New compounds

Abstract

The invention relates to a compound of formula I, I wherein R1, R2, R3, R4, R5, R6, R7a, R7b, Q, A, E and L are as defined in the specification, or a pharmaceutically acceptable salt, solvate, or deuterated analogue thereof, said compound is useful in the treatment of a disease or condition which is responsive to treatment with an inhibitor of a transglutaminase.

Description

[0001] NEW COMPOUNDS Field of the Invention The present invention relates to novel compounds, and the use of such compounds in medicine. In particular, the present invention relates to compounds that are useful in treating a disorder or condition which is responsive to treatment with an inhibitor of a transglutaminase. Background of the Invention Transglutaminases (TGs or TGases) are a group of enzymes able to modify proteins by mediating an acyl-transfer reaction between the γ-carboxamide group of peptide-bound glutamine and a primary amine. The result of this reaction is post-translational modification, either through protein crosslinking, if the amine is the ε-amino group of peptide-bound lysine, or modification of the peptide glutamine by crosslinking to a primary amine such as a polyamine. Under certain conditions and in the absence of a suitable primary amine, the deamidation of peptide bound glutamine can also occur. Because of their ability to crosslink proteins into high molecular weight protein aggregates TGs have been termed as “Nature’s Biological glues” (Griffin et al., 2002). TGs are found widely in nature, but in mammals their enzymatic activity is Ca2+-dependent, and other factors including GTP / GDP can also affect the activity of some of the mammalian TGs (Verderio et al., 2004). Not all of the eight active members (TG1-7 and factor XIII) of the mammalian TG family have been fully characterised (Collighan and Griffin, 2009). Another member of this family, band 4.2, is catalytically inactive and is mainly associated with the regulation of the erythrocyte cytoskeleton. TG2 (tissue transglutaminase, TG2M, tTG) is probably the most ubiquitous member of the mammalian TG family which is found both in the intra- and extra-cellular environment. In addition to its transamidating, GTPase and ATPase activity (Nakaoka et al., 1994), further novel activities have recently been reported for TG2 e.g. the protein disulfide isomerase (PDI) (Hasegawa et al., 2003) and protein kinase activities (Mishra and Murphy, 2004), thus further extending the potential physiological and pathological importance of this diverse group of enzymes. Abnormal levels of transglutaminase particularly TG2 and / or activity have been observed in many disease states, like celiac sprue, neurodegenerative diseases (Alzheimer, Parkinson, Huntington disease), fibrosis, cataract, cancer metastasis, and the list is certainly not intended to be exhaustive. Moreover, proof of concept studies using either TG2- / - animal models (Bailey and Johnson, 2005; Mastroberardino et al., 2002) or inhibitor studies (Huang et al., 2009; Johnson et al., 2008) have shown the enzyme to be a potential novel candidate for therapeutic intervention. Due to its implication in a wide variety of biological processes and pathologies, developing chemicals tools to further investigate TG2s multifunctional roles is an active research area. Most of the inhibitors developed so far target the enzyme's catalytic site, but there are also reports of small molecules competing for the TG2 cofactor binding site. Depending on their ability to reach and react with the catalytic cysteine residue (CYS277 in case of hTG2), they can further be divided into reversible and irreversible inhibitors. Peptidic inhibitors bearing various electrophilic moieties (e.g. chloroacetamides (Pardin et al., 2006), α,β-unsaturated amides (Pardin et al., 2006), maleimides (Halim et al., 2007), sulfonium methyl ketones (Griffin et al., 2008), dihydroisoxazoles (Dafik and Khosla, 2011), cinnamoyl derivatives (Pardin et al., 2008a; Pardin et al., 2008b), oxindoles (Klock et al., 2011), sulfonamidopiperazines (Prime et al., 2012) are examples of such derivatives. The resolved TG2 structures co-crystallised either with irreversible inhibitors (Lindemann et al., 2012; Pinkas et al., 2007) or nucleotides (Han et al., 2010; Liu et al., 2002), revealed the huge conformational change of the enzyme when passing from the inactive to the active state, and will certainly enhance the design of more potent inhibitors in the future. It has been shown that small molecule inhibitors of TG2 may be effective treatments of various fibrotic diseases. For instance, Wang et al., 2018 report that cardiac fibrosis can be attenuated by blocking the activity of TG2 using a selective small-molecule inhibitor. Moreover, both Huang et al., 2009 and Johnson et al., 2007 report that TG2 inhibition ameliorates fibrotic kidney disease. Further still, Fell et al., 2021 identified TG2 as a potential therapeutic target for idiopathic pulmonary fibrosis. An example of a TG2 inhibitor is compound 1–155 (i.e. Reference Compound 1), which was first disclosed in WO 2014 / 057266. As an TG2 inhibitor, compound 1–155 is useful in the treatment or prevention of a disease or condition which is responsive to treatment with an inhibitor of tissue transglutaminase. Such compounds may be useful in the treatment of fibrosis, scarring, neurodegenerative diseases, autoimmune diseases, thrombosis, pathological angiogenesis, proliferative disorders, AIDS, psoriasis and inflammation. The present invention seeks to provide novel compounds which inhibit transglutaminase activity for use in medicine, said compounds possessing surprisingly improved pharmacokinetic properties compared to known TG2 inhibitors. The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge. Detailed Description of the Invention In a first aspect of the invention, there is provided a compound of formula I wherein: Q is selected from the group consisting of O and NH; A is selected from the group consisting of N and CH; E represents a direct bond or -C(O)-; L represents a direct bond or a group selected from the group consisting of C1-3alkylene, 4- to 6-membered cycloalkylene, 4- to 6-membered heterocycloalkylene, arylene and heteroarylene; or A, E and L together form a 4- to 6-membered cycloalkylene group; R1represents a naphthyl group substituted with one or more X groups or a 10-membered, bicyclic heteroaryl group, which is optionally substituted with one or more X groups; each X is independently selected from the group consisting of halogen (e.g. F,18F, Cl, Br or I), -N(R8a)R8b, -OR9, -C(O)OR10, -C(O)N(R11a)R11b, -CN, a C1-4alkyl group, and a C3-6cycloalkyl group, which C1-4alkyl and C3-6cycloalkyl groups are optionally substituted by one or more deuterium atoms and / or halogen (e.g. F,18F, Cl, Br or I) atoms; R2, R3and R4are each independently selected from the group consisting of hydrogen and C1-3alkyl, which C1-3alkyl group is optionally substituted by one or more halogen (e.g. F,18F, Cl, Br or I) atoms; or R2and R3together with the carbon atoms to which they are bound form a 5- or 6- membered heterocycloalkyl group; or R2and R4together with the carbon atoms to which they are bound form a 5- or 6- membered heterocycloalkyl group; R5is selected from the group consisting of hydrogen, C1-3alkyl, and C3-6cycloalkyl, which C1-3alkyl and C3-6cycloalkyl groups are optionally substituted by one or more groups selected from the group consisting of deuterium atoms and halogen (e.g. F,18F, Cl, Br or I) atoms; or L and R5together with the nitrogen atom to which R5is bound form a 4- to 6- membered heterocycloalkylene group; R6is selected from the group consisting of hydrogen, halogen (e.g. F,18F, Cl, Br or I), deuterium, and C1-3alkyl, which C1-3alkyl group is optionally substituted by one or more halogen (e.g. F,18F, Cl, Br or I) atoms, -CH2N(R12)Ph and -CH2OCH2Ph; R7aand R7bare each independently selected from the group consisting of hydrogen, halogen (e.g. F,18F, Cl, Br or I), methyl, and deuterium; R8a, R8b, R9, R10, R11aand R11b, are each independently selected from the group consisting of hydrogen, C1-3alkyl, and C3-6cycloalkyl, which C1-3alkyl and C3-6cycloalkyl groups are optionally substituted by one or more deuterium atoms and / or halogen (e.g. F,18F, Cl, Br or I) atoms; or or R8aand R8band / or R11aand R11b, together with the nitrogen atom to which they are bound form a 3- to 6-membered heterocycloalkyl group; R12is selected from the group consisting of hydrogen and C1-3alkyl, which C1-3alkyl group is optionally substituted by one or more halogen (e.g. F,18F, Cl, Br or I) atoms; and Ph is phenyl optionally substituted by one or more halogen (e.g. F,18F, Cl, Br or I) atoms or C1-3alkyl groups, which C1-3alkyl groups are optionally substituted by one or more halogen (e.g. F,18F, Cl, Br or I) atoms, or a pharmaceutically acceptable salt, solvate, or deuterated analogue thereof; provided that: (a) the compound of formula I or pharmaceutically acceptable salt, solvate, or deuterated analogue thereof is not: or a pharmaceutically acceptable salt, solvate, or deuterated analogue thereof; and (b) the compound of formula I or pharmaceutically acceptable salt, solvate, or deuterated analogue thereof is not: . These compounds, including pharmaceutically acceptable salts and solvates thereof, may be referred to herein as the “compounds of the invention”. In particular embodiments of the first aspect of the invention each X is independently selected from the group consisting of halogen (e.g. F,18F, Cl, Br or I), -N(R8a)R8b, -OR9, -C(O)OR10, -C(O)N(R11a)R11b, a C1-4alkyl group, and a C3-6cycloalkyl group, which C1-4alkyl and C3-6cycloalkyl groups are optionally substituted by one or more deuterium atoms and / or halogen (e.g. F,18F, Cl, Br or I) atoms. Pharmaceutically acceptable salts of potential utility include those discussed in J. Pharmaceutical Sciences, 66: 1-19 (1977), by Berge et al. Pharmaceutically acceptable salts of the compound of formula I may be prepared in accordance with techniques that are well known to those skilled in the art. Examples of pharmaceutically acceptable addition salts include acid addition salts, for example, salts formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric and phosphoric acid, with carboxylic acids or with organo-sulfonic acids; base addition salts; metal salts formed with bases, for example, the sodium and potassium salts. Pharmaceutically acceptable salts of the compound of formula I may be prepared in accordance with techniques that are well known to those skilled in the art. For example, the compound of formula I may be reacted with the appropriate organic acid or mineral acid. Salt switching techniques may also be used to convert one salt into another salt. The compounds disclosed herein may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water and ethanol, and it is intended that the invention embraces both solvated and unsolvated forms of the compounds of the invention. The term “solvate” refers to a complex of variable stoichiometry formed by a solute and solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, ethanol, and acetic acid. Solvates in which water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water. Unless otherwise specified, alkyl groups defined herein may be straight-chain or, when there is a sufficient number of carbon atoms, be branched-chain. When used herein, “alkylene” (i.e. alkanediyl) refers to a divalent alkyl group. Particular alkylene groups that may be mentioned include, for example, propylene (n-propylene or isopropylene), ethylene and, particularly, methylene (i.e. -CH2-). When there is a sufficient number (i.e. a minimum three, as appropriate) of carbon atoms, an alkyl group may be cyclic, so forming a cycloalkyl group. Cycloalkyl groups that may be mentioned include monocyclic groups, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Such cycloalkyl groups may be bridged (so forming, for example, fused ring systems such as three fused cycloalkyl groups). Further, such cycloalkyl groups may be saturated or unsaturated containing, e.g., one or more double bonds (forming for example a cycloalkenyl). Further, where there is a sufficient number (i.e. a minimum of four) such cycloalkyl groups may also be part cyclic, e.g. forming an alkylene-cycloalkyl group (for example, -CH2-C3H5). The points of attachment of cycloalkyl groups may be via any atom in the ring system. For the avoidance of doubt, optional substituents may also be other cyclic groups, which may be attached via a single carbon atom common to both rings, so forming a spiro-cycle. When used herein, “cycloalkylene” refers to a divalent cycloalkyl group. Particular cycloalkylene groups that may be mentioned include, for example, cyclobutylene (i.e. -(C4H6)-). Heterocycloalkyl groups that may be mentioned include non-aromatic monocyclic heterocycloalkyl groups in which at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom, e.g. sulphur, oxygen or, particularly, nitrogen), and in which the total number of atoms in the ring system is from three to ten. Such heterocycloalkyl groups may also be bridged. Further, such heterocycloalkyl groups may be saturated or unsaturated, e.g., containing one or more double bonds, forming a heterocycloalkenyl group. The point(s) of attachment of heterocycloalkyl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system. Heterocycloalkyl groups may also be in the N- or S- oxidised form (i.e. those heteroatoms may be substituted with one or two =O substituents, as appropriate). For the avoidance of doubt, optional substituents may also be other cyclic groups, which may be attached via a single carbon atom common to both rings, so forming a spiro-cycle. When used herein, “heterocycloalkylene” refers to a divalent heterocycloalkyl group. Particular heterocycloalkylene groups that may be mentioned include, for example, azetidinylene Aryl groups that may be mentioned include C6-10 aryl groups. Such groups may be monocyclic or bicyclic and have between 6 and 10 ring carbon atoms, in which at least one ring is aromatic. C6-10 aryl groups include phenyl, naphthyl and the like. The points of attachment of aryl groups may be via any atom of the ring system. However, when aryl groups are bicyclic, they are linked to the rest of the molecule via an aromatic ring. When used herein, “arylene” refers to a divalent aryl group. Particular arylene groups that may be mentioned include, for example, phenylene and naphthylene. The term “heteroaryl” when used herein refers to an aromatic group containing one or more heteroatom(s) (e.g. one to four heteroatoms) preferably selected from N, O and S. Heteroaryl groups include those which have from 5 to 10 members and may be monocyclic or bicyclic, provided that at least one of the rings is aromatic (so forming, for example, a mono- or bicyclic heteroaromatic group). The points of attachment of heteroaryl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system. Substituents on heteroaryl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. For the avoidance of doubt, optional substituents include those defined herein and also include =O substituents that may be attached to any non-aromatic rings of a bicyclic heteroaryl group (but, in an embodiment, =O substituents are not included). In the case where it is specified that the heteroaryl is bicyclic, then it may consist of a five, six- or seven-membered monocyclic ring (e.g. a monocyclic heteroaryl ring) fused with another a five-, six- or seven-membered ring (e.g. a monocyclic aryl or heteroaryl ring). Heteroaryl groups that may be mentioned include, for example, isoquinolinyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrahydroiso-quinolinyl (including 1,2,3,4-tetrahydroisoquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl), tetrahydroquinolinyl (including 1,2,3,4-tetrahydroquinolinyl and 5,6,7,8- tetrahydroquinolinyl) and the like. When used herein, “heteroarylene” refers to a divalent heteroaryl group. Particular heteroarylene groups that may be mentioned include, for example, pyridinylene. The term “halogen” includes fluorine (including its radioisotopes, e.g. fluorine-18 (i.e.18F)), chlorine, bromine, and iodine. For the avoidance of doubt, in cases in which the identity of two or more substituents in a compound of formula I may be the same, the actual identities of the respective substituents are not in any way interdependent. Where groups are referred to herein as being optionally substituted it is specifically contemplated that such optional substituents may be not present (i.e. references to such optional substituents may be removed), in which case the optionally substituted group may be referred to as being unsubstituted in certain embodiments. For the avoidance of doubt, in the instance where cyclic substituents (e.g. cycloalkyl or heterocycloalkyl groups) are present on groups (such as alkyl groups), then those cyclic substituents may be attached to the same carbon atom, so forming for example a spiro- cyclic group. For example, compounds of the invention where A, E and L together form a 4- to 6-membered cycloalkylene group (e.g. a cyclobutylene group) may be considered to be spiro-cyclic compounds. Compounds of formula I contain double bonds and may thus exist as E (entgegen) and Z (zusammen) geometric isomers about each individual double bond. All such isomers and mixtures thereof are included within the scope of the invention. Compounds of formula I may exist as regioisomers and may also exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention. Compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and / or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e. a ‘chiral pool’ method), by reaction of the appropriate starting material with a ‘chiral auxiliary’ which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution), for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person. All stereoisomers (including but not limited to diastereoisomers, enantiomers and atropisomers) and mixtures thereof (e.g. racemic mixtures) are included within the scope of the invention. In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds of the invention. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined. The present invention also embraces isotopically-labelled compounds of formula I which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature). All isotopes of any particular atom or element as specified herein are contemplated within the scope of the invention. Hence, the compounds of formula I also include deuterated compounds, i.e. compounds of formula I in which one or more hydrogen atoms are replaced by the hydrogen isotope deuterium. Thus, particular compounds of the invention that may be mentioned include compounds of formula I-M: wherein R1, R5, R6, R7a, R7b, A, E, L, and Q are as defined in respect of the compounds of formula I, or a pharmaceutically acceptable salt, solvate, or deuterated analogue thereof. In particular embodiments of the compound of formula I-M, Q is O. Additional isotopically-labelled compounds of formula I that may be mentioned include fluorine-18 (i.e.18F) compounds, i.e. compounds of formula I in which one or more fluorine atoms (where present) are replaced by the fluorine radioisotope fluorine-18. The compound may be referred to herein as compound 1–155 or Reference Compound 1. The compound may be referred to herein as CAS Registry Compound no. 2761566-98-5 or Test Compound 2. The skilled person will appreciate that compounds of the invention that are the subject of this invention include those that are stable. That is, compounds of the invention include those that are sufficiently robust to survive isolation from, e.g., a reaction mixture to a useful degree of purity. Throughout this specification, structures may or may not be presented with chemical names. Where any question arises as to nomenclature, the structure prevails. Where it is possible for the compound to exist as a tautomer (e.g. in an alternative resonance form) the depicted structure represents one of the possible tautomeric forms, wherein the actual tautomeric form(s) observed may vary depending on environmental factors such as solvent, temperature or pH. All tautomeric (and resonance) forms and mixtures thereof are included within the scope of the invention. Unless indicated otherwise, all technical and scientific terms used herein will have their common meaning as understood by one of ordinary skill in the art to which this invention pertains. For the avoidance of doubt, the skilled person will understand that references herein to particular aspects of the invention (such as the first aspect of the invention) will include references to all embodiments and particular features thereof, which embodiments and particular features may be taken in combination to form further embodiments and features of the invention. Particular compounds of the invention that may be mentioned are those where Q is O. For example, compounds of formula I-A: wherein R1, R2, R3, R4, R5, R6, R7a, R7b, A, E and L are as defined herein, or a pharmaceutically acceptable salt, solvate, or deuterated analogue thereof. As indicated herein, R1represents a naphthyl group substituted with one or more X groups or a 10-membered, bicyclic heteroaryl group, which is optionally substituted with one or more X groups. Accordingly, said naphthyl group is substituted by, for example, 1, 2, 3, 4, 5, 6 or 7 X groups. Said 10-membered, bicyclic heteroaryl group may be substituted by, for example, 0, 1, 2, 3, 4, 5, 6 or 7 X groups. It has been found that such compounds wherein R1represents a substituted naphthyl group or an optionally substituted 10 membered, bicyclic heteroaryl group display potent TG2 inhibition efficacy. It has also been found that structural variation is well tolerated at R1with good TG2 inhibition efficacy being found for a range of different structures at this position. As is evidenced by the data in the examples, it has also been found that compounds of the invention comprising particular substituted naphthyl groups or optionally substituted 10 membered, bicyclic heteroaryl groups at R1show surprisingly improved pharmacokinetic properties compared to known TG2 inhibitors. Particular compounds of the invention that may also be mentioned are those where R1 is selected from the group consisting of: wherein X1is selected from the group consisting of halogen (e.g. F,18F, Cl, Br or I), -OR9, -C(O)OR10, -C(O)N(R11a)R11b, -N(R13a)R13b, -CN, a C1-4alkyl group and a C3-6cycloalkyl group, which C1-4alkyl and C3-6cycloalkyl groups are optionally substituted by one or more halogen atoms (e.g. F,18F, Cl, Br or I); X1ais selected from the group consisting of hydrogen, halogen (e.g. F,18F, Cl, Br or I), -N(R8a)R8b, -OR9, -C(O)OR10, -C(O)N(R11a)R11b, -CN, a C1-4alkyl group and a C3-6cycloalkyl group, which C1-4alkyl and C3-6cycloalkyl groups are optionally substituted by one or more halogen (e.g. F,18F, Cl, Br or I) atoms, provided that X1ais not hydrogen when X3, X4, X5, X6and X7are all hydrogen; X1bis selected from the group consisting of hydrogen, halogen (e.g. F,18F, Cl, Br or I), -N(R8a)R8b, -OR9, -C(O)OR10, -C(O)N(R11a)R11b, -CN, a C1-4alkyl group, and a C3-6cycloalkyl group, which C1-4alkyl and C3-6cycloalkyl groups are optionally substituted by one or more halogen (e.g. F,18F, Cl, Br or I) atoms; X2, X3, X4, X5, X6and X7are each independently selected from the group consisting of hydrogen, halogen (e.g. F,18F, Cl, Br or I), -N(R8a)R8b, -OR9, -C(O)OR10, -C(O)N(R11a)R11b, -CN, a C1-4alkyl group and a C3-6cycloalkyl group, which C1-4alkyl and C3-6cycloalkyl groups are optionally substituted by one or more halogen (e.g. F,18F, Cl, Br or I) atoms; R8a, R8b, R9, R10, R11aand R11bare as defined herein; R13ais selected from the group consisting of C1-3alkyl, and C3-6cycloalkyl, which C1-3alkyl and C3-6cycloalkyl groups are optionally substituted by one or more deuterium atoms and / or halogen (e.g. F,18F, Cl, Br or I) atoms; and R13bis selected from the group consisting of C2-3alkyl, and C3-6cycloalkyl, which C2-3alkyl and C3-6cycloalkyl groups are optionally substituted by one or more deuterium atoms and / or halogen (e.g. F,18F, Cl, Br or I) atoms; or or R13aand R13b, together with the nitrogen atom to which they are bound form a 3- to 6-membered heterocycloalkyl group. In particular embodiments, R1is selected from the group consisting of: wherein X1is selected from the group consisting of halogen (e.g. F,18F, Cl, Br or I), -OR9, -C(O)OR10, -C(O)N(R11a)R11b, -N(R13a)R13b, a C1-4alkyl group and a C3-6cycloalkyl group, which C1-4alkyl and C3-6cycloalkyl groups are optionally substituted by one or more halogen atoms (e.g. F,18F, Cl, Br or I); X1ais selected from the group consisting of hydrogen, halogen (e.g. F,18F, Cl, Br or I), -N(R8a)R8b, -OR9, -C(O)OR10, -C(O)N(R11a)R11b, a C1-4alkyl group and a C3-6cycloalkyl group, which C1-4alkyl and C3-6cycloalkyl groups are optionally substituted by one or more halogen (e.g. F,18F, Cl, Br or I) atoms, provided that X1ais not hydrogen when X3, X4, X5, X6and X7are all hydrogen; X1bis selected from the group consisting of hydrogen, halogen (e.g. F,18F, Cl, Br or I), -N(R8a)R8b, -OR9, -C(O)OR10, -C(O)N(R11a)R11b, a C1-4alkyl group, and a C3-6cycloalkyl group, which C1-4alkyl and C3-6cycloalkyl groups are optionally substituted by one or more halogen (e.g. F,18F, Cl, Br or I) atoms; X2, X3, X4, X5, X6and X7are each independently selected from the group consisting of hydrogen, halogen (e.g. F,18F, Cl, Br or I), -N(R8a)R8b, -OR9, -C(O)OR10, -C(O)N(R11a)R11b, a C1-4alkyl group and a C3-6cycloalkyl group, which C1-4alkyl and C3-6cycloalkyl groups are optionally substituted by one or more halogen (e.g. F,18F, Cl, Br or I) atoms; and R8a, R8b, R9, R10, R11a, R11b, R13aand R13bare as defined herein. As provided herein, indicates a point of attachment to the compound of formula I. In particular embodiments, R1is selected from the group consisting of: wherein X1, X1a, X2, X3, X4, X5, X6and X7are as defined herein. In particular embodiments, R1is: wherein X1ais selected from the group consisting of halogen (e.g. F,18F, Cl, Br or I), -N(R8a)R8b, -OR9, -CN, a C1-4alkyl group and a C3-6cycloalkyl group, which C1-4alkyl and C3-6cycloalkyl groups are optionally substituted by one or more halogen (e.g. F,18F, Cl, Br or I) atoms; X3, X4, X5, X6and X7are each independently selected from the group consisting of hydrogen, halogen (e.g. F,18F, Cl, Br or I), -CN, and a C1-4alkyl group, which C1-4alkyl group is optionally substituted by one or more halogen (e.g. F,18F, Cl, Br or I) atoms; and R8a, R8band R9are as defined herein. In particular embodiments, R1is: wherein X1ais selected from the group consisting of halogen (e.g. F,18F, Cl, Br or I), -N(R8a)R8b, -OR9, a C1-4alkyl group and a C3-6cycloalkyl group, which C1-4alkyl and C3-6cycloalkyl groups are optionally substituted by one or more halogen (e.g. F,18F, Cl, Br or I) atoms; X3, X4, X5, X6and X7are each independently selected from the group consisting of hydrogen, halogen (e.g. F,18F, Cl, Br or I), and a C1-4alkyl group, which C1-4alkyl group is optionally substituted by one or more halogen (e.g. F,18F, Cl, Br or I) atoms; and R8a, R8band R9are as defined herein. In particular embodiments, R1is selected from the group consisting of: wherein X1ais selected from the group consisting of -OCHF2, -OCHF[18F], -OCHFCl, X3, X4, X5, X6and X7are each independently selected from the group consisting of hydrogen, F, -CN and methyl. In particular embodiments, R1is selected from the group consisting of: wherein X1ais selected from the group consisting of -OCHF2, -OCHF[18F], -OCHFCl, X3, X4, X5, X6and X7are each independently selected from the group consisting of hydrogen, F, and methyl. In particular embodiments, R1is selected from the group consisting of: wherein X1ais as defined herein; and X7is selected from the group consisting of F and -CN (particularly, F). In particular embodiments that may be mentioned, R1is: wherein X1ais as defined herein. For example, X1ais selected from the group consisting of -OCHF2, -OCHF[18F], -OCHFCl, -OCH2F, -OCF3, -OCF2Cl, -OCH3, In particular embodiments, X1ais selected from the group consisting of -OCHF2, -OCHF[18F], -OCHFCl, -OCH2F, -OCF3, -OCF2Cl, -OCH3, In certain embodiments, X1ais selected from the group consisting of -OCHF2, In other embodiments, X1ais selected from the group consisting of -OCHF2, In particular, X1ais selected from the group consisting of -OCHF2, -OCH3, -OCD3, For example, X1ais -OCHF2 or -OCH3. In other embodiments that may be mentioned, R1is: wherein X1aand X7are as defined herein. For example, X1ais selected from the group consisting of -OCHF2, -OCHF[18F], -OCHFCl, -OCH2F, -OCF3, -OCF2Cl, -OCH3, is selected from the group consisting of F and -CN (particularly, F). In particular embodiments, X1ais selected from the group consisting of -OCHF2, - OCHF[18F], -OCHFCl, -OCH2F, -OCF3, -OCF2Cl, -OCH3, In certain embodiments, X1ais selected from the group consisting of -OCHF2, is selected from the group consisting of F and -CN (particularly, F). In other embodiments, X1ais selected from the group consisting of -OCHF2, -OH, -N(CH3)2, selected from the group consisting of F and -CN (particularly, F). In particular, X1ais selected from the group consisting of -OCHF2, -OCH3, -OCD3, and -CH(CH3)2; and X7is selected from the group consisting of F and -CN (particularly, F). For example, X1ais -OCHF2or -OCH3; and X7is F. In alternative embodiments, R1is selected from the group consisting of: wherein X1bis selected from the group consisting of hydrogen, halogen (e.g. F,18F, Cl, Br or I), -N(R8a)R8b, -OR9, -CN, and a C1-4alkyl group, which C1-4alkyl group is optionally substituted by one or more halogen (e.g. F,18F, Cl, Br or I) atoms; and R8a, R8band R9are as defined herein. In particular embodiments, X1bis selected from the group consisting of hydrogen, halogen (e.g. F,18F, Cl, Br or I), -N(R8a)R8b, -OR9, and a C1-4alkyl group, which C1-4alkyl group is optionally substituted by one or more halogen (e.g. F,18F, Cl, Br or I) atoms; and R8a, R8band R9are as defined herein. In particular embodiments, X1bis selected from the group consisting of hydrogen, -OCHF2, -OCHF[18F], -OCHFCl, -OCH2F, -OCF3, -OCF2Cl, -OCH3, -OCH2CH3, -OCH(CH3)2, For example, X1bis selected from the group consisting of hydrogen, -OCHF2, In particular, X1bis selected from the group consisting of hydrogen, -OCHF2, -OCH3, and -OCH2CH3. For example, X1bis -OCHF2or -OCH3. In other alternative embodiments, R1is: wherein X1is selected from the group consisting of halogen (e.g. F,18F, Cl, Br or I), -N(R13a)R13b, -OR9, -CN, and a C1-4alkyl group, which C1-4alkyl group is optionally substituted by one or more halogen (e.g. F,18F, Cl, Br or I) atoms; and R9, R13aand R13bare as defined herein. For example: R9is selected from the group consisting of hydrogen, C1-3alkyl, and C3-6cycloalkyl, which C1-3alkyl and C3-6cycloalkyl groups are optionally substituted by one or more deuterium atoms and / or halogen (e.g. F,18F, Cl, Br or I) atoms; R13ais selected from the group consisting of C1-3alkyl, and C3-6cycloalkyl, which C1-3alkyl and C3-6cycloalkyl groups are optionally substituted by one or more deuterium atoms and / or halogen (e.g. F,18F, Cl, Br or I) atoms; and R13bis selected from the group consisting of C2-3 alkyl, and C3-6cycloalkyl, which C2-3 alkyl and C3-6cycloalkyl groups are optionally substituted by one or more deuterium atoms and / or halogen (e.g. F,18F, Cl, Br or I) atoms; or or R13aand R13b, together with the nitrogen atom to which they are bound form a 3- to 6-membered heterocycloalkyl group. In particular embodiments, X1is selected from the group consisting of halogen (e.g. F,18F, Cl, Br or I), -N(R13a)R13b, -OR9, and a C1-4alkyl group, which C1-4alkyl group is optionally substituted by one or more halogen (e.g. F,18F, Cl, Br or I) atoms; and R9, R13aand R13bare as defined herein. In particular embodiments, X1is selected from the group consisting of -OCHF2, and F. In certain embodiments, X1is selected from the group consisting of -OCHF2, and Cl. In particular, X1is selected from the group consisting of -OCHF2, -OCH3, -OCH2CH3, -OCH(CH3)2, -N(CH2CH3)CH3, and Cl. For example, X1is -OCHF2or -OCH3. In particular embodiments of the invention, R1is selected from the group consisting of:

