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 characterized (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-crystallized 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 a 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. For example, 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 N; the -E-L- linker represents: R1represents a 9-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, 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 C1-3 alkyl, which C1-3 alkyl 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, 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; R6is selected from the group consisting of hydrogen, halogen (e.g. F,18F, Cl, Br or I), deuterium, and C1-3 alkyl, which C1-3 alkyl 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. These compounds, including pharmaceutically acceptable salts, solvates and deuterated analogues thereof (particularly pharmaceutically acceptable salts and solvates thereof), may be referred to herein as the “compounds of the invention”. In an alternative first aspect of the invention, there is provided a compound of the invention (i.e. a compound of formula I or a pharmaceutically acceptable salt, solvate, or deuterated analogue thereof (particularly a pharmaceutically acceptable salt or solvate thereof), wherein: 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; or L and R5together with the nitrogen atom to which R5is bound form a 4- to 6- membered heterocycloalkylene group. 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 group). 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 (e.g. 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. C6-10aryl 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 (e.g. a 9-membered, bicyclic heteroaryl group), then it may consist of a five- or six-membered monocyclic ring (e.g. a monocyclic heteroaryl ring) fused with another a five- or six-membered, as appropriate, ring (e.g. a monocyclic aryl or heteroaryl ring). Heteroaryl groups that may be mentioned include, for example, pyrrolopyridinyl, pyrrolopyrimidinyl, thienopyridinyl, indolyl, thienopyrimidinyl, benzothiophenyl, and indazolyl, 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 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 9-membered, bicyclic heteroaryl group, which is optionally substituted with one or more X groups. Accordingly, said 9-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 9-membered, bicyclic heteroaryl group, which is optionally substituted with one or more X groups comprising 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 9-membered, bicyclic heteroaryl groups at R1are relatively bioavailable and therefore show surprisingly improved pharmacokinetic properties compared to known TG2 inhibitors. Particular compounds of the invention that may also be mentioned are those where the 9-membered, bicyclic heteroaryl group: (a) contains 1, 2, 3 or 4 ring heteroatoms each independently selected from the group consisting of N and S; and (b) is substituted by 0, 1, 2, 3, 4 or 5 X groups. Particular X groups that may be mentioned include hydrogen, -OCH3, -OCHF2, -OCHF[18F], -OCHFCl, -CF3, -OCH2F, -OCF3, -OCF2Cl, -OCH2CH3, -OCH(CH3)2, -OCD3, -OH, -NH2, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH3)CH3, , -CH3, -CH2CH3, -CH(CH3)2, , -CD3, Cl, and F. In particular embodiments, R1is selected from the group consisting of: wherein Z1is selected from the group consisting of C and N; Z2is selected from the group consisting of S, NR13and CR14; Z3, Z4and Z5are each independently selected from the group consisting of CR15or N; X1, X2, X3, X5, X6, X7, X8, R14and R15are each independently selected from the group consisting of hydrogen, halogen (e.g. F,18F, Cl, Br or I), -OR9, a C1-4 alkyl group, and a C3-6 cycloalkyl group, which C1-4 alkyl and C3-6 cycloalkyl groups are optionally substituted by one or more deuterium atoms and / or halogen (e.g. F,18F, Cl, Br or I) atoms; X4and R13are each independently selected from the group consisting of hydrogen, a C1-4 alkyl group, and a C3-6 cycloalkyl group, which C1-4 alkyl and C3-6 cycloalkyl groups are optionally substituted by one or more deuterium atoms and / or halogen (e.g. F,18F, Cl, Br or I) atoms; and R9is as defined herein (e.g. selected from the group consisting of hydrogen, C1-3 alkyl, and C3-6 cycloalkyl, which C1-3 alkyl and C3-6 cycloalkyl groups are optionally substituted by one or more deuterium atoms and / or halogen (e.g. F,18F, Cl, Br or I) atoms). As provided herein, indicates a point of attachment to the compound of formula I. The skilled person will recognise that indicates a double or a single bond. Accordingly, will be understood as representing: In particular embodiments, R1is: wherein Z1, Z2, Z3, Z4, Z5, X1, X2, X3, X5, X6, X7, and X8are as defined herein (i.e. as described in the first aspect of the invention, including all embodiments and particular features, and combinations thereof). In particular embodiments, R1is selected from the group consisting of:

[0002] wherein X1, X2, X3, X4, X5, X6, X7, X8, R13, R14and R15are as defined herein. In particular embodiments, R1is selected from the group consisting of: wherein X1, X2, X3, R14and R15are as defined herein. In particular embodiments, R1is selected from the group consisting of: wherein X1, X2, X4, R13, R14and R15are as defined herein. In particular embodiments, R1is: , wherein X1, X2, R14and R15are as defined herein. In particular embodiments, X1, X2, X3, X5, X6, X7, X8, R14and R15are each independently selected from the group consisting of hydrogen, -OCH3, -OCHF2, -OCHF[18F], -OCHFCl, -CF3, -OCH2F, -OCF3, -OCF2Cl, -OCH2CH3, -OCH(CH3)2, -OCD3, -OH, -CH3, -CH2CH3, -CH(CH3)2, -CD3, Cl and F; and X4and R13are each independently selected from the group consisting of hydrogen, -CH3, -CH2CH3, -CH(CH3)2, , and -CD3 . In certain embodiments: X1is selected from the group consisting of hydrogen, -OCH3, -OCHF2, -OCHF[18F], -OCHFCl, -CF3, -OCH2F, -OCF2Cl, and -OH; X4is selected from the group consisting of hydrogen -CH3 and -CH2CH3; R14is selected from the group consisting of hydrogen, F, Cl and -CH3; X2, R13and R14are each independently selected from the group consisting of hydrogen and -CH3; and X3, X5, X6, X7and X8are each hydrogen. In particular 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: 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: Preferably: 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 C1-3 alkylene, 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:

[0003] 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 the invention that may be mentioned include compounds of formula I-B and compounds of formula I-C, as defined hereinabove. Particular compounds of formula I-C that may be mentioned are those where R1is selected from the group consisting of: wherein Z1, Z2, Z3, Z4, Z5, X1, X2, X3, X5, X6, X7, and X8are as defined herein (i.e. as described in the first aspect of the invention, including all embodiments and particular features, and combinations thereof). More particularly, compounds of formula I-C that may be mentioned are those where R1is selected from the group consisting of: wherein X1, X2, X3, X4, X5, X6, X7, X8, R13, R14and R15are as defined herein (i.e. as described in the first aspect of the invention, including all embodiments and particular features, and combinations thereof). Certain compounds of formula I-C that may be mentioned are those where R1is selected from the group consisting of: wherein X1, X2, X3, X4, X5, X6, X7, X8, R13, R14and R15are as defined herein (i.e. as described in the first aspect of the invention, including all embodiments and particular features, and combinations thereof). 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, particular compounds of the invention that may be mentioned include compounds of 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. Particular compounds of the invention that may be mentioned include compounds of formula I where R2, R3and R4are each hydrogen. 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 hydrogen or methyl. Preferably, R5is 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. In particular embodiments, R12is methyl. 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. 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] 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 C1-3 alkyl (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 XII 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 X1is -OR9may be prepared by reaction of a compound of formula XV, wherein R2, R3, R4, X2, X3, Z2, Z3, Z4and P2are as defined hereinabove, 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. Alternatively, the compound of formula IV may be prepared by reaction of a compound of formula XVI, as defined hereinabove, with a suitable heteroaryl (e.g. indole) in the presence of a suitable coupling agent (e.g. MSDI, as described in Chem., A Eur Journal, 2019, 25, 8, 1906-1909), a suitable base (e.g. N,N-diisopropylethylamine) and a suitable solvent (e.g. dichloromethane) according to procedures know to the person skilled in the art. Alternatively, the compound of formula IV (for example, those compounds where A is N; E is -C(O)-; and L is a C1-3alkylene (e.g. methylene) group) may be prepared by reaction of a compound of formula XVII, with a compound of formula XVI as defined hereinabove, wherein R1is as defined hereinabove, in the presence of a suitable chlorinating reagent (e.g. thionyl chloride), 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 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 XVIII, wherein R1is as defined hereinabove, with a suitable oxidizing agent (e.g. 3-chloroperbenzoic acid) in the presence of a suitable solvent (e.g. dichloromethane) 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 XIII as defined hereinabove with a suitable sulfonylation reagent (e.g. 1,4-diazabicylco[2.2.2]octane bis(sulfur dioxide) adduct) in the presence of a suitable palladium coupling reagent (e.g. bis(di-tert-butyl(4- dimethylaminophenyl)phosphine)dichloropalldium (II)), a suitable base (e.g. N- cyclohexyl-N-methylcyclohexanemine) and a suitable solvent (e.g. iso-propanol) 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) 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 XIX 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 XIX may be prepared by reaction of a compound of formula XX, wherein R5, R6, R7aand R7bare as defined hereinabove and R16is 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 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. For example, the compound of formula XX may be prepared by reaction of a compound of formula XXI, with a compound of formula III as described hereinabove, wherein R5and R16are as defined hereinabove, 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 XX and 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, XXII wherein Q, R1, R2, R3, R4, R5, A, E and L are as defined hereinabove and each R17is independently a C1-3 alkyl (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 XXIIII, wherein R17is 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 (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 (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, 19thed., 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 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 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, as hereinbefore defined (i.e. a compound as defined in the first aspect of the invention), 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) 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 IC50for 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 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. 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. 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. 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. In particular embodiments, the invention may be defined according to the following paragraphs. 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 C1-3 alkylene, 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 9-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, 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; 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, C1-3 alkyl, C3-6 cycloalkyl, 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 C1-3 alkyl, which C1-3 alkyl 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 C1-3 alkyl, which C1-3 alkyl 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 or solvate thereof. 2. The compound of paragraph 1, wherein Q is O. 3. The compound of paragraph 1 or paragraph 2, wherein the 9-membered, bicyclic heteroaryl group: (a) contains 1, 2, 3 or 4 ring heteroatoms each independently selected from the group consisting of N and S; and (b) is substituted by 0, 1, 2, 3, 4 or 5 X groups. 4. The compound of any one of paragraphs 1 to 3, wherein R1is selected from the group consisting of: wherein Z1is selected from the group consisting of C and N; Z2is selected from the group consisting of S, NR13and CR14; Z3, Z4and Z5are each independently selected from the group consisting of CR15or N; X1, X2, X3, X5, X6, X7, X8, R14and R15are each independently selected from the group consisting of hydrogen, halogen, -OR9, a C1-4 alkyl group, and a C3-6 cycloalkyl group, which C1-4 alkyl and C3-6 cycloalkyl groups are optionally substituted by one or more deuterium atoms and / or halogen atoms; X4and R13are each independently selected from the group consisting of hydrogen, a C1- 4 alkyl group, and a C3-6 cycloalkyl group, which C1-4 alkyl and C3-6 cycloalkyl groups are optionally substituted by one or more deuterium atoms and / or halogen atoms; and R9is as defined in paragraph 1. 5. The compound of any one of paragraphs 1 to 4, wherein R1is selected from the group consisting of:

