2-azabicyclo[2.1.1]hexane derivatives useful in the treatment of mitochondrial disorders

Abstract

This invention relates to compounds of the formula (1) or a salt or tautomer thereof; wherein: R1 is C(O)ORa; Ra is selected from hydrogen, an optionally substituted methyl or C2-12 hydrocarbyl group and a group A-B-Cyc; A is selected from a bond and a C1-6 alkylene linker group; B is absent, -C(O)NRD- or -NRDC(O)-, provided that when A is a bond, B is absent; RD is selected from hydrogen and a C1-4 hydrocarbyl group; Cyc is an optionally substituted 5-6 membered cyclic aromatic group or 3-6 membered cyclic non-aromatic group R2 is selected from hydrogen, an optionally substituted C1-4 hydrocarbyl group, and optionally substituted 5-6 membered cyclic aromatic groups or 3-6 membered cyclic non-aromatic groups; one of R3 and R4 is selected from hydrogen and an optionally substituted C1-4 hydrocarbyl group; and the other of R3 and R4 is hydrogen. 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

2-AZABICYCLO[2.1.1]HEXANE DERIVATIVES USEFUL IN THE TREATMENT OF MITOCHONDRIAL DISORDERSThis 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, calcium regulation, 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 do not possess all 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 approximately one in every 5000 people, that are often incurable, genetically and clinically heterogeneous diseases [DiMauro 2008], This heterogeneous group of disorders can manifest as childhood or adulthood encephalopathies, myopathies or multiorgan syndromes. 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 of formula (1):Compounds of formula (1) 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):or a salt or tautomer thereof; whereinR1is C(O)ORa;Rais selected from: i) hydrogen; ii) a group Hyd, in which Hyd is a methyl group or a C2-12 hydrocarbyl group wherein one of the carbon atoms in the C2-12 hydrocarbyl group may optionally be replaced with O, N, S, S(O) or S(O)2 and wherein the group Hyd is optionally substituted with a hydroxyl, halogen, cyano or oxo group; and iii) a group A-B-Cyc;A is selected from a bond and a C1-6 alkylene linker group;B is absent, -C(O)NRD- or -NRDC(O)-, provided that when A is a bond, B is absent;RDis selected from hydrogen and a C1-4 hydrocarbyl group;Cyc is a 5-6 membered cyclic aromatic group or a 3-6 membered cyclic non-aromatic group, wherein the cyclic aromatic group and cyclic non-aromatic group of Cyc are each optionally substituted with one or more substituents selected from hydroxyl, halogen, oxo (as appropriate), cyano, SChR3, C1-4 alkyl, C1-4 alkoxy, C1-4 alkanoyl and a 5-6 membered cyclic aromatic group;Rsis a C1-4 alkyl group, hydroxyl or fluorine;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 of R2are 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 groupis 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;Particular and preferred compounds of the formula (1) are as defined in the Embodiments1.2 to 1.112 below.1.2 A compound according to Embodiment 1.1 wherein Rais hydrogen.1.3 A compound according to Embodiment 1.1 wherein Rais selected from: ii) a group Hyd, in which Hyd is a methyl group or a C2-12 hydrocarbyl group wherein one of the carbon atoms in the C2-12 hydrocarbyl group may optionally be replaced with O, N, S, S(O) or S(O)2 and wherein the group Hyd is optionally substituted with a hydroxyl, halogen, cyano or oxo group; and iii) a group A-B-Cyc.1.4 A compound according to Embodiment 1.3 wherein Rais a methyl group or a C2-12 hydrocarbyl group wherein one of the carbon atoms in the C2-12 hydrocarbyl group may optionally be replaced with O, N, S, S(O) or S(O)2 and wherein the methyl group and C2-12 hydrocarbyl group are optionally substituted with a hydroxyl, halogen, cyano or oxo group.1.5 A compound according to Embodiment 1.3 wherein Rais a group A-B-Cyc.1.6 A compound according to any one of Embodiments 1.1 to 1.5 wherein when Rais or is selected from Hyd, Hyd is an optionally substituted methyl group or a C2-6 hydrocarbyl group wherein one of the carbon atoms in the C2-6 hydrocarbyl group may optionally be replaced with S, S(O) or S(O)2.1.7 A compound according to any one of Embodiments 1.1 to 1.6 wherein when Rais or is selected from Hyd, Hyd is an optionally substituted methyl group or a C2-6 hydrocarbyl group wherein one of the carbon atoms in the C2-6 hydrocarbyl group may optionally be replaced with S.1.8 A compound according to any one of Embodiments 1.1 to 1.7 wherein when Rais or is selected from Hyd, Hyd is an optionally substituted methyl group or a C2-6 hydrocarbyl group.1.9 A compound according to any one of Embodiments 1.1 to 1.8 wherein when Rais or is selected from Hyd, Hyd is an optionally substituted methyl group or a C2-4 hydrocarbyl group.1.10 A compound according to any one of Embodiments 1.1 to 1.8 wherein when Rais or is selected from Hyd, Hyd is an optionally substituted methyl, ethyl, propyl, iso-propyl or cyclopropyl group.1.11 A compound according to Embodiment 1.10 wherein when Rais or is selected from Hyd, Hyd is an optionally substituted methyl group.1.12 A compound according to Embodiment 1.10 wherein when Rais or is selected from Hyd, Hyd is an optionally substituted ethyl group.1.13 A compound according to Embodiment 1.10 wherein when Rais or is selected from Hyd, Hyd is an optionally substituted iso-propyl group.1.14 A compound according to any one of Embodiments 1.1 to 1.13 wherein Hyd is optionally substituted with a substituent selected from hydroxyl, fluorine or cyano.1.15 A compound according to any one of Embodiments 1.1 to 1.13 wherein Hyd is optionally substituted with a hydroxyl group.1.16 A compound according to any one of Embodiments 1.1 to 1.13 wherein Hyd is optionally substituted with a fluorine group.1.17 A compound according to any one of Embodiments 1.1 to 1.13 wherein Hyd is optionally substituted with a cyano group.1.18 A compound according to any one of Embodiments 1.1 to 1.13 wherein Hyd is unsubstituted.1.19 A compound according to any one of Embodiments 1.1 to 1.5 wherein when Rais or is selected from the group A-B-Cyc, A is a bond.1.20 A compound according to any one of Embodiments 1.1 to 1.5 wherein when Rais or is selected from the group A-B-Cyc, A is a C1-6 alkylene linker group.1.21 A compound according to any one of Embodiments 1.1 to 1.5 wherein when Rais or is selected from the group A-B-Cyc, A is a C1-4 alkylene linker group.1.22 A compound according to any one of Embodiments 1.1 to 1.5 wherein when Rais or is selected from the group A-B-Cyc, A is a methylene (-CH2-) or ethylene (-CH2CH2-) linker group.1.23 A compound according to any one of Embodiments 1.1 to 1.5 wherein when Rais or is selected from the group A-B-Cyc, A is a methylene linker group (-CH2-).1.24 A compound according to any one of Embodiments 1.19 to 1.23 wherein B is absent.1.25 A compound according to any one of Embodiments 1.20 to 1.23 wherein B is - C(O)NRD- or -NRDC(O)-.1.26 A compound according to Embodiment 1.25 wherein B is -C(O)NRD-.1.27 A compound according to Embodiment 1.25 wherein B is -NRDC(O)-.1.28 A compound according to any one of Embodiments 1.1 to 1.27 wherein RDis hydrogen, methyl or ethyl.1.29 A compound according to Embodiment 1.28 wherein RDis hydrogen.1.30 A compound according to Embodiment 1.28 wherein RDis methyl.1.31 A compound according to any one of Embodiments 1.1 to 1.30 wherein when Rais or is selected from the group A-B-Cyc, Cyc is an optionally substituted 5-6 membered cyclic aromatic group or an optionally substituted 3-6 membered cyclic non-aromatic group, the cyclic aromatic group and cyclic non-aromatic group each containing 0, 1 or 2 heteroatom ring members selected from N, O, S, S(O) and SO2.1.32 A compound according to any one of Embodiments 1.1 to 1.31 wherein when Rais or is selected from the group A-B-Cyc, Cyc is an optionally substituted 5-6 membered cyclic aromatic group, the cyclic aromatic group containing 0, 1 or 2 heteroatom ring members selected from N, O, S, S(O) and SO2.1.33 A compound according to any one of Embodiments 1.1 to 1.31 wherein when Rais or is selected from the group A-B-Cyc, Cyc is an optionally 3-6 membered cyclic non- aromatic group, the cyclic non-aromatic group each containing 0, 1 or 2 heteroatom ring members selected from N, O, S, S(O) and SO2.1.34 A compound according to any one of Embodiments 1.1 to 1.31 wherein when Rais or is selected from the group A-B-Cyc, Cyc is an optionally substituted 5-6 membered cyclic aromatic group or an optionally substituted 4-6 membered cyclic non-aromatic group, the cyclic aromatic group and cyclic non-aromatic group each containing 0, 1 or 2 heteroatom ring members selected from N, O, S, S(O) and SO2.1.35 A compound according to any one of Embodiments 1.1 to 1.31 wherein when Rais or is selected from the group A-B-Cyc, Cyc is an optionally substituted 5-6 membered cyclic aromatic group or an optionally substituted 4-6 membered cyclic non-aromatic group, the cyclic aromatic group and cyclic non-aromatic group each containing 0 or 1 heteroatom ring members selected from N, O, S, S(O) and SO2.1.36 A compound according to any one of Embodiments 1.1 to 1.31 wherein when Rais or is selected from the group A-B-Cyc, the 5-6 membered cyclic aromatic group is selected from optionally substituted phenyl, pyridinyl, pyrimidinyl, piperidinyl, pyrrolyl, oxazolyl and imidazolyl groups.1.37 A compound according to any one of Embodiments 1.1 to 1.36 wherein when Rais or is selected from the group A-B-Cyc, the 5-6 membered cyclic aromatic group is selected from optionally substituted phenyl, pyridinyl, oxazolyl and imidazolyl groups.1.38 A compound according to any one of Embodiments 1.1 to 1.37 wherein when Rais or is selected from the group A-B-Cyc, the 5-6 membered cyclic aromatic group is selected from optionally substituted phenyl and pyridyl groups.1.39 A compound according to any one of Embodiments 1.1 to 1.38 wherein when Rais or is selected from the group A-B-Cyc, the 5-6 membered cyclic aromatic group is an optionally substituted phenyl group.1.40 A compound according to any one of Embodiments 1.1 to 1.39 wherein when Rais or is selected from the group A-B-Cyc, the 5-6 membered cyclic aromatic group is an optionally substituted pyridyl group.1.41 A compound according to any one of Embodiments 1.1 to 1.40 wherein when Rais or is selected from the group A-B-Cyc, the cyclic non-aromatic group is an optionally substituted 5-6 membered cyclic non-aromatic group containing 0 or 1 heteroatom ring members selected from N, O, S, S(O) and SO2.1.42 A compound according to any one of Embodiments 1.1 to 1.41 wherein when Rais or is selected from the group A-B-Cyc, the cyclic non-aromatic group is an optionally substituted 6 membered cyclic non-aromatic group containing 0 or 1 heteroatom ring members selected from N, O, S, S(O) and SO2.1.43 A compound according to any one of Embodiments 1.1 to 1.31 or 1.33 to 1.35 wherein when Rais or is selected from the group A-B-Cyc, the cyclic non-aromatic group is an optionally substituted 4-6 membered heterocyclic non-aromatic group containing 1 or 2 heteroatom ring members selected from N, O, S, S(O) and SO2.1.44 A compound according to any one of Embodiments 1.1 to 1.43 wherein when Rais or is selected from the group A-B-Cyc, the cyclic non-aromatic group is an optionally substituted 6 membered heterocyclic non-aromatic group containing 1 heteroatom ring member selected from N, O, S, S(O) and SO2.1.45 A compound according to any one of Embodiments 1.1 to 1.40 wherein when Rais or is selected from the group A-B-Cyc, the cyclic non-aromatic group is an optionally substituted cyclobutyl, cyclopropyl, cyclohexyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl-1 -oxide or tetrahydrothiopyranyl-1 ,1 -dioxide group.1.46 A compound according to any one of Embodiments 1.1 to 1.45 wherein when Rais or is selected from the group A-B-Cyc, the cyclic non-aromatic group is an optionally substituted cyclobutyl, cyclohexyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl-1 - oxide or tetrahydrothiopyranyl-1 , 1 -dioxide group.1.47 A compound according to any one of Embodiments 1.1 to 1.46 wherein when Rais or is selected from the group A-B-Cyc, the cyclic non-aromatic group is an optionally substituted, cyclohexyl, piperidinyl, tetrahydropyranyl or tetrahydrothiopyranyl-1 , 1 -dioxide group.1.48 A compound according to any one of Embodiments 1.1 to 1.47 wherein when Rais or is selected from the group A-B-Cyc, the cyclic non-aromatic group is an optionally substituted tetrahydrothiopyranyl-1, 1 -dioxide group.1.49 A compound according to any one of Embodiments 1.1 to 1.48 wherein when Rais or is selected from the group A-B-Cyc, Cyc is substituted with one or two substituentsselected from hydroxyl, halogen, oxo (as appropriate), cyano, SO2R3, C1-4 alkyl, C1-4 alkoxy, C1-4 alkanoyl and a 5-6 membered cyclic aromatic group.1.50 A compound according to any one of Embodiments 1.1 to 1.49 wherein when Rais or is selected from the group A-B-Cyc, Cyc is substituted with one or two substituents selected from hydroxyl, fluorine, oxo (as appropriate), cyano, SO2R3, methyl, ethyl, methoxy, ethoxy, -C(O)CH3and phenyl.1.51 A compound according to any one of Embodiments 1.1 to 1.50 wherein when Rais or is selected from the group A-B-Cyc, Cyc is substituted with one or two substituents selected from fluorine, methoxy and methyl. 1.52 A compound according to any one of Embodiments 1.1 to 1.50 wherein Rsis selected from methyl and fluorine.1.53 A compound according to Embodiment 1.52 wherein Rsis fluorine.1.54 A compound according to any one of Embodiments 1.1 to 1.53 wherein when Rais or is selected from the group A-B-Cyc, Cyc is substituted with one substituent. 1.55 A compound according to any one of Embodiments 1.1 to 1.47 wherein when Rais or is selected from the group A-B-Cyc, Cyc is unsubstituted.1.56 A compound according to Embodiment 1.1 wherein Rais selected from groups AA to BN in Table 1 below, wherein the asterisk marks the point of connection to -O(C=O):1 .57 A compound according to Embodiment 1.56 wherein Rahas the formula (AE):wherein the asterisk marks the point of connection to -O(C=O). 1 .58 A compound according to Embodiment 1.56 wherein Rahas the formula (AO):wherein the asterisk marks the point of connection to -O(C=O) when Rais C(O)ORa.1 .59 A compound according to Embodiment 1.56 wherein Rahas the formula (AP):wherein the asterisk marks the point of connection to -O(C=O) when Rais C(O)ORa.1 .60 A compound according to Embodiment 1.56 wherein Rahas the formula (AQ):wherein the asterisk marks the point of connection to -O(C=O) when Rais C(O)ORa.1.61 A compound according to any one of Embodiments 1.1 to 1.60 wherein R2is selected from a C1-4 hydrocarbyl group optionally substituted with a hydroxyl group and a5-6 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.1.62 A compound according to any one of Embodiments 1.1 to 1.60 wherein R2is selected from hydrogen, a C1-4 saturated hydrocarbyl 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.1.63 A compound according to any of Embodiments 1.1 to 1.62 wherein R2is selected from a C1-4 saturated hydrocarbyl 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.1.64 A compound according to any one of Embodiments 1.1 to 1.60 or 1.62 wherein R2is selected from 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.1.65 A compound according to any of Embodiments 1.1 to 1.64 wherein R2is selected from 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 .66 A compound according to any one of Embodiments 1.1 to 1.60, 1 .62 or 1 .64 wherein R2is selected from hydrogen, a C1-4 alkyl group and a 5-6 membered cyclic aromatic group.1.67 A compound according to any of Embodiments 1.1 to 1.66 wherein R2is selected from a C1-4 alkyl group and a 5-6 membered cyclic aromatic group.1.68 A compound according to any one of Embodiments 1.1 to 1.60, 1.62, 1.64 or 1.66 wherein R2is selected from hydrogen, a C1-4 alkyl group and an unsubstituted phenyl group.1 .69 A compound according to any one of Embodiments 1 .1 to 1 .68 wherein R2is selected from a C1-4 alkyl group and an unsubstituted phenyl group.1.70 A compound according to any one of Embodiments 1.1 to 1.60, 1.62, 1.64, 1.66 or 1.68 wherein R2is selected from hydrogen, methyl, ethyl and phenyl.1.71 A compound according to any one of Embodiment 1.1 to 1.70 wherein R2is selected from methyl, ethyl and phenyl.1.72 A compound according to any one of Embodiments 1.1 to 1.60, 1.62, 1.64, 1.66, 1 .68 or 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 1.72 wherein R2is a C1- 4 alkyl group.1.74 A compound according to any one of Embodiments 1.1 to 1.60, 1.62, 1.64, 1.66,1.68, 1.70 or 1.72 wherein R2is selected from hydrogen and a C1-3 alkyl group.1.75 A compound according to any one of Embodiments 1.1 to 1.74 wherein R2is a C1- 3 alkyl group.1.76 A compound according to any one of Embodiments 1.1 to 1.60, 1.62, 1.64, 1.66,1.68, 1.70, 1.72 or 1.74 wherein R2is selected from hydrogen, methyl and ethyl.1.77 A compound according to any one of Embodiments 1.1 to 1.76 wherein R2is selected from methyl and ethyl.1.78 A compound according to any one of Embodiments 1.1 to 1.60, 1 .62, 1 .64, 1 .66,1 .68, 1.70, 1.72, 1.74 or 1 .76 wherein R2is hydrogen.1.79 A compound according to any one of Embodiments 1.1 to 1.77 wherein R2is methyl.1.80 A compound according to any one of Embodiments 1.1 to 1.71 wherein R2is phenyl.1.81 A compound according to any one of Embodiments 1 .1 to 1.80 wherein R4is hydrogen.1.82 A compound according to any one of Embodiments 1.1 to 1.81 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 optionallysubstituted with one or more substituents selected from halogen, cyano, hydroxy, C1-4 alkyl and C1-4 alkoxy.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 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.1.84 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 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.1.85 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 or pyridyl group, wherein the phenyl or pyridyl 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 1.85 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.1.87 A compound according to any one of Embodiments 1.1 to 1.86 wherein R3is selected from hydrogen and a C1-3 hydrocarbyl group optionally substituted with a phenyl group, wherein the phenyl is optionally substituted with one or more substituents selected from cyano, C1-2 alkyl and C1-2 alkoxy.1.88 A compound according to any one of Embodiments 1.1 to 1.87 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.1.89 A compound according to any one of Embodiments 1.1 to 1.82 wherein R3is selected from hydrogen and a C1-4 hydrocarbyl group (e.g. a C1-4 saturated hydrocarbyl group).1.90 A compound according to Embodiment 1.89 wherein R3is selected from hydrogen and an acyclic C1-4 hydrocarbyl group.1.91 A compound according to Embodiment 1.90 wherein R3is selected from hydrogen and an acyclic C1-3 hydrocarbyl group. 