[0002] In certain embodiments of the invention, R1is selected from the group consisting of: In certain embodiments of the invention, R1is selected from the group consisting of: Particular compounds of the invention that may be mentioned are those where R1is selected from the group consisting of:

[0003] In certain embodiments of the invention, R1is selected from the group consisting of: Other compounds of the invention that may be mentioned are those where: A is N; E is -C(O)- or a direct bond; and L is a C1-3alkylene, or L and R5together with the nitrogen atom to which R5is bound form an azetidine ring. In particular embodiments: A is N; and the -E-L- linker represents: . Thus, particular compounds of the invention that may be mentioned include compounds of formula I-B: wherein R1, R2, R3, R4, R5, R6, R7a, R7band Q are as defined in respect of the compounds of formula I, or a pharmaceutically acceptable salt, solvate, or deuterated analogue thereof. In particular embodiments of the compound of formula I-B, Q is O. In alternative embodiments: A is CH; E is a direct bond; and L represents direct bond, a C1-3alkylene, or L and R5together with the nitrogen atom to which R5is bound form an azetidine ring. For the avoidance of doubt, for those compounds of the invention where A is CH and E and L both represent a direct bond, A is bonded directly to the portion of the compound of formula I. Thus, particular compounds of the invention that may be mentioned include compounds of formula I-C, compounds of formula I-D or compounds of formula I-E: wherein R1, R2, R3, R4, R5(where present), R6, R7a, R7band Q are as defined in respect of the compounds of formula I, or a pharmaceutically acceptable salt, solvate, or deuterated analogue thereof. In particular embodiments of the compound of formula I- C, formula I-D or formula I-E, Q is O. In other alternative embodiments, A, E and L together form a cyclobutyl ring, so forming spiro-cyclic compounds of the invention. Thus, particular compounds of the invention that may be mentioned include compounds of formula I-F: wherein R1, R2, R3, R4, R5, R6, R7a, R7band Q are as defined in respect of the compounds of formula I, or a pharmaceutically acceptable salt, solvate, or deuterated analogue thereof. In particular embodiments of the compound of formula I-F, Q is O. Particular compounds of formula I-C, formula I-D, formula I-E, formula I-D, or formula I-F that may be mentioned are those where R1is selected from the group consisting of: wherein X1, X1a, X1b, X2, X3, X4, X5, X6and X7are as defined herein. Certain compounds of formula I-C, formula I-D, formula I-E, formula I-D, or formula I- F that may be mentioned are those where R1is: , wherein X1a, X3, X4, X5, X6and X7are as defined herein. More particularly, compounds of formula I-C, formula I-D, formula I-E, formula I-D, or formula I-F that may be mentioned are those where R1is selected from the group consisting of: wherein X1a, X3, X4, X5, X6and X7are as defined herein. Other compounds of formula I-C, formula I-D, formula I-E, formula I-D, or formula I-F that may be mentioned are those where R1is: , wherein X1, X2, X3, X4, X5, X6and X7are as defined herein. In particular, compounds wherein X2, X3, X4, X5, X6and X7are each hydrogen and X1is as defined herein. In particular embodiments, R2, R3and R4are each independently selected from the group consisting of hydrogen, methyl and ethyl; or R2and R4together with the carbon atoms to which they are bound form a 5-membered heterocycloalkyl group. In particular embodiments, R2, R3and R4are each hydrogen. As described herein, compounds of the first aspect of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and / or diastereoisomerism. For example, compounds of formula I where R2and R3are independently C1-3alkyl (e.g. methyl or ethyl). For the avoidance of doubt, when both R2and R3are C1-3alkyl groups, said C1-3alkyl groups may be the same or different. For example, the compound of formula I may be a compound of formula I-G, a compound of formula I-H, a compound of formula I-I, a compound of formula I-J, a compound of formula I-K, or a compound of formula I-L:

[0004] wherein R1, R2, R3, R4, R5, R6, R7a, R7b, A, E, L, and Q are as defined herein (i.e. as defined in the first aspect of the invention, including all embodiments and particular features, and combinations thereof), or a pharmaceutically acceptable salt, solvate, or deuterated analogue thereof. In particular embodiments of the compound of formula I- G, the compound of formula I-H, the compound of formula I-I, the compound of formula I-J, the compound of formula I-K, and the compound of formula I-L, Q is O. Particular compounds of the invention that may be mentioned are compounds where R3is methyl and R2and R4are each hydrogen and may show improved solubility properties. Thus, in particular embodiments, the compound of formula I may be a compound of formula I-N, a compound of formula I-O, or a compound of formula I-P (for example a compound of formula I-N): wherein R1, R5, R6, R7a, R7b, A, E, L, and Q are as defined herein (i.e. as defined in the first aspect of the invention, including all embodiments and particular features, and combinations thereof), or a pharmaceutically acceptable salt, solvate, or deuterated analogue thereof. In particular embodiments of the compound of formula I-N, the compound of formula I-O, and the compound of formula I-P, Q is O. Other compounds of the invention that may be mentioned are compounds where R4is methyl and R2and R3are each hydrogen and may show improved solubility properties. Thus, in particular embodiments, the compound of formula I may be a compound of formula I-Q, a compound of formula I-R, or a compound of formula I-S: wherein R1, R5, R6, R7a, R7b, A, E, L, and Q are as defined herein (i.e. as defined in the first aspect of the invention, including all embodiments and particular features, and combinations thereof), or a pharmaceutically acceptable salt, solvate, or deuterated analogue thereof. In particular embodiments of the compound of formula I-Q, the compound of formula I-R, and the compound of formula I-S, Q is O. In particular embodiments, R5is selected from the group consisting of hydrogen, methyl, ethyl and cyclopropyl, which methyl, ethyl and cyclopropyl groups are optionally substituted by one, two or three deuterium atoms. For example, R5is methyl, ethyl, or, preferably, hydrogen. In particular embodiments, R6is selected from the group consisting of hydrogen and halogen (e.g. F,18F, Cl, Br or I), C1-3alkyl (e.g. methyl, ethyl or propyl), which C1-3alkyl group is optionally substituted by one or more halogen (e.g. F,18F, Cl, Br or I) atoms (e.g. -CF3), -CH2N(R12)Ph and -CH2OCH2Ph. I ti l b di t R12i th l In particular embodiments, Ph is phenyl. Thus, in particular embodiments, R6is selected from the group consisting of hydrogen, In other embodiments, R6is hydrogen. In particular embodiments, R7aand R7bare each independently selected from the group consisting of hydrogen and deuterium. For example, R7aand R7bare each hydrogen. Particular compounds of the first aspect of the invention (including all embodiments and particular features, and combinations thereof) that may be mentioned are those where R6is hydrogen; and R7aand R7bare each independently selected from the group consisting of hydrogen and deuterium. Particular embodiments of the invention include compounds of formula I (including all embodiments and particular features, and combinations thereof) wherein: R6is hydrogen; R5is selected from the group consisting of hydrogen, methyl, ethyl, and cyclopropyl, which methyl, ethyl and cyclopropyl groups are optionally substituted by one, two or three deuterium atoms; and R7aand R7bare each independently selected from the group consisting of hydrogen and deuterium. Particular embodiments of the invention include compounds of formula I (including all embodiments and particular features, and combinations thereof) wherein: R2, R4and R6are each hydrogen; R3is selected from the group consisting of hydrogen and methyl; R5is selected from the group consisting of hydrogen, methyl, ethyl, and cyclopropyl, which methyl, ethyl and cyclopropyl groups are optionally substituted by one, two or three deuterium atoms; and R7aand R7bare each independently selected from the group consisting of hydrogen and deuterium. Particular embodiments of the invention include compounds of formula I (including all embodiments and particular features, and combinations thereof) wherein: R2, R3, R4and R6are each hydrogen; R5is selected from the group consisting of hydrogen, methyl, ethyl, and cyclopropyl, which methyl, ethyl and cyclopropyl groups are optionally substituted by one, two or three deuterium atoms; and R7aand R7bare each independently selected from the group consisting of hydrogen and deuterium. Particular embodiments of the invention include compounds of formula I (including all embodiments and particular features, and combinations thereof) wherein: R2, R4and R6are each hydrogen; R3is selected from the group consisting of hydrogen and methyl; R5is selected from the group consisting of hydrogen, methyl, ethyl, and cyclopropyl, which methyl, ethyl and cyclopropyl groups are optionally substituted by one, two or three deuterium atoms; and R7aand R7bare each independently selected from the group consisting of hydrogen and deuterium. In particular embodiments: R2, R3, R4and R6are each hydrogen; R5is selected from the group consisting of hydrogen, methyl, ethyl, -CD3, and cyclopropyl; and R7aand R7bare each independently selected from the group consisting of hydrogen and deuterium. In particular embodiments: R2, R4and R6are each hydrogen; R3is selected from the group consisting of hydrogen and methyl; R5is selected from the group consisting of hydrogen, methyl, ethyl, -CD3, and cyclopropyl; and R7aand R7bare each independently selected from the group consisting of hydrogen and deuterium. In a further particular embodiment: R2, R3, R4, R6, are R7aand R7beach hydrogen; and R5is selected from the group consisting of hydrogen, methyl, ethyl, -CD3, and cyclopropyl. In a further particular embodiment: R2, R4, R6, are R7aand R7beach hydrogen; R3is selected from the group consisting of hydrogen and methyl; and R5is selected from the group consisting of hydrogen, methyl, ethyl, -CD3, and cyclopropyl. In another embodiment: R2, R3, R4, R5and R6are each hydrogen; and R7aand R7bare each independently selected from the group consisting of hydrogen and deuterium. In another embodiment: R2, R4, R5and R6are each hydrogen; R3is selected from the group consisting of hydrogen and methyl; and R7aand R7bare each independently selected from the group consisting of hydrogen and deuterium. In another embodiment: R2, R4, R5and R6are each hydrogen; R3is methyl; and R7aand R7bare each independently selected from the group consisting of hydrogen and deuterium. Other embodiments of the invention include those where R2, R3, R4, R5, R6, R7aand R7bare each hydrogen. Other embodiments of the invention include those where R2, R4, R5, R6, R7aand R7bare each hydrogen and R3is methyl. Particularly preferred compounds of the invention (or pharmaceutically acceptable salts, solvates, or deuterated analogues thereof) are depicted in Table 1, below.

[0005] Table 1. Certain preferred compounds of the invention (or pharmaceutically acceptable salts, solvates, or deuterated analogues thereof) are depicted in Table 2, below.

[0006] Table 2. Preferred compounds of the invention (or pharmaceutically acceptable salts, solvates, or deuterated analogues thereof) are depicted in Table 3, below.