[0008] wherein X1, X2, X3, X4, X5, X6, X7, X8, R13, R14and R15are as defined in paragraph 4. 6. The compound of any one of paragraphs 1 to 5, wherein R1is selected from the group consisting of: wherein X1, X2, X4, R13, R14and R15are as defined paragraphs 4 or 5. 7. The compound of any one of paragraphs 4 to 6, wherein: X1, X2, X3, X5, X6, X7, X8, R14and R15are each independently selected from the group consisting of hydrogen, -OCH3, -OCHF2, -OCHF[18F], -OCHFCl, -CF3, -OCH2F, -OCF3, -OCF2Cl, -OCH2CH3, -OCH(CH3)2, -OCD3, -OH, -CH3, -CH2CH3, -CH(CH3)2, , -CD3, Cl and F; and X4and R13are each independently selected from the group consisting of hydrogen, - CH3, -CH2CH3, -CH(CH3)2, d -CD3. 8. The compound of any one of paragraphs 1 to 7, wherein: X1is selected from the group consisting of hydrogen, -OCH3, -OCHF2, -OCHF[18F], -OCHFCl, -CF3, -OCH2F, -OCF2Cl, and -OH; X4is selected from the group consisting of hydrogen -CH3 and -CH2CH3; R14is selected from the group consisting of hydrogen, F, Cl and -CH3; X2, R13and R14are each independently selected from the group consisting of hydrogen and -CH3; and X3, X5, X6, X7and X8are each hydrogen. 9. The compound of any one of paragraphs 1 to 8, 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 R5is bound form an azetidine ring. 10. The compound of any one of paragraphs 1 to 9, wherein A is N; and the -E-L- linker represents: . 11. The compound of any one of paragraphs 1 to 8, 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. 12. The compound of any one of paragraphs 1 to 8, wherein A, E and L together form a cyclobutyl ring. 13. The compound of any one of paragraphs 1 to 12, 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. 14. The compound of any one of paragraphs 1 to 13, 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. 15. The compound of any one of paragraphs 1 to 14, wherein: R6is hydrogen; and R7aand R7bare independently selected from the group consisting of hydrogen and deuterium. 16. The compound of paragraph 1, wherein the compound is selected from the group consisting of:

[0009] , or a pharmaceutically acceptable salt or solvate thereof. 17. A pharmaceutical formulation comprising a compound of formula Ia as defined in any one of paragraphs 1 to 16, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. 18. A compound of formula I as defined in any one of paragraphs 1 to 16, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical formulation as defined in paragraph 17, for use in medicine. 19. 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 paragraphs 1 to 16, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical formulation as defined in paragraph 17, to a subject in need thereof. 20. The method according to paragraph 19, 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. 21. The method of paragraph 20, wherein the disease or condition is selected from the group consisting of cystic fibrosis, 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, 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. 22. A method for preventing or treating rejection of a transplanted organ comprising contacting the organ with a compound as defined in any one of paragraphs 1 to 16, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical formulation of paragraph, 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. 23. A process for preparing a compound of formula I as defined in any one of paragraph 1 to 16, 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 in any one of paragraphs 1 to 16 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 XIXa, wherein Q, R1, R2, R3, R4, R5, R6, R7a, R7band L are as defined in any one of paragraphs 1 to 16 and M is a suitable metal atom; (c) for compounds of formula I where R7aand R7bare both deuterium, reaction of a compound of formula with a suitable source of deuterium, wherein Q, R1, R2, R3, R4, R5, A, E and L are as defined in any one of paragraphs 1 to 16 and each R17is independently a C1-3 alkyl group. 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 starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents and catalysts utilised to synthesise the compounds of the invention are either commercially available or can be routinely prepared by procedures described in the literature, for example, Houben-Weyl “Science of Synthesis” volumes 1-48, Georg Thieme Verlag, and subsequent versions thereof. 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 (“phase separators”) were used to separate an organic layer from an aqueous layer during work up. 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. aq.: Aqueous as: Apparent singlet br: Broad CDCl3: Deuterochloroform CV: Column volume d: Doublet dd: Doublet of doublets DCM: Dichloromethane DIPEA: N,N-Diisopropylethylamine DMF: N,N-Dimethylformamide DMSO-d6: Dimethyl sulfoxide-d6 ESI: Electrospray ionisation EtOAc: Ethyl acetate 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 J: Coupling constant LC-MS: Liquid chromatography-mass spectrometry m: Multiplet 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 Na2SO4: Sodium sulfate t: Triplet td: Triplet of doublets TFA: Trifluoroacetic acid Analytical Methods A number of 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: Waters Sunfire C183.5 μm, 50 x 4.6 mm; A = water + 0.1% formic acid; B = MeCN; 45 °C; %B: 0.0 min 5% 2.25 mL / min, 1.0 min 37.5% 2.2 mL / min, 3.0 min 95% 2.2 mL / min, 3.5 min 95% 2.3 mL / min, 3.51 min 100% 2.3 mL / min, 4.0 min 100% 2.3 mL / min. Method D: 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 min 5% 2.25 mL / min, 1 min 37.5% 2.2 mL / min, 3 min 95% 2.2 mL / min, 3.50 min 95% 2.30 mL / min, 3.51 min 5% 2.3 mL / min, 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_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:1H-NMR: Spectra are obtained on 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. GENERAL PROCEDURES General Route for Preparing Certain Example Compounds Example compounds of formula I3, R4, R6, R7aand R7bare each hydrogen, Q is O, A is N, and the -E-L- linker were synthesised according to the routes depicted in Schemes 1 and 2 below. Scheme 1: General procedure for preparing piperazine intermediates. Scheme 2: General procedure for preparing Example compounds of formula I. Other Example compounds of formula I, e.g. those where A is CH and E and L each represent a direct bond, were prepared by analogous methods. Preparation of Intermediates (A) Literature Intermediates A1 and A2. Intermediates A1 and A2 were synthesised in accordance with literature methods, as indicated in Table 4 below. Table 4. Literature methods for preparing compounds A1 and A2. (B) Key Intermediate A4. Synthesis of tert-butyl 4-chlorosulfonylpiperazine-1-carboxylate (A4) To a stirred solution of sulfuryl chloride (261 µL, 3.22 mmol) in DCM (10 mL) at 0oC was added a solution of 1-Boc-piperazine (A3; 500 mg, 2.68 mmol) and pyridine (326 µL, 4.03 mmol) in DCM (10 mL) and the mixture stirred for 2 h at RT. The reaction mixture was poured into 1 M HCl solution (50 mL). DCM (50 mL) was added to the solution, and the layers separated. The aq. layer was washed with DCM (2 x 25 mL), and the organic layers combined, dried (MgSO4), filtered, and concentrated in vacuo to afford tert-butyl 4-chlorosulfonylpiperazine-1-carboxylate (A4; 616 mg, 81 %) as a pale yellow solid, which was used without further purification. (C) Acrylamide Intermediate A7. Acrylamide intermediate potassium acryloyl glycinate A7 was prepared from glycine ester hydrochloride A5 in 2 steps as detailed in Scheme 3 below: Scheme 3: general procedure for preparing Acrylamide intermediate A7. Example Step 7: Synthesis of ethyl acryloyl glycinate (A6) 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 at that temperature 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). Example Step 8: Synthesis of potassium acryloyl glycinate (A7) 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). (D) Hetero-Aryl Intermediates. Sodium carbonate (790 mg, 7.45 mmol) was added to a stirred suspension of 1H- pyrrolo[3,2-c]pyridin-4(5H)-one (A8; 250 mg, 1.86 mmol) in toluene (5 mL) under nitrogen. The resulting mixture was heated at 60 °C for 30 min then cooled to RT, after which trimethylsilyl fluorosulfonyldifluoroacetate (1.40 g, 5.59 mmol) was added. The resulting reaction mixture was heated at 100 °C for 16 h. The reaction mixture was cooled to RT, concentrated, diluted with EtOAc (10 mL) and washed with water (10 mL), followed by brine (10 mL). The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography using 0-50 % EtOAc in iso-hexane to afford 4-(difluoromethoxy)-1H- pyrrolo[3,2-c]pyridine (A9; 171 mg, 50 %) as an off-white solid. LCMS (Method A) Rt 1.48 min, (ESI+) m / z 185 .2 [M+H]+. To a solution of 4-chloro-1H-pyrrolo[3,2-c]pyridine (A10; 300 mg, 1.97 mmol) dissolved in nitroethane (5 mL) at 0 °C was added portionwise, Selectfluor (2.09 g, 5.90 mmol). The reaction mixture was warmed to RT then stirred for 5 h after which further Selectfluor (698 mg, 1.97 mmol) was added, and the mixture was stirred for a further 24 h. The reaction mixture was quenched with ice-water (20 mL) and neutralised with sodium hydroxide (1 M solution in water, 1 mL). The resulting mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was pre-purified by silica gel column chromatography (25g Sfar Biotage column), eluting with 0-50 % EtOAc in iso- hexane then purified by reverse phase chromatography. Fractions containing desired product were combined and the solvents evaporated in vacuo. The residue was dissolved in 1:1 MeCN-H2O (4 mL) and the solution frozen. The solvent was evaporated in vacuo by lyophilisation to afford 4-chloro-3-fluoro-1H-pyrrolo[3,2-c]pyridine (A11; 32.0 mg, 10 %) as a white solid. LC-MS (Method A). Rt1.32 min, (ESI+) m / z 171.1, 173.0 [M+H]+. Synthesis of 4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (A13) 4-Chloro-7H-pyrrolo(2,3-d)pyrimidine (A12; 150 mg, 0.977 mmol) was suspended in sodium methoxide, 0.5 M in MeOH (8.00 mL, 4.00 mmol) and the mixture heated to reflux for 18 h. On cooling to RT, the solvent was evaporated in vacuo and the residue partitioned between EtOAc (50 mL) and satd. aq. sodium bicarbonate (50 mL). The organic phase was washed with brine (50 mL), then dried (MgSO4), filtered and the solvent evaporated in vacuo, to afford 4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (A13; 100 mg, 69 %) as a white solid. The compound was used without further purification.^ LC-MS (Method B). Rt1.19 min, (ESI+) m / z 150.1 [M+H]+. Intermediate compounds A14 and A15 depicted in Table 5 were prepared from corresponding commercially available chloro reagents using analogous procedures to that for preparing compound A13, with reaction times ranging from 1 to 18 h.