1.92 A compound according to Embodiment 1.91 wherein R3is selected from hydrogen, methyl, ethyl, propyl, / so-propyl and prop-2-enyl.1.93 A compound according to Embodiment 1.92 wherein R3is hydrogen.1.94 A compound according to any one of Embodiments 1.1 to 1.93 having the formula (1-A):wherein R1, R2and R3are as defined in any one of Embodiments 1.1 to 1.93.1.95 A compound according to any one of Embodiments 1.1 to 1.93 having the formula (1-B):wherein R1, R2and R3are as defined in any one of Embodiments 1.1 to 1.93.1.96 A compound according to any one of Embodiments 1.1 to 1.93 having the formula (1-C):wherein R1, R2and R3are as defined in any one of Embodiments 1.1 to 1.93.1.97 A compound according to any one of Embodiments 1.1 to 1.93 having the formula (1-D):wherein R1, R2and R3are as defined in any one of Embodiments 1.1 to 1.93.1.98 A compound according to any one of Embodiments 1.1 to 1.97 wherein when R2is hydrogen, R1is not C(O)OCH3.1.99 A compound according to any one of Embodiments 1.1 to 1.97 wherein when R2is hydrogen and R1is C(O)O, then Rais not methyl.1.100 A compound according to Embodiment 1.1 or any Embodiment dependent thereon, but excluding the compound methyl (1 R,4S,5S)-2-azabicyclo[2.1.1]hexane-5- carboxylate.1.101 A compound according to Embodiment 1.1 or any Embodiment dependent thereon, wherein the compound is other than methyl (1S,4R,5R)-2- azabicyclo[2.1.1]hexane-5-carboxylate.1 .102 A compound according to Embodiment 1.1 or any Embodiment dependent thereon, but excluding one or more, for example all, of the compounds:4-methyltetrahydrofuran-3-yl 2-azabicyclo[2.1 .1 ]hexane-5-carboxylate; tetrahydro-2H-pyran-4-yl 2-azabicyclo[2.1.1]hexane-5-carboxylate;1 -methylpyrrolidin-3-yl 2-azabicyclo[2.1.1]hexane-5-carboxylate;1-methylpiperidin-4-yl 2-azabicyclo[2.1.1]hexane-5-carboxylate; oxetan-3-yl 2-azabicyclo[2.1.1]hexane-5-carboxylate; tetrahydrofuran-3-yl 2-azabicyclo[2.1.1]hexane-5-carboxylate and salts thereof.1 .103 A compound according to Embodiment 1.1 or any Embodiment dependent thereon, but excluding one or more, for example all, of the compounds:4-methyltetrahydrofuran-3-yl 2-azabicyclo[2.1 .1 ]hexane-5-carboxylate; tetrahydro-2H-pyran-4-yl 2-azabicyclo[2.1.1]hexane-5-carboxylate;1 -methylpyrrolidin-3-yl 2-azabicyclo[2.1.1]hexane-5-carboxylate;1-methylpiperidin-4-yl 2-azabicyclo[2.1.1]hexane-5-carboxylate; oxetan-3-yl 2-azabicyclo[2.1.1]hexane-5-carboxylate; tetrahydrofuran-3-yl 2-azabicyclo[2.1.1]hexane-5-carboxylate; tert-butyl (1S,3S,4R,5R)-3-methyl-2-azabicyclo[2.1.1]hexane-5-carboxylate; ethyl (1 R,3R,4S,5S)-3-methyl-2-azabicyclo[2.1.1]hexane-5-carboxylate; methyl (1 R,4S,5R)-2-azabicyclo[2.1.1]hexane-5-carboxylate; methyl (1 R,4S)-3-methyl-2-azabicyclo[2.1.1]hexane-5-carboxylate; methyl (1 R,4S,5S)-2-azabicyclo[2.1.1]hexane-5-carboxylate; methyl (1 R,3R,4S,5S)-3-methyl-2-azabicyclo[2.1.1]hexane-5-carboxylate; tert-butyl (1 R,4S,5S)-2-azabicyclo[2.1.1]hexane-5-carboxylate; ethyl (1 R,4S,5S)-2-azabicyclo[2.1.1]hexane-5-carboxylate; tert-butyl (1 R,4S,5R)-2-azabicyclo[2.1.1]hexane-5-carboxylate; ethyl (1 R,4S,5R)-2-azabicyclo[2.1.1]hexane-5-carboxylate; methyl (1S,4R,5R)-2-azabicyclo[2.1.1]hexane-5-carboxylate ethyl (1 S,4R)-2-azabicyclo[2.1.1]hexane-5-carboxylate; tert-butyl (1S,4R)-2-azabicyclo[2.1 ,1]hexane-5-carboxylate; methyl (1 S,4R)-2-azabicyclo[2.1.1]hexane-5-carboxylate;2-(prop-2-yn-1-yloxy)ethyl (1 R,4S)-2-azabicyclo[2.1.1]hexane-5-carboxylate;2-cyclopropylpropyl (1 R,4S)-2-azabicyclo[2.1.1]hexane-5-carboxylate; ethyl (1S,4R,5R)-2-azabicyclo[2.1.1]hexane-5-carboxylate; tert-butyl (1S,4R,5R)-2-azabicyclo[2.1.1]hexane-5-carboxylate;1 -cyclobutylethyl 2-azabicyclo[2.1.1 ]hexane-5-carboxylate;1 -ethylpropyl 2-azabicyclo[2.1.1]hexane-5-carboxylate; cyclobutylmethyl 2-azabicyclo[2.1.1 ]hexane-5-carboxylate;1 -cyclopropylethyl 2-azabicyclo[2.1.1 ]hexane-5-carboxylate;2-propyn-1 -yl 2-azabicyclo[2.1.1 ]hexane-5-carboxylate;3-butyn-1 -yl 2-azabicyclo[2.1.1 ]hexane-5-carboxylate;2,2-dimethyl-3-buten-1-yl 2-azabicyclo[2.1.1]hexane-5-carboxylate;3-methyl-3-buten-1-yl 2-azabicyclo[2.1.1]hexane-5-carboxylate;5-methylhexyl 2-azabicyclo[2.1.1 ]hexane-5-carboxylate;1 -methyl-2-butyn-1 -yl 2-azabicyclo[2.1.1 ]hexane-5-carboxylate;2-fluoroethyl 2-azabicyclo[2.1.1 ]hexane-5-carboxylate;3-buten-1-yl 2-azabicyclo[2.1.1]hexane-5-carboxylate;4-pentyn-1-yl 2-azabicyclo[2.1.1]hexane-5-carboxylate;1 -methyl-2-propyn-1 -yl 2-azabicyclo[2.1.1 ]hexane-5-carboxylate;2-propen-1-yl 2-azabicyclo[2.1.1]hexane-5-carboxylate;2-cyclopropylpropyl 2-azabicyclo[2.1.1 ]hexane-5-carboxylate;(5-oxo-2-pyrrolidinyl)methyl 2-azabicyclo[2.1.1]hexane-5-carboxylate;2-methylpentyl 2-azabicyclo[2.1.1 ]hexane-5-carboxylate;2-(2-methylpropoxy)ethyl 2-azabicyclo[2.1.1 ]hexane-5-carboxylate;2-methoxy-3-methylbutyl 2-azabicyclo[2.1 .1 ]hexane-5-carboxylate;2-methoxy-2-methylpropyl 2-azabicyclo[2.1 .1 ]hexane-5-carboxylate;2-(1 , 1 -dimethylethoxy)ethyl 2-azabicyclo[2.1 .1 ]hexane-5-carboxylate;1 -methylbutyl 2-azabicyclo[2.1.1]hexane-5-carboxylate;2-propoxyethyl 2-azabicyclo[2.1.1]hexane-5-carboxylate;2-(dimethylamino)-1 -methylethyl 2-azabicyclo[2.1.1]hexane-5-carboxylate; propyl 2-azabicyclo[2.1.1 ]hexane-5-carboxylate;(tetrahydro-2H-pyran-4-yl)methyl 2-azabicyclo[2.1.1]hexane-5-carboxylate; hexyl 2-azabicyclo[2.1.1 ]hexane-5-carboxylate;(tetrahydro-2H-pyran-2-yl)methyl 2-azabicyclo[2.1.1]hexane-5-carboxylate;2- (2-th ie ny I) ethy I 2-azabicyclo[2.1.1 ]hexane-5-carboxylate;1-(methoxymethyl)-2-methylpropyl 2-azabicyclo[2.1.1]hexane-5-carboxylate;3-methoxypropyl 2-azabicyclo[2.1.1 ]hexane-5-carboxylate; heptyl 2-azabicyclo[2.1.1 ]hexane-5-carboxylate;2-methoxy-2-methylbutyl 2-azabicyclo[2.1 .1 ]hexane-5-carboxylate;3-methoxy-3-methylbutyl 2-azabicyclo[2.1 .1 ]hexane-5-carboxylate;2-ethoxy-1 -methylethyl 2-azabicyclo[2.1.1]hexane-5-carboxylate;2-(1 -methylethoxy)ethyl 2-azabicyclo[2.1 .1 ]hexane-5-carboxylate; cyclopentylmethyl 2-azabicyclo[2.1.1 ]hexane-5-carboxylate;2-methylpropyl 2-azabicyclo[2.1.1]hexane-5-carboxylate;3.3-dimethylbutyl 2-azabicyclo[2.1.1]hexane-5-carboxylate;2-cyclobutylethyl 2-azabicyclo[2.1.1 ]hexane-5-carboxylate;1 -methylpropyl 2-azabicyclo[2.1.1]hexane-5-carboxylate; cyclopropylmethyl 2-azabicyclo[2.1.1]hexane-5-carboxylate;2-cyclobutylpropyl 2-azabicyclo[2.1.1 ]hexane-5-carboxylate;4-methylpenyl 2-azabicyclo[2.1.1 ]hexane-5-carboxylate;3-methylbutyl 2-azabicyclo[2.1.1]hexane-5-carboxylate; cyclohexylmethyl 2-azabicyclo[2.1.1]hexane-5-carboxylate;2-cyclopropylethyl 2-azabicyclo[2.1.1 ]hexane-5-carboxylate;2-butoxyethyl 2-azabicyclo[2.1.1]hexane-5-carboxylate;2-methoxyethyl 2-azabicyclo[2.1.1 ]hexane-5-carboxylate;2-methoxy-1 -methylethyl 2-azabicyclo[2.1 .1 ]hexane-5-carboxylate; butyl 2-azabicyclo[2.1.1 ]hexane-5-carboxylate;1.3-dimethylbutyl 2-azabicyclo[2.1.1]hexane-5-carboxylate;2-ethylbutyl 2-azabicyclo[2.1.1]hexane-5-carboxylate;2-thienylmethyl 2-azabicyclo[2.1.1 ]hexane-5-carboxylate;(tetrahydro-3-furanyl)methyl 2-azabicyclo[2.1.1 ]hexane-5-carboxylate;(tetrahydro-2-furanyl)methyl 2-azabicyclo[2.1.1 ]hexane-5-carboxylate;4.4-dimethylpentyl 2-azabicyclo[2.1.1 ]hexane-5-carboxylate;1.2-dimethylpropyl 2-azabicyclo[2.1.1]hexane-5-carboxylate;2-ethoxyethyl 2-azabicyclo[2.1.1]hexane-5-carboxylate; pentyl 2-azabicyclo[2.1.1 ]hexane-5-carboxylate;1 ,1 -dimethylethyl 2-azabicyclo[2.1.1]hexane-5-carboxylate; ethyl 2-azabicyclo[2.1.1]hexane-5-carboxylate;1 -methylethyl 2-azabicyclo[2.1.1]hexane-5-carboxylate; phenylmethyl 2-azabicyclo[2.1.1]hexane-5-carboxylate; methyl 2-azabicyclo[2.1.1 ]hexane-5-carboxylate;3.3-difluorocyclobutyl 2-azabicyclo[2.1.1]hexane-5-carboxylate;3-methylcyclopentyl 2-azabicyclo[2.1.1]hexane-5-carboxylate; cyclopropyl 2-azabicyclo[2.1.1]hexane-5-carboxylate;3-methylcyclohexyl 2-azabicyclo[2.1.1 ]hexane-5-carboxylate;4-methylcyclohexyl 2-azabicyclo[2.1.1 ]hexane-5-carboxylate;2-methylcyclohexyl 2-azabicyclo[2.1.1 ]hexane-5-carboxylate; cyclohexyl 2-azabicyclo[2.1.1]hexane-5-carboxylate; cyclo-butyl 2-azabicyclo[2.1.1]hexane-5-carboxylate; cyclopentyl 2-azabicyclo[2.1.1 ]hexane-5-carboxylate;(1 S,4R,5R)-4-methyl-2-azabicyclo[2.1.1]hexane-5-carboxylic acid and salts thereof.1.104 A compound according to Embodiment 1.1 wherein one or more of R2, R3and R4is a substituent other than hydrogen.1.105 A compound according to Embodiment 1.1 wherein R2is a substituent other than hydrogen.1.106 A compound selected from the compounds of Examples 1 to 50 herein.1 .107 A compound according to any one of Embodiments 1.1 to 1.106 which is in the form of a salt.1.108 A compound according to Embodiment 1.107 wherein the salt is an acid addition salt.1.109 A compound according to Embodiment 1.107 or Embodiment 1.108 wherein the salt is a pharmaceutically acceptable salt.1.110 A compound according to any one of Embodiments 1.1 to 1.106 which is in the form of a non-salt (e.g. free base).1.111 A compound according to any one of Embodiments 1.1 to 1.110 which is in the form of a solvate.1.112 A compound according to Embodiment 1.111 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 scopearomatic, 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, 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.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 O-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, 1.111 and 1.112 may be presented in the form of salts.The salts referred to above (and also defined in embodiments 1.107, 1.108 and 1.109) 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 a mixture 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 formula (1).Acid addition salts (as defined in Embodiment 1.108) 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 1.109), 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:1.113 A compound according to any one of Embodiments 1.1 to 1.109, 1.111 and 1.112 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).1.114 A compound according to any one of Embodiments 1.1 to 1.109, 1.111 and 1.112 which is in the form of an acid addition salt formed with an acid having a pKa of 3.0 or lower.1.115 A compound according to Embodiment 1.113 or Embodiment 1.114 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.1.116 A compound according to Embodiment 1.115 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 1.117), 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 1.118 to 1.121), the invention provides:1.118 An acid addition salt of a compound of formula (1) in substantially crystalline form which is at least 90% crystalline.1.119 An acid addition salt of a compound of formula (1) in substantially crystalline form which is at least 95% crystalline.1.120 An acid addition salt of a compound of formula (1) in substantially crystalline form which is at least 99% crystalline.1.121 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, New York, 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 formula (1) as defined in Embodiments 1.1 to 1.121 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 1.121 , the compounds of formula (1) 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 formula (1).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 formula (1) 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 1.122 to 1.125), the invention provides:1.122 A compound as defined in any one of Embodiments 1.1 to 1.121 wherein the compound of formula (1), 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%.1.123 A compound according to Embodiment 1.122 wherein the compound of formula (1), as the case may be, has an optical purity of at least 98%.1.124 A compound according to Embodiment 1.122 wherein the compound of formula (1), as the case may be, has an optical purity of at least 99%.1.125 A compound according to Embodiment 1.122 wherein the compound of formula (1), 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 1.125 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 Discovery 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 1.125 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 1.125 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 1.125 are complexes (e.g. inclusion complexes or clathrates with compounds such as cyclodextrins, or complexes with metals) of the compounds.Compounds as defined in any one of Embodiments 1.1 to 1.125 can be used 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 2.7), the invention provides:2.1 A compound as defined in any one of Embodiments 1.1 to 1.125 for use in medicine or therapy.2.2 A compound as defined in any one of Embodiments 1.1 to 1.125 for use in preventing or treating a mitochondrial disease.2.3 A compound as defined in any one of Embodiments 1.1 to 1.125 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 1.125 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 1.125 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 1.125.2.7 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 1.125.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 cancerAlzheimer'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 2.21), the invention provides:2.8 A compound as defined in any one of Embodiments 1.1 to 1.125 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 1.125 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 1.125.2.11 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 retinitispigmentosa (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 (MSLID), 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 1.125 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 1.125 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 1.125.2.15 A compound as defined in any one of Embodiments 1.1 to 1.125 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 1.125 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 fatiguesyndrome, 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 1.125.2.18 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 .125.2.19 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 .125.2.20 The use of a compound as defined in any one of Embodiments 1 .1 to 1 .125 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 .125 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 1.125 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 (Ai M) 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 for mitochondrial 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 (Cox8) 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 1.125 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 1.125 having a mitochondrial size activity of 102% or greater.2.23 A compound according to any one of Embodiments 1.1 to 1.125 having a mitochondrial size activity of 103% or greater.2.24 A compound according to any one of Embodiments 1.1 to 1.125 having a mitochondrial size activity of 104% or greater.2.25 A compound according to any one of Embodiments 1.1 to 1.125 having a mitochondrial size activity of 105% or greater.2.26 A compound according to any one of Embodiments 1.1 to 1.125 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 .125.Compounds of formula (1) in which R1is C(O)ORa(referred herein as compounds of formula (4)), can be prepared according to the scheme below, by reacting a compound of the formula (17), wherein PG is a suitable nitrogen protecting group (e.g. N-Boc), with an acid in a polar solvent in order to remove the PG.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 1.125, which method comprises:(a) removing protecting group, PG, from a compound of formula (17):to form a compound of formula (4);Further embodiments are provided below: 3.2 A method according to Embodiment 3.1 wherein PG has the formula C(O)ORN, wherein RNis an optionally substituted C1-4 hydrocarbyl group.3.3 A method according to Embodiment 3.2 wherein RNis tert-butyl.3.4 A method according to any one of Embodiments 3.1 to 3.3 wherein step (a) is carried out in the presence of an acid. 3.5 A method according to Embodiment 3.4 wherein the acid is selected from trifluoroacetic acid and hydrochloric acid.3.6 A method according to any one of Embodiments 3.1 to 3.5 wherein step (a) is carried out in a polar, aprotic solvent.3.7 A method according to any one of Embodiments 3.1 to 3.6 wherein step (a) is carried out in dichloromethane or diethyl ether.Alternatively, compounds of formula (1) in which R1is C(O)ORa(referred herein as compounds of formula (4)), wherein Rais other than hydrogen, can be prepared according to the scheme below, by reacting a compound of the formula (18) with:i) an alcohol having the formula Ra-OH; or ii) an alkylating agent having the formula X-Ra, wherein X is a suitable leaving group, such as a halogen or an arylsulphonyloxy group (such as tosylate).Accordingly, in further embodiments, the invention provides:3.8 A method of preparing a compound as defined in any one of Embodiments 1.1 to1.125, wherein Rais other than hydrogen, which method comprises:(a) reacting a compound of formula (18):with an alcohol having the formula Ra-OH or an alkylating agent having the formula X-Rawherein X is a suitable leaving group; to form a compound of formula (4);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-2oaryl-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 1.125 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 1.125 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 1.125 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 1.125 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 1.125 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 1.125 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 parenteraladministration, 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 containing a compound according to any one of Embodiments 1.1 to 1.125 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 Embodiment 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. For administration 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, moreusually 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 1.125 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);• 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 1.125 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 1.125, 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 enzymaticanalysis 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 dysfunction in 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 integration of information from these tests allows for the diagnosis in the majority of patients with mitochondrial myopathies [Ahmed 2018],Ex Vivo Uses As described above, the compounds of Embodiment 1.1 to 1.125 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 1.125 into contact with the cell.EXAMPLESEXAMPLES 1 TO 50 The compounds of Examples 1 to 50 in Table 1 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-butyloxycarbonylCV for column volumesDCC for dicyclohexylcarbodiimideDCE for 1 ,2-dichloroethane - DCM for dichloromethaneDEAD for diethyl azodicarboxylateDIAD for diisopropyl azodicarboxylateDIBAL for diisobutylaluminium hydrideDI PEA for / V, / V-diisopropylethylamine, Hunig’s base - DMA for N,N -dimethylacetamideDMAP for 4-(dimethylamino) pyridineDMF for N,N -dimethylformamideDMSO for dimethylsulfoxide.EDC for 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide h for hoursFCC for flash column chromatographyHATLI for / V-[(dimethylamino)-1 / 7-1 ,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]- / \ / - methylmethanaminium hexafluorophosphate N-oxideHBTLI for (1H-benzotriazol-1-yloxy)(dimethylamino)- / V, / V-dimethylmethaniminium hexafluorophosphateHOBT for / V-hydroxybenzotriazoleHPLC for High Pressure Liquid Chromatography.LAH for lithium aluminium hydrideI PA for isopropyl alcoholLCMS for Liquid Chromatography-Mass SpectrometryLDA for lithium diisopropylamideMin for minutesMTBE for methyl tert-butyl etherMW for microwaveNBS for / V-bromosuccinamideNCS for / V-chlorosuccinamideNMR for nuclear magnetic resonanceRbf for round bottomed flaskRT for retention timeSCX-2 for a silica-based sorbent with a chemically bonded propylsulfonic acid functional groupSFC for supercritical fluid chromatographySPE for solid phase extractionTFA for trifluoroacetic acidTH F for tetrahydrofuranGeneral Methods:Analytical MethodsLiquid Chromatography-Mass SpectrometryLCMS-Method 1UPLC-MS was performed on a Waters DAD + Waters SQD2, single quadrupole UPLC- MS spectrometer using an Acquity UPLC HSS Shield RP18 1.7um 100 x 2.1mm (Plus guard cartridge), maintained at temperature of 40 °C, the column being initially held at 5% acetonitrile (far UV grade) with 0.1% (v / v) formic acid I water (high purity via PureLab Option unit) with 0.1% formic acid for 0.4 minutes, followed by a linear gradient of 5-95% within 6.4 minutes and then held at 95% for 1.2 minutes (F = 0.4 mL / min).LCMS-Method 2LC-MS was performed on an Agilent 1290 Infinity II UHPLC system with an Agilent 1290 DAD and an Agilent Model 6125C Single Quadrupole Mass Spectrometer using an Acquity UPLC CSH C18 1.7um 50x2.1mm column, maintained at a temperature 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 0.4 minutes, followed by a linear gradient of 5-95% acetonitrile in 1.5 minutes and then held at 95% acetonitrile for 0.5 minutes at a flow rate of 0.8 mL / min.LCMS-Method 3LC-MS was performed on an HPLC-ESI-MS instrument equipped with a UV-VIS (Nexera- I LC-2040C Plus) and a MS detector (LCMS2020 single quadrupole Shimadzu) using a reverse phase column (HaloC18®, C18, 2.7 pm, 50 x 4.6 mm), maintained at a temperature 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.LCMS-Method 4LC-MS was performed on an Agilent UHPLC-ESI-MS instrument comprising binary pump (Agilent G7120A), MS detector (Agilent single quadrupole G6125C), Diode Array Detector (Agilent G7117B) and ELSD (Agilent 1260 Infinity II G4260B). A reverse phase column was used (ACQUITY UPLC HSS T3, 100A, 1.8 pm, 2.1 mm X 100 mm), maintained at a temperature of 40 °C, the column being held initially at 95% LC-MS grade water withNH4OAC (0.1% v / v) for 0.4 minutes, followed by a linear gradient of 5-95% acetonitrile in 1.5 minutes then held isocratically at 95% acetonitrile for 0.5 minutes at a flow rate of 0.8 mL / min.LCMS-Method 5LC-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 6LC-MS was performed on an Agilent UHPLC-ESI-MS instrument comprising binary pump (Agilent G7120A), MS detector (Agilent single quadrupole G6125C), Diode Array Detector (Agilent G7117B) and ELSD (Agilent 1260 Infinity II G4260B). A reverse phase column was used (ACQUITY UPLC HSS T3, 100A, 1.8 pm, 2.1 mm X 100 mm), maintained at a temperature of 40 °C, the column being held initially at 100% LC-MS grade water with NH4OAC (0.1% v / v) for 0.4 minutes, followed by a linear gradient of 0-50% acetonitrile in 1.5 minutes then held isocratically at 50% acetonitrile for 0.5 minutes at a flow rate of 0.8 mL / min.NMR1H Nuclear magnetic resonance (NMR) spectroscopy was carried out using a Bruker or Jeol Resonance instrument operating at 400 MHz or 500 MHz a 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.Chiral Supercritical Fluid Chromatography (SFC) method 1The enatiomeric analysis of compounds was achieved by Supercritical Fluid Chromatography (SFC) using a Waters Acquity UPC2 system with UV detector and QDA detector. The standard SFC method used a Daicel Chiralpak IC-3 (3.0 x 150 mm; 3 pm),40 °C column temperature; flow rate of 1.2 mL / Min; Gradient Conditions (2:98 methanol:CC>2 0 - 4 min; 25:75 4 - 4.1 min; 98:2 4.1 - 5 min (0.2% v / v NH3), 125 Bar backpressure, with an injection volume of 1.0 pL, and analysed by SFC (Waters / Thar SFC systems with Waters SQD) at 212 nm.Chiral Supercritical Fluid Chromatography (SFC) Method 2The enantiomeric analysis of compounds was achieved by Supercritical Fluid Chromatography (SFC) using a Waters SFC system. The standard SFC method used a Chiralpak IG (4.6mm x 250mm, 5um) column, 40 °C column temperature; flow rate of 4 mL / min; Isocratic Conditions (25:75 ethanol:CO2 (0.2% v / v NH3), 125 Bar backpressure, with an injection volume of 1.0 pL, and analysed by SFC (Waters / Thar SFC systems with Waters SQD) at 210-400 nm.Purification methodsPreparative reverse-phase HPLC conditionsPreparative HPLC purification was performed by reverse phase HPLC using a Waters Fractionlynx preparative HPLC system (2525 pump, 2996 / 2998 UV / VIS detector, 2767 liquid handler) or an equivalent HPLC system such as a Gilson Trilution UV directed system. The Waters 2767 liquid handler acted as both auto-sampler and fraction collector. The columns used for the preparative purification of the compounds were a YMC Triart C18 100x20mm, 5 pm or Chromatorex 18 SMB100-5T 100x19mm 5pm. 