[0007] Table 3. Compounds of the invention as described herein may be prepared in accordance with techniques that are well known to those skilled in the art, such as those described in the examples provided hereinafter. Compounds of formula I may be obtained by analogy with the processes known in the literature, or by conventional synthetic procedures, in accordance with standard techniques, from available starting materials using appropriate reagents and reaction conditions. In this respect, the skilled person may refer to inter alia “Comprehensive Organic Synthesis” by B. M. Trost and I. Fleming, Pergamon Press, 1991. For example, there is provided a process for the preparation of a compound of the invention as hereinbefore defined, which process comprises reaction of a compound of formula II, with a compound of formula III, wherein Q, R1, R2, R3, R4, R5, R6, R7a, R7b, A, E and L are as defined hereinabove and G1is a suitable leaving group (such as a chlorine atom), in the presence of a suitable base (e.g. triethylamine) and a suitable solvent (e.g. dichloromethane) according to procedures know to the person skilled in the art. Similarly, compounds of formula II or formula III are either commercially available, are known in the literature, or may be obtained either by analogy with the processes described herein, or by conventional synthetic procedures, in accordance with standard techniques, from available starting materials using appropriate reagents and reaction conditions. For example, compounds of formula II may be prepared by reaction of a compound of formula IV, wherein R1, R2, R3, R4, R5, A, E and L are as defined hereinabove and P1is a suitable protecting group (such as a tert-butyloxycarbonyl group), with a suitable deprotecting agent (e.g. trifluoroacetic acid) in the presence of a suitable solvent (e.g. dichloromethane) according to procedures know to the person skilled in the art. The compound of formula IV (for example, those compounds where A is N, E is -C(O)- and L is C1-3alkyl (e.g. methyl), 4- to 6-membered cycloalkylene, 4- to 6-membered heterocycloalkylene, arylene or heteroarylene) may be prepared by reaction of a compound of formula V, with a compound of formula VI, wherein R1, R2, R3, R4, R5and P1is as defined hereinabove, with a suitable coupling agent (e.g. 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- oxid hexafluorophosphate) in the presence of a suitable base (e.g. N,N- diisopropylethylamine) and a suitable solvent (e.g. dichloromethane and dimethylformamide) according to procedures know to the person skilled in the art. The compound of formula V may be prepared by reaction of a compound of formula VII, wherein R1, R2, R3and R4are as defined hereinabove and P2is a suitable protecting group (such as a tert-butyloxycarbonyl group), with a suitable deprotecting agent (e.g. trifluoroacetic acid) in the presence of a suitable solvent (e.g. dichloromethane) according to procedures know to the person skilled in the art. The compound of formula VII may be prepared by reaction of a compound of formula VIII, with a compound of formula IX wherein Q, R1, R2, R3, R4and P2are as defined hereinabove and G2is a suitable leaving group (such as a chlorine atom), in the presence of a suitable base (e.g. triethylamine) and a suitable solvent (e.g. dichloromethane) according to procedures know to the person skilled in the art. Compounds of formulae VIII and IX may be commercially available, known in the literature, or may be obtained by conventional synthetic procedures, in accordance with standard techniques, from available starting materials using appropriate reagents and reaction conditions. Alternatively, compounds of formula VII where Q is O may be prepared by reaction of a compound of formula X, with a compound of formula IX as defined hereinabove, wherein R1is as defined hereinabove and M1is a suitable metal cation (such as a sodium cation), in the presence of a suitable halide reagent (e.g. iodine) and a suitable solvent (e.g. ethanol) according to procedures know to the person skilled in the art. Compounds of formula X may be commercially available, known in the literature, or may be obtained by conventional synthetic procedures, in accordance with standard techniques, from available starting materials using appropriate reagents and reaction conditions. For example, the compound of formula X may be prepared by reaction of a compound of formula XI, wherein R1is as defined hereinabove, with a suitable base (e.g. sodium ethoxide) in the presence of a suitable solvent (e.g. ethanol) according to procedures know to the person skilled in the art. Compounds of formula XI may be commercially available, known in the literature, or may be obtained by conventional synthetic procedures, in accordance with standard techniques, from available starting materials using appropriate reagents and reaction conditions. For example, the compound of formula XI may be prepared by reaction of a compound of formula XII, wherein R1is as defined hereinabove, with a suitable oxidizing agent (e.g. 3-chloroperbenzoic acid or Oxone®) in the presence of a suitable solvent (e.g. ethanol) according to procedures know to the person skilled in the art. Compounds of formula XII may be commercially available, known in the literature, or may be obtained by conventional synthetic procedures, in accordance with standard techniques, from available starting materials using appropriate reagents and reaction conditions. For example, the compound of formula XI may be prepared by reaction of a compound of formula XIII, with a compound of formula XIV, wherein R1is as defined hereinabove and J is a suitable halide atom (e.g. a Br atom), in the presence of a suitable palladium coupling reagent (e.g. tris(dibenzylideneacetone)dipalladium(0)), a suitable diphosphine ligand (e.g. xantphos), a suitable base (e.g. N,N-diisopropylethylamine) and a suitable solvent (e.g. toluene) according to procedures know to the person skilled in the art. Compounds of formulae XIII and XIV may be commercially available, known in the literature, or may be obtained by conventional synthetic procedures, in accordance with standard techniques, from available starting materials using appropriate reagents and reaction conditions. Alternatively, compounds of formula VII where R1is: and X1ais -OR9may be prepared by reaction of a compound of formula XV, wherein R2, R3, R4, X1a, X3, X4, X5, X6and X7are as defined hereinabove and P2is a suitable protecting group (such as a tert-butyloxycarbonyl group), with a suitable metal alkoxide (e.g. sodium methoxide) in the presence of a suitable solvent (e.g. methanol) according to procedures know to the person skilled in the art. Compounds of formula XV may be prepared in accordance with the procedures for preparing compounds of formula VII as described herein. Alternatively, the compound of formula IV (for example, those compounds where A is N or CH; E is a direct bond or -C(O)-; and L is a direct bond, a C1-3alkylene (e.g. methylene) or a 4- to 6-membered cycloalkylene, or L and R5together form a 4- to 6- membered heterocycloalkylene group (e.g. an azetidinylene group), or those compounds where A, E and L together form a 4- to 6-membered cycloalkylene group (e.g. a cyclobutylene group)) may be prepared by reaction of a compound of formula XVI, wherein R2, R3, R4, R5, A, E, L and P1are as defined hereinabove, with a compound of formula VIII as defined hereinabove, in the presence of a suitable base (e.g. triethylamine) and a suitable solvent (e.g. dichloromethane) according to procedures know to the person skilled in the art. In addition, there is provided a process for the preparation of a compound of the invention as hereinbefore defined (e.g. those compounds of the invention where A is N and E is -C(O)-), which process comprises reaction of a compound of formula V, with a compound of formula wherein Q, R1, R2, R3, R4, R5, R6, R7a, R7band L are as defined hereinabove and M is a suitable metal atom (such as a potassium atom), in the presence of a suitable base (e.g. N,N-diisopropylethylamine), with a compound of formula V as defined hereinabove, in the presence of a suitable coupling agent (e.g. (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), a suitable base (e.g. N,N-diisopropylethylamine) and a suitable solvent (e.g. N,N-dimethylformamide) according to procedures know to the person skilled in the art. Compounds of formula XVII may be commercially available, known in the literature, or may be obtained by conventional synthetic procedures, in accordance with standard techniques, from available starting materials using appropriate reagents and reaction conditions. For example, the compound of formula XVII may be prepared by reaction of a compound of formula wherein R5, R6, R7aand R7bare as defined hereinabove and R14is a C1-3alkyl (e.g. ethyl) group, with a suitable base (e.g. potassium hydroxide) in the presence of a suitable solvent (e.g. ethanol) according to procedures know to the person skilled in the art. Compounds of formula XVIII may be commercially available, known in the literature, or may be obtained by conventional synthetic procedures, in accordance with standard techniques, from available starting materials using appropriate reagents and reaction conditions. For example, the compound of formula XVIII may be prepared by reaction of a compound of formula XIX, with a compound of formula XX, wherein R5, R7a, R7b, R14are as defined hereinabove and G3is a suitable leaving group (such as a chlorine atom), in the presence of a suitable base (e.g. N,N- diisopropylethylamine) and a suitable solvent (e.g. tetrahydrofuran) according to procedures know to the person skilled in the art. Compounds of formulae XIX and XX may be commercially available, known in the literature, or may be obtained by conventional synthetic procedures, in accordance with standard techniques, from available starting materials using appropriate reagents and reaction conditions. Additionally, there is provided a process for the preparation of a compound of the invention as hereinbefore defined, which process comprises reaction a compound of formula XXI, wherein R2, R3, R4, R5, R6, R7a, R7b, A, E and L are as defined hereinabove, with a compound of formula VIII as defined hereinabove, in the presence of a suitable base (e.g. triethylamine) and a suitable solvent (e.g. dichloromethane) according to procedures know to the person skilled in the art. Compounds of formula XXI may be commercially available, known in the literature, or may be obtained by conventional synthetic procedures, in accordance with standard techniques, from available starting materials using appropriate reagents and reaction conditions. In addition, there is provided a process for the preparation of a compound of the invention where R6is hydrogen and R7aand R7bare both deuterium, which process comprises reaction of a compound of formula XXII, wherein Q, R1, R2, R3, R4, R5, A, E and L are as defined hereinabove and each R15is independently a C1-3alkyl (e.g. ethyl) group, with a suitable source of deuterium (e.g. paraformaldehyde-d2) in the presence of a suitable base (e.g. lithium hydroxide monohydrate and / or potassium hydroxide) and a suitable solvent (e.g. a mixture of tetrahydrofuran and water) according to procedures know to the person skilled in the art. The compound of formula XXII may be prepared by reaction of a compound of formula II as defined hereinabove with a compound of formula XXIII, wherein R15is as defined hereinabove, with a suitable coupling agent (e.g. 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) in the presence of a suitable base (e.g. N,N- diisopropylethylamine) and a suitable solvent (e.g. dichloromethane and dimethylformamide) according to procedures know to the person skilled in the art. Compounds of formula XXIII may be commercially available, known in the literature, or may be obtained by conventional synthetic procedures, in accordance with standard techniques, from available starting materials using appropriate reagents and reaction conditions. It will be appreciated by those skilled in the art that, in the processes described above and hereinafter, the functional groups of intermediate compounds may need to be protected by protecting groups. The protection and deprotection of functional groups may take place before or after the above-mentioned reactions. Protecting groups may be removed in accordance with techniques that are well known to those skilled in the art and as described hereinafter. For example, protected compounds / intermediates described herein may be converted chemically to unprotected compounds using standard deprotection techniques. The use of protecting groups is fully described in “Protective Groups in Organic Synthesis”, 3rd edition, T.W. Greene & P.G.M. Wutz, Wiley-Interscience (1999). Specific transformation steps that may be employed in order to form compounds of formula I therefore include deprotection steps, such as deprotection of an N-Boc protecting group by reaction in the presence of an acid, or, a hydroxy group protected as a silyl ether (e.g. a tert-butyl-dimethylsilyl protecting group) may be deprotected by reaction with an acid or a source of fluoride ions, e.g. by employing the reagent tetrabutylammonium fluoride (TBAF). Compounds of the invention may be isolated from their reaction mixtures and, if necessary, purified using conventional techniques as known to those skilled in the art. Thus, processes for preparation of compounds of the invention as described herein may include, as a final step, isolation and optionally purification of the compound of the invention. Pharmaceutical Formulations As indicated herein, the compounds of the invention are useful as therapeutic agents for treating a variety of medical disorders or conditions. Typically, compounds of the invention will be administered to a subject in need thereof in the form of a pharmaceutical formulation. According to a second aspect of the invention, there is provided a pharmaceutical formulation comprising the compound of formula I excluding proviso (b) (or a pharmaceutically acceptable salt, solvate, or deuterated analogue thereof). Such formulations are referred to herein as the formulations of the invention. All embodiments and particular features thereof described herein in respect of the first aspect of the invention are disclosed herein in respect of the third aspect of the invention. The pharmaceutical formulations of the second aspect of the invention may be prepared in accordance with standard and / or accepted pharmaceutical practice. The formulations of the second aspect of the invention will generally be provided as a mixture comprising the compound of the invention excluding proviso (b) (or a pharmaceutically acceptable salt, solvate, or deuterated analogue thereof) and one or more pharmaceutically acceptable excipients, carriers or diluents. The one or more pharmaceutically acceptable excipients, carriers or diluents may be selected with due regard to the intended route of administration in accordance with standard pharmaceutical practice. Such pharmaceutically acceptable excipients, carriers or diluents are preferably chemically inert to the active compound and preferably have no detrimental side effects or toxicity under the conditions of use. Suitable pharmaceutical formulations may be found in, for example, Remington The Science and Practice of Pharmacy, 19th ed., Mack Printing Company, Easton, Pennsylvania (1995). A brief review of methods of drug delivery may also be found in e.g. Langer, Science 249, 1527 (1990). Suitable pharmaceutical carriers are well known in the art of pharmacy. The carrier(s) must be “acceptable” in the sense of being compatible with the compound of the invention and not deleterious to the recipients thereof. Typically, the carriers will be water or saline which will be sterile and pyrogen free; however, other acceptable carriers may be used. Thus, “pharmaceutically acceptable carrier” and “pharmaceutically acceptable excipient” includes any compound(s) used in forming a part of the formulation that is intended to act merely as a carrier, i.e., not intended to have biological activity itself. The pharmaceutically acceptable carrier or excipient is generally safe, non-toxic, and neither biologically nor otherwise undesirable. A pharmaceutically acceptable carrier or excipient as used herein includes both one and more than one such carrier or excipient. The excipient may be one or more of carbohydrates, polymers, lipids and minerals. Examples of carbohydrates include lactose, sucrose, mannitol, and cyclodextrines, which are added to the composition, e.g. for facilitating lyophilisation. Examples of polymers are starch, cellulose ethers, cellulose carboxymethylcellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, ethylhydroxyethyl cellulose, alginates, carageenans, hyaluronic acid and derivatives thereof, polyacrylic acid, polysulphonate, polyethylene-glycol / polyethylene oxide, polyethyleneoxide / polypropylene oxide copolymers, polyvinyl-lalcohol / polyvinylacetate of different degree of hydrolysis, and polyvinylpyrrolidone, all of different molecular weight, which are added to the composition, e.g., for viscosity control, for achieving bioadhesion, or for protecting the lipid from chemical and proteolytic degradation. Examples of lipids are fatty acids, phospholipids, mono-, di-, and triglycerides, ceramides, sphingolipids and glycolipids, all of different acyl chain length and saturation, egg lecithin, soy lecithin, hydrogenated egg and soy lecithin, which are added to the composition for reasons similar to those for polymers. Examples of minerals are talc, magnesium oxide, zinc oxide and titanium oxide, which are added to the composition to obtain benefits such as reduction of liquid accumulation or advantageous pigment properties. The term “diluent” is intended to mean an aqueous or non-aqueous solution with the purpose of diluting the peptide in the pharmaceutical preparation. The diluent may be one or more of saline, water, polyethylene glycol, propylene glycol, ethanol or oils (such as safflower oil, corn oil, peanut oil, cottonseed oil or sesame oil). The diluent may also function as a buffer. The term “buffer” is intended to mean an aqueous solution containing an acid-base mixture with the purpose of stabilising pH. Examples of buffers are Trizma, Bicine, Tricine, MOPS, MOPSO, MOBS, Tris, Hepes, HEPBS, MES, phosphate, carbonate, acetate, citrate, glycolate, lactate, borate, ACES, ADA, tartrate, AMP, AMPD, AMPSO, BES, CABS, cacodylate, CHES, DIPSO, EPPS, ethanolamine, glycine, HEPPSO, imidazole, imidazolelactic acid, PIPES, SSC, SSPE, POPSO, TAPS, TABS, TAPSO and TES. The formulations according to the second aspect of the invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient (i.e. a compound according to the first aspect of the invention) with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product. Formulations in accordance with the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste. It will be appreciated by those skilled in the art that the compounds for oral administration should preferably be formulated so as to be protected in the gut and to permit bioadsorption. Preferred unit dosage formulations are those containing a daily dose or unit, daily sub- dose or an appropriate fraction thereof, of an active ingredient. Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. For treatment of diseases and conditions of the eye, the compound may be formulated in accordance with routine procedures as a pharmaceutical composition adapted for application to the eye. Thus, the pharmaceutical composition may be for topical ophthalmic use, for example aqueous eye drops, oily eye drops, eye ointments, eye lotions, ocuserts, hydrogel contact lenses, collagen shields and ophthalmic rods. Topical compositions for the eye will typically have a pH in the range of 4.5 to 8.0. The ophthalmic compositions must also be formulated to have osmotic values that are compatible with the aqueous humor of the eye and ophthalmic tissues. Such osmotic values will generally be in the range of from about 200 to about 400 milliosmoles per kilogram of water ("mOsm / kg"), but will preferably be about 300 mOsm / kg. In yet another embodiment, the compounds of the invention excluding proviso (b) can be delivered in a controlled release system. For example, a pump may be used (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989); the disclosures of which are incorporated by reference). In another embodiment, polymeric materials can be used (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, J., Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983); see also Levy et al., Science 228:190 (1985); During et al., Ann. Neurol. 25:351 (1989); Howard et al., J. Neurosurg. 71:105 (1989); the disclosures of which are incorporated by reference). It will be appreciated by persons skilled in the art that the formulations of the invention may comprise one or more additional active agents, such as anti-inflammatory agents, local anaesthetics and anti-biotic agents. The compounds of the invention excluding proviso (b) may be formulated at various concentrations, depending on the efficacy of the particular compound being used. Preferably, the composition comprises the compound at a concentration of from about 1 nM to about 1 M, for example from about 0.1 µM to about 1 mM, about 1 µM or about 100 µM, from about 5 µM to about 50 µM, from about 10 µM to about 50 µM, from about 20 µM to 40 µM or about 30 µM. For ex vivo and in vitro applications, compositions may comprise a lower concentration of a modified osteopontin polypeptide, for example of from about 0.0025 µM to about 1 µM. The term “about” as used herein when referring to a measurable value such as an amount of a compound, dose, time, temperature, and the like, refers to variations of 20%, 10%, 5%, 1%, 0.5%, or even 0.1% of the specified amount. It is contemplated that, at each instance, such terms may be replaced with the notation “±10%”, or the like (or by indicating a variance of a specific amount calculated based on the relevant value). It is also contemplated that, at each instance, such terms may be deleted. For the avoidance of doubt, the dose administered to a subject, particularly a human subject, in the context of the present invention should be sufficient to effect a therapeutic response in the subject over a reasonable timeframe. One skilled in the art will recognize that the selection of the exact dose and composition and the most appropriate delivery regimen will also be influenced by inter alia the pharmacological properties of the formulation, the nature and severity of the condition being treated, and the physical condition and mental acuity of the recipient, as well as the potency of the specific compound, the age, condition, body weight, sex and response of the subject to be treated, and the stage / severity of the disease. In any event, the medical practitioner, or other skilled person, will be able to determine routinely the actual dosage which will be most suitable for an individual subject. The above-mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention. Medical uses As indicated herein, the compounds of the invention are useful as pharmaceuticals. Compounds of the invention are useful because they possess pharmacological activity, and / or are metabolised in the body following oral or parenteral administration to form a compound that possesses pharmacological activity. Thus, according to a third aspect of the invention there is provided a compound of the invention excluding proviso (b), as hereinbefore defined (i.e. a compound as defined in the first aspect of the invention excluding proviso (b)), or a pharmaceutical formulation as defined in respect of the second aspect of the invention, for use in medicine. For the avoidance of doubt, references to compounds as defined in the first aspect of the invention include references to compounds of formula I (including all embodiments thereof) excluding proviso (b) and pharmaceutically acceptable salts, solvates, and deuterated analogues thereof. Compounds of the invention (i.e. a compound as defined in the first aspect of the invention) are inhibitors of transglutaminase enzymes, such as TG2 (i.e. tissue transglutaminase), as evidenced by the data in the examples. Eight transglutaminase enzymes are currently known (TG1-7 and factor XIII). By “transglutaminase” we include enzymes as defined in accordance with Enzyme Commission System of Classification 2.3.2.13. By the term “inhibitors of transglutaminase enzymes” (or “transglutaminase inhibitors”) we include any compound that inhibits, in part or in whole, the transamidating activity of a transglutaminase enzyme (preferably in vivo). In a preferred embodiment, the transglutaminase enzyme is TG2. Inhibition of the transamidating activity of TG2 also results in the inhibition, in part or in whole, of the enzyme’s GTP-binding activities. The transamidase activity of TG2 is inhibited by an inhibitor binding at the transamidase site, and GTP binding is blocked because inhibitor interaction at the transamidase site locks the protein in the extended / open conformation to disorganize / inactivate the GTP binding / GTPase site (Kerr et al. 2017; Seo et al. 2019). The transglutaminase enzyme, e.g. TG2, is preferably human. In one embodiment, the compounds of the invention are irreversible inhibitors of TG2. In one embodiment, the compounds of the invention are selective inhibitors of TG2. By “selective”, we mean that the compound inhibits TG2 (preferably human TG2) to a greater extent than it inhibits other transglutaminase enzymes, such as Factor XIII, TG1 and TG3. Advantageously, the compounds exhibit an IC50 for TG2 (preferably human TG2) which is at least one order of magnitude lower than its IC50 for other transglutaminase enzymes, such as Factor XIIIa, TG1 and TG3. Thus, the compounds of the invention, and formulations containing the same, may be particularly useful in treating a disorder or condition which is responsive to treatment with a transglutaminase inhibitor. Therefore, in a fourth aspect of the invention, there is provided a method of treating or preventing a disease or condition which is responsive to treatment with an inhibitor of a transglutaminase comprising administering a compound of the invention (or a formulation comprising said compound) to a subject (e.g. a human) in need thereof. Similarly, there is provided the use of a compound of the invention, or a formulation comprising said compound, in the manufacture of a medicament for the treatment or prevention of a disease or condition which is responsive to treatment with an inhibitor of a transglutaminase. In a further alternative fourth aspect of the invention, there is provided a compound of the invention, or a formulation comprising said compound, for use in the treatment or prevention of a disease or condition which is responsive to treatment with an inhibitor of a transglutaminase. For example, the disease or condition may be responsive to treatment with an inhibitor of TG2. In one embodiment, the disease or condition is responsive to treatment with an angiogenesis inhibitor. Thus, the compounds of the invention may be used to inhibit angiogenesis, especially pathological angiogenesis (i.e. the formulation of new vasculature associated with a disease or disorder; see Chung & Ferrera, 2011, Ann. Rev. Cell Dev. Biol. 27:563-584, the disclosures of which are incorporated by reference). By “inhibiting angiogenesis” we mean that administration of the compound is capable of reducing, at least in part, the formation of new blood vessels in vivo. Thus, the compound may inhibit angiogenesis in vivo by at least 10% compared to the level of angiogenesis in the absence of the compound, for example by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more. It will be appreciated that inhibition may require repeated (i.e. chronic) administration of the compound. In a further embodiment, the disease or condition is selected from the group consisting of fibrosis (such as cystic fibrosis, cardiac fibrosis, fibrosis of the kidney, liver fibrosis, and pulmonary fibrosis (e.g. idiopathic pulmonary fibrosis)), scarring, neurodegenerative diseases (such as Alzheimer’s disease, Huntington’s disease and Parkinson’s disease), autoimmune diseases (such as multiple sclerosis and coeliac disease), thrombosis, proliferative disorders (such as cancers), AIDS, psoriasis, inflammation (such as a chronic inflammatory disease, for example inflammatory bowel disease, e.g. Crohn's disease), pulmonary hypertension, and diseases or conditions associated with pathological angiogenesis. For example, the disease or condition may be a fibrosis. Particular fibrotic diseases that may be mentioned include cystic fibrosis, cardiac fibrosis, fibrosis of the kidney (e.g. chronic kidney disease (including chronic kidney disease associated with Alport syndrome), and diabetic nephropathy), liver fibrosis, and pulmonary fibrosis (e.g. idiopathic pulmonary fibrosis). In particular embodiments, the disease or condition is idiopathic pulmonary fibrosis or cardiac fibrosis, preferably, idiopathic pulmonary fibrosis. Alternatively, the disease or condition may be a neurodegenerative disease (such as Alzheimer’s disease, Huntington’s disease or Parkinson’s disease), In a further alternative embodiment, the disease or condition is an autoimmune disease (such as multiple sclerosis or coeliac disease). In one embodiment, the disease or condition is associated with pathological angiogenesis. By “disease or disorder associated with pathological angiogenesis”, we mean a disease or disorder in which abnormal or otherwise undesirable angiogenesis occurs, such that partial or complete inhibition of angiogenesis provides a beneficial effect to the patient (e.g. alleviates one or more symptoms and / or slows or prevents progression of the disease or disorder). For example, the disease or condition may be selected from the group consisting of hemangiomas, psoriasis, Kaposi's sarcoma, ocular neovascularisation, rheumatoid arthritis, endometriosis, atherosclerosis and tumour growth and metastasis. In one embodiment, the disease or condition may be a cancer. For example, the cancer may be associated with solid tumours (such as prostate cancer, breast cancer, lung cancer, colorectal cancer, melanomas, bladder cancer, brain / CNS cancer, cervical cancer, oesophageal cancer, gastric cancer, head / neck cancer, kidney cancer, liver cancer, lymphomas, ovarian cancer, pancreatic cancer, and sarcomas). In a further embodiment, the disease or condition is of the eye, such as a disease or disorder of the retina and / or choroid. Thus, the disease or condition may be a retinopathy. For example, the disease or condition may be selected from the group consisting of diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity, central retinal vein occlusion, sickle cell retinopathy, branch and central retinal vein occlusion and retinal trauma. Alternatively, the disease or condition may be selected from the group consisting of chronic inflammation or infection (e.g. HSV infection of the ocular surface resulting in blood vessel formation), corneal scarring, wound repair, pterygium and neovascular glaucoma (i.e. growth of blood vessels on iris and into anterior chamber angle; robeosis iridis). In a further embodiment, the disease or condition may be responsive to treatment with an inhibitor of factor XIII. For example, the disease or condition may be associated with the formation of fibrin clots. It will be appreciated that the compound should be administered in a therapeutically effective amount to inhibit transglutaminase activity (at least in part). A ‘therapeutically effective amount’, or ‘effective amount’, or ‘therapeutically effective’, as used herein, refers to that amount which provides a therapeutic effect for a given condition and administration regimen (via an inhibition of transglutaminase activity). This is a predetermined quantity of the compound of the invention calculated to produce a desired therapeutic effect in association with the required additive and diluent, i.e. a carrier or administration vehicle. Further, it is intended to mean an amount sufficient to reduce and most preferably prevent, a clinically significant deficit in the activity, function and response of the subject. Alternatively, a therapeutically effective amount is sufficient to cause an improvement in a clinically significant condition in a subject. As is appreciated by those skilled in the art, the amount of a compound may vary depending on its specific activity. Suitable dosage amounts may contain a predetermined quantity of active composition calculated to produce the desired therapeutic effect in association with the required diluent. In the methods and use for manufacture of compositions of the invention, a therapeutically effective amount of the active component is provided. A therapeutically effective amount can be determined by the ordinary skilled medical or veterinary worker based on patient characteristics, such as age, weight, sex, condition, complications, other diseases, etc., as is well known in the art. Suitable diseases and conditions for which the compounds may be used are identified above in relation to the fourth aspect of the invention. Preferably, the compound according to the first aspect of the invention or a pharmaceutical formulation according to the second aspect of the invention is administered in an amount sufficient to inhibit, at least in part, tTGase-mediated protein modification (i.e. cross-linking). More preferably, the compound or formulation is administered in an amount sufficient to inhibit tTGase-mediated protein cross-linking by at least 10%, for example, at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95%. Most preferably, the compound or formulation is administered in an amount sufficient to inhibit completely tTGase-mediated protein cross-linking. TGase-mediated protein modification may be measured by methods known in the art. For example, detection of the isodipeptide ^( ^-glutamyl)lysine in body fluids can be used as an indirect measure of the frequency of crosslinking in diseases which involve this protein cross link. Hence, a reduction of the isodipeptide in the body fluid provides an indirect measure of reduced protein crosslinking (see Nemes et al., 2002, Minerva Biotechnology 14, 183). Alternatively, a tissue biopsy may be taken and analysed, for example by ion exchange or reversed phase HPLC after proteolytic digestion of the material (Griffin & Wilson, 1984, Mol. Cell Biochem. 58:37- 49), or by staining biopsy sections and analysing by immunohistochemistry (Skill et al., 2001, 81:705-716). In a further embodiment, the compound or formulation is administered in an amount sufficient to inhibit, at least in part, angiogenesis. For example, the subject may have or be at risk of developing a disease or condition selected from the group consisting of fibrosis (such as cystic fibrosis, liver fibrosis, cardiac fibrosis, fibrosis of the kidney, and pulmonary fibrosis (e.g. idiopathic pulmonary fibrosis)), scarring, neurodegenerative diseases (such as Alzheimer’s disease, Huntington’s disease and Parkinson’s disease), autoimmune diseases (such as multiple sclerosis and coeliac disease), thrombosis, proliferative disorders (such as cancers), AIDS, psoriasis, inflammation (such as a chronic inflammatory disease, for example inflammatory bowel disease, e.g. Crohn's disease) and diseases or conditions associated with pathological angiogenesis. It will be appreciated by those skilled in the art that treatment may be prophylactic and / or therapeutic. For example, the compounds and formulations of the invention may be used to slow and / or to prevent the onset of a disease / disorder in the subject being treated. Alternatively, or in addition, the compounds and formulations of the invention may be used to reduce or eradicate the symptoms of a disease / disorder in the subject being treated. The skilled person will understand that such treatment or prevention will be performed in a subject in need thereof. The need of a subject for such treatment or prevention may be assessed by those skilled the art using routine techniques. In the context of the present invention, a “subject in need” of the compound of the invention includes a subject that is suffering a disease or condition which is responsive to treatment with an inhibitor of a transglutaminase. As used herein, the terms “disease” and “condition” (and, similarly, the terms disorder, illness, medical problem, and the like) may be used interchangeably. It will be further appreciated by those skilled in the art that the compound or formulation of the first and second aspects of the invention, respectively, may be administered by any route known or developed in the art. For example, the compound or formulation may be administered by parenteral injection (e.g. intravenous, subcutaneous or intramuscular), orally, topically or by inhalation. In one embodiment, the compound or formulation is administered systemically, for example intravenously. Alternatively, the compound or formulation is administered topically, e.g. at or near a target site where TGase-mediated protein modification is to be inhibited. Treatment with a compound or formulation according to the invention may consist of a single dose or a plurality of doses over a period of time. Advantageously, the compound or formulation is administered repeatedly. Compounds and formulations of the invention may also be administered by a surgically implanted device that releases the compound or formulation directly to the required site, for example in the vicinity of a solid tumour. It will be appreciated by persons skilled in the art that the compounds of the invention may be used for the treatment of any mammal. Preferably, the subject is human. Alternatively, the subject may be a dog, cat, horse, or other domestic or farm mammalian animal. A further aspect of the invention provides a method for preventing or treating rejection of a transplanted organ comprising contacting the organ with a compound according to the first aspect of the invention excluding proviso (b) or a formulation according to the second aspect of the invention. Thus, the invention provides the use of a compound according to the first aspect of the invention in the preparation of a medicament for preventing or treating rejection of a transplanted organ. In one embodiment, the organ is a heart, lung, kidney or liver. Thus, the organ may be a kidney. Kidneys that are to be transplanted often show some upregulation of TG2 and possibly other transglutaminases. Moreover, kidneys which are rejected after transplantation often exhibit excessive scarring and upregulation of transglutaminase activity and crosslinking (Abo-Zenah et al., 2001, J. Am. Soc. Nephrol. 12, 4454A). Such tissue degeneration and subsequent organ rejection may be prevented by treating the kidney (or other organ) with a transglutaminase inhibitor. It will be appreciated that the compound or formulation may be delivered before, during and / or after transplantation of the organ. Thus, in one embodiment, the organ is treated prior to transplantation, for example by perfusing and / or bathing with a solution containing a compound according to the first aspect of the invention. In an alternative embodiment, the organ is treated during and / or after transplantation into a patient. Advantageously, the compound or formulation is delivered at or near the site of the transplant, for example by local administration. Without wishing to be bound by theory, the compounds of the invention are thought to be potent inhibitors of transglutaminases, as evidenced by the data in the examples. In addition, it is believed that the compounds of the invention are relatively bioavailable. Compounds of the invention have therefore been found to possess surprisingly improved pharmacokinetic properties compared to known TG2 inhibitors. As indicated herein, the present invention embraces isotopically-labelled compounds of formula I. In particular, fluorine-18 (i.e.18F) compounds, i.e. compounds of formula I. Certain compounds of invention may therefore be useful for in vivo imaging to allow diagnosis of disease s or conditions with imaging techniques such as, but not limited to, positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). Particular diseases or conditions that may be mentioned are those which are responsive to treatment with an inhibitor of a transglutaminase (e.g. fibrosis, scarring, neurodegenerative diseases, autoimmune diseases, thrombosis, proliferative disorders, AIDS, psoriasis, inflammation and diseases or conditions associated with pathological angiogenesis). Isotopically-labelled compounds of the invention may also be used for measuring clinical efficacy of therapeutic agents useful for treating diseases or conditions which are responsive to treatment with an inhibitor of a transglutaminase. Certain compounds of formula I may also be suitable as precursors to isotopically- labelled compounds of formula I. Thus, there is provided the use of a compound of formula I (e.g. compounds of formula I where at least one of X1, X2, X3, X5, X6, X7, and X8are, if present, -OCHFCl or -OH), as a synthetic precursor in a process for the preparation of an isotopically-labelled compound. Preferably, the label is an18F atom. Compounds of the invention (and formulations thereof) may have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and / or have a better pharmacokinetic profile (e.g. higher oral bioavailability and / or lower clearance) than, and / or have other useful pharmacological, physical, or chemical properties over, other therapies known in the prior art, whether for use in the above-stated indications or otherwise. In particular, compounds of the invention may have the advantage that they are more efficacious and / or exhibit advantageous properties in vivo. Examples The present invention is explained in greater detail in the following non-limiting examples. The reaction schemes described below are intended to provide a general description of the methodology employed in the preparation of the compounds of the invention. The examples provided herein are offered to illustrate but not limit the compounds of the invention, as well as the preparation of such compounds and intermediates. All reagents were either purchased from commercial vendors or synthesised in accordance with known literature procedures unless otherwise described. Commercial reagents were used without further purification. Microwave reactions were conducted using a CEM Discover (200 W). Flash column chromatography was conducted using pre- packed Biotage® Sfar silica (High Capacity Duo 20 µm) cartridges or flash chromatography. Ion exchange chromatography was performed using Isolute® SCX-2 cartridges. Biotage® phase separators were used to separate the organic from the aqueous layer during work up. These are referred to as phase separators. A reaction may be carried out in the presence of a suitable solvent or diluent or of mixture thereof in a manner known to those skilled in the art of organic synthesis. A reaction may also be carried out, if needed, in the presence of an acid or a base, with cooling or heating, for example in a temperature range from about -30 °C to about 150 °C. In some embodiments, a reaction is carried out in a temperature range from about 0 °C to about 100 °C, and more particularly, in a temperature range from room temperature to about 80 °C, in an open or closed reaction vessel and / or in the atmosphere of an inert gas, for example nitrogen. Abbreviations Abbreviations as used herein will be known to those skilled in the art. In particular, the following abbreviations may be used herein. a: apparent aq.: aqueous Boc: tert-butyloxycarbonyl br: broad CDCl3: Deutero-chloroform Cpd #: Compound number CV: column volume d: doublet dd: doublet of doublets DCM: dichloromethane DIPEA: N,N-diisopropylethylamine DMF: N,N-dimethylformamide DMSO-d6: Dimethyl sulfoxide-d6ESI: electrospray ionisation EtOAc: ethyl acetate EtOH: ethanol Et2O: Diethyl ether h: hour(s) HATU: N-[(Dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3- yloxy)methylidene]-N-methylmethylaminium hexafluorophosphate HPLC: high-performance liquid chromatography HPLC-MS: high-performance liquid chromatography-mass spectrometry Int.: Intermediate J: coupling constant LC-MS: liquid chromatography-mass spectrometry m: multiplet MC: methyl cellulose MeCN: acetonitrile MeOH: methanol min: minute(s) m / z: mass / charge ratio NH3: ammonia NMR: nuclear magnetic resonance PS: polymer supported q: quartet quant: quantitative RT: room temperature Rt: retention time s: singlet satd.: saturated SCX-2: strong cation exchange, Si-propylsulfonic acid t: triplet td: triplet of doublets THF: tetrahydrofuran TFA: trifluoroacetic acid Analytical Methods Several compounds were purified by reversed phase preparative HPLC-MS: Mass- directed purification by preparative LC-MS using a preparative C-18 column (Phenomenex Luna C18 (2), 250 x 21.2 mm, 5 μm or Waters Exbridge OBD C18, 250 x 19 mm, 5 μm). Analysis of products and intermediates has been carried out using reversed phase analytical HPLC-MS using the parameters set out below. HPLC Analytical Methods: Method A: AnalpH2_MeCN_2MIN: ACQUITY UPLC BEH C181.7 μm, 50 x 2.1 mm; A = water + 0.1% formic acid; B = MeCN; 45 °C; %B: 0.0 min 5% 0.6 mL / min, 0.05 min 5% 0.6 mL / min, 1.6 min 95% 0.6 mL / min, 2.25 min 95% 0.75 mL / min, 2.26 min 5% 0.6 mL / min, 2.6 min 5% 0.6 mL / min. Method B: AnalpH9_MeCN_2MIN: ACQUITY UPLC BEH C181.7 μm, 50 x 2.1 mm; A = 10mM ammonium bicarbonate; B = MeCN; 45 °C; %B: 0.0 min 5% 0.6 mL / min, 0.05 min 5% 0.6 mL / min, 1.6 min 95% 0.6 mL / min, 2.25 min 95% 0.75 mL / min, 2.26 min 5% 0.6 mL / min, 2.6 min 5% 0.6 mL / min. Method C: AnalpH2_MeOH_4MIN: Phenomenex Luna C18 (2) 3 μm, 50 x 4.6 mm; A = water + 0.1% formic acid; B = MeOH + 0.1% formic acid; 45 °C; %B: 0.0 min 5%, 1.0 min 37.5%, 3.0 min 95%, 3.5 min 95%,3.51 min 5%, 4.0 min 5%; 2.25 mL / min. Method D: AnalpH2_MeOH_4min: Waters Sunfire C183.5 μm, 50 x 4.6 mm; A = water + 0.1% formic acid; B = MeOH; 45 °C; %B: 0.0 min 5%, 1.0 min 37.5%, 3.0 min 95%, 3.5 min 95%,3.51 min 5%, 4.0 min 5%; 2.25 mL / min. Method E: QC_AnalpH2_MeCN_8MIN: ACQUITY UPLC CSH C181.7 μm, 100 x 2.1 mm; A = water + 0.1% formic acid; B = MeCN; 45 °C; %B: 0.0 min 5% 0.35 mL / min, 0.05 min 5% 0.35 mL / min, 5 min 95% 0.35 mL / min, 6.5 min 95% 0.35 mL / min, 6.6 min 5% 0.35 mL / min, 9 min 5% 0.35 mL / min. Method F: AnalpH2_MeCN_QC: Phenomenex Gemini C18 5 μm, 150 x 4.6 mm; A = water + 0.1% formic acid; B = MeCN + 0.1% formic acid; 40 °C; %B: 0.0 min 5%, 0.5 min 5%, 7.5 min 95%, 10.0 min 95%, 10.1 min 5%, 13.0 min 5%; 1.5 mL / min. Method G: AnalpH2_MeOH_QC_V1: Phenomenex Gemini NX C18 (2) 5 μm, 150 x 4.6 mm; A = water + 0.1% formic acid; B = MeOH + 0.1% formic acid; 40 °C; %B: 0 min 5% 1.5 mL / min, 0.5 min 5% 1.5 mL / min, 7.5 min 95% 1.5 mL / min, 10 min 95% 1.5 mL / min, 10.10 min 5% 1.5 mL / min,13.0 min 5% 1.5 mL / min. NMR Spectra NMR: Spectra are obtained on either a Jeol ECS 400MHz or Bruker Avance 400MHz spectrometer. Spectra are measured at 294K (unless otherwise stated) and chemical shifts (δ-values) are reported in parts per million (ppm). Coupling constants (J) are reported in Hertz (Hz), spectra splitting pattern are designated as singlet (s), doublet (d), triplet (t), quadruplet (q), multiplet or more overlapping signals (m), broad signal (br); solvent is given in parentheses.