[0010] Table 5. Analytical data of intermediate compounds A14 and A15. Sodium methoxide (562 mg, 1.04 mmol) was added to a stirred solution of 7-bromo-4- chlorothieno[3,2-d]pyrimidine (A16; 2.00 g, 8.02 mmol) in THF (15 mL) under argon at RT. The resulting mixture was heated at 60 ºC for 12 h then cooled to RT and concentrated in vacuo. The crude residue was diluted with ice-cold water (20 mL), then extracted with EtOAc (2 x 15 mL). The combined organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The crude compound was purified by silica gel column chromatography using 10-20 % EtOAc in petroleum ether to afford 7-bromo-4- methoxythieno[3,2-d]pyrimidine (A17; 1.00 g, 50 %) as an off-white solid.1H NMR (400 MHz, CDCl3)1H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 7.88 (s, 1H), 4.22 (s, 3H). Synthesis of 4-bromo-1-ethyl-1H-indazole (A19) To a stirred solution of 4-bromo-1H-indazole (A18; 5.00 g, 25.4 mmol) in DMF (30 mL) at 0 °C, sodium hydride (1.32 g, 32.9 mmol) was added portion wise over 15 min. The mixture was allowed to stir for a further 15 min, then iodoethane (2.64 mL, 32.9 mmol) was slowly added and the resulting mixture was stirred for 4 h. The reaction mixture was quenched by pouring into crushed ice then extracted with EtOAc (50 mL). The combined organic layer was washed with brine (3 x 30 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography using 5 – 30 % EtOAc in petroleum ether to afford 4-bromo-1-ethyl- 1H-indazole (A19; 3.50 g, 95 %) as a pale yellow oil.1H NMR (400 MHz, CDCl3)1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 1.0 Hz, 1H), 7.36 (dt, J = 8.3, 0.9 Hz, 1H), 7.29 (dd, J = 7.4, 0.8 Hz, 1H), 7.22 (dd, J = 8.3, 7.4 Hz, 1H), 4.42 (q, J = 7.2 Hz, 2H), 1.51 (t, J = 7.3 Hz, 3H). 7-Chlorothieno[2,3-c]pyridine (A20; 250 mg, 1.47 mmol) was suspended in chlorosulfonic acid, 97% (3.00 mL, 45.1 mmol) and the mixture heated to 100oC for 1.5 h. The mixture was cooled to RT and poured over ice water. The pH of the mixture was adjusted to 8 using aqueous sodium hydroxide, and the mixture extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with satd. aq. sodium bicarbonate (50 mL), and brine (50 mL), then dried (MgSO4), filtered, and concentrated in vacuo, to afford 7-chlorothieno[2,3-c]pyridine-3-sulfonyl chloride (A21; 200 mg, 51 %) as a pale yellow gum, which used without further purification. LC-MS (Method B). Rt 1.86 min, (ESI+) m / z 247.9, 249.9 [M-H+O]+(evidence of sulfonic acid formation). (E) Sodium Sulfinate Intermediates A32 to A34. Exemplary sodium sulfinates A32 to A34 were prepared from the corresponding aryl bromide in 3 steps as detailed in Scheme 4 below:

[0011] Scheme 4: general procedure for preparing sodium sulfinate intermediates. Example Step 9 - Preparation of sulfides: A mixture of 7-bromo-4-methoxythieno[3,2-d]pyrimidine (A17; 1.00 g, 4.08 mmol), 4,5-bis(diphenylphospheno)-9,9-dimethylxanthene (Xantphos; 236 mg, 0.408 mmol), tris(dibenzylideneacetone) dipalladium (0) (187 mg, 0.204 mmol) and DIPEA (1.5 mL, 8.16 mmol) in toluene (30 mL) was degassed with nitrogen for 5 min after which methyl 3-mercaptopropionate (450 µL, 4.08 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-((4-methoxythieno[3,2-d]pyrimidin-7-yl)thio)propanoate (A26; 1.00 g, 86 %) as an off-white solid.1H NMR (400 MHz, CDCl3)1H NMR (400 MHz, CDCl3) δ 8.84 (s, 1H), 7.75 (s, 1H), 4.18 (s, 3H), 3.67 (s, 3H), 3.31 (t, J = 7.3 Hz, 2H), 2.66 (t, J = 7.3 Hz, 2H). Intermediate compounds A27 and A28 depicted in Table 6 below were prepared from the corresponding aryl halide intermediate and methyl 3-mercaptopropionate using analogous procedures to Example Step 9 (to compound A26). Example Step 10a - Preparation of sulfones using Oxone®: Synthesis of methyl 3-((4-methoxythieno[3,2-d]pyrimidin-7-yl)sulfonyl)propanoate (A29) Oxone® (2.70 g, 8.8 mmol) was added to a stirred solution of methyl 3-((4- methoxythieno[3,2-d]pyrimidin-7-yl)thio)propanoate (A26; 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-((4-methoxythieno[3,2-d]pyrimidin-7- yl)sulfonyl)propanoate (A29; 1.10 g, 98 %) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 8.91 (s, 1H), 8.70 (s, 1H), 4.22 (s, 3H), 3.92 (m, 2H), 3.64 (s, 3H), 2.85 (dd, J = 8.2, 7.2 Hz, 2H). Intermediate compound A30 depicted in Table 7 below was prepared using analogous procedures to Example Step 10a (to compound A29). Table 7. Analytical data of intermediate compound A30. Example Step 10b - Oxidation of sulfone using 3-chloroperbenzoic acid: Synthesis of 3-((1-methyl-1H-indazol-4-yl)sulfonyl)propanoate (A31) 3-Chloroperbenzoic acid (345 mg, 2.00 mmol) was added portion wise to a stirred solution of methyl 3-((1-methyl-1H-indazol-4-yl)thio)propanoate (A27; 200 mg, 0.80 mmol) in DCM (20 mL) at 0 °C. The resulting reaction mixture was warmed to RT then stirred for 4 h. The reaction mixture was stirred for 5 min with satd. aq. sodium sulfite (20 mL) then washed with satd. aq. sodium bicarbonate (20 mL). The organic layer was separated then concentrated in vacuo. The crude residue was purified by silica gel column chromatography eluting with 75 % EtOAc in n-hexane to afford 3-((1-methyl- 1H-indazol-4-yl)sulfonyl)propanoate (A31; 175 mg, 78 %) as an off-white solid.1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.74 (ddd, J = 9.6, 7.9, 0.8 Hz, 2H), 7.54 (ddd, J = 8.2, 7.1, 0.9 Hz, 1H), 4.17 (s, 3H), 3.62 (s, 3H), 3.52 (dd, J = 8.2, 7.2 Hz, 2H), 2.76 (dd, J = 8.2, 7.3 Hz, 2H). Example Step 11 - Preparation of sodium sulfinates: Synthesis of sodium 4-methoxythieno[3,2-d]pyrimidine-7-sulfinate (A32) To a solution of methyl 3-[(8-methyl-1,5-naphthyridin-4-yl)sulfonyl]propanoate (A29; 1.00 g, 3.32 mmol) in THF (10 mL) was added sodium ethoxide (271 mg, 3.99 mmol). The resulting mixture was stirred at RT for 3 h. The precipitated solid was collected by filtration, washed with EtOAc (10 mL), followed by Et2O (2 x 10 mL), then dried under vacuum to afford sodium 4-methoxythieno[3,2-d]pyrimidine-7-sulfinate (A32; 800 mg, 95 %) as a yellow solid. The compound was used without further purification. Intermediate compounds A33 and A34 depicted in Table 8 below were prepared from the corresponding the corresponding sulfonyl intermediate using analogous procedures to Example Step 11 (to compound A32). Table 8. Analytical data of intermediate compounds A33 and A34. Preparation of Sulfonamide Intermediates (A) Example of Route 1: Step 1a - Coupling Of Heteroaryl Sulfonyl Chlorides. Exemplary sulfonamide intermediates B1 and B2 were prepared from coupling of corresponding sulfonyl chlorides with corresponding amines, as detailed in Scheme 5 below: Scheme 5: general procedure for preparing sulfonamide intermediates. Example Step 1a: Synthesis of tert-butyl 4-(7-chlorothieno[2,3-c]pyridin-3- To a stirred solution of 7-chlorothieno[2,3-c]pyridine-3-sulfonyl chloride (A21; 200 mg, 0.75 mmol) in DCM (5 mL) was added triethylamine (208 µL, 1.49 mmol) and 1-Boc- piperazine (170 mg, 0.90 mmol) and the mixture stirred at RT for 18 h. The reaction was quenched through addition of 10% w / v citric acid (10 mL) and diluted with DCM (20 mL). The phases were separated using a phase separator, and the aq. layer washed with DCM (20 mL). The organic layers were combined, washed with brine (20 mL), dried (MgSO4), filtered, and concentrated in vacuo, to afford tert-butyl 4-(7- chlorothieno[2,3-c]pyridin-3-yl)sulfonylpiperazine-1-carboxylate (B1; 250 mg, 80 %) as a white solid. LC-MS (Method A). Rt 1.94 min, (ESI+) m / z 418.1 [M+H]+. Intermediate compound B2 depicted in Table 9 below was prepared from the corresponding sulfonyl chloride with compound A3 using analogous procedures to Example Step 1a (to compound B1). Table 9. Analytical data of intermediate compound B2. Synthesis of tert-butyl (1-(benzo[b]thiophen-3-ylsulfonyl)piperidin-4-yl)carbamate (B3) Tert-butylpiperidin-4-ylcarbamate (A23; 516 mg, 2.58 mmol) and DIPEA (417 mg, 3.22 mmol) were dissolved in THF (10 mL). 1-Benzothiophene-3-sulfonyl chloride (A22; 580 mg, 2.15 mmol) was added in portions over 5 min and the reaction mixture was stirred at 60 °C for 1 h. On cooling the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (20 mL) and washed consecutively with satd. aq. sodium hydrogen sulfate (10 mL), satd. aq. sodium bicarbonate (10 mL) and brine (10 mL). The organic layer was dried (MgSO4), filtered and the solvent was removed under reduced pressure to afford tert-butyl (1-(benzo[b]thiophen-3-ylsulfonyl)piperidin-4- yl)carbamate (B3; 726 mg, 99 %) as a beige solid. This was used in the next step without purification.1H NMR (400 MHz, CDCl3) δ 8.27 - 8.22 (m, 1H), 8.17 (s, 1H), 7.91 (m, 1H), 7.52 - 7.44 (overlapping m, 2H), 4.41 (broad s, 1H), 3.79 (d, 2H, J = 11.84 Hz, 2H), 3.40 (broad s, 1H), 2.70 - 2.60 (overlapping m, 2H), 2.01 - 1.93 (overlapping m, 2H), 1.52 - 1.41 (overlapping m, 2H), 1.40 (s, 9H). Intermediate compound B4 depicted in Table 10 below was prepared from the corresponding commercially available sulfonyl chloride with compound A3 using analogous procedures to the synthesis of compound B3. Table 10. Analytical data of intermediate compound B4. (B) Coupling Of Piperazine Intermediate With Sulfonyl Chlorides Prepared In Situ. Exemplary sulfonamide intermediates B5 to B8 were prepared from in situ preparation of corresponding sulfonyl chlorides followed by coupling with corresponding amines, as detailed in Scheme 6 below:

[0012] Scheme 6: general procedure for preparing sulfonamide intermediates in situ. Example Step 12a / 12b: Synthesis of tert-butyl 4-((7-bromo-1-methyl-1H-indol-3- yl)sulfonyl)piperazine-1-carboxylate (B5) To a stirred solution of 7-bromo-1-methyl-1H-indole (A24; 1.00 g, 4.76 mmol) in MeCN (10 mL) at 0 °C was added chlorosulfonic acid (1.10 mL, 16.7 mmol). The resulting mixture was stirred at RT for 2 h then concentrated to afford crude sulfonyl chloride (A25). The residue was diluted with THF (10 mL) under argon and cooled to 0 °C. DIPEA (2.60 mL, 14.3 mmol) and 1-Boc-piperazine (1.32 g, 7.14 mmol) were added. The reaction mixture was then heated at 50 °C for 12 h allowed to cool and concentrated in vacuo. The residue was diluted with EtOAc (25 mL), washed with brine (25 mL), and the organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography using 30-40 % EtOAc / petroleum ether to afford tert-butyl 4-((7-bromo-1-methyl-1H-indol-3- yl)sulfonyl)piperazine-1-carboxylate (B5; 300 mg, 13 %) as an off-white solid.1H NMR (400 MHz, CDCl3) δ 7.89 (dd, J = 8.1, 1.0 Hz, 1H), 7.52 (s, 1H), 7.48 (dd, J = 7.7, 1.0 Hz, 1H), 7.09 (t, J = 7.9 Hz, 1H), 4.23 (s, 3H), 3.54 – 3.47 (overlapping m, 4H), 3.05 - 2.99 (overlapping m, 4H), 1.39 (s, 9H). Intermediate compounds B6 to B8 depicted in Table 11 below were prepared from commercially available reagents, where available(*), using analogous procedures to Example Step 12a / 12b (to compound B5).

[0013] Table 11. Analytical data of intermediate compounds B6 to B8. (C) Oxidative Coupling Of Sodium Sulfinates With Boc-Protected Intermediates. Exemplary sulfonamide intermediates B9 to B11 were prepared from the corresponding sodium sulfinates via an oxidative coupling with corresponding amines, as detailed in Scheme 7 below: Scheme 7: general procedure for preparing sulfonamide intermediates B9 to B11. Example Step 13: Oxidative coupling of sodium sulfinates with Boc-protected piperazine intermediate: Synthesis of tert-butyl 4-((4-methoxythieno[3,2-d]pyrimidin-7- yl)sulfonyl)piperazine-1-carboxylate (B9) Iodine (645 mg, 2.54 mmol) was added to a stirred solution of sodium 4- methoxythieno[3,2-d]pyrimidine-7-sulfinate (A32; 800 mg, 3.17 mmol) in EtOH (10 mL), followed by the addition of 1-Boc-piperazine (680 mg, 3.65 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 homogeneous 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- ((4-methoxythieno[3,2-d]pyrimidin-7-yl)sulfonyl)piperazine-1-carboxylate (B9; 100 mg, 8 %) as an off-white solid.1H NMR (400 MHz, CDCl3) δ 8.88 (s, 1H), 8.53 (s, 1H), 4.21 (s, 3H), 3.52 - 3.47 (overlapping m, 4H), 3.35 - 3.31 (overlapping m, 4H), 1.41 (s, 9H). Intermediate compounds B10 and B11 depicted in Table 12 below were prepared from the corresponding sodium sulfinate or sulfonyl chloride with the corresponding amine intermediate using analogous procedures to Example Step 13 (to compound B9). Table 12. Analytical data of intermediate compounds B10 and B11. (D) Preparation Of Sulfonamide Intermediate B12 In Situ. Example sulfonamide intermediate B12 was prepared from indole A35 as detailed below: To a stirred suspension of 1-imidazol-1-ylsulfonyl-3-methylimidazol-3-ium; trifluoromethanesulfonate (A1; 200 mg, 0.55 mmol) in MeCN (3 mL), indole (A35; 32.3 mg, 0.28 mmol), tert-butylpiperidin-4-ylcarbamate (A23; 221 mg, 1.10 mmol) and DIPEA (96.1 µL, 0.55 mmol) were added at RT. The resulting mixture was heated at 70 °C for 10 h then cooled to RT and quenched with ice-cold water (10 mL). The mixture was extracted with 5% MeOH / DCM (2 x 15 mL) and the organics were concentrated in vacuo. The crude residue was partially purified by silica gel column chromatography to afford tert-butyl (1-((1H-indol-1-yl)sulfonyl)piperidin-4-yl)carbamate (B12; 100 mg, 5 %, <25% purity)] as an orange oil. The product was taken through to next step without any further purification. LC-MS (Method C). Rt 1.48 min, (ESI+) m / z 380.2 [M+H]+. (E) Coupling of Boc-Protected Intermediate B13 With Sulfonyl Chloride Prepared In Situ. Example sulfonamide intermediate B13 was prepared from intermediate A2 as detailed below:

[0014] Synthesis of 1-methyl-1H-indazole-4-sulfinic acid (A37) A mixture of 4-bromo-1-methylindazole (A2; 500 mg, 2.37 mmol), 1,4- diazabicylco[2.2.2]octane bis(sulfur dioxide)adduct (A36; 610 mg, 2.54 mmol) and N- cyclohexyl-N-methylcyclohexanemine (1.64 mL, 7.66 mmol) in dry iso-propanol (10 mL) was degassed for 5 min after which bis(di-tert-butyl(4- dimethylaminophenyl)phosphine)dichloropalldium (II) (100 mg, 0.14 mmol) was added. The resulting mixture was degassed for a further 5 min then heated in the microwave at 110 °C for 2.5 h (CEM, 200W). The mixture was cooled to RT, filtered through a pad of celite then washed with iso-propanol l (2 x 10 mL) and the organics were concentrated in vacuo to afford crude 1-methyl-1H-indazole-4-sulfinic acid (A37; 1.00 g, quant.) as a pale-yellow gummy oil. The compound was used in the subsequent step without any further purification. LC-MS (Method D). Rt 2.08 min, (ESI+) m / z 197.2 [M+H]+. 3-Chloroperbenzoic acid (291 mg, 1.69 mmol) was added in a single portion to a stirred solution of 1-methyl-1H-indazole-4-sulfinic acid (A37; 500 mg, 1.27 mmol) in DCM (5 mL) at 0 °C, under nitrogen. The resulting mixture was allowed to stir at RT for 3 h. The reaction mixture was diluted with ice-water and extracted with 10% MeOH / DCM (3 x 20 mL). The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo to afford 1-methyl-1H-indazole-4-sulfonic acid (A38; 270 mg, quant.) as an off- white solid. The compound was used in the next step without any further purification. LC-MS (Method D). Rt1.54 min, (ESI+) m / z 213.1 [M+H]+. Synthesis of tert-butyl (2-(4-((1-methyl-1H-indazol-4-yl)sulfonyl)piperazin-1-yl)-2- oxoethyl)carbamate (B13) Thionyl chloride (1.00 mL, 13.8 mmol) was added to 1-methylindazole-4-sulfonic acid (A38; 500 mg, 1.65 mmol) and the mixture was heated at 70 °C for 2 h. The reaction mixture was cooled to RT, concentrated in vacuo to give a crude sulfonyl chloride (A39) which was diluted with DCM (10 mL). In a separate flask, 1-(Boc- aminoacetyl)piperazine (A40; 401 mg, 1.65 mmol) and triethylamine (1.15 mL, 8.25 mmol) in DCM (10 mL) was stirred at 0 °C after which a solution of the sulfonyl chloride (A39) in DCM was slowly added. The resulting mixture was warmed to RT then stirred for 16 h. The mixture was diluted with ice-cold water (10 mL) and washed with satd. aq. sodium bicarbonate solution. The organic layer was separated, dried (Na2SO4), and concentrated in vacuo. The crude residue was purified by column chromatography using 0-2 % MeOH in DCM to afford tert-butyl (2-(4-((1-methyl-1H-indazol-4- yl)sulfonyl)piperazin-1-yl)-2-oxoethyl)carbamate (B13; 120 mg, 11%, 66% purity) as an off-white solid. LC-MS (Method D). Rt 2.25 min, (ESI+) m / z 460.1 [M+Na]+. (F) Coupling Of Sulfonyl Chloride With N-Heteroaryl Intermediates. Exemplary sulfonamide intermediates B14 to B24 were prepared from coupling sulfonyl chloride A4 with corresponding N-heteroaryl intermediates, as detailed in Scheme 8 below: Scheme 8: general procedure for preparing sulfonamide intermediates B14 to B24. Example Step 1b: Synthesis of tert-butyl 4-((4-(difluoromethoxy)-1H-pyrrolo[3,2- c]pyridin-1-yl)sulfonyl)piperazine-1-carboxylate (B14) 4-(Difluoromethoxy)-1H-pyrrolo[3,2-c]pyridine (A9; 100 mg, 0.543 mmol) and tetrabutylammonium bromide (21 mg, 0.0652 mmol) were dissolved in a mixture of DCM (5 mL) and sodium hydroxide (434 mg, 10.9 mmol) dissolved in 1.1 mL water then, tert-butyl 4-chlorosulfonylpiperazine-1-carboxylate (A4; 170 mg, 0.597 mmol) was added. Reaction mixture was vigorously stirred for 16 h. Reaction mixture was quenched by adding water (50 mL), brine (50 mL), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by silica gel column chromatography using gradient eluent 0-100 % EtOAc in iso-hexane to afford tert-butyl 4-((4- (difluoromethoxy)-1H-pyrrolo[3,2-c]pyridin-1-yl)sulfonyl)piperazine-1-carboxylate (B14; 178 mg, 76 %) as a yellow solid. LC-MS (Method A). Rt 1.99 min, (ESI+) m / z 433.2 [M+H]+;19F NMR (377 MHz, CDCl3): δ = -88.89 (d, JHF = 80 Hz). Intermediate compounds B15 to B24 depicted in Table 13 below were prepared from the coupling of sulfonyl chloride A4 with the corresponding N-heteroaryl intermediates (commercially available*), using analogous procedures to Example Step 1b (to compound B14).

[0015] Table 13. Analytical data of intermediate compounds B15 to B24.aReaction carried out with tetrabutyl ammonium iodide I as a substitute for tetrabutyl ammonium bromide.bIsolated as an inseparable mixture of compounds with chlorination of indole observed. Preparation of Methoxy Intermediates Exemplary methoxy intermediates B25 to B32 were prepared from the corresponding chloro intermediates as detailed in Scheme 9 below: Scheme 9: general procedure for preparing methoxy intermediates B25 to B32. (A) Palladium Catalysed Methoxylation. Example Step 14: Synthesis of tert-butyl 4-((4-methoxy-7-methyl-1H-pyrrolo[3,2- A mixture of palladium (II) acetate (32.1 mg, 0.14 mmol), 2-[di(tert-butyl)phosphino]- 2',4',6'-triisopropyl-1,1'-biphenyl (tBu X-phos) (122 mg, 0.29 mmol), cesium carbonate (2.33 g, 7.16 mmol) in toluene (10 mL) was degassed for 5 min then heated at 80 °C under microwave irradiation for 5 min (200 W, CEM). The reaction mixture was cooled and a solution of tert-butyl 4-((4-chloro-7-methyl-1H-pyrrolo[3,2-c]pyridin-1- yl)sulfonyl)piperazine-1-carboxylate (B17; 1.98 g, 4.77 mmol) in MeOH (10 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), 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 tert-butyl 4-((4-methoxy-7-methyl-1H- pyrrolo[3,2-c]pyridin-1-yl)sulfonyl)piperazine-1-carboxylate (B25; 1.70 g, 87 %) as an off-white solid. LC-MS (Method A). Rt 1.99 min, (ESI+) m / z 411.3 [M+H]+. Intermediate compounds B26 to B32 depicted in Table 14 below were prepared from chloro intermediates, using analogous procedures to Example Step 14 (to compound B25).

[0016] Table 14. Analytical data of intermediate compounds B26 to B31.CConventional heating at 80 °C used in place of microwave heating. (B) Synthesis of Methoxy Intermediate B32 Via Displacement. Synthesis of tert-butyl 4-(7-methoxythieno[2,3-c]pyridin-3-yl)sulfonylpiperazine-1- Tert-butyl 4-(7-chlorothieno[2,3-c]pyridin-3-yl)sulfonylpiperazine-1-carboxylate (B1; 250 mg, 0.60 mmol) was suspended in a solution of sodium methoxide in MeOH (5.4 M, 2 mL, 10.8 mmol), and the mixture stirred at RT until complete. The reaction was quenched through addition of brine (10 mL), and MeOH was removed in vacuo. The aq. layer was extracted with EtOAc (3 x 50 mL), and the combined organic layers were separated, dried (MgSO4), filtered, and concentrated in vacuo to afford tert-butyl 4-(7- methoxythieno[2,3-c]pyridin-3-yl)sulfonylpiperazine-1-carboxylate (B32; 128 mg, 52 %) as a white solid. LCMS (Method A). Rt 1.93 min, (ESI+) m / z 414.2 [M+H]+. N-Boc Deprotection Exemplary amine intermediates C1 to C23 were prepared from the corresponding N- boc intermediates as detailed in Scheme 10 below: Scheme 10: general procedure for preparing intermediates C1 to C23. Example Step 2: Synthesis of 4-(difluoromethoxy)-1-(piperazin-1-ylsulfonyl)-1H- TFA (500 µL, 6.53 mmol) was added dropwise to a stirred solution of tert-butyl 4-((4- (difluoromethoxy)-1H-pyrrolo[3,2-c]pyridin-1-yl)sulfonyl)piperazine-1-carboxylate (B14; 175 mg, 0.405 mmol) in DCM (2 mL) at RT. The resulting mixture was stirred for 30 min. The reaction mixture was then concentrated in vacuo to afford a residue which was dissolved in DCM (5 mL) and passed through a SCX-2 cartridge (5 g), washing with MeOH (3 CV), followed by DCM (3 CV). The product was eluted with 1 M NH3 in MeOH (6 CV) and the organics were concentrated in vacuo to afford 4-(difluoromethoxy)-1- (piperazin-1-ylsulfonyl)-1H-pyrrolo[3,2-c]pyridine (C1; 132 mg, 98 %) as a pale brown solid. LC-MS (Method B). Rt 1.66 min, (ESI+) m / z 333.1 [M+H]+. Intermediate compounds C2 to C23 depicted in Table 15 below were prepared using analogous procedures Example Step 2 (to compound C1) with reaction times ranging from 10 minutes to 18 hours.