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 (0.1% v / v) or NH4OH (0.1% v / v) respectively. The purification was controlled by Waters Fractionlynx software through monitoring at 210-400 nm and triggered a threshold collection value at 260 nm and, when using the Fractionlynx, the presence of target molecular ion as observed under API conditions. Collected fractions were analysed by LCMS (Waters Acquity systems with Waters SQD).SynthesesSeveral methods for the chemical synthesis of heterocyclic carboxamide compounds of the present application are described herein. These and / or other well-known methods may be modified and / or adapted in various ways to facilitate the synthesis of additional compounds within the scope of the present application and claims. Such alternativemethods and modifications should be understood as being within the spirit and scope of this application and claims. Accordingly, 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. Scheme 1In one approach (Scheme 1), compounds of formula (13) were prepared by reaction of an allyl-amine of general formula (11) with (3E)-4-methoxybut-3-en-2-one (12) in a polar aprotic solvent such as THF or dioxane. The reaction was conducted at ambient temperature, and after reaction work up, typically by a liquid-liquid extraction, the reaction product was purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation to yield the secondary allyl-amine of general formula (13).N-Boc protected allyl-amine compounds of general formula (14) were prepared by reaction of a secondary allyl-amine of general formula (13) with a such as di-tert-butyl decarbonate in a polar aprotic solvent such as THF or dioxane in the presence of a sterically hindered base such as potassium tert-butoxide. The reaction was suitably conducted at ambient temperature, and after reaction work up, typically by a liquid-liquidextraction, the reaction product was purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation to yield the N-Boc protected allyl-amine of general formula (14).Bicyclic Boc-protected amino compounds of general formula (15) were prepared through a photocyclization reaction of compounds of general formula (14) by irradiation with a UV- radiation source, in particular UV light in the 300-400 nm wavelength in a polar aprotic solvent such as ACN. The reaction was conducted at ambient temperature in a batch reactor or in continuous flow reaction apparatus. After reaction work up, typically by a liquid-liquid extraction, the reaction product was purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation to yield bicyclic N-Boc-protected amino compounds of general formula (15).Carboxylic acid derivatives of general formula (16) were prepared by oxidation of bicyclic N-Boc-protected amino compounds of general formula (15) under a haloform reaction by reaction with bromine with a strong inorganic base such a sodium hydroxide or potassium hydroxide, the reaction is suitably conducted at 0 °C in H2O as a solvent. After reaction work up, typically by the addition of a sodium sulphite solution, followed by acidified to pH 2 with NaHSCL solution and liquid-liquid extraction, the reaction product was purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation to yield the carboxylic acid derivative of general formula (16).Intermediate A: 2-r(tert-butoxy)carbonyl1-4-methyl-2-azabicvclof2.1.1]hexane-5- carboxylic acidSTEP ASynthesis of (3E)-4-f(2-methylprop-2-en-1-yl)amino1but-3-en-2-oneTo a stirred solution of 2-methylprop-2-en-1 -amine (20 g, 281 mmol, 26 mL, 1.05 eq.) in THF (500 mL) was added (3E)-4-methoxybut-3-en-2-one (27 g, 267 mmol). After stirring for 18 h at room temperature, the reaction mixture was concentrated under reduced pressure to give (3E)-4-[(2-methylprop-2-en-1-yl)amino]but-3-en-2-one as a pale yellowoil (40.0 g, 97% yield) that was used in the next step without further purification. LCMS (Method 1) RT = 0.85 min, m / z [ESP] 140.2 (M+H)+.STEP BSynthesis of tert-butyl / V-(2-methylprop-2-en-1-yl)- / \ / -r(1E)-3-oxobut-1-en-1-yl1carbamateTo a stirred solution of (3E)-4-[(2-methylprop-2-en-1-yl)amino]but-3-en-2-one (40 g, 287 mmol) in THF (1000 mL) cooled to 0 °C, was added portion wise sodium tert-butoxide (27 g, 284 mmol, 1.1 eq.). After complete addition, di-tert-butyl dicarbonate (56 g, 258 mmol, 1 .0 eq.) was added and the mixture was stirred for a further 3 h. Upon complete reaction, 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 give tert-butyl / V-(2-methylprop-2-en-1-yl)- / \ / -[(7E)-3-oxobut-1- en-1-yl]carbamate as a pale yellow oil (52 g, 84% yield). LCMS (Method 1) RT = 1.29 min, m / z: [ESP] 140.2 (M+H-56)+.1H NMR (400 MHz, CDCI3): 6 8.18 (d, 1 H); 5.48 (d, 1 H); 4.88 (s, 1 H); 4.69 (s, 1 H); 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-azabicyclo[2.1.11hexane-2-carboxylateA stirred solution of tert-butyl / V-(2-methylprop-2-en-1-yl)- / \ / -[(7E)-3-oxobut-1-en-1- yl]carbamate (10.0 g, 42 mmol) in ACN (1000 mL) was irradiated by UV-lamp (350 nm) in flow-reactor 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 was purified by flash column chromatography to give tert-butyl 5-acetyl-4-methyl-2-azabicyclo[2.1.1]hexane-2- carboxylate as a pale yellow oil (4.0 g, 47% yield).1H NMR (400 MHz, CDCI3): 6 4.55 (br d, 1 H); 3.26 (br d, 1 H); 2.99 (m, 1 H); 2.40 (s, 1 H); 2.05 (s, 3H); 1.48 (m, 2H); 1.43 (s, 9H); 1.37 (s, 3H).STEP DSynthesis of 2-r(tert-butoxy)carbonyl1-4-methyl-2-azabicyclo[2.1.11hexane-5-carboxylic acidTo a 0 °C stirred solution of sodium hydroxide (836 mg, 21 mmol, 10.0 eq.) in water (4 mL) was added dropwise bromine (1.67 g, 10 mmol, 5.0 eq.). The reaction mixture wasthen stirred for 0.5 h and 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 cautiously added. The solution was then stirred at room temperature for a further 4 h. The reaction mixture was quenched with sodium sulfite solution and the resulting mixture was extracted with diethyl ether. The organic layers were washed with brine, dried (Na2SO4) and filtered. The resulting filtrate was concentrated under reduced pressure to give 2- [(tert-butoxy)carbonyl]-4-methyl-2-azabicyclo[2.1.1]hexane-5-carboxylic acid as a colourless solid (400 mg, 93% yield). LCMS (Method 1) RT = 1.15 min, m / z: [ESI+] 240.2 (M-H)-.1H NMR (400 MHz, CDCI3): 54.50 (br s, 1 H); 3.36 (d, 1H); 3.05 (d, 1 H); 2.48 (s, 1 H); 1.56 (d, 1H); 1.43 (s, 9H); 1.43 (d, 1 H); 1.35 (s, 3H), exchangeable protons not observed.Scheme 2Using the procedure (Scheme 2), compounds of formula (17) were prepared by the reaction of a carboxylic acid derivative of general formula (16) with a suitable alkyl halide of formula Hal-Ra(wherein Hal is selected from Cl, Br and I) in a polar aprotic solvent such as DMF or DMA with a suitable base such as potassium carbonate or caesium carbonate. The reaction was conducted at ambient temperature or at high temperature dependant on reactivity. After reaction work up, typically by liquid-liquid extraction, thereaction product is purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation.In examples where Rais methyl, compounds of formula (17) were prepared by the reaction of a carboxylic acid derivative of general formula (16) with a methylating agent such as diazomethane in polar aprotic solvent such as MTBE or THF, the reaction was conducted at 0 °C or at ambient temperature. After reaction work up, typically by a liquidliquid extraction, the reaction product is purified by flash column chromatography, reverse phase preparative HPLC, or re-crystallisation.Compounds of general formula (4) are prepared by general N-Boc deprotection step such reaction with TFA or hydrochloric acid in a polar solvent such as 1,4-dioxane with a cosolvent 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 : Methyl (7 / ?,4S,5S)-2-azabicvclor2.1.1lhexane-5-carboxylate hydrochlorideSTEP ASynthesis of (1 ?,4S,5S)-2-(tert-butoxycarbonyl)-2-azabicyclof2.1.11hexane-5-carboxylic acidTo a stirred solution of 2-[(tert-butoxy)carbonyl]-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (CAS 1279894-35-7, 81.7 g, 0.35 mol) in THF (2000 mL) at room temperature was added / ?-(+)- 1 -phenylethylamine (47 mL, 0.37 mol, 1.1 eq.) over 0.1 h. After this time, the mixture was filtered and the resulting solid was collected and re-crystal ised from minimum THF and filtered. The resulting crystalline material was further recrystalised from minimum ACN and filtered. The filtered solid was suspended in ethyl acetate (200 mL) and partitioned with 2 / V hydrochloric acid (200 mL). The organic phase was extracted, dried (Na2SO4) and concentrated under reduced pressure to give (1R,4S,5S)-2-[(tert- butoxy)carbonyl]-2-azabicyclo[2.1.1]hexane-5-carboxylic acid as a pale-yellow oil (20g,49% yield).1H NMR (400 MHz, CDCI3): 6 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); Chiral SFC (Method 1) RT 3.28 min (99% e.e.).STEP BSynthesis of methyl (1 ?,4S,5S)-2-azabicyclof2.1.11hexane-5-carboxylate hydrochlorideTo a stirred 0 °C suspension of (7R,4S,5S)-2-(tert-butoxycarbonyl)-2- azabicyclo[2.1.1]hexane-5-carboxylic acid (CAS 615575-74-1 , 20.0 g, 88 mmol) in methanol (100 mL) was added dropwise thionyl chloride (19 mL, 260 mmol). The mixture was then allowed to warm to room temperature and stirred overnight. After this time, the resulting solid was collected by filtration and dried in the air to afford the title compound as a colourless solid (15 g, 96% yield). LCMS (Method 1) RT = 0.69 min, m / z: [ESI+] 142.12 (M+H)+. Chiral SFC (Method 2) RT 1.77 min (98% e.e.);1H NMR (400 MHz, CDCI3): 5 10.42 (br s, 1 H), 9.18 (br s, 1 H), 4.47 - 4.44 (m, 1 H), 3.72 (s, 3H), 3.59 - 3.57 (m, 2H), 3.04 - 3.01 (m, 1 H), 2.85 - 2.82 (m, 1 H), 1.87 - 1 .85 (m, 1 H), 1.68 - 1.62 (m, 1 H).X-Ray Crystallographic AnalysisA single crystal of the compound of Example 1 was prepared and subjected to X-ray crystallographic studies as described below.Experimental:Single colourless block crystals of the compound were obtained by recrystallisation from methanol. A suitable crystal 0.05x0.04x0.03 mm3was selected and using Hampton Research CryoLoopTM, mounted on a Rigaku XtaLAB Synergy-S diffractometer equipped with a HyPix-6000HE detector and an Oxford Cryosystems Cobra cooling device. The crystal was kept constant at 100 K during data collection.Data were generated using CuKa radiation. The maximum resolution that was achieved was 0 = 69.977° (0.82 A). Data reduction, scaling and absorption corrections were performed. The final completeness was 100% out to 69.977° in 0. The 8295 reflections were measured in total (12.204° < 2 0 < 139.954°) and 1619 unique reflections (Rint = 0.0306, Rsigma = 0.0204) which were used in all calculations. The absorption coefficient p of the compound was determined as being 3.580 mm-1at the wavelength (A = 1.54184 A).The data were collected and processed using Rigaku CrysAlisPro software (Rigaku Oxford Diffraction, 2020) and the structure was solved with the SheIXTL (Sheldrick, 2013) structure solution program using the direct methods and by using Olex2 (Dolomanov et al., 2009) as the graphical interface. The model was refined with version 2014 / 6 of ShelXL (Sheldrick, 2014) using Least Squares minimisation.”All non-hydrogen atoms were refined anisotropically. Hydrogen atom positions were calculated geometrically and refined using the riding model.From the data collected, the characteristics of the crystal structure of the compound were determined as being as follows:Crystal system: OrthorhombicSpace group P212121Unit cell dimensions a = 7.96499(16) A a = 90° b = 9.35289(19)A b = 90° c = 11.4872(2) A g = 90°Volume = 855.75(3) A3R factor = 2.04%Absolute Stereochemistry: C2: S configuration; C4: R configuration; C5: S configuration.Flack Parameter (x) = -0.003(7)References: O.V. Dolomanov and L.J. Bourhis and R.J. Gildea and J.A.K. Howard and H.Puschmann, Olex2: A complete structure solution, refinement and analysis program, J. Appl. Cryst, (2009), 42, 339-341.Sheldrick, G.M., Crystal structure refinement with ShelXL, Acta Cryst., (2015), C71 , 3-8.Sheldrick, G.M., SheIXT-lntegrated space-group and crystal-structure determination, Acta Cryst., (2015), A71 , 3-8.EXAMPLE 2: Methyl 4-methyl-2-azabicvclor2.1.1lhexane-5-carboxylate hydrochlorideSTEP ASynthesis of 2-(tert-butyl) 5-methyl 4-methyl-2-azabicyclo[2.1.11hexane-2,5-dicarboxylateTo a stirred 0 °C suspension of 2 -[(tert-butoxy) carbonyl]-4-methyl-2-azabicyclo [2.1.1] hexane-5-carboxylic acid (3.7 g, 15.3 mmol) in MTBE (150 mL), was added dropwise diazomethane (1.2 eq.) in MTBE (100 mL). The reaction mixture was stirred at room temperature over 0.5 h, then concentrated under reduced pressure to afford 2-(tert-butyl) 5-methyl 4-methyl-2-azabicyclo[2.1.1]hexane-2,5-dicarboxylate as a pale-yellow oil (3.2 g, 95% yield). LCMS (Method 1) RT = 1.31 min, m / z [ESP] 156.2 (M+H-100)*.1H NMR (400 MHz, CDCI3): 5 4.48 (br d, 1 H); 3.59 (s, 3H); 3.30 (dd, 1 H); 3.01 (br d, 1 H); 2.43 (s, 1 H); 1.51 (d, 1 H); 1.42 (s, 9H); 1 .34 (d, 1 H); 1.34 (s, 3H).STEP BSynthesis of methyl 4-methyl-2-azabicyclo[2.1.11hexane-5-carboxylate hydrochlorideTo 2-tert-butyl 5-methyl 4-methyl-2-azabicyclo[2.1.1]hexane-2,5-dicarboxylate (1.0 g, 3.92 mmol) was added 4 N hydrogen chloride solution in 1,4-dioxane (10 mL). The mixture was stirred for 18 h at room temperature and filtered. The resulting solid was washed with diethyl ether to afford methyl 4-methyl-2-azabicyclo[2.1.1]hexane-5-carboxylate hydrochloride as a colourless solid (447 mg, 69% yield). LCMS (Method 1) RT = 0.24 min, m / z: [ESI+] 156.2 (M+H)+.1H NMR (400 MHz, DMSO-cfe): 6 10.17 (br s, 1 H); 8.79 (br s, 1 H); 4.27 (s, 1 H); 3.61 (s, 1H); 3.06 (s, 2H); 2.95 (s, 1H); 1.73 (d, 1 H); 1.51 (d, 1 H); 1.31 (s, 3H).EXAMPLE 3: Methyl 4-phenyl-2-azabicvclor2.1.1lhexane-5-carboxylate trifluoroacetateSTEP ASynthesis of 2-(tert-butyl) 5-methyl 4-phenyl-2-azabicyclof2.1.11hexane-2,5-dicarboxylateTo a stirred solution of 2-(tert-butoxycarbonyl)-4-phenyl-2-azabicyclo[2.1.1]hexane-5- carboxylic acid (1.4 g, 4.6 mmol, 1.0 eq.) in toluene (46 mL) and methanol (23 mL), was added dropwise TMS-diazomethane (2.8 mL, 2.0 M in diethyl ether, 5.5 mmol, 1.2 eq.). The mixture was then stirred at room temperature for 20 h. After this time, the reaction mixture was concentrated under reduced pressure and purified by flash column chromatography to afford 2-(tert-butyl) 5-methyl 4-phenyl-2-azabicyclo[2.1.1]hexane-2,5- dicarboxylate as a colourless oil (1.09 g, 74% yield).1H NMR (400 MHz, CDCh) 6 7.36 -7.30 (m, 3H), 7.23 - 7.20 (m, 2H), 4.60 (d, J = 2.03 Hz, 1 H) 3.68 (dd, J = 8.8, 1.6 Hz, 1 H), 3.48 (d, J = 8.84, 3H), 3.19 (dt, J= 7.7, 1.9 Hz, 1H), 3.06 (d, J = 7.2, 1.8 Hz, 1 H), 1.97 (t, J = 7.7, 1 H) 1.99 - 1.95 (m, 1 H), 1.49 (s, 9H).STEP BSynthesis of methyl 4-phenyl-2-azabicyclof2.1.11hexane-5-carboxylate trifluoroacetateTo a stirred solution of 2-(tert-butyl) 5-methyl 4-phenyl-2-azabicyclo[2.1.1]hexane-2,5- dicarboxylate (100 mg, 0.32 mmol, 1.00 eq.) in DCM (9.2 mL), was added TFA (485 pL,6.30 mmol, 10.0 eq.) and the mixture was stirred at room temperature for 3 h. After this time, the mixture was concentrated under reduced pressure. The resulting residue was dissolved in methanol and the mixture was stirred at 40 °C overnight. The solution was concentrated under reduced pressure to afford methyl 4-phenyl-2- azabicyclo[2.1.1]hexane-5-carboxylate trifluoroacetate as a yellow oil (71 mg, 68% yield). LCMS (Method 3) RT 2.94 min, m / z: [ESP] 218 (M+H)+.1H NMR (400 MHz, CDCh) 611.67 (s, 1 H), 8.69 (s, 1 H), 7.42 - 7.32 (m, 3H), 7.32 - 7.27 (m, 2H), 4.52 (t, J = 1.8 Hz, 1 H), 3.87 - 3.81 (m, 1 H), 3.78 (s, 3H), 3.75 - 3.68 (m, 1 H), 3.14 - 3.10 (m, 1 H), 2.27 (dd, J = 9.0, 1.0 Hz, 1 H), 2.15 (dt, J = 9.0, 1.9 Hz, 1 H).Scheme 3[Fl-5]Using the procedure (Scheme 3), compounds of formula [F3-1] were prepared by the reaction of a carboxylic acid derivative of general formula [F1-5] with an alcohol derivative of formula [F3-2] with a chlorinating agent such as thionyl chloride. The reaction is conducted at 0 °C or ambient temperature. After reaction work up, typically by a liquidliquid extraction, the reaction product was purified by flash column chromatography, reverse phase preparative HPLC, or re-crystallisation.EXAMPLE 4: Ethyl 2-azabicyclor2.1.1]hexane-5-carboxylate hydrochlorideTo a stirred 0 °C solution of 2-[(tert-butoxy)carbonyl]-2-azabicyclo[2.1 ,1]hexane-5- carboxylic acid (50 mg, 0.22 mmol) in ethanol (1 mL), was added thionyl chloride (16 pL, 0.22 mmol, 1 eq.). The mixture was allowed to warm to room temperature and stirred overnight. After this time, the crude reaction mixture was concentrated under reduced pressure to afford ethyl 2-azabicyclo[2.1.1]hexane-5-carboxylate hydrochloride as an off- white solid (35.9 mg, 86% yield). LCMS (Method 2) RT = 0.15 min, m / z: [ESI+] 156.0 (M+H)+.1H NMR (400 MHz, DMSO-cfe): 6 9.98 (br s, 1 H), 8.76 (br s, 1 H), 4.38 - 4.32 (m, 1 H), 4.19 - 4.11 (m, 2H), 3.46 - 3.39 (m, 2H), 3.24 - 3.15 (m, 1 H), 3.12 - 3.04 (m, 1 H), 1.97 - 1.91 (m, 1 H), 1.75 - 1.70 (m, 1 H), 1.39 - 1.31 (m, 3H).The following compounds were made according to Scheme 3 in the method above:EXAMPLE 9: Methyl (7 / ?,4S,5S)-4-methyl-2-azabicvclor2.1.1lhexane-5-carboxylate hydrochlorideSTEP ASynthesis of tert-butyl (E)-(2-methylallyl)(3-oxobut-1-en-1-yl)carbamateTo a stirred 0 °C solution of methylallylamine (147 g, 2.1 mol) in DCM (1500 mL) was added dropwise a solution of butynone (147 g, 2.16 mol, 1.03 eq.) in DCM (400 mL). The reaction mixture was then stirred for 16 h at room temperature. After this time, the mixture was concentrated under reduced pressure, dissolved in DCM and cooled to 0 °C. Boc anhydride (450 g, 2.07 mol, 1.0 eq.) was added, followed by DMAP (3 g, 0.02 mol, 0.001 eq.). The mixture was then stirred at room temperature for 80 h. After this time, the reaction mixture was concentrated under reduced pressure and filtered through a plug of silica gel eluting with mixtures of ethyl acetate / DCM to afford tert-butyl (E)-(2- methylallyl)(3-oxobut-1-en-1-yl)carbamate as a dark syrup (385 g, 78% yield). This material was used directly in STEP B without further purification.STEP BSynthesis of tert-butyl 5-acetyl-4-methyl-2-azabicyclof2.1.11hexane-2-carboxylateTo a stirred solution of tert-butyl (E)-(2-methylallyl)(3-oxobut-1-en-1-yl)carbamate (41 g, 170 mmol) in 2-butanone (900 mL), was added tes[2-(4,6-difluorophenyl)pyridinato- C2, A / ]iridium(l 11) (1.2 g, 1.6 mmol, 0.01 eq.). The mixture was transferred to a photoreactor and was subjected to two light sources (UV + blue) and passed through the reactor. Upon completion, the reaction mixture was concentrated under reduced pressure to afford tert-butyl 5-acetyl-4-methyl-2-azabicyclo[2.1.1]hexane-2-carboxylate which was used in the next step without further purification.STEP CSynthesis of 