[0008] GENERAL PROCEDURES Preparation of acrylamides via coupling of sulfonyl chlorides with amines Several examples of formula (Ex) were synthesised according to Route A as detailed in Scheme 1: Synthesis of Intermediates in accordance with literature methods Intermediates A1 to A4 were synthesised in accordance to literature methods, as indicated in Table 4 below. Table 4: Literature methods for preparing compounds A1-A4. Preparation of Key acrylamide intermediates The following acrylamide intermediate (A7) was prepared from glycine ester hydrochloride (A5) in 2 steps as detailed in Scheme 2: Scheme 2: Synthesis of potassium acryloyl glycinate (A7) Step To a stirred suspension of glycinethylester hydrochloride (A5) (1.00 g, 7.17 mmol) in anhydrous THF (9 mL), was added DIPEA (2.49 mL, 14.3 mmol) at 0 °C and the resulting mixture was stirred for 15 min. Acryloyl chloride (464 µL, 5.74 mmol) was added and the temperature of the reaction mixture was slowly warmed from 0 °C to 45 °C then heated for 1 h. Subsequently, the reaction was cooled to RT, washed with water (50 mL) and extracted with EtOAc (2 x 50 mL). The organic phase was then washed with brine (50 mL), dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by silica gel column chromatography using 40-50 % EtOAc in n-hexane to afford ethyl acryloyl glycinate (A6) (600 mg, 67 %) as a pale yellow oil.1H NMR (400 MHz, CDCl3): δ 6.32 (dd, J = 17.0, 1.4 Hz, 1H), 6.16 (dd, J = 17.0, 10.2 Hz, 1H), 5.69 (dd, J = 10.2, 1.4 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 4.12 (d, J = 5.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H). Step To a stirred solution of ethyl acryloyl glycinate (A6) (585 mg, 3.72 mmol) in EtOH (2.3 mL) at 0 °C was added potassium hydroxide (313 mg, 5.60 mmol). The reaction mixture was stirred for 2 h at 0 °C. After completion of the reaction, the solvent was evaporated in vacuo and the residue was washed with Et2O (2 x 10 mL). The solid was then filtered, washed again with Et2O (2 x 10 mL) and dried to afford compound potassium acryloyl glycinate (A7) (443 mg, 71 %) as a white solid. The compound was used without further purification.^1H NMR (400 MHz, DMSO-d6): δ 7.44 (s, 1H) 6.39 (dd, J = 17.1, 10.2 Hz, 1H), 6.00 (dd, J = 17.1, 2.3 Hz, 1H), 5.48 (dd, J = 10.2, 2.3 Hz, 1H), 3.33 (d, J = 4.6 Hz, 2H). The acrylamide intermediate (A10) was prepared from the piperazine intermediate (A8) in 2 steps as detailed in Scheme 3: Scheme 3: Synthesis of N-(2-oxo-2-(piperazin-1-yl)ethyl)acrylamide trifluoroacetate salt (A10) Step Tert-butyl 4-glycylpiperazine-1-carboxylate (A8) (973 mg, 4.00 mmol) and DIPEA (0.75 mL, 4.4 mmol) were suspended in dry THF (20 mL). Acryloyl chloride (0.35 mL, 4.2 mmol) was added at 0 °C. The reaction mixture was allowed to warm to RT and stirred for 14 h. The solvent was removed and the crude residue was purified by silica gel column chromatography using 100 % EtOAc to afford tert-butyl 4- (acryloylglycyl)piperazine-1-carboxylate (A9) (459 mg, 39 %) as a white solid.1H NMR (400 MHz, CDCl3) δ 6.77 (broad s, 1H), 6.32 (ddd, J = 17.0, 3.1, 1.6 Hz, 1H), 6.20 (ddd, J = 17.1, 10.1, 1.0 Hz, 1H), 5.69 (ddd, J = 10.1, 3.9, 1.6 Hz, 1H), 4.15 (dd, J = 4.2, 1.4 Hz, 2H), 3.66 – 3.59 (overlapping m, 2H), 3.51 – 3.37 (overlapping m, 6H), 1.47 (d, J = 2.6 Hz, 9H). Step 10: Synthesis of N-(2-oxo-2-(piperazin-1-yl)ethyl)acrylamide trifluoroacetate salt (A10): TFA (1.04 mL, 13.5 mmol) was added dropwise to a solution of tert-butyl 4- (acryloylglycyl)piperazine-1-carboxylate (A9) (400 mg, 1.35 mmol) in DCM (10 mL). The resulting mixture was stirred at RT for 3 h after which the solvent was removed to afford N-(2-oxo-2-(piperazin-1-yl)ethyl)acrylamide trifluoroacetate salt (A10) (419 mg, 99 %) as an orange oil. The compound was used directly in the next step without any further purification. l intermediates Sodium carbonate (15.4 g, 115 mmol) was added to a stirred suspension of 5- bromoisoquinolin-1-ol (A11) (6.00 g, 41.4 mmol) in toluene (80 mL) under nitrogen. The resulting mixture was heated at 100 °C for 1 h then cooled to RT, after which simultaneous addition of trimethylsilyl fluorosulfonyldifluoroacetate (16.3 mL, 82.8 mmol) and chlorodifluoroacetic acid (9.31 mL, 82.8 mmol) was carried out. The resulting reaction mixture was heated at 110 °C for 8 h then cooled to RT, concentrated, diluted with EtOAc (80 mL) and washed with water (50 mL), followed by brine (50 mL). The separated organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography using 2 % EtOAc in n- hexane to afford 5-bromo-1-(difluoromethoxy)isoquinoline (A12) (5.60 g, 76 %) as an off-white solid. LC-MS (Method A). Rt2.00 min, (ESI+) m / z 274.0, 276.0 [M+H]+;1H NMR (400 MHz, CDCl3) δ 8.25 (dt, J = 8.3, 1.0 Hz, 1H), 8.11 (dd, J = 6.1, 1.4 Hz, 1H), 8.01 (dt, J = 7.6, 1.2 Hz, 1H), 7.78 (dt, J = 5.9, 1.2 Hz, 1H), 7.70 (t, J = 72.4 Hz, 1H), 7.61 (d, J = 72.4 Hz, 1H), 7.51 – 7.45 (m, 1H);19F NMR (376 MHz, CDCl3) δ -89.4 (d, J = 72.2 Hz). The following 7-fluoroisoquinoline compound was prepared from (A18) in 5 steps from commercially available nitro-substituted compound (A13): Scheme 4 Step 11: Synthesis of 7-fluoro-5-nitro-1H-isochromen-1-one (A14): A mixture of 1-(5-fluoro-2-methyl-3-nitrophenyl)ethan-1-one (A13) (4.60 g, 21.6 mmol) and N,N-dimethylformamide dimethyl acetal (8.60 mL, 64.7 mmol) in N,N- dimethylformamide (20 mL) was heated at 110 °C for 16 h. The reaction mixture was then cooled to RT, poured into water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography using 0-100 % EtOAc in iso-hexane to afford 7-fluoro-5-nitro-1H-isochromen-1-one (A14) (2.70 g, 60 %) as a pale-yellow solid. LC-MS (Method A). Rt1.51 min, (ESI-) m / z 274.0, 182.1 [M-H2O-H]- or (ESI-) m / z 208.1 [M-H2O-H]-. Step 12: A mixture of 7-fluoro-5-nitro-1H-isochromen-1-one (A14) (2.34 g, 11.2 mmol) and NH3 in MeOH solution (25 mL, 175 mmol, 7.0 M) was heated at 60 °C in as sealed tube for 6 h. The reaction mixture was cooled in an ice bath, the resulting precipitate was collected by filtration and washed with cold MeOH (20 mL). The crude solid was purified by silica gel column chromatography using 0-100 % EtOAc in iso-hexane to afford 7- fluoro-5-nitroisoquinoline-1(2H)-one (A15) (1.40 g, 60 %) as a yellow solid. LC-MS (Method A). Rt1.35 min, (ESI+) m / z 209.1 [M+H]+. Step 13: Phosphorus oxychloride (8.90 mL, 95.1 mmol) was added to 7-fluoro-5-nitro-2H- isoquinolin-1-one (A15) (1.65 g, 7.93 mmol) and the mixture was heated at 100 °C for 2 h. The reaction mixture was cooled and slowly poured into ice water. The pH was then carefully adjusted to 8 with aqueous ammonia and then extracted with EtOAc (2 x 50 mL). The organic layer was separated, dried (Na2SO4), concentrated to give a residue which was purified by silica gel column chromatography using 0-100 % EtOAc in iso- hexane to afford 1-chloro-7-fluoro-5-nitro-isoquinoline (A16) (1.66 g, 92 %) as a yellow solid. LC-MS (Method A). Rt 1.74 min, (ESI+) m / z 227.1, 229.1 [M+H]+. Step A solution of 1-chloro-7-fluoro-5-nitroisoquinoline (A16) (1.56 g, 6.88 mmol) in acetic acid (15 mL) was heated at 75 °C, iron (1.92 g, 34.4 mmol) was slowly added, and the mixture was heated at 75 °C for 1 h. The reaction mixture was cooled to RT, filtered and the filtrate was poured into water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The crude solid was purified by column chromatography using 0-100 % EtOAc in iso-hexane to afford 1-chloro-7-fluoroisoquinolin-5-amine (A17) (606 mg, 45 %) as an off-white solid. LC-MS (Method A). Rt 1.57 min, (ESI+) m / z 197.1, 199.1 [M+H]+. Step To a solution of 1-chloro-7-fluoroisoquinolin-5-amine (A17) (525 mg, 2.67 mmol) in MeCN (70 mL) was added isopentyl nitrite (0.72 mL, 5.34 mmol), copper (I) bromide (383 mg, 2.67 mmol) and copper (II) bromide (596 mg, 2.67 mmol). The resulting mixture was stirred at RT for 2 h. The reaction mixture was concentrated, and the residue was twice purified by silica gel column chromatography using 0-100 % EtOAc followed by 0-7 % EtOAc in iso-hexane to afford 5-bromo-1-chloro-7- fluoroisoquinoline (A18) (265 mg, 38 %) as an off-white solid. LC-MS (Method A). Rt 1.96 min, (ESI+) m / z 259.9, 261.9 [M+H]+. Palladium catalysed methoxylation A mixture of palladium (II) acetate (9.4 mg, 0.0420 mmol), 2-[di(tert- butyl)phosphino]-2',4',6'-triisopropyl-1,1'-biphenyl (tBu X-phos) (36 mg, 0.0839 mmol), cesium carbonate (684 mg, 2.10 mmol) in toluene (2.0 mL) was degassed for 5 min then heated in the microwave at 80 °C for 5 min (200 W, CEM). The reaction mixture was cooled and a solution of 1-chloro-4-fluoroisoquinoline (A19) (254 mg, 1.40 mmol) in MeOH (2.0 mL) was added. The resulting mixture was degassed for a further 5 min then heated in the microwave at 90 °C for 30 min. The reaction mixture was filtered through a celite cartridge (2.5 g) and washed with MeOH (3 CV). The combined organics were concentrated in vacuo and the crude residue was purified by silica gel column chromatography using gradient eluent 0-10 % MeOH in DCM to afford 4-fluoro- 1-methoxyisoquinoline (A20) (226 mg, 91 %) as an off-white solid. LC-MS (Method A). Rt1.89 min, (ESI+) m / z 178.2 [M+H]+. The sulfonyl chloride (A2) was prepared from intermediate (A20) in accordance to literature procedure detailed in Table 4. Chlorosulfonic acid, 97% (10 mL, 150 mmol) was added slowly to 1-methylisoquinoline (A21) (1.00 g, 6.98 mmol) at 0 °C with stirring under nitrogen. The resultant mixture was heated at 130 °C for 16 h. The mixture was cooled to ambient temperature and poured slowly onto ice. The mixture was then extracted with DCM (300 mL). The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo to afford 1- methylisoquinoline-5-sulfonyl chloride (A22) (200 mg, 12 %) as pale yellow oil. LC-MS (Method C). Rt 0.31, 0.63 min, (ESI+) m / z 224.1 [M + H2O - Cl]+. To a stirred solution of 5-bromo-3,4-dihydronaphthalen-1(2H)-one (A23) (3.00 g, 13.3 mmol), 1,3-bis(2,4,6-trimethylphenyl)imidazolinium chloride (90.0 mg, 0.266 mmol), sodium carbonate (353 mg, 3.33 mmol) and trimethylsilyl fluorosulfonyldifluoroacetate (3.14 mL, 16.0 mmol) were added and the resulting mixture was heated at 80 °C for 2 h. The mixture was cooled to RT, diluted with toluene (10 mL) and 2,3-dichloro-5,6- dicyano-1,4-benzoquinone [DDQ] (6.05 g, 26.7 mmol) was added to the mixture containing (A24). The resulting mixture was heated at 80 °C for 8 h then cooled to RT and concentrated in vacuo. The crude residue was diluted with EtOAc (10 mL), filtered through celite and the filtrate concentrated in vacuo. The crude residue was purified by silica gel column chromatography using gradient eluent 1 - 5 % EtOAc in n-hexane to afford 1-bromo-5-(difluoromethoxy)naphthalene (A25) (1.00 g, 27 %) as an off-white solid.1H NMR (400 MHz, CDCl3) δ 8.18 (dt, J = 8.5, 1.0 Hz, 1H), 8.12 (dt, J = 8.7, 0.9 Hz, 1H), 7.85 (dd, J = 7.4, 1.1 Hz, 1H), 7.54 (dd, J = 8.6, 7.7 Hz, 1H), 7.40 (dd, J = 8.5, 7.4 Hz, 1H), 7.26 (m, 1H), 6.67 (t, J = 73.7 Hz, 1H). Synthesis of 5-bromo-8-fluoroisoquinoline 2-oxide (A77) 3-Chloroperbenzoic acid (6.63 g, 28.8 mmol) was added to a stirred solution of 5- bromo-8-fluoroisoquinoline (A76) (3.72 g, 16.5 mmol) in DCM (40 mL) at 0oC. The resulting stirred reaction mixture was warmed to RT. After 5 h the reaction mixture was quenched with satd. aq. sodium sulfite (20 mL) and the organic layer separated. The aq. layer was extracted with DCM (2 x 20 mL) and the combined organic extracts dried (Na2SO4) and concentrated in vacuo to afford 5-bromo-8-fluoroisoquinoline 2-oxide (A77) (3.85 g, 97%) as a yellow oil, which was used without further purification. LC-MS (Method A). Rt1.28 min, (ESI+) m / z 241.8, 243.8 [M+H]+. Synthesis of 5-bromo-8-fluoroisoquinolin-1-ol (A78) A solution of 5-bromo-8-fluoroisoquinoline 2-oxide (A77) was stirred in acetic anhydride (35 mL) at 120oC for 16 h. On cooling to RT the reaction mixture was concentrated in vacuo to afford a dark brown solid. The crude product was purified by repeat (3x) silica gel column chromatography using gradient eluent of 0-100 % EtOAc in iso-hexane to afford 5-bromo-8-fluoroisoquinolin-1-ol (A78) (2.2 g, 57%) as a pale yellow solid. LC- MS (Method A). Rt 1.41 min, (ESI+) m / z 241.8, 243.8 [M+H]+. Synthesis of 5-bromo-1-(difluoromethoxy)-8-fluoroisoquinoline (A79) Sodium carbonate (920 mg, 8.68 mmol) was added to a stirred suspension of 5-bromo- 8-fluoroisoquinolin-1-ol (A78) (700 mg, 2.89 mmol) in toluene (10 mL) under nitrogen. The resulting mixture was heated at 70 °C for 1 h then cooled to RT, after which simultaneous addition of trimethylsilyl fluorosulfonyldifluoroacetate (1.5 mL, 7.23 mmol) and chlorodifluoroacetic acid (245 ^L, 2.89 mmol) was carried out. The resulting reaction mixture was heated at 110 °C. After 18 h a further aliquot of trimethylsilyl fluorosulfonyldifluoroacetate (292 ^L, 1.45 mmol) was added and the heating continued for a further 3 h. On cooling to RT the reaction mixture was concentrated, diluted with EtOAc (80 mL) and washed with water (50 mL), followed by brine (50 mL). The separated organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography, using initially gradient eluent of 0-100 % EtOAc in iso-hexane, followed by a second purification using 0-10% EtOAc in iso-hexane to afford of 5-bromo-1-(difluoromethoxy)-8-fluoroisoquinoline (A79) (130 mg, 15 %) as an off-white solid. LC-MS (Method A). Rt1.94 min, (ESI+) m / z 291.7, 293.8 [M+H]+. Example of S 1a: of sulfonamides via coupling of h chlorides Synthesis of tert-butyl 4-[(1-chloroisoquinolin-5-yl)sulfonyl]piperazine-1-carboxylate (B1): To a stirred suspension of 1-chloroisoquinoline-5-sulfonyl chloride (A1) (531 mg, 2.03 mmol) in DCM (10 mL) was added triethylamine (770 µL, 5.52 mmol) and 1-Boc- piperazine (A26) (350 mg, 1.84 mmol) at 0 °C and the resulting mixture stirred at RT for 1 h. The reaction mixture was then diluted with DCM (20 mL) and washed with ice cold water (20 mL), followed by brine (20 mL). The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo. The resulting crude residue was purified by column chromatography using gradient eluent 0 - 60 % EtOAc in iso-hexane to afford tert-butyl 4-[(1-chloroisoquinolin-5-yl)sulfonyl]piperazine-1-carboxylate (B1) (759 mg, quant.) as a white solid. LC-MS (Method A). Rt 1.91 min, (ESI+) m / z 312.0, 314.1 [M-Boc+H]+. The sulfonamides (B2 to B10) detailed in Table 5 was prepared using analogous procedure to compound (B1) from the corresponding sulfonyl chloride intermediates with reaction times ranging from 30 min – 18 h: a synthesis from commercially available reagent (amines);b d with MeOH. Table 5: Boc-protected intermediate examples Example of S 1a: of sulfonamides via coupling of h chlorides Synthesis of tert-butyl 3-(4-((1-methoxyisoquinolin-5-yl)sulfonyl)piperazin-1- To a stirred solution of 1-methoxyisoquinoline-5-sulfonyl chloride (A3) (50 mg, 0.194 mmol) in THF (2 mL) at RT was added 1-(tert-butoxycarbonyl)-3-(1- piperazinyl)azetidine (A27) (56.0 mg, 0.233 mmol) and triethylamine (68 µL, 0.485 mmol) and the mixture stirred for 2 h. The solvent was evaporated in vacuo and the residue partitioned between DCM (20 mL) and 10% w / v aq. citric acid solution (20 mL). The aq. phase was washed with DCM (20 mL), then dried (MgSO4), filtered and the solvent evaporated in vacuo, to afford tert-butyl 3-(4-((1-methoxyisoquinolin-5- yl)sulfonyl)piperazin-1-yl)azetidine-1-carboxylate (B11) (80 mg, 89 %), as an orange gum in sufficient purity to continue. LC-MS (Method A). Rt 1.93 min, (ESI+) m / z 463.2 [M+H]+. The sulfonamides (B12 → B15) detailed in Table 6 was prepared using analogous procedure to compound (B11) from the corresponding sulfonyl chloride intermediates with reaction times ranging from 2 h – 18 h:

[0009] then stirred RT for 15 h;dDIPEA used instead of Et3N, 50 °C, 3 h. Table 6: Boc protected intermediate examples Formation of chloroisoquinoline via N-oxide intermediate 3-Chloroperbenzoic acid (281 mg, 1.22 mmol) was added to a stirred solution 5-bromo- 3-methylisoquinoline (A28) (247 mg, 1.11 mmol) in chloroform (5 mL) at RT and the mixture was stirred for 1 h. The resulting reaction mixture was diluted with DCM (5 mL), stirred for 5 min with satd. aq. sodium sulfite (10 mL) then washed with satd. aq. sodium bicarbonate (10 mL). The organic layer was further washed with brine (20 mL), dried (Na2SO4) and concentrated in vacuo. The crude compound was twice purified by silica gel column chromatography using 0-100 % EtOAc / iso-hexane followed by 0-10 % MeOH / DCM to afford 5-bromo-3-methylisoquinoline 2-oxide (A29) (244 mg, 92 %) as a white solid. LC-MS (Method A). Rt1.36 min, (ESI+) m / z 238.1, 240.0 [M+H]+. Phosphorus oxychloride (273 µL, 2.92 mmol) was added to a suspension of 5-bromo-3- methylisoquinoline 2-oxide (A29) (240 mg, 1.01 mmol) in chloroform (4 mL), and the mixture was refluxed for 3 h, then allowed to cool to RT. The reaction solution was neutralised with an aqueous sodium hydroxide solution with cooling in an ice bath and partitioned into organic and aq. layers. The organic layer was washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude compound was triturated with chloroform and Et2O and the resulting solid dried under vacuum to afford 5-bromo-1-chloro-3-methylisoquinoline (A30) (259 mg, quant.) as an off-white solid. LC-MS (Method A). Rt2.02 min, (ESI+) m / z 256.0, 258.0 [M+H]+. Synthesis of methoxy-substituted heteroaryl intermediates via displacement reactions Synthesis of 5-bromo-7-fluoro-1-methoxyisoquinoline (A31) To a stirred suspension of 5-bromo-1-chloro-7-fluoroisoquinoline (A18) (200 mg, 0.768 mmol) in MeOH (3.5 mL) was added sodium methoxide (62 mg, 1.15 mmol). The resulting mixture was heated at 70 °C for 28 h. The reaction mixture was then allowed to cool to RT, poured into water (10 mL) then extracted with EtOAc (2 x 10 mL). The combined organics were washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The resulting crude residue was purified by silica gel column chromatography using gradient eluent of 0 - 10 % EtOAc in n-hexane to afford 5-bromo- 7-fluoro-1-methoxy-isoquinoline (A31) (168 mg, 85 %) as a white solid. LC-MS (Method A. Rt 2.06 min, (ESI+) m / z 256.0, 258.0 [M+H]+. The following methoxy-isoquinoline intermediates (A32 → A36) depicted in Table 7 were synthesised from the corresponding chloro intermediates in an analogous procedure to (A31) with reaction times ranging between 18- 72 h unless otherwise stated:

[0010] Table 7: Methoxy-substituted heteroaryl examples Preparation of sulfonamides via oxidative coupling of sulfinates The compounds detailed in Scheme 5 were prepared via the oxidative coupling of sodium sulfinates with the amine. The sulfinates were prepared in 3 steps from the corresponding bromo intermediates: Scheme 5: Synthesis of sulfonamides via coupling of sulfinates Example of Step 16: Preparation of sulfides A mixture of 5-bromo-1-(difluoromethoxy)isoquinoline (A12) (5.60 g, 20.4 mmol), 4,5- bis(diphenylphospheno)-9,9-dimethylxanthene (Xantphos) (591 mg, 1.02 mmol), tris(dibenzylideneacetone) dipalladium (0) (467 mg, 0.51 mmol) and DIPEA (6.60 mL, 40.9 mmol) in toluene (60 mL) was degassed with nitrogen for 5 min after which methyl 3-mercaptopropionate (2.71 mL, 24.5 mmol) was added. The resulting mixture was heated at 70 °C for 6 h. On cooling, the reaction mixture was filtered through celite, and the pad of celite washed with 10% MeOH / DCM (20 mL). The resulting mixture was concentrated in vacuo to give a crude residue which was purified by silica gel column chromatography using gradient eluent of 30-50 % EtOAc in n-hexane to give methyl 3-((1-(difluoromethoxy)isoquinolin-5-yl)thio)propanoate (A37) (6.00 g, 93 %) as an off-white solid. LC-MS (Method A). Rt1.92 min, (ESI+) m / z 314.1 [M+H]+;1H NMR (400 MHz, CDCl3) δ 8.19 (dd, J = 8.3, 1.1 Hz, 1H), 8.08 (dd, J = 6.2, 1.3 Hz, 1H), 7.93 (dt, J = 6.1, 1.4 Hz, 1H), 7.83 (dt, J = 7.2, 1.5 Hz, 1H), 7.69 (t, J = 72.6 Hz, 1H), 7.56 (ddd, J = 8.3, 7.3, 1.6 Hz, 1H), 3.67 (s, 4H), 3.22 (t, J = 7.3 Hz, 3H), 2.63 (t, J = 7.3 Hz, 3H);19F NMR (376 MHz, CDCl3) δ -89.4 (d, J = 72.2 Hz). The following sulfides (A38 → A46 and A80) depicted in Table 8 were prepared using analogous procedure to compound (A37) with reaction times ranging between 6 – 14 h:

[0011] CEM) at 90 – 100 °C for 1 h -8.5 h. Table 8: Sulfide examples Example of Step 17a: Preparation of sulfones using oxone Synthesis of methyl 3-((1-(difluoromethoxy)isoquinolin-5-yl)sulfonyl)propanoate (A47): Oxone (2.70 g, 8.8 mmol) was added to a stirred solution of methyl 3-((1- (difluoromethoxy)isoquinolin-5-yl)thio)propanoate (A37) (1.00 g, 3.52 mmol) in MeCN / H2O (30 mL) at RT. The resulting mixture was stirred for 12 h. The reaction mixture was diluted with EtOAc (100 mL). The organic layer was separated, washed with brine (30 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography eluting with 30-50 % n- hexane in EtOAc to afford methyl 3-((1-(difluoromethoxy)isoquinolin-5- yl)sulfonyl)propanoate (A47) (1.10 g, 98 %) as a yellow solid. LC-MS (Method A). Rt 1.69 min, (ESI+) m / z 346.1 [M+H]+;1H NMR (400 MHz, CDCl3) δ 8.64 (dt, J = 8.4, 1.1 Hz, 1H), 8.52 (dd, J = 7.4, 1.3 Hz, 1H), 8.30 (dd, J = 6.2, 0.9 Hz, 1H), 8.25 (d, J = 6.2 Hz, 1H), 7.80 (dd, J = 8.4, 7.4 Hz, 1H), 7.73 (t, J = 72.1 Hz, 1H), 3.61 (s, 3H), 3.59 (t, J = 7.6 Hz, 2H), 2.79 (t, J = 7.5 Hz, 2H);19F NMR (376 MHz, CDCl3) δ -89.7 (d, J = 72.2 Hz). The following sulfones (A48 → A50) depicted in Table 9 was prepared using analogous procedure to compound (A47) with reaction times ranging between 12 – 18 h:

[0012] Table 9: Sulfone examples Example of Step 17b: Oxidation of sulfone using 3-chloroperbenzoic acid Synthesis of methyl 3-((1-methoxy-3-methylisoquinolin-5-yl)sulfonyl)propanoate (A51): 3-Chloroperbenzoic acid (213 mg, 0.927 mmol) was added to a stirred solution of methyl 3-((1-methoxy-3-methylisoquinolin-5-yl)thio)propanoate (A38) (108 mg, 0.371 mmol) in DCM (5 mL) at 0 °C. The resulting reaction mixture was warmed to RT then stirred for 2 h. The reaction mixture was quenched with satd. aq. sodium sulfite (20 mL) and the layers were separated. The aq. layer was extracted with DCM (2 x 20 mL) and organic layer was combined then washed with satd. aq. sodium bicarbonate (30 mL), dried (Na2SO4), filtered and concentrated in vacuo to give crude residue which was purified by silica gel column chromatography, eluting with 0-50 % EtOAc in iso- hexane to afford methyl 3-((1-methoxy-3-methylisoquinolin-5-yl)sulfonyl)propanoate (A51) (93.7 mg, 78 %) as an off-white solid. LC-MS (Method A). Rt 1.61 min, (ESI+) m / z 327.9 [M+H]+. The following sulfones (A52 → A54 and A81) depicted in Table 10 were prepared using analogous procedure to compound (A51) with reaction times ranging between 1 – 24 h: Example of Step 17c: Oxidation of sulfone using KMNO4 and FeCl3 Synthesis of methyl 3-(quinolin-4-ylsulfonyl)propanoate (A55): Methyl 3-(quinolin-4-ylthio)propanoate (A43) (124 mg, 0.50 mmol) was dissolved in MeCN (5 mL), iron (III) chloride (24 mg, 0.15 mmol), and then potassium permanganate (237 mg, 1.50 mmol) was added and the reaction was stirred at RT for 90 min. Water (10 mL) and EtOAc (10 mL) were added, and the mixture was filtered through a plug of celite, the organic layer was separated and filtered through a plug of silica. The solvent was removed under evaporation to afford methyl 3-(quinolin-4- ylsulfonyl)propanoate (A55) (109 mg, 78 %) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 9.05 (d, J = 4.6 Hz, 1H), 8.58 (d, J = 8.7 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 4.4 Hz, 1H), 7.81-7.64 (overlapping m, 2H), 3.57 (t, J = 7.5 Hz, 2H), 2.70 (t, J = 7.5 Hz, 2H). The following sulfone (A56) depicted in Table 11 was prepared using analogous procedure to compound (A55): Table 11: Sulfone example Example of Step 18: Preparation of sodium sulfinates Synthesis of sodium 1-(difluoromethoxy)isoquinoline-5-sulfinate (A57) To a solution of methyl 3-((1-(difluoromethoxy)isoquinolin-5-yl)sulfonyl)propanoate (A47) (6.00 g, 3.32 mmol) in THF (50 mL) at 0 °C was slowly added a solution of sodium ethoxide in EtOH (7.76 mL, 20.9 mmol). The resulting mixture was stirred at RT for 3 h then concentrated in vacuo. The resulting solid was triturated with Et2O collected by filtration, washed with Et2O (10 mL), then dried under vacuum to afford sodium 1- (difluoromethoxy)isoquinoline-5-sulfinate (A57) (4.90 g, quant.) as a pale yellow solid. The compound was used in the subsequent step without further purification.1H NMR (400 MHz, DMSO-d6) δ 8.46 (dd, J = 6.0, 0.9 Hz, 1H), 8.10 - 8.06 (overlapping m, 3H), 7.95 (t, J = 72.5 Hz, 1H), 7.73 (dd, J = 8.3, 7.0 Hz, 1H);19F NMR (376 MHz, DMSO-d6) δ -87.7 (d, J = 72.2 Hz). The following sulfinates (A58 → A67 and A82) depicted in Table 12 were prepared using analogous procedure to compound (A57) with reaction times ranging between 1 h – 18 h:

[0013] compounds;h21% NaOEt solution was used as the source for the base;tNaOtBu was used as the source for the base with THF as the solvent. Table 12: Sodium sulfinate examples Step 20: Synthesis of 1-(difluoromethoxy)isoquinoline-5-sulfonyl chloride (A68) Methyl 3-((1-(difluoromethoxy)isoquinolin-5-yl)sulfonyl)propanoate (A47) (200 mg, 0.58 mmol) was suspended in sodium methoxide (0.5 M, 4.0 mL, 2.0 mmol) and stirred at RT for 2h. The solvent was removed in vacuo, and the intermediate sulfinate salt isolated through co-distillation with Et2O (3 x 20 mL). The residue was then resuspended in DCM (5 mL) at 0oC and N-chlorosuccinimide (120 mg, 0.899 mmol) was then added to the mixture. The mixture was stirred at RT for 2 h, then the resulting mixture was quenched with brine (5 mL) and the organic layer collected through a phase separator. The aqueous layer was washed with DCM (2 x 10 mL), the combined organic layers dried (MgSO4), filtered and concentrated in vacuo to afford 1- (difluoromethoxy)isoquinoline-5-sulfonyl chloride (A68) (154 mg, 90 %) as a pale yellow glassy solid. LC-MS (Method A). Rt 1.94 min, (ESI+) m / z 274.0 [M-Cl+OH]+. To a stirred solution of 1-(difluoromethoxy)isoquinoline-5-sulfonyl chloride (A68) (75 mg, 0.26 mmol) in THF (3.0 mL) at RT was added tert-butyl (1R,4R)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (60.8 mg, 0.31 mmol) and triethylamine (0.08 mL, 0.54 mmol) and the mixture stirred for 3 h at RT. The solvent was evaporated in vacuo and the residue partitioned between EtOAc (25 mL) and satd. aq. sodium bicarbonate solution (25 mL). The organic phase was washed with 10% w / v citric acid solution (25 mL) and brine (25 mL), then dried (MgSO4), filtered and the solvent evaporated in vacuo. The crude product was purified by column chromatography eluting with 5 - 95 % EtOAc in iso-hexane to afford tert-butyl (1R,4R)-5-((1- (difluoromethoxy)isoquinolin-5-yl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2- carboxylate (B16) (110 mg, 91 %) as a white solid in sufficient purity to continue. LC-MS (Method A). Rt 1.91 min, (ESI+) m / z 473.6 [M+H]+. The following sulfonamide (B17) depicted in Table 13 was also prepared in an analogous procedure to the compound (B16): Table 13: Boc-protected corresponding (S, S) (B17) enantiomer Example of Step 19a: Oxidative coupling of sodium sulfinates with Boc-protected intermediate using iodine Synthesis of tert-butyl 4-((1-(difluoromethoxy)isoquinolin-5-yl)sulfonyl)piperazine-1- carboxylate (B18) Iodine (4.50 g, 17.8 mmol) was added to a stirred solution of sodium 1- (difluoromethoxy)isoquinoline-5-sulfinate (A57) (5.00 g, 17.8 mmol) in EtOH (30 mL), followed by the addition of 1-Boc-piperazine (3.98 g, 21.3 mmol). The resulting mixture was stirred at RT for 12 h. The reaction mixture was quenched by adding crushed ice and solid sodium thiosulfate until a clear solution was observed. The mixture was extracted with EtOAc (50 mL), washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography using 30-40 % n-hexane in EtOAc to afford tert-butyl 4-((1- (difluoromethoxy)isoquinolin-5-yl)sulfonyl)piperazine-1-carboxylate (B18) (4.60 g, 58 %) as an off-white solid. LC-MS (Method A). Rt 1.99 min, (ESI+) m / z 388.1 [M-tBu+H]+;1H NMR (400 MHz, CDCl3) δ 8.58 (dt, J = 8.4, 1.1 Hz, 1H), 8.41 (dd, J = 7.5, 1.3 Hz, 1H), 8.30 (dd, J = 6.3, 0.9 Hz, 1H), 8.18 (d, J = 6.3 Hz, 1H), 7.75 (dd, J = 8.4, 7.5 Hz, 1H), 7.71 (d, J = 72.2 Hz, 1H), 3.49 – 3.44 (m, 4H), 4.14-3.10 (overlapping m, 4H);19F NMR (376 MHz, CDCl3) δ -89.7 (d, J = 72.2 Hz). The following Boc protected compounds (B19 → B21) depicted in Table 14 were also prepared using an analogous procedure to compound (B18):

[0014] Table 14: Boc-protected intermediate examples

[0015] Example of Step 19b: Oxidative coupling of sodium sulfinates with Boc-protected intermediate using phenyltrimethylammonium tribromide. Synthesis of tert-butyl 4-((1-methoxy-3-methylisoquinolin-5-yl)sulfonyl)piperazine-1- To a stirred solution of sodium 1-methoxy-3-methylisoquinoline-5-sulfinate (A58) (68 mg, 0.262 mmol) and 1-Boc-piperazine (A26) (48.85 mg, 0.26mmol) in THF (5.0 mL) in a flask, which was opened to the air, was added phenyltrimethylammonium tribromide (PTAT) (99 mg, 0.262 mmol). The resulting mixture was stirred at RT for 16 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic extracts was then washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residual crude material was then subjected to silica gel column chromatography over silica gel, eluting with 0-50% EtOAc in iso-hexane to afford tert-butyl 4-((1-methoxy-3-methylisoquinolin-5- yl)sulfonyl)piperazine-1-carboxylate (B22) (71.2 mg, 64 %) as an off-white solid. LC- MS (Method A). Rt2.03 min, (ESI+) m / z 422.1 [M+H]+. The following Boc-protected compounds (B23 → B26 and B54 → B57) detailed in Table 15 were prepared using analogous procedure to compound (B23) with reactions times ranging between 30 min – 18 h:

[0016] Example of Step 19c: Oxidative coupling of sodium sulfinates with Boc-protected intermediate using NBS Sodium quinoline-4-sulfinate (A63) (108 mg, 0.5 mmol) was suspended in THF (5 mL), then 1-Boc-piperazine (A26) (186 mg, 1.00 mmol) was added and the reaction mixture was cooled to 0°C. NBS (128 mg, 1.00 mmol) was added slowly, and the reaction was allowed to warm to RT and stirred for 14 h. The solvent was removed, and the product was purified by silica gel column chromatography, eluting with 60 % EtOAc in n-hexane to afford tert-butyl 4-(quinolin-4-ylsulfonyl)piperazine-1-carboxylate (B27) (124 mg, 65 %) as an off-white solid.1H NMR (400 MHz, CDCl3) δ 9.09 (d, J = 4.5 Hz, 1H), 8.71 (ddd, J = 8.6, 1.4, 0.6 Hz, 1H), 8.25 (ddd, J = 8.5, 1.3, 0.6 Hz, 1H), 7.92 (d, J = 4.4 Hz, 1H), 7.85 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.72 (ddd, J = 8.4, 6.9, 1.3 Hz, 1H), 3.46 – 3.50 (overlapping m, 4H), 3.14 - 3.19 (overlapping m, 4H), 1.39 (s, 9H). The following Boc-protected compound (B28) detailed in Table 16 was prepared using analogous procedure to compound (B27): Table 16: Boc-protected intermediate examples To a suspension of 5-hydroxynaphtalene-1-sulfonic acid (A69) (100 mg, 0.44 mmol) in EtOH (3 mL), under argon atmosphere, sodium ethoxide (90 mg, 1.32 mmol) was added at RT and the reaction was stirred for 15 mins at the same temperature. Iodomethane (106 µL, 1.32 mmol) was added and the reaction mixture was stirred at 60 °C overnight. The reaction mixture was cooled to RT, then acidified with 1 M HCl and the aq. phase was washed with DCM (10 mL) and evaporated under reduced pressure to afford sodium 5-ethoxynaphthalene-1-sulfonate (A70) (110 mg, 91% yield) as a dark yellow solid.1H NMR (400 MHz, DMSO-d6): δ 8.38 (d, J = 8.7 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.96 (dd, J = 7.1, 1.2 Hz, 1H), 7.39 (q, J = 8.4 Hz, 2H), 6.93 (d, J = 7.6 Hz, 1H), 4.20 (q, J = 7.0 Hz, 2H), 1.46 (t, J = 6.9 Hz, 3H). The following sulfonate (A71) depicted in Table 17 was prepared from the corresponding alcohol using procedure to compound (A70): Table 17: Sulfonate examples Synthesis of tert-butyl 4-((5-methoxynaphthalen-1-yl)sulfonyl)piperazine-1- carboxylate (B29) To a stirred solution of sodium 5-methoxynaphthalene-1-sulfonate (A4) (1.00 g, 3.84 mmol) in thionyl chloride (2.80 mL, 38.4 mmol) was added a drop of anhydrous DMF and the resulting mixture was heated at reflux (80 °C) under argon for 2 h. The mixture was allowed to cool to ambient temperature and the thionyl chloride was concentrated in vacuo. The residue was dissolved in anhydrous THF (15 mL) and a solution of DIPEA (2.1 mL, 6.45 mmol) and 1-Boc-piperazine (A26) (930 mg, 4.99 mmol) in anhydrous THF (5 mL) was added dropwise at 0 °C to the solution and the resultant mixture was warmed to RT, then stirred for 4 h. The reaction mixture was diluted with EtOAc (30 mL) and the solution was washed with satd. aq. sodium bicarbonate solution (15 mL) and brine (15 mL) respectively and dried (MgSO4), concentrated and purified by silica gel column chromatography eluting with 30 -50 % EtOAc / pet. ether 40 – 60 °C to afford tert-butyl 4-((5-methoxynaphthalen-1-yl)sulfonyl)piperazine-1-carboxylate (B29) (210 mg, 13 %) as a brown solid.1H NMR (400 MHz, CDCl3) δ 8.59 (dt, J = 8.5, 1.1 Hz, 1H), 8.30 (dt, J = 8.9, 0.8 Hz, 1H), 8.23 (dd, J = 7.4, 1.3 Hz, 1H), 7.51 - 7.58 (overlapping m, 2H), 6.93 (dd, J = 7.8, 0.8 Hz, 1H), 4.03 (s, 3H), 3.41 – 3.46 (m, 4H), 3.11 - 3.15 (overlapping m, 4H), 1.39 (s, 9H). The following Boc-protected compounds (B30, B31) detailed in Table 18 were prepared using analogous procedure to compound (B29) using a reaction time of 12 h:

[0017] Table 18: Boc protected examples Synthesis of methoxy intermediate via displacement reactions Synthesis of tert-butyl 4-((1-methoxyisoquinolin-5-yl)sulfonyl)piperazine-1- carboxylate (B32): To a stirred suspension of tert-butyl 4-((1-chloroisoquinolin-5-yl)sulfonyl)piperazine-1- carboxylate (B1) (764 mg, 1.85 mmol) in MeOH (20 mL) was added sodium methoxide (301 mg, 5.56 mmol). The resulting mixture was heated at 70 °C for 18 h. The reaction mixture was then allowed to cool to RT, poured into water (10 mL) then extracted with EtOAc (2 x 10 mL). The combined organics were washed with brine (20 mL), dried (NaSO4), filtered and concentrated in vacuo. The resulting crude residue was purified by silica gel column chromatography using gradient eluent of 0 - 50 % EtOAc in n- hexane to afford tert-butyl 4-((1-methoxyisoquinolin-5-yl)sulfonyl)piperazine-1- carboxylate (B32) (610 mg, 81 %) as a white solid. LC-MS (Method A). Rt1.93 min, (ESI+) m / z 408.2 [M+H]+. The following methoxy compounds (B33 → B44) depicted in Table 19 were prepared using an analogous procedure to compound (B32) with reaction times ranging between 3 – 24 h:

[0018] Table 19: methoxy substituted heteroaryl examples Synthesis of dialkylaminoisoquinolines via Buchwald amination Synthesis of tert-butyl (R)-4-((1-(ethyl(methyl)amino)isoquinolin-5-yl)sulfonyl)-3- methylpiperazine-1-carboxylate (B44) A mixture of tert-butyl (R)-4-((1-chloroisoquinolin-5-yl)sulfonyl)-3-methylpiperazine-1- carboxylate (B13) (800 mg, 1.88 mmol), tris(dibenzylideneacetone) dipalladium (0) (43.0 mg, 0.046 mmol), 2-dicyclohexylphosphino-2’,4’,6’-triisoproylbipheny [X-Phos] (54.0 mg, 0.094 mmol), ethylmethyl amine (485 µL, 5.64 mmol) and DIPEA (1.00 mL, 5.64 mmol) in toluene (20 mL) was degassed with argon for 5 min then heated at reflux for 14 h. The resulting mixture was filtered through a pad of celite and washed with DCM (10 mL). The organics were concentrated in vacuo to give a crude residue which was twice purified by silica gel column chromatography using gradient eluent of 50 % EtOAc in n-hexane then 8 % MTBE in DCM to afford tert-butyl (R)-4-((1- (ethyl(methyl)amino)isoquinolin-5-yl)sulfonyl)-3-methylpiperazine-1-carboxylate (B44) (230 mg, 48 %) as an off-white solid.1H NMR (400 MHz, CDCl3) δ 8.66 (dt, J = 8.5, 1.1 Hz, 1H), 8.52 (dd, J = 7.4, 1.2 Hz, 1H), 8.45 (d, J = 6.0 Hz, 1H), 8.29 (m, 1H), 7.79 (dd, J = 8.5, 7.4 Hz, 1H), 4.22- 3.76 (overlapping m, 4H), 3.52 (m, 1H), 3.21 (ddd, J = 13.2, 12.3, 3.4 Hz, 1H), 3.06- 2.57 (overlapping m, 2H), 1.43 (s, 9H), 1.11 (d, J = 7.5 Hz, 4H). The following (S) enantiomer (B45) depicted in Table 20 was also prepared using a similar procedure to the (R) enantiomer (B44):

[0019] a Synthesis from commercially available reagent (piperazine compound). Table 20 Synthesis of dialkylamino intermediates via displacement reaction Synthesis of tert-butyl (2-(4-((1-(dimethylamino)isoquinolin-5-yl)sulfonyl)piperazin-1- A mixture of tert-butyl (2-(4-((1-chloroisoquinolin-5-yl)sulfonyl)piperazin-1-yl)-2- oxoethyl)carbamate (B4) (200 mg, 0.43 mmol) and dimethylamine in MeOH solution (215 µL, 0.43 mmol, 2.0 M) was heated in the microwave (200 W, CEM) at 130 °C for 1 h. The crude mixture was concentrated and the resulting solid was collected by filtration, washed with iso-hexane (5 mL) followed by Et2O (5 mL) to afford tert-butyl (2-(4-((1-(dimethylamino)isoquinolin-5-yl)sulfonyl)piperazin-1-yl)-2- oxoethyl)carbamate (B46) (190 mg, 98 %) as a pale yellow solid. LC-MS (Method D). Rt1.80 min, (ESI+) m / z 478.3 [M+H]+. The following dialkyl amino compounds (B47 → B49) detailed in Table 21 were prepared using analogous procedure to compound (B46):