[0017]

[0018]

[0019]

[0020]

[0021] Table 15. Analytical data of intermediate compounds C2 to C23.dIsolated as a TFA salt.eSeparated as a mixture of des-chloro and chlorinated compounds via reverse phase chromatography. Preparation of Difluoromethoxy Intermediate C24 Example difluoromethoxy intermediate C24 was prepared from intermediate C4 as detailed below:

[0022] N-Benzylation Reaction: Synthesis of 1-((4-benzylpiperazin-1-yl)sulfonyl)-4-methoxy- 7-methyl-1H-pyrrolo[3,2-c]pyridine (B33) Benzyl bromide (514 µL, 4.32 mmol) was added to a mixture of 4-methoxy-7-methyl- 1-(piperazin-1-ylsulfonyl)-1H-pyrrolo[3,2-c]pyridine (C4; 1.34 g, 4.32 mmol) and potassium carbonate (1.19 g, 8.63 mmol) in MeCN (20 mL). The resulting mixture was stirred at RT for 30 min then concentrated in vacuo. The residue was treated with water (50 mL) and extracted with DCM (2 x 50 mL). The combined organic layer was washed with brine (50 mL), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by silica gel column chromatography (25 g Biotage Sfar) using gradient eluent 0-50 % EtOAc in iso-hexane to afford 1-((4-benzylpiperazin-1- yl)sulfonyl)-4-methoxy-7-methyl-1H-pyrrolo[3,2-c]pyridine (B33; 1.32 g, 76 %) as an off-white solid. LC-MS (Method A). Rt 1.58 min, (ESI+) m / z 401.3 [M+H]+. O-Demethylation Reaction: Synthesis of 1-((4-benzylpiperazin-1-yl)sulfonyl)-7- methyl-1H-pyrrolo[3,2-c]pyridin-4-ol (B34) Iodotrimethylsilane (931 µL, 6.54 mmol) was added to a suspension of 1-((4- benzylpiperazin-1-yl)sulfonyl)-4-methoxy-7-methyl-1H-pyrrolo[3,2-c]pyridine (B33; 1.31 g, 3.27 mmol) in MeCN (20 mL) at RT. The resulting mixture was heated at 65 °C for 3 h. The mixture was then cooled to RT and then satd. aq. sodium bicarbonate (5 mL) and satd. aq. sodium thiosulfate (5 mL) were both added. The aq. layer was extracted with EtOAc (3 x 5 mL) and the combined organic phases were washed with water (5 mL), dried (Na2SO4), and the solvents were evaporated in vacuo. The crude residue was purified by silica gel column chromatography (25 g Sfar Biotage) using gradient eluent 0-20 % MeOH in DCM to afford 1-((4-benzylpiperazin-1-yl)sulfonyl)-7- methyl-1H-pyrrolo[3,2-c]pyridin-4-ol (B34; 1.15 g, 91 %) as an off-white solid. LC-MS (Method A). Rt 1.21 min, (ESI+) m / z 387.2 [M+H]+. O-Difluoromethoxylation: Synthesis of 1-((4-benzylpiperazin-1-yl)sulfonyl)-4- To a stirred suspension of 1-((4-benzylpiperazin-1-yl)sulfonyl)-7-methyl-1H- pyrrolo[3,2-c]pyridin-4-ol (B34; 793 mg, 2.05 mmol) in toluene (15 mL) under nitrogen was added, sodium carbonate (544 mg, 5.13 mmol). The resulting mixture was heated at 60 °C for 30 min then cooled to RT after which trimethylsilyl fluorosulfonyldifluoroacetate (621 µL, 3.08 mmol) was added. The resulting reaction mixture was heated at 100 °C for 16 h. The reaction mixture was cooled to RT, concentrated, diluted with EtOAc (10 mL) and washed with water (10 mL), followed by brine (10 mL). The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (25 g Biotage Sfar) using 0-50 % EtOAc in iso-hexane to afford 1-((4- benzylpiperazin-1-yl)sulfonyl)-4-(difluoromethoxy)-7-methyl-1H-pyrrolo[3,2- c]pyridine (B35; 482 mg, 54 %) as an off-white solid. LC-MS (Method A). Rt 1.71 min, (ESI+) m / z 437.2 [M+H]+;19F NMR (377 MHz, CDCl3): δ = -88.35 (d, JHF = 76.8 Hz).

[0023] N-Benzyl Deprotection: Synthesis of 4-(difluoromethoxy)-7-methyl-1-(piperazin-1- ylsulfonyl)-1H-pyrrolo[3,2-c]pyridine (C24) A solution of 1-((4-benzylpiperazin-1-yl)sulfonyl)-4-(difluoromethoxy)-7-methyl-1H- pyrrolo[3,2-c]pyridine (B35; 440 mg, 1.01 mmol) in EtOH (10 mL) using 10% Pd / C CatCart cartridge (70 x 4 mm) was pumped through the H-cube at RT, atmospheric pressure and 1 mL / min flow rate. The cycle was repeated once more, and the system was washed with EtOH (10 mL) after which the organics were concentrated in vacuo. The crude solid was dissolved in DCM (5 mL) and passed through a SCX-2 cartridge (2 g), washing with MeOH (3 CV), followed by DCM (3 CV). The product was eluted with 1 M NH3 in MeOH (6 CV) and the organics were concentrated in vacuo to afford 4-(difluoromethoxy)-7-methyl-1-(piperazin-1-ylsulfonyl)-1H-pyrrolo [3,2-c] pyridine (C24; 250 mg, 72 %) as an off-white solid. LC-MS (Method A). Rt 1.69 min, (ESI+) m / z 347.1 [M+H]+. Amide Coupling Exemplary amide intermediates B36 to B45 were prepared from the corresponding amine intermediates as detailed in Scheme 11 below: Scheme 11: general procedure for preparing amide intermediates B36 to B45. Example Step 4: Synthesis of tert-butyl (2-(4-((4-(difluoromethoxy)-1H-pyrrolo[3,2- A mixture of Boc-N-methylglycine (27 mg, 0.141 mmol), HATU (54 mg, 0.141 mmol) and DIPEA (74 µL, 0.424 mmol) in DCM (5 mL) was stirred for 5 min after which 4-(difluoromethoxy)-1-(piperazin-1-ylsulfonyl)-1H-pyrrolo[3,2-c]pyridine (C1; 47 mg, 0.141 mmol) was added. The resulting mixture was stirred at RT for 16 h. The reaction mixture was diluted with DCM (10 mL) and washed with satd. aq. sodium bicarbonate (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 (Sfar 25g), eluting with 0-10 % MeOH in DCM to afford tert-butyl (2-(4-((4-(difluoromethoxy)-1H-pyrrolo[3,2- c]pyridin-1-yl)sulfonyl)piperazin-1-yl)-2-oxoethyl)(methyl)carbamate (B36; 65.4 mg, 92 %) as an off-white solid. LC-MS (Method A). Rt 1.84 min, (ESI+) m / z 526.2 [M+Na]+. Intermediate compounds B37 to B45 depicted in Table 16 were prepared using analogous procedures to Example Step 4 (to compound B36) with reaction times ranging from 1 to 16 hours.

[0024] eReaction carried out in DMF as a substitute for DCM. N-Deprotection Exemplary amine intermediates D1 to D11 were prepared from the corresponding N- boc intermediates as detailed in Scheme 12 below: Scheme 12: general procedure for preparing intermediates D1 to D11. Example Step 4: Synthesis of 1-(4-((4-(difluoromethoxy)-1H-pyrrolo[3,2-c]pyridin-1- TFA (0.50 mL, 6.53 mmol) was added dropwise to a stirred solution of tert-butyl (2-(4- ((4-(difluoromethoxy)-1H-pyrrolo[3,2-c]pyridin-1-yl)sulfonyl)piperazin-1-yl)-2- oxoethyl)(methyl)carbamate (B36; 65 mg, 0.129 mmol) in DCM (2 mL) at RT. The resulting mixture was stirred for 30 min. The reaction mixture was then concentrated in vacuo to afford a residue which was dissolved in DCM (5 mL) and passed through a SCX-2 cartridge (5 g), washing with MeOH (3 CV), followed by DCM (3 CV). The product was eluted with 1 M NH3in MeOH (6 CV) and the organics were concentrated in vacuo to afford 1-(4-((4-(difluoromethoxy)-1H-pyrrolo[3,2-c]pyridin-1-yl)sulfonyl)piperazin- 1-yl)-2-(methylamino)ethan-1-one (D1; 52.1 mg, 98 %) as a pale brown solid. LC-MS (Method B). Rt 1.61 min, (ESI+) m / z 404.2 [M+H]+. Intermediate compounds D2 to D11 depicted in Table 17 below were prepared using analogous procedures to Example Step 4 (to compound D1) with reaction times varying between 30 mins to 16 hours.

