 mL of medium (RPMI / 10% FBS / PS) containing the cells, that have either been treated with test compound or DMSO control and counted just before the run6. 5 pL of a 20 pM Oligomycin solution is added and readings are taken until stable7. 5 pL of a 250 pM CCCP solution is added until the maximum readings are reached. For U937 cells, the maximum is reached following a second injection of 5 pL of 250 pM CCCP. A third injection is carried out to verify readings are lower than the previous reading8. 4 pL of 1 mM Rotenone solution is added followed by 3 pL of a 2.5 mM Antinimycin A solution to inhibit mitochondrial respiration9. Once finished the experiment save the file and wash the chambers three times with 100% ethanol, three times with 70% ethanol and three times with mQ water10. For the analysis, select the longest regions of stable readings quantify using DatLab programResults are presented as % increase in ATP-linked respiration with the compound at the given test concentration (A = 101% - 104.9%; B = 105% - 108.9%; C = 109% - 112.9%; D = > 113%).Data table.EXAMPLE 57 - PHARMACEUTICAL FORMULATIONS(i) Tablet FormulationA tablet composition containing a compound as defined in any one of Embodiments 1.1 to 1.122 may be prepared by mixing 50 mg of the compound with 197 mg of lactose (BP) as diluent, and 3 mg magnesium stearate as a lubricant and compressing to form a tablet in known manner.(ii) Capsule FormulationA capsule formulation is prepared by mixing 100 mg of a compound as defined in any one of Embodiments 1.1 to 1.122 with 100 mg lactose and filling the resulting mixture into standard opaque hard gelatin capsules.(iii) Injectable Formulation IA parenteral composition for administration by injection can be prepared by dissolving a compound as defined in any one of Embodiments 1.1 to 1.122 in water containing 10%propylene glycol to give a concentration of active compound of 1.5 % by weight. The solution is then sterilised by filtration, filled into an ampoule and sealed.(iv) Injectable Formulation IIA parenteral composition for injection is prepared by dissolving in water a compound as defined in any one of Embodiments 1.1 to 1.122 (2 mg / ml) and mannitol (50 mg / ml), sterile filtering the solution and filling into sealable 1 ml vials or ampoules. v) Injectable formulation IIIA formulation for i.v. delivery by injection or infusion can be prepared by dissolving the compound as defined in any one of Embodiments 1.1 to 1.122 (e.g. in a salt form) in water at 20 mg / ml. The vial is then sealed and sterilised by autoclaving. vi) Injectable formulation IVA formulation for i.v. delivery by injection or infusion can be prepared by dissolving the compound as defined in any one of Embodiments 1.1 to 1.122 (e.g. in a salt form) in water containing a buffer (e.g. 0.2 M acetate pH 4.6) at 20mg / ml. The vial is then sealed and sterilised by autoclaving.(vii) Subcutaneous Injection FormulationA composition for sub-cutaneous administration is prepared by mixing a compound as defined in any one of Embodiments 1.1 to 1.122 with pharmaceutical grade corn oil to give a concentration of 5 mg / ml. The composition is sterilised and filled into a suitable container. viii) Lyophilised formulationAliquots of formulated compound as defined in any one of Embodiments 1.1 to 1.122 are put into 50 ml vials and lyophilized. During lyophilisation, the compositions are frozen using a one-step freezing protocol at (-45 °C). The temperature is raised to -10 °C for annealing, then lowered to freezing at -45 °C, followed by primary drying at +25 °C for approximately 3400 minutes, followed by a secondary drying with increased steps if temperature to 50 °C. The pressure during primary and secondary drying is set at 80 millitor.EquivalentsThe foregoing examples are presented for the purpose of illustrating the invention and should not be construed as imposing any limitation on the scope of the invention. It willreadily be apparent that numerous modifications and alterations may be made to the specific embodiments of the invention described above and illustrated in the examples without departing from the principles underlying the invention. All such modifications and alterations are intended to be embraced by this application.References1. Andreux, Penelope A., Riekelt H. Houtkooper, and Johan Auwerx. "Pharmacological approaches to restore mitochondrial function." Nature reviews Drug discovery 12.6 (2013): 465-483.2. Ahmed, Syeda T., et al. "Diagnosis and treatment of mitochondrial myopathies." Neurotherapeutics 15.4 (2018): 943-953.3. Baertling, Fabian, et al. "A guide to diagnosis and treatment of Leigh syndrome." 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Claims