[0020] i 110 °C, 2 h;jrefluxed in pressure vessel in THF for 14-72 h. Table 21: Boc-protected intermediate examples Deuteration method with sodium and deuterated methanol Synthesis of tert-butyl 4-((1-methoxy-d3)isoquinolin-5-yl)sulfonyl)piperazine-1- Sodium (14 mg, 0.589 mmol) was added to a solution of methanol-d4(2.0 mL) and the mixture was stirred until all the metal had dissolved. A solution of tert-butyl 4-((1- chloroisoquinolin-5-yl)sulfonyl)piperazine-1-carboxylate (B1) (97 mg, 0.235 mmol) in methanol-d4 (1.0 mL) was added and the resulting mixture was heated at 60 °C for 12 h. The mixture was cooled to RT, diluted with water (10 mL) and extracted with EtOAc ( 3 x 10 mL). The combined organic layers was washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography using 0 - 10 % MeOH in DCM to afford tert-butyl 4- ((1-methoxy-d3)isoquinolin-5-yl)sulfonyl)piperazine-1-carboxylate (B50) (96.7 mg, quant.) as an off-white solid. LC-MS (Method A). Rt1.92 min, (ESI+) m / z 411.2 [M+H]+. Reductive amination procedure Synthesis of tert-butyl (2-(4-((1-(cyclopropylamino)isoquinolin-5- To a stirred suspension of tert-butyl N-[2-[4-[[1-(cyclopropylamino)-5- isoquinolyl]sulfonyl]piperazin-1-yl]-2-oxo-ethyl]carbamate (B47) (80 mg, 0.163 mmol) in DCE (2 mL), formaldehyde 37% solution (formalin) (40 µL, 0.490 mmol) was added followed by addition of glacial acetic acid (9.4 µL, 0.163 mmol). The resulting reaction mixture was stirred at RT for 1 h, then heated at 55 °C for a further 12 h. The reaction mixture was cooled to 0 °C, then sodium triacetoxyborohydride (42 mg, 0.196 mmol) was added portion wise and the mixture was stirred for a further 4 h. The reaction mixture was diluted with EtOAc (10 mL), then quenched with satd. aq. sodium bicarbonate solution The organic layer was separated then concentrated in vacuo The crude residue was purified by silica gel column chromatography using 1 - 5 % MeOH in DCM to afford tert-butyl (2-(4-((1-(cyclopropyl(methyl)amino)isoquinolin-5- yl)sulfonyl)piperazin-1-yl)-2-oxoethyl)carbamate (B51) (60.0 mg, 57 %) as a pale yellow oil. LC-MS (Method C). Rt2.01 min, (ESI+) m / z 504.3 [M+H]+. Conversion to alkyl isoquinolines using Grignard reagents Synthesis of tert-butyl (2-(4-((1-isopropylisoquinolin-5-yl)sulfonyl)piperazin-1-yl)-2- To a stirred solution of tert-butyl (2-(4-((1-chloroisoquinolin-5-yl)sulfonyl)piperazin-1- yl)-2-oxoethyl)carbamate (B4) (150 mg, 0.320 mmol) in THF (1.5 mL): 1-methyl-2- pyrrolidinone (0.50 mL) at RT, iron(III) acetylacetonate, Fe(acac)3(8.5 mg, 0.0240 mmol) was added and the reaction mixture cooled to -10 °C using ice-salt (3:1) mixture, after which a solution of isopropyl magnesium chloride in THF solution (272 µL, 0.544 mmol, 2.0 M) was added slowly. The resulting reaction mixture was stirred at -10 °C for 30 min, then filtered through a pad of celite. The filtrate was washed with 1 M HCl, then basified by using sodium carbonate solution, then extracted with EtOAc (2 x 10 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford tert-butyl (2-(4-((1- isopropylisoquinolin-5-yl)sulfonyl)piperazin-1-yl)-2-oxoethyl)carbamate (B52) (80 mg, 52 %) as a colourless oil. LC-MS (Method C). Rt2.98 min, (ESI+) m / z 477.4 [M+H]+. The following Boc-protected compound (B53) detailed in Table 22 was prepared using analogous procedure to compound (B52) using a similar reaction time: Table 22: Boc-protected intermediate example Example of Step 2: Boc Deprotection Method A: Synthesis of 1-(difluoromethoxy)-5-(piperazin-1-ylsulfonyl)isoquinoline as TFA (4.00 mL, 51.9 mmol) was added dropwise to a stirred solution of tert-butyl 4-((1- (difluoromethoxy)isoquinolin-5-yl)sulfonyl)piperazine-1-carboxylate (B18) (4.60 g, 10.4 mmol) in DCM (30 mL) at RT. The resulting mixture was stirred for 12 h. The reaction mixture was then concentrated in vacuo to afford a residue, which was triturated with Et2O. The resulting solid was collected by filtration and dried under vacuum to afford 1-(difluoromethoxy)-5-(piperazin-1-ylsulfonyl)isoquinoline as a trifluoroacetate salt (C1) (4.20 g, 99 %), as a pale yellow solid. LC-MS (Method B). Rt1.62 min, (ESI+) m / z 344.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.62 (dt, J = 8.5, 1.1 Hz, 1H), 8.50 (dd, J = 7.5, 1.2 Hz, 1H), 8.33 (d, J = 6.1 Hz, 1H), 8.29 (dd, J = 6.2, 1.0 Hz, 1H), 7.99 (t, J = 71.9 Hz, 1H), 7.98 (m, 1H), 3.31 -3.27 (overlapping m, 4H), 3.18 - 3.14 (overlapping To a stirred solution of tert-butyl 4-((1-(difluoromethoxy)isoquinolin-5- yl)sulfonyl)piperazine-1-carboxylate (B18) (141 mg, 0.32 mmol) in DCM (2.0 mL) at 20oC was added TFA (0.36 mL, 4.77 mmol) and the mixture stirred for 2 h, upon which full conversion was observed. The solvent was evaporated in vacuo. The residue was dissolved in MeOH (5 mL) and the solution passed through a catch release cartridge (Biotage SCX-2; 1 g) washing with MeOH (5 CV) and eluting with 1 M NH3-MeOH (5 c.v.). Concentration of the relevant fractions to dryness afforded 1-(difluoromethoxy)- 5-piperazin-1-ylsulfonylisoquinoline (C1) (100 mg, 92 %) as a colourless oil. LC-MS (Method B). Rt 1.60 min, (ESI+) m / z 344.0 [M+H]+. The following amines (C2 → C42 and C60 → C63) detailed in Table 23 were prepared using analogous procedure to compound (C1) with reaction time varying between 10 min - 18 h. All compounds were prepared by Method A unless otherwise stated:

[0021] k Isolated TFA salt was washed with 5% NaOH to provide free base. Table 23: Boc deprotected intermediates Synthesis of N-(tert-butoxycarbonyl)-N-(methyl-d3)glycine (A73) To a stirred suspension of sodium hydride (60% dispersion in oil) (264 mg, 6.61 mmol) in THF (8 mL) at 0oC was added methyl (tert-butoxycarbonyl)glycine (A72) (250 mg, 1.32 mmol), and the mixture stirred at 0oC for 1 h upon which iodomethane-d3(0.2 mL, 2.83 mmol) was added and the mixture stirred for a further 3 h, upon which a further aliquot of iodomethane-d3 (0.2 mL, 2.83 mmol) was added, and the mixture stirred overnight, allowing the temperature to come to RT. The reaction was quenched through the careful addition of water (8 mL), and the mixture stirred until a clear solution was observed. The mixture was concentrated to aqueous in vacuo, and the mixture extracted twice with Et2O (2 x 10 mL), and the aq. layers discarded. The mixture was carefully acidified to pH ~4 with aqueous citric acid and the mixture extracted with DCM (3 x 25 mL). The combined organic layer was washed with brine (25 mL), dried (MgSO4), filtered, and concentrated in vacuo, affording N-(tert- butoxycarbonyl)-N-(methyl-d3)glycine (A73) (250 mg, 98 %) in sufficient purity to continue.1H NMR (400 MHz, DMSO-d6) δ 3.83 (d, 2H, J = 6.8 Hz), 1.40 (s, 4.5H), 1.35 (s, 4.5H). Example of Step 4: Amide coupling Synthesis of tert-butyl (2-(4-((1-(difluoromethoxy)isoquinolin-5-yl)sulfonyl)piperazin- 1-yl)-2-oxoethyl)carbamate (D1) A mixture of Boc-glycine (2.25 g, 12.8 mmol), HATU (5.76 g, 15.1 mmol), 1- (difluoromethoxy)-5-(piperazin-1-ylsulfonyl)isoquinoline (C1) (4.00 g, 11.6 mmol) and DIPEA (4.05 mL, 23.2 mmol) in DMF (35 mL) was stirred at RT for 12 h. The reaction mixture was quenched with ice cold water (50 mL) then extracted with EtOAc (2 x 30 mL). The organic layer was separated, then washed with satd. aq. sodium bicarbonate (30 mL), brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with 2-3 % MeOH in EtOAc to afford tert-butyl (2-(4-((1-(difluoromethoxy)isoquinolin-5- yl)sulfonyl)piperazin-1-yl)-2-oxoethyl)carbamate (D1) (4.80 g, 82 %) as an off-white solid. LC-MS (Method A). Rt 1.81 min, (ESI+) m / z 523.1 [M+Na]+;1H NMR (400 MHz, CDCl3) δ 8.60 (dt, J = 8.5, 1.1 Hz, 1H), 8.42 (dd, J = 7.5, 1.3 Hz, 1H), 8.27 (dd, J = 6.3, 0.9 Hz, 1H), 8.19 (d, J = 6.2 Hz, 1H), 7.76 (dd, J = 8.4, 7.5 Hz, 1H), 7.71 (t, J= 72.1 Hz, 1H), 6.55 (t, J = 4.1 Hz, 1H), 6.28 (dd, J = 17.0, 1.5 Hz, 1H), 6.14 (dd, J = 17.0, 10.2 Hz, 1H), 5.66 (dd, J = 10.2, 1.5 Hz, 1H), 4.06 (d, J = 4.2 Hz, 2H), 3.74 - 3.69 (overlapping m, 2H), 3.54 – 3.47 (overlapping m, 2H), 3.22 - 3.16 (overlapping m, 4H);19F NMR (376 MHz, CDCl3) δ -89.8 (d, J = 72.2 Hz). The following Boc-protected amines (D2 → D14) detailed in Table 24 were prepared using analogous procedure to compound (D1) with reaction times varying between 15-16 h:

[0022] l Table 24: Boc protected intermediates Reductive amination Synthesis of tert-butyl (2-(4-((1-(difluoromethoxy)isoquinolin-5-yl)sulfonyl)piperazin- To a stirred solution of tert-butyl methyl(2-oxoethyl) carbamate (A74) (54 mg, 0.314 mmol) in THF (5 mL) at 0oC was added 1-(difluoromethoxy)-5-(piperazin-1- ylsulfonyl)isoquinoline (C1) (108 mg, 0.314 mmol) and sodium triacetoxyborohydride (100 mg, 0.472 mmol) and the mixture stirred for 18 h at RT. The solvent was evaporated in vacuo and the residue partitioned between EtOAc (50 mL) and satd. aq. sodium bicarbonate solution (50 mL). The organic phase was washed with brine (50 mL), then dried (MgSO4), filtered and the solvent evaporated in vacuo, affording the crude product. The crude product was purified by silica gel column chromatography, eluting with 5-95% EtOAc in iso-hexane to give tert-butyl (2-(4-((1- (difluoromethoxy)isoquinolin-5-yl)sulfonyl)piperazin-1-yl)ethyl)(methy)carbamate (D15) (100 mg, 64 %) as a white solid. LC-MS (Method B). Rt2.03 min, (ESI+) m / z 501.2 [M+H]+. The following Boc protected compound (D16) detailed in Table 25 was also prepared using analogous procedure to compound (D15) using a similar reaction time: Table 25: Boc protected intermediate example Example of Step 5: Boc Deprotection Synthesis of 2-amino-1-(4-((1-(difluoromethoxy)isoquinolin-5-yl)sulfonyl)piperazin-1- TFA (7.35 mL, 95.9 mmol) was added dropwise to a stirred solution of tert-butyl (2-(4- ((1-(difluoromethoxy)isoquinolin-5-yl)sulfonyl)piperazin-1-yl)-2-oxoethyl)carbamate (D1) (4.80 g, 9.59 mmol) in DCM (50 mL) at RT. The resulting mixture was stirred for 4 h. The reaction mixture was then concentrated in vacuo to afford a residue which was dissolved in DCM (30 mL), washed with 5% NaOH solution (2 x 30 mL) and the organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with 8-10 % MeOH in DCM to afford 2-amino-1-(4-((1-(difluoromethoxy)isoquinolin-5- yl)sulfonyl)piperazin-1-yl)ethan-1-one (C43) (3.50 g, 91 %) as an off-white solid. LC-MS (Method A). Rt1.53 min, (ESI+) m / z 401.1 [M+H]+. The following amines (C44 → C59) detailed in Table 26 were prepared using analogous procedure to compound (C43) with reaction times varying between 30 min – 2.5 h: Table 26: Boc deprotected compounds Example of Step 3: Preparation of Acrylamides using EDCI Preparation of N-(2-(4-((1-(difluoromethoxy)isoquinolin-5-yl)sulfonyl)piperazin-1-yl)- DIPEA (5.70 mL, 30.8 mmol) was added to a stirred solution of 1-(difluoromethoxy)-5- piperazin-1-ylsulphonyl)isoquinoline as its trifluoroacetate salt (C1) (4.70 g, 10.3 mmol) in DCM (50 mL), followed by the addition of potassium acryloyl glycinate (A7) (1.72 g, 10.3 mmol), N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDC.HCl) (2.56 g, 13.4 mmol) and 1-hydroxybenzotriazole (HOBt) (180 mg, 1.34 mmol). The resulting mixture was stirred at RT for 12 h. After completion of the reaction by TLC crushed ice was added to the mixture, which was extracted with EtOAc (100 mL). The organic layer was separated, washed with satd. aq. sodium bicarbonate solution (20 mL), followed by brine (100 mL), then dried (Na2SO4) and the solvent was removed in vacuo. The crude product was purified by silica gel column chromatography using 50 -60 % EtOAc in iso-hexane to afford N-(2-(4-((1-(difluoromethoxy)isoquinolin- 5-yl)sulfonyl)piperazin-1-yl)-2-oxoethyl)acrylamide (Ex-1) (3.50 g, 75 %) as an off- white solid. LC-MS (Method E). Rt 4.23 min, (ESI+) m / z 455.1 [M+H]+;1H NMR (400 MHz, CDCl3): δ 8.60 (dt, J = 8.5, 1.1 Hz, 1H), 8.42 (dd, J = 7.5, 1.3 Hz, 1H), 8.27 (dd, J = 6.3, 0.9 Hz, 1H), 8.19 (d, J = 6.2 Hz, 1H), 7.76 (dd, J = 8.4, 7.5 Hz, 1H), 7.71 (t, J= 72.1 Hz, 1H), 6.55 (t, J = 4.1 Hz, 1H), 6.28 (dd, J = 17.0, 1.5 Hz, 1H), 6.14 (dd, J = 17.0, 10.2 Hz, 1H), 5.66 (dd, J = 10.2, 1.5 Hz, 1H), 4.06 (d, J = 4.2 Hz, 2H), 3.74 - 3.69 (overlapping m, 2H), 3.54 – 3.47 (overlapping m, 2H), 3.22 - 3.16 (overlapping m, 4H). The acrylamides depicted in Table 27 were prepared using analogous procedure to compound (Ex-1) with reaction time varying between 3 h - 14 h:

[0023]

[0024]

[0025]

[0026]

[0027] m Triethylamine used instead of DIPEA;nmethoxy and ethoxy compounds were separated by reverse phase chromatography;oDMF used instead of DCM. Table 27: acrylamide examples (Ex-2 → Ex-12) Example of Step 3: Preparation of acrylamides using HATU Preparation of N-(2-(4-((1-(methoxy-d3)isoquinolin-5-yl)sulfonyl)piperazin-1-yl)-2- oxoethyl)acrylamide (Ex-13) A mixture of 1-(methoxy-d3)-5-(piperazin-1-ylsulfonyl)isoquinoline (C3) (86 mg, 0.28 mmol), potassium acryloyl glycinate (A7) (46 mg, 0.277 mmol), HATU (116 mg, 0.305 mmol) and DIPEA (145 µL, 0.83 mmol) in DMF (5 mL) was stirred at RT for 3 h. The reaction mixture was diluted with DCM (10 mL) and washed with satd. aq. sodium bicarbonate solution (30 mL). The layers were separated, and the organic layer washed with brine (40 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography using 0 - 5 % MeOH in DCM then purified by reverse phase chromatography. Fractions containing desired product were concentrated in vacuo, and then lyophilised from 1:1 MeCN-H2O to afford N-(2-(4- ((1-(methoxy-d3)isoquinolin-5-yl)sulfonyl)piperazin-1-yl)-2-oxoethyl)acrylamide (Ex- 13) (30.2 mg, 26 %) as a white solid. LC-MS (Method E). Rt 3.85 min, (ESI+) m / z 422.2 [M+H]+. The following acrylamides detailed in Table 28 were prepared using analogous procedure to compound (Ex-13) with reaction time varying between 30 min - 18 h:

[0028]

[0029]

[0030] Table 28: acrylamide examples (Ex-14 → Ex-18 ; Ex-59 → Ex-62 ) Example of Step 6: Preparation of acrylamides using acryloyl chloride Synthesis of N-(2-(4-((1-(difluoromethoxy)isoquinolin-5-yl)sulfonyl)piperazin-1-yl)-2- To a stirred solution of 1-(4-((1-(difluoromethoxy)isoquinolin-5-yl)sulfonyl)piperazin-1- yl)-2-(methylamino)ethan-1-one (C50) (49 mg, 0.121 mmol) in DCM (5 mL) was added triethylamine (51 µL, 0.363 mmol), followed by dropwise addition of acryloyl chloride (15 µL, 0.181 mmol) at 0 °C. The solution was left to warm to RT and stirred for 30 min. The reaction mixture was partitioned between DCM (10 mL) and satd. aq. sodium bicarbonate (10 mL). The organic phase was separated, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by reverse phase chromatography. Fractions containing desired product were concentrated in vacuo, and then lyophilised from 1:1 MeCN-H2O to afford N-(2-(4-((1- (difluoromethoxy)isoquinolin-5-yl)sulfonyl)piperazin-1-yl)-2-oxoethyl)-N- methylacrylamide (Ex-19) (26.0 mg, 46 %) as a white solid. LC-MS (Method E). Rt 4.30 min, (ESI+) m / z 469.2 [M+H]+;1H NMR (400 MHz, CDCl3): δ 8.58 (d, J = 8.0 Hz, 1H), 8.39 (dd, J = 7.2, 1.2 Hz, 1H), 8.26 (dd, J = 6.4, 1.2 Hz), 8.16 (d, J = 6.0 Hz, 1H) 7.74 (dd, J = 8.4, 7.6 Hz, 1H), 7.70 (t, J = 72.0 Hz, 1H), 6.56 (dd, J = 17.2, 10.8 Hz, 1H), 6.28 (dd, J = 16.8, 1.6 Hz, 1H), 5.69 (dd, J = 10.4, 2.0 Hz, 1H), 4.15 (s, 2H), 3.66 (br s, 2H), 3.56 (br s, 2H), 3.19 (br s, 2H), 3.15 (br s, 2H), 3.10 (s, 3H). The acrylamides detailed in Table 29 were prepared using analogous procedure to compound (Ex-19) with reaction time varying between 30 mins - 16 h:

[0031]

[0032] Table 29: acrylamide examples (Ex-10 → Ex-50) Synthesis of N-(2-(4-((5-(diethylamino)naphthalen-1-yl)sulfonyl)piperazin-1-yl)-2- oxoethyl)acrylamide (Ex-51) N-(2-oxo-2-(piperazin-1-yl)ethyl)acrylamide (A10) (420 mg, 1.35 mmol), triethylamine (750 µL, 5.4 mmol) and phenothiazine (110 mg, 0.54 mmol) in DCM (10 mL). 5-(diethylamino)naphthalene-1-sulfonyl chloride (A75) (250 mg, 0.84 mmol) and the resulting mixture was stirred at RT for 14 h then concentrated in vacuo. The crude residue was purified by silica gel column chromatography using 0 -100 % EtOAc in iso- hexane to afford N-(2-(4-((5-(diethylamino)naphthalen-1-yl)sulfonyl)piperazin-1-yl)-2- oxoethyl)acrylamide (Ex-51) (302 mg, 78 %) as a yellow solid. LC-MS (Method G). Rt 6.87 min, (ESI+) m / z 459.4 [M+H]+;1H NMR (400 MHz, CDCl3) δ 7.77 (dt, J = 7.7, 0.9 Hz, 2H), 7.62 (dd, J = 7.7, 1.2 Hz, 2H), 7.43 – 7.37 (m, 2H), 7.31 (td, J = 7.4, 1.2 Hz, 2H), 5.88 (broad s, 1H), 4.39 (d, J = 7.2 Hz, 2H), 4.24 (t, J = 7.2 Hz, 1H), 4.05 (d, J = 4.3 Hz, 2H), 3.65 – 3.60 (overlapping, 2H), 3.50 – 3.32 (overlapping m, 6H), 1.48 (s, 9H). Example compound Ex-55 was prepared using analogous procedures for preparing compounds Ex-1 to Ex-51. The following deuterium-substituted acrylamides (Ex-52 → Ex-54) was prepared from the corresponding amines using a phosphonate ester with poly(oxymethylene-d2): Scheme 6 Example of Step 22: Preparation of phosphonate esters Synthesis of diethyl (2-((2-(4-((1-(difluoromethoxy)isoquinolin-5- yl)sulfonyl)piperazin-1-yl)-2-oxoethyl)amino)-2-oxoethyl)phosphonate (E1) A solution of 2-amino-1-(4-((1-(difluoromethoxy)isoquinolin-5-yl)sulfonyl)piperazin-1- yl)ethan-1-one (C43) (3.50 g, 8.74 mmol), 2-(diethoxyphosphoryl)acetic acid (1.89 g, 9.62 mmol), HATU (4.32 g, 11.4 mmol) and DIPEA (2.26 mL, 17.5 mmol) in DCM (50 mL) was stirred at RT for 12 h. The reaction mixture was then quenched with ice cold water (50 mL) and extracted with DCM (2 x 30 mL). The combined organic layers were washed with satd. aq. sodium bicarbonate solution (50 mL) and brine (50 mL) successively, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography to afford crude of diethyl (2-((2-(4-((1- (difluoromethoxy)isoquinolin-5-yl)sulfonyl)piperazin-1-yl)-2-oxoethyl)amino)-2- oxoethyl)phosphonate (E1) (5.50 g, 88 %). LCMS (Method A). Rt1.60 min, (ESI+) m / z 579.5 [M+H]+. The following phosphonate esters detailed in Table 30 was also prepared using an analogous procedure to (E1) with a reaction time of 1 h:s THF used instead of DCM. Table 30: phosphonate intermediate examples Example of Step 23: Preparation of deuterium substituted acrylamides via phosphonate ester Synthesis of N-(2-(4-((1-difluoromethoxy)isoquinolin-5-yl)sulfonyl)piperazin-1-yl)-2- To a solution of diethyl (2-((2-(4-((1-(difluoromethoxy)isoquinolin-5- yl)sulfonyl)piperazin-1-yl)-2-oxoethyl)amino)-2-oxoethyl)phosphonate (E1) (5.50 g, 9.51 mmol) in THF (24 mL): water (6 mL) was added paraformaldehyde-d2(305 mg, 9.51 mmol), lithium hydroxide monohydrate (599 mg, 14.3 mmol) and potassium hydroxide (1.60 g, 28.5 mmol). The resulting mixture was stirred for 15 h at RT. The reaction mixture was then quenched with ice cold water (40 mL) and extracted with EtOAc (2 x 40 mL). The combined organic layer was washed with brine (40 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography eluting with 1-3 % MeOH in EtOAc then further purified by reverse phase chromatography. Fractions containing desired product were concentrated in vacuo, and then lyophilised from 1:1 MeCN-H2O to afford N-(2-(4-((1- difluoromethoxy)isoquinolin-5-yl)sulfonyl)piperazin-1-yl)-2-oxoethyl)acrylamide-3,3- d2 (Ex-52) (2.05 g, 47 %) as an off-white solid. LC-MS (Method E). Rt 4.21 min, (ESI+) m / z 457.1 [M+H]+. The following deuterated-substituted acrylamide detailed in Table 31 were prepared using analogous procedures to compound (Ex-52) with a reaction time of 5 - 6 h: Table 31: Deuterated substituted acrylamide examples (Ex-53 and Ex-54) Preparation of Fluorine-18 Analogues Example compound Ex-58 is prepared from the corresponding hydroxy compound (Ex-56) or the corresponding chlorofluoromethoxy compound (Ex-57) according to procedures know to the person skilled in the art (e.g. Gouverneur et al., Angew. Chem. Int. Ed., 2015, 54, 9991; Gouverneur et al., Nature, 2022, 606, 102) as detailed in Scheme 7 below. Compounds Ex-56 and Ex-57 are prepared using analogous methods to those described herein. Scheme 7: general procedure for preparing Example compound Ex-58. Biological Example 1 – Inhibition of TG2 Activity Methodology TG2 activity was measured using recombinant human Transglutaminase 2 (rhTG2) by biotin X-cadaverine incorporation into N,N′-dimethylcasein. After coating 96 well plates with 50 μL of 10 mg / mL N,N′-dimethylcasein in 50 mM Tris-HCl, pH 8.0, plates were washed with TBS / Tween, pH 7.6, and TBS, pH 7.6. 100 µL / well of rhTG2 reaction containing 400 ng / mL rhTG2, 0.1 mM biotin-cadaverine (BTC), 1 mM DTT and 10 mM CaCl2in 50 mM Tris-HCl, pH 7.4, with or without the test compounds (at various concentrations) was added into each well. The reaction was allowed to proceed for 90 min at 37 °C. The plate was then washed once with TBS / Tween, pH 7.6, and TBS, pH 7.6, before being blocked with 100 μL of SuperBlock reagent for 30 min at 37 °C. BTC incorporation into N,N′-dimethylcasein was detected by incubation for 1 hr at 37 °C with 100 μL of Extravidin-peroxidase diluted 1:2000 in Superblock buffer. After another set of washes, TG2 activity was measured using the ABTS substrate. The absorbance at 405 nm was measured using a microplate reader. Results The results of the TG2 IC50 assay are shown in Table 32 below. The results show that exemplified compounds of formula I are good inhibitors of TG2.