[0025] Table 17. Analytical data of intermediate compounds D2 to D11. Preparation of Acrylamides Example compounds Ex-1 to Ex-18 were prepared from the corresponding piperazine intermediates as detailed in Scheme 13 below: Scheme 13: general procedure for preparing Example compounds Ex-1 to Ex-18. (A) Preparation Of Acrylamides Using HATU. Example Step 3: Synthesis of N-(2-(4-((4-(difluoromethoxy)-1H-pyrrolo[3,2-c]pyridin- A mixture of potassium acryloyl glycinate (A7; 38 mg, 0.226 mmol), HATU (86 mg, 0.226 mmol) and DIPEA (157 µL, 0.903 mmol) in DCM (5 mL) was stirred for 5 min after which 4-(difluoromethoxy)-1-(piperazin-1-ylsulfonyl)-1H-pyrrolo[3,2-c]pyridine (C1; 75 mg, 0.226 mmol) in DCM (2 mL) was added. The resulting mixture was stirred at RT for 30 min. The reaction mixture was diluted with DCM (10 mL) and washed with satd. aq. sodium bicarbonate (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 reverse phase chromatography to afford N-(2-(4-((4- (difluoromethoxy)-1H-pyrrolo[3,2-c]pyridin-1-yl)sulfonyl)piperazin-1-yl)-2- oxoethyl)acrylamide (Ex-1; 82 mg, 82 %) as a white solid. LC-MS (Method E). Rt 4.27 min, (ESI+) m / z 444.2 [M+H]+. Example compounds Ex-2 to Ex-11 depicted in Table 18 below were prepared using analogous procedures to Example Step 3 (to compound Ex-1) with reaction times varying between 30 minutes to 2 hours.

[0026] Table 18. Analytical data of Example compounds Ex-2 to Ex-11. (B) Preparation Of Acrylamides Using EDCI. Example Step 3: Preparation of N-(2-(4-((4-methoxythieno[3,2-d]pyrimidin-7- DIPEA (560 µL, 3.05 mmol) was added to a stirred solution of 4-methoxy-7-(piperazin- 1-ylsulfonyl)thieno[3,2-d]pyrimidine 2,2,2-trifluoroacetate (C14; 500 mg, 1.22 mmol) in DCM (10 mL), followed by the addition of potassium acryloyl glycinate (A7; 203 mg, 1.59 mmol), N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDC.HCl) (304 mg, 1.59 mmol) and 1-hydroxybenzotriazole (HOBt) (82.0 mg, 0.61 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 (20 mL). The organic layer was separated, washed with satd. aq. sodium bicarbonate (20 mL), followed by brine (20 mL), then dried (Na2SO4) and the solvent was removed in vacuo. The crude product was purified by silica gel column chromatography using 80 % EtOAc in iso-hexane to afford N-(2-(4-((4-methoxythieno[3,2-d]pyrimidin-7- yl)sulfonyl)piperazin-1-yl)-2-oxoethyl)acrylamide (Ex-12; 25.0 mg, 31 %) as an off- white solid. LC-MS (Method E). Rt 3.35 min, (ESI+) m / z 426.2 [M+H]+;1H NMR (400 MHz, CDCl3) δ 8.86 (s, 1H), 8.56 (s, 1H), 6.57 (br s, 1H), 6.29 (dd, J = 17.0, 1.5 Hz, 1H), 6.15 (dd, J = 17.0, 10.2 Hz, 1H), 5.67 (dd, J = 10.2, 1.5 Hz, 1H), 4.20 (s, 3H), 4.09 (d, J = 4.1 Hz, 2H), 3.76 – 3.72 (overlapping m, 2H), 3.56 – 3.50 (overlapping m, 2H), 3.46 (overlapping m, 2H), 3.39 (overlapping m, 2H). Example compounds Ex-13 to Ex-16 depicted in Table 19 below were prepared using analogous procedures to Example Step 3 (to compound Ex-12) with reaction times varying between 30 minutes to 2 hours.

[0027]

[0028] (C) Preparation Of Acrylamides Using Acryloyl Chloride Example compounds Ex-17 to Ex-30 were prepared from the corresponding amine intermediates as detailed in Scheme 14 below:

[0029] Scheme 14: general procedure for preparing Example compounds Ex-17 to Ex-30. Example Step 6: Synthesis of N-(2-(4-((4-(difluoromethoxy)-1H-pyrrolo[3,2-c]pyridin- To a stirred solution of 1-(4-((4-(difluoromethoxy)-1H-pyrrolo[3,2-c]pyridin-1- yl)sulfonyl)piperazin-1-yl)-2-(methylamino)ethan-1-one (D1; 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 to afford N-(2-(4-((4- (difluoromethoxy)-1H-pyrrolo[3,2-c]pyridin-1-yl)sulfonyl)piperazin-1-yl)-2-oxoethyl)- N-methylacrylamide (Ex-17; 43.8 mg, 79 %) as a white solid. LC-MS (Method E). Rt 4.36 min, (ESI+) m / z 458.2 [M+H]+. Example compounds Ex-18 to Ex-30 depicted in Table 20 below were prepared using analogous procedures to Example Step 6 (to compound Ex-17) with reaction times varying between 30 minutes to 2 hours.

[0030]

[0031] fReaction carried out with acryloyl chloride (1.2 eq) and DIPEA (3eq) in THF.gDIPEA (3 eq) was used instead of Et3N. Preparation of Deuterium-Substituted Acrylamides Example compounds Ex-31 and Ex-32 were prepared from the corresponding amine via the corresponding phosphonate ester followed by reaction with poly(oxymethylene-d2) as detailed in Scheme 15 below: Scheme 15: general procedure for preparing Example compounds Ex-31 and Ex-32. (A) Preparation Of Phosphonate Esters. Example Step 15: Synthesis of diethyl (2-((2-(4-((4-methoxy-7-methyl-1H- pyrrolo[3,2-c]pyridin-1-yl)sulfonyl)piperazin-1-yl)-2-oxoethyl)amino)-2- oxoethyl)phosphonate (D12) A mixture of 2-amino-1-(4-((4-methoxy-7-methyl-1H-pyrrolo[3,2-c]pyridin-1- yl)sulfonyl)piperazin-1-yl)ethan-1-one (D5; 66 mg, 0.180 mmol), 2- (diethoxyphosphoryl)acetic acid (39 mg, 0.198 mmol), HATU (82 mg, 0.216 mmol) and DIPEA (38 µL, 0.216 mmol) in THF (5 mL) was stirred at RT for 5 h. The reaction mixture was then quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL) successively, dried (Na2SO4), filtered, and concentrated in vacuo to afford crude diethyl (2-((2-(4-((4-methoxy-7-methyl-1H-pyrrolo[3,2-c]pyridin-1- yl)sulfonyl)piperazin-1-yl)-2-oxoethyl)amino)-2-oxoethyl)phosphonate (D12; 98 mg, quant.) as a yellow oil, which was carried on to the next step without further purification. LCMS (Method A). Rt1.52 min, (ESI+) m / z 546.3 [M+H]+. Phosphonate ester intermediate D13 depicted in Table 21 was prepared using an analogous procedures to Example Step 15 (to compound D12) with a reaction time of 2 hour. Table 21. Analytical data of intermediate compound D13. (B) Preparation Of Deuterium Substituted Acrylamides Via Phosphonate Esters. Example Step 16: Synthesis of N-(2-(4-((4-methoxy-7-methyl-1H-pyrrolo[3,2- To a solution of crude diethyl (2-((2-(4-((4-methoxy-7-methyl-1H-pyrrolo[3,2- c]pyridin-1-yl)sulfonyl)piperazin-1-yl)-2-oxoethyl)amino)-2-oxoethyl) phosphonate (D12; 98 mg, 0.180 mmol) in THF (4 mL): water (1 mL) was added paraformaldehyde-d2(2.8 mg, 0.0449 mmol), lithium hydroxide monohydrate (8.3 mg, 0.198 mmol) and potassium hydroxide (20 mg, 0.359 mmol). The resulting mixture was stirred for 6 h at RT. The reaction mixture was then quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layer was washed with water (20 mL) and brine (20 mL) successively, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was pre-purified by silica gel column chromatography (Sfar 25g), eluting with 0-5% MeOH in DCM then purified by reverse phase purification. Fractions containing desired product were combined and the solvents evaporated in vacuo. The residue was dissolved in 1:1 MeCN-H2O (4 mL) and the solution frozen. The solvent was evaporated in vacuo by lyophilisation to afford N-(2- (4-((4-methoxy-7-methyl-1H-pyrrolo[3,2-c]pyridin-1-yl)sulfonyl)piperazin-1-yl)-2- oxoethyl)acrylamide-3,3-d2 (Ex-31; 18.8 mg, 25 %) as a white solid. LC-MS (Method E). Rt 3.88 min, (ESI+) m / z 424.3 [M+H]+. Example compound Ex-32 depicted in Table 22 below was prepared using analogous procedures to Example Step 16 (to compound Ex-31) with a reaction time of 6 hours. Table 22. Analytical data of Example compound Ex-32. Route 10 – Preparation of Fluorine-18 Analogues Example compound Ex-35 is prepared from the corresponding hydroxy compound Ex-33 or the corresponding chlorofluoromethoxy compound Ex-34 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 16 below. Compounds Ex-33 and Ex-34 are prepared using analogous methods to those described herein.

[0032] Scheme 16: general procedure for preparing Example compound Ex-35. 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 CaCl2 in 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 IC50assay are shown in Table 23 below. The results indicate that exemplified compounds of formula I are good inhibitors of TG2.

[0033] Table 23. TG2 IC50 values 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 summarized in Table 24 and Table 25, respectively. Table 25. 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 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: 1, 5, 15, 30 minutes and 60 minutes post dose. For oral dosing, samples were collected at: 5, 15, 30 minutes and 1, 2, 4, 6 and 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. Results The results for the pharmacokinetic study in mice are tabulated in Tables 26 and 27 below. The results show that certain exemplary compounds of formula I show good pharmacokinetic properties. Said pharmacokinetic properties are improved compared to known TG2 inhibitors.