2-(tert-butoxycarbonyl)-4-methyl-2-azabicyclof2.1.11hexane-5-carboxylic acidA round bottom flask was charged with sodium hypochlorite solution (-14%, 400 mL) and cooled to 15 °C. To the above solution was added tert-butyl 5-acetyl-4-methyl-2- azabicyclo[2.1.1]hexane-2-carboxylate in ACN (200 mL). Upon complete addition the reaction mixture was stirred for 16 h at room temperature. After this time, the mixture was partitioned with MTBE (200 mL) and the aqueous phase was acidified to pH = 2 and extracted with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure to afford 2-(tert-butoxycarbonyl)-4-methyl-2- azabicyclo[2.1.1]hexane-5-carboxylic acid as syrup (31 g, 50% yield over 2 steps).STEP DSynthesis of (1R,4S,5S)-2-(tert-butoxycarbonyl)-4-methyl-2-azabicyclof2.1.11hexane-5- carboxylic acidA 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 refluxed. A stirred solution of (S)- phenylglycinol (94 g, 0.69 mol, 1.01 eq.) was dissolved in ACN (2 L) and added dropwise to the refluxing mixture. The reaction was stirred at reflux for 0.5 h and then allowed to cool to room temperature. The resulting suspension was filtered and the filter cake washed with ACN, 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 (1 L) was added an aqueous solution of KHSO4 (21 g, 0.15 mol, 500 mL). The biphasic mixture was stirred for 0.2 h and then the phases were extracted. The aqueous layer was extracted with DCM and the combined organic layers were dried (Na2SC>4), filtered and concentrated under reduced pressure to afford (7R,4S,5S)-2-(tert-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: [ESI+] 242.2 (M+H)+.X-Ray Crystallographic AnalysisA single crystal of intermediate (7R,4S,5S)-2-(ferf-butoxycarbonyl)-4-methyl-2- azabicyclo[2.1.1]hexane-5-carboxylic acid as phenylglycinol salt was prepared and subjected to X-ray crystallographic studies as described below.Experimental:Data collection. Single colorless block single crystals of the compound were obtained by recrystallisation from methanol / ACN. The measured crystals were prepared under inert conditions immersed in perfluoropolyether as protecting oil for manipulation. Crystal structure determinations were carried out using an Apex DUO Kappa 4-axis goniometer equipped with an APPEX 2 4K CCD area detector, a Microfocus Source E025 luS using CuKa radiation (1.54178 A), Quazar MX multilayer Optics as monochromator and an Oxford Cryosystems low temperature device Cryostream 700 plus (T = -173 °C). Fullsphere data collection was used with111and <P scans. Programs used: Data collection APEX-21, data reduction Bruker Saint2V / .60A and absorption correction SADABS3.Structure Solution and Refinement. Crystal structure solution was achieved using direct methods as implemented in SHELXT4and visualized using the program SHELXe5. Missing atoms were subsequently located from difference Fourier synthesis and added to the atom list. Least-squares refinement on F2using all measured intensities was carried out using the program SHELXL6. All non hydrogen atoms were refined including anisotropic displacement parameters.Description of the structure. This compound crystallizes in the monoclinic chiral space group P2i. The absolute configuration was determined relatively to the known chiral center with S(C7A), S(C1 B), R(C4B), S(C5B). Additionally, the absolute configuration was assigned directly based on anomalous dispersion effects. The absolute structure could be determined reliable with a Flack value based on Parsons’ quotients of 0.11 (10)7. The Flack parameter value for the correct absolute structure determination should be 0; the inverted structure would give 1; always taking into account the standard deviation. The structure measured is of excellent quality (no A- or B-alerts) with R1 value of 3.38%.From the data collected, the characteristics of the crystal structure of the compound were determined as being as follows:Crystal system: monoclinicSpace group: P2iUnit cell dimensions a = 11.922(3) A a = 90 ° b = 6.0887(18)A P = 110.765(7) c = 15.212(4) A y = 90 °Volume = 1032.5(5) A3References1Data collection with APEX II versions v2013.4-1. Bruker (2007). Bruker AXS Inc., Madison, Wisconsin, USA.2Data reduction with Bruker SAINT versions V8.30c. Bruker (2007). Bruker AXS Inc., Madison, Wisconsin, USA.3SADABS: V2012 / 1 Bruker (2001). Bruker AXS Inc., Madison, Wisconsin, USA. Blessing, Acta Cryst. (1995) A51 33-38.4SHELXT V2014 / 4 (Sheldrick 2014). Sheldrick, G.M. Acta Cryst. 2015, A71 , 3-8.5SHELXIe; C.B. Huebschle, G.M. Sheldrick & B. Dittrich; J. Appl. Cryst. 2011 , 44, 1281- 1284.6SHELXL; SHELXL-2014 / 7 (Sheldrick 2014). Sheldrick, G.M. Acta Cryst. 2015, C71 , 3-8.7Flack H.D., Acta Cryst. A39 (1983) 876, Parsons S.;, Flack H., Acta Cryst. A39 (2004) S61 , Parson, Flack and Wagner, Acta Cryst. B69 (2013) 249-259; E.C. Escudero-Adan, J. Benet-Buchholz, P. Ballester; Acta Cryst. (2014) B70, 660-668; Flack X determined using 1202 quotients [(l+)-(l-)] / [(l+)+(l-)])STEP ESynthesis of methyl (1 ?,4S,5S)-4-methyl-2-azabicyclof2.1.11hexane-5-carboxylate hydrochlorideTo a stirred 0 °C solution of (7R,4S,5S)-2-(terf-butoxycarbonyl)-4-methyl-2- azabicyclo[2.1.1]hexane-5-carboxylic acid (160 mg, 0.66 mmol, 1 eq.) in methanol (5 mL) was added thionyl chloride (150 mL, 2.1 mmol, 3 eq.). The reaction mixture was allowed to warm to room temperature and stirred for 1 h. After this time, the mixture was concentrated under reduced pressure to afford methyl (7 R,4S,5S)-4-methyl-2- azabicyclo[2.1.1]hexane-5-carboxylate hydrochloride as a brown syrup (125 mg, 99%yield). LCMS (Method 3) RT = 0.34 min, m / z: [ESI+] 156.40 (M+H)+.1H NMR (400 MHz, CD3OD): 5 4.40 (t, J = 1.6 Hz, 1 H), 3.80 (s, 3H), 3.28 - 3.35 (m, 3H), 1.98 (d, J = 8.9 Hz, 1 H), 1.64 (dd, 3J = 8.9 Hz, 4J = 0.8 Hz, 1 H), 1.50 (s, 3H). Scheme 4In one approach (Scheme 4), compounds of formula [F3-1] were prepared by the reaction of a carboxylic acid derivative of general formula [F1-5] with an amine of general formula [F4-3] with a suitable coupling agent such as HBTLI or HATLI in a polar aprotic solvent such as DMA or DMF in the presence of a tertiary amine base such as triethylamine, DIPEA or NMM. After reaction work up, typically by a liquid-liquid extraction, the reaction product was purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation to yield the amido-heterocyclic compound of general formula [F3-1 ]. Compounds of general formula [F3-3] are prepared by general N-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, thereaction product is purified by flash column chromatography, reverse phase preparative HPLC, or re-crystallisation. Compounds of general formula [F3-4] are prepared from a compound of general formula [F3-3] by treatment with a base such as amino polystyrene resin in a halogenated solvent such as DCM. The reaction is conducted at ambient temperature and after reaction work-up typically filtration, the reaction product is purified by flash column chromatography, reverse phase preparative HPLC, or re-crystallisation. In some examples, compounds of general formula [F3-4] are prepared directly from a compound of general formula [F3-1] by general N-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 treatment with a weak base such as a saturated aqueous solution of NaHCCh followed by liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse phase preparative HPLC, or re-crystallisation.EXAMPLE 10: Methyl (7S,4 / ?,5 / ?)-2-azabicyclor2.1.1]hexane-5-carboxylate hydrochlorideSTEP ASynthesis of (1S,4 ?,5 ?)-2-(tert-butoxycarbonyl)-2-azabicyclof2.1.11hexane-5-carboxylic acidTo a stirred solution of 2-[(tert-butoxy)carbonyl]-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (CAS 1279894-35-7, 290 g, 1.28 mol) in THF (1500 mL) at room temperature, was added S-(-)-1 -phenylethylamine (75 g, 0.62 mol, 0.5 eq.) over 0.1 h. After this time, the mixture was filtered and the resulting solid was collected and re-crystalised from minimum THF and filtered. The resulting crystalline material was further recrystalised from minimum ACN and filtered. The filtered solid was suspended in ethyl acetate (200 mL) and 2 / V HCI (600 mL) was added. The organic phase was separated, dried (Na2SO4),filtered and concentrated under reduced pressure to give (1 S,4R,5R)-2-(tert- butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid as a yellow oil (42 g, 28% yield). Chiral SFC (Method 1) RT 4.06 min (99% e.e.).1H NMR (400 MHz, CDCI3): 5 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).STEP BSynthesis of methyl -2-azabicyclof2.1.11hexane-5-carboxylate hydrochlorideTo a stirred, 0 °C suspension of (7S,4R,5R)-2-(tert-butoxycarbonyl)-2- azabicyclo[2.1.1]hexane-5-carboxylic acid (40 g, 0.18 mmol) in methanol (240 mL) was added dropwise thionyl chloride (62 mL, 0.52 mmol). The mixture was allowed to warm to room temperature and stirred for 16 h. After this time, the resulting solid was collected by filtration and air dried to afford methyl (7S,4R,5R)-2-azabicyclo[2.1.1]hexane-5- carboxylate hydrochloride as a colourless solid (25 g, 80% yield). LCMS (Method 1) RT = 0.69 min, m / z: [ESI+] 142.12 (M+H)+. Chiral SFC (Method 2) RT 2.63 min (98% e.e.).1H NMR (400 MHz, CDCI3): 5 10.42 (br s, 1 H), 9.18 (br s, 1 H), 4.49 - 4.38 (m, 1 H), 3.72 (s, 3H), 3.63 - 3.55 (m, 2H), 3.09 - 3.00 (m, 1 H), 2.86 - 2.81 (m, 1 H), 1.91 - 1.79 (m, 1 H), 1.69 - 1.62 (m, 1 H).Scheme 5In one approach (Scheme 5), compounds of formula [F5-2] were prepared by the reaction of a carboxylic acid derivative of general formula [F1-5] with an alcohol of general formula [F5-1] with a suitable carbodiimide coupling agent such as DCC, in a polar aprotic solvent such as THF or DMF in the presence of a nucleophilic catalytic base such as DMAP. After reaction work up, typically by a liquid-liquid extraction, the reaction product was purified by flash column chromatography, reverse phase preparative HPLC or recrystallisation to yield the azabicyclic ester compound of general formula [F5-2] . Compounds of general formula [F5-3] are prepared by general N-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 11 : 1 ,1 -Di oxotetra hydro-2 / - / -thiopyran-4-yl 2-azabicyclor2.1.1]hexane-5- carboxylate hydrochlorideSTEP ASynthesis of 2-(tert-butyl) 5-(1,1-dioxotetrahydro-2H-thiopyran-4-yl) 2- azabicyclof2.1.11hexane-2,5-dicarboxylateTo a stirred 0 °C solution of 2-[(tert-butoxy)carbonyl]-2-azabicyclo[2.1.1]hexane-5- carboxylic acid (600 mg, 2.64 mmol) and 4-hydroxytetrahydro-2 / 7-thiopyran 1,1 -dioxide (360 mg, 2.4 mmol, 0.9 eq.) in anhydrous DCM, was slowly added DCC (594 mg, 2.88 mmol, 1.2 eq.) and DMAP (87.9 mg, 0.72 mmol, 0.35 eq.). 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- (1 ,1-dioxotetrahydro-2 / 7-thiopyran-4-yl) 2-azabicyclo[2.1.1]hexane-2,5-dicarboxylate (280 mg, 36% yield). LCMS (Method 1) RT 1.04 min, m / z: [ESI+] 360.16 (M+H)+.1H NMR (400MHz, DMSO-cfe) 64.92 (s, 1 H), 4.42 (s, 1 H), 3.24 - 3.05 (m, 5H), 3.01 (s, 2H), 2.20 - 1.91 (m, 5H), 1.81 (d, J = 7.2 Hz, 1 H), 1.37 (s, 9H), 1.19 (d, J = 7.4 Hz, 1 H).STEP B Synthesis of 1,1-dioxotetrahydro-2 / - / -thiopyran-4-yl 2-azabicyclo[2.1.11hexane-5- carboxylate hydrochlorideTo a stirred 0 °C solution of 2-(tert-butyl) 5-(1,1-dioxotetrahydro-2 / 7-thiopyran-4-yl) 2- azabicyclo[2.1.1]hexane-2,5-dicarboxylate (280 mg, 0.78 mmol) in methanol was added acetyl chloride (122 mg, 1.56 mmol, 2.0 eq.). The mixture was stirred for 16 h and then concentrated under reduced pressure. To the residue was added MTBE and the mixture was stirred for 15 min. The resulting precipitate was collected by filtration and air dried to afford 1 ,1-dioxotetrahydro-2 / 7-thiopyran-4-yl 2-azabicyclo[2.1.1]hexane-5-carboxylate hydrochloride as a pale-yellow solid (167 mg, 72% yield). LCMS (Method 1) RT = 0.18 min, m / z [ESP] 260.1 (M+H)+.1H NMR (400 MHz, DMSO-cfe) 6 9.25 (s, 1H), 8.50 (s, 1 H), 5.12 - 4.93 (m, 1 H), 4.42 (d, J = 6.0 Hz, 1H), 3.33 - 3.07 (m, 8H), 2.19 - 2.05 (m, 4H),1.95 (d, J = 8.7 Hz, 1 H), 1.26 (d, J = 8.6 Hz, 1 H).The following compounds were made according to Scheme 5 in the method above:EXAMPLE 47: 3-Hvdroxypropyl 2-azabicyclo[2.1.1]hexane-5-carboxylate trifluoroacetateSTEP ASynthesis of 2-tert-butyl 5-(3-hydroxypropyl) 2-azabicyclo[2.1.11hexane-2,5-dicarboxylateTo a stirred 0 °C solution of 2-[(tert-butoxy)carbonyl]-2-azabicyclo[2.1.1]hexane-5- carboxylic acid (700 mg, 3.1 mmol) and propane-1 , 3-diol (270 mg, 3.5 mmol, 1.1 eq.) in anhydrous DCM, were slowly added DCC (830 mg, 4.0 mmol) and DMAP (21 mg, 0.17 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 (Na2SC>4), filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford 2-tert-butyl 5-(3-hydroxypropyl) 2-azabicyclo[2.1.1]hexane- 2,5-dicarboxylate (316 mg, 40% yield). LCMS (Method 1) RT = 1.04 min, m / z [ESP]186.2 (M+H-100)+.STEP BSymthesis of 3-hydroxypropyl 2-azabicyclo[2.1.1]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 (240 mg, 0.8 mmol) in DCM, was added TFA (288 mg, 2.5 mmol, 30 eq.). The solution was then stirred at room temperature overnight. After this time, the mixture was concentrated under reduced pressure and the residue lyophilized to afford 3- hydroxypropyl 2-azabicyclo[2.1.1]hexane-5-carboxylate trifluoroacetate as a brown oil (175 mg, 95% yield). LCMS (Method 6) RT = 1.53 min, m / z: [ESP] 186.3 (M+H)+.1H NMR (400 MHz, DMSO-cfe) 6 9.34 (s, 1 H), 8.56 (s, 1 H), 4.38 (d, J = 5.8 Hz, 1 H), 4.20 - 4.00 (m, 2H), 3.46 (t, J = 6.1 Hz, 2H), 3.28 (s, 2H), 3.20 (d, J = 2.9 Hz, 1 H), 3.10 (dt, J = 6.3,3.2 Hz, 1 H), 1.96 (d, J = 8.6 Hz, 1 H), 1.75 - 1.72 (m, 2H), 1.35 - 1.19 (m, 1 H).EXAMPLE 48: 3-((Cyclopentanecarbonyl)oxy)propyl 2-azabicyclor2.1.1]hexane-5- carboxylate trifluoroacetateSTEP ASynthesis of 2-tert-butyl 5-(3-((cyclopentanecarbonyl)oxy)propyl) 2- azabicyclof2.1.11hexane-2,5-dicarboxylateTo 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 [ESI+] 282.2 (M-100+H)+.STEP BSynthesis of 3-((cyclopentanecarbonyl)oxy)propyl 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: [ESI+] 282.19 (M+H)+.1H NMR (400 MHz, DMSO- cfe) 6 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 49: 3-Acetoxypropyl 2-azabicyclof2.1.11hexane-5-carboxylate trifluoroacetateSTEP ASynthesis of 5-(3-acetoxypropyl) 2-tert-butyl 2-azabicyclof2.1.11hexane-2,5-dicarboxylateTo a stirred 0 °C solution of 2-tert-butyl 5-(3-hydroxypropyl) 2-azabicyclo[2.1.1]hexane-2,5-dicarboxylate (97 mg, 0.34 mmol) and triethylamine (0.41 mmol, 57 pL, 1.2 eq.) in anhydrous DCM, was added acetyl chloride (32 mg, 0.41 mmol, 1.2 eq.). The resulting solution was stirred overnight at room temperature. After this time, the reaction was quenched with water and extracted with DCM. The combined organic layers were dried (Na2SC>4), filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford 5-(3-acetoxypropyl) 2-tert-butyl 2-azabicyclo[2.1.1]hexane-2,5-dicarboxylate (83 mg, 75% yield). LCMS (Method 1) RT = 1.14 min, m / z [ESI+] 228.19 (M-100+H)+.STEP BSynthesis of 3-acetoxypropyl 2-azabicyclof2.1.11hexane-5-carboxylate trifluoroacetateTo a stirred 0 °C solution of 5-(3-acetoxypropyl) 2-tert-butyl 2-azabicyclo[2.1.1]hexane-2,5-dicarboxylate (83 mg, 0.25 mmol) in DCM, was added TFA (30 mg, 0.51 mmol, 2 eq.). The reaction mixture was then stirred at room temperature overnight. After this time, the solvent was evaporated and the residue was purified by preparative HPLC to afford 3- acetoxypropyl 2-azabicyclo[2.1.1]hexane-5-carboxylate trifluoroacetate as a colourless oil (23.5 mg 27% yield). LCMS (Method 1) RT = 0.62 min, m / z: [ESF] 228.13 (M+H)+.1H NMR (400 MHz, DMSO-cfe) 6 9.31 (s, 1 H), 8.57 (s, 1 H), 4.38 (dt, J = 6.1 , 1.7 Hz, 1 H), 4.13 - 4.10 (m, 4H), 3.28 (s, 2H), 3.22 (d, J = 3.2 Hz, 1 H), 3.11 (dt, J = 6.3, 3.2 Hz, 1 H), 2.07 - 1.81 (m, 6H), 1.26 (d, J = 8.6 Hz, 1 H).EXAMPLE 50: 3-(4-(Fluorosulfonyl)benzamido)propyl 2-azabicyclor2.1.1]hexane-5- carboxylate trifluoroacetateTo a stirred 0 °C solution of 4-(fluorosulfonyl)benzoic acid (1.0 g, 4.9 mmol) and 3- aminopropan-1-ol (334 mg, 4.5 mmol, 0.9 eq.) in anhydrous DCM, was added HOBT (120 mg, 0.89 mmol, 0.2 eq.) and DIPEA (1.1 g, 5.3 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 flash column chromatography to obtain 4- [(3-hydroxypropyl)carbamoyl]benzene-1 -sulfonyl fluoride (362 mg, 31% yield). LCMS (Method 2) RT = 0.80 min, m / z: [ESI+] 262.2 [M+H]+.STEP B2-To a stirred 0 °C solution of 4-[(3-hydroxypropyl)carbamoyl]benzene-1-sulfonyl fluoride(362 mg, 1.4 mmol) and 2-[(tert-butoxy)carbonyl]-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (346 mg, 1.5 mmol, 1.1 eq.) in anhydrous DCM, were slowly added DCC (343 mg,1.7 mmol, 1.2 eq.) and DMAP (51 mg, 0.42 mmol, 0.33 eq.). 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 to afford 2-tert-butyl 5-{3-r(4-fluorosulfonylbenzoyl)aminolpropyl} 2-!-2,5-di (549 mg, 91% yield). LCMS (Method 2) RT =1.23 min, m / z: [ESI+] 371.2 (M-100+H)+.STEP CSynthesis of 3-(4-(fluorosulfonyl)benzamido)propyl 2-azabicyclof2.1.11hexane-5- carboxylate trifluoroacetateTo a stirred 0 °C solution of 2-tert-butyl 5-{3-f(4-fluorosulfonylbenzoyl)aminolpropyl} 2- azabicyclof2.1.11hexane-2,5-dicarboxylate (549 mg, 1.2 mmol) in DCM, was added TFA (2.7 g, 23.3 mmol, 20.0 eq.). The solution was then stirred at room temperature overnight. After this time, the mixture was concentrated under reduced pressure and the residue purified by preparative HPLC to give 3-(4-(fluorosulfonyl)benzamido)propyl 2- azabicyclo[2.1.1]hexane-5-carboxylate trifluoroacetate as a yellow oil (138 mg, 26% yield). LCMS (Method 2) RT = 0.73 min, m / z: [ESI+] 371.0 (M+H)+.1H NMR (400 MHz, DMSO-cfe) 6 9.29 (s, 1 H), 8.94 (t, J = 5.8 Hz, 1 H), 8.49 (s, 1 H), 8.27 (d, J = 8.3 Hz, 2H), 8.16 (d, J = 8.3 Hz, 2H), 4.38 (d, J = 5.9 Hz, 1 H), 4.16 - 4.04 (m, 2H), 3.43 - 3.23 (m, 4H), 3.21 (s, 1 H), 3.10 (dt, J = 6.5, 3.2 Hz, 1 H), 1.96 (d, J = 8.9 Hz, 1 H), 1.89 - 1.85 (m, 2H), 1.26 (d, J = 8.7 Hz, 1 H).EXAMPLE 51 - 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. Reagents: RPMI (Gibco, ref. 61870-010), FBS (Gibco, Brazil origin, ref.10270- 106), Pen-Strep (Gibco™ 15140122), MitoTracker RedCMXRos (ThermoFisher Scientific, ref. M7512.The analysis of the data comprises PC5.5 median fluorescence of the live cells, % of live cells and cells / pL. All data points are normalised to the vehicle CTL. Results are presented as % increase in MTR signal vs control at the given test concentration (A = 101% - 104.9%; B = 105% - 108.9%; C = 109% - 112.9%; D = > 113%).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 48 h 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 points are normalised to the vehicle CTL. Results are presented as % increase in Cox8 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 water 10. For the analysis, select the longest regions of stable readings quantify using DatLab programData is 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 TableEXAMPLE 52 - PHARMACEUTICAL FORMULATIONS(i) Tablet FormulationA tablet composition containing a compound as defined in any one of Embodiments 1.1 to 1.125 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 1.125 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 1.125 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 1.125 (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 1.125 (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 1.125 (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 1.125 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 1.125 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 will readily 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):or a salt or tautomer thereof; whereinR1is C(O)ORa;Rais selected from: i) hydrogen; ii) a group Hyd, in which Hyd is a methyl group or a C2-12 hydrocarbyl group wherein one of the carbon atoms in the C2-12 hydrocarbyl group may optionally be replaced with O, N, S, S(O) or S(O)2 and wherein the group Hyd is optionally substituted with a hydroxyl, halogen, cyano or oxo group; and iii) a group A-B-Cyc;A is selected from a bond and a C1-6 alkylene linker group;B is absent, -C(O)NRD- or -NRDC(O)-, provided that when A is a bond, B is absent;RDis selected from hydrogen and a C1-4 hydrocarbyl group;Cyc is a 5-6 membered cyclic aromatic group or a 3-6 membered cyclic non-aromatic group, wherein the cyclic aromatic group and cyclic non-aromatic group of Cyc are each optionally substituted with one or more substituents selected from hydroxyl, halogen, oxo (as appropriate), cyano, SChR3, C1-4 alkyl, C1-4 alkoxy, C1-4 alkanoyl and a 5-6 membered cyclic aromatic group;Rsis a C1-4 alkyl group, hydroxyl or fluorine;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 of R2areoptionally 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; excluding the compounds (4S,5S)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid and methyl (1S,4R,5R)-2-azabicyclo[2.1.1]hexane-5-carboxylate.

2. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of the formula (1):or a salt or tautomer thereof; whereinR1is C(O)ORa;Rais selected from: i) hydrogen; ii) a group Hyd, in which Hyd is a methyl group or a C2-12 hydrocarbyl group wherein one of the carbon atoms in the C2-12 hydrocarbyl group may optionally be replaced with O, N, S, S(O) or S(O)2 and wherein the group Hyd is optionally substituted with a hydroxyl, halogen, cyano or oxo group; and iii) a group A-B-Cyc;A is selected from a bond and a C1-6 alkylene linker group;B is absent, -C(O)NRD- or -NRDC(O)-, provided that when A is a bond, B is absent;RDis selected from hydrogen and a C1-4 hydrocarbyl group;Cyc is a 5-6 membered cyclic aromatic group or a 3-6 membered cyclic non-aromatic group, wherein the cyclic aromatic group and cyclic non-aromatic group of Cyc are each optionally substituted with one or more substituents selected from hydroxyl, halogen, oxo (as appropriate), cyano, SChR3, C1-4 alkyl, C1-4 alkoxy, C1-4 alkanoyl and a 5-6 membered cyclic aromatic group;Rsis a C1-4 alkyl group, hydroxyl or fluorine;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 of R2are optionally substituted with one or more substituents selected from halogen, C1-4 alkyl, hydroxyl, C1-4 alkoxy and C1-4 alkanoyl; 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.