[0033] Table 32. TG2 IC50values for Example compounds. Biological Example 2: In Vivo Pharmacokinetic Study of Example Compounds in C57Bl / 6 Mice The in vivo pharmacokinetics of example compounds in C57Bl / 6 mice were studied as follows. Formulations Details of the intravenous and oral formulations are summarised in Table 33 and Table 34, respectively. Formulation Details Table 33. Intravenous formulations of Example compounds. Table 34. Oral formulations of Example compounds. Methodology Male C57Bl / 6 mice, 20.6-26.7 g, were dosed with a cassette of test compounds either intravenously or orally. In some cases individual compounds were dosed orally. Test compounds were formulated as a solution and administered either (a) intravenously at a dose of 0.5 mg / kg per compound, or (b) orally at a dose of 2.5 mg / kg, 5 mg / kg or 10 mg / kg. Animals were given free access to food and water throughout the study. Blood samples were collected under anaesthesia (isoflurane) by terminal cardiac puncture into labelled microcentrifuge tubes containing heparin as an anticoagulant from a set of three mice at each of the following timepoints: For intravenous dosing, samples were collected at: (a) 1, 5, 15, 30 minutes and 1 hour post dose, or (b) 1, 5, 15, 30 minutes and 1, 2, 4 and 8 hours post dose. For oral dosing, samples were collected at: 5, 15, 30 minutes and 1, 2, 4, 6 & 8 hours post dose. The blood samples were separated by centrifugation and the resultant plasma samples were transferred to labelled microcentrifuge tubes and frozen at -20 °C pending analysis. All samples were processed for analysis by protein precipitation using acetonitrile containing an internal standard (tolbutamide) and analysed using LC-MS / MS methods to determine the plasma concentration of all the compounds dosed at each time point. Pharmacokinetic parameters were calculated from the plasma concentration-time profiles using non-compartmental analysis. The compound , which may be referred to herein as compound 1–155 or Reference Compound 1, was prepared in accordance with the procedures described in WO 2014 / 057266. Reference Compound 1 was tested in accordance with the procedures described herein. As shown below, the mouse plasma clearance of 1-155 was found to be 198 mL / min / kg, which is above the liver blood flow of a mouse (90 mL / min / kg; B Davis, T Morris, Pharma. Res., 10, 1093-1095 (1993). Results The results for the pharmacokinetic study in mice are tabulated in Tables 35 and 36 below. The results show that certain exemplary compounds of formula I show improved pharmacokinetic properties. Said pharmacokinetic properties are improved compared to known TG2 inhibitors.

[0034] Table 35. Pharmacokinetic Parameters For Example Compounds Following Intravenous Dosing.

[0035] Dosing. Biological Example 3 – Inhibition of FXIIaI, TG1 and TG3 Activity Methodology - FXIIIa and TG1 Commercial microassays were used (TG-CovTest; Covalab) (Hitomi et al., 2009, Amino Acids 36, 619–624), according to the manufacturer’s instructions. For comparable purposes, a number of TG2 assays were also undertaken using this assay. Briefly, TG- specific biotinylated peptides, including pepF11KA, pre-activated FXIII and pepK5 (TG1) (Hitomi et al., 2009) were incubated with suitable TG family members in the presence of polyamine substrates immobilised onto 96-well microplates. The incorporated biotinylated peptides were measured using horseradish peroxidase-conjugated streptavidin and then measured using o-phenylenediamine dihydrochloride substrates. The absorbance was measured at 490 nm using a microplate reader. Methodology – TG3 The fluorescent TG3 assay was performed as described. The assay conditions were 10 nM preactivated TG3 in 50 mM Hepes, pH 8.0, 20 mM CaCl2, 0.2 mM DTT, 0.05% Pluronic F-127 at 37 °C. A kinetic measurement was recorded (excitation, 350 nm; emission, 535 nm), and the reaction velocity derived from a linear fit was used as a measure for enzyme activity. All data points were normalised between 0% and 100% inhibition using the appropriate positive (full inhibition) and negative (no inhibition) controls. Results The results of the FXIIIa, TG1 and TG3 IC50 assays are shown in Table 37 below alongside the results for the TG2 IC50 assays described above. The results revealed a selective inhibition of TG2 for exemplary compounds of formula

[0036] Table 37. TG2, FXIIIa, TG1, TG3 IC50 values for Example compounds. Biological Example 4: In Vivo Pharmacokinetic Study of Example Compounds in Rat The in vivo pharmacokinetics of example compounds in rats (Sprague-Dawley; SD) rats were studied as follows. Formulations Details of the intravenous formulation are summarised in Table 38. Table 38. Intravenous formulations of Example compounds. Methodology Male SD rats, 200-250 g, were dosed intravenously either as a single compound or within a cassette of test compounds. Test compounds were formulated as a solution and administered intravenously at a dose of 1 mg / kg per compound. Animals were given free access to food and water throughout the study. Blood samples were collected under anaesthesia (isoflurane) by terminal cardiac puncture into labelled microcentrifuge tubes containing heparin as an anticoagulant from a set of three mice at each of the following timepoints: For intravenous dosing, samples were collected at: (a) 1, 5, 15, 30 minutes and 1, 2, 4 and 8 hours post dose, or (b) 1, 5, 15, 30 minutes and 1, 2, 4, 6, 8 and 24 hours post dose. The blood samples were separated by centrifugation and the resultant plasma samples were transferred to labelled microcentrifuge tubes and frozen at -20 °C pending analysis. All samples were processed for analysis by protein precipitation using acetonitrile containing an internal standard (tolbutamide) and analysed using LC-MS / MS methods to determine the plasma concentration of all the compounds dosed at each time point. Pharmacokinetic parameters were calculated from the plasma concentration-time profiles using non-compartmental analysis. The compound , which may be referred to herein as compound 1–155 or Reference Compound 1, was prepared in accordance with the procedures described in WO 2014 / 057266. Reference Compound 1 was tested in accordance with the procedures described herein. As shown below, the rat plasma clearance of 1-155 was found to be 127 mL / min / kg, which is above the liver blood flow of a rat (55 mL / min / kg; B Davis, T Morris, Pharma. Res., 10, 1093-1095 (1993). Results The results for the pharmacokinetic study in rats are tabulated in Table 39 below. The results show that certain exemplary compounds of formula I show improved pharmacokinetic properties. Said pharmacokinetic properties are improved compared to known TG2 inhibitors. Table 39. Pharmacokinetic Parameters For Example Compounds Following Intravenous Dosing.

[0037] References Bailey, C.D., and G.V. Johnson. 2005. Tissue transglutaminase contributes to disease progression in the R6 / 2 Huntington's disease mouse model via aggregate- independent mechanisms. J Neurochem. 92:83-92. Collighan, R.J., and M. Griffin. 2009. Transglutaminase 2 cross-linking of matrix proteins: biological significance and medical applications. Amino Acids. 36:659- 670. Dafik, L., and C. Khosla. 2011. Dihydroisoxazole analogs for labeling and visualization of catalytically active transglutaminase 2. Chem Biol. 18:58-66. Fell, S., · Z. Wang, A. Blanchard, · C. Nanthakumar and M. Griffin. 2021 Transglutaminase 2: a novel therapeutic target for idiopathic pulmonary fibrosis using selective small molecule inhibitors. Amino Acids. 53:205–217 Griffin, M., R. Casadio, and C.M. Bergamini. 2002. Transglutaminases: nature's biological glues. Biochem J. 368:377-396. Griffin, M., A. Mongeot, R. Collighan, R.E. Saint, R.A. Jones, I.G. Coutts, and D.L. Rathbone. 2008. 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Claims

Claims 1. A compound of formula I,wherein: Q is selected from the group consisting of O and NH; A is selected from the group consisting of N and CH; E represents a direct bond or -C(O)-; L represents a direct bond or a group selected from the group consisting of C1-3alkylene, 4- to 6-membered cycloalkylene, 4- to 6-membered heterocycloalkylene, arylene and heteroarylene; or A, E and L together form a 4- to 6-membered cycloalkylene group; R1represents a naphthyl group substituted with one or more X groups or a 10-membered, bicyclic heteroaryl group, which is optionally substituted with one or more X groups; each X is independently selected from the group consisting of halogen, -N(R8a)R8b, -OR9, -C(O)OR10, -C(O)N(R11a)R11b, -CN, a C1-4alkyl group, and a C3-6cycloalkyl group, which C1-4alkyl and C3-6cycloalkyl groups are optionally substituted by one or more deuterium atoms and / or halogen atoms; R2, R3and R4are each independently selected from the group consisting of hydrogen and C1-3alkyl, which C1-3alkyl group is optionally substituted by one or more halogen atoms; orR2and R3together with the carbon atoms to which they are bound form a 5- or 6-membered heterocycloalkyl group; or R2and R4together with the carbon atoms to which they are bound form a 5- or 6-membered heterocycloalkyl group; R5is selected from the group consisting of hydrogen, C1-3alkyl, and C3-6cycloalkyl, which C1-3alkyl and C3-6cycloalkyl groups are optionally substituted by one or more groups selected from the group consisting of deuterium atoms and halogen atoms ; or L and R5together with the nitrogen atom to which R5is bound form a 4- to 6-membered heterocycloalkylene group; R6is selected from the group consisting of hydrogen, halogen, deuterium, and C1-3alkyl, which C1-3alkyl group is optionally substituted by one or more halogen atoms, -CH2N(R12)Ph and -CH2OCH2Ph; R7aand R7bare each independently selected from the group consisting of hydrogen, halogen, methyl, and deuterium; R8a, R8b, R9, R10, R11aand R11b, are each independently selected from the group consisting of hydrogen, C1-3alkyl, and C3-6cycloalkyl, which C1-3alkyl and C3-6cycloalkyl groups are optionally substituted by one or more deuterium atoms and / or halogen atoms; or or R8aand R8band / or R11aand R11b, together with the nitrogen atom to which they are bound form a 3- to 6-membered heterocycloalkyl group; R12is selected from the group consisting of hydrogen and C1-3alkyl, which C1-3alkyl group is optionally substituted by one or more halogen atoms; and Ph is phenyl optionally substituted by one or more halogen atoms or C1-3alkyl groups, which C1-3alkyl groups are optionally substituted by one or more halogen atoms, or a pharmaceutically acceptable salt, solvate, or deuterated analogue thereof;provided that: (a) the compound of formula I or pharmaceutically acceptable salt, solvate, or deuterated analogue thereof is not:or a pharmaceutically acceptable salt, solvate, or deuterated analogue thereof; and (b) the compound of formula I or pharmaceutically acceptable salt, solvate, or deuterated analogue thereof is not:.

2. The compound according to Claim 1, wherein Q is O.

3. The compound according to Claim 1 or Claim 2, wherein R1is selected from the group consisting of: ,X1is selected from the group consisting of halogen, -OR9, -C(O)OR10, -C(O)N(R11a)R11b, -N(R13a)R13b, -CN, a C1-4alkyl group, and a C3-6cycloalkyl group, which C1-4alkyl and C3-6cycloalkyl groups are optionally substituted by one or more halogen atoms; X1ais selected from the group consisting of hydrogen, halogen, -N(R8a)R8b, -OR9, -C(O)OR10, -C(O)N(R11a)R11b, -CN, a C1-4alkyl group, and a C3-6cycloalkyl group, which C1-4alkyl and C3-6cycloalkyl groups are optionally substituted by one or more halogen atoms, provided that X1ais not hydrogen when X3, X4, X5, X6and X7are all hydrogen; X1bis selected from the group consisting of hydrogen, halogen, -N(R8a)R8b, -OR9, -C(O)OR10, -C(O)N(R11a)R11b, -CN, a C1-4alkyl group, and a C3-6cycloalkyl group, which C1-4alkyl and C3-6cycloalkyl groups are optionally substituted by one or more halogen atoms; X2, X3, X4, X5, X6and X7are each independently selected from the group consisting of hydrogen, halogen, -N(R8a)R8b, -OR9, -C(O)OR10, -C(O)N(R11a)R11b, -CN, a C1-4alkyl group, and a C3-6cycloalkyl group, which C1-4alkyl and C3-6cycloalkyl groups are optionally substituted by one or more halogen atoms; R8a, R8b, R9, R10, R11aand R11bare as defined in Claim 1; R13ais selected from the group consisting of C1-3alkyl, and C3-6cycloalkyl, which C1-3alkyl and C3-6cycloalkyl groups are optionally substituted by one or more deuterium atoms and / or halogen atoms; and R13bis selected from the group consisting of C2-3alkyl, and C3-6cycloalkyl, which C2-3 alkyl and C3-6cycloalkyl groups are optionally substituted by one or more deuterium atoms and / or halogen atoms; or or R13aand R13b, together with the nitrogen atom to which they are bound form a 3- to 6-membered heterocycloalkyl group.

4. The compound according to any one of Claims 1 to 3, wherein R1is:, wherein X1ais selected from the group consisting of halogen, -N(R8a)R8b, -OR9, -CN, a C1-4alkyl group, and a C3-6cycloalkyl group, which C1-4alkyl and C3-6cycloalkyl groups are optionally substituted by one or more halogen atoms; X3, X4, X5, X6and X7are each independently selected from the group consisting of hydrogen, halogen, -CN, and a C1-4alkyl group, which C1-4alkyl group is optionally substituted by one or more halogen atoms; and R8a, R8band R9are as defined in Claim 1.

5. The compound according to any one of Claims 1 to 4, wherein R1is selected from the group consisting of:X1ais selected from the group consisting of -OCHF2, -OCHF[18F], -OCHFCl, -OCH2F, -OCF3, -OCF2Cl, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCD3, -OH, -NH2,X3, X4, X5, X6and X7are each independently selected from the group consisting of hydrogen, F, -CN, and methyl.

6. The compound according to any one of Claims 1 to 5, wherein R1is selected from the group consisting of:wherein X1aand X7are as defined in any one of Claims 3 to 5.

7. The compound according to any one of Claims 1 to 3, wherein R1is selected from the group consisting of:wherein X1bis selected from the group consisting of hydrogen, halogen, -N(R8a)R8b, -OR9, -CN, and a C1-4alkyl group, which C1-4alkyl group is optionally substituted by one or more halogen atoms; and R8a, R8band R9are as defined in Claim 1.

8. The compound according to Claim 7, wherein X1bis selected from the group consisting of hydrogen, -OCHF2, -OCHF[18F], -OCHFCl, -OCH2F, -OCF3, -OCF2Cl, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCD3, -OH, -NH2, -N(CH3)2,9. The compound according to any one of Claims 1 to 3, wherein R1is:, wherein X1is selected from the group consisting of halogen, -N(R13a)R13b, -OR9, -CN, and a C1-4alkyl group, which C1-4alkyl group is optionally substituted by one or more halogen atoms; R9is defined in Claim 1; and R13aand R13bare as defined in Claim 3.

10. The compound according to Claim 9, wherein X1is selected from the group consisting of -OCHF2, -OCHF[18F], -OCHFCl, -OCH2F, -OCF3, -OCF2Cl,11. The compound according to any one of Claims 1 to 10, wherein: A is N; E is -C(O)- or a direct bond; and L is a C1-3alkylene, or L and R5together with the nitrogen atom to which R5i b d f tidi i12. The compound according to any one of Claims 1 to 11, wherein A is N; and the -E-L- linker represents:.

13. The compound according to any one of Claims 1 to 10, wherein A is CH; E is a direct bond; and L represents direct bond, a C1-3alkylene, or L and R5together with the nitrogen atom to which R5is bound form an azetidine ring.

14. The compound according to any one of Claims 1 to 10, wherein A, E and L together form a cyclobutyl ring.

15. The compound according to any one of Claims 1 to 14, wherein: R2, R3and R4are each independently selected from the group consisting of hydrogen, methyl and ethyl; or R2and R4together with the carbon atoms to which they are bound form a 5-membered heterocycloalkyl group.

16. The compound according to any one of Claims 1 to 15, wherein: R2and R4are each hydrogen; and R3is hydrogen or methyl.

17. The compound according to any one of Claims 1 to 16, wherein R5is selected from the group consisting of hydrogen, methyl, ethyl and cyclopropyl, which methyl, ethyl and cyclopropyl groups are optionally substituted by one, two or three deuterium atoms.

18. The compound according to any one of Claims 1 to 17, wherein: R6is hydrogen; and R7aand R7bare each independently selected from the group consisting of hydrogen and deuterium.

19. The compound according to Claim 1, wherein the compound is selected from the group consisting of:or a pharmaceutically acceptable salt, solvate, or deuterated analogue thereof.

20. A pharmaceutical formulation comprising a compound of formula I as defined in any one of Claims 1 to 19 excluding proviso (b), or a pharmaceutically acceptable salt, solvate, or deuterated analogue thereof, and a pharmaceutically acceptable excipient.

21. A compound of formula I as defined in any one of Claims 1 to 19 excluding proviso (b), or a pharmaceutically acceptable salt, solvate, or deuterated analogue thereof, or a pharmaceutical formulation as defined in Claim 20, for use in medicine.

22. A method of treating or preventing a disease or condition which is responsive to treatment with an inhibitor of a transglutaminase comprising administering a compound of formula I as defined in any one of Claims 1 to 19 excluding proviso (b), or a pharmaceutically acceptable salt, solvate, or deuterated analogue thereof, or a pharmaceutical formulation as defined in any one of Claim 20, to a subject in need thereof.

23. The method according to Claim 22, wherein the disease or condition which is responsive to treatment with an inhibitor of a transglutaminase is selected from the group consisting of fibrosis, scarring, neurodegenerative diseases, autoimmune diseases, thrombosis, proliferative disorders, AIDS, psoriasis, inflammation, pulmonary hypertension, and diseases or conditions associated with pathological angiogenesis.

24. The method according to Claim 23, wherein the disease or condition is selected from the group consisting of idiopathic pulmonary fibrosis, pulmonary fibrosis, cardiac fibrosis, cystic fibrosis, liver fibrosis, fibrosis of the kidney, scarring, Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, multiple sclerosis, coeliac disease, thrombosis, prostate cancer, breast cancer, lung cancer, colorectal cancer, melanomas, bladder cancer, brain / CNS cancer, cervical cancer, oesophageal cancer, gastric cancer, head / neck cancer, kidney cancer, liver cancer, lymphomas, ovarian cancer, pancreatic cancer, sarcomas, AIDS, psoriasis, chronic inflammatory disease, inflammatory bowel disease, Crohn's disease, diabetic retinopathy, age- related macular degeneration, retinopathy of prematurity, central retinal vein occlusion, sickle cell retinopathy, branch and central retinal vein occlusion and retinal trauma.

25. A method for preventing or treating rejection of a transplanted organ comprising contacting the organ with a compound as defined in any one of Claims 1 to 19 excluding proviso (b), or a pharmaceutically acceptable salt, solvate, or deuterated analogue thereof, or a pharmaceutical formulation as defined in Claim 20, optionally wherein the organ is treated: (a) prior to transplantation; or (b) during and / or after transplantation into a patient, and preferably wherein the organ is a heart, lung, kidney or liver.

26. A process for preparing a compound of formula I as defined in any one of Claims 1 to 19 excluding proviso (b), which process comprises reaction of a compound of formula II,II with a compound of formula III,wherein Q, R1, R2, R3, R4, R5, R6, R7a, R7b, A, E and L are as defined in any one of Claims 1 to 18 and G1is a suitable leaving group; (b), for compounds of formula I where A is N, E is -C(O)-, reaction of a compound of formula V,with a compound of formula III,XVII, wherein Q, R1, R2, R3, R4, R5, R6, R7a, R7band L are as defined in any one of Claims 1 to 19 and M is a suitable metal atom; (c) reaction of a compound of formula XXI,with a compound of formula VIII,VIII,wherein Q, R1, R2, R3, R4, R5, R6, R7a, R7b, A, E and L are as defined in any one of Claims 1 to 18 and G2is a suitable is a suitable leaving group; or (d), for compounds of formula I where R7aand R7bare both deuterium, reaction of a compound of formula V, formula XXII,with a suitable source of deuterium, wherein Q, R1, R2, R3, R4, R5, A, E and L are as defined in any one of Claims 1 to 19 and each R15is independently a C1-3alkyl group.

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