[0034] Table 26. Pharmacokinetic Parameters For Example Compounds Following Intravenous Dosing. Table 27. Pharmacokinetic Parameters For Example Compounds Following Oral 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 immobilized 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 normalized 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 28 below alongside the results for the TG2 IC50assays described above. The results revealed a selective inhibition of TG2 for exemplary compounds of formula I.

[0035] 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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El Nahas, and T.S. Johnson. 2009. Transglutaminase inhibition ameliorates experimental diabetic nephropathy. Kidney Int. 76:383- 394. Johnson, T., M. Fisher, J. Haylor, Z. Hau, N. Skill, R. Jones, R. Saint, I. Coutts, A. El Nahas, and M. Griffin. 2008. Transglutaminase inhibition ameliorates tissue scarring and fibrosis: experience in a kidney model. J Am Soc. 14:2052. Kerr, C, H. Szmacinski, M.L. Fisher, B. Nance, J.R. Lakowicz, A. Akbar, J.W. Keillor, T.L. Wong, R. Godoy-Ruiz, E.A. Toth, D.J. Weber, and R.L. Eckert. 2017. Oncogene. 36(21): 2981–2990 Klock, C., X. Jin, K. Choi, C. Khosla, P.B. Madrid, A. Spencer, B.C. Raimundo, P. Boardman, G. Lanza, and J.H. Griffin. 2011. Acylideneoxoindoles: A new class of reversible inhibitors of human transglutaminase 2. Bioorg Med Chem Lett. 21:2692-2696. Lindemann, I., A. Heine, and G. Klebe. 2012. Transglutaminase 2 in complex with a novel inhibitor. PDB codes: 3S3P, 3S3S, 3S3J. Liu, S., R.A. Cerione, and J. Clardy. 2002. Structural basis for the guanine nucleotide- binding activity of tissue transglutaminase and its regulation of transamidation activity. Proc Natl Acad Sci U S A. 99:2743-2747. Mastroberardino, P.G., C. Iannicola, R. Nardacci, F. Bernassola, V. De Laurenzi, G. Melino, S. Moreno, F. Pavone, S. Oliverio, L. Fesus, and M. Piacentini. 2002. 'Tissue' transglutaminase ablation reduces neuronal death and prolongs survival in a mouse model of Huntington's disease. Cell Death Differ. 9:873-880. Mishra, S., and L.J. Murphy. 2004. Tissue transglutaminase has intrinsic kinase activity: identification of transglutaminase 2 as an insulin-like growth factor-binding protein-3 kinase. J Biol Chem. 279:23863-23868. Nakaoka, H., D.M. Perez, K.J. Baek, T. Das, A. Husain, K. Misono, M.J. Im, and R.M. Graham. 1994. Gh: a GTP-binding protein with transglutaminase activity and receptor signaling function. Science. 264:1593-1596. Pardin, C., S.M. Gillet, and J.W. Keillor. 2006. 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Wityak. 2012. Discovery and structure-activity relationship of potent and selective covalent inhibitors of transglutaminase 2 for Huntington's disease. J Med Chem. 55:1021-1046. Seo, S., Y. Moon, J. Choi, S. Yoon, K. H. Jung, J. Cheon, W. Kim, D. Kim, C. H. Lee, S- W. Kim, K-S. Park, D. H. Lee.2019. The GTP binding activity of transglutaminase 2 promotes bone metastasis of breast cancer cells by downregulating microRNA- 205. Am J Cancer Res. 9(3):597-607 Verderio, E.A., T. Johnson, and M. Griffin. 2004. Tissue transglutaminase in normal and abnormal wound healing: review article. Amino Acids. 26:387-404. Wang. A., D. J. Stuckey, C. E. Murdoch, P. Camelliti, G. Y. H. Lip and M. Griffin. 2018. Cardiac fibrosis can be attenuated by blocking the activity of transglutaminase 2 using a selective small-molecule inhibitor. Cell Death and Disease. 9:613.

Claims

Claims 1. A compound of formula I,wherein: Q is selected from the group consisting of O and NH; A is N; the -E-L- linker represents:R1represents a 9-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, a C1-4 alkyl group, and a C3-6 cycloalkyl group, which C1-4 alkyl and C3-6 cycloalkyl groups are optionally substituted by one or more deuterium atoms and / or halogen atoms; R2, R3, and R4are each independently selected from the group consisting of hydrogen and C1-3 alkyl, which C1-3 alkyl group is optionally substituted by one or more halogen 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, C1-3 alkyl, C3-6 cycloalkyl, which C1-3 alkyl and C3-6 cycloalkyl groups are optionally substituted by one or more groups selected from the group consisting of deuterium atoms and halogen atoms; 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, C1-3 alkyl, and C3-6 cycloalkyl, which C1-3 alkyl and C3-6 cycloalkyl 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 C1-3 alkyl groups, which C1-3 alkyl groups are optionally substituted by one or more halogen atoms, or a pharmaceutically acceptable salt, solvate, or deuterated analogue thereof.

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

3. The compound according to Claim 1 or Claim 2, wherein the 9-membered, bicyclic heteroaryl group: (a) contains 1, 2, 3 or 4 ring heteroatoms each independently selected from the group consisting of N and S; and (b) is substituted by 0, 1, 2, 3, 4 or 5 X groups.

4. The compound according to any one of Claims 1 to 3, wherein R1is selected from the group consisting of:wherein Z1is selected from the group consisting of C and N; Z2is selected from the group consisting of S, NR13and CR14; Z3, Z4and Z5are each independently selected from the group consisting of CR15or N; X1, X2, X3, X5, X6, X7, X8, R14and R15are each independently selected from the group consisting of hydrogen, halogen, -OR9, a C1-4 alkyl 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; X4and R13are each independently selected from the group consisting of hydrogen, 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; and R9is 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:wherein X1, X2, X3, X4, X5, X6, X7, X8, R13, R14and R15are as defined in Claim 4.

6. The compound according to any one of Claims 1 to 5, wherein R1is selected from the group consisting of:wherein X1, X2, X4, R13, R14and R15are as defined in Claim 4 or Claim 5.

7. The compound according to any one of Claims 4 to 6, wherein: X1, X2, X3, X5, X6, X7, X8, R14and R15are each independently selected from the group consisting of hydrogen, -OCH3, -OCHF2, -OCHF[18F], -OCHFCl, -CF3, -OCH2F, -OCF3, -OCF2Cl, -OCH2CH3, -OCH(CH3)2, -OCD3, -OH, -CH3, -CH2CH3, -CH(CH3)2,, -CD3, Cl and F; and X4and R13are each independently selected from the group consisting of hydrogen, -CH3, -CH2CH3, -CH(CH3)2, , and -CD3.

8. The compound according to any one of Claim 1 to 7, wherein: X1is selected from the group consisting of hydrogen, -OCH3, -OCHF2, -OCHF[18F], -OCHFCl, -CF3, -OCH2F, -OCF2Cl, and -OH; X4is selected from the group consisting of hydrogen -CH3 and -CH2CH3; R14is selected from the group consisting of hydrogen, F, Cl and -CH3; X2, R13and R14are each independently selected from the group consisting of hydrogen and -CH3; and X3, X5, X6, X7and X8are each hydrogen.

9. The compound according to any one of Claims 1 to 8, 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.

10. The compound according to any one of Claims 1 to 9, wherein R5is selected from the group consisting of hydrogen, methyl, ethyl, and cyclopropyl, which methyl, ethyl, and cyclopropyl groups are optionallysubstituted by one, two or three deuterium atoms.

11. The compound according to any one of Claims 1 to 10, wherein: R6is hydrogen; and R7aand R7bare independently selected from the group consisting of hydrogen and deuterium.

12. 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.

13. A compound selected from the group consisting of:, or a pharmaceutically acceptable salt, solvate, or deuterated analogue thereof.

14. A pharmaceutical formulation comprising a compound of formula I as defined in any one of Claims 1 to 12 or a compound as defined in Claim 13, or a pharmaceutically acceptable salt, solvate, or deuterated analogue thereof, and a pharmaceutically acceptable excipient.

15. A compound of formula I as defined in any one of Claims 1 to 12 or a compound as defined in Claim 13, or a pharmaceutically acceptable salt, solvate, or deuterated analogue thereof, or a pharmaceutical formulation as defined in Claim 14, for use in medicine.

16. 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 to12 or a compound as defined in Claim 13, or a pharmaceutically acceptable salt, solvate, or deuterated analogue thereof, or a pharmaceutical formulation as defined in any one of Claim 14, to a subject in need thereof.

17. The method according to Claim 16, 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.

18. The method according to Claim 17, 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.

19. 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 12 or a compound as defined in Claim 13, or a pharmaceutically acceptable salt, solvate, or deuterated analogue thereof, or a pharmaceutical formulation as defined in Claim 14, 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.

20. A process for preparing a compound of formula I as defined in any one of Claims 1 to 12 or a compound as defined in Claim 13, which process comprises: (a) 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 in any one of Claims 1 to 13 and G1is a suitable leaving group; (b) compounds of formula I, reaction of a compound of formula V,with a compound of formula XIX,wherein Q, R1, R2, R3, R4, R5, R6, R7a, R7band L are as defined in any one of Claims 1 to 13 and M is a suitable metal atom; or(c) for compounds of formula I where R7aand R7bare both deuterium, reaction of a compound of 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 13 and each R17is independently a C1-3 alkyl group.

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