CLAIMS1. A compound of the formula (1):X1-L-X2(1) or a salt or tautomer thereof; whereinX1and X2are independently selected from formulae (2A), (2B), (2C) and (2D):wherein * indicates the point of attachment to group L, provided that at least one of X1and X2is of formula (2A)R2is selected from hydrogen, a C1-4 hydrocarbyl group optionally substituted with a hydroxyl group, and a 5-6 membered cyclic aromatic group or a 3-6 membered cyclic non-aromatic group, wherein the cyclic aromatic and cyclic non-aromatic groups areoptionally substituted with one or more substituents selected from halogen, C1-4 alkyl, hydroxyl, C1-4 alkoxy and C1-4 alkanoyl; and one of R3and R4is selected from hydrogen and a C1-4 hydrocarbyl group optionally substituted with a 5-6 membered cyclic aromatic group, wherein the cyclic aromatic group is optionally substituted with one or more substituents selected from halogen, cyano, hydroxy, C1-4 alkyl and C1-4 alkoxy; and the other of R3and R4is hydrogen;L is an optionally substituted cyclic or acyclic linker group having a chain length between X1and X2of 2 to 8 carbon atoms wherein one of the carbon atoms may optionally be replaced with a heteroatom selected from O, N, S and oxidized forms thereof, provided that there are always at least two carbon atoms between the heteroatom when present and each of X1and X2.

2. A compound according to claim 1 wherein L is an optionally substituted cyclic or acyclic linker group with a chain length between X1and X2of from 2 to 6 carbon atoms, wherein one of the carbon atoms may optionally be replaced with a heteroatom or heteroatom group selected from O, N, S, S(O) and SO2, provided that there are always at least two carbon atoms between the heteroatom when present and each of X1and X2.

3. A compound according to claim 1 wherein L is an optionally substituted cyclic or acyclic linker group with a chain length between X1and X2of from 2 to 5 carbon atoms, wherein one of the carbon atoms may optionally be replaced with a heteroatom selected from O, N and S, provided that there are always at least two carbon atoms between the heteroatom when present and each of X1and X2.

4. A compound according to claim 1 wherein L has the formula A1-B-A2wherein:A1and A2are independently selected from a bond and a C1-4 hydrocarbyl linker optionally substituted with one or more hydroxy or halogen;B is selected from a bond, C(Rb)2, N(Rb), O, S, S(O), SO2, a 3 to 6 membered cyclic non-aromatic group and a 5- or 6-membered cyclic aromatic group wherein the cyclic non-aromatic group and the cyclic aromatic group are optionally substituted with one or more groups Rb; andRbis selected from hydrogen, hydroxyl, C1-4 hydrocarbyl and -O-C1-4 hydrocarbyl, wherein each hydrocarbyl group may optionally be substituted with hydroxy, halogen and cyano;provided that A1-B-A2has a chain length between Xi and X2 of at least 2 atoms.

5. A compound according to claim 4 wherein A1and A2are the same.

6. A compound according to claim 4 wherein:A1and A2are independently selected from a Ci -4 hydrocarbyl linker;B is selected from a bond, a 3- to 6- membered carbocyclic non-aromatic group and a 6-membered carbocyclic aromatic group.

7. A compound according to any one of claims 1 to 6 wherein A1and A2are both a bond; or are both a CH2 linker; and B is a 4- to 6- membered carbocyclic non-aromatic group or a 6-membered carbocyclic aromatic group.

8. A compound according to any one of claims 1 to 6 wherein L is a C2-5 hydrocarbyl linker (e.g. has the formula (CH2)n wherein n is from 2 to 5).

9. A compound according to any one of claims 1 to 8 wherein X1and X2both have formula (2A).

10. A compound according to any one of claims 4 to 9 wherein A1and A2are the same and X1and X2both have formula (2A).

11. A compound according to any one of claims 1 to 10 wherein R2is selected from hydrogen, methyl and phenyl.

12. A compound according to any one of claims 1 to 11 wherein R3and R4are both hydrogen.

13. A compound according to any one of claims 1 to 12 wherein X1and / or X2have the following formula (AE):wherein * indicates the point of attachment to group L.

14. A compound selected from any of Exmaples 1-56 in Table 1.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 and a pharmaceutically acceptable excipient.

16. A compound according to any one of claims 1 to 14 for use in medicine, for example for use in treating a mitochondrial disease.

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