3. A compound for use in medicine, the compound being of the formula (1):or a salt or tautomer thereof; whereinR1is C(O)ORa;Rais selected from: i) hydrogen; ii) a group Hyd, in which Hyd is a methyl group or a C2-12 hydrocarbyl group wherein one of the carbon atoms in the C2-12 hydrocarbyl group may optionally be replaced with O, N, S, S(O) or S(O)2 and wherein the group Hyd is optionally substituted with a hydroxyl, halogen, cyano or oxo group; andiii) a group A-B-Cyc;A is selected from a bond and a C1-6 alkylene linker group;B is absent, -C(O)NRD- or -NRDC(O)-, provided that when A is a bond, B is absent;RDis selected from hydrogen and a C1-4 hydrocarbyl group;Cyc is a 5-6 membered cyclic aromatic group or a 3-6 membered cyclic non-aromatic group, wherein the cyclic aromatic group and cyclic non-aromatic group of Cyc are each optionally substituted with one or more substituents selected from hydroxyl, halogen, oxo (as appropriate), cyano, SChR3, C1-4 alkyl, C1-4 alkoxy, C1-4 alkanoyl and a 5-6 membered cyclic aromatic group;Rsis a C1-4 alkyl group, hydroxyl or fluorine;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 of R2are optionally substituted with one or more substituents selected from halogen, C1-4 alkyl, hydroxyl, C1-4 alkoxy and C1-4 alkanoyl; 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.

4. A compound for use in treating a mitochondrial disease, the compound being of the formula (1):or a salt or tautomer thereof; wherein R1is from C(O)ORa;Rais selected from: i) hydrogen; ii) a group Hyd, in which Hyd is a methyl group or a C2-12 hydrocarbyl group wherein one of the carbon atoms in the C2-12 hydrocarbyl group may optionally be replaced with O, N, S, S(O) or S(O)2 and wherein the group Hyd is optionally substituted with a hydroxyl, halogen, cyano or oxo group; and iii) a group A-B-Cyc;A is selected from a bond and a C1-6 alkylene linker group;B is absent, -C(O)NRD- or -NRDC(O)-, provided that when A is a bond, B is absent;RDis selected from hydrogen and a C1-4 hydrocarbyl group;Cyc is a 5-6 membered cyclic aromatic group or a 3-6 membered cyclic non-aromatic group, wherein the cyclic aromatic group and cyclic non-aromatic group of Cyc are each optionally substituted with one or more substituents selected from hydroxyl, halogen, oxo (as appropriate), cyano, SChR3, C1-4 alkyl, C1-4 alkoxy, C1-4 alkanoyl and a 5-6 membered cyclic aromatic group;Rsis a C1-4 alkyl group, hydroxyl or fluorine;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 of R2are optionally substituted with one or more substituents selected from halogen, C1-4 alkyl, hydroxyl, C1-4 alkoxy and C1-4 alkanoyl; 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.

5. A compound, a pharmaceutical composition or a compound for use according to any one of claims 1 to 4 wherein Rais selected from: i) a group Hyd, in which Hyd is a methyl group or a C2-6 hydrocarbyl group in which one but not all of the carbon atoms in the C2-6 hydrocarbyl group may optionally be replaced with O, N, S, S(O) or S(O)2 and wherein the C1- 6 hydrocarbyl group is optionally substituted with a hydroxyl, halogen, cyano or oxo group; andii) a group A-B-Cyc;A is selected from a bond, a C1-6 alkylene linker group;B is absent, -C(O)NRD- or -NRDC(O), provided that when A is a bond, B is absent;Cyc is a 5-6 membered cyclic aromatic or a 3-6 membered cyclic nonaromatic group, wherein the cyclic aromatic group and cyclic non-aromatic group of Cyc are each optionally substituted with one or more substituents selected from hydroxyl, halogen, C1-4 alkyl and C1-4 alkoxy.

6. A compound, a pharmaceutical composition or a compound for use according to any one of claims 1 to 5 wherein A is a bond or a methylene linker group and B is absent.

7. A compound, a pharmaceutical composition or a compound for use according to any one of claims 1 to 6 wherein Cyc is a 4-6 membered cyclic non-aromatic group containing one or two heteroatoms or heteroatom groups selected from O, N, S, S(O) and SO2, wherein the 4-6 membered cyclic non-aromatic group of Cyc is optionally substituted with one or more substituents selected from hydroxyl, halogen, C1-4 alkyl and C1-4 alkoxy.

8. A compound, a pharmaceutical composition or a compound for use according to any one of claims 1 to 7 wherein Cyc is a 6 membered cyclic non-aromatic group containing one heteroatom or heteroatom group selected from N, O, S, S(O) and SO2, wherein the 4-6 membered cyclic non-aromatic group of Cyc is optionally substituted with one or more substituents selected from hydroxyl, halogen, C1-4 alkyl and C1-4 alkoxy.

9. A compound, a pharmaceutical composition or a compound for use according to any one of claims 1 to 8 wherein Rahas the following formula:wherein * indicates the point of connection to the oxygen atom to which Rais attached.

10. A compound, a pharmaceutical composition or a compound for use according to any one of claims 1 to 9 wherein R2is selected from hydrogen, methyl and phenyl.

11. A compound, a pharmaceutical composition or a compound for use according to any one of claims 1 to 9 wherein R2is selected from 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 nonaromatic groups of R2are optionally substituted with one or more substituents selected from halogen, C1-4 alkyl, hydroxyl, C1-4 alkoxy and C1-4 alkanoyl.

12. A compound, a pharmaceutical composition or a compound for use according to any one of claims 1 to 11 wherein R3and R4are hydrogen.

13. A compound, a pharmaceutical composition or a compound for use according to any one of claims 1 to 12, wherein the compound has the formula (1-A):wherein R1, R2and R3are as defined in any one of claims 1 to 12.

14. A compound selected from any of Examples 1-50 in Table 1 and salts and tautomers thereof.

15. A pharmaceutical composition or a compound for use according to any one of claims 2 to 13 wherein the compound is selected from any of Examples 1-50 in Table 1 and salts and tautomers thereof.

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